Publisher：Human Pathology: Case Reports  

DOI： 10.1016/j.ehpc.2020.200402

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DOI： 10.1186/s40792-020-00940-8

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Publisher：Springer Berlin Heidelberg  

症例は47歳女性で、甲状腺左葉乳頭癌と食道粘膜下腫瘍を検出され当院に紹介された。食道鏡検査で切歯から18cmの部位に径50mmの腫瘍を認め、正常粘膜に被覆され頸部食道左壁に局在していた。造影CTでは限局性の石灰化を有する楕円形の52×34×21mm大の腫瘤を頸部食道に認め、リンパ節腫脹や遠隔転移はみられなかった。甲状腺乳頭癌、頸部食道の平滑筋腫と初期診断を下し、甲状腺左葉切除と食道腫瘍摘出術を施行した。術後の組織学的所見から、食道腫瘍は平滑筋腫と診断した。術後4年、頸部食道腫瘍の再発を認め、内視鏡下生検による顕微観察で紡錘細胞像を呈する非定型細胞浸潤と少数の有糸分裂がみられた。免疫染色所見とあわせ、平滑筋腫ではなく滑膜肉腫が疑われた。さらに、RT-PCR解析を行ったところSS18-SSX2融合転写因子が検出され、頸部食道に生じた単相性滑膜肉腫と診断した。頸部食道切除+空腸間置再建術を行い、病理検査から完全切除を確認した。さらに再手術の3年後、空腸-食道間の吻合遠位部に滑膜肉腫の再発を認め、胸腔鏡下食道切除+胃導管再建後に術後補助化学療法を行った。再々手術の3ヵ月後、再発を認めていない。

Publisher：(一社)日本膵臓学会  

膵原発の悪性リンパ腫は,節外性悪性リンパ腫の2%以下,膵悪性腫瘍の0.5%未満と稀である.画像所見のみでは鑑別が難しく,病理組織学的評価による正確な診断が重要である.今回,膵腫瘤に対し超音波内視鏡下穿刺吸引法(EUS-FNA)でB細胞リンパ腫と診断した3例を経験し,うち2例は化学放射線療法で改善した.EUS-FNAは,リンパ腫の病型診断および治療方針決定に有用と考えられた.(著者抄録)

Publisher：鹿児島県臨床外科学会  

症例1(70歳代、男性)。検診の腹部超音波検査にて肝外側区に18mm大の低エコー結節を指摘され、二次検診のため当院へ受診となった。CTおよびMRI所見より肝内胆管癌や非典型的な肝細胞癌が疑われ、肝左葉切除術が行われた。症例2(70歳代、女性)。検診の腹部超音波検査にて肝外側区に10mm大の低エコー結節を指摘され、二次検診のため当院へ受診となった。単純CTおよびMRI所見より肝細胞癌や混合型肝癌が疑われ、肝外側区域切除術が行われた。病理組織学的に症例1は早期の肝内胆管癌、症例2は早期の細胆管細胞癌と診断され、それぞれ切除後3年10ヵ月、切除後6ヵ月の時点で無再発生存中である。

Publisher：鹿児島県臨床外科学会  

58歳男性。右鼠径ヘルニアの術前CT検査で臍下に74mmの辺縁平滑な腫瘤が指摘され、腸間膜腫瘍が疑われた。腹部超音波や腹部造影CT、MRI所見より非上皮系腫瘍が考えられ、由来としては腸間膜が推察され、悪性疾患の可能性から開腹手術が施行された。手術所見では小腸の腸間膜に弾性硬の腫瘤が認められ、近傍の小腸への浸潤もみられたため腫瘤を含めた小腸部分切除術を行った。その結果、病理組織学的に小腸間膜原発デスモイド腫瘍と診断された。目下、術後4ヵ月経過現在、無再発生存中である。尚、本症例はデスモイド腫瘍の発生で多いFAP(家族性大腸ポリポーシス)および開腹手術の既往歴はなかった。

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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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 clinicopathological 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 non-neoplastic 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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Publisher：(株)癌と化学療法社  

症例は78歳、女性。65歳時、左乳癌に対して左非定型乳房切除術を施行された。術後5年間内分泌療法が行われ、以後転移再発なく経過していた。術後13年目のCTで肝S4に46mm大の単発性腫瘍を指摘された。腫瘍マーカーの上昇なく、画像検査で肝内胆管癌との鑑別は困難であった。肝内胆管癌であった場合の生検後播種のリスクを考慮し生検は行わず、肝左葉+左尾状葉切除術を施行した。最終病理で乳癌肝転移の診断であった。肝切除術後は内分泌療法を開始し、術後3年無再発生存中である。乳癌術後晩期単発性肝転移はまれであり、肝内胆管癌との鑑別が困難な場合もある。生検による播種のリスクを考慮すると、診断的治療としての肝切除は選択肢になり得る。(著者抄録)

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Publisher：Japanese Journal of Cancer and Chemotherapy  

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Publisher：Pancreatology  

DOI： 10.1016/j.pan.2019.11.015

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Publisher：Japan Pancreas Society  

<p>Three patients with pancreatic lymphoma were seen. Primary pancreatic lymphoma accounts for less than 2% of extranodal malignant lymphomas and less than 0.5% of malignant tumors of the pancreas. In patients with pancreatic lymphoma, an accurate diagnosis is crucial because the tumor is difficult to distinguish from other pancreatic tumors-especially pancreatic cancer-based on imaging findings alone, and because the treatment depends on the specific type of lymphoma. Two of these patients improved after chemoradiation therapy. EUS-FNA was useful for determining the type of lymphoma and determining the treatment strategy.</p>

DOI： 10.2958/suizo.35.213

Publisher：Japan Pancreas Society  

<p>The patient is a 46-year-old woman admitted with epigastric pain and nausea. She was found to have elevated pancreatic enzymes and treated for acute pancreatitis. Imaging findings showed uneven contrast enhancement of the pancreatic body to tail and enlargement of the caudal pancreatic duct. A pancreatic tumor was suspected. Although no definitive histologic diagnosis was obtained using endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA), the possibility of pancreatic body cancer could not be ruled out, and resection was performed. The resected specimen showed characteristic histologic findings, leading to a diagnosis of type 2 autoimmune pancreatitis.</p>

DOI： 10.2958/suizo.35.447

Publisher：Oncology Letters  

DOI： 10.3892/ol.2019.11101

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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)

DOI： 10.1055/a-0810-0398

PubMed

DOI： 10.1186/s40792-019-0679-5

PubMed

Publisher：Springer Berlin Heidelberg  

右卵巣静脈原発平滑筋肉腫(LMS)の無症状の71歳日本人女性症例について検討した。腹部超音波のルーチン検査において異常所見が認められた。腹部造影CTでは、右腹膜後隙に直径5.5cmの境界明瞭の分葉状充実性腫瘤を認めた。18F-fluorodeoxyglucose PET時、腫瘤の取り込みは比較的低かった。これらの所見に基づき、鑑別診断は類腱腫、平滑筋腫、LMS、悪性中皮腫などの後腹膜腫瘍を含んだ。手術所見により腫瘤が右卵巣血管原発であることを確認し、腫瘤と右卵巣血管の一括切除を実施した。最終的な病理診断は右卵巣静脈原発LMSで、外科切除断端に腫瘍細胞は認めなかった。組織学的所見でLMSの診断を確認した後にアジュバント放射線療法を施行し、術後6ヵ月目経過時点で局所再発または転移の徴候は認められなかった。

Publisher：Abdominal Radiology  

DOI： 10.1007/s00261-019-01958-9

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Publisher：European Radiology  

DOI： 10.1007/s00330-018-5570-4

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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)

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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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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Publisher：John Wiley & Sons Australia, Ltd  

