Language：Japanese   Publisher：(一社)日本病理学会  

血管芽腫は腫瘍性間質細胞と豊富な血管からなる腫瘍である。縦隔進展を伴う稀な脊髄血管芽腫を経験したので報告する。70代女性で,胸髄から上縦隔へ進展し,左胸腔へ突出するダンベル型腫瘤を認めた。組織学的には淡明な細胞質を有する腫瘍細胞のシート状配列と豊富な血管網を認め,免疫組織化学的に腫瘍細胞はα-inhibinとS100蛋白に陽性であった。稀ではあるが縦隔や胸腔に及ぶ脊髄腫瘍の鑑別に血管芽腫を挙げることは重要であり,脊髄血管芽腫ではvon Hippel-Lindau病の精査と経過観察が必要である。(著者抄録)

Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景 肺の悪性黒色腫のほとんどは他臓器からの転移であり,肺原発の症例は極めて稀である.今回,神経内分泌腫瘍との鑑別に苦慮した肺原発悪性黒色腫の一例を経験したので報告する.症例 80代,男性.右肺上葉の充実性結節に対して気管支鏡検査が施行された.気管支洗浄細胞診では,粗顆粒状の核クロマチンを有する裸核状の小型異型細胞集塊を認めた.核小体は目立たず,索状やロゼット様の配列と思われる部分を認め,神経内分泌腫瘍が示唆された.異型細胞の内外に褐色色素を散見し,核内封入体を有する異型細胞も認められた.気管支生検では,大小不同の目立つ類円形核と広い胞体を有した腫瘍細胞を認めた.免疫組織化学では,HMB-45およびMelan A陽性であり悪性黒色腫と診断した.全身検索の結果,原発巣を示唆する部位は他に認められず,肺原発の悪性黒色腫と考えられた.結語 メラニン顆粒などの色素顆粒を鑑別し,顆粒含有細胞の形態を注意深く観察することで,特徴的な細胞所見に乏しい症例においても,悪性黒色腫を鑑別診断に挙げることが可能であると考えられた.(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)  

A female in her 60's presented with a left-sided breast mass. A core needle biopsy specimen showed diffuse proliferation of a round cell tumor, which was positive for vimentin, NKX2.2, BCOR, and focal CD99 on immunohistochemistry (IHC). No fusion genes of the Ewing family sarcomas were detected. With a tentative diagnosis of primary breast sarcoma (PBS), total mastectomy was performed after chemotherapy. The resected tissues showed proliferation of round or spindle-shaped tumor cells with a high nuclear-to-cytoplasmic ratio, exhibiting solid and fascicular arrangements but no epithelial component or organoid pattern. While IHC indicated no particular histological diagnosis, genomic examination revealed gene alterations in MED12 p.G44D, MLL2 (KMT2D) p.T1496fs*27, and EGFR variant III (vIII). Moreover, a retrospective IHC study showed overexpression of EGFRvIII. A malignant phyllodes tumor (PT) with extensive sarcomatous overgrowth was indicated as an integrative diagnosis. This is a rare case of a malignant PT harboring EGFRvIII. The present case provides an importance of accurate diagnosis and genomic analysis of rare breast tumors, as malignant PT and PBS are different in its treatment strategy and prognosis.

DOI： 10.1016/j.prp.2024.155389

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Ovarian endometriomas (OEs) are rarely found in the pediatric population, especially before menstruation. We report a 6-year-old girl who was postoperatively diagnosed with OE before menstruation. CASE PRESENTATION: A 6-year-old girl presented to a local pediatrician with abdominal pain and vomiting. Abdominal ultrasonography revealed a multilocular cystic lesion to the left of the bladder. Magnetic resonance imaging (MRI) revealed similar findings, with the contents of the cyst showing a low signal on T1-weighted imaging and a high signal on T2-weighted imaging. The patient was referred to our institution for further examination. Enhanced computed tomography (CT) showed a multilocular cystic lesion sized 56 × 44 × 30 mm with partial calcification. The left ovarian vein was dilated, suggesting the origin of the tumor to be the left ovary. Extirpation of the lesion was performed under laparoscopic assistance. Pathological findings indicated an ovarian endometrioma. To our knowledge, this is the youngest report of an OE diagnosed in a patient prior to menstruation. CONCLUSIONS: OEs in children before menstruation are extremely rare; thus, the long-term prognosis is yet to be determined.

DOI： 10.1186/s40792-024-01951-5

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Language：English   Publisher：Springer Berlin Heidelberg  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Krüppel-like transcription factor 4(KLF4) mutations are more frequently observed in low-grade lesions than in high-grade lesions of intraductal papillary mucinous neoplasms (IPMN) of the pancreas. However, the role of KLF4 mutations in IPMNs with concomitant pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study clarified the rate and effect of KLF4 mutations in IPMN with concomitant PDAC. METHODS: DNA was extracted from 65 formalin-fixed and paraffin-embedded samples from 52 patients including 13 IPMN with concomitant PDAC and 39 IPMN alone. A comprehensive screening was performed using next-generation sequencing (NGS) for the 5 IPMNs with concomitant PDAC and 5 IPMNs alone, followed by targeted sequencing for KLF4, GNAS, and KRAS mutations. RESULTS: In NGS screening, KRAS mutations were observed in all samples except for one, GNAS mutation in two IPMNs with concomitant PDAC, and a KLF4 mutation in one IPMN with concomitant PDAC. Targeted sequence detected KLF4 mutations in 11 of the 52 IPMNs. Concomitant PDAC developed only in the non-intestinal, non-invasive, and branch duct IPMN cases, and KLF4 mutations were more frequent in this IPMN type than in the other type (36% vs. 10%, p = 0.04). For this IPMN type with KLF4 mutation, PDAC-prediction sensitivity, specificity, and accuracy were 63%, 82%, and 79%, respectively. CONCLUSION: For selected IPMNs with non-intestinal, non-invasive, and branch duct, genetic assessment might be a helpful tool for predicting the possible development of concomitant PDAC, although a prospective validation study using a larger study population is needed.

DOI： 10.1097/MPA.0000000000002373

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

Astroblastomaは大脳に好発する境界明瞭なグリア系腫瘍で,WHO分類第5版ではAstroblastoma,MN1-alteredとして記載されている。脊髄や脳幹のAstroblastomaはMN1再構成ではなくEWSR1::BEND2融合遺伝子を有する頻度が高い。6歳女児の頸髄から延髄に境界明瞭で嚢胞変性を伴う腫瘍を認めた。組織学的には,血管壁や間質の硝子化を伴って腫瘍細胞がastroblastic pseudorosetteや偽乳頭状構造を示して増殖し,免疫組織化学ではEMA,GFAP,Olig2陽性を示し,Fluorescence in situ hybridizationでEWSR1::BEND2融合遺伝子を確認した。大脳のAstroblastomaと異なる融合遺伝子を有する稀な脊髄/脳幹のAstroblastomaの診断にはependymomaやpiloytic astrocytoma等の鑑別と共に,特徴的なEWSR1::BEND2融合遺伝子の検索が重要である。(著者抄録)

Language：Japanese   Publisher：(一社)日本病理学会  

Astroblastomaは大脳に好発する境界明瞭なグリア系腫瘍で,WHO分類第5版ではAstroblastoma,MN1-alteredとして記載されている。脊髄や脳幹のAstroblastomaはMN1再構成ではなくEWSR1::BEND2融合遺伝子を有する頻度が高い。6歳女児の頸髄から延髄に境界明瞭で嚢胞変性を伴う腫瘍を認めた。組織学的には,血管壁や間質の硝子化を伴って腫瘍細胞がastroblastic pseudorosetteや偽乳頭状構造を示して増殖し,免疫組織化学ではEMA,GFAP,Olig2陽性を示し,Fluorescence in situ hybridizationでEWSR1::BEND2融合遺伝子を確認した。大脳のAstroblastomaと異なる融合遺伝子を有する稀な脊髄/脳幹のAstroblastomaの診断にはependymomaやpiloytic astrocytoma等の鑑別と共に,特徴的なEWSR1::BEND2融合遺伝子の検索が重要である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Major advances have been made in cancer treatment, but the prognosis for elderly cancer patients with sarcopenia and frailty remains poor. Myokines, which are thought to exert preventive effects against sarcopenia, have been reported to be associated with the prognosis of various cancers, but their effect on head and neck squamous cell carcinoma (HNSCC) is unknown. The aim of this study was to clarify the influence of exercise on the control of HNSCC and to examine the underlying mechanism involved. Mice were injected with HSC-3-M3 cells, a human cell line of highly metastatic and poorly differentiated tongue cancer, at the beginning of the study. Just prior to transplantation, blood was collected from the mice, and the levels of myokines were measured by ELISA. Oncostatin M (OSM), a selected myokine, was added to HSC-3-M3 cells, after which the cell proliferation ability, cell cycle, and protein expression were analyzed in vitro. Tumor cell viability was lower (control: 100%, exercise: 75%), tumors were smaller (control: 26.2 mm3, exercise: 6.4 mm3), and survival was longer in the exercise group than in the control group in vivo. OSM inhibited HSC-3-M3 cell proliferation in a concentration-dependent manner in vitro. The addition of OSM increased the proportion of cells in the G0/G1 phase, decreased the proportion of cells in the G2/M phase, and increased the expression of the CDK inhibitors p21 and p27. These results indicate that exercise may directly inhibit the proliferation of HNSCC cell lines via OSM.

DOI： 10.3390/cancers16061187

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Language：English   Publishing type：Part of collection (book)   Publisher：Springer US  

Methylation of CpG sites in the promoter region of genomic DNA is an important epigenetic modification that plays a critical role in gene regulation, particularly in gene silencing. Epigenetic abnormalities, along with genetic alterations, are implicated in carcinogenesis and cancer progression. Numerous studies have investigated the role of epigenetics in cancer using various tools to assess DNA methylation. However, conventional analysis methods for DNA methylation require a large amount of DNA but lack higher sensitivity, making them unsuitable for analysis of samples with high heterogeneity, such as tumor tissues. In this study, we introduce a novel electrophoresis method named "methylation-specific electrophoresis (MSE)," which utilizes a denaturing gradient acrylamide gel. We demonstrate the applicability of the MSE method for DNA methylation analysis of the mucin gene as an example.

DOI： 10.1007/978-1-0716-3670-1_22

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：医学図書出版(株)  

膵臓は元来,腸内細菌叢(マイクロバイオータ)とは無縁と考えられていたが,近年の研究で腸内細菌や真菌が膵内に移行すること,膵癌の腫瘍内には活発な細菌が豊富に存在すること,腫瘍内細菌叢が局所の免疫機能を抑制することで癌の増殖と進展を促進していることが明らかとなった。われわれは膵癌の危険因子の一つである膵管内乳頭粘液性腫瘍(intraductal papillary mucinous neoplasm:IPMN)の発生や進展にも腫瘍内細菌叢が関与しているという仮説を立てて,IPMNの腫瘍内細菌叢を調査し,腫瘍内細菌叢が腫瘍と宿主に及ぼす影響について検証した。その結果を踏まえてIPMNにおける腫瘍内細菌叢の病的意義について概説する。(著者抄録)

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

症例は24歳男性。倦怠感や体重減少の精査のため実施した下部消化管内視鏡検査で回盲部潰瘍を認め,生検でびまん性大細胞型B細胞リンパ腫と診断された。その後の精査中にニューモシスチス肺炎を併発し,後天性免疫不全症候群(AIDS)の合併が判明した。回盲部潰瘍以外に明確な病変はなく,生検組織のin situ hybridization法により腫瘍細胞はEpstein-Barr encoding region(EBER)がびまん性に強陽性であったため,EBV陽性粘膜皮膚潰瘍(EBVMCU)と診断した。免疫再構築により病変が改善することを期待し,抗レトロウイルス療法(ART)を開始した。ART開始79日後には回盲部潰瘍の完全消失を確認し,その後3年以上にわたって寛解を維持している。EBVMUCは種々の免疫抑制状態を背景に発症することが知られておりAIDSもその一つであるが,ARTによる免疫再構築によってEBVMCUが寛解に至った初めての報告である。(著者抄録)

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Hematology  

<p>A 24-year-old man was found to have an ileocecal ulcer by colonoscopy. A pathological diagnosis of diffuse large B-cell lymphoma (DLBCL) with diffuse positive reaction of Epstein-Barr encoding region (EBER) by <i>in situ</i> hybridization was made based on analysis of the specimen. Acquired immunodeficiency syndrome (AIDS) complicated by pneumocystis jirovecii pneumonia was also diagnosed. As no other significant lymphomatous lesions were identified by further examination, a clinical diagnosis of EBV-positive mucocutaneous ulcer (EBVMCU) was made. Rather than performing systemic chemotherapy, the lesion was closely monitored and antiretroviral therapy (ART) for AIDS was started with the hope of treating the lesion through immune reconstitution. The lesion had completely disappeared by day 79 after starting ART, and has not recurred for over 3 years. EBVMCU is known to develop secondary to various immunosuppressive states including AIDS. Here we report a rare case of EBVMCU detected at diagnosis of AIDS that entered complete remission after immune reconstitution by ART.</p>

DOI： 10.11406/rinketsu.65.13

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: Atherosclerosis is known as a major risk factor for cardiovascular disease, and development of an animal model of atherosclerosis is required to investigate its clinical pathogenesis. We studied the optimal amount of cholesterol in the diet and the optimal experimental period for development of a Microminipig model of atherosclerosis for the evaluation of a hydroxymethylglutaryl-CoA reductase (HMGCR) inhibitor (atorvastatin). MATERIALS AND METHODS: Eighteen male animals (3-4 months old) were divided into 3 groups. Group 1 consisted of control animals receiving a normal chow diet, Group 2 animals received a high fat (12% w/w) and low cholesterol (0.1% w/w) diet (HFLCD), and Group 3 animals received HFLCD+statin for 12 weeks. Animals received statin at 3 mg/kg body weight per day. HFLCD did not down-regulate the hepatic expression of HMGCR mRNA. RESULTS: HFLCD increased body, omentum, and mesenteric adipose tissue weight, and induced hypercholesterolemia and atherosclerotic lesions in the abdominal aorta. HFLCD+statin inhibited hypercholesterolemia and atherosclerotic lesions, but not obesity. CONCLUSION: A microminipig atherosclerosis model induced by HFLCD can be used in the evaluation of HMGCR inhibitors for the treatment of hypercholesterolemia and atherosclerosis.

DOI： 10.21873/invivo.13415

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: Among the four genomic subtypes of endometrial cancer, distinguishing between the DNA polymerase epsilon mutation (POLEmut) and no specific molecular profile (NSMP) subtypes requires genomic profiling owing to the lack of surrogate immunohistochemical markers. We have previously found that, histologically, the POLEmut-subtype exhibits surface epithelial slackening (SES). Therefore, to improve subtype identification, we aimed to extract cytological features corresponding to SES in POLEmut-subtype cervical cytology specimens. MATERIALS AND METHODS: We analyzed 104 endometrial cancer cervical cytology specimens, with integrative diagnosis confirmation via histology, immunohistochemistry, and genomic profiling. Cytological features were evaluated for the presence of atypical glandular cells, atypical cell appearance in single cells and clusters, and cytological SES and the presence of tumor-infiltrating inflammatory cells in clusters. RESULTS: Based on cervical cytology, the POLEmut- and p53mut-subtypes exhibited more frequent atypical cells in smaller clusters, giant tumor cells, and cytological SES patterns than the NSMP-subtype. Tumor-infiltrating lymphocytes were frequent in the POLEmut- and mismatch repair-deficient subtypes. CONCLUSION: Histologically-detected SES as well as other endometrial cancer features may be preserved in the atypical cell clusters observed in cervical cytology specimens. Cytological detection of SES and of smaller clusters of atypical cells and inflammatory cells with moderate atypia are suggestive of POLEmut-subtype. Integrative diagnosis including genomic profiling remains critical for diagnostic confirmation.

DOI： 10.21873/invivo.13442

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Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Patients with polymerase epsilon (POLE) mutation (POLEmut) subtype, MMR-deficient (MMR-d) subtype as classified by The Cancer Genome Atlas (TCGA), and a high tumor mutation burden (TMB-high) potentially benefit from immunotherapy. However, characteristics of the cytological morphology within these populations remain unknown. METHODS: DNA extracted from formalin-fixed paraffin-embedded tissues was subjected to next-generation sequencing analysis. Genomic mutations related to gynecological cancers, TMB, and microsatellite instability were analyzed and were placed in four TCGA classification types. The following morphological cytological investigations were conducted on endometrial cancer using a liquid-based preparation method, prior to the commencement of initial treatment: (i) cytological backgrounds; (ii) differences between each count of neutrophils and lymphocytes as described below. RESULTS: Insignificant differences in the cytological background patterns of TCGA groups and TMB status were found. Although there was no significant difference in neutrophil count (p = 0.955) in the TCGA groups, POLEmut and MMR-d had significantly higher lymphocyte counts than no specific molecular profile (NSMP) (p = 0.019 and 0.037, respectively); furthermore, p53mut also tended to be significant (p = 0.064). Lymphocyte counts in TMB-high were also significantly greater than TMB-low (p = 0.002). POLEmut showed a positive correlation between TMB levels and lymphocyte counts. For predicting patients with POLEmut plus MMR-d, lymphocyte counts demonstrated a superior diagnostic accuracy of area under the curve (AUC) (0.70, 95% CI: 0.57-0.84), with a cutoff value of 26 high-power field. CONCLUSION: Lymphocyte count using liquid-based cytology for patients with endometrial cancer may predict POLEmut plus MMR-d of TCGA groups and TMB-high in those who can benefit from immunotherapy.

DOI： 10.1159/000538288

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Language：English   Publisher：The Japan Neurosurgical Society  

<p>Hemorrhagic pilocytic astrocytomas (PAs) are rare, accounting for 1.1%-8.0% of all PA cases. They are reported to occur more frequently in older populations, with a male predominance. In this study, we report a case of a 14-year-old boy who presented with a headache, vertigo, and diplopia. As per his brain computed tomography scan, a small hematoma was observed in the left inferior cerebellar peduncle. Follow-up magnetic resonance imaging (MRI) revealed repeated minor bleeding from the lesion and mild expansion, with no neurological deficits. Four years later, the patient developed nausea, vomiting, and left abducens palsy. MRI revealed a mulberry-shaped mass surrounded by a hypointense rim, suggesting a cavernous angioma. The lesion was surgically resected via midline occipital craniotomy with the opening of the cerebellomedullary fissure. Histopathological examination of the lesion revealed PA. Next-generation sequencing analyses revealed that PAs harbored mutations in the <i>ARID1A</i>, <i>ATM</i>, and <i>POLE</i> genes but not in the <i>BRAF</i> gene. To the best of our knowledge, there are yet no reported studies on these mutations in PAs to date. Thus, PA should be considered in the differential diagnosis of cerebellar hemorrhage, especially in young adults and children. </p>

DOI： 10.2176/jns-nmc.2023-0152

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Language：English   Publisher：(一社)日本脳神経外科学会  

症例は14歳男児。バスケットボール中に頭部を負傷した後、頭痛、めまい、複視を呈した。CTで左下小脳小帯に小さな血腫を認めた。MRIによる経過観察では、血腫からの軽度の出血と軽度の拡張を繰り返されたが、神経学的障害は認められなかった。しかし、4年後に悪心、嘔吐、左外転麻痺を発症した。MRIにより腫瘤が認められ、mulberry-shaped腫瘍が示唆された。病変は外科的切除された。病変の病理組織学的検査の結果、毛様細胞性星細胞腫が認められた。次世代シーケンス解析の結果、毛様細胞性星細胞腫はARIDIA遺伝子、ATM遺伝子、POLE遺伝子変異を有していたが、BRAJ遺伝子には変異は認められなかった。

Language：Japanese   Publisher：(公社)日本臨床細胞学会  

背景:子宮頸部原発明細胞癌はまれであり,液状化検体細胞診(liquid-based cytology:LBC)の細胞像の報告はほとんどない.われわれは,LBC標本で診断しえた子宮頸部明細胞癌の1例を経験したので,塗抹標本所見との異同および他の腺癌との鑑別点について検討し報告する.症例:70歳代,女性.約1年前より持続する性器出血があり,子宮頸部のポリープ状腫瘍を指摘された.擦過細胞診および組織診で明細胞癌と診断された.LBC標本では,異型細胞が重積性のある集塊状や孤立性に認められ,腺腔構造や乳頭状構造およびhobnail状の核の突出も認めた.異型細胞の核は軽度の腫大を示す類円形を呈しており,大型で明瞭な核小体を認め,細胞質は豊富で,淡く微細顆粒状を呈していた.結論:LBC標木においても,塗抹標本と同様に明細胞癌の特徴とされる,大型で明瞭な核小体および豊富な細胞質を有する異型細胞を認め,LBC標本で明細胞癌の診断を行う際にも重要な細胞所見である.(著者抄録)

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

症例は38歳の女性で、下腹部痛により来院した。超音波とMRIにて右卵巣と付属器に腫瘍を認め、腹腔鏡下にて切除した。子宮内膜及び卵巣において病理学的にグレード3の類内膜癌が認められた。進行度の検査にて子宮内膜と播種結節に腫瘍を認め、直腸への浸潤も含め切除し、卵管卵巣摘除術を行った。子宮内膜癌はグレード1、子宮漿膜内の播種結節はグレード3の類内膜腺癌と診断された。synchronous endometrial and ovarian cancer(SEOC)を疑い、DNA解析を行った。その結果、SEOCではなく子宮内膜癌の卵巣転移と診断された。パクリタキセルとカルボプラチンによるアジュバント化学療法を受け、再発は認められていない。

Language：Japanese   Publisher：(公社)日本臨床細胞学会  

背景:子宮頸部原発明細胞癌はまれであり,液状化検体細胞診(liquid-based cytology:LBC)の細胞像の報告はほとんどない.われわれは,LBC標本で診断しえた子宮頸部明細胞癌の1例を経験したので,塗抹標本所見との異同および他の腺癌との鑑別点について検討し報告する.症例:70歳代,女性.約1年前より持続する性器出血があり,子宮頸部のポリープ状腫瘍を指摘された.擦過細胞診および組織診で明細胞癌と診断された.LBC標本では,異型細胞が重積性のある集塊状や孤立性に認められ,腺腔構造や乳頭状構造およびhobnail状の核の突出も認めた.異型細胞の核は軽度の腫大を示す類円形を呈しており,大型で明瞭な核小体を認め,細胞質は豊富で,淡く微細顆粒状を呈していた.結論:LBC標木においても,塗抹標本と同様に明細胞癌の特徴とされる,大型で明瞭な核小体および豊富な細胞質を有する異型細胞を認め,LBC標本で明細胞癌の診断を行う際にも重要な細胞所見である.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01209&link_issn=&doc_id=20231208230002&doc_link_id=%2Few5saibo%2F2023%2F006206%2F003%2F0287-0292%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Few5saibo%2F2023%2F006206%2F003%2F0287-0292%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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The diagnosis of synchronous endometrial and ovarian cancer or metastatic cancer of the same histological type is difficult. In this study, molecular biology analysis was performed to determine ovarian metastasis from endometrial cancer. A 38-year-old woman had pathological evidence of endometrial cancer (endometrioid carcinoma, grade 1) and ovarian cancer (endometrioid carcinoma, grade 3); a disseminated nodule in the serosa uteri was also diagnosed as endometrioid carcinoma (grade 3). Customized panel sequencing revealed a common mutation pattern in ovarian cancer and disseminated nodules. Furthermore, endometrial cancer showed the same mutation patterns for FGFR3 and PTEN as ovarian cancer and disseminated nodules. All tumors were microsatellite instability high. Clinicopathological and molecular biology analyses suggested that the patient had ovarian metastasis from endometrial cancer. The patient underwent adjuvant chemotherapy with paclitaxel and carboplatin, with no recurrence. Molecular biology techniques may enable appropriate treatment based on clinically accurate diagnosis.

DOI： 10.1111/jog.15773

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Amplification of the epidermal growth factor receptor gene (EGFR) and its variants are the most commonly detected pathogenic gene alterations in glioblastoma. Herein, we report a case of molecularly defined glioblastoma harboring an EGFR variant III (EGFRvIII) without EGFR amplification. The initial histological diagnosis was isocitrate dehydrogenase (IDH)-wildtype low-grade glioma, due to an absence of anaplasia, necrosis, and microvascular proliferation, and a low Ki-67 labeling index. DNA-based next-generation sequencing (NGS) panel analysis revealed a TERTp promoter mutation but no EGFR mutation or amplification, supporting the diagnosis of "molecular glioblastoma." However, RNA-based NGS panel analysis revealed mRNA expression of EGFRvIII. Therefore, the final integrative diagnosis was glioblastoma with non-amplified EGFRvIII. Our report suggests that non-amplified EGFRvIII might be an early molecular event in glioblastoma tumorigenesis. In addition to the usual DNA-based analysis, RNA-based analysis is required to identify exon-skipping EGFR variants without EGFR amplification.

DOI： 10.1016/j.prp.2023.154712

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Language：English   Publishing type：Research paper (scientific journal)  

The circadian rhythm-related genes BHLHE40/DEC1 and BHLHE41/DEC2 have various functions under different cell and tissue conditions. BHLHE41/DEC2 has been reported to be both a cancer-suppressive and an oncogenic gene during cancer development. The effects of BHLHE41/DEC2 on differentiation have been examined using Bhlhe41/Dec2 knockout mice and/or in vitro differentiation models, and research has been conducted using genetic analysis of tumor cells, in vitro analysis of cancer cell lines, and immunohistochemical studies of the clinical samples. We summarize some of these studies, detail several problems, and consider possible reasons for contradictory results and the needs for further research.

DOI： 10.3390/ijms241411731

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Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景 類上皮肉腫は形態および免疫組織学的に上皮様を呈する腫瘍細胞が胞巣形成性に増殖する稀な悪性軟部腫瘍で,しばしばラブドイド細胞が出現する.今回,右臀部に発生した類上皮肉腫を経験したので報告する.症例 30代,女性.右臀部の筋肉内腫瘤および右鼠径部腫瘤を認めた.穿刺吸引細胞診では血性背景に上皮様結合を有した異型細胞が集塊状に出現していた.異型細胞の結合性は緩く,豊富な細胞質を有し,核は偏在傾向を示し,核縁は菲薄で平滑で,クロマチンは細顆粒状で均等に分布していた.癌の転移や肉腫が疑われたが,組織型の推定は困難であった.摘出された腫瘍は,組織学的に好酸性胞体の上皮様腫瘍細胞が線維性間質内に索状やシートに増殖し,腫瘍中心に壊死を伴っていた.免疫組織化学的に腫瘍細胞は,cytokeratin(AE1/AE3,CAM5.2),Vimentin,CD34陽性を示し,INI-1の欠失を認めた.細胞所見,免疫組織化学を含む組織所見より類上皮肉腫と診断した.結語 類上皮肉腫の細胞像では,豊富な細胞質を有する上皮様結合を示す異型細胞を認めるが,結合性は緩いこと,肉腫を示唆する菲薄で平滑な核縁であることに着目することが重要であると考えられた.(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)  

Endometrial cancers are classified into mismatch repair (MMR) deficient- (MMRd), p53 mutation- (p53mut), DNA polymerase epsilon (POLE) mutation (POLEmut), and no specific molecular profile (NSMP) subtypes according to The Cancer Genome Atlas (TCGA). The distinction between POLEmut and NSMP subtypes is made on the basis of molecular analysis because the specific histological and immunohistochemical features of these two subtypes are still unknown. In this study, we analyzed histological features by scoring the presence of a mucinous pool, giant cells, clear cells, keratinization, neutrophilic abscess, and surface proliferating pattern in 82 cases of endometrial cancers in which an integrative diagnosis was confirmed by immunohistochemistry and genomic profiles showing POLE mutations, tumor mutation burden, and microsatellite instability. In contrast to the hierarchical branching of micropapillary proliferation observed in serous carcinoma, POLEmut-subtype endometrioid carcinomas often showed a surface epithelial slackening (SES) pattern in the tumor cells facing the uterine surface. The POLEmut subtype exhibited higher scores for clear cells and SES patterns than the other three subtypes. The scores for giant cells, clear cells, and the SES pattern were significantly higher in the POLEmut subtype than in the NSMP subtype, suggesting that these morphometric parameters are useful for differentiating POLEmut- and NSMP-subtype endometrioid carcinomas, although genomic profiling is still necessary for a definite molecular diagnosis.

DOI： 10.1016/j.prp.2023.154563

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DOI： 10.1002/dc.25149

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DOI： 10.1186/s12885-023-10867-6

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OBJECTIVE: For patients with endometrial cancer, the POLE (polymerase epsilon) mutation (POLEmut)-subtype, one of four molecular-analysis-based categories in the Cancer Genome Atlas (TCGA), has the best prognosis. The following histological characteristics are typically observed in endometroid carcinoma cases with the POLEmut-subtype: (1) the presence of tumour giant cells, (2) numerous tumour-infiltrating lymphocytes (TILs) and/or peri-tumoral lymphocytes, and (3) a high grade. However, in the context of cytology, the morphological characteristics of this subtype remain unknown. METHODS: DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues was subjected to next-generation sequencing analysis and categorised according to the TCGA classifications. Genomic mutation, tumour mutation burden (TMB), and microsatellite instability were also assessed. Cytological specimens of resected uteri obtained using the Papanicolaou method were histologically separated into three types. RESULTS: Seven out of 112 patients (6%) with endometrial cancer were diagnosed with the POLEmut-subtype between January 2019 and August 2021. Tumour giant cells were observed in three cases (43%) on histology and cytology. TIL and/or peritumoral lymphocytes with inflammatory cells were detected in five cases (71%) on histology and three cases (43%) on cytology. Cases in which these three characteristics were observed on both cytology and histology may have belonged to the POLEmut-subtype. There were no cases in which these characteristics were absent on histology but present on cytology. TMB tended to be higher in cases when the three characteristics were observed in both cytological and histological findings. CONCLUSIONS: Preoperative endometrial cytology highlighted the characteristics of the POLEmut-subtype in the histological analysis of resected uterine specimens and has the potential to play an important role in treatment decisions.

DOI： 10.1111/cyt.13215

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Combination chemotherapy with gemcitabine and cisplatin (GC) is recommended as the primary treatment for advanced bladder cancer (BC). However, the benefits of this approach are limited owing to the acquisition of drug resistance. Here, we found report that gemcitabine-resistant and cisplatin-resistant BCs do not exhibit cross-resistance, and that these BCs exhibit different mRNA patterns, as revealed using RNA sequence analysis. To overcome drug resistance, we used the newly developed pan-RAS inhibitor Compound 3144. Compound 3144 inhibited cell viability through suppression of RAS-dependent signaling in gemcitabine- and cisplatin-resistant BCs. RNA sequencing revealed that several genes and pathways, particularly those related to the cell cycle, were significantly downregulated in Compound 3144-treated BCs. These findings provide insights into potential therapeutic strategies for treating BC.

DOI： 10.1002/2211-5463.13616

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This study evaluated the feasibility and clinical utility of liquid-based cytology (LBC) specimens via endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) for next-generation sequencing (NGS) of pancreatic cancer (PC). We prospectively evaluated the performance of DNA extraction and NGS using EUS-FNB samples obtained from PC. Thirty-three consecutive patients with PC who underwent EUS-FNB at our hospital were enrolled. DNA samples were obtained from 96.8% of the patients. When stratified with a variant allele frequency (VAF) > 10% tumor burden, the NGS success rate was 76.7% (n = 23) in formalin-fixed paraffin-embedded (FFPE), 83.3% (n = 25) in LBC, and 76.7% (n = 23) in frozen samples. The overall NGS success rate was 86.7% (n = 26) using FFPE, LBC, or frozen samples. The detection rates for the main mutated genes were as follows: 86.7% for KRAS, 73.3% for TP53, 66.7% for CDKN2A, 36.7% for SMAD4, and 16.7% for ARID1A. LBC had the highest median value of VAF (23.5%) for KRAS and TP53. PC mutation analysis using NGS was successfully performed using LBC compared with FFPE and frozen samples. This approach provides an alternative and affordable source of molecular testing materials.

DOI： 10.3390/diagnostics13061078

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OBJECTIVE: This multicenter study aimed to evaluate the accuracy of the one-step nucleic acid amplification (OSNA) assay in diagnosing lymph node metastasis (LNM) in patients with cervical and endometrial cancers. METHODS: Surgically removed LNs from patients with cervical and endometrial cancer were sectioned at 2-mm intervals along the short axis direction and alternately examined using the OSNA assay and conventional histopathological examination. Ultrastaging (200-μm LN sections) was performed for metastatic LNs using hematoxylin and eosin staining and immunostaining with an anti-CK19 antibody in cases where the OSNA assay and histopathological examination (performed using 2-mm LN sections) results showed discordance. RESULTS: A total of 437 LNs from 133 patients were included; 61 patients (14%) showed metastasis by histopathological examination, with a concordance rate of 0.979 (95% confidence interval [CI]: 0.961-0.991) with the OSNA assay. The sensitivity and specificity of the OSNA assay were 0.918 (95% CI: 0.819-0.973) and 0.989 (95% CI: 0.973-0.997), respectively. Discordance between the two methods was observed in nine LNs (2.1%), and allocation bias of metastatic foci was identified as the major cause of discordance. CONCLUSIONS: The OSNA assay showed equally accurate detection of LN metastasis as the histopathological examination. We suggest that the OSNA assay may be a useful tool for the rapid intraoperative diagnosis of LN metastasis in patients with cervical and endometrial cancers.

DOI： 10.1016/j.ygyno.2022.12.016

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BACKGROUND: Microbiota have been reported to influence the development of various gastrointestinal neoplasms through the mechanism of sustained inflammation; however, few data are available regarding their influence on intraductal papillary mucinous neoplasms. The aim of this study was to assess the association between specific microbiota and the clinicopathologic characteristics of intraductal papillary mucinous neoplasms of the pancreas. METHODS: DNA was extracted from formalin-fixed, paraffin-embedded samples of 30 patients who underwent pancreatectomy for intraductal papillary mucinous neoplasm, and polymerase chain reaction was used to create sequence libraries using the primer set for the V3 and V4 region of 16S recombinant DNA. Filtered sequence reads were then processed into operational taxonomic units with a 97% identity threshold and the relative abundance of bacteria compared between the 2 groups using operational taxonomic units. RESULTS: There was a trend toward fewer Firmicutes and more Proteobacteria and Fusobacteria in the relative abundance of main duct operational taxonomic units than in branch duct operational taxonomic units. The relative abundances of Bacteroidetes (P < .01) and Fusobacteria (P = .04) were significantly higher in invasive intraductal papillary mucinous neoplasms than in noninvasive intraductal papillary mucinous neoplasms. The relative abundance of the intestinal type was significantly lower in Firmicutes than the relative abundance of the nonintestinal type (P = .04). Notably, main duct operational taxonomic units with the intestinal subtype were affected by increased proportions of Proteobacteria and Fusobacteria, and Fusobacteria were abundant in the intestinal type of invasive main duct operational taxonomic units. CONCLUSION: Intratumoral microbiota may be involved in the progression of operational taxonomic units.

DOI： 10.1016/j.surg.2022.10.003

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Language：English   Publisher：(公社)日本医学放射線学会  

2017年1月～2020年12月にかけ、当院で治療前に平衡相デュアルエネルギーCT(DECT)を受けた胸腺上皮性腫瘍(TET)の治療継続患者33例(男性11例、女性22例、年齢34～89歳)を対象に、ヨウ素濃度(IC)と細胞外容積(ECV)分画測定がTET診断に実現可能か後向きに調査した。なお、TET病理診断の内訳は低リスク胸腺腫が11例(Aが0例、ABが4例、B1が7例)、高リスク胸腺腫が11例(B2が6例、B3が5例)、胸腺癌が11例であった。平衡相でICを測定し、胸腺病変と大動脈ICからECV分画を求めTETサブタイプ間でICとECV分画を比較した。次に、ROC曲線解析によりICとECV分画の胸腺癌に対する診断能を評価した結果、平衡相のICとECV分画ではTET群間で異なったが、胸腺癌に対する平衡相ICとECV分画では胸腺腫に比べ有意に高く、胸腺癌を診断するための平衡相ICとECV分画の最適なカットオフ値が、各々1.5mg/mLおよび26.8%であることが確認された。以上の結果から、DECTを用いたICとECV分画測定がTET診断に有用で、平衡相高ICと高ECV分画から胸腺癌が推察されることが明らかにされた。

Language：Japanese   Publisher：(一社)日本病理学会  

症例は80代女性。リウマチ性多発筋痛症の治療中に胸部大動脈瘤を指摘され,人工血管置換術が行われた。大動脈では内膜に軽度の粥状硬化を認めた。中膜ではリンパ球や形質細胞,少数の多核巨細胞の浸潤,内膜側優位の弾性線維の配列の乱れと消失を認めたが,外膜の線維化や炎症細胞浸潤は軽度であり,巨細胞性動脈炎と診断した。大動脈瘤において巨細胞性動脈炎と病理診断される症例では,側頭動脈炎の既往がなく臨床症状に乏しいことがあり,大動脈瘤を注意深く検索することで,巨細胞性動脈炎の可能性を見落とさないことが重要である。(著者抄録)

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PURPOSE: To assess the diagnostic feasibility of iodine concentration (IC) and extracellular volume (ECV) fraction measurement using the equilibrium phase dual-energy CT (DECT) for the evaluation of thymic epithelial tumors (TETs). MATERIALS AND METHODS: This study included 33 TETs (11 low-risk thymomas, 11 high-risk thymomas, and 11 thymic carcinomas) that were assessed by pretreatment DECT. IC was measured during the equilibrium phases and ECV fraction was calculated using IC of the thymic lesion and the aorta. IC and ECV fraction were compared among TET subtypes using the Kruskal-Wallis H test and Mann-Whitney U test. Receiver-operating characteristic (ROC) curve analysis was performed to evaluate the ability of IC and ECV fraction to diagnose thymic carcinoma. RESULTS: IC during the equilibrium phase and ECV fraction differed among the three TET groups (both p < 0.001). IC during the equilibrium phase and ECV fraction was significantly higher in thymic carcinomas than in thymomas (1.9 mg/mL vs. 1.2 mg/mL, p < 0.001; 38.2% vs. 25.9%, p < 0.001; respectively). The optimal cutoff values of IC during the equilibrium phase and of ECV fraction to diagnose thymic carcinoma were 1.5 mg/mL (AUC, 0.955; sensitivity, 100%; specificity, 90.9%) and 26.8% (AUC, 0.888; sensitivity, 100%; specificity, 72.7%), respectively. CONCLUSION: IC and ECV fraction measurement using DECT are helpful in diagnosing TETs. High IC during the equilibrium phase and high ECV fraction are suggestive of thymic carcinoma.

