Faculty Profiles - akihide Tanimoto

Papers - akihide Tanimoto

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Noguchi M, Miura N, Ando T, Kubota C, Hobo S, Kawaguchi H, Tanimoto A . Profiles of reproductive hormone in the microminipig during the normal estrous cycle. . In vivo (Athens, Greece)29 ( 1 ) 17 - 22 2015.1Reviewed

Miyoshi N, Horiuchi M, Inokuchi Y, Miyamoto Y, Miura N, Tokunaga S, Fujiki M, Izumi Y, Miyajima H, Nagata R, Misumi K, Takeuchi T, Tanimoto A, Yasuda N, Yoshida H, Kawaguchi H . Novel microminipig model of atherosclerosis by high fat and high cholesterol diet, established in Japan. . In vivo (Athens, Greece)24 ( 5 ) 671 - 80 2010.9Reviewed

Miki Murakami, Hirotsugu Noguchi, Ryosuke Matsushita, Shuichi Tatarano, Mari Kirishima, Takashi Tasaki, Ikumi Kitazono, Michiyo Higashi, Hideki Enokida, Akihide Tanimoto . Urothelial carcinoma arising in orthotopic ileal neobladder reconstruction: A case report. . World journal of clinical cases13 ( 26 ) 104876 - 104876 2025.9Reviewed International journal

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

BACKGROUND: An ileal neobladder is a standardized form of urinary diversion that provides acceptable outcomes in terms of long-term quality of life. Urothelial carcinomas (UCs) arising in the ileal neobladder are extremely rare, and few reports on this have been published in the English language. CASE SUMMARY: We report a case of UC that developed in the ileal neobladder of a 63-year-old man. The patient was diagnosed with UC in situ and underwent radical cystoprostatectomy and ileal neobladder creation. Ten years after the surgery and neoadjuvant chemotherapy, an UC developed in the ileal neobladder. CONCLUSION: Ileal neobladder urothelial carcinoma can originate from the implanted urothelium and the intestinal mucosa can migrate intraluminally.

DOI： 10.12998/wjcc.v13.i26.104876

Shintaro Yanazume, Ikumi Kitazono, Shinichi Togami, Akihide Tanimoto, Hiroaki Kobayashi . Potential biomarkers for predicting the efficacy of a pembrolizumab-containing regimen in advanced cervical cancer: A real-world analysis. . Turkish journal of obstetrics and gynecology22 ( 3 ) 246 - 256 2025.9Reviewed International journal

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

OBJECTIVE: Prognostic biomarkers in patients with advanced cervical cancer treated with immune checkpoint inhibitors remain unclear. An evaluation of combined positive score (CPS) and tumor proportion score (TPS), and a comparison of their usefulness with inflammatory biomarkers in real-world data could be informative. MATERIALS AND METHODS: We analyzed 28 patients who were treated with the KEYNOTE-826 regimen between November 2022 and June 2024. The complete cohort (group 1), patients with no prior chemotherapy (group 2), and treatment-naïve (group 3) were evaluated as follows: 1) CPS, TPS, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and hemoglobin, albumin, lymphocyte, and platelets (HALP score) in peripheral blood samples were obtained prior to initial treatment and KEYNOTE-826 regimen, and receiver operating curve analysis was used to compare them. The optimal cut-off values that showed the highest level of discrimination for progression-free survival were identified. RESULTS: The areas under the curve (AUC) for progression-free survival in group 2 were measured for CPS, TPS, NLR, PLR, and HALP scores before the KEYNOTE-826 regimen. The AUC values for these scores were 0.644, 0.662, 0.852, 0.667, and 0.700, respectively. The lower NLR (≤5.52) group had a significantly longer median survival than the higher NLR (>5.52) group (p˂0.001), with median survivals of 14.0 vs. 7.6 months, respectively. In group 3, CPS and TPS were highest at 0.700 for predicting progression-free survival, compared to NLR, PLR, and HALP score. CPS and TPS appear positively correlated with progression-free survival. CONCLUSION: CPS and TPS showed a modest correlation with progression-free survival and NLR prior to immunotherapy demonstrated the best treatment efficacy for advanced cervical cancer.

DOI： 10.4274/tjod.galenos.2025.93607

Takahiro Matsuyama, Kentaro Tanaka, Ikumi Kitazono, Kiyotaka Kondo, Midori Satomura, Hiromi Matsuyama, Hiromi Sasaki, Akihide Tanimoto, Noboru Taniguchi, Hiromasa Inoue . Pulmonary metastasis of chondrosarcoma diagnosed by transbronchial lung biopsy after differentiation from organizing pneumonia: A case report. . Respiratory investigation63 ( 5 ) 998 - 1001 2025.9Reviewed International journal

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

A 49-year-old woman presented with abdominal distention and right leg numbness. Bone biopsy from a huge tumor in her pelvis revealed chondrosarcoma, and proton beam therapy was performed. Although there were no abnormalities at 6 months, dry cough, dyspnea and fever with elevated inflammation appeared at 9 months. Computed tomography showed multiple consolidations in both lungs, different from typical images of nodular shadows with calcification in pulmonary metastases of chondrosarcoma. We first suspected infection or organizing pneumonia, but biopsy revealed chondrosarcoma metastases with severely infiltrated inflammatory cells. Imaging patterns we experienced may reflect inflammatory pathogenesis due to rapid cancer progression.