肝粘液性嚢胞性腫瘍(MCN)と膵MCNの卵巣様間葉系間質(OLS)におけるステロイド産生について検討した。肝切除術または開窓術後に低悪性度上皮内腫瘍を有する肝MCNと診断した25例(女性、21〜78歳)および低悪性度上皮内腫瘍および遠位膵切除を伴う膵MCN患者24例(女性、23〜65歳)を対象とした。肝MCNは肝内側部分、膵MCNは膵尾部に位置した。エストロゲン受容体(ER)α/ER-β比は、肝MCNおよび膵MCNよりも正常卵巣の方が有意に高く、肝および膵のMCNよりも卵巣MCNの方が高い傾向があった。3β-ヒドロキシステロイドデヒドロゲナーゼHスコアは、膵MCNおよび卵巣MCNよりも肝MCNにおいて有意に高かった。cytochrome P450 17α-hydroxylase/c17-20 lyase(P450c17)Hスコアは、卵巣MCNおよび正常卵巣よりも肝MCNで意に高く、卵巣MCNおよび正常卵巣よりも膵MCNで有意に高かった。5α-レダクターゼ-1 Hスコアは、卵巣MCNおよび正常卵巣よりも肝MCNで有意に高く、卵巣MCNおよび正常卵巣よりも膵MCNで有意に高かった。肝MCNでは、上皮のアンドロゲン受容体(AR)HスコアとOLSのP450c17との間に有意な正の相関が検出された。膵MCNでは、上皮のAR HスコアとOLSのP450c17 Hスコアの間に有意な正の相関が検出された。上皮におけるAR HスコアとOLSにおける5α-レダクターゼ-1 Hスコアとの間に有意な正の相関があった。

Publisher：Hepatology Research  

DOI： 10.1111/hepr.13201

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Publisher：Biomedical Reports  

DOI： 10.3892/br.2018.1141

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Publisher：Oncotarget  

DOI： 10.18632/oncotarget.25651

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Publisher：日本臨床細胞学会-九州連合会  

50歳代、女性。子宮癌検診時の頸部細胞診にてASC-USと判定され、前医を受診した。前医ではハイリスクHPV陽性で、コルポ下生検にてSCCと診断され、精査加療目的で当院へ紹介となった。本症例は組織診断では扁平上皮癌であったにも関わらず、細胞診では多数出現していた淡明細胞の核異型が軽度であったためASC-Hと判定された。しかし、改めて詳細に観察すると、核の腫大、多形性は悪性と判ずるに十分であり、CIN3相当の集塊や角化細胞、対細胞もみられたことからSCCと判定し得たと考えられた。

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 &lt;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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Publisher：Minimally Invasive Therapy and Allied Technologies  

DOI： 10.1080/13645706.2017.1416409

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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)

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

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

Publisher：Heart  

DOI： 10.1136/heartjnl-2017-312151

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Publisher：(一社)日本消化器外科学会  

症例は69歳の女性で,背部痛を主訴に近医を受診し膵腫瘍を指摘され,当科紹介となった.生検結果は腺癌であり,膵体部癌,TS3(35mm),cT3,cS1,cRP1,cPV1(PVp,PVsp),cA1(Asp),cPL1,cN0,cM1(HEP),cStage IVの診断であった.遠隔転移を伴う切除不能膵癌に対してgemcitabine+nab-paclitaxel療法を施行した.6コース施行後に肝転移の消失を確認した.残存する原発巣に対してS-1+放射線療法(56 Gy)を施行し,その後S1による維持療法を施行した.治療開始から12ヵ月後の効果判定ではcomplete response(以下,CRと略記)であり,CA 19-9は1,846U/mlから13.3U/mlまで著明に低下した.組織学的な癌遺残の可能性を考慮し,脾合併膵体尾部切除術+肝部分切除術を施行した.病理組織学的検査では切除した膵臓,肝臓ともに腫瘍細胞を認めず,最終病理診断はCRであった.遠隔転移と局所進行を伴う切除不能膵癌の予後は極めて不良であるが,集学的治療が著効し,病理組織学的CRを得られた症例を経験したので報告する.(著者抄録)

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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PubMed

DOI： 10.1038/labinvest.2017.67

PubMed

Publisher：Clinical nuclear medicine  

DOI： 10.1097/RLU.0000000000001702

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Minimally Invasive Therapy and Allied Technologies  

PURPOSE: To test the splenic blood flow change after radiofrequency ablation (RFA) of the spleen in a porcine experimental model. MATERIAL AND METHODS: Six pigs underwent RFA of the spleen via laparotomy. During the procedure of RFA, clamping of splenic artery (one) and both splenic artery/vein (one) was also performed. Measurement of blood flow of both splenic artery (SA) and splenic vein (SV) with flow-wire at pre- and post-RFA of the spleen was also performed. RESULTS: Ablated splenic lesions were created as estimating approximately 50% area of the spleen in all pigs. Resected specimens reveal not only the coagulated necrosis but also the congestion of the spleen. On the SA hemodynamics, maximum peak velocity (MPV) changed from 37 +/- 7 to 24 +/- 8 cm/s (normal), 11 to 10 cm/s (clamp of the SA), and 12 to 7.5 cm/s (clamp of both SA/SV), respectively. On the SV hemodynamic, MPV changed from 15 +/- 5 to 13 +/- 4 cm/s (normal), 17 to 15 cm/s (clamp of the SA), and 17 to 26 cm/s (clamp of both SA/SV), respectively. CONCLUSIONS: RFA of the spleen could induce coagulation necrosis and reduce the splenic arterial blood flow.

DOI： 10.1080/13645706.2017.1281315

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PubMed

Other Link： http://www.ncbi.nlm.nih.gov/pubmed/28145148

Publisher：日本外科系連合学会  

症例は53歳の男性.検診の腹部エコーで多量の腹水と左上腹部に15cm大の腫瘤を指摘され,経超音波内視鏡的生検で胃GISTと診断された.腹水の細胞診は陰性で,明らかな播種病変は指摘できなかった.胃GISTに対して,グリベックと利尿剤を投与したが,内服治療は奏効せず,腹部膨満が増悪し,持続的な腹水穿刺,1日に約1,500ccの排液を要した.腹水原因の精査と腫瘍の根治切除を目的に手術を行った.GIST内の巨大な嚢腫性病変の薄い被膜が穿破しており,嚢胞内部から腹腔内へ嚢胞内溶液が持続的に漏出しており,これが腹水の原因と判明した.腫瘍は胃大彎から茎状に発生しており,横行結腸を圧排,浸潤が疑われた.腫瘍茎部でsafety marginを確保した胃部分切除と浸潤部分の横行結腸を部分切除して,巨大GISTを根治切除した.腫瘍切除により難治性の腹水は完全に消失した.術後経過は良好で,14日目に自宅へ退院となった.巨大胃GISTに伴う難治性腹水の合併は稀であり,報告した.このような病態による腹水のコントロールは手術による腫瘍の切除が有用な治療法と考えられた.(著者抄録)

Authorship：Lead author   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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PubMed

Other Link： http://www.ncbi.nlm.nih.gov/pubmed/28680536

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

BACKGROUND AND AIM: There is a paucity of data on the diagnostic efficacy of liquid-based cytology (LBC) for pancreatic samples obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Using propensity score matching, we retrospectively analyzed the additional diagnostic value of LBC compared to a conventional Papanicolaou smear (CPS) for samples of solid pancreatic lesions obtained by EUS-FNA. METHODS: This cohort study included 126 matched patients who underwent initial EUS-FNA for solid pancreatic lesions between January 2009 and August 2014. CPS was used for cytology of EUS-FNA samples obtained until May 2012 (63 patients). Subsequently, LBC was used for cytological analysis (63 patients). Diagnostic yields of CPS and LBC for malignancy were compared. Risk factors for cytological misdiagnosis with LBC were investigated. RESULTS: Overall rate of malignancy was 86% after matching. LBC had higher diagnostic sensitivity and accuracy than CPS (96.6% vs 84.0%, P = 0.03; and 96.8% vs 87.3%, P = 0.05). LBC was significantly more sensitive for diagnosing pancreatic head lesions (96.4% vs 78.1%, P = 0.04). The sensitivity for pancreatic ductal adenocarcinoma (PDAC) with LBC was higher (98.1% vs 83.0%, P = 0.009). Multivariate analysis revealed that malignant tumors other than PDAC (P = 0.004) and lesion size </=20 mm (P = 0.046) were risk factors for LBC misdiagnosis in all participants. CONCLUSIONS: For solid pancreatic lesions, LBC of EUS-FNA samples contributes to the diagnosis of malignancy. Malignant tumors other than PDAC and small tumors are difficult to diagnose using EUS-FNA and LBC.