DOI： 10.1007/s11604-022-01331-9

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Language：Japanese   Publisher：The Japanese Society of Clinical Cytology  

<p><i><b>Background</b></i> : Few studies have investigated the usefulness of liquid-based cytology (LBC) specimens in patients with primary clear cell carcinoma of the cervix, a rare neoplasm. Herein, we report the case of a patient who was diagnosed as having primary clear cell carcinoma of the cervix based on LBC, and discuss the differences between LBC and smear cytology, and useful findings for differentiation from other adenocarcinomas.</p><p><i><b>Case</b></i> : The patient was a 70-year-old woman. LBC examination revealed both isolated tumor cells and tumor cells in clusters ; glandular, papillary, and hobnail-like formations were also observed. On LBC, tumor cells with abundant and fine granular cytoplasm, enlarged round nuclei, and large and prominent nucleoli were observed.</p><p><i><b>Conclusion</b></i> : These findings could be helpful in the diagnosis of cervical cell carcinoma using LBC.</p>

DOI： 10.5795/jjscc.62.287

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BACKGROUND: Glioblastoma (GBM) is a malignant brain tumor, with radiological and genetic heterogeneity. We examined the association between radiological characteristics and driver gene alterations. METHODS: We analyzed the driver genes of 124 patients with IDH wild-type GBM with contrast enhancement using magnetic resonance imaging. We used a next-generation sequencing panel to identify mutations in driver genes and matched them with radiological information. Contrast-enhancing lesion localization of GBMs was classified into 4 groups based on their relationship with the subventricular zone (SVZ) and cortex (Ctx). RESULTS: The cohort included 69 men (55.6%) and 55 women (44.4%) with a mean age of 66.4 ± 13.3 years. EGFR and PDGFRA alterations were detected in 28.2% and 22.6% of the patients, respectively. Contrast-enhancing lesion touching both the SVZ and Ctx was excluded because it was difficult to determine whether it originated from the SVZ or Ctx. Contrast-enhancing lesions touching the SVZ but not the Ctx had significantly worse overall survival than non-SVZ lesions (441 days vs. 897 days, P = .002). GBM touching only the Ctx had a better prognosis (901 days vs. 473 days, P < .001) than non-Ctx lesions and was associated with EGFR alteration (39.4% vs. 13.2%, P = .015). Multiple contrast lesions were predominant in PDGFRA alteration and RB1-wild type (P = .036 and P = .031, respectively). CONCLUSIONS: EGFR alteration was associated with cortical lesions. And PDGFRA alteration correlated with multiple lesions. Our results suggest that clarifying the association between driver genes and tumor localization may be useful in clinical practice, including prognosis prediction.

DOI： 10.1093/noajnl/vdad110

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BACKGROUND: Telomerase reverse transcriptase promoter (TERTp) mutations are a biological marker of glioblastoma; however, the prognostic significance of TERTp mutational status is controversial. We evaluated this impact by retrospectively analyzing the outcomes of patients with isocitrate dehydrogenase (IDH)- and TERTp-wild-type glioblastomas. METHODS: Using custom next-generation sequencing, we analyzed 208 glioblastoma samples harboring wild-type IDH. RESULTS: TERTp mutations were detected in 143 samples (68.8%). The remaining 65 (31.2%) were TERTp-wild-type. Among the TERTp-wild-type glioblastoma samples, we observed a significant difference in median progression-free survival (18.6 and 11.4 months, respectively) and overall survival (not reached and 15.7 months, respectively) in patients with and without phosphatase and tensin homolog (PTEN) loss and/or mutation. Patients with TERTp-wild-type glioblastomas with PTEN loss and/or mutation were younger and had higher Karnofsky Performance Status scores than those without PTEN loss and/or mutation. We divided the patients with TERTp-wild-type into 3 clusters using unsupervised hierarchical clustering: Good (PTEN and TP53 alterations; lack of CDKN2A/B homozygous deletion and platelet-derived growth factor receptor alpha (PDGFRA) alterations), intermediate (PTEN alterations, CDKN2A/B homozygous deletion, lack of PDGFRA, and TP53 alterations), and poor (PDGFRA and TP53 alterations, CDKN2A/B homozygous deletion, and lack of PTEN alterations) outcomes. Kaplan-Meier survival analysis indicated that these clusters significantly correlated with the overall survival of TERTp-wild-type glioblastoma patients. CONCLUSIONS: Here, we report that PTEN loss and/or mutation is the most useful marker for predicting favorable outcomes in patients with IDH- and TERTp-wild-type glioblastomas. The combination of 4 genes, PTEN, TP53, CDKN2A/B, and PDGFRA, is important for the molecular classification and individual prognosis of patients with IDH- and TERTp-wild-type glioblastomas.

DOI： 10.1093/noajnl/vdad078

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There are several methods to control a heart rate, such as electrical stimulation and drug administration. However, these methods may be invasive or affect other organs. Recently, an optogenetic-based cardiac pacing method has enabled us to stimulate the cardiac muscle in non-contact. In many previous studies, the pacing was applied ex vivo or in anesthetized animals. Therefore, the physiologic response of animals during optogenetic pacing remains unclear. Here, we established a method of optogenetic-based cardiac pacing in awake, freely moving mice and simultaneously measured electrocardiogram, blood pressure, and respiration. As a result, light-induced myocardial contraction produces blood flow and indirectly affects the respiration rhythm. Additionally, light illumination enabled heart rate recovery in bradycardic mice. These findings may be employed for further research that relates a heartbeat state to animal behavior. Together, this method may drive the development of less invasive pacemakers without pacing leads.

DOI： 10.3389/fphys.2023.1130956

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DOI： 10.1111/1346-8138.16698

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Many variants of uncertain significance (VUS) have been detected in clinical cancer cases using next-generation sequencing-based cancer gene panel analysis. One strategy for the elucidation of VUS is the functional analysis of cultured cancer cell lines that harbor targeted gene variants using genome editing. Genome editing is a powerful tool for creating desired gene alterations in cultured cancer cell lines. However, the efficiency of genome editing varies substantially among cell lines of interest. We performed comparative studies to determine the optimal editing conditions for the introduction of platelet-derived growth factor receptor alpha (PDGFRA) variants in human glioblastoma multiforme (GBM) cell lines. After monitoring the copy numbers of PDGFRA and the expression level of the PDGFRα protein, four GBM cell lines (U-251 MG, KNS-42, SF126, and YKG-1 cells) were selected for the study. To compare the editing efficiency in these GBM cell lines, the modes of clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) delivery (plasmid vs. ribonucleoprotein (RNP)), methods of transfection (lipofection vs. electroporation), and usefulness of cell sorting were then evaluated. Herein, we demonstrated that electroporation-mediated transfer of Cas9 with single-guide RNA (Cas9 RNP complex) could sufficiently edit a target nucleotide substitution, irrespective of cell sorting. As the Cas9 RNP complex method showed a higher editing efficiency than the Cas9 plasmid lipofection method, it was the optimal method for single-nucleotide editing in human GBM cell lines under our experimental conditions.

DOI： 10.3390/ijms24010500

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Our understanding of metabolic reprogramming in cancer has tremendously improved along with the technical progression of metabolomic analysis. Metabolic changes in cancer cells proved much more complicated than the classical Warburg effect. Previous studies have approached metabolic changes as therapeutic and/or chemopreventive targets. Recently, several clinical trials have reported anti-cancer agents associated with metabolism. However, whether cancer cells are dependent on metabolic reprogramming or favor suitable conditions remains nebulous. Both scenarios are possibly intertwined. Identification of downstream molecules and the understanding of mechanisms underlying reprogrammed metabolism can improve the effectiveness of cancer therapy. Here, we review several examples of the metabolic reprogramming of cancer cells and the therapies targeting the metabolism-related molecules as well as discuss practical approaches to improve the next generation of cancer therapies focused on the metabolic reprogramming of cancer.

DOI： 10.1016/j.bbagen.2022.130301

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DOI： 10.1002/pbc.30041

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Language：English  

We reported a case of molecularly defined isocitrate dehydrogenase (IDH)-mutant astrocytoma that recurred twice with aggressive behavior and increased anaplastic morphology. Primary and recurrent tumors were analyzed using custom-made DNA-based cancer gene and RNA-based fusion panels for next-generation sequencing (NGS). NGS analyses revealed that recurrent astrocytoma, in addition to IDH1 and tumor protein 53 mutations detected in the primary lesion, harbored cyclin-dependent kinase inhibitor (CDKN) 2 A/B homozygous deletion and neurotrophic tropomyosin receptor kinase 2 (NTRK2) fusion genes that consisted of golgin A1- and cyclin-dependent kinase 5 regulatory subunit associated protein 2-NTRK2 fusions. Anaplasia and necrosis were observed in the recurrent tumors, but not in the primary lesion. Therefore, the integrative diagnosis was primary IDH-mutant astrocytoma grade 2 and recurrent IDH-mutant astrocytoma grade 4 with NTRK2 fusions. This is a worthwhile report describing a case of IDH-mutant astrocytoma that showed genomic evolution during tumor recurrence. Our report suggests that NTRK fusion and CDKN2A/B homozygous deletion promote high-grade transformation and indicate an unfavorable prognosis of IDH-mutant astrocytoma.

DOI： 10.1016/j.prp.2022.154163

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Language：Japanese   Publisher：(一社)日本病理学会  

遺残副腎は異所性に認められる副腎皮質組織であり,腫瘍化は非常に稀である。80代女性の骨盤腔内にFDGの高集積を呈する腫瘍を認めた。腫瘍は右子宮広間膜内に卵巣とは離れて存在し,好酸性顆粒状の豊富な細胞質を有する腫瘍細胞のびまん性増殖からなり,腫瘍辺縁には非腫瘍性の副腎皮質組織を伴っていた。免疫染色でSF-1,mitochondria陽性であった。Lin-Weiss-Bisceglia criteriaを満たす所見はなく,遺残副腎由来のoncocytomaと診断した。(著者抄録)

Language：English   Publisher：(一社)日本脳神経外科学会  

日本人患者のびまん性神経膠腫にみられる、分子遺伝学的プロファイルについて調査した。著者等の大学で収集した、びまん性神経膠腫患者303例の腫瘍組織試料を用いて、神経膠腫に特化した遺伝子パネルから、分子遺伝学的プロファイルを解析した。その結果、膠芽腫(GBM)患者185例に最も変異が多く認められた遺伝子は、TERTp遺伝子、TP53遺伝子、PTEN遺伝子、NF1遺伝子とPDGFRA遺伝子であった。また、欠失が最も多く認められた遺伝子は、PTEN遺伝子およびCDKN2A/B及びRB1遺伝子で、増加/増幅が最も多く認められた遺伝子は、EGFR遺伝子とPDGFRA遺伝子およびCDK4遺伝子であった。さらに、グレードIII乏突起膠腫22例のうち3例には、CDKN2A/B遺伝子のホモ接合性欠失が、4例にはARID1A遺伝子変異が検出され、ARID1A遺伝子変異が無増悪生存転帰不良と関連することが示唆された。なお、WHO脳腫瘍分類2021により、グレードII/IIIでIDH野生型星状細胞腫の62.5%が、IDH野生型のGBMに再分類された。本報により、神経膠腫に特化した遺伝子パネルが、WHO脳腫瘍分類2021に準じた分子診断に適用可能であることが確認された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japan Neurosurgical Society  

Rapid technological advances in molecular biology, including next-generation sequencing, have identified key genetic alterations in central nervous system (CNS) tumors. Accordingly, the fifth edition of the World Health Organization (WHO) CNS tumor classification was published in 2021. We analyzed 303 patients with diffuse glioma using an amplicon-based glioma-tailored gene panel for detecting 1p/19q codeletion and driver gene mutations such as IDH1/2, TERTp, EGFR, and CDKN2A/B on a single platform. Within glioblastomas (GBMs), the most commonly mutated genes were TERTp, TP53, PTEN, NF1, and PDGFRA, which was the most frequently mutated tyrosine kinase receptor in GBM, followed by EGFR. The genes that most commonly showed evidence of loss were PTEN, CDKN2A/B, and RB1, whereas the genes that most commonly showed evidence of gain/amplification were EGFR, PDGFRA, and CDK4. In 22 grade III oligodendroglial tumors, 3 (14%) patients had CDKN2A/B homozygous deletion, and 4 (18%) patients had ARID1A mutation. In grade III oligodendroglial tumors, an ARID1A mutation was associated with worse progression-free survival. Reclassification based on the WHO 2021 classification resulted in 62.5% of grade II/III isocitrate dehydrogenase (IDH) -wildtype astrocytomas being classified as IDH-wildtype GBM and 37.5% as not elsewhere classified. In summary, our glioma-tailored gene panel was applicable for molecular diagnosis in the WHO 2021 classification. In addition, we successfully reclassified the 303 diffuse glioma cases based on the WHO 2021 classification and clarified the genetic profile of diffuse gliomas in the Japanese population.

DOI： 10.2176/jns-nmc.2022-0103

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

BACKGROUND: As liquid-based cytology (LBC) specimens preserve high-quality DNA, clinical sequencing of LBC specimens using next-generation sequencing (NGS) is becoming a common strategy. This study aimed to evaluate the feasibility of NGS-based custom-made panels for evaluating MUC promoter methylation in LBC specimens. METHODS: Thirty-one patients with pancreatic cancer were enrolled in the study. Cancer tissue samples were obtained using endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB). LBC, formalin-fixed paraffin-embedded (FFPE), and fresh frozen specimens were prepared for DNA extraction after pathological diagnosis. These specimens were then subjected to NGS analysis using custom-made cancer gene screening and methylation panels comprising 28 cancer-related genes and 13 gene promoter regions, including MUC1, MUC2, and MUC4. RESULTS: The success rate of NGS using the cancer gene panel was comparable among the LBC, FFPE, and frozen specimens, and the presence of cancer cell-derived somatic mutations in each specimen was confirmed. The specimens were then tested using a methylation panel that revealed the sequential methylation status of CpG islands located in the promoter regions of MUC genes. The methylation status results obtained from LBC specimens were almost comparable with those from FFPE and frozen specimens. CONCLUSIONS: MUC and other gene methylation analyses using an NGS-based panel were successfully performed in residual LBC specimens obtained by EUS-FNA/FNB. Therefore, this approach provides an alternative source of molecular tests for gene mutations and methylation, especially in the pancreatic cancers, which are often unresectable and unsuitable for obtaining FFPE specimens.

DOI： 10.1002/dc.25022

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/dc.25022

Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景 膵solid-pseudopapillary neoplasm(以下、SPN)は、膵外分泌腫瘍の1～3%を占める稀な腫瘍である。今回、乳腺細胞診において原発性乳癌との鑑別に苦慮した膵SPNの乳腺転移の1例を経験したので報告する。症例 50代女性。7年前に手術された膵SPN術後の定期検診にて左乳腺外側に1cm大の結節を指摘された。原発性乳癌が疑われ、針生検及び穿刺針洗浄細胞診が施行された。穿刺針洗浄細胞診で、血性背景に乳頭状、管状あるいは孤立散在性の異型細胞を多数認め、血管性間質を軸とした重積性を示す集塊も存在していた。核偏在傾向や核溝も見られ、浸潤性乳管癌充実型や粘液癌Type Bを疑った。摘出生検では、シート状構造を示す腫瘍細胞と淡好塩基性を示す疎な線維性間質を認め、偽乳頭状構造も認めた。免疫染色では、β-cateninが腫瘍細胞の核・細胞質に陽性であった。以上の所見から膵SPNの乳腺転移と判断した。結論 原発性乳癌との鑑別に苦慮した膵SPNの乳腺転移の一例を経験した。膵SPNの肝や腹腔以外への転移は稀ではあるが、臨床情報に留意し検鏡することで診断し得ると考えられた。(著者抄録)

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

症例は16歳女性で、4ヵ月前から断続的な左腰背部痛および下肢痛を呈し総合病院を受診した。急性リンパ性白血病と診断され、直ちにプレドニゾロン投与が開始されたが、治療反応は不良であった。その後、小児固形腫瘍の骨髄浸潤が疑われたため当科に転科となった。病理診断の結果、悪性小円形細胞腫瘍であり、小細胞神経内分泌癌の可能性が高かった。PET-CTにて複数の骨、骨髄、腹腔内に異常集積を認めたが、原発巣は特定できなかった。シスプラチン・エトポシド療法後、骨髄検査にて異常細胞の消失が認められ、NSE値の低下も認められた。しかし、2回目の化学療法後、左腸骨病変が拡大し、骨髄に異常細胞が再び出現し、NSEは再び上昇した。がんゲノムプロファイリング検査を実施したが、有効な治療候補は見つからなかった。その後、ビンクリスチン/イリノテカン、左腸骨病変放射線療法、イホスファミド/エトポシド、アムルビシン、エベロリムスなどの治療が行われた。しかし、病状進行に伴い、肝不全、腎不全が再発し、144日目に死亡した。

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞目的:上眼瞼Merkel細胞癌の症例について報告する。症例:83歳,男性。所見:左上眼瞼の腫瘤を主訴に来院した。細隙灯顕微鏡検査では,左上眼瞼に8×9mm大の赤色調の球状腫瘤を認めた。急速に増大したためMerkel細胞癌を疑い,初診から6日後に左上眼瞼悪性腫瘍拡大切除術を施行した。腫瘍辺縁から5mmのsafety marginをとって拡大切除を行い,術中迅速病理診断で断端の腫瘍細胞が陰性であることを確認した。その後,switch flap法を用いて欠損した眼瞼を再建した。免疫組織学的検査の結果はMerkel細胞癌であった。術翌日に抗凝固薬を再開したところ,創部より多量の出血を認めたため,術後5日目および6日目に止血術を行った。2ヵ月後に同部位に再び腫瘤を認めたが,切除したところ化膿性肉芽腫の診断で再発ではなかった。結論:上眼瞼のMerkel細胞癌を経験した。術後に再度腫瘤を認めたが,再発ではなかった。ただし,再発しやすい腫瘍であるため,今後も慎重な経過観察が必要である。

Language：English   Publisher：Springer Berlin Heidelberg  

症例は77歳男性で、体重減少をきたして受診した。血清CEA 371.5ng/mLを示し、食道胃十二指腸鏡検査で胃上部から中部1/3にかけて半周性の2型腫瘍を認め、生検後の病理診断では高分化型腺癌であった。造影CTにて腫瘍部における胃壁肥厚、小彎に沿ったリンパ節腫大、肝S3転移を認め、ステージIV HER2陽性胃癌の診断のもと、カペシタビン、シスプラチン、トラスツズマブ投与を予定した。しかし、トラスツズマブの初回投与後に重度の注入部反応を示したため、S-1+シスプラチン(SP療法)に切り替えた。3コース施行後にリンパ節と肝転移巣のサイズ縮小が得られたが、6コース終了後に血清CEAの上昇をきたして腫瘍コントロール不良と判断し、セカンドライン化学療法としてラムシルマブ+パクリタキセルを開始した。6コース終了後、原発巣と肝転移巣の著明な縮小がみられPRと判定、コンバージョン手術を行う方針とした。胃全摘術、D2リンパ節郭清、S3およびS4に対する肝部分切除を施行し、病理所見では原発腫瘍は固有筋層に浸潤しており組織学的グレード1aと考えられた。合併症の発症なく術後10日目に退院となり、42ヵ月後も再発徴候は認めていない。

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

症例は63歳の男性.十二指腸下行部に15mm大の側面に陥凹を伴う粘膜下腫瘍様病変で,陥凹面に大小不同の絨毛様構造を認め,管状腺腫もしくは高分化型腺癌が疑われた.超音波内視鏡検査では,腫瘍内部に無エコー域を認めた.早期十二指腸癌も否定できず,EMRを施行した.病理組織検査では,側面の陥凹面は管状腺腫と診断した.また,十二指腸内腔側と嚢胞内腔側は粘膜筋板を共有しており,腺腫を合併した十二指腸重複症が疑われたが,十二指腸腔内憩室(Intraluminal duodenal diverticulum:IDD)との鑑別が困難であった.両疾患は,稀ではあるものの十二指腸腫瘍性病変の鑑別の一つとして考慮すべき疾患と考えられた.(著者抄録)

Language：Japanese   Publisher：Japan Gastroenterological Endoscopy Society  

<p>A 63-year-old man showed a duodenal elevated lesion on esophagogastroduodenoscopy, which was suspected to be an adenocarcinoma or adenoma on the basis of endoscopic findings. He was subsequently referred to our hospital for further examination and treatment. Endoscopic ultrasonography showed a hypoechoic area inside the tumor. The tumor was located on the second part of the duodenum and had a depression on its lateral side. On the basis of these findings, the patient underwent endoscopic mucosal resection. Histological examination of the resected specimen revealed that the depressed area was a tubular adenoma, and the luminal side of the duodenum and cystic area shared muscularis mucosae. The lesion was eventually diagnosed as duodenal duplication or intraluminal duodenal diverticulum with tubular adenoma. Although extremely rare, these diseases should be considered in the differential diagnosis of duodenal elevated lesions.</p>

DOI： 10.11280/gee.64.1011

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞緒言:マンソン孤虫症は,マンソン裂頭条虫の幼虫であるプレロセルコイドがヒトに寄生する比較的稀な疾患である。皮下への感染報告がほとんどであり,眼窩内への寄生は,わが国での報告はわずかである。今回,眼窩内のマンソン孤虫症を経験したので報告する。症例:33歳,男性。2017年7月に右眼瞼腫脹が出現し,近医で右眼の結膜炎の診断を受けた。点眼加療で改善しなかったため精査目的で2018年10月に鹿児島大学病院眼科を初診した。右上眼瞼に移動性の腫脹を認め,さらに2年後の造影MRIでは右上直筋付近に占拠性病変が出現した。特発性眼窩炎症の疑いでステロイド内服加療を開始したが,その後の皮膚生検の結果からIgG4関連疾患の診断となった。ステロイド内服を継続したが,改善・増悪を繰り返し寛解には至らなかった。2020年6月に右眼結膜に白色病変を認めたため,摘出術を施行した。摘出後,右眼瞼腫脹は改善した。摘出された白色病変は,病理組織学的検査および寄生虫抗体検査でマンソン孤虫症であると考えられた。結論:眼窩内の寄生虫感染症は稀であり,特発性眼窩炎症やIgG4関連疾患と症状が類似しているため誤診されやすい。ステロイド抵抗性の繰り返す眼瞼腫脹や外眼筋炎の診断には寄生虫感染症も念頭に置くべきである。

Language：English   Publisher：(一社)日本動脈硬化学会  

非アルコール性脂肪性肝疾患(NAFLD)マイクロミニブタモデルを用いて、NAFLDの病態進展に伴うマクロファージ表現型の変化について検討した。マイクロミニブタ25頭を普通食群、コレステロール添加高脂肪食(HcD)(0.2%、0.5%、1.5%コレステロール)群、HcD(1.5%コレステロール)+コール酸群の5群に各5頭ずつ分けて、1日1回8週間給餌した。肝臓標本を用いた免疫組織化学染色(マクロファージ、リンパ球、星細胞)を実施した。その結果、Iba-1陽性マクロファージ数は、食餌中コレステロール含量の増加に伴い増加していた。また、CD163陽性マクロファージ数およびCD204陽性マクロファージ数も食餌中コレステロール含量の増加に伴い増加したが、Iba-1陽性マクロファージ中のCD204陽性マクロファージの割合は、コール酸の補給により有意に減少していた。以上から、ブタの肝臓では脂質蓄積によりマクロファージ動員が誘導され、NAFLD初期にはM2様マクロファージが増加し、NAFLD後期にはM1様マクロファージが増加し、非アルコール性脂肪肝炎様状態の肝臓になることが示唆された。

Language：English  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: This study aimed to elucidate the impact of effective diffusion time setting on apparent diffusion coefficient (ADC)-based differentiation between primary central nervous system lymphomas (PCNSLs) and glioblastomas (GBMs) and to investigate the usage of time-dependent diffusion magnetic resonance imaging (MRI) parameters. METHODS: A retrospective study was conducted involving 21 patients with PCNSLs and 66 patients with GBMs using diffusion weighted imaging (DWI) sequences with oscillating gradient spin-echo (Δeff = 7.1 ms) and conventional pulsed gradient (Δeff = 44.5 ms). In addition to ADC maps at the two diffusion times (ADC7.1 ms and ADC44.5 ms), we generated maps of the ADC changes (cADC) and the relative ADC changes (rcADC) between the two diffusion times. Regions of interest were placed on enhancing regions and non-enhancing peritumoral regions. The mean and the fifth and 95th percentile values of each parameter were compared between PCNSLs and GBMs. The area under the receiver operating characteristic curve (AUC) values were used to compare the discriminating performances among the indices. RESULTS: In enhancing regions, the mean and fifth and 95th percentile values of ADC44.5 ms and ADC7.1 ms in PCNSLs were significantly lower than those in GBMs (p = 0.02 for 95th percentile of ADC44.5 ms, p = 0.04 for ADC7.1 ms, and p < 0.01 for others). Furthermore, the mean and fifth and 95th percentile values of cADC and rcADC were significantly higher in PCNSLs than in GBMs (each p < 0.01). The AUC of the best-performing index for ADC7.1 ms was significantly lower than that for ADC44.5 ms (p < 0.001). The mean rcADC showed the highest discriminating performance (AUC = 0.920) among all indices. In peritumoral regions, no significant difference in any of the three indices of ADC44.5 ms, ADC7.1 ms, cADC, and rcADC was observed between PCNSLs and GBMs. CONCLUSIONS: Effective diffusion time setting can have a crucial impact on the performance of ADC in differentiating between PCNSLs and GBMs. The time-dependent diffusion MRI parameters may be useful in the differentiation of these lesions.

DOI： 10.1186/s40644-023-00639-7

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Delays in breast cancer diagnosis can allow the disease to progress to an incurable stage. However, factors that cause patients to delay seeking treatment are unclear. In this study, we aimed to identify behavioral economic factors and personality characteristics of patients with breast cancer who had a delayed diagnosis. METHODS: We analyzed questionnaires completed by 41 patients with breast cancer. A delayed diagnosis was defined if the time between the first symptom and the medical visit was more than 6 months. RESULTS: We found 11 patients who had a delayed diagnosis. The significant characteristics associated with patients with breast cancer who had delayed diagnosis were: (i) less experience with breast cancer screening; (ii) progressive disease stage; and (iii) low time and future time preference. We found no significant behavioral economic factors other than time preference, and personality that differed between patients with breast cancer who did and did not have a delayed diagnosis. CONCLUSION: Low time preference rate is a characteristic of patients with breast cancer who had a delayed diagnosis.

DOI： 10.31557/APJCP.2023.24.10.3437

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景 類上皮肉腫は形態および免疫組織学的に上皮様を呈する腫瘍細胞が胞巣形成性に増殖する稀な悪性軟部腫瘍で,しばしばラブドイド細胞が出現する.今回,右臀部に発生した類上皮肉腫を経験したので報告する.症例 30代,女性.右臀部の筋肉内腫瘤および右鼠径部腫瘤を認めた.穿刺吸引細胞診では血性背景に上皮様結合を有した異型細胞が集塊状に出現していた.異型細胞の結合性は緩く,豊富な細胞質を有し,核は偏在傾向を示し,核縁は菲薄で平滑で,クロマチンは細顆粒状で均等に分布していた.癌の転移や肉腫が疑われたが,組織型の推定は困難であった.摘出された腫瘍は,組織学的に好酸性胞体の上皮様腫瘍細胞が線維性間質内に索状やシートに増殖し,腫瘍中心に壊死を伴っていた.免疫組織化学的に腫瘍細胞は,cytokeratin(AE1/AE3,CAM5.2),Vimentin,CD34陽性を示し,INI-1の欠失を認めた.細胞所見,免疫組織化学を含む組織所見より類上皮肉腫と診断した.結語 類上皮肉腫の細胞像では,豊富な細胞質を有する上皮様結合を示す異型細胞を認めるが,結合性は緩いこと,肉腫を示唆する菲薄で平滑な核縁であることに着目することが重要であると考えられた.(著者抄録)

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

症例は80代女性。リウマチ性多発筋痛症の治療中に胸部大動脈瘤を指摘され,人工血管置換術が行われた。大動脈では内膜に軽度の粥状硬化を認めた。中膜ではリンパ球や形質細胞,少数の多核巨細胞の浸潤,内膜側優位の弾性線維の配列の乱れと消失を認めたが,外膜の線維化や炎症細胞浸潤は軽度であり,巨細胞性動脈炎と診断した。大動脈瘤において巨細胞性動脈炎と病理診断される症例では,側頭動脈炎の既往がなく臨床症状に乏しいことがあり,大動脈瘤を注意深く検索することで,巨細胞性動脈炎の可能性を見落とさないことが重要である。(著者抄録)

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BACKGROUND: Low-grade fibromyxoid sarcoma (LGFMS) is a rare type of sarcoma which is observed in the soft tissue of proximal extremities, typically in young and middle-aged adults. It consists of a solid proliferation of bland spindle cells within collagenous and myxoid stroma. CASE REPORT: Herein, we report a case of LGFMS with massive degeneration and hyalinization. A 30-year-old man presented with a well-circumscribed mass measuring 15 cm in diameter in his left biceps femoris muscle. Marginal tumor resection was performed under the clinical diagnosis of an ancient schwannoma or chronic expanding hematoma (CEH). The resected tissue revealed a well-demarcated tumor mass with massive degeneration and hyalinization with focal calcification. Proliferation of spindle tumor cells with abundant collagenous stroma, which resembled the fibrous capsule of CEH, was observed exclusively in a small area of the periphery of the tumor. No nuclear palisading, myxoid stroma, or collagen rosettes were identified. Immunohistochemical analysis demonstrated that the spindle tumor cells expressed mucin 4 and epithelial membrane antigen. Reverse transcriptase-polymerase chain reaction analysis detected mRNA expression of fused in sarcoma::CAMP-responsive element binding protein 3-like protein 2 (FUS::CREB3L2) fusion gene. Thus, a final diagnosis of LGFMS with massive degeneration and FUS::CREB3L2 fusion was made. CONCLUSION: The recognition of massive degeneration and hyalinization as unusual features of LGFMS might be helpful to differentiate it from CEH and other benign spindle-cell tumors.

DOI： 10.21873/invivo.13404

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BACKGROUND: Chronic granulomatous disease (CGD) is an inborn immune disorder in which the phagocytic system cannot eradicate pathogens, and autoinflammation occurs. Approximately half of the patients have associated gastrointestinal symptoms. Although most cases with CGD-associated colitis present nonspecific histology, colonoscopy in some cases shows brownish dots over a yellowish oedematous mucosa, which is termed a "leopard sign". However, the significance of these signs remains unclear. METHODS: We collected data from patients with CGD whose colonoscopic findings showed the leopard sign. RESULTS: Three patients with CGD and leopard signs were enrolled in this study. One patient underwent colonoscopy for frequent diarrhoea and weight gain failure, and another for anal fistula. The third patient was without gastrointestinal symptoms and underwent colonoscopy as a screening test before allogeneic haematopoietic cell transplantation (HCT). Endoscopic findings showed a mild leopard sign in the first case; however, non-contiguous and diffuse aphthae were observed throughout the colon. The other two cases were unremarkable except for the leopard sign. All the patients achieved remission with oral prednisolone or HCT. One patient underwent colonoscopy after HCT; results revealed improvements in endoscopy (including the leopard sign) and histological findings. However, another patient underwent colonoscopy after prednisolone treatment; this revealed no change in the leopard sign. CONCLUSION: The leopard sign in the colon may be a characteristic endoscopic finding of CGD, even in patients who do not develop severe gastrointestinal symptoms; however, it does not reflect the severity of CGD-associated colitis.

DOI： 10.3389/fimmu.2023.1208590

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Language：Japanese   Publisher：(一社)日本病理学会  

遺残副腎は異所性に認められる副腎皮質組織であり,腫瘍化は非常に稀である。80代女性の骨盤腔内にFDGの高集積を呈する腫瘍を認めた。腫瘍は右子宮広間膜内に卵巣とは離れて存在し,好酸性顆粒状の豊富な細胞質を有する腫瘍細胞のびまん性増殖からなり,腫瘍辺縁には非腫瘍性の副腎皮質組織を伴っていた。免疫染色でSF-1,mitochondria陽性であった。Lin-Weiss-Bisceglia criteriaを満たす所見はなく,遺残副腎由来のoncocytomaと診断した。(著者抄録)

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Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景 膵solid-pseudopapillary neoplasm(以下、SPN)は、膵外分泌腫瘍の1～3%を占める稀な腫瘍である。今回、乳腺細胞診において原発性乳癌との鑑別に苦慮した膵SPNの乳腺転移の1例を経験したので報告する。症例 50代女性。7年前に手術された膵SPN術後の定期検診にて左乳腺外側に1cm大の結節を指摘された。原発性乳癌が疑われ、針生検及び穿刺針洗浄細胞診が施行された。穿刺針洗浄細胞診で、血性背景に乳頭状、管状あるいは孤立散在性の異型細胞を多数認め、血管性間質を軸とした重積性を示す集塊も存在していた。核偏在傾向や核溝も見られ、浸潤性乳管癌充実型や粘液癌Type Bを疑った。摘出生検では、シート状構造を示す腫瘍細胞と淡好塩基性を示す疎な線維性間質を認め、偽乳頭状構造も認めた。免疫染色では、β-cateninが腫瘍細胞の核・細胞質に陽性であった。以上の所見から膵SPNの乳腺転移と判断した。結論 原発性乳癌との鑑別に苦慮した膵SPNの乳腺転移の一例を経験した。膵SPNの肝や腹腔以外への転移は稀ではあるが、臨床情報に留意し検鏡することで診断し得ると考えられた。(著者抄録)

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We aimed to evaluate the mutation profile, transcriptional variants, and prognostic impact of the epidermal growth factor receptor (EGFR) gene in isocitrate dehydrogenase (IDH)-wildtype glioblastomas (GBMs). METHODS: We sequenced EGFR, evaluated the EGFR splicing profile using a next-generation sequencing oncopanel, and analyzed the outcomes in 138 grade IV IDH-wildtype GBM cases. RESULTS: EGFR mutations were observed in 10% of GBMs. A total of 23.9% of the GBMs showed EGFR amplification. Moreover, 25% of the EGFR mutations occurred in the kinase domain. Notably, EGFR alterations were a predictor of good prognosis (p = 0.035). GBM with EGFR alterations was associated with higher Karnofsky Performance Scale scores (p = 0.014) and lower Ki-67 scores (p = 0.005) than GBM without EGFR alterations. EGFRvIII positivity was detected in 21% of EGFR-amplified GBMs. We identified two other EGFR variants in GBM cases with deletions of exons 6-7 (Δe 6-7) and exons 2-14 (Δe 2-14). In one case, the initial EGFRvIII mutation transformed into an EGFR Δe 2-14 mutation during recurrence. CONCLUSIONS: We found that the EGFR gene profiles of GBM differ among cohorts and that EGFR alterations are good prognostic markers of overall survival in patients with IDH-wildtype GBM. Additionally, we identified rare EGFR variants with longitudinal and temporal transformations of EGFRvIII.

DOI： 10.1002/cam4.4939

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The microbial population of the intestinal tract and its relationship to specific diseases has been extensively studied during the past decade. However, reports characterizing the bile microbiota are rare. This study aims to investigate the microbiota composition in patients with pancreaticobiliary cancers and benign diseases by 16S rRNA gene amplicon sequencing and to evaluate its potential value as a biomarker for the cancer of the bile duct, pancreas, and gallbladder. RESULTS: We enrolled patients who were diagnosed with cancer, cystic lesions, and inflammation of the pancreaticobiliary tract. The study cohort comprised 244 patients. We extracted microbiome-derived DNA from the bile juice in surgically resected gallbladders. The microbiome composition was not significantly different according to lesion position and cancer type in terms of alpha and beta diversity. We found a significant difference in the relative abundance of Campylobacter, Citrobacter, Leptotrichia, Enterobacter, Hungatella, Mycolicibacterium, Phyllobacterium and Sphingomonas between patients without and with lymph node metastasis. CONCLUSIONS: There was a significant association between the relative abundance of certain microbes and overall survival prognosis. These microbes showed association with good prognosis in cholangiocarcinoma, but with poor prognosis in pancreatic adenocarcinoma, and vice versa. Our findings suggest that pancreaticobiliary tract cancer patients have an altered microbiome composition, which might be a biomarker for distinguishing malignancy.

DOI： 10.1186/s12866-022-02557-3

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214373

Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Plexiform fibromyxoma (PFM) is a rare gastrointestinal tract tumor that develops in the stomach in most cases. Here, we report an extremely rare case of esophageal PFM. A female in her mid-30 s presented with difficulty in swallowing and breathing. Endoscopic examination revealed a submucosal tumor measuring approximately 45 × 50 mm in the upper thoracic esophagus. The biopsied specimen did not show definite histological evidence of gastrointestinal stromal tumors (GISTs). Since imatinib administration based on a clinical diagnosis of GIST did not show a therapeutic effect for tumor reduction, tumor resection was performed. The resected tumor exhibited proliferation of spindle tumor cells with abundant myxoid and vascular stroma separated by a muscular layer, indicating a plexiform arrangement. Immunohistochemical analysis demonstrated that the tumor cells diffusely expressed vimentin and alpha-smooth muscle actin, but not desmin, c-kit, DOG1, and CD34. MALAT1-GLI1 fusion was detected in formalin-fixed paraffin-embedded tissue using RT-PCR and Sanger sequencing. The results suggested that a fibromyxoid tumor can develop in the esophagus, showing an identical histology and MALAT1-GLI1 fusion to gastric PFM.

DOI： 10.1016/j.prp.2022.153878

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: In recent years, conversion surgery after chemotherapy has been considered a promising strategy for improving the prognosis of patients with stage IV gastric cancer. However, there are few reports on conversion gastrectomy after second-line chemotherapy. Here, we report a case of long-term survival of a patient with liver metastases from gastric cancer who underwent conversion surgery after second-line chemotherapy with ramucirumab and paclitaxel. CASE PRESENTATION: A 77-year-old man complaining of weight loss was diagnosed with human epidermal growth factor receptor 2-positive gastric cancer with multiple liver metastases. Although the patient initially received trastuzumab-based chemotherapy, it was discontinued, because he experienced trastuzumab-induced infusion reactions. Thereafter, he was treated with six courses of S-1 plus cisplatin and six courses of ramucirumab plus paclitaxel as the first- and second-line regimens, respectively. The primary tumor and liver metastases remarkably shrank, and the reduction rate of the measurable metastatic liver lesions was 81.1%. According to the Response Evaluation Criteria in Solid Tumors, the patient responded partially. Therefore, he underwent total gastrectomy with D2 lymphadenectomy and partial hepatectomy of segments 3 and 4. Pathological examination revealed tumor invasion into the muscularis propria, a grade 1a histological response, and no lymph node metastases. No viable cancer cells were identified in the specimens resected from liver segments 3 and 4. Accordingly, the patient was pathologically diagnosed with stage IB (ypT2N0M0). Postoperatively, the patient received adjuvant chemotherapy with S-1 for 6 months, and he survived without recurrence for 42 months after conversion surgery. CONCLUSIONS: Conversion surgery might be clinically useful for improving survival in certain patients with gastric cancer, including those who previously received second-line chemotherapy.