DOI： 10.1016/j.resinv.2025.07.017

Toshiaki Akahane, Ikumi Kitazono, Seiya Yokoyama, Yuriko Higashi, Hiroaki Kobayashi, Akihide Tanimoto . Endometrial Liquid-Based Cytology Specimens Preserve High Genome Quality for Molecular Classification After Long-Term Storage. . Diagnostic cytopathology 2025.8Reviewed International journal

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

BACKGROUND: Molecular classification of endometrial cancer is useful for predicting prognosis. Genomic examinations are performed using formalin-fixed paraffin-embedded (FFPE) tissues; however, we previously reported that liquid-based cytology (LBC) specimens can be used for next-generation sequencing (NGS). In this study, we evaluated long-term storage effects of LBC specimens on NGS-based genomic profiling, including gene mutations, tumor mutation burden (TMB), and microsatellite instability (MSI). METHODS: Four LBC fixatives (CellPrep, ThinPrep, CytoRich Red, and SurePath) were used to prepare NGS samples from cultured endometrioid carcinoma HEK-251 cells. Twelve endometrial LBC specimens from patients with endometrioid carcinoma were fixed with CytoRich Red. The TMB, MSI, and gene mutations were analyzed after 1 week, 6 months, and 12 months of storage in cultured HEK-251 cells. Paired LBC and FFPE specimens of endometrioid carcinoma stored for 15-45 months were subjected to NGS-based analysis, and their molecular profiles were compared to those at the initial diagnosis. RESULTS: The TMB and MSI did not differ during the storage periods for any of the LBC fixatives in the cultured cells; in addition to gene mutations, they were comparable between the initial and second analyses of the clinical FFPE and LBC specimens. There were no changes in the integrative diagnosis of the endometrioid carcinoma subtype classification. CONCLUSION: LBC specimens, which preserved high-quality genomes for molecular classification after long-term storage, may be an alternative source of genomic examination for the integrative diagnosis of endometrial cancer.

DOI： 10.1002/dc.70008

Kosuke Fukuda, Yuto Hozaka, Hideyuki Oi, Miyo Tomita, Tetsuya Idichi, Yoichi Yamasaki, Yota Kawasaki, Yodai Hayashi, Yuichi Goto, Tsuyoshi Sugiura, Toshiaki Akahane, Michiyo Higashi, Akihide Tanimoto, Takao Ohtsuka . Association between intra-tumoral microbiome and genetic alterations in intraductal papillary mucinous neoplasms of the pancreas. . Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 2025.8Reviewed International journal

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

BACKGROUND/OBJECTIVES: We previously demonstrated that intra-tumoral microbiome infection may affects the clinicopathological characteristics of pancreatic intraductal papillary mucinous neoplasms (IPMNs) and showed that these characteristics are also influenced by gene mutations. The aim of this study was to investigate whether specific microbiome infections lead to alterations in the expression of specific genes in IPMNs. METHODS: DNA was extracted from 26 resected IPMN samples and subjected to genetic mutation assessment and microbiome analysis. The relationship between intra-tumoral microbiome and genetic alterations was investigated. RESULTS: There was an increasing trend in the percentage of Firmicutes in KRAS- and GNAS-mutated IPMNs, whereas Proteobacteria tended to decrease in KRAS-mutated IPMNs. KLF4-mutated IPMNs, particularly within the KRAS-mutated group, had significantly low α-diversity (p < 0.05). The relative abundance of Firmicutes and Proteobacteria was significantly higher in KLF4-mutated IPMNs, especially in KLF4-mutated IPMNs among the KRAS-mutated groups. An increased relative abundance of Firmicutes and Proteobacteria, along with the associated reduction in microbial diversity, was associated with a higher frequency of gene mutations, including KLF4. CONCLUSIONS: This study suggest that the intratumoral microbiome may be linked to the genetic characteristics of IPMNs and potentially contribute to their malignant progression.