DOI： 10.1111/den.12827

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PubMed

Other Link： http://www.ncbi.nlm.nih.gov/pubmed/28160342

Publisher：John Wiley & Sons Australia, Ltd  

超音波内視鏡下穿刺吸引法(EUS-FNA)で採取した膵腫瘤性病変検体に対するliquid-based cytology(LBC)法とconventional Papanicolaou smear(CPS)法の診断的有効性を比較するため後向き研究を実施した。対象は2009年1月〜2014年8月に当院で腫瘤性病変に対して初回EUS-FNAを施行した患者126例で、このうち63例は2012年5月迄にCPSによる細胞診を施行し、その後63例にLBCによる細胞診を施行した。悪性腫瘍の全発生率は86%であった。LBCはCPSと比較して感度および正診率が高かった。LBCは膵頭部病変の診断において感度が高かった。膵管腺癌(PDAC)の感度もLBCが高かった。多変量解析により、PDAC以外の悪性腫瘍と20mm以下の病変は全参加者においてLBCによる誤診の危険因子であることが明らかになった。以上から、膵腫瘤性病変に対するEUS-FNAにおいてLBCは悪性腫瘍の診断に有用であるが、PDAC以外の悪性腫瘍と小型腫瘍の場合はEUS-FNAとLBCの診断は困難であることが示された。

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)

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

Clinical tissue specimens are useful for pathological diagnosis, which is, in some cases, supported by visualization of biomolecule localization. In general, diagnostic specificity in molecular pathology is increased by the acquisition of a probe to distinguish the modification of isomers. Although glycosylation is one of the candidate modifications in a protein, comparative glycan analysis of disease-associated proteins derived from a single tissue section is still challenging because of the lack of analytical sensitivity. Here we demonstrate a possible method for differential glycoform analysis of an endogenous tumor-associated glycoprotein MUC1 by an antibody-overlay lectin microarray. Tissue sections (5 mum thick) of patients with cholangiocarcinoma (CCA; n=21) and pancreatic ductal adenocarcinoma (PDAC; n=50) were stained with an anti-MUC1 antibody MY.1E12 that was established as a monoclonal antibody recognizing an MUC1 glycosylation isoform with a sialyl-core 1 structure (NeuAcalpha2-3galactosyl beta1-3-N-acetylgalactosamine). MY.1E12-positive tissue areas (2.5 mm2) were selectively dissected with a laser capture microdissection procedure. The membrane MUC1 was enriched by immunoprecipitation with MY.1E12 and subjected to lectin microarray analysis. Even though the reactivities of MY.1E12 between CCA and PDAC were similar, the lectin-binding patterns varied. We found Maackia amurensis leukoagglutinin and pokeweed lectin distinguished MY.1E12-reactive MUC1 of CCA from that of PDAC. Moreover, MUC1 with M. amurensis hemagglutinin (MAH) reactivity potentially reflected the degree of malignancy. These results were confirmed with MAH-MY.1E12 double fluorescent immunostaining. These glycan changes on MUC1 were detected with high sensitivity owing to the cluster effect of immobilized lectins on a tandem repeat peptide antigen covered with highly dense glycosylation such as mucin. Our approach provides the information to investigate novel glycodynamics in biology, for example, glycoalteration, as well as diseases related to not only MUC1 but also other membrane proteins.Laboratory Investigation advance online publication,

DOI： 10.1038/labinvest.2017.53

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PubMed

Other Link： http://www.ncbi.nlm.nih.gov/pubmed/28581490

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)

Publisher：(一社)日本小児血液・がん学会  

症例は5ヵ月の男児。水平性眼振と嘔吐を主訴に受診し、造影CT・MRI検査で両側硬膜下水腫、鞍上部腫瘍、および延髄、脊髄に多発転移病変を認めた。鞍上部腫瘍の生検術により、繊維形成性乳児星細胞腫(DIA:desmoplastic infantile astrocytoma、WHO grade 1)と診断した。低悪性度神経膠腫に対する化学療法レジメンであるvincristine、carboplatin(VC)療法を開始した。すぐに腫瘍径は縮小し始め、治療開始10週後には転移巣も消失した。現在、治療終了後13ヵ月であり、鞍上部腫瘍はわずかに残存するものの、再増大は認めない。現在、症状はなく、精神運動発達の遅れもない。症状を有するDIAに対しては外科的切除が推奨されるが、切除不能もしくは多発転移病変を有するDIAに対してはVC療法が有効な治療法の一つであると考えられた。(著者抄録)

Publisher：(一財)日本消化器病学会  

症例は77歳男性。胃噴門部O-IIc病変にESDを施行、病理診断は深達度SMの分化型優位混在癌、垂直断端(±)のため追加外科切除を施行した。1年10ヵ月後、肝腫瘍を認め肝部分切除を施行、NECと診断された。ESD病変は病理再検討により、胃NECと診断した。Stage IAのR0手術であったが、肝転移再発をきたした。肝切後の補助療法はS-1投与が有効で、1年4ヵ月無再発生存中である。(著者抄録)

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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PubMed

Other Link： http://www.ncbi.nlm.nih.gov/pubmed/28103910

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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PubMed

Publisher：Japanese College of Surgeons  

<p>A 59-years-old male admitted to Kagoshima Ohshima Hospital with a complaint of Right upper abdomen. Abdominal CT revealed giant gastric GIST 15cm in diameter arising from extra-gastric wall and large amount of fluid collection. Cytology of the fluid revealed negative of malignancy. Imatinib mesylate and diuretics have been administrated to control ascites and to shrink tumor size. However, ascites was aggravated, the patient needed to aspiration and drainage. Giant gastric GIST with ascites unknown etiology was diagnosed preoperatively, R0 resection of gastric GIST was performed. On entering abdominal cavity, small hole was identified in the cystic wall of gastric GIST and translucent fluid was flowed out from the tumor. The tumor was resected with extensive resection of transverse colon and stomach. After the surgery, refractory ascites was improving completely. Refractory ascites derived from the perforative cystic part of the gastric GIST is very rare. Surgery with curative intent is the only way to control fluid collection.</p>

DOI： 10.4030/jjcs.42.632

Publisher：The Japanese Society of Gastroenterological Surgery  

<p>A 69-year-old woman was initially given a diagnosis of unresectable pancreatic body cancer with liver metastasis and involvement of the celiac plexus. The pretreatment diagnosis according to the General Rules of the Study of Pancreatic Cancer (7th edition) was TS3 (35 mm), cT3, cS1, cRP1, cPV1 (PVp, PVsp), cA1 (Asp), cPL1, cN0, cM1 (HEP), cStage IV. After 6 courses of systemic chemotherapy (gemcitabine and nab-paclitaxel), the liver metastasis disappeared, however, the primary tumor invading the root of the splenic artery remained. Therefore, we performed chemoradiotherapy (CRT: S-1+56 Gy) for further local treatment. After CRT, we continued S-1 administration. Reassessment 12 months after the initial treatment by imaging examinations was complete response (CR). Serum CA 19-9 levels decreased from 1,846 U/ml to 13.3 U/ml. In consideration of remaining histological cancer cells, we performed resection of the pancreatic body and tail with regional lymph node dissection, splenectomy, and partial hepatectomy. Histopathological examination revealed that the tumor was replaced by fibrosis and no cancer cells were observed in the pancreas and liver. The evaluation of histopathological response to the preoperative therapy was CR. The patient remains alive without recurrence at 18 months after initial treatment and 6 months after surgical resection.</p>

DOI： 10.5833/jjgs.2016.0228

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Publisher：The Japanese Society of Gastroenterology  