DOI： 10.1186/s40792-022-01412-x

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

POLE mutation-type endometrial cancer is characterized by an extremely high tumor mutation burden. Most POLE mutation-type endometrial cancers are histologically endometrioid carcinomas, and POLE mutation-type carcinosarcomas are rare among endometrial cancers. We report a case of endometrial and pelvic cancer in a 53-year-old woman who was analyzed using next-generating sequencing. The endometrial lesion harbored a p.T457del POLE mutation with an elevated tumor mutation burden and low microsatellite instability. The pelvic lesion showed divergent histological features, consisting of high-grade endometrioid carcinoma, neuroendocrine carcinoma, and chondrosarcoma. In addition to the common POLE mutation detected in the endometrial lesion, the pelvic lesion in each element showed additional gene mutations in a hierarchical manner. Therefore, it is indicated that the p.T457del POLE mutation is a pathogenic mutation and may be related to POLE mutation-induced carcinogenesis and divergent morphogenesis in endometrial cancer.

DOI： 10.1177/10668969221088880

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: The present study investigated whether or not pleural anthracosis is associated with changes in the pleural lymphatic structures or function, which would interfere with nodal skip metastasis. METHODS: This study comprised 2 different case series. In the first series, we observed pleural lymphatic drainage using near-infrared fluorescent endoscopy by the subpleural injection of indocyanine green immediately after thoracotomy for lung cancer. We also performed a histological assessment of the pleura. In the second series, we reviewed the nodal metastatic pattern (skip or non-skip metastasis) in pathological N2 lung cancer involving the pleura. These findings were compared with the severity of pleural anthracosis, which was quantified by thoracoscopic vision and a software-based imaging analysis. RESULTS: In the first series (n = 42), pleural lymphatic drainage was not visualized in 19 (45%) patients who had relatively severe anthracosis, while it was visualized in the remaining 23 (55%) patients who had relatively minimal anthracosis. Histologically, severe anthracosis was associated with pleural thickening accompanied by a decreased incidence of straight-running lymphatic vessels and, in turn, an increased incidence of short lymphatic vessels, which was suggested to be the result of pleural remodelling. In the second series (n = 53), a skip metastatic pattern was found in 24 (45%) patients who predominantly had less-severe anthracosis, while a non-skip metastatic pattern was found in 29 (55%) patients who predominantly had severe anthracosis. CONCLUSIONS: Pleural anthracosis was associated with pathological changes in the pleural lymphatics and decreased pleural lymphatic drainage, thereby interfering with nodal skip metastasis.

DOI： 10.1093/ejcts/ezac123

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Ancillary immunohistochemical tools can facilitate an integrated diagnosis of endometrial pathology. According to The Cancer Genome Atlas classification, endometrial cancers are of four molecular subtypes: mismatch repair (MMR)-deficient (MMR-d), p53 mutation (p53mut), DNA polymerase epsilon (POLE) mutation (POLEmut), and no specific molecular profile (NSMP). As the specific histological and immunohistochemical features of POLEmut and NSMP subtypes are unknown, these cancers are categorized based on molecular analysis. In this study, we analyzed POLEmut-subtype endometrioid carcinoma (EC) using a custom-made cancer gene panel and the Catalog of Somatic Mutations in Cancer (COSMIC) database, extracted a characteristic genome profile, and identified an immunohistochemical marker that could be used as a diagnostic tool. The results indicated that the POLEmut-subtype EC exhibited nonsense mutations in the ataxia telangiectasia mutated (ATM) gene and a subsequent loss of ATM expression, which was monitored through immunohistochemical analysis. Moreover, analyses using the COSMIC database indicated that POLEmut-subtype EC cases often harbored similar ATM nonsense mutations. These results suggest that ATM expression is a potential immunohistochemical marker for the differential diagnosis of POLEmut- and NSMP-subtype EC. DATA AVAILABILITY: The data supporting the findings of this study are available upon request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.

DOI： 10.1016/j.prp.2021.153743

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Understanding human genome alterations is necessary to optimize genome-based cancer therapeutics. However, some newly discovered mutations remain as variants of unknown significance (VUS). Here, the mutation c.1403A > G in exon 10 of the platelet-derived growth factor receptor-alpha (PDGFRA) gene, a VUS found in adult glioblastoma multiforme (GBM), was introduced in human embryonal kidney 293 T (HEK293T) cells using genome editing to investigate its potential oncogenic functions. Genome editing was performed using CRISPR/Cas9; the proliferation, drug sensitivity, and carcinogenic potential of genome-edited cells were investigated. We also investigated the mechanism underlying the observed phenotypes. Three GBM patients carrying the c.1403A > G mutation were studied to validate the in vitro results. The c.1403A > G mutation led to a splice variant (p.K455_N468delinsN) because of the generation of a 3'-acceptor splice site in exon 10. PDGFRA-mutated HEK293T cells exhibited a higher proliferative activity via PDGFRα and the cyclin-dependent kinase (CDK)4/CDK6-cyclin D1 signaling pathway in a ligand-independent manner. They showed higher sensitivity to multi-kinase, receptor tyrosine kinase, and CDK4/CDK6 inhibitors. Of the three GBM patients studied, two harbored the p.K455_N468delinsN splice variant. The splicing mutation c.1403A > G in PDGFRA is oncogenic in nature. Kinase inhibitors targeting PDGFRα and CDK4/CDK6 signaling should be evaluated for treating GBM patients harboring this mutation.

DOI： 10.1038/s41598-022-05391-9

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Authorship：Last author,　Corresponding author   Language：English  

DOI： 10.1111/pin.13197

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Background

Platelet-derived growth factor receptor alpha (PDGFRA) is the second most frequently mutated tyrosine kinase receptor in glioblastoma (GBM). However, the prognostic impact of PDGFRA amplification on GBM patients remains unclear. Herein, we evaluated this impact by retrospectively analyzing outcomes of patients with IDH wild-type GBM.

Methods

Using a custom-made oncopanel, we evaluated PDGFRA gain/amplification in 107 GBM samples harboring wild-type IDH, along with MGMT promoter (MGMTp) methylation status.

Results

We detected PDGFRA gain/amplification in 31 samples (29.0%). PDGFRA gain/amplification predicted poor prognosis (P = .003). Compared to unamplified PDGFRA, PDGFRA gain/amplification in GBM was associated with higher patient age (P = .031), higher Ki-67 score (P = .019), and lower extent of surgical resection (P = .033). Unmethylated MGMTp also predicted poor prognosis (P = .005). As PDGFRA gain/amplification and unmethylated MGMTp were independent factors for poor prognosis in multivariate analyses, we grouped GBM cases based on PDGFRA and MGMTp status: poor (PDGFRA gain/amplification and unmethylated MGMTp), intermediate (PDGFRA gain/amplification or unmethylated MGMTp), and good (PDGFRA intact and methylated MGMTp) prognosis. The Kaplan-Meier survival analysis indicated that these groups significantly correlated with the OS of GBM patients (P &amp;lt; .001).

Conclusions

Here we report that PDGFRA gain/amplification is a predictor of poor prognosis in IDH wild-type GBM. Combining PDGFRA gain/amplification with MGMTp methylation status improves individual prognosis prediction in patients with IDH wild-type GBM.

DOI： 10.1093/noajnl/vdac097

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Other Link： https://academic.oup.com/noa/article-pdf/4/1/vdac097/45178840/vdac097.pdf

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/ped.15158

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Mucoepidermoid carcinoma (MEC) is one of the most common malignant salivary gland carcinomas, but no effective treatment strategy has been established other than surgical resection. Purkinje cell protein (PCP) 4/peptide (PEP) 19 is a calmodulin-binding antiapoptotic peptide that is expressed and inhibits apoptosis in human breast cancer cells. Human epidermal growth factor receptor 2 (HER2) is an epidermal growth factor that has been implicated in the pathogenesis of many carcinomas, particularly breast and gastric carcinomas. In the present study, we performed immunohistochemical analyses of samples from 73 patients who underwent surgical resection for MEC of the salivary gland using antibodies against PCP4/PEP19 and HER2. PCP4/PEP19 expression was related to better prognosis, while HER2 expression was associated with worse prognosis. Patients that were PCP4/PEP19-positive and HER2-negative showed similar outcomes to PCP4/PEP19 and HER2 alone. Therefore, PCP4/PEP19 and HER2 are predicted to play important roles in the pathogenesis and progression of MEC.

DOI： 10.3390/cancers14010054

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214248

Language：Japanese   Publisher：日本臨床外科学会  

肝細胞癌(HCC)を合併したDubin-Johnson症候群(DJS)の肝予備能評価と周術期経過を報告する.66歳の男性がRickettsia属による感染の際に肝障害と肝S4,S2にHCCを指摘された.T-bil 4.6(D-bil 3.4)mg/dL,Alb 4.2g/dL,PT 92%,indocyanine green 15分停滞率(ICGR15)11%,Child-Pugh B(7点),肝障害度Aであった,99mTc-galactosyl human serum albumin(GSA)シンチグラフィのLHL15は0.909で,肝予備能はほぼ正常と判断し,肝内側区域切除術+S2部分切除術を行った.術後3日目にT-bilが15.7mg/dLまで上昇したが28日目に術前値に復した.ICGR15とGSAシンチグラフィは正確に肝予備能を反映した.術後のT-bilの上昇は一過性であった.(著者抄録)

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞目的:インターフェロン-β(IFN-β)結膜下注射の頻回投与で縮小に至った結膜悪性黒色腫の症例を報告する。症例:患者は91歳,女性。20XX年8月に増大と出血を伴う右下眼瞼結膜の隆起性腫瘤を自覚し,加療を目的として鹿児島大学病院眼科を紹介された。高血圧症,糖尿病,ネフローゼ症候群の既往があった。所見:初診時,右下眼瞼結膜に15mm大の出血を伴う隆起性腫瘤を認めた。拡大切除術を提案したが,高齢のため外科的治療を希望しなかった。下眼瞼結膜腫瘤を部分切除し,悪性黒色腫と組織診断した。全身検査では遠隔転移は検出されなかった。出血傾向の改善のため放射線治療(線量28Gy/14Fr)を行ったのち,IFN-β結膜下注射(300万単位/回)の継続で経過観察した。1回目の注射後から出血傾向は改善した。さらに週1回で注射を継続したところ,投与開始後3回目より隆起性病変は縮小を認め,8回目でほぼ消失した。副作用として視力低下を認めたため,投与間隔を延ばし,1回量を半減して投与を継続した。その後も病変の増悪や遠隔転移は認めなかったが,投与開始から8ヵ月後に既往のネフローゼ症候群の悪化を認めたため治療を中止した。結論:IFN-β結膜下注射は結膜悪性黒色腫の治療に有効であった。しかし,眼局所および全身に副作用を及ぼす可能性があり,投与量および投与間隔に注意が必要である。

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To evaluate the accuracy of the one-step nucleic acid amplification (OSNA) assay for the diagnosis of lymph node (LN) metastasis in uterine cancer. METHODS: A total of 116 LNs from 30 patients with cervical and endometrial cancer, enrolled in this prospective study, were used. Excised LNs were cut into 4 to 6 blocks at 2 mm intervals, and nonadjacent blocks were alternately subjected to either histological examination or the OSNA assay. RESULTS: The concordance rate between histological examination and the OSNA assay in cervical cancer and in endometrial cancer was 95.9% and 95.2%, respectively. The sensitivity, specificity, and negative predictive value of the OSNA assay were 80%, 97.7%, and 97.7% in cervical cancer, and 85.7%, 93.3%, and 98.2% in endometrial cancer, respectively. In cervical cancer, discordant results were observed in 2 out of 49 LNs (4.1%); 1 was OSNA assay-positive and histological examination-negative, and 1 was OSNA assay-negative and histological examination-positive. In endometrial cancer, discordant results were observed in 5 out of 67 LNs (7.5%); 4 were OSNA assay-positive and histological examination-negative, and 1 was OSNA assay-negative and histological examination-positive. CONCLUSION: The OSNA assay showed high concordance rate with histological examination, sensitivity, and specificity in uterine cancer, suggesting that it could enhance the accuracy of conventional pathological examination for the detection of LN metastasis by reducing false negative rate.

DOI： 10.3802/jgo.2022.33.e11

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The roles of endogenous nitric oxide (NO) derived from the entire NO synthases (NOSs) system have yet to be fully elucidated. We addressed this issue in mice in which all three NOS isoforms were deleted. Under basal conditions, the triple n/i/eNOSs-/- mice displayed significantly longer mean alveolar linear intercept length, increased alveolar destructive index, reduced lung elastic fiber content, lower lung field computed tomographic value, and greater end-expiratory lung volume as compared with wild-type (WT) mice. None of single NOS-/- or double NOSs-/- genotypes showed such features. These findings were observed in the triple n/i/eNOSs-/- mice as early as 4 weeks after birth. Cyclopaedic and quantitative comparisons of mRNA expression levels between the lungs of WT and triple n/i/eNOSs-/- mice by cap analysis of gene expression (CAGE) revealed that mRNA expression levels of three Wnt ligands and ten Wnt/β-catenin signaling components were significantly reduced in the lungs of triple n/i/eNOSs-/- mice. These results provide the first direct evidence that complete disruption of all three NOS genes results in spontaneous pulmonary emphysema in juvenile mice in vivo possibly through down-regulation of the Wnt/β-catenin signaling pathway, demonstrating a novel preventive role of the endogenous NO/NOS system in the occurrence of pulmonary emphysema.

DOI： 10.1038/s41598-021-01453-6

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Lung cancer constitutes a threat to human health. BHLHE41 plays important roles in circadian rhythm and cell differentiation as a negative regulatory transcription factor. This study investigates the role of BHLHE41 in lung cancer progression. We analyzed BHLHE41 function via in silico and immunohistochemical studies of 177 surgically resected non-small cell lung cancer (NSCLC) samples and 18 early lung squamous cell carcinoma (LUSC) cases. We also examined doxycycline (DOX)-inducible BHLHE41-expressing A549 and H2030 adenocarcinoma cells. BHLHE41 expression was higher in normal lung than in lung adenocarcinoma (LUAD) tissues and was associated with better prognosis for the overall survival (OS) of patients. In total, 15 of 132 LUAD tissues expressed BHLHE41 in normal lung epithelial cells. Staining was mainly observed in adenocarcinoma in situ and the lepidic growth part of invasive cancer tissue. BHLHE41 expression constituted a favorable prognostic factor for OS (p = 0.049) and cause-specific survival (p = 0.042) in patients with LUAD. During early LUSC, 7 of 18 cases expressed BHLHE41, and this expression was inversely correlated with the depth of invasion. DOX suppressed cell proliferation and increased the autophagy protein LC3, while chloroquine enhanced LC3 accumulation and suppressed cell death. In a xenograft model, DOX suppressed tumor growth. Our results indicate that BHLHE41 expression prevents early lung tumor malignant progression by inducing autophagic cell death in NSCLC.

DOI： 10.3390/ijms222111509

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Extramedullary hematopoiesis (EMH) in adults usually occurs in the liver, spleen, and lymph nodes when bone marrow hematopoiesis fails. EMH has also been recognized in benign or malignant hepatic tumors, such as hepatoblastoma, hepatocellular adenoma, and vascular tumors. However, it is rarely encountered in hepatocellular carcinoma (HCC) in elderly adults, and the molecular mechanism of EMH in hepatic tumors remains unclear. We present a case of a 74-year-old man without any hematopoietic disorders and hepatitis viral infection who underwent hepatic resection for HCC. Histological examination revealed a well-differentiated HCC with trilineage hematopoiesis in the tumor and non-neoplastic liver. The coexistence of HCC and EMH in adult patients with no hematopoietic disorders is very rare and must be distinguished from poorly differentiated or dedifferentiated HCC and hepatoblastoma.

DOI： 10.1177/10668969211050904

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BACKGROUND: Perivascular epithelioid cell neoplasm (PEComa) in a child is very rare. We herein report the first malignant case of PEComa developing in the liver of a pediatric patient. CASE PRESENTATION: A 10-year-old boy visited a private clinic with prolonged fever of unknown etiology. Abdominal ultrasonography was performed to evaluate the fever's origin, revealing a large tumor in the liver. He was thus referred to a nearby hospital to investigate the tumor further. Enhanced computed tomography (CT) showed a 6.8 × 5.9 × 10.5-cm solid lesion on S4 and S5. On magnetic resonance imaging (MRI), the tumor had a low signal intensity on T1 imaging and high signal intensity on T2 imaging, with partial diffusion restriction. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) showed a marked uptake in the mass lesion with no evidence of metastasis. The patient was negative for all tumor markers, including AFP, CEA and PIVKA-II. The results of a needle biopsy suggested hepatocellular carcinoma. The tumor's rapid growth suggested malignancy. Hepatic segmentectomy (S4 + S5 + S8) was performed. The tumor was resected en bloc with a margin. Microscopically, the tumor showed atypical spindle, polygonal or oval-shaped cells with a high nuclear grade, and vascular invasion. Immunohistochemistry was positive for alpha-smooth muscle antigen (α-SMA), human melanin black-45 (HMB-45) and melan A. The pathological diagnosis was malignant PEComa. In the 6 months after surgery, the patient complained of shoulder pain. MRI showed a dumbbell-shaped tumor at the 2nd thoracic vertebrae, which was confirmed to be bone metastasis of PEComa. After chemotherapy, including ifosfamide and doxorubicin, vertebrectomy was performed. Two years later, thoracoabdominal CT showed a 10-cm solid mass occupying the pelvis and a 15-mm nodule in the middle lobe of the right lung. Under a diagnosis of peritoneal and lung metastases, they were surgically removed and metastasis of PEComa was pathologically confirmed. Four months after the 2nd relapse, pelvic metastasis appeared again and mTOR (mammalian target of rapamycin) inhibitor was initiated. To our knowledge, this is the first report of malignant hepatic PEComa in a pediatric patient. CONCLUSION: Although extremely rare, malignant hepatic PEComa can develop in a child.

DOI： 10.1186/s40792-021-01300-w

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The diagnostic value of 18F-fluorodeoxyglucose (FDG) uptake in the management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas remains unclear. This study aimed to assess the role of FDG uptake in the diagnosis of different degrees of dysplasia of IPMNs. We retrospectively analyzed the following three points in 84 patients with IPMNs: (1) risk factors to predict high-grade dysplasia (HGD) and invasive carcinoma (INV); (2) the relationship between FDG uptake and glucose transporter 1 (GLUT-1) expression; and (3) the relationship between FDG uptake and the presence of mural nodules. The histopathological diagnosis was low-grade dysplasia (LGD) in 43 patients, HGD in 16, and INV in 25. The maximum standardized uptake value (SUV-max) was significantly higher in INV than in LGD/HGD (p < 0.0001, p = 0.0136). The sensitivity and specificity to discriminate INV from LGD/HGD were 80.0% and 86.2%, respectively, using the receiver operator characteristic curve, when the optimal cutoff score of SUV-max was set at 4.03. Those values were not different between HGD and LGD. More than half of HGD patients had low GLUT-1 expression. Taken together, FDG-PET/CT is useful in distinguishing between non-invasive and invasive IPMN. Our results offer critical information that may determine surgical treatment strategies.

DOI： 10.3390/cancers13184633

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Language：Japanese   Publisher：(株)メディカル葵出版  

外傷時に迷入したと考えられる涙嚢内異物の症例を報告する。症例は34歳、男性。約20年前に左眼下涙点付近を竹で受傷した既往がある。受傷後から慢性的に左鼻汁を自覚していた。最近になって左眼の眼脂を自覚し、近医で涙道閉塞を疑われ当科へ紹介となった。初診時に左眼内眼角部に外傷の痕跡はなかった。通水検査で左側の通水を認めなかった。単純CT検査を行ったところ左眼涙嚢内に10mm大で高信号の棒状陰影を認めた。涙道内視鏡検査では左眼涙嚢内の異物が疑われた。涙道内視鏡による摘出は困難と考え涙嚢鼻腔吻合術(DCR)鼻内法を行った。摘出した異物は、病理組織学的検査で放線菌が全周に付着した植物片と診断された。術直後より左眼の眼脂は消失し、通水は改善した。異物は涙小管や鼻涙管の通過が困難な大きさであり、また外傷の既往があることから、受傷時に涙嚢内へ迷入したものと考えられた。大型の涙嚢内異物であったがDCR鼻内法で抽出が可能であった。(著者抄録)

Language：English   Publisher：Springer Berlin Heidelberg  

症例は10歳男児で、1ヵ月前から高熱が続いており、血液検査でCRP高値を認めたため精査目的に前医を受診した。腹部超音波検査では肝に大型固形腫瘍を認め、造影CTで肝S4とS5に局在する腫瘍がみられ、MRIではT1強調像で低信号、T2強調像で高信号を呈し、18F-FDG-PETにてFDGの著明な取り込みがみられた。AFP、PIVKA-II、CEA、CA19-9はいずれも正常範囲内にあり、未分化癌疑いにて手術目的に当院紹介となった。コア針生検を施行したところ肝細胞癌が疑われ、術前の造影CTでは腫瘍サイズの著明な増大が生じていた。開腹下に腫瘍切除を行い、術中所見では大型腫瘍は肝中心部に位置しており、腹膜播種や腹腔内転移は認めなかった。胆嚢切除後に肝実質を切離し、S8背側は温存した。切除標本の肉眼所見では出血と壊死を伴った黄白色の10×9cm大の腫瘍であり、境界明瞭であったが腫瘍細胞に浸潤性増殖パターンと脈管浸潤がみられ、血管周囲の多角形ないし楕円形細胞を呈し、束状配列の紡錘細胞、淡明な細胞質を有する円形類上皮細胞が認められた。また、免疫組織化学染色では細胞の一部はα-SMAとメランAに陽性を示しており、血管周囲類上皮細胞腫瘍(PEComa)と診断した。術後6ヵ月、肩関節痛を訴え、生検にてPEComaの骨転移と診断、化学療法後に脊椎切除術を施行した。その2年後に骨盤転移と肺転移をきたして転移巣に対する手術を行い、さらに骨盤転移を認めたためmTOR阻害剤にて治療中である。

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Primary vaginal carcinosarcoma (VCS) is an extremely rare and aggressive tumor consisting of admixed malignant epithelial and mesenchymal elements. We report a case of VCS that was subjected to analysis by immunohistochemistry and next-generation sequencing (NGS). A 53-year-old woman with post-menopausal vaginal bleeding underwent surgical excision followed by concurrent chemoradiation. A well demarcated tumor was growing in a discontinuous fashion at a location some distance from both the cervix and vulva. Microscopically, the tumor consisted of adenocarcinoma components and sarcoma components consisting of a sheet-like growth of spindle-shaped cells, and we diagnosed this tumor as primary vaginal carcinosarcoma. NGS analysis of each component identified the following variants, TP53, PIK3CA, KRAS and FBXW7. A comparison of microsatellite instability (MSI) and tumor mutation burden (TMB) showed that within both tissues the sarcomatous components had a higher MSI and TMB than the carcinomatous components. This case supports "a monoclonal theory" with the genome profile being similar to other malignant mixed Müllerian tumors.

DOI： 10.1177/10668969211037915

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214064

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BACKGROUND: Genomic examination of cytology specimens is often performed on cell blocks or conventional smears rather than on liquid-based cytology (LBC) specimens. Since LBC specimens preserve high-quality DNA, cancer genome profiling using next-generation sequencing (NGS) is also attainable from residual LBC specimens. One of the advantages of using LBC specimens for NGS is that it allows direct extraction of DNA from residual specimens, avoiding a sacrifice of smear slides and minimizing genomic profiling processing time. METHODS: Endometrial LBC specimens were subjected to NGS analysis to validate the practicality of rapid cancer genomic profiling in a pathology laboratory. The extracted DNA was subjected to NGS using a customized cancer gene panel comprising 56 genes and 17 microsatellite regions. The workflow strategy was defined, and the processing time estimated for specimen sampling, cell counting, NGS run, and genome profiling. RESULTS: NGS analysis of most LBC specimens revealed somatic mutations, tumor mutation burden, and microsatellite instability, which were almost identical to those obtained from formalin-fixed paraffin-embedded tissues. The processing time for direct NGS analysis and cancer genomic profiling of the residual LBC specimens was approximately 5 days. CONCLUSION: The residual LBC specimens collected using endometrial cytology were verified to carry a high tumor fraction for NGS analysis and could serve as an alternate source for rapid molecular classification and diagnosis of endometrial cancers, as a routine process in a pathology laboratory.

DOI： 10.1002/dc.24841

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DOI： 10.1111/pin.13109

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BACKGROUND/AIM: The reproducibility of athero - sclerotic lesions was evaluated after the production of cloned-microminipigs and their offspring. MATERIALS AND METHODS: Cloned-microminipig-parents were produced by microminipigsomatic cell nuclei. These parents were crossbred and delivered males (F1-offspring) were divided into two groups: normal chow diet (NcD)-fed and high-fat/high-cholesterol diet (HcD)-fed groups. One of the F1-offsprings was subjected to cloning, and delivered males (F1-clones) were fed with HcD. After 8 weeks, all animals were necropsied for patho - physiological studies compared to non-cloned-microminipigs. RESULTS: HcD-fed F1-offspring and F1-clones, but not NcD-fed F1-offspring, exhibited increased serum lipid levels and systemic atherosclerosis, which were comparable to those of HcD-fed non-cloned-microminipigs. Homogeneity of variance analysis demonstrated that standard deviation values of serum lipoprotein and aortic atherosclerosis area from HcD-fed animals decreased in F1-offspring and F1-clones. CONCLUSION: HcD-induced atherogenesis was highly reproducible in F1-offsprings and F1-clones, indicating that the atherosclerosis-prone genomic background was preserved in the cloned-microminipigs, which can be used for studies on human atherosclerosis and related diseases.

DOI： 10.21873/invivo.12471

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

症例は60歳女性で、喀血を主訴とした。喀血は手術の5ヵ月前から始まり、2ヵ月間断続的に続いていた。血管炎や膠原病を示唆する皮膚病変や関節痛などの徴候はなく、関節リウマチや他の膠原病の既往歴もなかった。臨床検査では、血清アンジオテンシンI変換酵素や血清腫瘍マーカーが正常で、細菌、真菌、マイコバクテリウムも全て陰性であった。造影剤を用いた胸部CTでは、右上葉に気管支閉塞と無気肺様の腫瘤が認められ、両側の上葉には気管支や肺血管に沿って小さな結節が認められた。顕著な肺門リンパ節腫脹は認められなかった。18F-FDG PET/CTでは、右上葉の無気肺様腫瘤にFDGの取り込みが増加していた。肺癌との臨床診断の下、右上葉切除およびS6区域切除術を実施した。肉眼検査で、臓側胸膜の下に境界明瞭な暗褐色の領域が認められ、組織学的検査により、暗褐色の部分は古い梗塞であり、出血、ヘモシデローシス、線維化、軽度のリンパ球浸潤から構成されていた。弾性肺動脈では肉芽腫が副膜と中膜に浸潤し、弾性線維の崩壊と破壊を起こしていた。梗塞部位の端には肉芽腫による動脈閉塞が認められ、動脈サルコイドーシスの肉芽腫浸潤が肺梗塞の原因であると考えられた。

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An immune response for a nasal ovalbumin (OVA) powder formulation with an applied nasal delivery platform technology, consisting of a powdery nasal carrier and a device, was evaluated in monkeys with similar upper respiratory tracts and immune systems to those of humans, in order to assess the applicability to a vaccine antigen. Nasal distribution and retention studies using a 3D nasal cavity model and manganese-enhanced MRI were conducted by administering nasal dye and manganese powder formulations with the applied technology. Systemic and mucosal immune responses for the nasal OVA powder formulation were evaluated by determining serum IgG and nasal wash IgA antibody titers. The nasal dye and manganese powder formulations showed wider distribution and longer retention time than did a nasal liquid formulation. The nasal OVA powder formulation also showed comparable and higher antigen-specific IgG antibody titer to an injection and nasal liquid formulation, respectively. Furthermore, antigen-specific IgA antibody response was detected only for the nasal OVA powder formulation. The present study suggests that the technology, originally designed for drug absorption, is promising for nasal vaccines, enabling both a mucosal immunity response as the first line of defense and systemic immunity response as a second line of defense against infection.

DOI： 10.1016/j.xphs.2020.11.023

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Sarcoidosis is a systemic granulomatous disease. In pulmonary sarcoidosis, granulomatous vascular involvement is a common feature that occurs in all types of vessels, including large elastic arteries to venules, but sarcoidosis complicated with pulmonary infarction has not been reported. We report a case of a 60 years old female, who was operated on a clinical diagnosis of lung cancer, and histological examination revealed a pulmonary infarction and sarcoidosis. In the pulmonary elastic arteries, granulomas infiltrated the adventitia and media, and caused elastic fiber collapse and destruction. Arterial occlusion by granulomas was observed in the edge of the infarcted area. It was considered that the arterial sarcoidosis granuloma involvement was the cause of pulmonary infarction. Sarcoidosis is a significant risk factor for cardiovascular events. However, pulmonary infarction is an extremely rare complication of sarcoidosis. Our case suggests that sarcoidosis may cause vascular events in the lungs.

DOI： 10.1111/pin.13104

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BACKGROUND: Carcinoma of the ampulla of Vater is an uncommon ampullo-pancreatobiliary neoplasm, and the most common histological type is adenocarcinoma with a tubular growth pattern. Invasive micropapillary carcinoma (IMPC) is an aggressive variant of adenocarcinoma in several organs that is associated with lymph node metastasis and poor prognosis. IMPC was first described as a histological subtype of breast cancer; however, IMPC of the ampulla of Vater is extremely rare, with only three articles reported in the English literature. CASE SUMMARY: We have reported a case of IMPC of the ampulla of Vater in an 80-year-old man. Microscopically, the surface area of the carcinoma was composed of tubulopapillary structures mimicking intra-ampullary papillary-tubular neoplasm, and the deep invasive front area exhibited a pattern of IMPC. The carcinoma showed lymphatic invasion and extensive lymph node metastasis. The immunohistochemical study revealed mixed intestinal and gastric/pan-creatobiliary phenotypes. CONCLUSION: This rare subtype tumor in the ampulla of Vater showed a histologically mixed phenotype and exhibited aggressive behavior.

DOI： 10.12998/wjcc.v9.i11.2671

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Primary vaginal neuroendocrine carcinoma (NEC) is extremely rare among female genital tract tumors. Here, we report 2 cases of vaginal small cell NEC (SCNEC) using immunohistochemistry and next-generation sequencing (NGS) analysis. The 2 patients were in their mid-to-late 70s, presented with abnormal vaginal bleeding and had a vaginal submucosal mass. The biopsied or resected tumors showed a typical neuroendocrine morphology consisting of solid nests of atypical tumor cells, with no specific organoid patterns, and proliferating in the vaginal submucosa. Immunohistochemical analysis showed strong and diffuse expression of chromogranin A, synaptophysin, and p16, but no thyroid transcription factor 1 expression. Additionally, both cases were positive for human papillomavirus (HPV) 18. An NGS-based cancer panel analysis revealed that the tumors carried NF1 and AR mutations, but no major driver mutations were detected. The results of this study suggested that HPV18 infection is linked to vaginal SCNEC.

DOI： 10.1177/10668969211007569

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research USA Inc.  

Background/Aim: The number of vertebrae in swine varies from 19 to 23 and is associated with body size. Nuclear receptor subfamily 6 group A member 1 (NR6A1) is considered a strong candidate for affecting the number of vertebrae in swine. Wild boars, which uniformly have 19 vertebrae, have the wild type allele while multi-vertebrae European commercial pigs have the mutated allele. Our aim was to confirm the factor of the miniaturization. Materials and Methods: We examined vertebrae number and NR6A1 polymorphism in the Microminipig and three domestic breeds that vary in body size. Results: The Microminipig had 19 or less vertebrae and a wild type NR6A1 genotype. Three domestic breeds had more than 21 vertebrae while the largest vertebrae number was observed in multi-vertebrae-fixed Large White. Heterozygous genotypes were observed in the middle-sized indigenous pig while homozygous NR6A1 mutations were observed in European commercial breeds. Conclusion: NR6A1 could be a useful index for both miniaturizing and increasing pig body size.

DOI： 10.21873/invivo.12244

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Language：Japanese   Publisher：Japan Surgical Association  

<p>A case of hepatocellular carcinoma in a patient with Dubin-Johnson syndrome (DJS) focusing on evaluation of hepatic functional reserve and the perioperative clinical course is presented.</p><p>A 66-year-old man with a medical history of DJS and diabetes mellitus was diagnosed with hepatocellular carcinoma (HCC) when he had a rickettsial infection. The preoperative liver function tests showed an increased bilirubin level (total 4.6, direct 3.4 mg/dl), and normal PT (92%) and albumin (4.2 g/dl) levels without ascites or encephalopathy. The Child-Pugh score was B (7). The ICGR₁₅ level was 11%. The LHL₁₅ value of the GSA scintigram was almost normal (0.909). S4 segmentectomy and S2 partial resection were performed uneventfully except for transient elevation of the T-Bil level that recovered to the preoperative level on the 28^th postoperative day. DJS was confirmed on histopathological examination. Both the ICG test and the GSA scintigram evaluated hepatic functional reserve accurately. Inchin-ko-to may be effective for hyperbilirubinemia after hepatectomy in DJS cases.</p>

DOI： 10.3919/jjsa.82.2262

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

It is often difficult to histologically differentiate among endometrial dedifferentiated carcinoma (DC), endometrioid carcinoma (EC), serous carcinoma (SC), and carcinosarcoma (CS) due to the presence of solid components. In this study, we aimed to categorize these carcinomas according to The Cancer Genome Atlas (TCGA) classification using a small custom-made cancer genome panel (56 genes and 17 microsatellite regions) for integrated molecular diagnosis. A total of 36 endometrial cancer cases with solid components were assessed using IHC, next-generation sequencing (NGS), and the custom-made panel. Among 19 EC cases, six were categorized as MMR-deficient (MMR-d) and eight were classified as having a nonspecific molecular profile. Three EC cases were classified as POLE mutation (POLEmut)-type, which had a very high tumor mutation burden (TMB) and low microsatellite instability (MSI). Increased TMB and MSI were observed in all three DC cases, classified as MMR-d with mutations in MLH1 and POLD1. Except for one case classified as MMR-d, all SC cases exhibited TP53 mutations and were classified as p53 mutation-type. SC cases also exhibited amplification of CCND1, CCNE1, and MYC. CS cases were classified as three TCGA types other than the POLEmut-type. The IHC results for p53 and ARID1A were almost consistent with their mutation status. NGS analysis using a small panel enables categorization of endometrial cancers with solid proliferation according to TCGA classification. As TCGA molecular classification does not consider histological findings, an integrated analytical procedure including IHC and NGS may be a practical diagnostic tool for endometrial cancers.

DOI： 10.3389/pore.2021.1610013

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BACKGROUND: Mesenteric cysts have various histological forms, including mesenteric cystadenomas and borderline cystic neoplasms. Primary cystadenocarcinoma of the mesentery is extremely rare; therefore, the clinical and radiological features of this tumor have not been fully elucidated. CASE PRESENTATION: A 50-year-old Japanese woman had a complaint of a left-sided abdominal distention. Enhanced computed tomography and magnetic resonance imaging revealed a unilocular cystic lesion measuring approximately 10 cm located in the left side of the abdomen. 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) revealed mottled mild FDG uptake in the cyst wall and intense FDG uptake in several mural nodules. The cystic mass with the descending colon was completely removed. Pathological examination of the specimens revealed various histologic patterns of adenocarcinoma, including mucin production in the mural nodules. We eventually diagnosed a primary cystadenocarcinoma arising from the mesentery of the descending colon. CONCLUSIONS: Malignancy should be suspected in mesenteric or retroperitoneal cystic tumors with high FDG uptake, and complete resection should be performed with adequate margins.

DOI： 10.1186/s40792-020-01079-2

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Purkinje cell protein 4/peptide 19 (PCP4/PEP19) is 7.6 kDa peptide originally found in Purkinje cells. PCP4/PEP19 is a differentiation maker of Purkinje cells, where it functions as an antiapoptotic factor. Cerebral neuronal cells also express PCP4/PEP19, which may be related to neuronal cell survival. However, evidence suggests that PCP4/PEP19 may also be involved in neuronal differentiation. Here, we investigated the effects of PCP4/PEP19 expression on neuronal differentiation by analyzing neurite outgrowth, and expression of neuronal differentiation markers in cultured human neuroblastoma M17 cells. When PCP4/PEP19 expression was reduced by siRNA-mediated knockdown, neurite outgrowth was significantly increased. Among many differentiation markers tested, expression of NeuroD1 was increased, while that of Ascl1 was decreased upon PCP4/PEP19 knockdown. Furthermore, luciferase reporter assays revealed that PCP4/PEP19 knockdown upregulated NeuroD1 and downregulated Ascl1 expression, at the transcriptional level. These results suggest a new function of PCP4/PEP19, which suppresses neurite outgrowth and neuronal differentiation through the regulation of NeuroD1 and Ascl1 expression in M17 cells. Furthermore, immunohistochemical studies showed that PCP4/PEP19 localizes in the nuclei of human neuroblastoma cells. Therefore, PCP4/PEP19 may also be an intranuclear negative regulator of neuronal differentiation and may thus be a potential therapeutic target to promote cellular differentiation in human neuroblastoma.