DOI： 10.1016/j.pan.2025.08.001

Keisuke Masuda, Nayuta Higa, Toshiaki Akahane, Shingo Baba, Kazutaka Yatsushiro, Hajime Yonezawa, Hiroyuki Uchida, Ryutaro Makino, Tomoko Takajo, Mari Kirishima, Takuro Isoda, Daisuke Kuga, Koji Yoshimoto, Akihide Tanimoto, Ryosuke Hanaya . Potential of Preoperative 11C-Methionine Positron Emission Tomography in Predicting EGFR Alterations and CDKN2A/B Homozygous Deletion in Diffuse Astrocytic Gliomas. . Cureus17 ( 7 ) e87747 2025.7Reviewed International journal

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

Objective L-methyl-11C-methionine (MET)- and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) are used to detect gliomas. However, the efficacy of MET-PET and FDG-PET in detecting gene alterations in gliomas remains unclear. Therefore, in this study, we evaluated the relationship between genetic alterations and PET tracer uptake in diffuse astrocytic glioma. Methods Thirty-two patients who had been newly diagnosed with astrocytic gliomas at Kagoshima University and Kyushu University and had undergone MET-PET and FDG-PET were enrolled. They underwent analysis of glioma-related gene expression using a customized 48-gene panel. Results The tumors identified in this study were classified as follows: glioblastomas, isocitrate dehydrogenase (IDH) wildtype (n = 15); astrocytic glioma, IDH-mutant, World Health Organization (WHO) grade 4 (n = 2); astrocytic glioma, IDH-mutant, WHO grade 3 (n = 4); astrocytic glioma, IDH-mutant, WHO grade 2 (n = 7); and diffuse astrocytic glioma, not elsewhere classified (n = 4). Astrocytic tumors with IDH mutations, ATRX mutations, and/or loss of function (mut/loss) had a significantly lower tumor-to-normal tissue (T/N) ratio on the MET-PET and FDG-PET images compared with those without these alterations. Astrocytic tumors with CDKN2A/B homozygous deletions (HD), EGFR mutation and/or amplification (mut/amp), or PTEN mut/loss had a significantly higher T/N ratio on the MET-PET images compared with those without these alterations. Astrocytic tumors with NF1 mut/loss had a significantly higher T/N ratio on their FDG-PET images compared with those without these alterations. The cut-off T/N ratio for the MET-PET images for the identification of EGFR mut/amp was 4.50 (sensitivity: 95%; specificity: 56%, AUC: 0.77), and that for detecting CDKN2A/B HDwas 2.32 (sensitivity: 72%; specificity: 86%; AUC: 0.85). Conclusion These findings from our small, retrospective cohort study suggest that MET-PET and FDG-PET are potentially valuable approaches for preoperatively predicting the molecular status of gliomas, particularly for assessing tumors with EGFR mut/amp and CDKN2A/B HD. Preoperative genetic alteration prediction in astrocytic gliomas based on PET tracer uptake may provide accurate information for patients and inform clinical decision-making. Multicenter prospective trials are essential.

DOI： 10.7759/cureus.87747

Yuriko Higashi, Mika Mizuno, Ikumi Kitazono, Toshiaki Akahane, Takashi Tasaki, Hirotsugu Noguchi, Masanori Hisaoka, Hiroaki Kobayashi, Akihide Tanimoto . Heterochronic pelvic high-grade myxoinflammatory fibroblastic sarcoma and uterine endometroid carcinoma harboring common gene mutations: a rare case report with genomic analysis. . Diagnostic pathology20 ( 1 ) 71 - 71 2025.6Reviewed International journal

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

OBJECTIVE: This report presents a rare case involving an extreme epithelial-to-mesenchymal transition, in which a specific type of sarcoma developed heterochronically as a recurrence of endometrioid carcinoma. CASE PRESENTATION: A female in her 50's presented with abnormal genital bleeding, and an endometrial biopsy revealed endometrioid carcinoma. Following the diagnosis of stage IA endometrioid carcinoma according to the 2008 classification system of the International Federation of Gynecology and Obstetrics, a robot-assisted simple hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node navigation surgery were performed. Six months postoperatively, a tumor mass developed in the pelvis. A transrectal needle biopsy revealed spindle cell proliferation, and pelvic tumor resection was conducted for diagnostic therapy. The patient received no adjuvant chemotherapy or radiotherapy after the second surgery and remained free of tumor recurrence for 8 months. The resected yellowish solid tumor mass, measuring 16 × 12 × 9 cm, exhibited hemorrhage, necrosis, and cystic degeneration and was composed of fascicular proliferation of spindle tumor cells showing nuclear pleomorphism and frequent mitotic figures within a myxoid and inflammatory stroma. No epithelial component or organoid patterns were observed. Immunohistochemically, the tumor cells were positive for factor XIIIa, CD10, and cyclin D1, but negative for keratins (AE1/AE3 and CAM5.2) and other specific markers, supporting a diagnosis of high-grade myxoinflammatory fibroblastic sarcoma (MIFS). CONCLUSION: Genomic analysis revealed identical mutations in PTEN, PIK3R1, CDKN2 A, and TP53 in both the primary uterine endometrioid carcinoma and heterochronic pelvic MIFS. An integrative approach involving histology, immunohistochemistry, and genomic analysis is critical for elucidating the pathogenesis of rare pelvic and uterine tumors.