<p>A 77-year-old man underwent endoscopic submucosal dissection (ESD) of a type 0-IIc tumor located in the cardiac part of the stomach. The pathological diagnosis of the tumor was poorly differentiated tubular adenocarcinoma with submucosal invasion depth;therefore, radical gastrectomy was also performed. After 1 year and 10 months, liver metastasis was detected because of which partial liver resection was performed. The pathological diagnosis of the tumor was neuroendocrine carcinoma (NEC). The pathology of the ESD specimen was re-examined, and a diagnosis of gastric NEC was made;furthermore, the liver tumor was regarded as metachronous metastasis. Despite the radical excision of the stage IA tumor, metastasis occurred. Chemotherapy with S-1 alone was successfully performed after the liver resection while considering the advanced age of the patient. Follow-up revealed no signs of recurrence at 1 year and 4 months after the treatment, indicating that the S-1 therapy may be considered for treating NEC in elderly and medically compromised patients owing to its mild side effects.</p>

DOI： 10.11405/nisshoshi.114.238

PubMed

Publisher：Journal of Japanese Society of Gastroenterology  

Scopus

Publisher：The Japanese Society of Pediatric Hematology / Oncology  

<p>In a 5-month-old boy with a history of horizontal nystagmus and vomiting, computed tomography and magnetic resonance imaging (MRI) demonstrated bilateral subdural hygroma and contrast-enhanced lesions in the suprasellar region, medulla oblongata, and the spinal axis. Histopathological examination of a suprasellar tumor biopsy specimen revealed a World Health Organization (WHO) grade I desmoplastic infantile astrocytoma (DIA). A regimen of vincristine and carboplatin (VC) chemotherapy for low-grade astrocytoma was started. The tumor size immediately decreased, and the metastatic lesions also disappeared after the initial 10 weeks of chemotherapy. Although a residual tumor remained in the suprasellar region, no tumor regrowth was detected 13 months after finishing the chemotherapy. The patient showed no symptoms or developmental delay. Although surgical resection is the recommended therapy for symptomatic DIA, our experience suggests that VC chemotherapy might be a therapeutic option for DIA in infants with unresectable tumor or multiple metastasis.</p>

DOI： 10.11412/jspho.54.39

Authorship：Lead author   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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PubMed

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

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

Publisher：RADIOLOGICAL SOC NORTH AMERICA  

Purpose: To examine whether dexamethasone suppression can reduce fluorine 18 fluorodeoxyglucose (FDG) uptake in false-positive (FP) findings in pulmonary and mediastinal lymph nodes in non-small cell lung cancer (NSCLC).
Materials and Methods: Institutional ethics review board approved this prospective study with written informed consent. The study population was composed of 17 patients with NSCLC who underwent both baseline and dexamethasone suppression (24 hours after oral administration of 8 mg dexamethasone) FDG positron emission tomography/computed tomography and surgery. FDG uptake was evaluated by using a five-point visual scoring system (negative findings, score of 0-1; positive findings, score of 2-4) and maximum standardized uptake value (SUVmax). The Mann-Whitney U, Wilcoxon signed-rank, Kruskal-Wallis, or Spearman rank correlation tests were used as necessary for statistical evaluations.
Results: In 17 primary lesions, no significant difference was noted in visual score between baseline (mean, 3.4 +/- 1.2) and dexamethasone suppression scans (mean, 3.3 +/- 1.2; P = .16), although SUVmax was significantly lower on dexamethasone suppression scans (mean, 7.1 +/- 5.2) than on baseline scans (mean, 8.6 +/- 6.6; P = .005). In eight nodes with true-positive (TP) findings, there were no significant differences in visual score (mean for both, 3.8 +/- 0.5) and SUVmax (mean, 5.3 +/- 2.3 vs 5.5 +/- 2.5, respectively; P = .81) between baseline and dexamethasone suppression scans. In 19 nodes with FP findings at baseline, dexamethasone suppression resulted in significantly lowered visual score (mean, 3.4 +/- 0.6 vs 2.4 +/- 0.8, respectively; P &lt; .001) and SUVmax (mean, 3.5 +/- 0.8 vs 2.7 +/- 0.7, respectively; P &lt; .001), and four nodes with FP findings were rated as true-negative findings on dexamethasone suppression scans, which resulted in a significant difference in SUVmax between nodal lesions with TP and FP findings (P = .014).
Conclusion: Oral dexamethasone has the potential to reduce FDG uptake in pulmonary and mediastinal nodes with FP findings in NSCLC. (C) RSNA, 2015

DOI： 10.1148/radiol.2015150883

Web of Science

PubMed

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

Web of Science

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

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

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

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

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

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

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

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

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

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

Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objectives The aim of this study was to further examine the utility of mucin (MUC) expression profiles as prognostic factors in pancreatic ductal adenocarcinoma (PDAC).
Methods Mucin expression was examined by immunohistochemistry analysis in endoscopic ultrasound-guided fine-needle aspiration specimens obtained from 114 patients with PDAC. The rate of expression of each MUC was compared with clinicopathologic features.
Results The expression rates of MUCs in cancer lesions were MUC1, 87.7%; MUC2, 0.8%; MUC4, 93.0%; MUC5AC, 78.9%; MUC6, 24.6%; and MUC16, 67.5%. MUC1 and MUC4 were positive, and MUC2 was negative in most PDACs. Patients with advanced stage of PDAC with MUC5AC expression had a significantly better outcome than those who were MUC5AC-negative (P = 0.002). With increasing clinical stage, total MUC6 expression decreased (P for trend = 0.001) and MUC16 cytoplasmic expression increased (P for trend = 0.02). The prognosis of patients with MUC16 cytoplasmic expression was significantly poorer than those without this expression. Multivariate survival analysis revealed that MUC16 cytoplasmic expression was a significant independent predictor of a poor prognosis after adjusting for the effects of other prognostic factors (P = 0.002).
Conclusions Mucin expression profiles in ultrasound-guided fine-needle aspiration specimens have excellent diagnostic utility and are useful predictors of outcome in patients with PDAC.

DOI： 10.1097/MPA.0000000000000362

Web of Science

PubMed

Publisher：SPRINGER JAPAN KK  

Both MUC1 and MUC4 are high molecular weight glycoproteins and are independent indicators of worse prognosis in many human epithelial cancers including oral squamous cell carcinoma (OSCC). However, there has been no investigation of the clinical importance of the co-expression of MUC1 and MUC4 in OSCC. The aim of this study was to evaluate the co-expression profile of MUC1/MUC4 and analyze the prognostic significance in OSCC.
We examined the expression profile of MUC1 and MUC4 in OSCC tissues from 206 patients using immunohistochemistry. The co-expression profile of MUC1/MUC4 and its prognostic significance in OSCC was statistically analyzed.
MUC1 and MUC4 overexpression were strongly correlated with each other (p &lt; 0.0001) and a combination of both MUC1 and MUC4 expression was a powerful indicator for tumor aggressiveness such as tumor size (p = 0.014), lymph node metastasis (0.0001), tumor stage (p = 0.006), diffuse invasion (p = 0.028), and vascular invasion (p = 0.014). The MUC1/MUC4 double-positive patients showed the poorest overall and disease-free survival. Multivariate analysis revealed that MUC1/MUC4 double-positivity was the strong independent prognostic factor for overall and disease-free survival (p = 0.007 and (p = 0.0019), in addition to regional recurrence (p = 0.0025).
Taken together, these observations indicate that the use of a combination of MUC1/MUC4 can predict outcomes for patients with OSCC. This combination is also a useful marker for predicting regional recurrence. MUC1 and MUC4 may be attractive targets for the selection of treatment methods in OSCC.