DOI： 10.1038/s41374-020-0462-z

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Language：English   Publisher：Springer Berlin Heidelberg  

左腹部膨満を主訴とする50歳日本人女性症例について検討した。増強CT検査およびMRI検査では左腹部に約10cmの単房性嚢胞性病変を認めた。18F-フルオロデオキシグルコース(FDG)-PET/CT検査では、嚢胞壁に斑点状のFDG軽度取り込みを認め、いくつかの壁在性結節に強度FDG取り込みを認めた。嚢胞性腫瘤は下行結腸とともに完全に切除した。検体の病理検査では腺癌の様々な組織学的パターンを認め、その中に壁在性結節におけるムチン産生も含まれた。最終診断は下行結腸の腸間膜から生じた原発性嚢胞腺癌であった。

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Cancer genome profiling of cytology specimens using next-generation sequencing (NGS) requires adequate and good-quality DNA. Genomic examination of cytology samples was conventionally performed on cell block (CB) or smear specimens than on residual liquid-based cytology (LBC) specimens, which are high-quality DNA sources even after long-term storage. METHODS: We estimated tumor fractions of 37 residual LBC specimens, including 30 fine needle aspiration (FNA) samples from the thyroid (12 papillary thyroid carcinomas and two malignant lymphomas), lymph node (13 metastatic carcinomas and one malignant lymphoma), and breast cancer (one phyllodes tumor and one invasive ductal carcinoma), two pancreatic carcinoma samples, and five liquid (ascites, pleural effusion, and cerebrospinal fluid) samples. The DNA was extracted from all samples and subjected to NGS using a customized cancer gene panel comprising 28 cancer-related genes. RESULTS: NGS analysis revealed somatic mutations corresponding to pathological diagnosis with adequate variant allele frequency (VAF) in 24 LBC specimens, which had significantly higher tumor fraction (72.5% ± 4.9%). Ten cases, including the five fluid samples, had very small tumor fractions (7.5% ± 2.3%) to obtain sufficient VAF. Other two samples had high tumor fractions but showed very low VAF, indicating the presence of fusion genes. The remaining one sample yielded no DNA recovery. CONCLUSION: The residual LBC specimens collected by FNA from the thyroid gland and lymph node were verified to carry high tumor fraction and could serve as an alternate source for molecular testing to screen and diagnose cancers without the use of CB or smears.

DOI： 10.1002/dc.24511

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Language：Japanese   Publisher：医学図書出版(株)  

膵管内乳頭粘液性腫瘍(intraductal papillary mucinous neoplasm:IPMN)の大きな特徴は「粘液の産生」である。ムチンは「粘液」の主成分であり、細胞の保護を行い恒常性維持に大きな役目を果たしている。ムチンの骨格であるコア蛋白が「MUC」という総称でよばれており、クローニングされた順に番号が付いている。IPMNは亜型によってMUCの発現形式が異なっていることは現在ではよく知られている。しかし、IPMNが認識されはじめた当初はMUC2(+)の症例がほとんどであった。症例数の蓄積とともにMUC2(-)の症例が認識され、臨床病理学的特徴も大きく異なることがわかり、2004年頃に亜型として確立された。MUC発現は亜型のみでなく予後などの悪性度とも関連しており、早期診断などへの臨床応用も期待される。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Atherosclerosis Society  

AIM: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders associated with metabolic syndrome, and its prevalence has been on the rise. The pathogenesis of NAFLD has not yet been sufficiently elucidated due to the multifactorial nature of the disease, although the activation of macrophages/Kupffer cells is considered to be involved. We previously reported an animal model of NAFLD using MicrominipigsTM (µMPs) fed high-fat diets containing cholesterol with or without cholic acid. The aim of this study was to investigate the phenotypic changes of macrophages that occur during the development of NAFLD. METHODS: Immunohistochemistry of macrophages, lymphocytes, and stellate cells was performed using liver samples, and the density of positive cells was analyzed. RESULTS: The number of Iba-1-positive macrophages increased with increasing cholesterol content in the diet. The numbers of CD163-positive macrophages and CD204-positive macrophages also increased with increasing cholesterol content in the diet; however, the proportion of CD204-positive macrophages among Iba-1-positive macrophages was significantly reduced by cholic acid supplementation. CONCLUSION: The results suggest that lipid accumulation induced macrophage recruitment in swine livers, and that the number of M2-like macrophages increased at the early stage of NAFLD, while the number of M1-like macrophages increased at the late stage of NAFLD, resulting in a liver condition like non-alcoholic steatohepatitis. We provide evidence of the phenotypic changes that occur in macrophages during the development of NAFLD that has never been reported before using µMPs.

DOI： 10.5551/jat.57703

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BACKGROUND: Next-generation sequencing (NGS) has shown that recurrent/metastatic breast cancer lesions may have additional genetic changes compared with the primary tumor. These additional changes may be related to tumor progression and/or drug resistance. However, breast cancer-targeted NGS is not still widely used in clinical practice to compare the genomic profiles of primary breast cancer and recurrent/metastatic lesions. METHODS: Triplet samples of genomic DNA were extracted from each patient's normal breast tissue, primary breast cancer, and recurrent/metastatic lesion(s). A DNA library was constructed using the QIAseq Human Breast Cancer Panel (93 genes, Qiagen) and then sequenced using MiSeq (Illumina). The Qiagen web portal was utilized for data analysis. RESULTS: Successful results for three or four samples (normal breast tissue, primary tumor, and at least one metastatic/recurrent lesion) were obtained for 11 of 35 breast cancer patients with recurrence/metastases (36 samples). We detected shared somatic mutations in all but one patient, who had a germline mutation in TP53. Additional mutations that were detected in recurrent/metastatic lesions compared with primary tumor were in genes including TP53 (three patients) and one case each of ATR, BLM, CBFB, EP300, ERBB2, MUC16, PBRM1, and PIK3CA. Actionable mutations and/or copy number variations (CNVs) were detected in 73% (8/11) of recurrent/metastatic breast cancer lesions. CONCLUSIONS: The QIAseq Human Breast Cancer Panel assay showed that recurrent/metastatic breast cancers sometimes acquired additional mutations and CNV. Such additional genomic changes could provide therapeutic target.

DOI： 10.1186/s12885-020-07432-w

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Central nervous system tumors are classified based on an integrated diagnosis combining histology and molecular characteristics, including IDH1/2 and H3-K27M mutations, as well as 1p/19q codeletion. Here, we aimed to develop and assess the feasibility of a glioma-tailored 48-gene next-generation sequencing (NGS) panel for integrated glioma diagnosis. We designed a glioma-tailored 48-gene NGS panel for detecting 1p/19q codeletion and mutations in IDH1/2, TP53, PTEN, PDGFRA, NF1, RB1, CDKN2A/B, CDK4, and the TERT promoter (TERTp). We analyzed 106 glioma patients (grade II: 19 cases, grade III: 23 cases, grade IV: 64 cases) using this system. The 1p/19q codeletion was detected precisely in oligodendroglial tumors using our NGS panel. In a cohort of 64 grade Ⅳ gliomas, we identified 56 IDH-wildtype glioblastomas. Within these IDH-wildtype glioblastomas, 33 samples (58.9%) showed a mutation in TERTp. Notably, PDGFRA mutations and their amplification were more commonly seen in TERTp-wildtype glioblastomas (43%) than in TERTp-mutant glioblastomas (6%) (P = .001). Hierarchical molecular classification of IDH-wildtype glioblastomas revealed 3 distinct groups of IDH-wildtype glioblastomas. One major cluster was characterized by mutations in PDGFRA, amplification of CDK4 and PDGFRA, homozygous deletion of CDKN2A/B, and absence of TERTp mutations. This cluster was significantly associated with older age (P = .021), higher Ki-67 score (P = .007), poor prognosis (P = .012), and a periventricular tumor location. We report the development of a glioma-tailored NGS panel for detecting 1p/19q codeletion and driver gene mutations on a single platform. Our panel identified distinct subtypes of IDH- and TERTp-wildtype glioblastomas with frequent PDGFRA alterations.

DOI： 10.1111/cas.14597

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

今回、神経膠腫の分子病理学的統合診断を目的として、新たに48遺伝子で構成された次世代シークエンサー(NGS)用カスタム遺伝子パネルを構築し、その実行可能性について検討した。なお、本パネルは、1p/2q共欠失とIDH1/2遺伝子、TP53遺伝子、PTEN遺伝子、PDGFRA遺伝子、NF1遺伝子、RB1遺伝子、CDKN2A/B遺伝子およびCDK4遺伝子とTERT遺伝子のプロモーター領域(TERTp)変異を検出するために、神経膠腫診断に特化した遺伝子パネルである。当院で開発した中枢神経系腫瘍組織バンクから、神経膠腫患者106例(グレードII:19例、グレードIII:23例、グレードIV:64例)を選択し、本パネルを用いて解析した結果、乏突起膠腫で1p/19q共欠失が正確に検出され、グレードIV患者64例中56例にはIDH遺伝子が野生型の膠芽腫が同定され、うち33例にTERTp変異が認められた。また、PDGFRA遺伝子の変異と増幅は、TERTp遺伝子が野生型の膠芽腫では43%に、TERTp変異を有する膠芽腫では6%に認められ、分子遺伝情報に基づいた階層分類により、IDH遺伝子が野生型の膠芽腫では、明確に3グループに分類された。さらに、PDGFRA遺伝子変異、CDK4遺伝子およびPFGFRA遺伝子の増幅、CDKN2A/B遺伝子でのホモ接合性欠失やTERTp変異の欠如により特徴付けられた主要なクラスタが、高年齢、Ki-67高スコア、予後不良および脳室周囲腫瘍と有意に関連することが明らかにされた。以上の解析結果から、本パネルにより、PDGFRA遺伝子異常が高頻度に認められ、IDH遺伝子およびTERTp遺伝子変異が野生型を示す膠芽腫患者の各サブタイプが同定された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc.  

Lymphoepithelioma-like carcinoma (LELC) of the liver is extremely rare, and lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is an uncommon variant form of HCC, exhibiting relatively good prognosis compared to conventional HCC. LELC is defined as a tumour composed of undifferentiated epithelial cells with densely infiltrating lymphoid stroma. LEL-HCC represents a unique immune response against tumour cells, which may contribute to the superior clinical outcomes. However, the exact aetiology remains unknown. We report a case of a 76-year-old man with a prior hepatitis B virus infection. A 20 mm tumour was detected in the liver. Microscopically, the tumour displayed characteristics of poorly differentiated HCC with a dense lymphocytic and plasma cell infiltration and was diagnosed as LEL-HCC. We describe a unique pathological finding with immunohistochemical data demonstrating T-cell dominant lymphocytic and polyclonal plasma cell infiltration, along with programmed death ligand 1 expression in the tumour cells and lymphocytes.

DOI： 10.1016/j.ehpc.2020.200402

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BACKGROUND: When diagnosing patients with bilateral breast cancer, it is challenging to determine the relationship between multiple breast cancer lesions at the individual patient level with certainty. CASE PRESENTATION: A 35-year-old Japanese woman was diagnosed with a left breast cancer. She was previously diagnosed with right pT3N3M0 stage IIIC breast cancer and underwent chemotherapy with targeted therapy, radiotherapy, and endocrine therapy as adjuvant treatment after mastectomy and axillary lymph node dissection. Approximately 2 years after the first surgery, her left breast cancer was preoperatively diagnosed as a contralateral primary breast cancer, and left mastectomy and axillary lymph node dissection were performed. Histopathologically, the tumor was determined to be invasive ductal carcinoma accompanied with several intraductal components. After a second surgery, mutation analysis of her bilateral breast cancer was performed in a clinical study, which revealed that her metachronous bilateral breast tumors had the same GATA3 and CSMD1 mutations. Thus, mutation analysis strongly supported her latter left breast cancer being a metastatic lesion from the former right breast cancer. Some difficulties in diagnosing bilateral breast cancer exist when determining whether they are double primary cancers or represent contralateral breast metastasis. The existence of intraductal components is a critical piece of information for suspecting primary lesions. However, this case demonstrated that metastatic contralateral breast lesions can have intraductal components. CONCLUSION: Herein we report a genetically proven contralateral breast metastasis with some intraductal components.

DOI： 10.1186/s40792-020-00966-y

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Language：English   Publisher：Springer Berlin Heidelberg  

症例は35歳女性で、左乳房に低エコー腫瘤を認めた。2年前に右乳癌と診断されて乳房切除術と腋窩リンパ節郭清を施行され、pT3N3M0ステージIIIC、Luminal HER2とされた。アジュバント療法として化学療法、放射線療法、内分泌療法を受け、トラスツズマブ投与終了の23ヵ月後、左乳房の上部外側に不規則な低エコー腫瘤が検出された。コア針生検にて病理学的に浸潤性乳管癌と診断し、CTと骨スキャンでは遠隔転移はみられなかった。術前診断ではT1N0M0ステージIAの対側原発性乳癌であり、左乳房切除術とセンチネルリンパ節生検を施行した。組織診の結果、浸潤性乳管癌であり、乳管内成分とリンパ浸潤がみられpT2N1M0とされた。乳管内成分を有することから左乳癌は原発性病変と考え、術後は化学療法と内分泌療法を行った。遺伝子解析を行ったところ、両側乳房に生じた異時性乳癌は同一のGATA3変異とCSMD1変異を有しており、左乳癌と右乳癌の転移であることを強く示唆する所見であった。この他に遺伝子変異は検出されず、ERBB2のコピー数は両病変とも同程度に増加していた。左乳房に対する術後12ヵ月、アジュバント療法を継続中であり、再発は認めていない。

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Liquid-based cytology (LBC) is now a widely used method for cytologic screening and cancer diagnosis. Since the cells are fixed with alcohol-based fixatives, and the specimens are stored in a liquid condition, LBC specimens are suitable for genetic analyses. METHODS: Here, we established a small cancer gene panel, including 60 genes and 17 microsatellite markers for next-generation sequencing, and applied to residual LBC specimens obtained by endometrial cancer screening to compare with corresponding formalin-fixed paraffin-embedded (FFPE) tissues. RESULTS: A total of 49 FFPE and LBC specimens (n = 24) were analyzed, revealing characteristic mutations for endometrial cancer, including PTEN, CTNNB1, PIK3CA, and PIK3R1 mutations. Eight cases had higher scores for both tumor mutation burden (TMB) and microsatellite instability (MSI), which agree with defective mismatch repair (MMR) protein expression. Paired endometrial LBC, and biopsied and/or resected FFPE tissues from 7 cases, presented almost identical mutations, TMB, and MSI profiles in all cases. CONCLUSION: These findings demonstrate that our ad hoc cancer gene panel enabled the detection of therapeutically actionable gene mutations in endometrial LBC and FFPE specimens. Endometrial cancer LBC specimens offer an alternative and affordable source of molecular testing materials.

DOI： 10.1186/s12920-020-00753-6

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DOI： 10.21873/invivo.11982

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DOI： 10.1111/cyt.12852

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Pancreatic cancer remains a disease of high mortality despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic cancers. MUC1 and MUC4 expression are related to the aggressive behavior of human neoplasms and a poor patient outcome. In contrast, MUC2 is a tumor suppressor, and we have previously reported that MUC2 is a favorable prognostic factor in pancreatic neoplasia. This study investigates whether the methylation status of three mucin genes from postoperative tissue specimens from patients with pancreatic neoplasms could serve as a predictive biomarker for outcome after surgery. EXPERIMENTAL DESIGN: We evaluated the methylation status of MUC1, MUC2, and MUC4 promoter regions in pancreatic tissue samples from 191 patients with various pancreatic lesions using methylation-specific electrophoresis. Then, integrating these results and clinicopathologic features, we used support vector machine-, neural network-, and multinomial-based methods to develop a prognostic classifier. RESULTS: Significant differences were identified between the positive- and negative-prediction classifiers of patients in 5-year overall survival (OS) in the cross-validation test. Multivariate analysis revealed that these prognostic classifiers were independent prognostic factors analyzed by not only neoplastic tissues but also nonneoplastic tissues. These classifiers had higher predictive accuracy for OS than tumor size, lymph node metastasis, distant metastasis, and age and can complement the prognostic value of the TNM staging system. CONCLUSIONS: Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with pancreatic ductal adenocarcinoma.

DOI： 10.1158/1078-0432.CCR-19-1247

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DOI： 10.1111/1346-8138.15304

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Verruciform xanthoma is a rare benign verrucopapillary lesion that develops in the oral mucosa and genital skin. Its development in the esophagus is extremely rare, with only 5 reported cases. We present 2 cases of verruciform xanthoma of the esophagus. Case 1 involved a 91-year-old woman, who had hypertension and chronic gastritis with Helicobacter pylori infection, with a 12-year history of a 10-mm white-yellow elevated lesion on the esophagus, 35 cm from the incisor teeth. Case 2 involved a 70-year-old man with fundic gland polyp, hyperlipidemia, and lung cancer, who had a 10-mm whitish granular/verrucoid lesion on the esophagus, 28 cm from the incisor teeth. Microscopically, these lesions show verrucous and papillomatous epithelial hyperplasia with neutrophilic intraepithelial exocytosis. The histological hallmark is the presence of numerous foamy histiocytes infiltrating the elongated squamous epithelial papillae. Although its etiology is unknown, irritation or trauma caused by radiotherapy has been suggested.

DOI： 10.1177/1066896919879495

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Language：English   Publisher：鹿児島産科婦人科学会  

症例は46歳の経産婦で、5年前から不正出血がみられ、38℃を超える発熱があったため来院した。白血球数、血小板数、C反応性蛋白質の上昇とヘモグロビン値の低下が認められた。子宮頸部のPapanicolaou生検で、印環細胞癌(SRCC)様腫瘍細胞と非定形扁平上皮細胞が存在することが明らかになった。子宮頸部腫瘍のパンチ生検により、粘液性SRCCとHPV18型感染が認められた。根治的子宮摘出術と両側付属器切除および腹腔リンパ節郭清を行った。各種検査の結果、最終的に子宮頸部のSRCCと扁平上皮癌の衝突癌(pT1b2N0M0)と診断した。次世代シーケンシングパネルを用いて生殖細胞変異の同定を試みたところ、両病変ともFLT3、BRCA2、R1遺伝子のChr13にヘテロ接合性消失が明らかになった。パクリタキセルとカルボプラチンによる術後化学療法を6コース行った。18ヵ月間の経過観察中、疾患の兆候は認められていない。

Language：Japanese   Publisher：鹿児島産科婦人科学会  

鹿児島大学病院では、これからのゲノム医療に対応するため、産婦人科学教室と共同で婦人科腫瘍の遺伝子パネル検査の臨床研究を昨年から開始した。高品質のホルマリン固定パラフィン包埋検体を作成する取り組みや、液状処理細胞診検体を使用したパネル検査の基礎研究を行っている。当講座では独自の遺伝子パネル検査を開発し臨床研究に使用している。産婦人科学教室との臨床研究で使用したパネルは、分子標的薬関連・ミスマッチ修復関連・NCCNガイドライン関連遺伝子を含む60遺伝子と17ヶ所のマイクロサテライト領域を標的としたオリジナルの固形腫瘍専用の遺伝子パネル検査である。本稿では以下の項目で解説した。1)遺伝子パネル検査、2)類内膜腺癌で認められる遺伝子異常、3)カスタム遺伝子パネル検査。

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Language：Japanese   Publisher：鹿児島産科婦人科学会  

鹿児島大学病院では、これからのゲノム医療に対応するため、産婦人科学教室と共同で婦人科腫瘍の遺伝子パネル検査の臨床研究を昨年から開始した。高品質のホルマリン固定パラフィン包埋検体を作成する取り組みや、液状処理細胞診検体を使用したパネル検査の基礎研究を行っている。当講座では独自の遺伝子パネル検査を開発し臨床研究に使用している。産婦人科学教室との臨床研究で使用したパネルは、分子標的薬関連・ミスマッチ修復関連・NCCNガイドライン関連遺伝子を含む60遺伝子と17ヶ所のマイクロサテライト領域を標的としたオリジナルの固形腫瘍専用の遺伝子パネル検査である。本稿では以下の項目で解説した。1)遺伝子パネル検査、2)類内膜腺癌で認められる遺伝子異常、3)カスタム遺伝子パネル検査。

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Considering the poor prognosis of most advanced cancers, prevention of invasion and metastasis is essential for disease control. Ras homologous (Rho) guanine exchange factors (GEFs) and their signaling cascade could be potential therapeutic targets in advanced cancers. We conducted in silico analyses of The Cancer Genome Atlas expression data to identify candidate Rho-GEF genes showing aberrant expression in advanced gastric cancer and found FERM, Rho/ArhGEF, and pleckstrin domain protein 1 (FARP1) expression is related to poor prognosis. Analyses in 91 clinical advanced gastric cancers of the relationship of prognosis and pathological factors with immunohistochemical expression of FARP1 indicated that high expression of FARP1 is significantly associated with lymphatic invasion, lymph metastasis, and poor prognosis of the patients (P = 0.025). In gastric cancer cells, FARP1 knockdown decreased cell motility, whereas FARP1 overexpression promoted cell motility and filopodium formation via CDC42 activation. FARP1 interacted with integrin β5, and a potent integrin αvβ5 inhibitor (SB273005) prevented cell motility in only high FARP1-expressing gastric cancer cells. These results suggest that the integrin αvβ5-FARP1-CDC42 axis plays a crucial role in gastric cancer cell migration and invasion. Thus, regulatory cascade upstream of Rho can be a specific and promising target of advanced cancer treatment.

DOI： 10.1038/s41389-020-0190-7

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Nivolumab and pembrolizumab are humanized IgG4 monoclonal antibodies against programmed cell death 1 (PD-1). Although these agents are effective in treating advanced melanoma, non-small-cell lung carcinoma, and other types of cancers, various adverse events have been reported. Cutaneous adverse events are particularly prevalent and, while granulomatous/sarcoid-like reactions are uncommon, they are increasingly recognized as immune-related adverse events associated with immune checkpoint inhibitors. Herein, we report two cases of granulomatous/sarcoid-like reaction with foreign material, mimicking metastatic malignancy after PD-1 inhibitor treatment. Clinicians should be aware of the existence of cutaneous lesions and perform biopsy if needed to prevent misdiagnosis and unnecessary adjustments to immunotherapy.

DOI： 10.1111/cup.13569

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Language：English   Publisher：The Japan Neurosurgical Society  

We report a 59-year-old woman with optic nerve coloboma and ophthalmic dysplasia associated with rheumatoid arthritis. She experienced progressive visual dysfunction over the course of several years and presented with headache and pain in the left eye. Since infancy the visual acuity of her left eye had been compromised and her eyesight worsened gradually until she was blind in the left eye. Macroscopic observation showed a reddish lesion on the sclera thought to be due to rheumatoid arthritis (RA). Magnetic resonance imaging and computed tomography disclosed a well-defined cystic lesion at the left retro-bulbar optic nerve within the optic nerve sheath. We selected the combined transcranial-supraorbital and transconjunctival approach to remove the eyeball after detaching the optic nerve. This technique was successful and the placement of an ocular prosthetic was cosmetically acceptable.

DOI： 10.2176/nmccrj.cr.2018-0302

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BACKGROUND/AIM: The aim of the present study was to compare human epidermal growth factor receptor 2 (HER2) expression before and after trastuzumab-based chemotherapy in patients with advanced HER2-positive gastric cancer. MATERIALS AND METHODS: We assessed HER2 expression using immunohistochemistry and/or fluorescence in situ hybridization in pre-treatment biopsied specimens and post-treatment resected specimens obtained from seven patients with advanced HER2-positive gastric cancer receiving trastuzumab-based chemotherapy. RESULTS: Four patients maintained the HER2-positive status and three patients had a change in HER2 expression from positive to negative. In patients showing the loss of HER2 expression after treatments, HER2-positive tumor cells with a dominant histological type disappeared, and HER2-negative tumor cells with another dominant histological type were identified. CONCLUSION: HER2 expression can change after trastuzumab-based chemotherapy in patients with advanced HER2-positive gastric cancer. Continuous monitoring of HER2 expression after treatments may be utilized to determine whether the continued use of trastuzumab is advisable.

DOI： 10.21873/anticanres.13927

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Language：English   Publisher：(一社)日本脳神経外科学会  

症例は59歳女性で、左眼の視力障害と重度疼痛をきたして近医を受診した。関節リウマチの既往を有し、メトトレキサートとNSAIDsにてコントロールされていた。受診時、左眼の強膜炎を認め、MRIにて左眼窩に嚢胞性病変がみられたため、当院眼科紹介となった。MRIと超音波検査で左眼球と交通する嚢胞性病変を認め、強膜炎、網膜剥離および水疱性角膜症を伴うコロボーマと診断し、有痛性水疱性角膜症の治療目的に神経外科に転科となった。著明な強膜充血と浮腫のほか、肥厚化した嚢胞性視神経と左眼球の変性が認められ、眼球摘出と義眼挿入の適応と判断し、神経外科医と眼科医の協働のもと球後手術を行う方針とした。経頭蓋眼窩上アプローチと経結膜アプローチを選択し、開頭術と眼窩切開術によって視神経鞘を切離後、顕微鏡下に経結膜眼球摘出術を施行した。術後の病理所見では嚢胞性病変は視神経に付着し、嚢胞壁は線維性結合組織で構成されていた。また、網膜萎縮と視神経変性が認められ、コロボーマに一致する所見が得られた。術後MRIでは眼球とコロボーマの摘出が確認され、整容的にも満足が得られる結果となった。

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Pembrolizumab, a humanized monoclonal antibody against programmed cell death 1, is used for various malignant neoplasms. Toll-like receptor (TLR) agonists, specifically targeting the TLR9 subfamily (TLR7-9), are treatment options for solid tumors and hematological malignancies. We experienced a case of eruptive squamous cell carcinoma (SCC) in a patient treated concomitantly with pembrolizumab and imiquimod, a TLR7 agonist. A 75-year-old woman who was given a diagnosis of bladder cancer with lung metastasis received pembrolizumab for 3 months when she was referred to our department for the evaluation of skin rashes on her hands. Her skin lesions were diagnosed as well-differentiated SCC and treated with topical imiquimod. Two months after the start of imiquimod, more than 10 reddish papules appeared on her hands. The histological diagnosis of a new plaque was the same as an earlier biopsy. We herein describe this case in detail and provide a published work review.

DOI： 10.1111/1346-8138.15101

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Publisher：(株)診断と治療社  

26歳女。右下腹部腫瘤を主訴とした。右鼠径部に4cm大の弾性軟の腫瘤を認め、腫瘤は立位で膨隆し、仰臥位または圧迫で縮小した。自発痛や圧痛は認められなかった。腹部CTおよび腹部超音波検査にて、右鼠径部に35mm×37.4mm大の多房性嚢胞性腫瘤を認め、血液検査では異常を認めなかった。以上より、Nuck管水腫と診断し、鼠径ヘルニア根治術の前方アプローチに準じて手術を施行した。病理組織学的検査では、悪性所見を認めず、Nuck管水腫と診断した。嚢胞壁内には子宮内膜症の所見を認めた。術後は経過良好で、術後6日目には退院し、術後1年の時点で、再発は認めなかった。

Undifferentiated pleomorphic sarcoma (UPS) is the second most common soft tissue sarcoma. For patients with unresectable or metastatic disease, chemotherapies are considered, but in many cases they are not curative. There is a need to identify specific molecular dysregulations that can be therapeutic targets. We focused on neurotensin receptor 1 (NTSR1), which belongs to the G-protein-coupled receptor. NTSR1 expression was upregulated in specimens from patients with UPS. Real-time polymerase chain reaction showed that expression of NTSR1 messenger RNA was 5- to 7-fold increased in UPS cells compared with myoblasts. Western blot showed a high expression of NTSR1 protein in UPS cell lines. Knockdown of NTSR1 prevented UPS cell proliferation and invasion. We confirmed that SR48692, an inhibitor of NTSR1, exhibited antitumor activities in UPS cells. The combination index showed that SR48692 and standard chemotherapeutic drugs prevented UPS cell proliferation synergistically. Mouse xenograft models showed that SR48692 inhibited extracellular signal-regulated kinase phosphorylation and enhanced the response to standard chemotherapeutic drugs. Inhibition of NTSR1 improved the effect of standard chemotherapeutic drugs for UPS. SR48692 may be a new drug for targeted UPS therapy.

DOI： 10.1002/mc.23111

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Language：English   Publishing type：Research paper (scientific journal)  

We report the first case of liver abscess due to Sterigmatomyces halophilus. Because this pathogen grows poorly in culture medium without added salts, it was identified by sequencing analysis targeting the rRNA gene internal transcribed spacer (ITS) region. This method could be useful for pathogens that cannot be cultured using standard methods.

DOI： 10.1016/j.jiac.2019.05.021

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

症例は75歳女性で、手の皮疹評価のため紹介された。15ヵ月前に肺転移を伴う膀胱癌と診断され、3ヵ月間のペンブロリズマブによる治療歴があった。身体検査では両手背部に僅かに隆起した赤色調斑と不規則な色素沈着が見られた。高分化扁平上皮癌(SCC)と診断しイミキモドによる局所治療を開始したが、治療開始2ヵ月後に赤色調丘疹数が増加し、当初よりも斑の大型化とさらなる隆起が認められた。またいくつかの斑では潰瘍化も見られた。患者希望によりイミキモドおよびペンブロリズマブの治療は中止とし、発疹性SCCに対する経口エトレチナートの治療を提案したが同意は得られなかった。2ヵ月後潰瘍は上皮化したが丘疹は持続しており、注意深い観察を行っている。

Language：English   Publisher：エルゼビア・ジャパン(株)  

6歳男児。急性リンパ性白血病にて同種骨髄移植(allo-BMT)を予定していた。導入療法にて完全寛解が得られ、大量化学療法後に発熱性好中球減少症を発症した(day 0)。抗菌薬による治療を行ったが、発熱が続き、day 28に腹部CTで肝膿瘍がみられた。真菌による肝膿瘍を疑い、アムホテリシンBリポソーム製剤を投与したが、発熱が続いた。day 37に腹腔鏡下肝生検を行い、類上皮細胞肉芽腫および酵母様真菌を認めた。真菌rRNA遺伝子のITS領域のPCR増幅により単一DNAバンドが得られ、塩基配列はSterigmatomyces halophilus CBS4609株と100%一致した。イトラコナゾールおよびフルシトシンの併用療法によりday 100頃に解熱し、day 106の腹部CTでは肝膿瘍は認められなかった。day 150にきょうだいからallo-BMTを行ったところ、急性リンパ性白血病を再発した。化学療法と父親からの造血幹細胞移植にて寛解し、肝膿瘍の再発は認めなかった。

Language：Japanese   Publisher：(株)診断と治療社  

26歳女。右下腹部腫瘤を主訴とした。右鼠径部に4cm大の弾性軟の腫瘤を認め、腫瘤は立位で膨隆し、仰臥位または圧迫で縮小した。自発痛や圧痛は認められなかった。腹部CTおよび腹部超音波検査にて、右鼠径部に35mm×37.4mm大の多房性嚢胞性腫瘤を認め、血液検査では異常を認めなかった。以上より、Nuck管水腫と診断し、鼠径ヘルニア根治術の前方アプローチに準じて手術を施行した。病理組織学的検査では、悪性所見を認めず、Nuck管水腫と診断した。嚢胞壁内には子宮内膜症の所見を認めた。術後は経過良好で、術後6日目には退院し、術後1年の時点で、再発は認めなかった。

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00697&link_issn=&doc_id=20191211080020&doc_link_id=%2Fae4digta%2F2019%2F010712%2F021%2F1547-1549%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4digta%2F2019%2F010712%2F021%2F1547-1549%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

PURPOSE: High-density tumor-infiltrating lymphocytes (TILs) are a prognostic marker for triple-negative breast cancer (TNBC). However, lymphocytic infiltration is heterogeneous in its pattern. We aimed to explore the utility of TIL distribution patterns against TIL density for predicting TNBC prognosis and chemotherapeutic effects. METHODS: Primary invasive TNBC cases were retrieved from a single institutional cohort, and archived samples were reviewed by two board-certificated pathologists. We used 154 consecutive surgical specimens from patients with standard adjuvant therapy, and 80 biopsies taken before primary systemic chemotherapy. The average density of stromal TILs was scored at 10% intervals, while the distribution pattern of TILs was evaluated as diffuse or non-diffuse. The association between TILs and prognosis or pathological complete response (pCR) was statistically analyzed. RESULTS: A diffuse pattern of TILs at primary surgery correlated with better prognosis (relapse-free survival [RFS], hazard ratio [HR] 3.71, 95% confidence interval [CI] 1.60-8.57; overall survival [OS], HR 3.87, 95% CI 1.46-10.27), as well as high TIL density (≥ 50%; RFS, HR 4.51, 95% CI 2.06-9.90; OS, HR 3.28, 95% CI 1.32-8.14). Diffuse TIL pattern and nodal status were independent prognostic factors in multivariate analysis. Diffuse TIL pattern upon biopsy was associated with higher pCR rate (diffuse, 46%; non-diffuse, 21%; P = 0.032). All high TIL cases had diffuse patterns and the best outcome. Interobserver concordance was moderate (k = 0.53-0.55; distribution pattern) to good (weighted k = 0.67-0.69; density), and it was faster to assess the distribution pattern than to assess the density of TIL. CONCLUSIONS: Showing similar clinical impacts to the TIL density, diffuse TILs could be a predictive marker for better prognosis and higher pCR. The assessment of TIL distribution pattern is simple, faster, and practical. Heterogeneous tumor immunity may contribute to further stratification of TNBC treatment.

DOI： 10.1007/s10549-019-05390-x

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Prominent dermal infiltration by Langerhans cells (LC) is a rare finding in patients with Omenn syndrome (OS). Here, we report the case study of a 7-month-old boy with OS and with prominent dermal infiltration by LC, which is a rare histological manifestation of the skin. Striking erythroderma appeared in the patient 2 weeks after birth. We also noted alopecia, lymphadenopathy, hepatosplenomegaly, eosinophilia and an elevated serum immunoglobulin E level with hypogammaglobulinemia. Peripheral blood flow cytometry showed the Tlow NK+ B+ immunophenotype and genetic analysis, a novel mutation in the IL2RG gene (c.337_339delTCT, p.Ser113del). The final diagnosis was that of OS. He responded well to an allograft umbilical cord blood transplantation that was performed when the patient was 8 months of age. We speculate that the LC accumulated in the dermis will eventually migrate to the regional lymph node, then stimulate autoreactive T cells by overpresenting antigens, thus causing OS-specific skin symptoms.

DOI： 10.1111/1346-8138.15054

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

症例は生後7ヵ月の男児で、複合免疫不全を伴い、出生2週間後に出現した皮膚病変評価のため紹介された。他院にてアトピー性皮膚炎と診断され治療が行われていたが、3ヵ月時に敗血症のため入院し重症複合免疫(SCID)が疑われた。紹介後の検査では紅皮症、脱毛症、両側腋窩リンパ節腫脹、軽度肝脾腫、好酸球増加症が見られ、また血清免疫グロブリンG、A、M値は極端に低く、血清免疫グロブリンE値は非常に高かった。末梢血フローサイトメトリーではCD3陽性T細胞が全リンパ球の35%まで減少し、CD19陽性B細胞およびCD56陽性ナチュラルキラー細胞が各々37%と26%に増加していた。さらにCD4陰性/CD8陽性T細胞品は顕著に増加していた。IL2RG遺伝子の配列解析では、当該遺伝子にc.337_339delTCT、p.Ser113delのインフレーム変異が明らかとなり、最終診断はOmenn症候群となった。8ヵ月時に施行した同種移植臍帯血移植によく反応し、症状は顕著に改善し、その後3年間の臨床検査所見は正常であった。

Publisher：(一社)日本病理学会  

唾液腺、とくに顎下腺に発生する扁平上皮癌は非常に稀である。今回、左顎下腺に発生した扁平上皮癌の1例を経験したので報告する。症例は60代女性、左顎下腺腫瘍の診断で腫瘍摘出術が施行された。腫瘍は浸潤傾向を認め内部に嚢胞様構造を認めた。組織学的には好酸性で厚い細胞質と大型核を有する癌細胞が大小の胞巣を形成し明らかな角化が認められた。CRTC1/CRTC3-MAML2癒合遺伝子は陰性で扁平上皮癌と診断した。唾液腺腫瘍では扁平上皮癌様の形態を示す腫瘍として粘表皮癌や唾液腺導管癌が挙げられ鑑別が必要である。(著者抄録)

Language：Japanese   Publisher：(一社)日本病理学会  

唾液腺、とくに顎下腺に発生する扁平上皮癌は非常に稀である。今回、左顎下腺に発生した扁平上皮癌の1例を経験したので報告する。症例は60代女性、左顎下腺腫瘍の診断で腫瘍摘出術が施行された。腫瘍は浸潤傾向を認め内部に嚢胞様構造を認めた。組織学的には好酸性で厚い細胞質と大型核を有する癌細胞が大小の胞巣を形成し明らかな角化が認められた。CRTC1/CRTC3-MAML2癒合遺伝子は陰性で扁平上皮癌と診断した。唾液腺腫瘍では扁平上皮癌様の形態を示す腫瘍として粘表皮癌や唾液腺導管癌が挙げられ鑑別が必要である。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

Porcine epidemic diarrhea virus (PEDV) induces an often fatal gastrointestinal disease in piglets. In this study, we performed a PEDV infection experiment with the Microminipig, the smallest of experimental minipigs, as a novel small animal model. We orally inoculated a neonatal Microminipig with an intestinal homogenate of a PEDV-infected pig and housed it in a small cage originally designed for rats in an animal biosafety level 2 facility. The infected Microminipig showed the typical signs of porcine epidemic diarrhea (PED), such as watery diarrhea, loss of appetite and weight loss. We also recognized a high amount of excreted PEDV in its rectal swabs and villus atrophy of the small intestine. These results suggest that the Microminipig is a good small animal model for PED, which may contribute to a better understanding of the pathogenesis of PEDV.

DOI： 10.1177/0300985819839236

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Publisher：(一社)日本小児血液・がん学会  

1歳9ヵ月の男児。左前腕部の腫脹に気付き紹介医を受診、MRI検査で6cm弱の充実性腫瘤を認め当科紹介となった。転移巣なく、生検術を行った。当初、生検材料の病理検索ではinfantile fibrosarcomaを考えたが、中央病理診断ではmyofibromaが疑われた。臨床的な判断に基づいて、vincristine、actinomycine、ifosfamideによる化学療法を開始したが、腫瘍径は変化なかった。中央病理診断の結果と治療反応から、化学療法は開始2ヵ月で中止した。中止3ヵ月後より腫瘤が増大し、中止4ヵ月後に腫瘍辺縁切除術を行った。この際の病理診断はspindle cell sarcoma、unclassifiedであった。局所照射、vincristine、ifosfamide、doxorubicinによる化学療法を3クール行い治療終了した。病理診断が臨床経過に合わない場合は、再度検体を採取し、病理検査を行うことを考慮する。(著者抄録)

Language：Japanese   Publisher：(一社)日本小児血液・がん学会  

1歳9ヵ月の男児。左前腕部の腫脹に気付き紹介医を受診、MRI検査で6cm弱の充実性腫瘤を認め当科紹介となった。転移巣なく、生検術を行った。当初、生検材料の病理検索ではinfantile fibrosarcomaを考えたが、中央病理診断ではmyofibromaが疑われた。臨床的な判断に基づいて、vincristine、actinomycine、ifosfamideによる化学療法を開始したが、腫瘍径は変化なかった。中央病理診断の結果と治療反応から、化学療法は開始2ヵ月で中止した。中止3ヵ月後より腫瘤が増大し、中止4ヵ月後に腫瘍辺縁切除術を行った。この際の病理診断はspindle cell sarcoma、unclassifiedであった。局所照射、vincristine、ifosfamide、doxorubicinによる化学療法を3クール行い治療終了した。病理診断が臨床経過に合わない場合は、再度検体を採取し、病理検査を行うことを考慮する。(著者抄録)

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞はじめに 今回,私(赤羽)が執筆するテーマは,"パラフィンブロックから病理組織診断とゲノム検査の両方の検査を両立させるには?"です.では,いきなり答えですが,完全に両立させる方法はありません……としてしまうと終ってしまいます.ですから頑張って続きを書きます.この病理組織診断とゲノム検査は,相反します.完全にそれぞれを理想的な状態で両立させるという意味では,"ありません"ということになってしまうわけです.というわけで,それぞれの落とし所を模索しながら本稿で述べたいと思います.