DOI： 10.1186/s13000-025-01669-4

Masako Noumi, Michiyo Higashi, Ikumi Kitazono, Seiya Yokoyama, Takashi Tasaki, Hirotsugu Noguchi, Mari Kirishima, Miki Nurakami, Akihide Tanimoto . Expression of mucins MUC1 and MUC4 in curative resected gallbladder adenocarcinoma. . Histology and histopathology 18928 - 18928 2025.4Reviewed International journal

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

BACKGROUND AND AIMS: Gallbladder adenocarcinoma (GBAC) is associated with high mortality because of the difficulty in its early detection and treatment. Therefore, identifying prognostic factors is crucial for managing patients with GBAC. We aimed to elucidate the relationship between immunohistochemical profiles of mucin expression, clinicopathological behavior, and prognosis for curatively resected gallbladder adenocarcinoma (GBAC) and to prove that mucin expression is a prognostic factor for GBAC. METHODS: We examined the expression of mucins (MUC1, MUC2, and MUC4) using immunohistochemical analyses and compared the prevalence of each mucin with clinicopathological features in patients with early-stage (stage 0 to IIB) GBAC. RESULTS: MUC1 expression was significantly expressed in patients with GBAC with lymphatic invasion, vascular invasion, perineural invasion, and recurrence. MUC2 was significantly expressed in patients with GBAC with perineural invasion and recurrence but not with prognosis. Patients with MUC1-high expression exhibited worse prognoses than those with MUC1-low expression. In contrast, patients with positive MUC4 expression had significantly better prognoses than those without MUC4 expression. CONCLUSION: The expression of MUC1 and MUC4 in GBAC is an independent prognostic factor for survival and a useful marker for predicting the outcomes of patients with GBAC.

DOI： 10.14670/HH-18-928

Ryutaro Makino, Madan Bajagain, Nayuta Higa, Toshiaki Akahane, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Mari Kirishima, Seiya Yokoyama, Ryosuke Otsuji, Yutaka Fujioka, Daisuke Kuga, Hitoshi Yamahata, Masamichi Kurosaki, Junkoh Yamamoto, Koji Yoshimoto, Akihide Tanimoto, Ryosuke Hanaya . Analysis of clinical, histological, and genomic information of molecular glioblastoma in a Japanese glioma cohort. . Brain tumor pathology 2025.4Reviewed

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

In the 2021 WHO Central Nervous System tumor classification, the "Glioblastoma, IDH-wildtype" diagnosis changed markedly. In a Japanese cohort, we compared the clinical backgrounds and prognoses of molecular glioblastoma (mGBM) and conventional glioblastoma (histological glioblastoma, hGBM). We included 270 patients with glioblastoma treated at five institutions during 2011-2023. Driver gene analysis was performed using a brain tumor-specific custom gene panel to verify the association between molecular and clinical information. Patients with mGBM had better preoperative KPS, lower Ki-67, and lower removal rates than did those with hGBM. Overall survival was longer in patients with mGBM than in those with hGBM (1207 vs 599 days, p = 0.037). TP53 mutation (hazard ratio: 5.33, 95% confidence interval: 0.26-108.7, p = 0.012) and histological grade 3 (p = 0.051) were poor prognostic factors for mGBM. Patients with mGBM had better preoperative KPS, worse removal rates, lower Ki-67 labeling index, and better overall survival than did those with hGBM. In addition, the histological grade of mGBM is potentially useful for estimating prognosis. In the WHO CNS5 2021, glioblastoma patients remain a heterogeneous population, and prognostic stratification based on the patient's clinical background and molecular information is desirable.

DOI： 10.1007/s10014-025-00500-8

Saeki Saito, Hirofumi Yoshino, Seiya Yokoyama, Mitsuhiko Tominaga, Gang Li, Junya Arima, Ichiro Kawahara, Ikumi Fukuda, Akihiko Mitsuke, Takashi Sakaguchi, Satoru Inoguchi, Ryosuke Matsushita, Yasutoshi Yamada, Shuichi Tatarano, Akihide Tanimoto, Hideki Enokida . Targeting Heat Shock Transcription Factor 4 Enhances the Efficacy of Cabozantinib and Immune Checkpoint Inhibitors in Renal Cell Carcinoma. . International journal of molecular sciences26 ( 4 ) 2025.2Reviewed International journal