DOI： 10.1007/s10147-014-0710-6

Web of Science

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

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

Publisher：PUBLIC LIBRARY SCIENCE  

Background: Mucins are implicated in survival in various cancers, but there have been no report addressed on survival in appendiceal carcinoma, an uncommon disease with different clinical and pathological features from those of other colon cancers. We aimed to investigate the clinical implications of expression of mucins in appendiceal carcinoma.
Methods: Expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6, MUC16 and MUC17 in cancer tissue were examined by immunohistochemistry in 108 cases of surgically resected appendiceal carcinoma.
Results: The following relationships of mucins with clinicopathologic factors were identified: MUC1 with positive lymphatic invasion (p=0.036); MUC2 with histological type (mucinous carcinoma, p&lt;0.001), superficial invasion depth (p=0.007), negative venous invasion (p=0.003), and curative resection (p=0.019); MUC3 with non-curative resection (p=0.017); MUC5AC with histological type (mucinous carcinoma, p=0.002), negative lymphatic invasion (p=0.021), and negative venous invasion (p=0.022); and MUC16 with positive lymph node metastasis (p=0.035), positive venous invasion (p&lt;0.05), and non-curative resection (p=0.035). A poor prognosis was related to positive lymph node metastasis (p=0.04), positive lymphatic invasion (p=0.02), positive venous invasion (p&lt;0.001), non-curative resection (p&lt;0.001), and positive expression of MUC3 (p=0.004). In multivariate analysis, positive venous invasion (HR: 6.93, 95% CI: 1.93-24.96, p=0.003), non-curative resection (HR: 10.19, 95% CI: 3.05-34.07, p&lt;0.001) and positive MUC3 expression (HR: 3.37, 95% CI: 1.13-10.03, p=0.03) were identified as significant independent prognostic factors in patients with appendiceal carcinoma.
Conclusions: Expression of MUC3 in appendiceal carcinoma is an independent factor for poor prognosis and a useful predictor of outcome in patients with appendiceal carcinoma after surgery.

DOI： 10.1371/journal.pone.0115613

Web of Science

PubMed

Publisher：SPRINGER  

To examine correlations of F-18-fluorothymidine (FLT) uptake with pathological tumour size and immunohistochemical Ki-67, and thymidine kinase 1 (TK-1) expressions in primary and metastatic node colorectal cancer foci.
Thirty primary cancers (PCs) and 37 metastatic nodes (MNs) were included. FLT uptake was assessed by visual scores (non-visible: 0-1 and visible: 2-4), standardized uptake value (SUV), and correlated with size, Ki-67, and TK-1. SUV was measured in visible lesions. FLT heterogeneity was assessed by visual scores (no heterogeneous uptake: 0 and heterogeneous uptake: 1-4).
Forty-two lesions were visible. The visible group showed significantly higher values than the non-visible group in size, Ki-67, and TK-1 (each p &lt; 0.05). Size correlated significantly with visual score (PC; rho = 0.74 and MN; rho = 0.63), SUVmax (PC; rho = 0.49, and MN; rho = 0.76), and SUVmean (PC; rho = 0.40 and MN; rho = 0.76) (each p &lt; 0.05). Visual score correlated significantly with size (rho = 0.86), Ki-67max (rho = 0.35), Ki-67mean (rho = 0.38), TK-1max (rho = 0.35) and TK-1mean (rho = 0.25) (each p &lt; 0.05). No significant correlations were found between FLT uptake and Ki-67 or TK-1 in 42 visible lesions (each p &gt; 0.05). Heterogeneous FLT uptake was noted in 73 % (22/30) of PCs.
FLT uptake correlated with size. Heterogeneous FLT distribution in colorectal cancers may be one of the causes of weak or lack of FLT uptake/Ki-67 or TK-1 correlation.
aEuro cent FLT uptake correlated well with tumour size in colorectal cancer
aEuro cent Weak or lack of FLT uptake/Ki-67 and TK-1 correlations were observed
aEuro cent Immunohistochemical Ki-67 and TK-1 expressions are not always correlated with FLT uptake.

DOI： 10.1007/s00330-014-3379-3

Web of Science

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

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

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

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

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

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

Publisher：PUBLIC LIBRARY SCIENCE  

Mucins have been associated with survival in various cancer patients, but there have been no studies of mucins in small bowel carcinoma (SBC). In this study, we investigated the relationships between mucin expression and clinicopathologic factors in 60 SBC cases, in which expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6 and MUC16 in cancer and normal tissues were examined by immunohistochemistry. MUC1, MUC5AC and MUC16 expression was increased in SBC lesions compared to the normal epithelium, and expression of these mucins was related to clinicopathologic factors, as follows: MUC1 [tumor location (p = 0.019), depth (p = 0.017) and curability (p = 0.007)], MUC5AC [tumor location (p = 0.063) and lymph node metastasis (p = 0.059)], and MUC16 [venous invasion (p = 0.016) and curability (p = 0.016)]. Analysis of 58 cases with survival data revealed five factors associated with a poor prognosis: poorly-differentiated or neuroendocrine histological type (p&lt;0.001), lymph node metastasis (p&lt;0.001), lymphatic invasion (p = 0.026), venous invasion (p&lt;0.001) and curative resection (p&lt;0.001), in addition to expression of MUC1 (p = 0.042), MUC5AC (p = 0.007) and MUC16 (p&lt;0.001). In subsequent multivariate analysis with curability as the covariate, lymph node metastasis, venous invasion, and MUC5AC and/or MUC16 expression were significantly related to the prognosis. Multivariate analysis in curative cases (n = 45) showed that SBC with MUC5AC and/or MUC16 expression had a significantly independent high hazard risk after adjusting for the effects of venous invasion (hazard ratio: 5.6, 95% confidence interval: 1.8-17). In conclusion, the study shows that a MUC5AC-positive and/or MUC16-positive status is useful as a predictor of a poor outcome in patients with SBC.

DOI： 10.1371/journal.pone.0086111

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PubMed

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

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

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

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

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

DOI： 10.1097/MPA.0b013e3182965915

PubMed

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

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

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

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

DOI： 10.1007/s10120-011-0125-2

PubMed

Publisher：BIOMED CENTRAL LTD  

Background: Methylation of CpG sites in genomic DNA plays an important role in gene regulation and especially in gene silencing. We have reported mechanisms of epigenetic regulation for expression of mucins, which are markers of malignancy potential and early detection of human neoplasms. Epigenetic changes in promoter regions appear to be the first step in expression of mucins. Thus, detection of promoter methylation status is important for early diagnosis of cancer, monitoring of tumor behavior, and evaluating the response of tumors to targeted therapy. However, conventional analytical methods for DNA methylation require a large amount of DNA and have low sensitivity.
Methods: Here, we report a modified version of the bisulfite-DGGE (denaturing gradient gel electrophoresis) using a nested PCR approach. We designated this method as methylation specific electrophoresis (MSE). The MSE method is comprised of the following steps: (a) bisulfite treatment of genomic DNA, (b) amplification of the target DNA by a nested PCR approach and (c) applying to DGGE. To examine whether the MSE method is able to analyze DNA methylation of mucin genes in various samples, we apply it to DNA obtained from state cell lines, ethanol-fixed colonic crypts and human pancreatic juices.
Result: The MSE method greatly decreases the amount of input DNA. The lower detection limit for distinguishing different methylation status is &lt; 0.1% and the detectable minimum amount of DNA is 20 pg, which can be obtained from only a few cells. We also show that MSE can be used for analysis of challenging samples such as human isolated colonic crypts or human pancreatic juices, from which only a small amount of DNA can be extracted.
Conclusions: The MSE method can provide a qualitative information of methylated sequence profile. The MSE method allows sensitive and specific analysis of the DNA methylation pattern of almost any block of multiple CpG sites. The MSE method can be applied to analysis of DNA methylation status in many different clinical samples, and this may facilitate identification of new risk markers.

