慶應義塾大学医学部 病理学教室 組織病理学分野

@article{pmid41882312,

title = {Tumor vessel phenotype in colorectal cancer microenvironment according to age at diagnosis},

author = {Kosuke Matsuda and Satoko Ugai and Satoshi Miyahara and Qian Yao and Jules Cazaubiel and Nobuhiro Nakazawa and Mayu Higashioka and Yuxue Zhong and Andrew T Chan and Jeffrey A Meyerhardt and Kimmie Ng and Mingyang Song and Juha P Väyrynen and Jonathan A Nowak and Marios Giannakis and Tomotaka Ugai and Shuji Ogino},

doi = {10.1038/s41416-026-03373-6},

issn = {1532-1827},

year  = {2026},

date = {2026-05-01},

urldate = {2026-05-01},

journal = {Br J Cancer},

volume = {134},

number = {10},

pages = {1375--1386},

abstract = {BACKGROUND: Given the global issue of the rising incidence of early-onset colorectal cancer (CRC), we tested the hypothesis that tumor vasculature phenotypes might vary with age at CRC diagnosis.nnMETHOD: We used in situ multispectral immunofluorescence combined with digital image analysis and machine learning to measure expression of endothelial cell markers [ACKR1 (DARC), CD34, CD36, KDR (VEGFR2), LAMB1 (laminin β1), MADCAM1] and KRT (keratin) in 843 tumors derived from 4476 CRC cases in U.S.-wide prospective cohorts under the prospective cohort incident-tumor biobank method.nnRESULTS: Overall CD34 vessel and CD34LAMB1 vessel densities inversely correlated with younger age at CRC diagnosis (both P < 0.0001). In the inverse probability-weighted multivariable-adjusted logistic regression analyses, compared to age ≥70, odds ratios (with 95% confidence interval) for high (vs. low) overall vessel density were 0.85 (0.74-0.99) for age 55-69 and 0.63 (0.48-0.81) for age <55, and those for high (vs. low/negative) CD34LAMB1 vessel density were 0.56 (0.47-0.65) for age 55-69 and 0.28 (0.20-0.40) for age <55.nnCONCLUSIONS: Hypovascularities of overall and CD34LAMB1 vessels may be microenvironmental characteristics of early-onset CRC if validated by independent studies. Our findings highlight age-related tumor pathobiological differences. Identifying specific biomarkers of early-onset CRC can provide pathogenetic and etiological clues.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid41770625,

title = {Cholangiolocellular Component Predicts a Biologically Distinct Subgroup of Mass-Forming Intrahepatic Cholangiocarcinoma},

author = {Naoto Kubota and Ken Yamazaki and Yasuhito Arai and Minoru Esaki and Nobuyoshi Hiraoka and Hirofumi Shirakawa and Moriaki Tomikawa and Tatsuhiro Shibata and Michiie Sakamoto and Hidenori Ojima},

doi = {10.1111/cas.70348},

issn = {1349-7006},

year  = {2026},

date = {2026-05-01},

journal = {Cancer Sci},

volume = {117},

number = {5},

pages = {1510--1523},

abstract = {Cholangiolocellular carcinoma (CLC) is a histopathological variant of primary liver tumor with unique morphologies, and intrahepatic cholangiocarcinomas (iCCAs) frequently contain a CLC component; however, the biological characteristics of iCCA with CLC remain undescribed. In this study, 36 mass-forming iCCAs (MF-iCCAs), histologically small-duct type iCCA, were classified into CLC(+) iCCAs and CLC(-) iCCAs by the presence/absence of the CLC component. Two genetic subgroups were generated using highly expressed genes in CLC(+) iCCA and CLC(-) iCCA. As the results of clinicopathological and genetic analyses, CLC(+) iCCA had better overall survival and upregulation of stromal- and oxidation-related genes, whereas CLC(-) iCCA showed upregulation of proliferation- and hypoxia-related genes. Two genetic subgroups of iCCA were identified: iCCA-G1, which was related to CLC, and iCCA-G2, which was unrelated to CLC. iCCA-G1 comprised all 14 CLC(+) iCCAs [CLC(+)G1] and 7 of 19 CLC(-) iCCAs [CLC(-)G1], whereas iCCA-G2 was composed only of CLC(-) iCCAs [CLC(-)G2]. CLC(+)G1 and CLC(-)G1 exhibited similar patterns of somatic gene alterations compared with CLC(-)G2. Angiogenesis-related genes were upregulated in CLC(+)G1, and the number of tumor vessels was larger in CLC(+)G1, followed by CLC(-)G1, compared with CLC(-)G2. Further, SPP1 (encoding osteopontin) was identified as a highly expressed angiogenesis-related gene in CLC(+) iCCA. Immunohistochemical expression of osteopontin was high in CLC(+) iCCA, showing apical and/or cytoplasmic expression patterns, which should facilitate the histopathological classification of iCCA-G1 and iCCA-G2. CLC component is useful for predicting a distinct genetic subgroup of MF-iCCA with better prognosis, high angiogenesis, and different gene alteration patterns, indicating different carcinogenic pathways of MF-iCCA.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid40168459,