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

Recently, immune checkpoint inhibitors (ICIs) and cabozantinib, a tyrosine kinase inhibitor (TKI), have been used to treat renal cell carcinoma (RCC); the combination of these agents has become a standard treatment for RCC. TKIs generally target vascular endothelial growth factor. However, cabozantinib is characterized by its targeting of MET. Therefore, cabozantinib can be used as a late-line therapy for TKI-resistant RCC. According to data from The Cancer Genome Atlas (TCGA), heat shock transcription factor 4 (HSF4) expression is higher in RCC tissues than in normal renal tissues. HSF4 binds to the MET promoter in colorectal carcinoma to enhance MET expression and promote tumor progression. However, the functional role of HSF4 in RCC is unclear. We performed loss-of-function assays of HSF4, and our results showed that HSF4 knockdown in RCC cells significantly decreased cell functions. Moreover, MET expression was decreased in HSF4-knockdown cells but elevated in sunitinib-resistant RCC cells. The combination of cabozantinib and HSF4 knockdown reduced cell proliferation in sunitinib-resistant cells more than each monotherapy alone. Furthermore, HSF4 knockdown combined with an ICI showed synergistic suppression of tumor growth in vivo. Overall, our strategy involving HSF4 knockdown may enhance the efficacy of existing therapies, such as cabozantinib and ICIs.

DOI： 10.3390/ijms26041776

Taiji Hamada, Seiya Yokoyama, Toshiaki Akahane, Kei Matsuo, Ikumi Kitazono, Tatsuhiko Furukawa, Akihide Tanimoto . Electroporation Induces Unexpected Alterations in Gene Expression: A Tip for Selection of Optimal Transfection Method. . Current issues in molecular biology47 ( 2 ) 2025.1Reviewed International journal

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

Electroporation is an efficient method for nucleotide and protein transfer, and is used for clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9)-mediated genome editing. In this study, we investigated the effects of electroporation on platelet-derived growth factor receptor alpha (PDGFRA) and receptor tyrosine kinase (RTK) expression in U-251 and U-87 MG cells. PDGFRA mRNA and protein expression decreased 2 days after electroporation in both cell lines, with recovery observed after 13 days in U-87 MG cells. However, in U-251 MG cells, PDGFRα expression remained suppressed, despite mRNA recovery after 13 days. Similar expression profiles were observed for lipofection in the U-251 MG cells. Comprehensive RNA sequencing confirmed electroporation-induced up- and down-regulation of RTK mRNA in U-251 MG cells 2 days post-electroporation. In contrast, recombinant adeno-associated virus (rAAV) transfected with mNeonGreen fluorescent protein or Cas9 did not affect PDGFRA, RTKs, or inflammatory cytokine expression, suggesting fewer adverse effects of rAAV on U-251 MG cells. These findings emphasize the need for adequate recovery periods following electroporation or the adoption of alternative methods, such as rAAV transfection, to ensure the accurate assessment of CRISPR-mediated gene editing outcomes.

DOI： 10.3390/cimb47020091

Ikumi Kitazono, Miki Murakami, Aya Takeda, Hirotsugu Noguchi, Takashi Tasaki, Mari Kirishima, Michiyo Higashi, Kazuhiro Ueda, Akihide Tanimoto . Pulmonary pleomorphic carcinoma: A rare case showing arterial carcinomatosis mimicking pulmonary artery intimal sarcoma. . Pathology international 2025.1Reviewed International journal

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

A male in his seventies presented with lung cancer in the right lower lobe. The surgically resected specimen revealed a pleomorphic carcinoma featuring an adenocarcinoma component with lepidic, acinar, and papillary patterns, alongside a spindle cell component spreading along the pulmonary artery wall, resembling intimal sarcoma. The spindle tumor cells were positive for keratins, TTF-1, napsin A, and vimentin, but negative for p40, CK14, desmin, alpha-smooth muscle actin, CDK4, and MDM2. This profile indicates that the spindle cells originated from the adenocarcinoma cells via epithelial-mesenchymal transition. The vascular spread of pleomorphic carcinoma, mimicking pulmonary artery intimal sarcoma, represents an extremely rare mode of tumor invasion, which could be termed "arterial carcinomatosis". Immunohistochemical analysis is crucial for distinguishing pleomorphic carcinoma from coexisting intimal sarcoma, as the latter's prognosis is markedly poor.

DOI： 10.1111/pin.13508

Kazuyuki Matsushita, Takayuki Ishige, Kousuke Watanabe, Toshiaki Akahane, Akihide Tanimoto, Michiko Yoshimoto, Munekazu Yamakuchi, Teruto Hashiguchi, Yoshinaga Okugawa, Makoto Ikejiri, Toshikazu Yamaguchi, Tadashi Yamasaki, Mayu Takeda, Masaaki Hibi, Naoki Akiyama, Kaho Shimizu, Naonori Hashimoto, Hiroko Sato, Yoshinori Tanaka, Fumie Amari . Importance of EQA/PT for the detection of genetic variants in comprehensive cancer genome testing. . Scientific reports15 ( 1 ) 1036 - 1036 2025.1Reviewed International journal