DOI： 10.1186/1471-2407-12-67

Web of Science

PubMed

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

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

DOI： 10.1371/journal.pone.0044108

PubMed

DOI： 10.1159/000335164

PubMed

DOI： 10.1371/journal.pone.0049251

PubMed

DOI： 10.1111/j.1440-1827.2011.02734.x

PubMed

DOI： 10.1007/s13148-011-0037-3

PubMed

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

DOI： 10.1093/glycob/cwq155

PubMed

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

DOI： 10.1007/s00534-010-0278-0

PubMed

Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

MUC3A is a membrane-bound glycoprotein that is aberrantly expressed in carcinomas and is a risk factor for a poor prognosis. However, the exact mechanism of MUC3A expression has yet to be clarified. Here, we provide the first evidence that MUC3A gene expression is controlled by the CpG methylation status of the proximal promoter region. We show that the DNA methylation pattern is intimately correlated with MUC3A expression in breast, lung, pancreas and colon cancer cell lines. The DNA methylation status of 30 CpG sites from -660 to +273 was mapped using MassARRAY analysis. MUC3A-negative cancer cell lines and those with low MUC3A expression (e.g., MCF-7) were highly methylated in the proximal promoter region, corresponding to 9 CpG sites (-345 to -75 bp), whereas MUC3A-positive cell lines (e.g., LS174T) had low methylation levels. Moreover, 5-aza-2'-deoxycytidine and trichostatin A treatment of MUC3A-negative cells or those with low MUC3A expression caused elevation of MUC3A mRNA. Our results suggest that DNA hypomethylation in the 5'-flanking region of the MUC3A gene plays an important role in MUC3A expression in carcinomas of various organs. An understanding of epigenetic changes in MUC3A may contribute to the diagnosis of carcinogenic risk and to prediction of outcome in patients with cancer. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2010.05.124

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PubMed

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

Publisher：SPANDIDOS PUBL LTD  

A number of studies have reported the presence of human papillomavirus (HPV) in lung carcinoma. Interestingly, its detection rate appears to differ histologically and geographically. The present study examined 30 adenocarcinomas and 27 squamous cell carcinomas of the lung in a southern area of Japan, and detected high-risk HPV genome in 9 (30%) adenocarcinomas and 2 (7%) squamous cell carcinomas, using PCR with SPF10 primers and INNO-LiPA HPV genotyping assay. The difference of HPV detection rates in adenocarcinomas and squamous Cell carcinomas was statistically significant (P=0.044, Fisher&apos;s exact test). HPV-16 was the most prevalent HPV genotype. and was detected in 27% (8/30) of adenocarcinomas and in 7% (2/27) of squamous cell carcinomas. High-risk-HPV positive carcinomas had decreased proportions of pRb (P=0.107) and significantly increased proportions of p16(INK4a) expressing cells (P=0.031) when Compared to HPV-negative lung carcinomas. All HPV-16-positive cases were considered to have an integrated form of HPV-16 but its viral load was low (geometric mean = 0.02 copy per cell). In 20 additional adenocarcinomas treated with gefitinib, a tyrosine kinase inhibitor specific for epidermal growth factor receptor, the presence of HPV was examined. Note that East Asian ethnicity is a predictive factor of gefitinib response. High-risk HPV genome was found in 75% (6/8) of adenocarcinomas with complete or partial response to gefitinib but Was not found in the remaining 12, which did not respond to gefitinib. In Conclusion, the present study suggests that high-risk HPV may be more strongly related to adenocarcinomas, particularly gefitinib-responsive adenocarcinomas, when compared to squamous cell carcinomas. However, its low viral load makes it difficult to determine the etiological significance of these findings.

DOI： 10.3892/or_00000736

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

DOI： 10.1007/s00534-009-0174-7

PubMed

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

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

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

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

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

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

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

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

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

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

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

Publisher：Springer Japan  

We experienced a rare case of spindle cell carcinoma of the pancreas. The patient was a 74-year-old man who complained of abdominal pain and loss of weight. Ultrasonographic scans revealed a hypoechoic solid mass in the head of the pancreas, 4 cm in diameter, with a high echoic spot suggestive of central necrosis or hemorrhage. The mass was hypodense on enhanced computed tomographic scans and hypovascular on angiograms. At laparotomy, the tumor had invaded to the mesocolon, but dissemination and distant metastasis were not found. We therefore performed pylorus-preserving pancreatoduodenectomy and ascending colectomy. The patient was discharged on postoperative day 26 after an uneventful recovery. Two months later, he was readmitted because of ascites, with positivity of spindle cells shown on cytology
he died on day 92 after surgery. In the resected specimen, the tumor had a mostly sarcomatous component, consisting of spindle-shaped cells, and a small glandular component. Immunohistochemically, both components were positive for cytokeratin and epithelial membrane antigen, but negative for vimentin and desmin. The tumor was diagnosed as a spindle cell carcinoma of the pancreas. Perinural invasion, lymphatic permeation, and blood vessel invasion were found, but lymph node metastasis was not found. Although a curative operation was performed, the outcome in this patient was very poor.

DOI： 10.1007/s005340050183

Scopus

PubMed

Publisher：(株)アークメディア  

Publisher：(株)アークメディア  

Publisher：(一社)日本病理学会  

Publisher：(一社)日本病理学会  

Publisher：(株)メジカルビュー社  

副腎疾患は、ほかの内分泌腫瘍と同様に診断が非常に難しいとされている。本稿では、比較的よく遭遇する疾患を中心に肉眼像、組織像を提示し、鑑別ポイントを挙げたい。(著者抄録)

Publisher：John Wiley & Sons Australia, Ltd  

Publisher：Pathology International  

DOI： 10.1111/pin.12541

Scopus

PubMed

Publisher：(一社)日本病理学会  

Publisher：(一社)日本病理学会  

Publisher：(一社)日本病理学会  

Publisher：(一社)日本病理学会  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2014-1897

Web of Science

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publisher：(一社)日本病理学会  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publisher：SPRINGER  

Web of Science

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publisher：(一社)日本病理学会  

Publisher：(一社)日本病理学会  

Publisher：(一社)日本病理学会  

Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2011-82

Web of Science

Publisher：(一社)日本病理学会  

Publisher：(一社)日本病理学会  

Publisher：BIOMED CENTRAL LTD  

Mucins are high molecular weight glycoproteins that play important roles in diagnostic and prognostic prediction and in carcinogenesis and tumor invasion. Regulation of expression of mucin genes has been studied extensively, and signaling pathways, transcriptional regulators, and epigenetic modification in promoter regions have been described. Detection of the epigenetic status of cancer-related mucin genes is important for early diagnosis of cancer and for monitoring of tumor behavior and response to targeted therapy. Effects of micro-RNAs on mucin gene expression have also started to emerge. In this review, we discuss the current views on epigenetic mechanisms of regulation of mucin genes (MUC1, MUC2, MUC3A, MUC4, MUC5AC, MUC5B, MUC6, MUC16, and MUC17) and the possible clinical applications of this epigenetic information.

DOI： 10.1007/s13148-011-0037-3

Web of Science

Publisher：日本癌学会  

Publisher：日本脳腫瘍病理学会  

Publisher：(一社)日本病理学会  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

DOI： 10.1111/j.1447-0756.2010.01221.x

PubMed

DOI： 10.1007/s00534-009-0176-5

PubMed

Publisher：日本癌学会  

Publisher：日本癌学会  

Publisher：日本癌学会  

Publisher：(株)医学書院  

DOI： 10.11477/mf.1403101672

Publisher：(株)医学書院  

DOI： 10.11477/mf.1403101611

Publisher：医学図書出版(株)  

第11回国際膵臓学会(2004年)でのコンセンサスミーティングにおいて、IPMNがムチン発現様式を加味して、以下の4つの組織亜型に分類された。Gastric type:明るい好酸性の胞体を有する胃腺窩上皮に似た円柱状細胞が乳頭状構造をつくり、ムチン発現様式はMUC1-・MUC2-・MUC5AC+である。Intestinal type:好塩基性で暗調の胞体を有する円柱状細胞が大腸絨毛腺腫に類似した増殖を呈しMUC1-・MUC2+・MUC5AC+である。Pancreatobiliary type:立方状細胞が複雑な樹枝状乳頭構造を形成し胆管系の乳頭性腫瘍に似ておりMUC1+/-・MUC2-・MUC5AC+である。Oncocytic type:好酸性の豊富な胞体を持つ細胞が内腔形成を伴う幅広く分枝した乳頭構造を形成しMUC1+(focal)・MUC2-・MUC5AC+である。本邦においてはPancreatobiliary typeとOncocytic typeは稀である。IPMNの「主膵管型」の多くがIPMN-intestinal typeであり、「分枝膵管型」の多くはIPMN-gastric typeである。intestinal typeはgastric typeに較べて有意に癌の発生率が高く予後不良である。ムチン発現様式を加味したIPMNの組織亜型分類は、「IPMN/MCN国際診療ガイドライン(2006年)」に記載されている「患者の余命がある程度長く手術リスクが低い場合には、主膵管型と混合型のIPMNの全例を切除の適応とすることを、われわれが推奨する現段階の指針としたい。一方、分枝膵管型は、嚢胞に由来すると考えられる症状の有無、壁在結節の有無、嚢胞径、主膵管径を参考に切除か経過観察かを選択する」という治療方針にも密接に関連する。(著者抄録)