title = {Macrotrabecular hepatocellular carcinoma: Unique immunovascular characteristics},

author = {Yutaka Kurebayashi and Michiie Sakamoto},

doi = {10.1097/HEP.0000000000001339},

issn = {1527-3350},

year  = {2026},

date = {2026-02-01},

urldate = {2026-02-01},

journal = {Hepatology},

volume = {83},

number = {2},

pages = {203--205},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41213665,

title = {Human chorionic gonadotropin-positive cystic duct carcinoma with trophoblastic differentiation that exhibited an aggressive clinical course},

author = {Yusuke Takemura and Kosuke Matsuda and Yuta Abe and Akinori Hashiguchi and Minoru Kitago and Yutaka Nakano and Keita Sonoda and Yuko Kitagawa},

doi = {10.1136/bcr-2025-266085},

issn = {1757-790X},

year  = {2025},

date = {2025-11-01},

urldate = {2025-11-01},

journal = {BMJ Case Rep},

volume = {18},

number = {11},

abstract = {A man in his 60s diagnosed with perihilar cholangiocarcinoma underwent radical surgery. CT on postoperative day 26 showed multiple liver metastases in the remnant liver that rapidly grew and spread to the entire liver. The patient died 70 days following surgery due to highly aggressive tumour progression. In the surgical specimen, the tumour at the margin was histologically identified as predominantly conventional adenocarcinoma, but a few components of the invasive carcinoma and liver metastasis exhibited significant nuclear atypia and rich cytoplasm. The autopsy revealed human chorionic gonadotropin (hCG)-positive multinucleated tumour cells like syncytiotrophoblast with haemorrhage at the metastatic sites in the liver, which finally diagnosed with cystic duct carcinoma with trophoblastic differentiation. hCG-positive carcinomas with trophoblastic differentiation generally carry poor prognoses. For those with significant nuclear atypia and rich cytoplasms with haemorrhage, additional immunostaining for hCG and progression to trophoblastic differentiation should be considered.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40317820,

title = {Human Papillomavirus-Related Adenosquamous Carcinoma of the Anorectum With Pagetoid Spread},

author = {Kenta Seki and Taiki Hashimoto and Hiroshi Nagata and Dai Ogata and Shunsuke Tsukamoto and Hiroyuki Takamaru and Yukihide Kanemitsu and Shigeki Sekine},

doi = {10.1111/pin.70018},

issn = {1440-1827},

year  = {2025},

date = {2025-06-01},

journal = {Pathol Int},

volume = {75},

number = {6},

pages = {315--319},

abstract = {Adenosquamous carcinoma is an uncommon type of cancer that comprises malignant squamous and glandular components. We present a case of human papillomavirus (HPV)-positive adenosquamous carcinoma of the anorectum, which exhibited extensive pagetoid spread, in a 70-year-old woman. The tumor had spread from the lower rectum to the perianal skin and was removed through a combined endoscopic and transanal surgical procedure. Histological examination revealed three morphologically distinct components: adenocarcinoma in the lower rectum, squamous intraepithelial neoplasia with a minor invasive squamous cell carcinoma component in the anal canal, and pagetoid spread of adenocarcinoma extending to the perianal skin. HPV18 DNA and diffuse p16 expression were detected in all three components, suggesting the integration of HPV and a histogenetic relationship among these morphologically distinct components. This case indicates that HPV-associated adenosquamous carcinoma also occurs in the anal canal, similar to the uterine cervix, and may present as secondary Paget's disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39670871,