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Language：English   Publishing type：Research paper (scientific journal)  

AIMS: Peroxiredoxin 4 (PRDX4) is a member of the peroxiredoxin family of antioxidant enzymes. Previously, we reported that PRDX4 can restrain the initiation and progression of nonalcoholic steatohepatitis by reducing local and systemic reactive oxygen species (ROS) levels. Oxidative stress is recognized as a key factor in hepatocarcinogenesis, and a high ROS level has also been found in hepatocellular carcinoma (HCC). Here, our aim is to investigate roles of PRDX4 in the initiation and progression of HCC. RESULTS: In this study, for hepatocarcinogenesis, wild-type (WT), PRDX4 knockout (PRDX4-/y), and human PRDX4 transgenic (hPRDX4+/+) mice were given a weekly intraperitoneal injection of diethylnitrosamine for 25 weeks. The HCC incidence was higher in PRDX4-/y mice than in WT or hPRDX4+/+ mice. Intrahepatic and circulating oxidative stress and inflammatory cell infiltration in the liver were obviously decreased in hPRDX4+/+ mice, compared with WT mice. Furthermore, in our cohort study, human HCC specimens with low expression of PRDX4 had higher ROS levels and a highly malignant phenotype, which was associated with a reduced overall survival, compared with those with high PRDX4 expression. However, in human HCC cell lines, PRDX4 knockdown led to a rapidly increased intracellular ROS level and suppressed cell proliferation, inducing cell death. Innovation and Conclusion: Our results clearly indicate that PRDX4 has an inhibitory effect in the initiation of HCC, but a dual (inhibitory or promoting) role in the progression of HCC, suggesting the potential utility of PRDX4 activators or inhibitors as therapy for different stages and phenotypes of HCC.

DOI： 10.1089/ars.2017.7426

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Language：Japanese   Publisher：医歯薬出版(株)  

ホスファチジルイノシトール3-キナーゼ(PI3K)経路に関わる遺伝子の変化は、さまざまな悪性腫瘍に認められている。そのため、治療標的や病理診断の補助マーカー、腫瘍マーカーとしても注目されるシグナル伝達経路である。本稿ではとくに、高率にPI3K経路の遺伝子に異常が認められる乳癌、子宮体部類内膜腺癌、神経膠腫について、実際の臨床例や臨床研究の結果とともに述べる。乳癌においてはPI3K経路の変異のほとんどがPIK3CAの変異であるが、AKT1変異を認めた乳癌の1例を経験したので提示したい。また子宮体部の類内膜腺癌は病理組織学的にはType 1とType 2に分類され、両者はゲノムプロファイルも異なることが知られている。当院のがん遺伝子診断外来症例のなかでERBB2増幅を認めたType 2類内膜腺癌の1例を経験したので紹介したい。神経膠腫は、先進的に分子異常と病理診断による統合診断がされてきた腫瘍である。神経膠芽腫におけるPI3K経路の異常としては、ホスファターゼテンシンホモログ(PTEN)に高頻度に機能欠失変異を認める。著者らの講座では脳腫瘍診断用の遺伝子パネル検査の臨床研究を行っており、そこから得られたPTENの知見も提示したい。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00060&link_issn=&doc_id=20190422030005&doc_link_id=%2Faa7ayuma%2F2019%2F026903%2F006%2F0207-0213%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2019%2F026903%2F006%2F0207-0213%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

We investigated the effect of silk fibroin (SF) on wound healing in mice. SF or an amorphous SF film (ASFF) prepared from silk produced by the wild-type silkworm Bombyx mori (WT-SF, WT-ASFF) or by transgenic worms that overexpress the Arg-Gly-Asp (RGD) sequence (TG-SF, TG-ASFF) was placed on 5-mm diameter full-thickness skin wounds made by biopsy punch on the back of 8-12 week-old BALB/c mice. Each wound was covered with WT-ASFF and urethane film (UF), TG-ASFF plus UF, or UF alone (control). Wound closure, histological thickness, the area of granulation tissue, and neovascularization were analyzed 4, 8, and 12 days later. The effect of SF on cell migration and proliferation was examined in vitro by scratch- and MTT-assay using human dermal fibroblasts. Wound closure was prompted by TG-ASFF, granulation tissue was thicker and larger in ASFF-treated wounds than the control, and neovascularization was promoted significantly by WT-ASFF. Both assays showed that SF induced the migration and proliferation of human dermal fibroblasts. The effects of TG-ASFF and TG-SF on wound closure, granulation formation, and cell proliferation were more profound than that of WT-ASFF and WT-SF. We document that SF accelerates cutaneous wound healing, and this effect is enhanced with TG-SF. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 97-103, 2019.

DOI： 10.1002/jbm.b.34098

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Publisher：(公財)日本眼科学会  

背景:Colobomatous cystは眼球発生時の視神経裂の閉鎖不全に起因して生じる神経外胚葉系の嚢腫である。典型例では小眼球を伴い、時に嚢腫による下眼瞼の膨隆を来すため、比較的幼少期に発見される。症例:59歳、女性。幼少期に左視力不良を指摘されていたが、精査は受けなかった。約1年前から左眼角膜混濁と眼痛が出現し、近医で受けた画像検査で左眼窩腫瘍を指摘され当科紹介となった。初診時の視力は右(1.2)、左光覚なしであった。右眼は軽度白内障のほかに特記すべき所見は認めなかった。左眼は角膜混濁のため前房、眼底の透見は不良であった。造影magnetic resonance imaging(MRI)で左眼球後方に硝子体腔内と連続する憩室状構造を認め、視神経は嚢腫に連続していた。画像所見からcolobomatous cystを疑った。眼痛が増悪したため、左眼球摘出術を施行した。術後に眼痛は消失した。病理組織学的検査では嚢腫は網膜様組織の内層と、強膜と連続する膠原線維の外層で構成されており、colobomatous cystと診断した。眼球には虹彩ルベオーシスや第一次硝子体過形成遺残を疑う所見を認め、角膜混濁や硝子体出血の起因となったと考えられた。眼痛の原因として続発緑内障による眼圧上昇が考えられた。結論:長期にわたって診断されず、片眼の角膜混濁と眼痛を契機に発見に至ったcolobomatous cystの症例を経験した。Colobomatous cyst例では長期経過後に角膜混濁や眼痛が出現する可能性があることが示唆された。(著者抄録)

Publisher：(一社)日本病理学会  

45歳男性。消化管出血の精査で十二指腸動静脈奇形を疑われ、経カテーテル動脈塞栓術後に膵頭十二指腸切除術を施行された。切除標本では十二指腸に出血や潰瘍は認めず、割面では十二指腸と膵に拡張した血管を認めた。組織学的には十二指腸から膵実質にかけて静脈様の拡張血管、動脈様血管や不整な小血管の集簇と部分的な吻合がみられ、動静脈奇形(AVM)と診断した。消化管出血を契機に発見された稀な膵十二指腸AVMの1例を報告し、消化管出血との関連について、文献を交えて考察する。(著者抄録)

Language：Japanese   Publisher：(公財)日本眼科学会  

背景:Colobomatous cystは眼球発生時の視神経裂の閉鎖不全に起因して生じる神経外胚葉系の嚢腫である。典型例では小眼球を伴い、時に嚢腫による下眼瞼の膨隆を来すため、比較的幼少期に発見される。症例:59歳、女性。幼少期に左視力不良を指摘されていたが、精査は受けなかった。約1年前から左眼角膜混濁と眼痛が出現し、近医で受けた画像検査で左眼窩腫瘍を指摘され当科紹介となった。初診時の視力は右(1.2)、左光覚なしであった。右眼は軽度白内障のほかに特記すべき所見は認めなかった。左眼は角膜混濁のため前房、眼底の透見は不良であった。造影magnetic resonance imaging(MRI)で左眼球後方に硝子体腔内と連続する憩室状構造を認め、視神経は嚢腫に連続していた。画像所見からcolobomatous cystを疑った。眼痛が増悪したため、左眼球摘出術を施行した。術後に眼痛は消失した。病理組織学的検査では嚢腫は網膜様組織の内層と、強膜と連続する膠原線維の外層で構成されており、colobomatous cystと診断した。眼球には虹彩ルベオーシスや第一次硝子体過形成遺残を疑う所見を認め、角膜混濁や硝子体出血の起因となったと考えられた。眼痛の原因として続発緑内障による眼圧上昇が考えられた。結論:長期にわたって診断されず、片眼の角膜混濁と眼痛を契機に発見に至ったcolobomatous cystの症例を経験した。Colobomatous cyst例では長期経過後に角膜混濁や眼痛が出現する可能性があることが示唆された。(著者抄録)

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Language：Japanese   Publisher：(一社)日本病理学会  

45歳男性。消化管出血の精査で十二指腸動静脈奇形を疑われ、経カテーテル動脈塞栓術後に膵頭十二指腸切除術を施行された。切除標本では十二指腸に出血や潰瘍は認めず、割面では十二指腸と膵に拡張した血管を認めた。組織学的には十二指腸から膵実質にかけて静脈様の拡張血管、動脈様血管や不整な小血管の集簇と部分的な吻合がみられ、動静脈奇形(AVM)と診断した。消化管出血を契機に発見された稀な膵十二指腸AVMの1例を報告し、消化管出血との関連について、文献を交えて考察する。(著者抄録)

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In addition to conventional cytology, liquid-based cytology (LBC) is also used for immunocytochemistry and gene analysis. However, an appropriate method to obtain high quality DNA for next-generation sequencing (NGS) using LBC specimens remains controversial. We determined the optimal conditions for fixation with an alcohol-based fixative for LBC and DNA extraction using cultured cancer cell lines and clinical specimens. The extracted DNA was processed for NGS after the DNA quality was confirmed based on the DNA concentration and degree of degradation. The optimal conditions for cultured cells to obtain high quality DNA were to fix the cells at a density of 6 × 103 or 2 × 104 cells/mL and to use the magnetic bead-based DNA extraction method. Even after storing the fixed cells for 90 days, DNA extracted using the above and other extraction kits, including membrane-based methods, did not undergo degradation. Furthermore, 5-year-old residual LBC samples demonstrated high DNA quality that was suitable for NGS. Furthermore, a cancer genome panel analysis was successfully performed with DNA extracted from cultured cells fixed at 6 × 103 cells/mL for 90 days, and with DNA from residual LBC samples even after 1 year of storage. Residual LBC samples may be a useful source of DNA for clinical NGS to promote genome-based cancer medicine.

DOI： 10.1371/journal.pone.0217724

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Language：English   Publisher：The Japanese Society of Pediatric Hematology / Oncology  

<p>A 1-year-and-9-month-old boy was referred to us for swelling of the left forearm. Magnetic resonance imaging revealed a solid tumor in the forearm about 6 cm in size. There was no metastatic lesion, and he underwent biopsy. Clinically, he was suspected of having infantile fibrosarcoma on the basis of the results of histopathological analysis and his clinical course. However, a central pathological review disclosed a suspicious myofibroma. Chemotherapy consisting of vincristine, actinomycin, and ifosfamide was carried out but the tumor size remained unchanged. Chemotherapy was discontinued 2 months after initiation. However, the tumor size increased 3 months after the discontinuation of chemotherapy; hence, he underwent marginal resection 4 months after the discontinuation of chemotherapy. The pathological diagnosis was unclassified spindle cell sarcoma. Local irradiation and 3 cycles of chemotherapy with vincristine, ifosfamide, and doxorubicin were carried out, and the treatment was completed. We recommend collecting another biopsy sample for histopathological examination if the pathological diagnosis is incompatible with the clinical course.</p>

DOI： 10.11412/jspho.56.212

BACKGROUND: Epignathus is a rare congenital orofacial teratoma infrequently associated with intracranial extension. Intracranial extension of an epignathus indicates a poor prognosis; however, only a small number of such cases have been reported. While there have been some studies reporting cases of epignathus expanding directly into the cranium, others have reported no communication between an epignathus and an intracranial tumor. CASE PRESENTATION: A fetus at gestational week 27 was suspected of having an epignathus with intracranial tumor as shown by ultrasonographic and magnetic resonance imaging. The fetus was stillborn and an autopsy was performed. An epignathus measuring 12 × 6 × 6 cm and weighing 270 g protruded from the mouth, with its base on the soft palate. An intracranial tumor weighing 14 g was located at the middle intracranial fossa and connected to the epignathus through the right side of the sella turcica. The intracranial tumor was encapsulated, and there was no invasion into the brain. Histologically, both the epignathus and intracranial tumor were immature teratomas, with neural and pulmonary components that were especially immature as compared to those of the internal organs and brain tissues of the fetus. CONCLUSION: There have been several reports of epignathus and intracranial tumors that did not communicate; therefore, careful evaluation is needed when a fetus is suspected of having an epignathus extending into an intracranial lesion. Our case supports the findings that an epignathus can directly expand into the cranium. Moreover, this is a rare case of an epignathus in which the intracranial lesion was encapsulated and did not invade the brain. These rare but important findings will provide additional, potential therapeutic strategies for gynecologists, neurosurgeons, and pathologists.

DOI： 10.1186/s13000-018-0776-y

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AIMS: Maspin is known to be a tumour suppressor protein, but its prognostic significance in breast cancer patients is controversial. There is no report focusing on maspin expression in metastatic carcinoma of sentinel lymph nodes (SLNs); we thus investigated maspin mRNA expression in SLNs using the remaining specimens after the one-step nucleic acid amplification (OSNA) assay. METHODS AND RESULTS: Ninety-three breast cancer patients with SLNs metastasis detected by the OSNA assay were enrolled. All patients experienced additional axillary lymph nodes (LNs) dissection and all dissected LNs were examined histopathologically. Maspin mRNA expression in SLNs was detected in 49.5% (46 of 93) and was correlated significantly with the presence of non-SLN metastasis (P < 0.0001) and ≥4 LN metastases (P = 0.029). In a multivariate logistic analysis, maspin mRNA expression in SLNs (P = 0.0015) had the most significant effect on predicting non-SLN metastasis, followed by pathological tumour size (P = 0.0039) and lymphovascular invasion (P = 0.009). The status of maspin mRNA expression in SLNs was correlated significantly with that of maspin protein expression in the primary carcinoma (P < 0.0001). CONCLUSIONS: This is the first study, to our knowledge, demonstrating that maspin mRNA expression in SLNs is an independent predictor of non-SLN metastasis and the presence of ≥4 LN metastases in breast cancer patients with SLN metastasis. The investigation of maspin mRNA expression in SLNs using the remaining specimens after the OSNA assay may be useful for predicting the further progression of metastatic carcinoma in breast cancer patients with SLNs metastasis.

DOI： 10.1111/his.13718

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AIMS AND OBJECTIVES: Fish oil (FO) lipid emulsion and a new lipid emulsion (SMOF) are important treatments for intestinal failure-associated liver disease. We evaluated the efficacy of FO and SMOF lipid emulsion on intestinal mucosal adaptation using a total parenteral nutrition (TPN)-supported rat model of short bowel syndrome. MATERIAL & METHODS: Sprague-Dawley rats underwent jugular vein catheterization and 90% small bowel resection and were divided into three groups: TPN with soy bean oil lipid emulsion (SO group), FO lipid emulsion (FO group), or SMOF (SMOF group). On day 13, the rats were euthanized, and the small intestine was harvested. The microscopic morphology and crypt cell proliferation rate (CCPR) were then evaluated. RESULTS: The villus height of the ileum in the SMOF group was significantly higher than in the SO group. The crypt depth of the intestine in the SMOF group was significantly lower than in the SO group. The CCPRs of the intestine in the FO and SMOF groups were both higher than in the SO group. CONCLUSIONS: Lipid emulsion affected the bowel morphology, such as the mucosa as well as the intestinal smooth muscle. Further studies are needed to clarify the mechanisms.

DOI： 10.1016/j.jpedsurg.2018.08.019

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Language：Japanese   Publisher：(一社)日本小児外科学会  

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BACKGROUND: The incidence of radiation-associated angiosarcoma (RAA) of the breast has been increasing, and its prognosis is reportedly poor. It is important to remove tumor tissues completely to prevent recurrence. CASE PRESENTATION: We report two cases of patients with RAA of the breast. Both patients had a nodule in their remaining breast a few years after undergoing breast-conserving surgery and radiation therapy for breast cancer. The nodules were diagnosed as angiosarcoma by skin biopsy and open biopsy, respectively. To determine the extent of lesion spread, mapping biopsy was performed before surgery. Both patients underwent mastectomy, extensive skin resection, and split skin grafting. Pathological findings showed that their tumors could be completely resected. After surgery, chemotherapy was performed. CONCLUSION: In our cases, no local or distant recurrence has been detected in either patient for over 4 years. We identified the range of tumor invasion by preoperative mapping biopsy and completely resected all tumor tissue.

DOI： 10.1186/s40792-018-0539-8

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Publisher：西日本整形・災害外科学会  

【はじめに】紡錘形細胞脂肪腫spindle cell lipomaは脂肪腫の特殊型で、中年男性の後頸部、肩、背部に好発する稀な腫瘍である。【症例】70歳男性、背部皮下に弾性軟、約8cm大の腫瘤を認めた。MRI上T2強調画像にて著明な高信号を主体とし、漸増性の増強効果を呈し内部に微小な脂肪成分を認め、分葉状の形態を呈していた。粘液型脂肪肉腫との鑑別が必要と考え、生検術を施行。肉眼的に粘液性の成分と一部線維性の組織を採取した。病理所見では粘液腫様の間質内に存在する短紡錘形の腫瘍細胞はCD34陽性、ロープ状膠原線維の存在やMDM2陰性から紡錘形細胞脂肪腫と診断し、辺縁切除術を施行した。【まとめ】紡錘形細胞脂肪腫は術前診断が難しく、他の脂肪系腫瘍である粘液型脂肪肉腫や異型脂肪腫様腫瘍との鑑別が重要である。画像所見や病理所見、臨床所見について文献的考察を加え報告する。(著者抄録)

Language：Japanese   Publisher：西日本整形・災害外科学会  

【はじめに】紡錘形細胞脂肪腫spindle cell lipomaは脂肪腫の特殊型で、中年男性の後頸部、肩、背部に好発する稀な腫瘍である。【症例】70歳男性、背部皮下に弾性軟、約8cm大の腫瘤を認めた。MRI上T2強調画像にて著明な高信号を主体とし、漸増性の増強効果を呈し内部に微小な脂肪成分を認め、分葉状の形態を呈していた。粘液型脂肪肉腫との鑑別が必要と考え、生検術を施行。肉眼的に粘液性の成分と一部線維性の組織を採取した。病理所見では粘液腫様の間質内に存在する短紡錘形の腫瘍細胞はCD34陽性、ロープ状膠原線維の存在やMDM2陰性から紡錘形細胞脂肪腫と診断し、辺縁切除術を施行した。【まとめ】紡錘形細胞脂肪腫は術前診断が難しく、他の脂肪系腫瘍である粘液型脂肪肉腫や異型脂肪腫様腫瘍との鑑別が重要である。画像所見や病理所見、臨床所見について文献的考察を加え報告する。(著者抄録)

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Accumulating evidence indicates that oxidative stress plays a critical role in initiating the progression of inflammatory and fibrotic liver diseases, including cholestatic hepatitis. Peroxiredoxin 4 (PRDX4) is a secretory antioxidase that protects against oxidative damage by scavenging reactive oxygen species (ROS) in both the intracellular compartments and extracellular space. In this study, we examined the in vivo net effects of PRDX4 overexpression in a murine model of cholestasis. To induce cholestatic liver injury, we subjected C57BL/6J wild-type (WT) or human PRDX4 (hPRDX4) transgenic (Tg) mice to sham or bile duct ligation (BDL) surgery for seven days. Our results showed that the liver necrosis area was significantly suppressed in Tg BDL mice with a reduction in the severity of liver injuries. Furthermore, PRDX4 overexpression markedly reduced local and systemic oxidative stress generated by BDL. In addition, suppression of inflammatory cell infiltration, reduced proliferation of hepatocytes and intrahepatic bile ducts, and less fibrosis were also found in the liver of Tg BDL mice, along with a reduced mortality rate after BDL surgery. Interestingly, the composition of the hepatic bile acids (BAs) was more beneficial for Tg BDL mice than for WT BDL mice, suggesting that PRDX4 overexpression may affect BA metabolism during cholestasis. These features indicate that PRDX4 plays an important role in protecting against liver injury following BDL and might be a promising therapeutic modality for cholestatic diseases.

DOI： 10.3390/ijms19092509

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BACKGROUND: Since short bowel syndrome (SBS) patients face life-threatening conditions, the development of therapeutic strategies to induce intestinal adaptation has been investigated. Ghrelin, a ligand of growth hormone (GH) secretagogue-receptor that stimulates the release of GH and insulin like growth factor-1 (IGF-1), has several pleiotropic effects. We investigated whether ghrelin induces intestinal adaptation in parenterally fed rats with SBS. METHODS: Sprague-Dawley rats underwent venous catheterization and were divided into 3 groups: those receiving 90% small bowel resection while leaving the proximal jejunum and distal ileum (90% SBR) with TPN (SBS/TPN group), those receiving 90% SBR with TPN + ghrelin (SBS/TPN/ghrelin group), and those receiving sham operation and fed chow (sham group). Ghrelin was administered intravenously at 10 μg/kg/day. On Day 13, the rats were euthanized and the small intestine harvested, and the histology and crypt cell proliferation rates (CCPR), apoptosis, and nutrient transporter protein levels were analyzed and the plasma hormones were measured. RESULTS: The villus height and crypt depth of the ileum in the SBS/TPN/ghrelin group were significantly higher than in the SBS/TPN group. The CCPR of the jejunum and the ileum significantly increased by the administration of ghrelin; however, the apoptosis rates did not significantly differ between the SBS/TPN and SBS/TPN/ghrelin groups. Significant differences did not exist in the plasma IGF-1 and nutrient transporter protein levels among three groups. CONCLUSIONS: The intravenous administration of ghrelin stimulated the morphological intestinal adaptation of the ileum to a greater degree than the jejunum due to the direct effect of ghrelin.

DOI： 10.1016/j.peptides.2018.06.009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：(公社)日本実験動物学会  

14-100日齢の雄Sprague-Dawleyラットの乳腺における経時的形態学的変化とホルモン・レセプター発現の関連について、性成熟後に出現する"oxyphilic cells(OCs)"(豊富な好酸性細胞質を有する細胞)を主体に形態学的検索を行った。肉眼的観察、Whole mount標本及びHE標本を用いた観察を行い、OCsについては透過型電子顕微鏡(TEM)を用いて精査した。更に、アンドロゲン・レセプター(AR)、エストロゲン・レセプター(ER)及びプロゲステロン・レセプター(PgR)について免疫組織学的検索を行った。肉眼的に成熟期(50-100日齢)の乳腺は褐色を帯びており、組織学的には若齢期(14-35日齢)と成熟期では構成細胞の形態が異なり、成熟期ではOCsが認められた。ER及びPgRはすべての時期で、ARは成熟期のみで発現した。OCsではAR発現が優位であり、その割合は経時的に増加した。以上の結果から成熟期の乳腺発達とAR発現は強く関連していると示唆された。また、TEMでは、OCsの細胞質に多数の脂肪滴、変形・大型化したミトコンドリア等が認められた。(著者抄録)

DOI： 10.1538/expanim.17-0134

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J04703&link_issn=&doc_id=20180802220007&doc_link_id=130007423739&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007423739&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Language：English   Publishing type：Research paper (scientific journal)  

The Purkinje cell protein 4/peptide 19 (PCP4/PEP19) is a novel breast cancer cell expressing peptide, originally found in the neural cells as an anti-apoptotic factor, could inhibit cell apoptosis and enhance cell migration and invasion in human breast cancer cell lines. The expression of PCP4/PEP19 is induced by estrogens in estrogen receptor-positive (ER+) MCF-7 cells but also highly expressed in ER- SK-BR-3 cells. In this study, we investigated the effects of PCP4/PEP19 on aromatase gene expression in MCF-7 and SK-BR-3 human breast cancer cells. In SK-BR-3 cells but not in MCF-7 cells, PCP4/PEP19 knockdown by siRNA silencing decreased the aromatase expression in gene transcriptional level. When PCP4/PEP19 was overexpressed by CMV promoter-driven PCP4/PEP19 expressing plasmid transfection, aromatase gene transcription increased in SK-BR-3 cells. This aromatase gene transcription is mainly mediated through promoter region PI.1, which is usually active in the placental tissue but not in the breast cancer tissue. These results indicate a new function of PCP4/PEP19 that would enhance aromatase gene upregulation to supply estrogens in heterogeneous cancer microenvironment.

DOI： 10.18632/oncotarget.25651

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Publisher：(公社)日本実験動物学会  

14-100日齢の雄Sprague-Dawleyラットの乳腺における経時的形態学的変化とホルモン・レセプター発現の関連について、性成熟後に出現する"oxyphilic cells(OCs)"(豊富な好酸性細胞質を有する細胞)を主体に形態学的検索を行った。肉眼的観察、Whole mount標本及びHE標本を用いた観察を行い、OCsについては透過型電子顕微鏡(TEM)を用いて精査した。更に、アンドロゲン・レセプター(AR)、エストロゲン・レセプター(ER)及びプロゲステロン・レセプター(PgR)について免疫組織学的検索を行った。肉眼的に成熟期(50-100日齢)の乳腺は褐色を帯びており、組織学的には若齢期(14-35日齢)と成熟期では構成細胞の形態が異なり、成熟期ではOCsが認められた。ER及びPgRはすべての時期で、ARは成熟期のみで発現した。OCsではAR発現が優位であり、その割合は経時的に増加した。以上の結果から成熟期の乳腺発達とAR発現は強く関連していると示唆された。また、TEMでは、OCsの細胞質に多数の脂肪滴、変形・大型化したミトコンドリア等が認められた。(著者抄録)

Language：English   Publisher：(公社)日本実験動物学会  

14-100日齢の雄Sprague-Dawleyラットの乳腺における経時的形態学的変化とホルモン・レセプター発現の関連について、性成熟後に出現する&quot;oxyphilic cells(OCs)&quot;(豊富な好酸性細胞質を有する細胞)を主体に形態学的検索を行った。肉眼的観察、Whole mount標本及びHE標本を用いた観察を行い、OCsについては透過型電子顕微鏡(TEM)を用いて精査した。更に、アンドロゲン・レセプター(AR)、エストロゲン・レセプター(ER)及びプロゲステロン・レセプター(PgR)について免疫組織学的検索を行った。肉眼的に成熟期(50-100日齢)の乳腺は褐色を帯びており、組織学的には若齢期(14-35日齢)と成熟期では構成細胞の形態が異なり、成熟期ではOCsが認められた。ER及びPgRはすべての時期で、ARは成熟期のみで発現した。OCsではAR発現が優位であり、その割合は経時的に増加した。以上の結果から成熟期の乳腺発達とAR発現は強く関連していると示唆された。また、TEMでは、OCsの細胞質に多数の脂肪滴、変形・大型化したミトコンドリア等が認められた。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The aim of this study was to evaluate whether intraoperative histopathological examination could predict the risk of relapse of infection in periprosthetic joint infections (PJI). METHODS: The study included 25 patients (14 women and 11 men, with a mean age of 67.0 years (range, 37-83 years)), who had two-staged revision surgery for a PJI. Following prosthetic removal in the first stage, all patient underwent an intraoperative histopathological examination during the second stage. The patients were divided into PMNs-positive group (≥five PMNs per high-powered field) or -negative group (<five PMNs). A relapse was defined as the occurrence of PJI. Median follow-up was 51 months (range, 32-80 months) following second-stage revision surgery. RESULTS: Intraoperative histopathological revealed that 8.0% of cases were PMNs-positive. Postoperative histopathological examination revealed that 28.0% of cases were PMNs-positive. 28.0% of cases showed discrepancy between the PMNs-positivity. Intraclass correlation coefficient indicates poor reproducibility. Infection relapse after revision surgery occurred in two cases (8.0%); both relapse cases were from the PMNs-negative group. There was no statistical relationship between the presence of PMNs in periprosthetic tissue by intraoperative or postoperative histopathological examination and relapse of infection. CONCLUSIONS: Our findings showed that intraoperative histopathological examination could not predict the relapse of infection. Intraoperative histopathological examination promotes overdiagnosis of the requirement for re-implantation of antibiotic-impregnated cement and prolonged treatment periods. LEVEL OF EVIDENCE: Level III, diagnostic study.

DOI： 10.1016/j.aott.2018.02.002

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

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Publisher：鹿児島県臨床外科学会  

症例は24歳女性で、手拳大の右乳房腫瘤が出現し、次第に小児頭大に増大した。右乳房に皮膚露出と出血を伴う腫瘍を認め、針生検にて悪性葉状腫瘍、紡錘細胞癌、間質肉腫などが疑われたため、貧血管理と手術目的で当院に緊急入院となった。右乳房に31×26×16cm大の巨大腫瘤を認めた。長径25cmにわたって腫瘍が露出しており、壊死と出血を認めた。造影CTで、右乳房に26cm大の内部不均一な腫瘤と右腋窩リンパ節の腫大を認めた。針生検病理像から悪性葉状腫瘍、紡錘細胞癌、間質肉腫が疑われたため、右乳房悪性腫瘍の術前診断で手術を施行した。術中の肉眼所見でも胸壁浸潤は認めず、腫瘍の完全切除が可能であった。病理組織学的所見では、大部分で強い核異型と多数の核分裂像を認め、悪性葉状腫瘍の診断であった。切除断端は陰性、摘出リンパ節にも転移は認めなかった。

Language：Japanese   Publisher：鹿児島県臨床外科学会  

症例は24歳女性で、手拳大の右乳房腫瘤が出現し、次第に小児頭大に増大した。右乳房に皮膚露出と出血を伴う腫瘍を認め、針生検にて悪性葉状腫瘍、紡錘細胞癌、間質肉腫などが疑われたため、貧血管理と手術目的で当院に緊急入院となった。右乳房に31×26×16cm大の巨大腫瘤を認めた。長径25cmにわたって腫瘍が露出しており、壊死と出血を認めた。造影CTで、右乳房に26cm大の内部不均一な腫瘤と右腋窩リンパ節の腫大を認めた。針生検病理像から悪性葉状腫瘍、紡錘細胞癌、間質肉腫が疑われたため、右乳房悪性腫瘍の術前診断で手術を施行した。術中の肉眼所見でも胸壁浸潤は認めず、腫瘍の完全切除が可能であった。病理組織学的所見では、大部分で強い核異型と多数の核分裂像を認め、悪性葉状腫瘍の診断であった。切除断端は陰性、摘出リンパ節にも転移は認めなかった。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：F HERNANDEZ  

In mucoepidermoid carcinoma (MEC), the most common salivary gland carcinoma, there is a lack of novel prognostic markers, but post-operative early recurrence strongly affects the clinical course and a poor outcome. It is critical to predict which MEC patients are prone to develop recurrence/metastases. Mucins play pivotal roles in influencing cancer biology, thus affecting cell differentiation, adhesion, carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to elucidate the significance of expression profiles for mucins, particularly MUC4 and MUC6, and their correlations with various clinicopathological features and recurrence in salivary gland MECs. We performed immunohistochemical analyses on patients with surgically resected primary MEC using antibodies against mucin core proteins MUC4/8G7 and MUC6/CLH5 in 73 paraffin-embedded samples. Recurrence was noted in 15 of 73 (20.5%) patients. MUC4 or MUC6 expression was considered to be negative when <30% or 0% of the MEC cells showed positive staining, respectively. MUC4- and/or MUC6-negative expression respectively and variably showed a significant relationship to pathological tumor high-grade, the presence of lymphovascular invasion, lymph node metastasis and/or tumor-related death. In addition, MUC4 showed significantly negative co-expression with MUC6. Kaplan-Meier analyses revealed that not only single MUC4/6-negative expression but also the combination of both predicted significantly shorter disease-free and disease-specific survivals in MECs, especially within the first two years postoperatively. Therefore, each mucin plays a pivotal role in the pathogenesis of MEC progression. The detection of MUC4 and/or MUC6 might be a powerful parameter in the clinical management of MECs in the early postsurgical phase.

DOI： 10.14670/HH-11-913

Web of Science

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Institute of Anticancer Research  

The effects of dietary and lighting conditions on diurnal rhythm of locomotor activity (LA) and body temperature (BT) using four adult male microminipigs were investigated. Different feeding times, diet and lighting conditions were applied sequentially for 3 weeks in each phase as follows: Phase I: Morning mealtime, normal diet, 12-h lights on
phase II: mealtime changed to afternoon
phase III: diet changed to high-fat diet
phase IV: lighting changed to 20-h on
and phase V: phase I repeated. LA was measured by an actigraph which was worn on the body of each pig. A BT recording module (Thermochron Type-SL) was implanted in the neck subcutaneously. Phase II increased BT compared with phase I. Phase III increased LA and BT compared with phase II. Phase IV increased LA compared with phase III. LA in phase V was higher compared with phase I. These results can be extrapolated to other diurnal animals such as humans. This study provides an example of the effects of diet and lighting on biological activities in microminipigs under low-invasive procedures measuring LA and BT, leading to low variations in these measures.

DOI： 10.21873/invivo.11204

Scopus

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Publisher：(一社)日本病理学会  

症例は60歳代、女性。右肺上葉の18mm大の腫瘍が切除された。組織学的に、豊富な粘液腫状基質を背景に小型類円形〜卵円形核を有する腫瘍細胞の増殖が認められた。RT-PCRでEWSR1-CREB1融合遺伝子が検出され、primary pulmonary myxoid sarcoma with EWSR1-CREB1 translocationと診断した。捺印細胞診では、粘液状基質や炎症細胞を混じる短紡錘形から多角形の異型に乏しい細胞集塊を認め、炎症性変化との鑑別が必要であった。(著者抄録)

Publisher：(一社)日本病理学会  

症例は32歳女性。胸部CTで右肺上葉の末梢から右上肺静脈を経て左心房内に達する数珠状の腫瘍を認め、右肺上葉切除が行われた。切除検体では最大4×2cmの白色充実性の腫瘍であった。組織学的には比較的均一な円形核を有する腫瘍細胞が充実性、シート状構造を呈し、免疫組織化学的にはvimentin、α-SMAにびまん性に強陽性、laminin、h-caldesmonは一部陽性であった。悪性度不明なグロムス腫瘍が肺静脈を経て心房内に達した症例は過去に報告がない。(著者抄録)

Authorship：Last author   Language：Japanese   Publisher：(一社)日本病理学会  

症例は32歳女性。胸部CTで右肺上葉の末梢から右上肺静脈を経て左心房内に達する数珠状の腫瘍を認め、右肺上葉切除が行われた。切除検体では最大4×2cmの白色充実性の腫瘍であった。組織学的には比較的均一な円形核を有する腫瘍細胞が充実性、シート状構造を呈し、免疫組織化学的にはvimentin、α-SMAにびまん性に強陽性、laminin、h-caldesmonは一部陽性であった。悪性度不明なグロムス腫瘍が肺静脈を経て心房内に達した症例は過去に報告がない。(著者抄録)

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本病理学会  

症例は60歳代、女性。右肺上葉の18mm大の腫瘍が切除された。組織学的に、豊富な粘液腫状基質を背景に小型類円形〜卵円形核を有する腫瘍細胞の増殖が認められた。RT-PCRでEWSR1-CREB1融合遺伝子が検出され、primary pulmonary myxoid sarcoma with EWSR1-CREB1 translocationと診断した。捺印細胞診では、粘液状基質や炎症細胞を混じる短紡錘形から多角形の異型に乏しい細胞集塊を認め、炎症性変化との鑑別が必要であった。(著者抄録)

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Language：English  

Optic nerve pilocytic astrocytoma is an uncommon but well-known entity; however, intraorbital ancient pilocytic astrocytoma of the optic nerve is extremely rarely reported. To our knowledge, this is the first detailed description regarding the intraorbital ancient pilocytic astrocytoma, reported in available English literature, to date. We presented an extremely unusual neurofibromatosis type 1 case of a 17-year-old male's sudden ocular pain secondary to intraorbital pilocytic astrocytoma of the optic nerve with markedly cystic degeneration, fluid production, and hemorrhage, due to ancient and possibly ruptured glioma. Future prospective studies are required to validate the significance of intraorbital ancient pilocytic astrocytoma arising from the optic nerve and the close correlation with ruptured cystic degeneration and ocular pain, after collecting and investigating a larger number of its cases examined.

DOI： 10.1177/2050313X18761310

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Publisher：西日本整形・災害外科学会  

<p>【はじめに】紡錘形細胞脂肪腫spindle cell lipomaは脂肪腫の特殊型で，中年男性の後頚部，肩，背部に好発する稀な腫瘍である．【症例】70歳男性，背部皮下に弾性軟，約8 cm大の腫瘤を認めた．MRI上T2強調画像にて著明な高信号を主体とし，漸増性の増強効果を呈し内部に微小な脂肪成分を認め，分葉状の形態を呈していた．粘液型脂肪肉腫との鑑別が必要と考え，生検術を施行．肉眼的に粘液性の成分と一部線維性の組織を採取した．病理所見では粘液腫様の間質内に存在する短紡錘形の腫瘍細胞はCD34陽性，ロープ状膠原線維の存在やMDM2陰性から紡錘形細胞脂肪腫と診断し，辺縁切除術を施行した．【まとめ】紡錘形細胞脂肪腫は術前診断が難しく，他の脂肪系腫瘍である粘液型脂肪肉腫や異型脂肪腫様腫瘍との鑑別が重要である．画像所見や病理所見，臨床所見について文献的考察を加え報告する．</p>

DOI： 10.5035/nishiseisai.67.857

Language：English   Publishing type：Research paper (scientific journal)  

The recent advancement in genome editing such a CRISPR/Cas9 system has enabled isolation of cells with knocked multiple alleles through a one-step transfection. Somatic cell nuclear transfer (SCNT) has been frequently employed as one of the efficient tools for the production of genetically modified (GM) animals. To use GM cells as SCNT donor, efficient isolation of transfectants with mutations at multiple target loci is often required. The methods for the isolation of such GM cells largely rely on the use of drug selection-based approach using selectable genes; however, it is often difficult to isolate cells with mutations at multiple target loci. In this study, we used a novel approach for the efficient isolation of porcine cells with at least two target loci mutations by one-step introduction of CRISPR/Cas9-related components. A single guide (sg) RNA targeted to GGTA1 gene, involved in the synthesis of cell-surface α-Gal epitope (known as xenogenic antigen), is always a prerequisite. When the transfected cells were reacted with toxin-labeled BS-I-B₄ isolectin for 2 h at 37 C to eliminate α-Gal epitope-expressing cells, the surviving clones lacked α-Gal epitope expression and were highly expected to exhibit induced mutations at another target loci. Analysis of these α-Gal epitope-negative surviving cells demonstrated a 100% occurrence of genome editing at target loci. SCNT using these cells as donors resulted in the production of cloned blastocysts with the genotype similar to that of the donor cells used. Thus, this novel system will be useful for SCNT-mediated acquisition of GM cloned piglets, in which multiple target loci may be mutated.