DOI： 10.1038/sj.bjc.6604845

Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Web of Science

Publisher：日本癌学会  

Publisher：日本癌学会  

Publisher：INT INST ANTICANCER RESEARCH  

Web of Science

Publisher：AMER SOC MICROBIOLOGY  

Buruli ulcer is a chronic skin disease caused by Mycobacterium ulcerans, which produces a toxic lipid mycolactone. Despite the extensive necrosis and tissue damage, the lesions are painless. This absence of pain prevents patients from seeking early treatment and, as a result, many patients experience severe sequelae, including limb amputation. We have reported that mice inoculated with M. ulcerans show loss of pain sensation and nerve degeneration. However, the molecules responsible for the nerve damage have not been identified. In order to clarify whether mycolactone alone can induce nerve damage, mycolactone A/B was injected to footpads of BALB/c mice. A total of 100 mu g of mycolactone induced footpad swelling, redness, and erosion. The von Frey sensory test showed hyperesthesia on day 7, recovery on day 21, and hypoesthesia on day 28. Histologically, the footpads showed epidermal erosion, moderate stromal edema, and moderate neutrophilic infiltration up to day 14, which gradually resolved. Nerve bundles showed intraneural hemorrhage, neutrophilic infiltration, and loss of Schwann cell nuclei on days 7 and 14. Ultra structurally, vacuolar change of myelin started on day 14 and gradually subsided by day 42, but the density of myelinated fibers remained low. This study demonstrated that initial hyperesthesia is followed by sensory recovery and final hypoesthesia. Our present study suggests that mycolactone directly damages nerves and is responsible for the absence of pain characteristic of Buruli ulcer. Furthermore, mice injected with 200 mu g of mycolactone showed pulmonary hemorrhage. This is the first study to demonstrate the systemic effects of mycolactone.

DOI： 10.1128/IAI.01588-07

Web of Science

PubMed

Publisher：(株)南江堂  

第11回国際膵臓学会(2004年)でのコンセンサスミーティングにおいて、膵管内乳頭粘液性腫瘍(IPMN)がgastric type,intestinal type,pancreatobiliary type,oncocytic typeの4つの組織亜型に分類されたが、頻度が高いのはgastric typeとintestinal typeである。「IPMN/MCN国際診療ガイドライン(2006年)」に述べられているIPMNの「主膵管型」の多くがIPMN-intestinal type(大腸絨毛腺腫に類似した組織像を呈し、MUC1陰性・MUC2陽性)であり、「分枝膵管型」の多くはIPMN-gastric type(胃腺窩上皮に似た円柱状細胞の増殖像を呈し、MUC1陰性・MUC2陰性)である。ムチン発現様式を加味したIPMNの組織分類は、上記ガイドラインに記載されている「主膵管型は悪性化をきたすことが多いので手術的切除の適応となるが、分枝膵管型は嚢胞径や壁在結節の有無ならびに症状の有無で切除か経過観察かを選択する」という治療方針にも密接に関連する。(著者抄録)

Publisher：(一社)日本病理学会  

Publisher：日本分子腫瘍マーカー研究会  

DOI： 10.1002/pmic.200800040

DOI： 10.1158/0008-5472.CAN-07-6844

Publisher：日本分子腫瘍マーカー研究会  

Publisher：日本癌学会  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publisher：(一社)日本外科学会  

DOI： 10.1007/s00534-006-1169-2

PubMed

Publisher：WILEY-LISS  

Mucins are highly glycosylated proteins that play important roles in carcinogenesis. In pancreatic neoplasia, MUC2 mucin has been demonstrated as a tumor suppressor and we have reported that MUC2 is a favorable prognostic factor. Regulation of MUC2 gene expression is known to be controlled by DNA methylation, but the role of histone modification for MUC2 gene expression has yet to be clarified. Herein, we provide the first report that the histone H3 modification of the MUC2 promoter region regulates MUC2 gene expression. To investigate the histone modification and DNA methylation of the promoter region of the MUC2 gene, we treated 2 human pancreatic cancer cell lines, PANC1 (MUC2-negative) and BxPC3 (MUC2-positive) with the DNA methyltransferase inhibitor 5-azacytidine (5-aza), the histone deacetylase inhibitor trichostatin A (TSA), and a combination of these agents. The DNA methylation level of PANC1 cells was decreased by all 3 treatments, whereas histone H3-K4/K9 methylation and H3-K9/K27 acetylation in PANC1 cells was changed to the level in BxPC3 cells by treatment with TSA alone and with the 5-aza/TSA combination. The expression level of MUC2 mRNA in PANC1 cells exhibited a definite increase when treated with TSA and 5-aza/TSA, whereas 5-aza alone induced only a slight increase. Our results suggest that histone H3 modification in the 5' flanking region play an important role in MUC2 gene expression, possibly affecting DNA methylation. An understanding of these intimately correlated epigenetic changes may be of importance for predicting the outcome of patients with pancreatic neoplasms. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/ijc.22047

Web of Science

Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Many of the patients with extrahepatic bile duct carcinoma (EHBDC) show a poor outcome. We have reported that MUC4 is a novel prognostic factor of pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma. The aim of this study is to evaluate the prognostic significance of MUC4 expression in EHBDC.
Experimental Design: We examined the expression profile of MUC4 in EHBDC tissues from 70 patients using immunohistochemistry. MUC4 is a membrane mucin like MUC1. In addition MUC4 is an intramembrane ligand for receptor tyrosine kinase ErbB2 and is related with regulation of p27. We compared the MUC4 expression with MUC1, ErbB2, or p27 expression in EHBDC.
Results: MUC4 was expressed in 36 of the 70 patients with EHBDC. There was no significant correlation between the MUC4 expression and MUC1, ErbB2, or p27 expression. The survival of 19 patients with high MUC4 expression (&gt;= 20% of carcinoma cells stained) was significantly worse than that of the 51 patients with low MUC4 expression (under 20% of carcinoma cells stained; P = 0.0072). The univariate analysis showed that high MUC4 expression (P = 0.0072), high MUC1 expression (P = 0.0092), histologic grading (P = 0.0029), surgical margin involvement (P = 0.0137), and nodal metastasis (P = 0.0036) were statistically significant risk factors. The backward stepwise multivariate analysis showed that high MUC4 expression (P = 0.0195) and surgical margin involvement (P = 0.0358) were statistically significant independent risk factors.
Conclusions: MUC4 expression in EHBDC is a new independent factor for poor prognosis and predicts the outcome of patients with EHBDC.