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

Comprehensive genomic profiling (CGP) is increasingly used as a clinical laboratory test and being applied to cancer treatment; however, standardization and external quality assessments (EQA) have not been fully developed. This study performed cost-effective EQA and proficiency tests (PT) for CGP testing among multiple institutions those belong to the EQA working group of Japan Association for Clinical Laboratory Science (JACLS). This study revealed that preanalytical processes, such as derived nucleic acids (NA) extraction from formalin fixed paraffine embedded (FFPE) samples, are critical. First, EQA with extracted DNA from cell lines showed a detection rate of 100% (9 out of 9) in KRAS (c.38G > A; p.G13D), PIK3CA (p.H1047R), and B-Raf proto-oncogene, serine/threonine kinase (BRAF) (c.1799 T > A; p.V600E) in cases of > 10% variant allele frequency (VAF). However, BRAF (c.1799 T > A; p.V600E) detection decreased to 67% (6 out of 9) for a VAF of 4.9%. Second, when DNA was extracted from FFPE samples, pathogenic variants and variants with companion diagnostic indications were detected in all 10 participating laboratories. Each variant had < 20% VAFs on average (8.1-19.1%) and wide variability among laboratories was observed (relative standard deviation, 13-60%). Nonetheless, BRAF (c.1798_1799delinsAA; p.V600K) of 8.1% VAF, EGFR (c.2235_2249del; p.E746_A750del) of 9.7% VAF, and EGFR (c.2254_2277del; p.S752_I759del) of 9.8% VAF were detected with 70% (7/10), 70% (7/10), and 60% (6/10) frequency, respectively. Therefore, 10% VAF in pre-analytic processing for DNA extraction from FFPE was critical for variant detection in CGP analysis. Further, incorrect results were reported in case independent variant calling of BRAF; c.1798_1799delinsAA (p.V600K) was mistakenly interpreted as c.1798G > A, and c.1799 T > A was on the other strand. In conclusion, the EQA/PT among 10 institutes with common samples revealed the importance of VAF in pre-analysis and helped us understand the significance of the pipeline and common pitfalls usually ignored by the internal quality control in a single institute.

DOI： 10.1038/s41598-024-84714-4

Shintaro Yanazume, Yusuke Kobayashi, Yukari Kirita, Ikumi Kitazono, Chikako Nagata, Ayumi Kozai, Akihide Tanimoto, Hiroaki Kobayashi . A potential inflammatory biomarker for advanced endometrial cancer treated with lenvatinib plus pembrolizumab. . The journal of obstetrics and gynaecology research51 ( 1 ) e16182 2025.1Reviewed International journal

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

INTRODUCTION: To identify prognostic biomarkers that could predict how well patients will respond to lenvatinib/pembrolizumab (LEN/PEM). The utility of certain inflammatory biomarkers in endometrial liquid-based cytology (LBC) or peripheral blood samples, such as neutrophil counts, lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR) were explored. METHODS: The study included 25 patients with advanced or recurrent endometrial cancer who had received LEN/PEM between August 2018 and March 2024. Predictors for overall response (OR), disease control, and progression-free survival, based on neutrophil/lymphocyte counts, NLR scores of the endometrial LBC prior to initial treatment, and peripheral blood prior to initial treatment and prior to LEM/PEM treatment were compared using a receiver operating characteristic curve. Significant predictors were evaluated using the log-rank test, and multivariate analysis. RESULTS: Although neutrophil counts and NLR score in endometrial LBC prior to initial treatment were better effective predictors for OR, the most accurate predictor of a progression-free status was NLR score in peripheral blood prior to LEM/PEM (0.722, 95% CI: 0.45-0.99, sensitivity: 57.1%, specificity: 94.4%). In peripheral blood prior to LEN/PEM, the lower NLR (NLR <5.39) group had a significantly longer PFS than the higher NLR (5.39 ≤ NLR) group (p = 0.023, median survival: 13.5 vs. 3.0 months), and tended to be independently correlated with PFS (hazard ratio = 2.571; 95% CI = 0.857-7.719; p = 0.092). CONCLUSION: Inflammatory biomarkers in endometrial LBC failed to predict the efficacy of LEN/PEM, while peripheral blood NLR score sampled prior to LEN/PEM potentially could be a significant predictor.