DOI： 10.3390/ijms18122610

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Publisher：(一社)日本消化器外科学会  

膠原病は結合組織の障害による消化管の運動異常により,しばしば消化管病変を合併する.症例は60歳の女性で,17年前に混合性結合組織病(mixed connective tissue disease;以下,MCTDと略記)の診断を受け,以後当院膠原病内科で加療を行っていた.腹痛を主訴に来院され,盲腸軸捻転症と診断し緊急手術を施行した.回結腸動脈を軸に360°捻転していたため,捻転解除術と盲腸固定術を行った.退院後の術後37日目に腹痛を来し,腹部CTで腸管捻転の所見を認めたため,緊急手術を施行した.捻転は解除されたが広範囲の回腸の拡張を認め,減圧処置後に腸管を切除する方針とした.初回手術から51日目に再々手術を行い,拡張し蠕動低下を認めた回腸を30cm切除した.病理検査で固有筋層の萎縮を認めた.限局した固有筋層の萎縮が限局性の蠕動低下,腸管内容物の停滞を起こし,軸捻転症が発症したものと推測した.MCTDに腸管軸捻転症の合併を認めた報告例はなく,病理所見も合わせて報告する.(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)  

AIM: We have recently established a novel swine model for studies of atherosclerosis using MicrominipigsTM (µMPs) fed a high-fat/high-cholesterol diet (HcD). Using this swine model, we re-evaluated the effects of dietary cholic acid (CA) on serum lipid profile, atherosclerosis and hepatic injuries. METHODS: The µMPs were fed HcD supplemented with 0.7% CA (HcD＋CA) for eight weeks, and the effect of CA on serum lipoprotein levels, expression of oxidative stress markers, adiposity and lesion formation in the aorta, liver, and other organs was investigated. RESULTS: The HcD＋CA-fed group exhibited more visceral adiposity, progression of atherosclerosis and higher serum levels of oxidative stress markers than the HcD-fed group, even though they showed similar serum lipid levels. The liver demonstrated increased lipid accumulation, higher expression of oxidative stress markers, accelerated activation of foamy Kupffer cells and stellate cells, and increased hepatocyte apoptosis, indicating non-alcoholic fatty liver disease (NAFLD). Intriguingly, foamy macrophage mobilization was observed in various organs, including the reticuloendothelial system, pulmonary capillary vessels and skin very often in HcD＋CA-fed µMPs. CONCLUSION: To our knowledge, this is the first large animal model, in which visceral obesity, NAFLD and atherosclerosis are concomitantly induced by dietary manipulation. These data suggest the detrimental effects of CA, potentially through local and systemic activation of oxidative stress-induced signaling to macrophage mobilization, on the acceleration of visceral adiposity, atherosclerosis and NAFLD.

DOI： 10.5551/jat.39909

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Adult T-cell leukemia/lymphoma(ATLL)can infiltrate throughout various organs and frequently involves the gastrointestinal tract. However, bowel perforation in ATLL patients is rare. Herein, we present a case of ATLL with bowel perforation. A 75-year-old man presented with bowel distension. Computed tomography showed a large mass of the cecum. Edema and stenosis of the ascending colon was seen on colonoscopy, and tumor on the anal side of the stenosis was also found. After admission, the patient complained of abdominal pain with a peritoneal irritation sign. Free air was seen around a large mass of the cecum on computed tomography and an emergency operation was performed under the diagnosis of bowel perforation. Microscopic examination revealed bowel infiltration of ATLL. Gastrointestinal perforation can be caused by ATLL itself and is associated with a poor prognosis. The standard treatment for ATLL is chemotherapy but emergency surgery is necessary in case of perforation. It is important to observe the patient with ATLL carefully.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Induction of corpus luteum regression and subsequent estrus using prostaglandin F-2 alpha (PGF(2 alpha)) in microminipigs was investigated. Microminipigs with normal estrous cycle were treated with PGF(2 alpha) as 0.75 mg (0.75 PG group, n=3) or 1.5 mg (1.5 PG group, n=4) dinoprost injected into the vulva at 24-h intervals at 10 days after the onset of estrus (D0), D1 and D2. Three microminipigs were not treated (control group). The estrous interval in the 1.5 PG group was significantly shortened compared to the control and 0.75 PG groups. Plasma progesterone levels started to decline and reached the base line in the 1.5 PG group significantly faster than in the control group. In conclusion, we demonstrate that multiple PGF(2 alpha) treatments can induce corpus luteum regression and estrous synchronization in female microminipigs.

DOI： 10.21873/invivo.11175

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Fibromuscular dysplasia (FMD) is an idiopathic, segmental, nonatherosclerotic, non-inflammatory vascular disease, which is often complicated by the occurrence of dissection. Although it is known to occur in all arteries, aortic involvement is relatively rare. To date, 33 cases of aortic FMD have been reported in available English literature, among which only three cases have been complicated by the occurrence of dissection. We describe the case of a 40-year-old woman diagnosed with aortic FMD complicated by the occurrence of a type A aortic dissection. Non-invasive imaging revealed an ascending to descending thoracic aneurysm measuring 8 cm in diameter associated with dissection. Histopathologically, a segment of the wall of the aneurysm showed architectural disorganization of the aortic wall with loss of elastic fibers, collagen deposition, and irregular proliferation of smooth muscle cells in the intima and media-features suggesting FMD. No atheromatous plaque or medial cystic degeneration was observed in the aorta. Although aortic FMD is sometimes fatal, it is often very difficult to diagnose using imaging techniques. Therefore, performing a histopathological diagnosis is very important and should be emphasized. (C) 2017 Published by Elsevier Inc.

DOI： 10.1016/j.carpath.2017.07.007

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Publisher：(株)癌と化学療法社  

成人T細胞性白血病リンパ腫(ATLL)は、全身諸臓器へ浸潤し、消化管へも高率に浸潤するが、穿孔を来すことはまれである。ATLLの消化管浸潤により、穿孔を来した症例を経験したため報告する。患者は腹部膨満感を主訴に受診した75歳、男性。腹部造影CTで回盲部に粗大な腫瘤を認め、下部消化管内視鏡検査では上行結腸に浮腫、狭窄があり、スコープは通過できず、上行結腸狭窄部肛門側に腫瘤を認めた。入院後、腹膜刺激症状を伴う腹痛が出現した。腹部造影CTで回盲部腫瘍周囲にfree airを認め、消化管穿孔の診断で緊急手術を施行した。術後の病理組織検査でATLLの消化管浸潤と診断された。ATLLの消化管浸潤は消化管穿孔を来すことがあり、穿孔を来した場合は予後不良である。ATLLの治療の主体は化学療法であるが、穿孔を来した場合は早急に手術が必要であり、慎重に経過をみる必要があると考えられた。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)  

Angiotensin (Ang) II is known to promote vascular disease and hypertension, partly through its effect on vascular endothelium. Bradykinin (BK) is an endothelium-dependent agonist that induces relaxation followed by contraction of the porcine basilar artery through release of NO and PGF2α, respectively. In this study, we evaluated the effect of Ang II-induced hypertension on basilar artery responsiveness to BK in the Microminipig (MMPig). Ang II (200ng/kg/min) or vehicle was infused into MMPigs for 14days using an osmotic mini-pump and blood pressure was monitored regularly. The responsiveness of subsequently isolated basilar arteries was then measured using a micro organ bath system. MMPig basilar artery endothelial cells were cultured and stimulated with Ang II or vehicle for 48h. Mean blood pressure was significantly (P<0.05; n=5) higher in Ang II-infused MMPigs than in vehicle-infused MMPigs. In vitro, BK-induced endothelium-dependent dilation of isolated basilar artery specimens was abolished and BK-induced contraction was significantly increased (Emax: 15.85±2.42% and 56.54±2.71% of 60mM KCl in control and Ang II group respectively at 10-7M concentration of BK; P<0.01; n=5) in Ang II-infused MMPigs. Ang II stimulation of the endothelial cells significantly decreased (54.15% at 24h; P<0.05; n=three independent experiment performed in triplicate) the amount of BK-elicited NO and increased (44.27% at 24h; P<0.05; n=three independent experiment performed in triplicate) the amount of BK-elicited PGF2α. These results suggest that the decrease of NO and increase of PGF2α production from endothelial cells are responsible for cerebrovascular dysfunction in hypertension, possibly causing cerebrovascular contraction and thus increasing the risk of brain infarction.

DOI： 10.1016/j.mvr.2017.06.001

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Authorship：Last author   Language：Japanese   Publisher：(株)癌と化学療法社  

成人T細胞性白血病リンパ腫(ATLL)は、全身諸臓器へ浸潤し、消化管へも高率に浸潤するが、穿孔を来すことはまれである。ATLLの消化管浸潤により、穿孔を来した症例を経験したため報告する。患者は腹部膨満感を主訴に受診した75歳、男性。腹部造影CTで回盲部に粗大な腫瘤を認め、下部消化管内視鏡検査では上行結腸に浮腫、狭窄があり、スコープは通過できず、上行結腸狭窄部肛門側に腫瘤を認めた。入院後、腹膜刺激症状を伴う腹痛が出現した。腹部造影CTで回盲部腫瘍周囲にfree airを認め、消化管穿孔の診断で緊急手術を施行した。術後の病理組織検査でATLLの消化管浸潤と診断された。ATLLの消化管浸潤は消化管穿孔を来すことがあり、穿孔を来した場合は予後不良である。ATLLの治療の主体は化学療法であるが、穿孔を来した場合は早急に手術が必要であり、慎重に経過をみる必要があると考えられた。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00296&link_issn=&doc_id=20171221480149&doc_link_id=%2Fab8gtkrc%2F2017%2F004412%2F149%2F1494-1496%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2017%2F004412%2F149%2F1494-1496%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc  

Cystadenocarcinoma (CAC) of the salivary gland poses a diagnostic challenge to us, as this uncommon entity is extremely difficult to diagnose pre-operatively on an inadequate sample. However, markedly few papers have described the cytological features of CAC. An 82-year-old male presented with a history of a gradual increase in size and occasional mucous drainage from a swollen reddish nodule on the right upper lip. A retrospective examination of the cytological specimens from the drainage revealed a small number of clusters and scattered single cells of severely degenerated and mildly atypical epithelial cells with hyperchromatic dense nuclei and abundant clear cytoplasm, in a background of a large amount of mucinous material. We first interpreted this finding merely as the presence of atypical cells. However, a gross examination revealed a non-capsulated and relatively well-demarcated cystic lesion, grayish to whitish in color and measuring 13 × 9 mm in diameter, filled with mucin. A microscopic examination showed that the tumor had a central cystic cavity filled with mucinous material and was predominantly composed of the papillary proliferation of atypical columnar mucous epithelial cells with enlarged hyperchromatic nuclei, mixed with mitotic hot spots often projecting and melting into the mucinous cystic lumen, and focally involving the surrounding connective tissue. Therefore, we ultimately made a diagnosis of CAC of the minor salivary gland arising in the upper lip. Given the characteristic features of CAC, cytopathologists should be able to correctly diagnose this lesion based on multiple adequate fine needle aspiration samples.

DOI： 10.1016/j.ehpc.2016.08.006

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J-GLOBAL

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Authorship：Lead author   Language：Japanese   Publisher：(株)文光堂  

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Language：English   Publisher：WILEY  

DOI： 10.1111/pin.12541

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Publisher：日本臨床細胞学会-九州連合会  

背景:術後長期を経た腎細胞癌の甲状腺への孤立性転移は非常に稀である。今回、我々は右腎細胞癌術後20年を経過して甲状腺内に孤立性転移を来たした症例を経験したので報告する。症例:70歳代、男性。前医のエコー検査にて甲状腺右葉内に45×41×32mm大の腫瘤を指摘され、当院を紹介受診された。穿刺吸引細胞診では、血性背景に濃縮コロイドや濾胞上皮細胞集塊に混じて、異型細胞が孤在性からシート状にごく少数認められた。異型細胞は淡明で豊富な細胞質と軽度腫大した核を有し、N/C比は小さいながらも核形不整と中心性の明瞭な核小体を認めた。異型細胞はごく少数で、且つ由来が不明であったため、「鑑別困難」(現:意義不明)と報告したところ、経過観察となっていた。その後、嗄声が出現したため再受診され、甲状腺癌による右反回神経麻痺と診断された。生検の結果、腎細胞癌の転移と判明し、CTにて周囲組織への広汎な浸潤が疑われたため、甲状腺全摘出術及び喉頭摘出術が施行された。結論:再検討では淡明細胞型腎細胞癌の細胞像であり、スクリーニング時に充分な情報があれば、腎細胞癌の転移を指摘しえた症例であった。甲状腺の単発性腫瘤であっても、病歴に留意し、腎細胞癌の転移も念頭においたスクリーニングが望まれる。(著者抄録)

Authorship：Last author   Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景:術後長期を経た腎細胞癌の甲状腺への孤立性転移は非常に稀である。今回、我々は右腎細胞癌術後20年を経過して甲状腺内に孤立性転移を来たした症例を経験したので報告する。症例:70歳代、男性。前医のエコー検査にて甲状腺右葉内に45×41×32mm大の腫瘤を指摘され、当院を紹介受診された。穿刺吸引細胞診では、血性背景に濃縮コロイドや濾胞上皮細胞集塊に混じて、異型細胞が孤在性からシート状にごく少数認められた。異型細胞は淡明で豊富な細胞質と軽度腫大した核を有し、N/C比は小さいながらも核形不整と中心性の明瞭な核小体を認めた。異型細胞はごく少数で、且つ由来が不明であったため、「鑑別困難」(現:意義不明)と報告したところ、経過観察となっていた。その後、嗄声が出現したため再受診され、甲状腺癌による右反回神経麻痺と診断された。生検の結果、腎細胞癌の転移と判明し、CTにて周囲組織への広汎な浸潤が疑われたため、甲状腺全摘出術及び喉頭摘出術が施行された。結論:再検討では淡明細胞型腎細胞癌の細胞像であり、スクリーニング時に充分な情報があれば、腎細胞癌の転移を指摘しえた症例であった。甲状腺の単発性腫瘤であっても、病歴に留意し、腎細胞癌の転移も念頭においたスクリーニングが望まれる。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：F HERNANDEZ  

Mucins play pivotal roles in influencing cancer biology, for example affecting carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to investigate the significance of expression profiles of two mucins in particular, MUC1 and MUC2, their correlations with various clinicopathological features, and prognosis in gallbladder adenocarcinoma (GBAC). We performed immunohistochemistry from patients with surgically resected GBAC, using antibodies against mucin core proteins MUC1/DF3 and MUC2/Ccp58 in 81 paraffin-embedded tumor samples. MUC1 or MUC2 expression was considered to be high when &gt;= 20% or 10% of the GBAC cells showed positive staining, respectively. High MUC1 expression was revealed to have a significant relationship to the presence of pathologically lymphatic and vascular invasion, and regional lymph node metastasis. By contrast, high MUC2 expression showed a significant correlation with pathologically perineural invasion, T stage &gt;= 3, and post-operative recurrence. Moreover, MUC1 showed significantly positive co-expression and potentially complementary correlations with MUC2. Multivariate analyses demonstrated that the high MUC1 expression group had significantly shorter disease-specific survival times. However, the combination of both high MUC1 and MUC2 expression did not predict worse outcome in GBACs. Therefore, although each mucin has a somewhat important role in the pathogenesis of GBAC progression, MUC1 can independently predict vessel invasion and poor prognosis in patients with GBAC. The detection of MUC1 might well offer a useful parameter for providing clinical management and treatment against postsurgical GBACs.

DOI： 10.14670/HH-11-824

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

AIMS/HYPOTHESIS: Nitric oxide (NO) is synthesised not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice. METHODS: To this end, we prepared a low-nitrite/nitrate diet (LND) consisting of an amino acid-based low-nitrite/nitrate chow, in which the contents of L-arginine, fat, carbohydrates, protein and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. RESULTS: Three months of the LND did not affect food or water intake in wild-type C57BL/6J mice compared with a regular diet (RD). However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance. Eighteen months of the LND significantly provoked increased body weight, hypertension, insulin resistance and impaired endothelium-dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS downregulation, adiponectin insufficiency and dysbiosis of the gut microbiota. CONCLUSIONS/INTERPRETATION: These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications.

DOI： 10.1007/s00125-017-4259-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

We demonstrated an extremely unusual case of an 83-year-old male's sudden death secondary to characteristic myocardial necrosis and fibrosis with calcification and multinucleated giant cells infiltration, possibly due to sepsis and Stage IV pulmonary pleomorphic carcinoma-induced cachexia after postmortem study. We propose that this calcifying giant cell cardiomyopathy (CGC) would be a new entity especially from the pathological viewpoints and should be considered in the classification of noninfectious myocarditis. Further prospective studies are needed to validate the presence and significance of CGC and the association with any triggers of somewhat microvascular dysfunction and/or toxic agents, after collecting and investigating a larger number of CGC cases examined. (C) 2017 The Authors. Published by Elsevier Inc.

DOI： 10.1016/j.carpath.2017.03.004

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Language：English   Publisher：WILEY  

DOI： 10.1111/1346-8138.13712

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：F HERNANDEZ  

Apoptosis plays pivotal in vivo roles in not only vital processes, such as cell turnover and embryonic development, but also various inflammatory disorders. However, the role of apoptosis by vascular and hepatic cells in the respective progression of atherosclerosis and liver injury remains controversial. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase family member that is activated through distinct mechanisms in response to various cytotoxic stressors. ASK1, ubiquitously expressed, is situated in an important upstream position for many signal transduction pathways, which subsequently induce inflammation and/or apoptosis. Our serial in vivo studies have uniquely reported that the expression of phosphorylated ASK1 is variably seen in atherosclerotic lesions or bile-duct- ligation (BDL)induced injury livers. In mice genetically deficient of ASK1 (ASK1(-/-)), activated ASK1 signaling accelerates high-cholesterol-diet-induced necrotic lipid core formation by inducing macrophage apoptosis and enhances ligation injury-induced vascular remodeling via pro-inflammatory reactions and by stimulating apoptosis of smooth muscle cells. In contrast, in models of BDL-induced cholestatic liver injury, the pathogenic roles of ASK1-mediated early necro-inflammation, but not apoptosis, and the proliferation of hepatocytes and cholangiocytes are crucial in subsequent peribiliary fibrosis/fibrogenesis. These animal models of acute to chronic inflammatory diseases show that stimulated ASK1 signaling critically and diversely regulates not only hypercholesterolemia-induced atherosclerosis and injury-induced arteriosclerosis, but also the acute and subacute-to-chronic phase of BDL-induced cholestasis. We herein review the diverse, key in vivo roles of ASK1 signaling in the pathogenesis of inflammatory disorders closely related to metabolic syndrome.

DOI： 10.14670/HH-11-840

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Publisher：(一社)日本病理学会  

40代、男性。右耳下腺部に20mm大の可動性良好な腫瘤を認め、摘出術が施行された。周囲とは境界明瞭で、一部に菲薄な線維性被膜を認めた。病変の大部分は基底細胞様細胞が大小の篩状構造を呈し増殖しており、胞巣内には好酸性細胞質を有する導管上皮様細胞からなる真の腺腔も散見された。腺様嚢胞癌や基底細胞腺癌等、篩状構造を示す悪性上皮性唾液腺腫瘍との鑑別が問題となったが、肉眼的に境界明瞭な病変であり、組織学的にも明らかな浸潤性増殖や神経侵襲、脈管侵襲を認めない事から基底細胞腺腫、篩状亜型と診断した。(著者抄録)

Authorship：Last author   Language：Japanese   Publisher：(一社)日本病理学会  

40代、男性。右耳下腺部に20mm大の可動性良好な腫瘤を認め、摘出術が施行された。周囲とは境界明瞭で、一部に菲薄な線維性被膜を認めた。病変の大部分は基底細胞様細胞が大小の篩状構造を呈し増殖しており、胞巣内には好酸性細胞質を有する導管上皮様細胞からなる真の腺腔も散見された。腺様嚢胞癌や基底細胞腺癌等、篩状構造を示す悪性上皮性唾液腺腫瘍との鑑別が問題となったが、肉眼的に境界明瞭な病変であり、組織学的にも明らかな浸潤性増殖や神経侵襲、脈管侵襲を認めない事から基底細胞腺腫、篩状亜型と診断した。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

Lung cancer remains a disease of high mortality, despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in lung neoplasms. Our immunohistochemistry (IHC) studies have shown that high MUC4 expression correlates with a poor outcome. We have also shown that the expression of several mucin genes in cancer cell lines is regulated by DNA methylation. We evaluated the expression level of MUC4, mRNA and several DNA hypomethylation factors in lung tissue samples from 33 patients with various lung lesions. The results indicated that the DNA methylation status of MUC4 matched the expression level of mRNA. In addition, the TET1 (Ten-Eleven Translocation) mRNA showed a significant correlation with the status of DNA methylation of MUC4. Furthermore, the treatment of a lung cancer cell line with TET1 siRNA caused a reduction in MUC4 mRNA expression. Thus, we suggest that TET1 mediated DNA hypomethylation plays a key role in the expression of MUC4. This is the first report that TET1 mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer. The analysis of these epigenetic changes may be useful for diagnosing carcinogenic risk.

DOI： 10.18632/genesandcancer.139

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVE: In the present study, we investigated the relationship between the single-nucleotide polymorphism (SNP) of caspase-3 rs1049216 (C > T), a miRNA target site, and the risk and progression of cervical cancer. MATERIALS AND METHODS: Using polymerase chain reaction-restriction fragment length polymorphism, we evaluated the genotype and distribution of caspase-3 rs1049216 in 515 patients with cervical squamous cell cancer and 415 controls. In additional experiments, we transfected luciferase reporter plasmids carrying T or C allele and/or miRNA mimics into the human cervical cell lines (HeLa and C-33A) to analyze its roles in the regulation of caspase-3 expression. By immunohistochemistry, the protein level of caspase-3 expression was examined in tumor tissues from 515 patients with cervical squamous cell cancer. RESULTS: We found that the TT genotype of caspase-3 rs1049216 conferred a significantly decreased risk of cervical cancer (adjusted odds ratio, 0.35; 95% confidence interval, 0.154-0.581) and may be associated with the progression of this cancer. Although the expression of caspase-3 in the TT genotype was higher than that in CC/CT genotype in peripheral blood mononuclear cells and tumor tissues. Additional luciferase analysis showed that the rs1049216 variant T allele was associated with significantly higher luciferase activity, compared with the C allele in the transfected cells, and when cotransfected with miRNAs, miRNA-181a could downregulate the luciferase activity in the cells that transfected the construct containing C allele, compared with T allele, which had not happened in the presence of other miRNAs selected. CONCLUSIONS: These data indicate that through upregulating the expression of caspase-3, the TT genotype of caspase-3 rs1049216 can be associated with not only the risk of cervical cancer but also the progression of this cancer.

DOI： 10.1097/IGC.0000000000000881

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

To establish treatments to improve the prognosis of cancer patients, it is necessary to find new targets to control metastasis. We found that expression of FilaminC (FLNC), a member of the actin binding and cross-linking filamin protein family is correlated with lymphatic invasion and lymphatic metastasis in esophageal squamous cell carcinoma (ESCC) by increasing cell motility through activation of Rho GTPase.Immunohistochemistry analysis showed that FLNC expression in ESCC is associated with lymphatic invasion, metastasis, and prognosis. FLNC knockdown in esophageal cancer cell lines decreased cell migration in wound healing and transwell migration assays, and invasion in transwell migration assays. Furthermore, FLNC knockdown reduced the amount of activated Rac-1 (GTP-Rac1) and activated Cdc42 (GTP-Cdc42). Our results suggest that FLNC expression is a useful biomarker of ESCC metastatic tendency and that inhibiting FLNC function may be useful to control the metastasis of ESCC.

DOI： 10.18632/oncotarget.14087

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

BACKGROUND: Epithelioid schwannoma as a rare variant poses a challenge to all pathologists, as this uncommon entity is extremely difficult to conclusively diagnose by morphological analyses on a resected sample alone owing to its unique histopathological features. However, few papers have described the detailed clinicopathological characteristics of epithelioid schwannoma. CASE PRESENTATION: A 65-year-old female presented with a history of a flat and slightly elevated firm and tan plaque accompanied by occasional tenderness, measuring 10 × 8 mm, in the right joint of her hand 1 year before resection. A gross examination of a locally resected specimen revealed an encapsulated nodular lesion, yellow-whitish in color, partly filled with blood. A microscopic examination showed that the tumor predominantly consisted of a solid proliferation of epithelioid cells having mildly enlarged and round to partially spindled nuclei and abundant vacuolated or clear cytoplasm with very few mitotic figures and modest nuclear size variation, associated with focal hyalinized, cystic and hemorrhagic degeneration. This well-demarcated tumor was surrounded by dense, hyalinized and layered fibrocollagenous stroma. Immunohistochemically, these tumor cells were diffusely positive for S-100 protein and had a very low MIB-1 labeling index, and type IV collagen was strongly reactive with reduplicated basal lamina of them. We ultimately made a diagnosis of cutaneous epithelioid schwannoma. CONCLUSION: We should be aware that, since pathologists might misinterpret epithelioid schwannoma as other soft tissue tumors, including its malignant counterpart, a wide panel of immunohistochemical antibodies can be powerful supplementary tools for identifying a very rare entity of conventional schwannoma.

DOI： 10.1186/s13000-017-0604-9

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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Language：Japanese   Publisher：The Japanese Society of Gastroenterological Surgery  

<p>A 60-year-old woman with mixed connective tissue disease (MCTD) was admitted because of abdominal pain and vomiting. Abdominal CT showed "whirl sign" around the cecum, so the patient was given a diagnosis of cecal volvulus. The patient underwent emergency operation. The cecum was twisted 360° clockwise around the ileocolic vessels. Although the jejunum and ileum were dilated, the cecum and intestine caused no ischemic change. The patient underwent detorsion of the cecum and cecopexy. The patient was discharged twelve days after surgery. Thirty-seven days after discharge, the patient was admitted for abdominal pain again. The patient underwent emergency operation since we diagnosed recurrence cecum volvulus. The ileum twisted 360° clockwise and detorsion of the twisting ileum was performed. We decided to reoperate the intestinal resection after decompression treatment, because the patient had a possibility of ileal volvulus again. Fifty-one days later from the initial surgery, we operated again. We resected the extended ileum 30 cm. Atrophy of the muscle layer was observed corresponding to the extend site pathologically. There was some possibility of hypoperistalsis due to atrophy of intestinal muscle of MCTD. It is better to evaluate peristalsis using gastrointestinal series in case of bowel volvulus with MCTD.</p>

DOI： 10.5833/jjgs.2016.0186

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J01117&link_issn=&doc_id=20180115390010&doc_link_id=10.5833%2Fjjgs.2016.0186&url=https%3A%2F%2Fdoi.org%2F10.5833%2Fjjgs.2016.0186&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Histamine, a classic low-molecular-weight amine, is synthesized from L-histidine by histidine decarboxylase (HDC), and histamine-specific receptors (HRs) are essential for its actions. Our serial in vivo studies have uniquely reported that expression of histamine/HRs is variably identified in atherosclerotic lesions, and that HDC-gene knockout mice without histamine/HRs signaling show a marked reduction of atherosclerotic progression. These data have convinced us that histamine plays a pivotal role in the pathogenesis of atherosclerosis. Among four subclasses of HRs, the expression profile of the main receptors (H1/2R) has been shown to be switched from H2R to H1R during monocyte to macrophage differentiation, and H1R is also predominant in smooth muscle and endothelial cells of atheromatous plaque. Using various animal models of H1/2R-gene knockout mice, H1R and H2R were found to reciprocally but critically regulate not only hypercholesterolemia-induced atherosclerosis and injury-induced arteriosclerosis, but also hyperlipidemia-induced nonalcoholic fatty liver disease (NAFLD). Metabolic syndrome manifests obesity, dyslipidemia, insulin resistance, atherosclerosis, and/or NAFLD, i.e. the dysregulation of lipid/bile acid/glucose metabolism. Therefore, although its etiology is complicated and multifactorial, histamine/HRs signaling has a close relationship with the development of metabolic syndrome. We herein review diverse, key in vivo roles of histamine/HR signaling in the pathogenesis of metabolic syndrome.

DOI： 10.1111/pin.12477

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Language：Japanese   Publisher：(一社)日本肝臓学会  

症例は66歳、男性。全身倦怠感、発熱、腹痛、食思不振で近医を受診し、血小板減少、肝腎機能障害を認め、当院へ緊急入院となった。腹部超音波検査、CT検査で著明な肝脾腫と脾内占拠性病変、脾出血を認めた。急速に肝不全が進行、播種性血管内凝固症候群(disseminated intravascular coagulation:DIC)も合併し、全身状態は増悪した。第3病日には腹腔内出血を来し、第5病日に死亡した。家族の同意を得て、剖検を行った。肝腫大、著明な脾腫大を認め、脾臓は被膜の破綻、出血を伴い脾破裂をきたしていた。肝臓、脾臓には腫瘍細胞がびまん性に増殖しており、免疫染色にて悪性リンパ腫(diffuse large B-cell lymphoma:DLBCL)と診断した。今回、我々は脾破裂を伴い急性肝不全様の急激な経過を呈した悪性リンパ腫の一例を経験したので文献的考察を含めて報告する。(著者抄録)

DOI： 10.2957/kanzo.57.674

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Long-term parenteral nutrition following massive bowel resection causes liver dysfunction, such as intestinal failure-associated liver disease (IFALD). IFALD includes two different states, cholestasis and steatosis, which represents a life-threatening complication. The previous reports have shown the protective role of ghrelin in the liver. The aim of this study was to evaluate the effects of the administration of ghrelin in the liver in a parenterally fed rat model of short bowel syndrome (SBS).
Rats underwent jugular vein catheterization, and were divided into three groups: 90 % small bowel resection (90 % SBR) and TPN (SBS/TPN group), 90 % SBR and TPN plus ghrelin (SBS/TPN/ghrelin group), and sham operation with normal chow (sham group). Ghrelin was administered continuously at a dose of 10 mu g/kg/day. On day 13, all rats were euthanized. The serum chemistry was analyzed, the lipid content of the liver was measured, and the liver tissue was histologically analyzed.
The AST and LDH levels significantly increased, and the accumulation of lipids in the liver was observed in the TPN/SBS group. The accumulation of lipids in the liver of the rats in the SBS/TPN group was attenuated by the administration of ghrelin.
The administration of ghrelin has a therapeutic potential for IFALD.

DOI： 10.1007/s00383-016-3975-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

BACKGROUND/PURPOSE: Total parenteral nutrition (TPN) has been reported to be associated with mucosal atrophy of the small intestine. Ghrelin has hormonal, orexigenic, and metabolic activities. We investigated whether ghrelin improved intestinal mucosal atrophy using a TPN-supported rat model. METHODS: Rats underwent jugular vein catheterization and were divided into four groups: TPN alone (TPN), TPN plus low-dose ghrelin (TPNLG), TPN plus high-dose ghrelin (TPNHG), and oral feeding with normal chow (OF). Ghrelin was administered continuously at dosages of 10 or 50 μg/kg/day. On day 6 rats were euthanized, and the small intestine was harvested and divided into the jejunum and ileum. Then the villus height (VH) and crypt depth (CD) were evaluated. RESULTS: The jejunal and ileal VH and CD in the TPN group were significantly decreased compared with those in the OF group. TPNHG improved only VH of the jejunum. TPNLG improved VH and CD of the jejunum and CD of the ileum. The improvement of TPNLG was significantly stronger than that in CD of the jejunum and ileum. CONCLUSIONS: TPN was more strongly associated with mucosal atrophy in the jejunum than in the ileum. Low-dose intravenous administration of ghrelin improved TPN-associated intestinal mucosal atrophy more effectively than high-dose administration.

DOI： 10.1016/j.jpedsurg.2016.09.035

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

In our previous study, we found that treatment of miniature pig somatic cell nuclear transfer (SCNT) embryos with 4 mM valproic acid (VPA), a histone deacetylase inhibitor, for 48 hours after activation enhanced blastocyst formation rate and octamer-binding transcription factor-3/4 (Oct-3/4) gene expression at the late blastocyst stage; however, the production of viable cloned pups failed, when those VPA-treated SCNT embryos were transferred to recipients. This failure suggests that the present VPA treatment is suboptimal. In the present study, we explored the optimal conditions for VPA to have beneficial effects on the development of SCNT embryos. When miniature pig SCNT embryos were treated with 8 mM VPA for 24 hours after activation, both the rates of blastocyst formation and blastocysts expressing the Oct-3/4 gene were significantly (p < 0.05) improved. A similar increase in blastocyst formation was also observed when microminipig-derived cells were used as SCNT donors. Five cloned piglets were obtained after the transfer of 152 microminipig SCNT embryos that had been treated with 8 mM VPA for 24 hours. The results indicated that a short duration of treatment with VPA improves the development of both miniature pig and microminipig SCNT embryos, possibly via an enhanced reprogramming mechanism.

DOI： 10.1089/cell.2016.0025

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Language：Japanese   Publisher：(一社)日本病理学会  

稀なフィンランド型先天性ネフローゼ症候群の1例を報告する。症例は4ヵ月、男児。緊急帝王切開により出生した低出生体重児で、出生直後より低アルブミン血症、高蛋白尿、発育不良、浮腫、甲状腺機能低下症、脂質異常症および胸腹水を認めたが、腎機能低下はみられなかった。蛋白尿コントロール目的に片腎摘出術が行われた。腎は腫大し、組織学的には特徴的な小嚢胞状に拡張した尿細管が皮質表層から皮髄境界部にかけて認められ、糸球体メサンギウム細胞の増加がみられた。また本疾患の責任遺伝子であるNPHS1遺伝子変異が確認された。(著者抄録)

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Language：Japanese   Publisher：(一社)日本病理学会  

Eccrine angiomatous hamartomaの1症例を報告する。症例は12歳男児。1年前より両手指背と右足背に多発する、淡紅色の結節が指摘された。自覚症状はなく、胼胝を疑われ、足背の皮疹から生検された。組織学的に、真皮中層から皮下脂肪組織にかけて、粘液腫状変性を示す線維性間質を背景に、境界不明瞭な結節性病変を認めた。病変部ではエクリン腺や導管が増加し、周囲に毛細血管の増生や脂肪組織、末梢神経線維の混在を認めた。(著者抄録)

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Publisher：日本心脈管作動物質学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOCIETY REPRODUCTION & DEVELOPMENT-SRD  

The induction of pseudopregnancy by the exogenous administration of estradiol dipropionate (EDP) was investigated in cyclic Microminipigs (MMpigs) and the effects of exogenous administration of prostaglandin (PG) F-2 alpha on estrus exhibition were assessed in pseudopregnant MMpigs. In experiment 1, ovariectomized MMpigs were given a single intramuscular injection of 0.5, 1.5, or 2.5 mg of EDP. The estradiol-17 beta level at each of these doses was significantly higher 1 to 3 days after EDP administration than on the day of the injection. In experiment 2, animals were given 1.5 mg of EDP once at 9 to 12 days after the end of estrus (D0) and then no (1.5 mg x 1 group), one (D0 and D4; 1.5 mg x 2 group), or two (D0, D4 and D7; 1.5 mg x 3 group) additional treatments. The pseudopregnancy rate was significantly higher in the 1.5 mg x 3 than in the 1.5 mg x 1 group. In experiment 3, PGF(2 alpha) was administered twice between 26 and 28 days after EDP treatment to five pseudopregnant gilts with a 24-h interval between the two injections. Estrus after PGF(2 alpha) treatment and LH surge were observed in 100% and 80% pseudopregnant MMpigs, respectively. The interval from the day of the first PGF(2 alpha) treatment to the onset of estrus was 6.5 +/- 0.2 days. These results indicate that multiple EDP treatments are required for induction of pseudopregnancy in MMpigs and estrus exhibition can be controlled in MMpigs by treatment with EDP and PGF(2 alpha).

DOI： 10.1262/jrd.2015-169

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

Purkinje cell protein (PCP) 4/peptide (PEP) 19 is expressed in Purkinje cells where it has a calmodulin-binding, anti-apoptotic function. We recently demonstrated that PCP4/PEP19 is expressed and inhibit apoptosis in human breast cancer cell lines. In the present study we investigated the role of PCP4/PEP19 in cell morphology, adhesion, migration, and invasion in MCF-7 and T47D human breast cancer cell lines. Knockdown of PCP4/PEP19 reduced the formation of filopodia-like cytoplasmic structures and vinculin expression, and enhanced E-cadherin expression. Activities of migration, invasion, and cell adhesion were also decreased after the knockdown of PCP4/PEP19 in MCF-7 and T47D cells. These results suggested that PCP4/PEP19 promotes cancer cell adhesion, migration, and invasion and that PCP4/PEP19 may be a potential target for therapeutic agents in breast cancer treatment which act by inhibiting epithelial-mesenchymal transition and enhancing apoptotic cell death.

DOI： 10.18632/oncotarget.7529

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Background: Malignant melanoma (MM) tends to be spontaneously regressed, however, complete regression of primary cutaneous MM is an extremely rare phenomenon. Our aim is to be aware that pathologists and/or dermatologists can readily misinterpret it as the other benign or malignant lesions. Case presentation: A gradually growing and verrucous hypopigmented macule had been noticed in the right sole of a 65-year-old Japanese male since 2 years before, and it turned to be a solitary bluish to black patch with surrounding depigmentation and was recently decreased in size. In parallel, the patient had a rapidly growing black-pigmented mass lesion at the right inguen. The cutaneous specimen from the sole showed an aggregation of many melanophages predominantly in the middle to deep layer of dermis, associated with surrounding fibrosis, reactive vascular proliferation and CD8-positive T-lymphocytic infiltrate, covered by attenuated epidermis with absence of rete ridge. However, no remnant MM cells were completely seen in the step-serial sections. We first interpreted it as blue nevus. By contrast, the inguinal mass revealed a diffuse proliferation of highly atypical mono- to multi-nucleated large cells having abundant eosinophilic cytoplasm in the enlarged lymph node tissue. Immunohistochemical findings demonstrated that these atypical cells were specifically positive for HMB45 and Melan A. Therefore, we finally made a diagnosis of complete regression of primary cutaneous MM associated with distant lymph node metastasis of MM. Conclusion: Careful, not only general/cutaneous but histopathological, examinations should be necessary and adjunctive aids for reaching the correct diagnosis of complete regression of cutaneous MM.