DOI： 10.1158/1078-0432.CCR-05-2814

Web of Science

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publisher：ELSEVIER IRELAND LTD  

Expression of the MUC2 gene is controlled by the methylation of CpG sites in the promoter region, but the detailed methylation status of this region has yet to be reported. We have mapped the complete methylation status of the MUC2 promoter from position -1989 to position +288 upstream, a region that contains 59 CpG sites, using bisulfite genomic sequencing in two pancreatic cancer cell lines (PANC1, BxPC3) and in isolated normal colon crypts as a control. The MUC2 promoter in PANC1, a cell line that does not express MUC2, was highly methylated (average 87%, complete methylation at 28 of the 59 CpG sites), while the promoter region in the MUC2-expressing BxPC3 cell line (average 43%, complete methylation at 2 of 59 CpG sites) and in MUC2-expressing normal colon crypts (average 33%, no CpG site was completely methylated) were only partially methylated (P&lt;0.0001). 5-Aza-2'-deoxycytidine treatment of PANC1 cells reduced the methylation level (average 36%) and induced MUC2 mRNA expression. However, mRNA expression of AP2, SP1 and CDX2 was not affected by this treatment. Our data provide the first detailed methylation map of the MUC2 promoter region for the first time, using the conversion-specific bisulfite genomic sequencing. Previously unproven methylation sites were detected, and some AP2 and SP1 binding sites showed different methylation levels among PANC1, BxPC3 and colonic crypt cells. Our mapping data provide an essential basis for further studies of methylation-regulated MUC2 inactivation. (C) 2005 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2004.11.058

Web of Science

Publisher：SPRINGER TOKYO  

A rare case of a carcinosarcoma of the extrahepatic bile duct demonstrating interesting features is described. A 75-year-old woman with a history of choledocholithotomy presented with acute obstructive suppurative cholangitis. Ultrasonography and computed tomography showed a thickened choledochal wall, with calcification. Percutaneous transhepatic and endoscopic retrograde cholangiography revealed a round filling defect accompanied by an irregular obstruction in the common bile duct. Carcinosarcoma was diagnosed from a protruding lesion in the common bile duct obtained by intraoperative frozen sectioning, and pylorus-preserving pancreatoduodenectomy was performed. Histological examination by light microscopy showed a transition between the carcinomatous and sarcomatous components and positive immunoreactivity for epithelial markers in the sarcomatous component. The patient died of a local recurrence 2 years after the surgery. Polypoid growth and ossification in the tumor could be representative features of carcinosarcoma of the extrahepatic bile duct.

DOI： 10.1007/s00534-005-0988-x

Web of Science

PubMed

Publisher：SPRINGER  

Purpose: CD227 (MUC1), a membrane-associated glycoprotein expressed by many types of ductal epithelia, including pancreas, breast, lung, and gastrointestinal tract, is overexpressed and aberrantly glycosylated by malignant cells. We sought to define epitopes on MUC1 recognized by the different cell-mediated immune responses by an in vivo assay. Epitopes identified by this assay were evaluated for efficacy to protect mice transgenic for human MUC1 (MUC1.Tg) against MUC1-expressing tumor growth. Methods: We investigated contributions of the tandem repeat (TR) and the cytoplasmic tail (CT) of MUC1 to the MUC1-specific immunological rejection of tumor cells. MUC1 cDNA constructs, in which the TR region was deleted or the CT was truncated, were transfected into two different murine tumor cell lines (B16 and Panc02), which were used to challenge mice and evaluate immunological rejection of the tumors. We used tumor rejection in vivo to define epitopes on the TR and CT of MUC1 recognized by T cell-mediated immune responses in a preclinical murine model. Results: Our findings demonstrated that the TR and a portion of the MUC1 CT contributed to CD4(+) T cell rejection of MUC1-expressing B16 tumor cells, but not rejection of MUC1-expressing Panc02 tumor cells. A separate epitope in the CT of MUC1 was necessary for CD8(+) T cell rejection of Panc02 tumor cells. Based on these studies, we sought to evaluate the efficacy of immunizing mice transgenic for (and immunologically tolerant to) human MUC1 with peptides derived from the amino acid sequence of the CT of MUC1. Results showed that survival can be significantly prolonged in vaccinated MUC1.Tg mice challenged with MUC1-expressing tumor cells, without induction of autoimmune responses. Conclusions: These studies demonstrated that MUC1 peptides may be utilized as an effective anticancer immunotherapeutic, and confirmed the importance of immunogenic epitopes outside of the TR.

DOI： 10.1007/s00262-004-0557-1

Web of Science

Publisher：JOHN WILEY & SONS INC  

Complete surgical resection of the tumor is the sole approach to improve the cure rate of patients with intrahepatic cholangiocarcinoma-mass forming type (ICC-MF). Although patients are treated by curative resection, many of them show poor outcome. Mucin (MUC)4 expression has been implicated as a marker for diagnosis and progression of pancreatic adenocarcinomas, but there is no study of the relationship between MUC4 expression and patient's prognosis in ICC-MF. In the present study, we examined the expression profile of MUC4 in ICC-MF tissue from 27 patients using immunohistochemistry. MUC4 was expressed in the carcinoma tissues of 10 (37%) of the 27 ICC-MF tumors, whereas it was not expressed in normal liver tissue. Because MUC4 is an intramembrane ligand for receptor tyrosine kinase ErbB2 and is related with regulation of p27, we also compared the MUC4 expression with ErbB2 and p27 expressions in ICC-MFs. The patients with MUC4 and ErbB2 double positive expression showed a short survival period compared to non-expressing patients. MUC4 and p27 showed no relationship. The univariate analysis showed that tumor size, intrahepatic metastasis, lymph node metastasis, MUC4 expression, and MUC1 expression were statistically significant risk factors affecting the outcome of the patients with ICC-MF. The multivariate analysis demonstrated that MUC4 expression, as well as surgical margin, were statistically significant independent risk factors. In conclusion, the results suggest that expression of MUC4 in ICC-MF is a new independent factor for poor prognosis and is a useful marker to predict the outcome of the patients with ICC-MF.

DOI： 10.1002/hep.20031

Web of Science

Publisher：AMER ASSOC CANCER RESEARCH  

MUC1 is a polymorphic, highly glycosylated, type I transmembrane protein expressed by ductal epithelial cells of many organs including pancreas, breast, gastrointestinal tract, and airway. MUC1 is overexpressed and differentially glycosylated by adenocarcinomas that arise in these organs, and is believed to contribute to invasive and metastatic potential by contributing to cell surface adhesion properties [via the tandem repeat (TR) domain] and through morphogenetic signal transduction [via the cytoplasmic tail (CT)]. The large extracellular TR of MUC1 consists of a heavily glycosylated, 20 amino acid sequence that shows allelic variation with respect to number of repeats. This portion of MUC1 may directly mediate adhesive or antiadhesive interactions with other surface molecules on adjacent cells and through these interactions initiate signal transduction pathways that are transmitted through the CT. We investigated the contribution of the TR domain and the CT of MUC1 to the in vivo invasive and metastatic potential, and the gene expression profile of the human pancreatic tumor cell line S2-013. Results showed that S2-013 cells overexpressing full-length MUC1 displayed a less invasive and metastatic phenotype compared with control-transfected cells and cells expressing MUC1 lacking the TR domain or CT. Clonal populations were analyzed by cDNA array gene expression analysis, which showed differences in the gene expression profiles between the different cell lines. Among the genes differentially expressed were several that encode proteins believed to play a role in invasion and metastasis.

Web of Science

Publisher：HISTOCHEMICAL SOC INC  

Sialyl-Tn (STn), a mucin-associated disaccharide antigen carried by apomucins such as MUC2, plays an important role in tumor biology. However, little is known about the subcellular localization and compartments involved in STn synthesis. In this study we used immunoelectron microscopy to localize STn and MUC2 apomucin in human colorectal tissues. MUC2 apomucin was localized predominantly in the rough endoplasmic reticulum (RER) in normal colorectal mucosa (n=6), colorectal adenoma (n=8), and colorectal adenocarcinoma (n=10). STn, recognized by monoclonal antibody TKH2, was not readily detectable in normal colorectal mucosa but becomes manifest in both trans-Golgi apparatus and mucin droplets in colorectal adenoma. In colorectal adenocarcinoma, STn was localized not only in late but also in early Golgi compartments, and particularly in some RER lumens. Furthermore, electron microscopic in situ hybridization revealed that gold particles representing MUC2 mRNA are primarily localized over the RER. Our findings indicate that in colorectal adenoma STn sialylation takes place in the trans-Golgi apparatus, whereas in colorectal cancer STn sialylation occurs in all the Golgi compartments and in the RER.

Web of Science

Event date： 2013.6

Language：Japanese  

Venue：北海道  

国内学会

Event date： 2012.4

Language：Japanese  

Venue：東京  

国内学会

Event date： 2011.8

Language：English  

Venue：フィンランド  

国際学会