DOI： 10.1111/jog.16182

Madan Bajagain, Akihisa Sakamoto, Tomoko Takajo, Ryutaro Makino, Hiroyuki Uchida, Keisuke Masuda, Nayuta Higa, Hajime Yonezawa, Kazutaka Yatsushiro, Akihide Tanimoto, Ryosuke Hanaya . Higher Uptake of Preoperative 11C-Methionine Positron Emission Tomography Related to Preoperative Seizure in Patients With Oligodendroglioma. . Cureus17 ( 1 ) e76991 2025.1Reviewed International journal

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

OBJECTIVE: Epileptic seizures are common in patients with low-grade gliomas (LGGs). 11C-methionine (MET) is a radiolabeled amino acid tracer commonly used in positron emission tomography (PET), and MET-PET is a valuable tool for the clinical characterization of gliomas. This study aimed to evaluate the factors associated with MET uptake in patients with suspected LGG and, specifically, to characterize MET uptake in the presence or absence of epilepsy. METHODS: MET uptake on preoperative MET-PET images was retrospectively reviewed in 40 patients with a presurgical diagnosis of LGG based on the absence of gadolinium enhancement on MRI. All patients underwent surgery and had their pathological diagnosis confirmed. The correlation between MET uptake and the occurrence of seizures in patients with LGGs was investigated during their clinical course. The ratio of the lesion to the contralateral normal region (L/N ratio) was calculated by dividing the maximum standardized uptake value of the tumor by the value of the contralateral region. Clinical parameters and MET uptake data were extracted from the medical records. RESULTS: The mean age of the patients was 48 years (range: 21-90 years), consisting of 26 males and 14 females. Preoperative seizures and 1p/19q codeletion were correlated with higher MET uptake (p < 0.01). Grade 2 oligodendrogliomas had significantly higher MET uptake than grade 2 astrocytomas and glioblastomas (p < 0.01). In particular, grade 2 oligodendrogliomas with preoperative seizures showed approximately twofold higher MET uptake than those without preoperative seizures (L/N ratio 2.01 vs. 1.20, p = 0.042). The optimal cutoff value of the lesion-to-contralateral-normal ratio of MET uptake for predicting preoperative seizures was 2.13, as calculated using a receiver operating characteristic curve and an area under the curve. Conversely, grade 2 astrocytoma and glioblastoma with or without seizures (L/N ratio 1.44 vs. 1.09, 1.40 vs. 1.34), as well as oligodendroglioma without seizures (L/N ratio 1.33), showed similar MET uptake. CONCLUSIONS: An epileptogenic formation mechanism may be involved in the increased uptake of MET in oligodendrogliomas. In patients with suspected LGGs, if there is a significant increase in MET uptake, the possibility of an oligodendroglioma should be considered and attention should be paid to the risk of epileptic seizures.

DOI： 10.7759/cureus.76991

Kiyohisa Kamimura, Tomohiro Tokuda, Junki Kamizono, Tsubasa Nakano, Tomohito Hasegawa, Masanori Nakajo, Fumitaka Ejima, Fumiko Kanzaki, Koji Takumi, Masatoyo Nakajo, Shingo Fujio, Ryosuke Hanaya, Akihide Tanimoto, Takashi Iwanaga, Hiroshi Imai, Thorsten Feiweier, Takashi Yoshiura . Time-dependent MR diffusion analysis of functioning and nonfunctioning pituitary adenomas/pituitary neuroendocrine tumors. . Journal of neuroimaging : official journal of the American Society of Neuroimaging35 ( 1 ) e13254 2025Reviewed International journal

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

BACKGROUND AND PURPOSE: Differentiation between functioning and nonfunctioning pituitary adenomas/pituitary neuroendocrine tumors (PAs) is clinically relevant. The goal of this study was to determine the feasibility of using time-dependent diffusion MRI (dMRI) for microstructural characterization of PAs. METHODS: The study included 54 participants, 24 with functioning PA and 30 with nonfunctioning PA. Time-dependent dMRI of the pituitary gland was performed using an inner field-of-view echo-planar imaging based on 2-dimensional-selective radiofrequency excitations with oscillating gradient and pulsed gradient preparation (effective diffusion time: 7.1 and 36.3 ms) at b-values of 0 and 1000 seconds/mm2. Each tumor had its apparent diffusion coefficients (ADCs) measured at two diffusion times (ADC7.1 ms and ADC36.3 ms), its ADC change (cADC), and relative ADC change. The mean values of diffusion parameters were compared between functioning and nonfunctioning PAs. We compared the diffusion parameters of nonfunctioning PAs with those of each type of hormone-producing PAs. The diagnostic performances of the diffusion parameters were assessed. RESULTS: The cADC was significantly higher in functioning PAs than nonfunctioning PAs (p = .0124). The receiver operating characteristic (ROC) curve analysis revealed that cADC (area under the ROC curve [AUC] = .677, p = .017) is effective in distinguishing between functioning and nonfunctioning PAs. The cADC was significantly higher in growth hormone (GH)-producing PAs compared to nonfunctioning PAs (p = .006). The ROC curve analysis indicated that cADC (AUC = .771, p < .001) effectively distinguishes between GH-producing and nonfunctioning PAs. CONCLUSIONS: The cADC derived from time-dependent dMRI could distinguish between functioning and nonfunctioning PAs, particularly those producing GH.