DOI： 10.1186/s13104-016-2174-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC.

DOI： 10.18632/oncotarget.9924

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Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景:明細胞肉腫は軟部悪性黒色腫とも呼ばれ、若年成人に多く、四肢の遠位部に好発する。今回、稀な右胸壁発生の明細胞肉腫を経験したので報告する。症例:30代、女性。半年前より背部痛があり、右胸壁に増大傾向のある腫瘤を認めた。穿刺吸引細胞診では、比較的きれいな背景に、N/C比の高い類円形から紡錐形の細胞が散在性から小集塊状にみられた。細胞は類円形ないし円形核を有し、核小体は明瞭で微細顆粒状のクロマチン増量を認めた。明細胞肉腫、悪性末梢神経腫瘍、滑膜肉腫などが疑われたが組織型の推定は困難であった。摘出された腫瘍は、組織学的に淡明から弱好酸性の胞体および核小体明瞭な類円形核を有する腫瘍細胞のシート状充実性増殖からなり、メラニン色素は認められなかった。免疫組織化学ではHMB-45及びS-100蛋白が陽性であった。遺伝子検索は行っていないが、細胞所見、免疫組織化学を含む組織所見および臨床情報より明細胞肉腫と診断した。結論:明細胞肉腫の細胞像ではメラニン色素や明瞭な核小体に着目することが重要と考えられるが、メラニン色素が認められない場合には遺伝子解析とともに既往歴や発生部位などの臨床情報が鑑別に重要である。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

We have reported that the function of histamine and its receptors (HRs) has a close relationship with the development of nonalcoholic fatty liver disease (NAFLD). However, much less is known regarding its pathogenic and molecular mechanism (s), including the early stage of hepatic and intestinal function for lipid and bile acid (BA) metabolism. We used H1R and H2R knockout mice (H1/2R-KO) to clarify those pivotal roles in cholesterol/BA metabolism, in which H1/2R-KO mice were separately fed a short-term 1% cholesterol or cholic acid (CA) diet. [H-3]Cholesterol absorption study revealed that significantly enhanced accumulation occurred in the jejunum, blood and liver, but not in the feces, of H2R-KO mice, compared to wild-type and H1R-KO mice. Furthermore, four weeks after the high-cholesterol diet, the H2R-KO jejunum but not liver exhibited increased expressions of cholesterol transporters, consistent with higher plasma lipoprotein levels. Five days after CA diet, the H2R-KO mice showed significantly higher expressions of ileal BA-reabsorption and hepatic BA-efflux factors, corresponding to higher serum but lower fecal BA levels. The following long-term CA diets resulted in severe injury to the H2R-KOliver. Histamine/H2R signaling might have a protective role in the initial phase during NAFLD progression, correlated with cholesterol and BA metabolism in the liver/intestine.

DOI： 10.1111/pin.12423

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background
Accumulating evidence has shown that methionine- and choline-deficient high fat (MCD+HF) diet induces the development of nonalcoholic fatty liver disease (NAFLD), in which elevated reactive oxygen species play a crucial role. We have reported that peroxiredoxin 4 (PRDX4), a unique secretory member of the PRDX antioxidant family, protects against NAFLD progression. However, the detailed mechanism and potential effects on the intestinal function still remain unclear.
Methods & Results
Two weeks after feeding mice a MCD+HF diet, the livers of human PRDX4 transgenic (Tg) mice exhibited significant suppression in the development of NAFLD compared with wildtype (WT) mice. The serum thiobarbituric acid reactive substances levels were significantly lower in Tg mice. In contrast, the Tg small intestine with PRDX4 overexpression showed more suppressed shortening of total length and villi height, and more accumulation of lipid in the jejunum, along with lower levels of dihydroethidium binding. The enterocytes exhibited fewer apoptotic but more proliferating cells, and inflammation was reduced in the mucosa. Furthermore, the small intestine of Tg mice had significantly higher expression of cholesterol absorption-regulatory factors, including liver X receptor-alpha, but lower expression of microsomal triglyceride-transfer protein.
Conclusion
Our present data provide the first evidence of the beneficial effects of PRDX4 on intestinal function in the reduction of the severity of NAFLD, by ameliorating oxidative stress-induced local and systemic injury. We can suggest that both liver and intestine are spared, to some degree, by the antioxidant properties of PRDX4.

DOI： 10.1371/journal.pone.0152549

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterized by alveolar accumulation of surfactant lipids and proteins. It is usually autoimmune and secondary to hematologic malignancy or infection. To date, only 5 case reports of PAP associated with lung cancers, including 2 cases of squamous cell carcinoma and 3 cases of adenocarcinoma, have been published. To the best of our knowledge, no case of PAP with small cell lung carcinoma has been reported thus far. We herein report the first case of PAP associated with small cell lung carcinoma.

DOI： 10.1177/1066896915614893

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Previously, we found that enteric lactoferrin (eLF) could reduce the visceral fat accumulation known to associate strongly with metabolic syndrome symptoms and consequently with an increased risk of atherosclerosis. In this study, the atherosclerosis-preventive potential of LF was assessed in a high-fat and high-cholesterol diet (HFCD)-induced hypercholesterolemia and atherosclerosis model using Microminipig. Eight-week orally administered eLF remarkably reduced the HFCD-induced serum total and low-density lipoprotein cholesterol levels but not high-density lipoprotein cholesterol levels. A histological analysis of 15 arteries revealed that eLF systemically inhibited the development of atherosclerotic lesions. Pathway analysis using identified genes that characterized eLF administration in liver revealed significant changes in the steroid biosynthesis pathway (ssc00100) and all affected genes in this pathway were upregulated, suggesting that cholesterol synthesis inhibited by HFCD was recovered by eLF. In summary, eLF could potentially prevent the hypercholesterolemia and atherosclerosis through protecting homeostasis from HFCD-induced dysfunction of cholesterol metabolism.

DOI： 10.1080/09168451.2015.1091713

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

High-dose chemotherapy and surgical intervention have improved long-term prognosis for non-metastatic osteosarcoma to 50-80%. However, metastatic osteosarcoma exhibits resistance to standard chemotherapy. We and others have investigated the function of Hedgehog pathway in osteosarcoma. To apply our previous findings in clinical settings, we examined the effects of Hedgehog inhibitors including arsenic trioxide (ATO) and vismodegib combined with standard anticancer agents. We performed WST-1 assays using ATO, cisplatin (CDDP), ifosfamide (IFO), doxorubicin (DOX), and vismodegib. Combination-index (CI) was used to examine synergism using CalcuSyn software. Xenograft models were used to examine the synergism in vivo. WST-1 assays showed that 143B and Saos2 cell proliferation was inhibited by ATO combined with CDDP, IFO, DOX, and vismodegib. Combination of ATO and CDDP, IFO, DOX or vismodegib was synergistic when the two compounds were used on proliferating 143B and Saos2 human osteosarcoma cells. An osteosarcoma xenograft model showed that treatment with ATO and CDDP, IFO, or vismodegib significantly prevented osteosarcoma growth in vivo compared with vehicle treatment. Our findings indicate that combination of Hedgehog pathway inhibitors and standard FDA-approved anticancer agents with established safety for human use may be an attractive therapeutic method for treating osteosarcoma.

DOI： 10.3892/ijo.2015.3236

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

A 55-year-old postmenopausal female presented with genital bleeding and lower abdominal mass. An abdominal MRI revealed a heterogeneously enhanced, 15 x 10 cm mass, completely filling the lumen of the enlarged uterus. The cytologic analysis of the mass showed tumor cells in small clusters and as individual cells showing hyperchromatic round to oval nuclei, and pleomorphic and occasionally unipolar "tadpole"-shaped cytoplasm, in a background of severe necrosis and many degenerated squamous cells. We first interpreted it merely as atypical cells, possibly originated from sarcoma. A total abdominal hysterectomy and salpingo-oophorectomy were performed, and gross examination showed an exophytic polypoid mass with a whitish to white-grayish, necrotic appearance, protruding from the endometrial mucosa. Microscopically, the tumor was composed of a diffuse proliferation of highly atypical spindle-shaped cells, admixed with many characteristic rhabdomyoblasts having abundant densely eosinophilic cytoplasm with sometimes distinct cross-striations, coexisted with cellular primitive small blue round to oval cells foci. However, neither carcinoma nor additional heterologous sarcoma components were completely seen within our thorough investigation. Therefore, we finally made a diagnosis of embryonal rhabdomyosarcoma arising from the uterine corpus. We should be aware that owing to its characteristic features, cytopathologists might be able to determine a genuine diagnosis, based on multiple and adequate cytology samplings.

DOI： 10.1186/s13000-016-0451-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Although most patients achieve favorable results following bipolar hip hemiarthroplasty (BHA), some experience rapid migration of the prosthesis. We retrospectively reviewed 18 patients with BHA that necessitated revision.
Methods: We examined soft tissues obtained from periprosthetic lesions. In total, 18 patients with pain and acetabular migration of the BHA prosthesis were included. The patients were divided into a polymorphonuclear leukocyte (PMN)-positive (&gt;= 5 PMNs per high-power field [HPF]) and PMN-negative (&lt; 5 PMNs/HPF) group.
Results: Pathological findings showed that 11 patients were PMN-positive, which was indicative of infection. All patients in the PMN-positive group showed no polyethylene particles or foreign body giant cells, while all patients in the PMN-negative group showed polyethylene debris or foreign body giant cells (p &lt; 0.001). BHA survival, C-reactive protein (CRP) levels, and the Japanese Orthopaedic Association (JOA) hip score were significantly different between the PMN-positive and PMN-negative group (p &lt; 0.01). A BHA survival cut-off value of 3270 days was diagnostic for PMN positivity (sensitivity: 100 %; specificity: 100 %). The cut-off values for CRP and the JOA hip score were 0.43 mg/dl and 56 points, respectively. Four of 11 PMN-positive patients showed no clinical symptoms of infection (asymptomatic PMN-positive group). BHA survival, CRP levels, and JOA hip scores were significantly different between the asymptomatic PMN-positive and PMN-negative group (p &lt; 0.05). A BHA survival cut-off of 3270 days was diagnostic for asymptomatic PMN positivity (sensitivity: 100 %; specificity: 100 %). The cut-off values for CRP and the JOA hip score were 0.43 mg/dl and 57 points, respectively.
Conclusion: Our findings suggest that some portion of rapid BHA prosthesis migration is caused by mild infection. Careful pathological examination should be performed to identify infection before removal of the BHA prosthesis in patients who develop migration within 9 years.

DOI： 10.1186/s12891-016-0876-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Osteoarthritis (OA) is a whole joint disease characterized by cartilage degradation, which causes pain and disability in older adults. Our previous work showed that growth arrest and DNA damage-inducible protein 45 beta (GADD45 beta) is upregulated in chondrocyte clusters in OA cartilage, especially in the early stage of this disease. CCAAT/enhancer binding protein beta (C/EBP beta) is expressed in the hypertrophic growth plate chondrocytes and functions in synergy with GADD45 beta. Here, the presence and localization of these proteins was assessed by immunohistochemistry using articular cartilage from OA patients, revealing colocalization of C/EBP beta and GADD45 beta in OA chondrocytes. GADD45 beta promoter analysis was performed to determine whether C/EBP beta directly regulates GADD45 beta transcription. Furthermore, we analyzed the effect of C/EBP beta on Gadd45 beta gene regulation in articular chondrocytes in vivo and in vitro. Immunohistochemical analysis of C/ebp beta-haploinsufficient mice (C/ebp beta(+/-)) cartilage showed that C/ebp beta haploinsufficiency led to reduced Gadd45 beta gene expression in these cells. In vitro, we evaluated the effects of conditional C/EB1 beta overexpression driven by the cartilage oligomeric matrix protein (Comp) promoter in mComp-tTA;pTRE-Tight-BI-DsRed-mC/ebp beta transgenic mice. C/EBP beta overexpression significantly stimulated Gadd45 beta gene expression in articular chondrocytes. Taken together, our data demonstrate that C/EBPP plays a central role in controlling Gadd45 beta gene expression in these cells. (C) 2016 The Authors. Published by Elsevier GmbH.

DOI： 10.1016/j.prp.2016.01.009

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Language：Japanese   Publisher：The Japanese Society of Toxicology  

DOI： 10.14869/toxpt.43.1.0_S9-3

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Language：Japanese   Publisher：(一社)日本病理学会  

第三脳室脊索腫様膠腫の1例を報告する。症例は44歳女性。12年前に無月経、頭痛があり精査。第三脳室内腫瘤性病変を指摘され、生検されたが、炎症所見のみで確定診断には至らなかった。病変の増大を認めたため摘出された。組織学的に、粘液腫状基質や炎症細胞浸潤を伴った上皮様腫瘍細胞の増殖を認めた。免疫組織学的検討では腫瘍細胞はGFAP、Vimentinにびまん性に陽性でCD34に部分的に陽性、EMAに一部が弱陽性を示した。以上の所見から第三脳室脊索腫様膠腫と診断した。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Background: To effectively treat orthopaedic infections by methicillin-resistant strains, an early diagnosis is necessary. Bacterial cultures and real-time polymerase chain reaction (PCR) have been used to define methicillin-resistant staphylococci. However, even when patients display clinical signs of infections, bacterial culture and real-time PCR often cannot confirm infection. The aim of this study was to prospectively compare the utility of real-time PCR for the mecA gene detection following centrifugation of human samples with suspected orthopaedic infections. Results: In addition to the conventional real-time PCR method, we performed real-time PCR following centrifugation of the sample at 4,830xg for 10 min in a modified real-time PCR (M-PCR) method. We suspended cultured methicillin-resistant Staphylococcus aureus and generated standard dilution series for in vitro experiments. The in vitro detection sensitivity of the M-PCR method was approximately 5.06 times higher than that of the conventional real-time PCR method. We performed bacterial culture, pathological examination, real-time PCR, and M-PCR to examine the infectious fluids and tissues obtained from 36 surgical patients at our hospital. Of these, 20 patients who had undergone primary total hip arthroplasty were enrolled as negative controls. In addition, 15 patients were examined who were clinically confirmed to have an infection, including periprosthetic joint infection (eight patients), pyogenic spondylitis (two patients), infectious pseudoarthrosis (two patients), and after spine surgery (three patients). In one sample from a patient who developed infectious pseudoarthrosis and two samples from surgical site infections after spine surgery, the mecA gene was detected only by the M-PCR method. In one patient with infectious pseudoarthrosis, one patient with infection after arthroplasty, and two patients with purulent spondylitis, the detection sensitivity of the M-PCR method was increased compared with PCR (clinical sample average: 411.6 times). Conclusions: These findings suggest that the M-PCR method is useful to detect methicillin-resistant strains infections. In addition, the centrifugation process only takes 10 min longer than conventional real-time PCR methods. We believe that the M-PCR method could be clinically useful to detect orthopaedic infections caused by methicillin-resistant strains.

DOI： 10.1186/s13104-015-1180-2

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Language：Japanese   Publisher：(株)文光堂  

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Language：Japanese   Publisher：(株)文光堂  

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Language：Japanese   Publisher：(株)文光堂  

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Language：Japanese   Publisher：(株)文光堂  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Histamine is not only essential for acute inflammatory reactions, but it also participates in a chronic inflammatory disorder. We generated apolipoprotein E (apoE) and histamine receptors (HHRs), including the major H1 and H2 receptors (HH1R, HH2R) double knockout mice (DKO) to clarify the role of HHRs in hyperlipidemia-induced atherosclerosis, in which apoE-KO and DKO mice were fed a high cholesterol diet. We found that pronounced hyperlipidemia-induced atherosclerotic progression occurred in HH1R/apoE-DKO mice, but in HH2R/apoE-DKO mice less atherosclerosis, despite pro-atherogenic serum cholesterol levels compared with apoE-KO mice. Furthermore, the increased expressions of scavenger receptors (SRs), such as SR-A, CD36 and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), nuclear factor-kappa B (NFB), monocyte chemoattractant protein (MCP-1), matrix metalloproteinases (MMPs) or liver X receptor (LXR)-related inflammatory signaling factors, were consistent with the pro-atherogenic phenotype of HH2R/apoE-DKO mice. We hypothesize that histamine/HH1R and HH2R signaling has conflicting innate functions, inflammatory/atherogenic and anti-inflammatory/anti-atherogenic actions, and that there are innate links between histamine signaling and hyperlipidemia-induced atherosclerosis, independently of serum cholesterol metabolism. Specific histamine signaling blockers, in particular, HH2R blockers, are a possible novel therapeutic target for hyperlipidemia-induced atherosclerosis.

DOI： 10.1111/pin.12246

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE PHARMACOLOGICAL SOC  

Nitric oxide (NO) is synthesized by three distinct NO synthases (neuronal, inducible, and endothelial NOSs), all of which are expressed in almost all tissues and organs in humans. The regulatory roles of NOSs in vivo have been investigated in pharmacological studies with non-selective NOS inhibitors. However, the specificity of the inhibitors continues to be an issue of debate, and the authentic significance of NOSs is still poorly understood. To address this issue, we generated mice in which all three NOS genes are completely disrupted. The triple NOSs null mice exhibited cardiovascular abnormalities, including hypertension, arteriosclerosis. myocardial infarction, cardiac hypertrophy, diastolic heart failure, and reduced EDHF responses, with a shorter survival. The triple NOSs null mice also displayed metabolic abnormalities, including metabolic syndrome and high-fat diet-induced severe dyslipidemia. Furthermore, the triple NOSs null mice showed renal abnormalities (nephrogenic diabetes insipidus and pathological renal remodeling), lung abnormalities (accelerated pulmonary fibrosis), and bone abnormalities (increased bone mineral density and bone turnover). These results provide evidence that NOSs play pivotal roles in the pathogenesis of a wide variety of disorders. This review summarizes the latest knowledge on the significance of NOSs in vivo, based on lessons learned from experiments with our triple mutant model. (C) 2015 Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.

DOI： 10.1016/j.jphs.2014.10.002

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

We investigated changes in the peripheral plasma concentrations of ovarian steroids and gonadotropins throughout the estrous cycle of the Microminipig (MMpig), a novel experimental animal model. The mean (+/- standard error of the mean (SEM)) duration of estrous and the estrous cycle in seven animals was 66.0 +/- 5.2 h and 20.6 +/- 0.3 days, respectively. A luteinizing hormone (LH) surge was observed 16.5 +/- 6.5 h after the onset of estrous in six out of the seven animals. The LH peak and the duration of the LH surge were 14.0 +/- 4.5 ng/ml and 34.0 +/- 2.0 h, respectively. Plasma progesterone concentrations started to decline on Day 7 (Day 0 = the day of the LH peak) and increased from Day 4. Estradiol-17 beta levels increased from Day 3 and reached a maximum (37.0 +/- 1.6 pg/ml) on Day 0.75. Follicle-stimulating hormone (FSH) concentrations showed a first and second surge on Days 0 and 1.75. An inverse relationship between FSH and estradiol-17 beta concentrations was noted before the LH surge. The characteristics of estrous and the gonadotropin and ovarian steroid profiles throughout the estrous cycle of MMpigs are similar to those of domestic pigs and other miniature pig strains.

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

We investigated changes in the peripheral plasma concentrations of ovarian steroids and gonadotropins throughout the estrous cycle of the Microminipig (MMpig), a novel experimental animal model. The mean (+/- standard error of the mean (SEM)) duration of estrous and the estrous cycle in seven animals was 66.0 +/- 5.2 h and 20.6 +/- 0.3 days, respectively. A luteinizing hormone (LH) surge was observed 16.5 +/- 6.5 h after the onset of estrous in six out of the seven animals. The LH peak and the duration of the LH surge were 14.0 +/- 4.5 ng/ml and 34.0 +/- 2.0 h, respectively. Plasma progesterone concentrations started to decline on Day 7 (Day 0 = the day of the LH peak) and increased from Day 4. Estradiol-17 beta levels increased from Day 3 and reached a maximum (37.0 +/- 1.6 pg/ml) on Day 0.75. Follicle-stimulating hormone (FSH) concentrations showed a first and second surge on Days 0 and 1.75. An inverse relationship between FSH and estradiol-17 beta concentrations was noted before the LH surge. The characteristics of estrous and the gonadotropin and ovarian steroid profiles throughout the estrous cycle of MMpigs are similar to those of domestic pigs and other miniature pig strains.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

We investigated the effect of subtotal nephrectomy on the incidence of acute myocardial infarction (AMI) in mice deficient in all three nitric oxide synthases (NOSs). Two-thirds nephrectomy (NX) was performed on male triple NOSs(-/-) mice. The 2/3NX caused sudden cardiac death due to AMI in the triple NOSs(-/-) mice as early as 4 months after the surgery. The 2/3NX triple NOSs(-/-) mice exhibited electrocardiographic ST-segment elevation, reduced heart rate variability, echocardiographic regional wall motion abnormality, and accelerated coronary arteriosclerotic lesion formation. Cardiovascular risk factors (hypertension, hypercholesterolemia, and hyperglycemia), an increased number of circulating bone marrow-derived vascular smooth muscle cell (VSMC) progenitor cells (a pro-arteriosclerotic factor), and cardiac up-regulation of stromal cell-derived factor (SDF)-1 alpha (a chemotactic factor of the progenitor cells) were noted in the 2/3NX triple NOSs(-/-) mice and were associated with significant increases in plasma angiotensin II levels (a marker of renin-angiotensin system activation) and urinary 8-isoprostane levels (a marker of oxidative stress). Importantly, combined treatment with a clinical dosage of an angiotensin II type 1 receptor blocker, irbesartan, and a calcium channel antagonist, amlodipine, markedly prevented coronary arteriosclerotic lesion formation and the incidence of AMI and improved the prognosis of those mice, along with ameliorating all those pro-arteriosclerotic parameters. The 2/3NX triple NOSs(-/-) mouse is a new experimentally useful model of AMI. Renin-angiotensin system activation, oxidative stress, cardiovascular risk factors, and SDF-1 alpha-induced recruitment of bone marrow-derived VSMC progenitor cells appear to be involved in the pathogenesis of AMI in this model. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.yjmcc.2014.09.021

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

The microminipig, which weighs less than 10 kg at an early stage of maturity, has been reported as a potential experimental model animal. Its extremely small size and other distinct characteristics suggest the possibility of a number of differences between the genome of the microminipig and that of conventional pigs. In this study, we analyzed the genomes of two healthy microminipigs using a next-generation sequencer SOLiD (TM) system. We then compared the obtained genomic sequences with a genomic database for the domestic pig (Sus scrofa). The mapping coverage of sequenced tag from the microminipig to conventional pig genomic sequences was greater than 96% and we detected no clear, substantial genomic variance from these data. The results may indicate that the distinct characteristics of the microminipig derive from small-scale alterations in the genome, such as Single Nucleotide Polymorphisms or translational modifications, rather than large-scale deletion or insertion polymorphisms. Further investigation of the entire genomic sequence of the microminipig with methods enabling deeper coverage is required to elucidate the genetic basis of its distinct phenotypic traits.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background and Aim: We previously identified an anti-inflammatory compound, zonarol, a hydroquinone isolated from the brown algae Dictyopteris undulata as a marine natural product. To ascertain the in vivo functions of zonarol, we examined the pharmacological effects of zonarol administration on dextran sulfate sodium (DSS)-induced inflammation in a mouse model of ulcerative colitis (UC). Our goal is to establish a safe and effective cure for inflammatory bowel disease (IBD) using zonarol.
Methods and Results: We subjected Slc:ICR mice to the administration of 2% DSS in drinking water for 14 days. At the same time, 5-aminosalicylic acid (5-ASA) at a dose of 50 mg/kg (positive control) and zonarol at doses of 10 and 20 mg/kg, were given orally once a day. DSS-treated animals developed symptoms similar to those of human UC, such as severe bloody diarrhea, which were evaluated by the disease activity index (DAI). Treatment with 20 mg/kg of zonarol, as well as 5-ASA, significantly suppressed the DAI score, and also led to a reduced colonic ulcer length and/or mucosal inflammatory infiltration by various immune cells, especially macrophages. Zonarol treatment significantly reduced the expression of pro-inflammatory signaling molecules, and prevented the apoptosis of intestinal epithelial cells. Finally, zonarol protected against in vitro lipopolysaccharide (LPS)-induced activation in the RAW264.7 mouse macrophage cell line.
Conclusions: This is the first report that a marine bioproduct protects against experimental UC via the inhibition of both inflammation and apoptosis, very similar to the standard-of-care sulfasalazine, a well-known prodrug that releases 5-ASA. We believe that the oral administration of zonarol might offer a better treatment for human IBDs than 5-ASA, or may be useful as an alternative/additive therapeutic strategy against UC, without any evidence of side effects.

DOI： 10.1371/journal.pone.0113509

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE PHARMACOLOGICAL SOC  

Metabolic syndrome (MetS) induces serious complications; therefore, we developed a noninvasive MetS model using an extremely small minipig, the Microminipig. For 8 weeks, Microminipigs were administrated a high-fat and high-cholesterol diet (HFCD) for atherosclerosis and N-G-nitro-L-arginine methyl ester (L-NAME) for inhibiting nitric oxide synthase. HFCD significantly increased serum low-density lipoprotein levels, L-NAME increased blood pressure and cardiac hypertrophy, and HFCD-induced aortal arteriosclerosis was accelerated by L-NAME administration. Endothelium-dependent relaxation of the coronary artery was remarkably decreased by L-NAME administration. This model may be useful for elucidating the mechanisms of MetS and developing new therapeutic medicines for its treatment.

DOI： 10.1254/jphs.14171SC

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

Castleman's disease in the pelvic cavity is rare. We present a 72-year-old woman with hyaline vascular type of Castleman's disease of the right ovary. Right ovarian enlargement was detected in the medical examination. Computed tomography revealed a solid mass, measured 2.5 cm in size, in the right ovary. A bilateral salpingo-oophorectomy was performed. Morphologically, lymphoid follicles with regressed germinal centers (GCs) were surrounded by a broad mantle zone composed of concentric rings of small lymphocytes, and the hyalinized blood vessels with plump endothelial cells penetrated radially into GCs. Proliferation of follicular dendritic cells, which were positive for CD21 and epidermal growth factor receptor, were detected in GCs and mantle zone. No other lesions were found. To the best of our knowledge, this is the first case of hyaline vascular type of Castleman's disease of ovarian primary.

DOI： 10.1177/1066896913517936

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

The PCP4/PEP19 is a calmodulin-binding anti-apoptotic peptide in neural cells but its potential role in human cancer has largely been unknown. We investigated the expression of PCP4/PEP19 in human breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 cells, and found that estrogen receptor (ER)-positive MCF-7 and ER-negative SK-BR-3 cells expressed PCP4/PEP19. In the MCF-7 cells, cell proliferation was estrogen-dependent, and PCP4/PEP19 expression was induced by estrogen. In both cell lines, PCP4/PEP19 knockdown induced apoptosis and slightly decreased Akt phosphorylation. Knockdown of calcium/calmodulin-dependent protein kinase kinase 1 (CaMKK1), resulting in decreased phospho-Akt(Thr308), enhanced apoptosis in SK-BR-3 but not in MCF-7 cells. CaMKK2 knockdown moderately decreased phospho-Akt(Thr308) and increased apoptosis in MCF-7 cells but not in SK-BR-3 cells. These data indicated that PCP4/PEP19 regulates apoptosis but exact mechanism is still unknown. PCP4/PEP19 can therefore potentially serve as independent oncotarget for therapy of PCP4/PEP19-positive breast cancers irrespective of ER expression.

DOI： 10.18632/oncotarget.2161

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Neurofibromatosis Type 1 (NF1) is a relatively common autosomal dominant disorder. Vascular involvement is a well-recognized manifestation of NF1, but venous aneurysm associated with NF1 is extremely rare. We present a case of an NF1 patient with a left internal jugular vein aneurysm with massive hemorrhage occurring during surgery. Due to the extreme fragility of both the aneurismal wall and the surrounding tissue, the patient developed severe intraoperative bleeding. Pathological examination confirmed aneurismal wall infiltration of the neurofibromatosis. Physicians should be aware that hemorrhagic complication in NF1 can occur and be fatal. (C) 2014 The Authors. Published by Elsevier Inc.

DOI： 10.1016/j.carpath.2014.02.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

A novel microminipig has been recently developed for use in biomedical research. In the present study, age- and sex-related differences, as well as 24-h fluctuations in plasma total homocysteine concentrations (tHcy), were investigated in these microminipigs. tHcy (mean +/- SD) was 10.2 +/- 3.4 mu M and significantly correlated with age. By contrast, neither the differences in tHcy between sexes nor the 24-h fluctuations in tHcy after feeding were significant. The kinetics of plasma tHcy after intravenous injection of reduced Hcy showed that its levels peaked within 5 min post-injection, as did the levels of tHcy. These results suggested that reduced Hcy is rapidly oxidized or metabolized. The half-lives of reduced Hcy, tHcy, and reduced cysteine in the blood were 47, 71, and 141 min, respectively. In conclusion, there was a significantly positive correlation between age and plasma tHcy in microminipigs. After intravenous injection of reduced Hcy, plasma tHcy quickly returned to pre-injection levels.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Metastasis to the breast from nonmammary malignancies is rare, and mostly involves patients in a pre-terminal condition with systemic metastases outside the breast. Lymphoma and leukemia, melanoma, and lung carcinoma are the most common primary malignancies to cause breast metastasis; metastasis of soft tissue sarcoma to the breast is very rare. Here, we report a case of primary lower-extremity myxoid liposarcoma with the development of a solitary metastasis to the breast. To the best of our knowledge, no isolated case reports of solitary breast metastasis by myxoid liposarcoma have been previously reported in the English-language literature.
Case presentation: The patient, a 66-year-old woman, had been previously diagnosed with myxoid liposarcoma of the right thigh. At 21 months after complete surgical resection of the primary tumor with negative margins, a palpable tumor was identified in the patient's left breast. Needle biopsy revealed the presence of metastatic liposarcoma; positron emission tomography/computed tomography examination confirmed the metastasis as solitary, and no local recurrence of the primary tumor was identified. The patient underwent lumpectomy with negative margins and did not provide consent for adjuvant chemotherapy. As with the biopsy specimen and the total cleavage specimen, myxoid liposarcoma with metastasis to the breast was diagnosed. No recurrence or new metastases were observed five years after resection of the metastatic breast lesion.
Conclusions: We have presented an extremely rare case of a solitary metastatic breast tumor arising from myxoid liposarcoma of the lower limbs. There is no standard treatment for the management of solitary breast metastasis from myxoid liposarcoma. Therefore, treatment should be guided by consideration of an individual patient's overall condition.

DOI： 10.1186/1471-2407-14-482

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Metastasis of a primary osteosarcoma to the muscles is extremely rare. As there have been few reported cases, the necessity of surgical treatment for such metastatic lesions remains controversial. We present the case of a primary osteosarcoma with development of a solitary metastasis to the trapezius muscle during chemotherapy for pulmonary metastasis. The patient was a 51-year-old man diagnosed with osteosarcoma of the right tibia. After undergoing chemotherapy and femoral amputation, he developed pulmonary metastasis. Chemotherapy was reinitiated, however, after approximately 1 year a palpable tumor was identified in the patient's right shoulder. This tumor grew and was associated with pain in the right shoulder. It was surgically removed 3 years after the reinitiation of chemotherapy. The pathological diagnosis was osteosarcoma with metastasis to the trapezius muscle. Although the patient died of respiratory failure due to pulmonary metastasis 14 months after resection of the metastatic lesion in the trapezius muscle, no new extrapulmonary metastasis was observed after the resection.

DOI： 10.1186/1477-7819-12-176

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Language：Japanese   Publisher：(株)文光堂  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Abcb10, member 10 of the ABC transporter family, is reportedly a part of a complex in the mitochondrial inner membrane with mitoferrin-1 (Slc25a37) and ferrochelatase (Fech) and is responsible for heme biosynthesis in utero. However, it is unclear whether loss of Abcb10 causes pathological changes in adult mice. Here, we show that Abcb10(-/-) mice lack heme biosynthesis and erythropoiesis abilities and die in midgestation. Moreover, we generated Abcb10(F/-); Mx1-Cre mice, with Abcb10 in hematopoietic cells deleted, which showed accumulation of protoporphyrin IX and maturation arrest in reticulocytes. Electron microscopy images of Abcb10(-/-) hematopoietic cells showed a marked increase of iron deposits at the mitochondria. These results suggest a critical role for Abcb10 in heme biosynthesis and provide new insights into the pathogenesis of erythropoietic protoporphyria and sideroblastic anemia.

DOI： 10.1128/MCB.00865-13

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase (MAP3K), is ubiquitously expressed and situated in an important upstream position of many signal transduction pathways. ASK1 plays a pivotal role in stressor-induced cell survival and inflammatory reactions. To ascertain the regulatory functions of ASK1 in bite duct ligation (BDL)-induced liver injury, we examined the net effects of ASK1 depletion on hepatic necroinflammation and/or fibrosis. We subjected C57BL/6 wild-type (WT) or ASK/-deficient (ASK(-/-)) mice to sham or BDL surgery for 14 days. In day 3 BDL animals, ASK(-/-) mice had significantly fewer bile infarcts along with more reduced interlobular or portal inflammatory infiltrate of various immune cells, including neutrophils, compared with WT mice in which ASK1 expression was markedly activated. Morphologically apoptotic hepatocytes or cholangiocytes were negligible in both the sham and BDL animals. In contrast, ASK(-/-) mice had significantly less proliferating activity of not only hepatocytes but also large cholangiocytes than WT mice. Day 14 BDL ASK(-/-) mice manifested potential antifibrogenic aspects of ASK1 deficiency, characterized by significantly fewer activated peribitiary fibrogenic cells and petibitiary fibrosis. These observations indicate that ASK1-mediated hepatic necroinfiammation and proliferation, but not apoptosis, are closely linked to Liver fibrosis and fibrogenesis. A specific ASK1 pathway blocker or inhibitor might offer a therapeutic strategy against human cholestatic diseases.

DOI： 10.1016/j.ajpath.2013.11.030

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Recently we established a Microminipig (MMPig) model of atherosclerosis induced by high fat/high cholesterol (Cho) diet containing sodium cholate (SC), which is known to cause hepatotoxicity. In the present study, we investigated whether SC is necessary as well as the minimum amount of dietary Cho required to induce atherosclerosis. Experiment A: Six MMPigs were divided into three groups of two, and were fed for 12 weeks as follows: a diet containing 12% fat and 5% Cho with or without 0.7% SC, or the diet including 12% fat and 0.5% Cho with SC. Although each diet induced a similar degree of hypercholesterolemia and atherosclerosis, the liver weights and severity of fatty change in the hepatocytes were maximal in the animals fed 5% Cho and SC. Experiment B: Six MMPigs were divided into two groups of three, and fed for 18 weeks as follows: normal diet, and a diet of increasing dose of Cho (0.03, 0.1, 0.3, 0.5, 1.5 and 5%) for the initial 14 weeks and 0.5% Cho/12% fat diet for the final four weeks. Serum levels of total Cho and low-density lipoprotein-Cho reached a plateau with 0.5% Cho diet, suggesting that the minimum amount of Cho required is 0.5%. The absorption of Cho in MMPigs was enhanced by 0.5% Cho and 12% fat diet compared to the 5% Cho-alone diet. In conclusion, a diet with 0.5% Cho and 12% fat without SC appears to be sufficient to induce atherosclerosis in the MMPig.

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Nitric Oxide (NO) exerts a variety of biological actions under both physiological and pathological conditions. NO is synthesized by three distinct NO synthase (NOS) isoforms, encoded by three distinct NOS genes, including neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS), all of which are expressed in the human vascular system. Although the roles of the NOSs in arteriosclerotic vascular diseases have been described in pharmacological studies with selective and non-selective NOS inhibitors, the selectivity and specificity of the NOS inhibitors continue to be an issue of debate. To solve this issue, genetically altered animals have been established. All types of NOS gene-deficient animals have been developed, including singly, doubly, and triply NOS-deficient mice and various types of NOS Gene-Transgenic (TG) animals have also been generated, including conditional and non-conditional TG mice bearing site-specific overexpression of each NOS gene. The roles of individual NOS isoforms as well as the entire NOSs system in arteriosclerotic vascular diseases have been extensively investigated in those mice, providing pivotal insights into an understanding of the pathophysiological significance of the NOSs in human arteriosclerotic vascular diseases. The present review, which is based on studies with the murine NOS genetic models, summarizes the latest knowledge about the NOSs and arteriosclerotic vascular diseases. © 2014 Tsutsui M, et al.

DOI： 10.4172/2155-9880.1000318

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ATHEROSCLEROSIS SOC  

Aim: Experimental studies of human atherogenesis require an appropriate animal model that mimics human physiology and pathology. Because swine physiology is similar to human physiology, we developed a hyperlipidemia-induced atherosclerosis model using the recently developed world's smallest Microminipig (TM).
Methods: These animals weigh only 5 kg at 3 months of age, much smaller than any other miniature pig. We found that the administration of a high-fat/high-cholesterol diet containing at least 0.2% cholesterol without cholic acid for as little as eight weeks induces hypercholesterolemia and subsequent atherosclerosis in these animals.
Results: The serum levels of low-density lipoprotein cholesterol (LDL-C) and the percent distribution of cholesterol in the LDL fractions were markedly increased. The hepatic expression of LDL receptor and hydroxymethylglutaryl-CoA reductase was coordinately decreased. The cholesteryl ester transfer protein activity, which plays a role in reverse cholesterol transport, was detected in the serum of the Microminipigs. Niemann-Pick C1-like 1 protein was expressed in both the liver and small intestine; however, hepatic apoB mRNA editing enzyme was not expressed. As in humans, and in contrast to that observed in mice, most of the hepatic lipase activity was localized in the liver. These results suggest that the hyperlipidemia-induced gene expression profile linked to cholesterol homeostasis and atherogenesis is similar in Microminipigs and humans.
Conclusion: We conclude that the characteristics of the Microminipig, including its easy handling size, make it an appropriate model for studies of atherosclerosis and related conditions.