DOI： 10.1111/jon.13254

Yuko Onishi, Naoki Miura, Akihide Tanimoto, Hiroaki Kawaguchi . Methotrexate Enhances Atherosclerosis Progression via Impairment of Folate Pathway in a Microminipig Model. . In vivo (Athens, Greece)39 ( 3 ) 1262 - 1274 2025Reviewed International journal

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

BACKGROUND/AIM: As the pathophysiology of Microminipigs (μMPs) is similar to that of human, μMPs are useful in atherosclerosis research. To clarify the effect of methotrexate (MTX) on atherosclerosis, we investigated the pathology of MTX-induced atherosclerosis lesion exacerbation in μMPs fed a high-fat and high-cholesterol diet (HFHCD). MATERIALS AND METHODS: The μMPs were divided into four groups: HFHCD, HFHCD+MTX, HFHCD+MTX+leucovorin (LV), and HFHCD+MTX+folic acid (FA), and fed for two weeks. Laboratory tests including blood lipid, FA, and homocysteine (Hcy) levels, and pathological evaluation of the atherosclerosis lesion area and thickness were performed. Hepatic and jejunal gene expressions related to lipid and folate metabolism pathways including 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) were monitored using RT-PCR. RESULTS: The HFHCD+MTX group showed increased blood Hcy (p<0.01) and decreased FA levels (p<0.05) in accordance with increased hepatic MTR mRNA expression (p<0.1) and exacerbation of atherosclerosis (p=0.051 for lesion area and p=0.045 for lesion thickness) compared to the HFHCD group. Administration of LV or FA attenuated the MTX-induced increase in the Hcy level (p<0.01), atherosclerosis lesion thickness (p<0.1), and MTR mRNA expression (p<0.1 in HFHCD+MTX vs. HFHCD+MTX+LV groups). CONCLUSION: MTX exacerbated HFHCD-induced atherosclerosis mediated through reduced blood FA and the subsequent increase of Hcy in μMPs, indicating that the μMP model may advance cardio-oncology research by providing useful experimental approaches. As MTX is administered for rheumatoid arthritis and malignant tumors in humans, atherosclerosis exacerbation should be acknowledged as a possible adverse effect of MTX treatment.

DOI： 10.21873/invivo.13930

Shinsuke Suzuki, Toshiaki Akahane, Akihide Tanimoto, Michiyo Higashi, Ikumi Kitazono, Mari Kirishima, Masakazu Nishigaki, Toshiro Ikeda, Shuichi Kanemitsu, Junichi Nakazawa, Erina Akahane, Hiroshi Nishihara, Kimiharu Uozumi, Makoto Yoshimitsu, Kenji Ishitsuka, Shin-Ichi Ueno . Comparison of actionable alterations in cancers with kinase fusion, mutation, and copy number alteration. . PloS one20 ( 1 ) e0305025 2025Reviewed International journal

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

Kinase-related gene fusion and point mutations play pivotal roles as drivers in cancer, necessitating optimized, targeted therapy against these alterations. The efficacy of molecularly targeted therapeutics varies depending on the specific alteration, with great success reported for such therapeutics in the treatment of cancer with kinase fusion proteins. However, the involvement of actionable alterations in solid tumors, especially regarding kinase fusions, remains unclear. Therefore, in this study, we aimed to compare the number of actionable alterations in patients with tyrosine or serine/threonine kinase domain fusions, mutations, and copy number alterations (CNAs). We analyzed 613 patients with 40 solid cancer types who visited our division between June 2020 and April 2024. Furthermore, to detect alterations involving multiple-fusion calling, we performed comprehensive genomic sequencing using FoundationOne® companion diagnostic (F1CDx) and FoundationOne® Liquid companion diagnostic (F1LCDx). Patient characteristics and genomic profiles were analyzed to assess the frequency and distribution of actionable alterations across different cancer types. Notably, 44 of the 613 patients had fusions involving kinases, transcriptional regulators, or tumor suppressors. F1CDx and F1LCDx detected 13 cases with kinase-domain fusions. We identified 117 patients with kinase-domain mutations and 58 with kinase-domain CNAs. The number of actionable alterations in patients with kinase-domain fusion, mutation, or CNA (median [interquartile range; IQR]) was 2 (1-3), 5 (3-7), and 6 (4-8), respectively. Patients with kinase fusion had significantly fewer actionable alterations than those with kinase-domain mutations and CNAs. However, those with fusion involving tumor suppressors tended to have more actionable alterations (median [IQR]; 4 [2-9]). Cancers with kinase fusions exhibited fewer actionable alterations than those with kinase mutations and CNAs. These findings underscore the importance of detecting kinase alterations and indicate the pivotal role of kinase fusions as strong drivers of cancer development, highlighting their potential as prime targets for molecular therapeutics.

DOI： 10.1371/journal.pone.0305025

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