DOI： 10.5551/jat.21246

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Proliferation of non-neoplastic striated muscle cells in the lung is rare and has been frequently observed in cases of cardiovascular and pulmonary congenital malformations. We present an extremely rare case of pulmonary rhabdomyomatous dysplasia (RD) in neurofibromatosis type 1 (NF-1). A male neonate was born at 35 weeks' gestation after normal pregnancy. Postnatally, besides patent ductus arteriosus and posterior mediastinal mass, abnormal cystic lesions in the left upper and lower lung were detected. No bronchial atresia and stenosis were identified. Partial lobectomy specimens showed hypoplastic lung parenchyma with cystic lesions resembling terminal bronchioles and distinctive proliferation of non-neoplastic striated muscle fibers in the interstitium. The posterior mediastinal mass consisted of neurofibroma. Considering that cafe au lait spots and freckling occurred at 2 months of age, a diagnosis of NF-1 was made. The patient died of aspiration pneumonia at the age of 30 months. To the best of our knowledge, this is the first case of pulmonary RD in NF-1. (C) 2013 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2013.10.008

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Language：English   Publishing type：Research paper (scientific journal)  

Aims: Consumption of a high-fructose diet (HFrD) can induce the development of a metabolic syndrome, manifesting as nonalcoholic steatohepatitis (NASH) and/or type 2 diabetes mellitus (T2DM), via a process in which oxidative stress plays a critical role. Peroxiredoxin 4 (PRDX4) is a unique and only known secretory member of the PRDX antioxidant family. However, its putative roles in the development of NASH and/or T2DM have not been investigated. Results: To elucidate the functions of PRDX4 in a metabolic syndrome, we established a nongenetic mouse model of T2DM by feeding mice a HFrD after injecting a relatively low dose of streptozotocin. Compared with wild-type (WT), human PRDX4 transgenic (Tg) mice exhibited significant improvements in insulin resistance, characterized by a lower glucose and insulin concentration and faster responses in glucose tolerance tests. The liver of Tg also showed less severe vesicular steatosis, inflammation, and fibrosis, along with lower lipid concentrations, lower levels of oxidative stress markers, more decreased expression of hepatic aminotransferase, and more reduced stellate cell activation than those in the WT liver, reminiscent of human early NASH. Hepatocyte apoptosis was also significantly repressed in Tg mice. By contrast, serum adiponectin levels and hepatic adiponectin receptor expression were significantly lower in WT mice, consistent with greater insulin resistance in the peripheral liver tissue compared with Tg mice. Innovation and Conclusion: Our data for the first time show that PRDX4 may protect against NASH, T2DM, and the metabolic syndrome by ameliorating oxidative stress-induced injury. Antioxid. Redox Signal. 19, 1983-1998. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

DOI： 10.1089/ars.2012.4946

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Histamine is synthesized as a low-molecular-weight amine from L-histidine by histidine decarboxylase (HDC). Recently, we demonstrated that carotid artery-ligated HDC gene-deficient mice (HDC-/-) showed less neointimal formation than wild-type (WT) mice, indicating that histamine participates in the process of arteriosclerosis. However, little is known about the roles of histamine-specific receptors (HHRs) in arteriosclerosis. To define the roles of HHRs in arteriosclerosis, we investigated intimal remodeling in ligated carotid arteries of HHR-deficient mice (H1R(-/-) or H2R(-/-)). Quantitative analysis showed that H1R(-/-) mice had significantly less arteriosclerogenesis, whereas H2R(-/-) mice had more, as compared with WT mice. Bone marrow transplantation from H1R(-/-) or H2R(-/-) to WT mice confirmed the above observation. Furthermore, the increased expression of monocyte chemoattractant protein (MCP-1), platelet-derived growth factor (PDGF), adhesion molecules and liver X receptor (LXR)-related inflammatory signaling factors, including Toll-like receptor (TLR3), interleukin-1 receptor (IL-1R) and tumor necrosis factor receptor (TNF-R), was consistent with the arteriosclerotic phenotype of H2R(-/-) mice. Peripheral progenitor cells in H2R(-/-) mice accelerate ligation-induced arteriosclerosis through their regulation of MCP-1, PDGF, adhesion molecules and LXR-related inflammatory signaling factors. In contrast, peripheral progenitor cells act to suppress arteriosclerosis in H1R(-/-) mice, indicating that HHRs reciprocally regulate inflammation in the ligation-induced arteriosclerosis.

DOI： 10.1111/pin.12091

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Swine have been used extensively in biomedical research, with a significant increase in recent decades. Minipigs are increasingly becoming an especially attractive animal model in life science research because of their physiological and anatomical similarities to humans. The Microminipig (MMPig) has emerged as a novel and small minipig for non-clinical pharmacological/toxicological use. The MMPig is docile, weighs less than 10 kg in early maturity, and has an easily manageable size. In this study, we report on sex and age patterns in serum biochemistry parameters, including lipid analysis items and lipid profiles in healthy MMPigs. In total, 58 males and 67 females aged 034 months underwent serum biochemistry parameter measurements. Most parameters showed no effect of age or sex (although some did). Lipid analyses showed that the serum levels of total cholesterol, but not those of triglycerides (TG), were consistently higher in females at 0-34 months of age. Lipid profiles in 5-month-old MMPigs were investigated in greater detail. Serum low-density lipoprotein-cholesterol (LDL-C) values were higher in females. The percentage of LDL-C against total cholesterol was also higher, although high-density lipoprotein-cholesterol was lower, in females. There were no sex differences in the TG fraction. Although the sex difference in the serum lipid profile remains unexplained, the reference values obtained in this study could help facilitate the use of MMPigs in life science research.

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Publisher：日本外科系連合学会  

症例は63歳女性.4年前,前医における尿路結石診断のためのCT検査にて,左腸骨前面に存在する2cm大の腫瘍を指摘されていた.徐々に増大してきたため当科紹介となった.左腸骨前面に接する4cm大の腫瘍を認めたが,経過ならびにCT・MRI検査にて積極的に悪性の所見を認めないことから骨盤内良性後腹膜腫瘍の術前診断にて,腹腔鏡下に腫瘍摘出術を施行した.特に周囲への癒着・浸潤はなく,腫瘍は完全に切除しえた.切除標本の病理組織学的診断にて,紡錘形の大型核多形性細胞を混在する腫瘍が束状増殖しており,免疫染色も併施し平滑筋肉腫と診断した.後腹膜腫瘍は症状もなく,CT検査にて偶然発見されることも多く,良悪性の術前診断に苦慮する場合も少なくない.画像診断の進歩により,比較的小さな腫瘍径で診断された後腹膜腫瘍は腹腔鏡下に安全かつ低侵襲に切除が可能であるが,悪性腫瘍を念頭においた完全切除が重要である.(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J01066&link_issn=&doc_id=20130904230035&doc_link_id=10.4030%2Fjjcs.38.909&url=https%3A%2F%2Fdoi.org%2F10.4030%2Fjjcs.38.909&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Paratesticular liposarcoma is a rare neoplasm, described in single case studies or components of larger studies, as histologically well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DL). However, leiomyosarcomatous differentiation is an extremely rare occurrence in WDL and DL. We report a case of leiomyosarcomatous differentiation in a 77-year-old man. The patient presented with a painless right scrotal mass. Magnetic resonance imaging showed a large mass along the right spermatic cord. The resected mass, measuring 17.5 x 12 x 5 cm, was composed of a high-grade pleomorphic undifferentiated sarcomatous component with necrosis. Atypical smooth muscle differentiation was also detected. Additional tumor sampling revealed the presence of a WDL component. Immunohistochemical analysis of the pleomorphic sarcomatous component showed positive staining for MDM2 and CDK4, and negative staining for alpha smooth muscle actin (alpha SMA) and desmin. The smooth muscle component was positive for alpha SMA and desmin, and negative for MDM2 and CDK4. Extension from primary retroperitoneal sarcoma was not proved. We diagnosed of DL with leiomyosarcomatous differentiation.

DOI： 10.1186/1746-1596-8-142

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

Background: Hormone replacement therapy has failed to reduce ischemic cardiovascular events in climacteric women. To explore alternative therapy, we examined whether san'o-shashin-to (TJ-113), a kampo medicine, ameliorates cardiac ischemia-reperfusion (IR) injury in a climacteric rat model.
Methods and Results: Cardiac function and infarct size after IR were significantly exacerbated in ovariectomized rats as compared with sham-operated rats, whereas long-term treatment with a clinical dosage of TJ-113 for 4 weeks markedly improved these functional and morphological changes. Myocardial inducible nitric oxide synthase (iNOS) expression and peroxynitrite levels were significantly higher in ovariectomized rats compared with sham-operated rats, and long-term TJ-113 treatment significantly reduced these oxidative changes. Furthermore, myocardial manganese superoxide dismutase (Mn-SOD) activity was significantly lower in ovariectomized than in sham-operated rats, and long-term TJ-113 treatment significantly restored antioxidant activity. Importantly, those beneficial actions of TJ-113 were significantly inhibited by the estrogen receptor antagonist, fulvestrant, and the phytoestrogen, emodin, a TJ-113 ingredient, mimicked the actions of TJ-113, suggesting involvement of emodin in the effects of TJ-113.
Conclusions: These results provide the first evidence that long-term treatment with a clinical dosage of TJ-113 markedly ameliorates cardiac IR injury in ovariectomized rats via inhibition of iNOS expression, suppression of peroxynitrite formation, and restoration of Mn-SOD activity. TJ-113 may be a novel therapeutic option in the treatment of ischemic heart disease in climacteric women.

DOI： 10.1253/circj.CJ-12-1434

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Swine are becoming increasingly attractive as animal models for clinical research and the recently developed Microminipig (MMPig) has emerged as a possible experimental animal model. In this study, we demonstrated age-dependent changes in hematological parameters and coagulation activity in healthy MMPigs (58 male and 67 females, aged 0-34 months), and investigated white thrombus formation (WTF) using an in vitro microchip flow-chamber system (four males and four females, aged 22-23 months). There was no clear sex or age-dependent differences in any hematological parameters. While activated partial thromboplastin time (APTT) was shorter than prothrombin time (PT), with APTT:PT of 0.88:1, microchip flow-chamber system analysis showed that WTF time was shorter than that in humans, suggesting a possible thrombotic tendency in the MMPig. These results could be useful to life science researchers in the use of the MMPig as an experimental model animal for thrombus formation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Children with short bowel syndrome face life-threatening complications. Therefore, there is an urgent need for a new therapy to induce effective adaptation of the remnant intestine. Adaptation occurs only during feeding. We focused on preprandial acyl ghrelin and des-acyl ghrelin, and postprandial glucagon-like peptide-2 (GLP-2), which are known to have active orexigenic and trophic actions. This study aims to clarify the secretion trends of these hormones after massive small bowel resection and to obtain basic data for developing a new treatment. Sixty-three growing male rats were used: 3 were designated as controls receiving no operation and 60 were randomized into the 80% small bowel resection (80% SBR) group and the transection and re-anastomosis group. Changes in body weight, food intake, and remnant intestine morphology were also assessed for 15 days after the operation. Acyl ghrelin and des-acyl ghrelin levels increased immediately, equivalently in both operation groups (P = 0.09 and 0.70). Interestingly, in 80% SBR animals, des-acyl ghrelin peaked on day 1 and acyl ghrelin peaked on day 4 (P = 0.0007 and P = 0.049 vs controls). GLP-2 secretion was obvious in 80% SBR animals (P = 2.25 x 10(-6)), which increased immediately and peaked on day 4 (P = 0.009 vs. controls). Body weight and food intake in 80% SBR animals recovered to preoperative levels on day 4. Morphological adaptations were evident after day 4. Our results may suggest a management strategy to reinforce these physiological hormone secretion patterns in developing a new therapy for short bowel syndrome. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.peptides.2013.03.006

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Publisher：医学図書出版(株)  

症例は73歳女性。黄疸を指摘され当院受診。胸腹部造影CTにて総胆管と膵管の拡張と完全内臓逆位を認めた。上部消化管内視鏡検査では十二指腸乳頭部に表面不整で発赤腫大した易出血性の腫瘍を認めた。生検にて十二指腸乳頭部癌と診断し、亜全胃温存膵頭十二指腸切除術(Child変法再建)を施行した。病理検査所見にてtubular adenocarcinoma、pT3N0M0であった。術後4年3ヵ月無再発生存中である。内臓逆位症は内臓の一部または全部が左右逆転し正常位に対して鏡面的位置関係にある比較的まれな先天疾患であるが、それ自体に病的意義はないといわれている。悪性疾患合併の報告も散見されるが、高難度手術の一つである膵頭十二指腸切除施行例の報告は極めて少ない。今回われわれは完全内臓逆位症に合併した十二指腸乳頭部癌に対して、安全に膵頭十二指腸切除術を遂行し得たので、若干の文献的考察を加えて報告する。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Apoptosis signal regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a crucial role in stress-induced apoptosis. Recently, we have reported that suppressed macrophage apoptosis in ASK1 and apolipoprotein E double-knockout mice accelerates atheromatous plaques in the hyperlipidemia-induced atherosclerotic model. However, the pathogenic role of smooth muscle cell (SMC) apoptosis in atherosclerosis still remains unclear. We investigated neointimal remodeling in ligated carotid arteries of ASK1-deficient mice (ASK1(-/-)) for 3 weeks. ASK1(-/-) mice had significantly more suppressed intimal formation, inversely manifesting as potential anti-atherogenic aspects of ASK1 deficiency, characterized by fewer SMCs and Less collagen synthesis; and fewer apoptotic SMCs, infiltrating T lymphocytes, and microvessels, associated with decreased apoptosis of Luminal endothelial cells, compared with those of wild-type mice. Injured arteries of ASK1(-/-) mice also showed significantly down-regulated expression of pro-apoptotic markers, adhesion molecules, and pro-inflammatory signaling factors. Moreover, tumor necrosis factor-alpha-induced apoptosis was markedly suppressed in cultured aortic SMCs from ASK1(-/-) mice. These findings suggest that ASK1 accelerates mechanical injury-induced vascular remodeling with activated SMC migration via increased neovascularization and/or enhanced SMC and endothelial cell apoptosis. ASK1 expression, especially in the SMCs, might be crucial, and reciprocally responsible for various pro-atherogenic functions, and SMC apoptosis seems to be detrimental in this model. (Am J Pathol 2013, 182: 597-609; http://dx.doi.org/10.1016/j.ajpath.2012.10.008)

DOI： 10.1016/j.ajpath.2012.10.008

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

The authors evaluated dermal phototoxicity using the world smallest minipig (MMPig: Microminipig). MMPigs were administered 100 mg/kg ciprofloxacin hydrochloride with an infusion pump. The dorsal area of each animal was irradiated with ultraviolet-A irradiation. The left dorsal skin was irradiated at intensities of 5, 10, 15, and 20 J/cm(2), and the right dorsal back skin was set as a nonirradiated site. Gross and histopathological examinations were conducted before irradiation and from 1 to 72 hr after irradiation. Initial changes in the skin were necrosis of the basal and/or prickle cell layer and cellular infiltration from 24 hr after irradiation. Vesicle formation observed from 48 hr after irradiation was considered similar to bullous eruptions, a known side effect of fluoroquinolones in humans. Therefore, the authors suggest that the MMPig may be a useful experimental animal model for dermal phototoxicity studies.

DOI： 10.1177/0192623312452489

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Language：English   Publisher：JAPANESE PHARMACOLOGICAL SOC  

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Language：Japanese   Publisher：(株)文光堂  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

Aim: A growing body of evidence has shown that increased formation of oxidized molecules and reactive oxygen species within the vasculature (i.e., the extracellular space) plays a crucial role in the initiation and progression of atherosclerosis and in the formation of unstable plaques. Peroxiredoxin 4 (PRDX4) is the only known secretory member of the antioxidant PRDX family. However, the relationship between PRDX4 and susceptibility to atherosclerosis has remained unclear. Results: To define the role of PRDX4 in hyperlipidemia-induced atherosclerosis, we generated hPRDX4 transgenic (Tg) and apolipoprotein E (apoE) knockout mice (hPRDX4(+/+)/apoE(-/-)). After feeding the mice a high-cholesterol diet, they showed fewer atheromatous plaques, less T-lymphocyte infiltration, lower levels of oxidative stress markers, less necrosis, a larger number of smooth muscle cells, and a larger amount of collagen, resulting in thickened fibrous cap formation and possible stable plaque phenotype as compared with apoE(-/-) mice. We also detected greater suppression of apoptosis and decreased Bax expression in hPRDX4(+/+)/apoE(-/-) mice than in apoE(-/-) mice. Bone marrow transplantation from hPRDX4(+/+) donors to apoE(-/-) mice confirmed the antiatherogenic aspects of PRDX4, revealing significantly suppressed atherosclerotic progression. Innovation: In this study, we demonstrated for the first time that PRDX4 suppressed the development of atherosclerosis in apoE(-/-) mice fed a high-cholesterol diet. Conclusion: These data indicate that PRDX4 is an antiatherogenic factor and, by suppressing oxidative damage and apoptosis, that it may protect against the formation of vulnerable (unstable) plaques. Antioxid. Redox Signal. 17, 1362-1375.

DOI： 10.1089/ars.2012.4549

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines and is synthesized by monocyte-derived macrophages and dendritic cells (DCs). In this study, we investigate the relationship between monocytes/macrophages and histamine in atherosclerosis and discover that histamine levels regulate various immunologically important molecules and influences atherosclerotic progression. Immunohistochemical analysis of human atherosclerotic lesions revealed that macrophages and DCs express CCL22. The human acute monocytic leukemia cell line (THP-1) adhered to culture plates and morphologically changed to macrophage-like cells when treated with tetradecanoylphorbol-13-acetate (TPA). Macrophage-like cells derived from THP-1 cells and cultivated peripheral blood mononuclear cells (PBMCs) show similar expression of CCL22. Gene expression of CCL22 was also detected in THP-1 cells treated with histamine and the expression of the protein produced by the CCL22 gene is similar in PBMCs and THP-1 cells. In addition, the histamine H2 receptor mediated these reactions. Our results suggest that CCL22 expression in monocytes is regulated by histamine, and that CCL22 is involved centrally in the development of human atherosclerotic lesions. In conclusion, CCL22 is a marker that is a characteristic of the monocytes/ macrophages migrating into atherosclerotic lesions and histamine plays a role in regulating its expression.

DOI： 10.1111/j.1440-1827.2012.02854.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

BACKGROUND: The one-step nucleic acid amplification (OSNA) assay is a rapid procedure for the detection of lymph node (LN) metastases using molecular biological techniques. The aim of this study was to assess the reliability of the whole sentinel lymph node (SLN) analysis by the OSNA assay as a predictor of non-SLN metastases.
METHODS: Consecutive 742 patients with breast cancer were enroled in the study. The association of non-SLN or &gt;= 4 LN metastases with clinicopathological variables was investigated using multivariate logistic analysis.
RESULTS: In total, 130 patients with a positive SLN who underwent complete axillary LN dissection were investigated. The frequency of non-SLN metastases in patients who were OSNA+ and + + was 19.3% and 53.4%, respectively, and that in patients with &gt;= 4 LN metastases who were OSNA+ and + + was 7.0% and 27.4%, respectively. The cytokeratin 19 (CK19) mRNA copy number (&gt;= 5.0 x 10(3); OSNA+ +) in the SLN was the most significant predictors of non-SLN metastases (P = 0.003). The CK19 mRNA copy number (&gt;= 1.0 x 10(5)) in the SLN was the only independent predictor of &gt;= 4 LN metastases (P = 0.014).
CONCLUSION: Whole SLN analysis using the OSNA assay could become a valuable method for predicting non-SLN and &gt;= 4 LN metastases. British Journal of Cancer (2012) 107, 1239-1243. doi:10.1038/bjc.2012.387 www.bjcancer.com Published online 28 August 2012 (C) 2012 Cancer Research UK

DOI： 10.1038/bjc.2012.387

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

A 78-year-old Japanese male noticed a difficulty in the beginning of standing up, followed by 7a progressive numbness of extremities with pain, Bell's palsy, dysarthria, and difficulty in swallowing. A clinician had suspected cancer of unknown primary origin, accompanied by the diverse and elusive neurological symptoms, likely presenting as painful mononeuropathy simplex and cranial neuropathy. He developed dysbasia over weeks and died 1 month after the symptom onset. At autopsy, an ill-defined large and soft tumor mass in the right lobe of the liver with direct invasion into the right adrenal gland was observed. The left adrenal gland or right iliopsoas muscle was also involved. Microscopic findings showed a monotonous proliferation of medium-sized to large atypical lymphoid cells, which were diffusely positive for CD20 in immunohistochemistry, consistent with diffuse large B-cell lymphoma (DLBL). Furthermore, the lymphoma cells aggressively infiltrated endoneurial and subperineurial spaces not only in the peripheral nerves and plexuses, but partly in the spinal nerve roots, and intravascular spaces in various tissues. Therefore, systemic lymphoma (DLBL) complicated with neurolymphomatosis (NL) and intravascular lymphoma (IVL) was diagnosed. Very early diagnosis and treatment are necessary for the NL patients with poor prognosis.

DOI： 10.1186/1746-1596-7-94

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Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

目的:神経内分泌への分化を示す非浸潤性乳管癌(Neuroendocrine ductal carcinoma in situ:NE-DCIS)の臨床所見と細胞像を明らかにする。方法:細胞診が行われたNE-DCIS 3例の臨床所見と細胞所見について検討を行った。成績:臨床所見では血性乳頭分泌を認めた(3/3例)。細胞所見は、出血性背景に多数の乳管上皮細胞が出現しており、充実性あるいは結合性に乏しい大小の重積集塊で、発達した血管を伴っていた(3/3例)。核は偏在性で緊満感があり均一であったが(3/3例)、一部に核形不整を認めた(1/3例)。細胞質はライトグリーン好染性で一部細顆粒状を示し、孤立細胞は明瞭な細胞質を有していた(3/3例)。診断は悪性で(3/3例)、組織推定はDCIS(2/3例)、充実腺管癌(1/3例)であった。結論:NE-DCISは細胞学的に特徴的な所見を示し、臨床所見なども考慮すれば、NE-DCISを推定病変として挙げることは可能であると思われた。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

We previously reported on a histological classification of cynomolgus monkey testis into six grades (1, immature; 2, prepuberty; 3, onset of puberty; 4, puberty; 5, early adult; 6, adult) based on spermatogenesis development. In this investigation, the accessory reproductive organs from the same animals underwent histomorphometric examination, in addition to being examined histologically and weighed, to evaluate relationships between these parameters and the six grades. Seminiferous tubule diameter increased corresponding to the testicular maturity grade and was notably increased at grade 6. Beginning from grade 3, increases in the areas of the ductus epididymis were noted, and reserved sperm was visible in the lumen. In the prostate, the glandular lumen area per unit area showed an increase beginning from grade 3 but no clear differences between grades 4 and 6; advanced development of epithelial height was observed at grade 6. In the seminal vesicle, development of the epithelial cell layer was markedly increased at grade 6. It was concluded that development of the male accessory reproductive organs began after reserved sperm was observed in the lumen of the ductus epididymis (grade 3) and that these organs were developed notably when the testis reached sexual maturity (grade 6).

DOI： 10.1177/0192623312444620

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

The testes from 136 male cynomolgus monkeys were examined histopathologically in order to investigate the relationship between the development of spermatogenesis and testis weight, age, and body weight. At Grade 1 (immature), Sertoli cells and spermatogonia were the only cell classes in the testis. At Grade 2 (pre-puberty), no elongated spermatids were observed in the testis, although a few round spermatids and small lumen formation were observed. At Grade 3 (onset of puberty), all classes of germ cells were observed in the testis, although seminiferous tubule diameters and numbers of germ cells were small. Slight debris in the epididymis was observed in almost all animals. At Grade 4 (puberty), almost complete spermatogenesis was observed in the seminiferous tubules and it was possible to ascertain the spermatogenesis stage as described by Clermont, although tubule diameters and numbers of germ cells were small. There was less debris in the epididymis than at Grade 3. At Grade 5 (early adult), complete spermatogenesis was observed in the seminiferous tubules. At Grade 6 (adult), complete spermatogenesis in the seminiferous tubules and a moderate or large number of sperm in the epididymis were observed. Moreover, sperm analysis using ejaculated sperm was possible. Logistic regression analysis showed that testis weight is a good indicator of testicular maturity.

DOI： 10.1177/0192623312444619

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC VET SCI  

In this study, we demonstrated growth curves and reference values for hematological and serum biochemical parameters of Microminipigs, the world smallest experimental minipigs. In both male and female animals, the body weights (BWs) at 3 and 6 months of age were &lt;5 kg and &lt;10 kg, respectively, and growth curve revealed almost plateau (approximately 20 kg BW) after 18 months of age. Major hematological and serum biochemical parameters showed no gender differences and the values were very similar to those in Gottingen and Yukatan minipigs. The values obtained in this study can serve as fundamental reference, and thereby facilitate the use of Microminipig in life science research.

DOI： 10.1292/jvms.11-0571

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Language：English   Publishing type：Research paper (scientific journal)  

In this article, we describe unilateral gynecomastia and pseudoangiomatous stromal hyperplasia (PASH) in a case of type-1 neurofibromatosis (NF-1). It is important to distinguish PASH from fibroadenoma clinically, and from true blood capillaries and angiosarcoma histologically. In the present case, giant multinucleated cells lined the pseudovascular spaces, which was markedly different from that of conventional breast PASH. The origin of PASH has been reported to be either the fibroblast or the myofibroblast phenotype and may be affected by endocrine signaling because many cases have been reported in premenopausal women, and cases are often estrogen (ER) and progesterone receptor (PR) positive. However, previous reports have identified PASH in NF-1 in juvenile males only, and the cases were negative for α-SMA, ER and PR. The cause and prognosis of PASH in NF-1 may be distinguished from that of conventional PASH, and mast cells, histiocytes and CD54 may play roles.

DOI： 10.1016/j.prp.2012.03.003

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Gestational trophoblastic disease in perimenopausal women is very rare. A 53-year-old perimenopausal woman complained about amenorrhea lasting over a period of 4 months. Ultrasound showed enlargement of the uterus with a complex echogeneous area in the uterine cavity. Serum human chorionic gonadotropin was 67,611 mIU/ml. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. The uterus contained hemorrhagic and fragile tumor with grape-like vesicles in the enlarged endometrial cavity. Microscopic examination revealed hydropically degenerated villi with circumferential hyperplasia of atypical trophoblast and cistern formation. p57(kip2) immnostaining was negative in villous cytotrophoblasts and stromal cells. Moreover, fluorescent in situ hybridization for HER2 was scored as diploid. These findings are consistent with complete hydatidiform mole. The diagnosis of hydatidiform mole must be considered in perimenopausal women, and the combination of p57(kip2) immunostaining and HER2 fluorescent in situ hybridization seems to be a very useful testing strategy for difficult situations regarding the differential diagnosis of completed and partial hydatidiform mole. (C) 2011 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2011.11.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI LTD  

Acupuncture, an alternative medicine, has been widely applied for people with sleep disturbances; therefore, the effects should be evaluated objectively. Micro-minipigs (MMPigs), the smallest miniature pigs for animal experiments, were used. Acupuncture was performed at two different points: Dafengmen is located on the head and is an anatomically similar point to human-Baihui (GV20), an effective acupoint for sleep disturbances in humans; pig-Baihui is on the back. The procedure was performed as follows: shallow, within 5 mm depth for several seconds; deep, 10-20 mm depth for 20 min. The sleep conditions were evaluated by actigraph, and the amount of catecholamine in pooled urine after acupuncture treatment. MMPigs with deep acupuncture at Dafengmen showed significantly efficient values on actigraph and catecholamine analysis as compared with untreated MMPigs. The effective acupoint for sleep conditions in the porcine model is at an anatomically similar point to humans, rather than the point determined by traditional Chinese medicine.

DOI： 10.1155/2012/472982

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aims: Aldehyde dehydrogenase 1 (ALDH1) has been identified as a reliable marker of breast cancer stem cells, and its clinical significance as a prognostic indicator of breast cancer has been reported by several investigators. However, the clinical significance of ALDH1 expression in triple-negative (TN) breast cancer, a high-risk breast cancer lacking the benefit of specific therapy, remains to be solved.
Methods and results: We performed immunohistochemical analyses of 106 TN breast cancers, using paraffin-embedded sections. The basal-like phenotype was also investigated with the use of basal cytokeratin 5/6 and epidermal growth factor receptor. ALDH1 expression in carcinoma cells was found in 59% of cases and was correlated with high histological grade alone (P &lt; 0.006), whereas ALDH1 expression in stromal cells was found in 49% of cases but was not correlated with any clinicopathological parameter. Patients with ALDH1 expression in carcinoma cells had a shorter relapse-free survival (RFS) according to the log-rank test (P = 0.015). According to Cox multivariate analysis, ALDH1 expression in carcinoma cells was an independent prognostic indicator of RFS (P = 0.025). The log-rank test revealed that stromal expression of ALDH1 had no effect on RFS.
Conclusions: ALDH1 expression in carcinoma cells is an independent prognostic factor in TN breast cancer patients.

DOI： 10.1111/j.1365-2559.2011.03884.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Although all three nitric oxide (NO) synthases (nNOS, iNOS, and eNOS) are expressed in injured arteries, it remains to be elucidated the role of the NOSs in their entirety in the vascular lesion formation. We addressed this issue in mice deficient in all NOS genes. Vascular injury was induced by permanent ligation of a unilateral carotid artery in wild-type (WT), singly, and triply NOS(-/-) mice. Two weeks after the procedure, constrictive vascular remodeling and neointimal formation were recognized in the ligated arteries. While constrictive remodeling was noted in the nNOS(-/-) and iNOS(-/-) genotypes, it was most accelerated in the nfi/eNOS(-/-) genotype. While neointimal formation was evident in the eNOS(-/-) and nNOS(-/-) genotypes, it was also most aggravated in the n/i/eNOS(-/-) genotype. Those lesions were reversed by long-term treatment with isosorbide dinitrate, a NO donor. Finally, we examined the involvement of bone marrow-derived cells in the vascular lesion formation. Bone marrow from the WT, singly, or triply NOS(-/-) mice was transplanted into the WT mice, and then the carotid ligation was performed. Intriguingly, constrictive remodeling and neointimal formation were both similarly most exacerbated in the case of the n/i/eNOS(-/-) bone marrow transplantation. These results indicate that the complete disruption of all the NOS genes causes markedly accelerated vascular lesion formation caused by blood flow disruption in mice in vivo, demonstrating the crucial vasculoprotective role of the whole endogenous NOS system. Our findings also suggest that the NOS system in bone marrow-derived cells may be involved in this vasculoprotective mechanism. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.niox.2011.06.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Diethlstilbestrol (DES) is a synthetic estrogen prescribed to several millions of pregnant women worldwide. The risk for breast cancer after age 40 in women prenatally exposed to DES has been reported; however, the precise mechanism of susceptibility to breast cancer remains to be resolved. We investigated the global gene expression profile of terminal end buds (TEBs), the target of carcinogen, in rat mammary glands neonatally exposed to a low- or high-dose DES at postnatal days (PND) 35 and 45, equivalent to the peripubertal stage in humans. In all groups, the number of TEBs gradually increased, peaked at PND35 and decreased at PND49. At PND35 and 49, the low-dose DES-treated group (low-DES group) showed the highest number of TEBs. In the low-DES group at PND35, beta-casein, gamma-casein and whey acidic protein (WAP) mRNA expression increased 8.2-fold, 26.1-fold and 13.3-fold, respectively, whereas gamma-casein and WAP mRNA decreased 17.6-fold and 27.7-fold, respectively, at PND49. The most significant network revealed by Ingenuity Pathway Analysis (IPA) software showed the relevance of NF-kappa B in low-DES group. The present findings suggest that the deregulation of mammary gland differentiation and development-related genes could be induced and cause the increased number of terminal duct lobular units (TDLUs) in human mammary glands of DES daughters in a critical period of mammary gland development. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.toxlet.2011.04.031

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective-The pathogenic role of macrophage apoptosis in atherosclerosis is still debatable, but it is considered to be a suppressor of plaque progression in early stages but a promoter of plaque necrosis in advanced stages. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a pivotal role in stress-induced apoptosis. In the current study, we investigated the functions of ASK1 in hyperlipidemia-induced atherosclerosis.
Methods and Results-We generated ASK1 and apolipoprotein E (apoE) double-knockout mice (ASK1(-/-)/apoE(-/-)) and analyzed atherosclerosis in ASK1(-/-)/apoE(-/-) mice fed a high-cholesterol diet for 12 weeks. ASK1(-/-)/apoE(-/-) mice had accelerated hyperlipidemia-induced atherosclerosis, which was characterized by less apoptosis of macrophages and fewer necrotic areas, and more macrophages and elastolysis compared with apoE(-/-) mice. Bone marrow transplantation from ASK1(-/-) or wild-type to apoE(-/-) mice confirmed the above observation that the recipient mice of ASK1(-/-) donors had more pronounced hyperlipidemia-induced atherosclerosis than recipient mice of wild-type donors.
Conclusion-These findings suggest that ASK1 suppresses hyperlipidemia-induced atherosclerosis via increased macrophage apoptosis and that ASK1 may cause pronounced plaque vulnerability via necrotic core development. (Arterioscler Thromb Vasc Biol. 2011; 31:1555-1564.)

DOI： 10.1161/ATVBAHA.111.227140

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: To determine safe surgical margins for soft tissue sarcoma, it is essential to perform a general evaluation of the extent of tumor, responses to auxiliary therapy, and other factors preoperatively using multiple types of diagnostic imaging. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is a tool for diagnostic imaging that has recently spread rapidly in clinical use. At present, the roles played by FDG-PET/CT in determination of margins for surgical resection of sarcoma are unclear. The present study was undertaken to explore the roles of FDG-PET/CT in determination of surgical margins for soft tissue sarcoma and to examine whether PET can serve as a standard means for setting the margins of surgical resection during reduced surgery.
Methods: The study involved 7 patients with sarcoma who underwent surgery in our department and in whom evaluation with FDG-PET/CT was possible. Sarcoma was histologically rated as MFH in 6 cases and leiomyosarcoma in 1 case. In all cases, sarcoma was superficial (T1a or T2a). The tumor border was defined by contrast-enhanced MRI, and SUVs were measured at intervals of 1 cm over a 5-cm long area from the tumor border. Mapping of viable tumor cells was carried out on whole-mount sections of resected tissue, and SUVs were compared with histopathological findings.
Results: Preoperative maximum SUVs (SUV-max) of the tumor averaged 11.7 (range: 3.8-22.1). Mean SUV-max was 2.2 (range: 0.3-3.8) at 1 cm from the tumor border, 1.1 (0.85-1.47) at 2 cm, 0.83 (0.65-1.15) at 3 cm, 0.7 (0.42-0.95) at 4 cm, and 0.64 (0.45-0.82) at 5 cm. When resected tissue was mapped, tumor cells were absent in the areas where SUV-max was below 1.0.
Conclusions: Our findings suggest that a safe surgical margin free of viable tumor cells can be ensured if the SUV cut-off level is set at 1.0. FDG-PET/CT is promising as a diagnostic imaging technique for setting of safe minimal margins for surgical resection of soft tissue sarcoma.

DOI： 10.1186/1471-2474-12-166

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective-Histamine and histamine receptors are found in atherosclerotic lesions, and their signaling and subsequent proatherogenic or proinflammatory gene expression are involved in atherogenesis. In the present study, we generated apolipoprotein E (apoE) and histamine synthesizing histidine decarboxylase double knockout (DKO) mice on a C57BL/6J (wild-type mice) background to clarify the roles of histamine in atherosclerosis.
Methods and Results-Wild-type, apoE knockout (KO), and DKO mice were fed a high-cholesterol diet to analyze hyperlipidemia-induced atherosclerosis. Compared with wild-type mice, apoE-KO mice showed increased expression of histamine and its receptors, corresponding to increased atherosclerotic lesion areas and expression of inflammatory regulators, such as nuclear factor-kappa B, scavenger receptors, inflammatory cytokines, and matrix metalloproteinases. Histamine deficiency after deletion of histidine decarboxylase reduced atherosclerotic areas and expression of a range of the inflammation regulatory genes, but serum cholesterol levels of DKO mice were higher than those of apoE-KO mice.
Conclusion-These results indicate that histamine is involved in the development of atherosclerosis in apoE-KO mice by regulating gene expression of inflammatory modulators, an action that appears to be independent of serum cholesterol levels. In addition to acute inflammatory response, histamine participates in chronic inflammation, such as hyperlipidemia-induced atherosclerosis, and might be a novel therapeutic target for the treatment of atherosclerosis. (Arterioscler Thromb Vasc Biol. 2011;31:800-807.)

DOI： 10.1161/ATVBAHA.110.215228

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Publisher：(一社)日本病理学会  

70代、女性。乳癌術後、右下葉に増大傾向のあるmixed-ground glass opacity陰影を認め、区域切除術を施行。組織学的には構造が保たれた肺胞上皮置換性の病変で、異型は弱く、粘液貯留や線毛を有する細胞が混在した複雑な像を認めた。免疫染色より転移は否定的で、粘液非産生性の単一な細胞の肺胞上皮置換性増殖より粘液非産生性細気管支肺胞上皮癌と診断した。粘液や線毛上皮の混在は背景の間質性変化に伴うものと考えられた。近年、末梢小型腺癌を診断する機会が増えているが、本症例のように異型が弱く、背景に間質性変化等が加わった複雑な像の場合には標本全体像の把握が重要である。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Maspin is a unique member of the serine protease inhibitor superfamily and its expression is found in myoepithelial cells of normal mammary glands; therefore, it has been considered to be a myoepithelial marker. We previously reported that maspin was frequently expressed in biologically aggressive breast cancers. In turn, triple-negative (TN) breast cancer is a subtype of tumor with aggressive clinical behavior and shows frequent expression of basal markers. We hypothesized that maspin expression may be frequent and correlate with basal rather than myoepithelial markers in TN breast cancer.
Methods: Paraffin-embedded 135 TN invasive ductal carcinoma tissue samples were immunohistochemically investigated using the Dako Envision+ kit and primary antibodies for maspin, basal (CK5/6, EGFR, CK14) and myoepithelial markers (p63, CD10). The correlation between maspin expression and relapse-free survival (RFS) was investigated by the log-rank test.
Results: The positive rate for maspin was 85.9% and significantly correlated with younger age (P = 0.0015), higher histological grade (P = 0.0013), CK5/6 positivity (P &lt; 0.0001), CK14 positivity (P = 0.0034) and the basal-like subtype defined by CK5/6, EGFR and CK14 positivity (P = 0.013). The positive rates for CK5/6, EGFR, CK14, CD10 and p63 were 59.2%, 48.9%, 34.1%, 17.8% and 12.6%, respectively. There was no significant correlation between maspin expression and RFS.
Conclusions: The positive rate for maspin is the highest among known basal and myoepithelial markers, and strongly correlates with basal markers in TN breast cancer. These results suggested that maspin could be a candidate for a therapeutic target for TN breast cancer.

DOI： 10.1186/1746-1596-6-36

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