title = {Vessels encapsulating tumor clusters contribute to the intratumor heterogeneity of HCC on Gd-EOB-DTPA-enhanced MRI},

author = {Kosuke Matsuda and Akihisa Ueno and Junya Tsuzaki and Yutaka Kurebayashi and Yohei Masugi and Ken Yamazaki and Masashi Tamura and Yuta Abe and Yasushi Hasegawa and Minoru Kitago and Masahiro Jinzaki and Michiie Sakamoto},

doi = {10.1097/HC9.0000000000000593},

issn = {2471-254X},

year  = {2025},

date = {2025-01-01},

journal = {Hepatol Commun},

volume = {9},

number = {1},

abstract = {BACKGROUND: Vessels encapsulating tumor clusters (VETC) pattern is tumor vasculature of HCC and is a predictor of prognosis and therapeutic efficacy. Recent radiological studies have demonstrated the predictability of VETC from preoperative images, but the mechanisms of image formation are not elucidated. This study aims to determine the relationship between VETC and intratumor heterogeneity in Gd-EOB-DTPA-enhanced magnetic resonance imaging (EOB-MRI) and to provide its pathological evidence.nnMETHODS: Radiologists visually classified preoperative arterial- and hepatobiliary-phase EOB-MRI images of 204 surgically resected HCCs into patterns based on heterogeneity and signal intensity; these classifications were validated using texture analysis. Single and multiplex immunohistochemistry for CD34, h-caldesmon, and OATP1B3 were performed to evaluate VETC, arterial vessel density (AVD), and OATP1B3 expression. Recurrence-free survival was assessed using the generalized Wilcoxon test. The contribution of clinicoradiological factors to the prediction of VETC was evaluated by random forest and least absolute shrinkage and selection operator regression.nnRESULTS: VETC was frequently found in tumors with arterial-phase heterogeneous hyper-enhancement patterns and in tumors with hepatobiliary-phase heterogeneous hyperintense/isointense patterns (HBP-Hetero). AVD and OATP1B3 expression positively correlated with signal intensity in the arterial and hepatobiliary phases, respectively. Intratumor spatial analysis revealed that AVD and OATP1B3 expression were lower in VETC regions than in tumor regions without VETC. Patients with HBP-Hetero tumors had shorter recurrence-free survival. Machine learning models highlighted the importance of serum PIVKA-II, tumor size, and enhancement pattern of arterial and hepatobiliary phase for VETC prediction.nnCONCLUSIONS: VETC is associated with local reductions of both AVD and OATP1B3 expression, likely contributing to heterogeneous enhancement patterns in EOB-MRI. Evaluation of the arterial and hepatobiliary phases of EOB-MRI would enhance the predictability of VETC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39417698,

title = {Spatial Dynamics of T- and B-Cell Responses Predicts Clinical Outcome of Resectable and Unresectable Hepatocellular Carcinoma},

author = {Yutaka Kurebayashi and Katsutoshi Sugimoto and Hanako Tsujikawa and Kosuke Matsuda and Rui Nomura and Akihisa Ueno and Yohei Masugi and Ken Yamazaki and Kathryn Effendi and Hirohito Takeuchi and Takao Itoi and Yasushi Hasegawa and Yuta Abe and Minoru Kitago and Hidenori Ojima and Michiie Sakamoto},

doi = {10.1158/1078-0432.CCR-24-0479},

issn = {1557-3265},

year  = {2024},

date = {2024-12-01},

journal = {Clin Cancer Res},

volume = {30},

number = {24},

pages = {5666--5680},

abstract = {PURPOSE: Immunotherapies have led to a paradigm shift in the treatment of hepatocellular carcinoma (HCC). Studies have revealed the single-cell catalogs of tumor-infiltrating immune cells and the trajectories of their differentiation. Nevertheless, the spatial distribution of these immune cells with distinct phenotypes in the tumor microenvironment and their clinicopathologic significance in resectable and unresectable HCCs are still largely unclear.nnEXPERIMENTAL DESIGN: We analyzed the spatial dynamics of intratumoral CD4 and CD8 T cells and their association with B and plasma cells using 283 surgically resected HCC samples, 58 unresectable HCC samples before combined immunotherapy [atezolizumab plus bevacizumab (Atezo + Bev)], and autopsy specimens from 50 cases of advanced-stage HCC through multiplex IHC combined with transcriptomic and driver gene mutation analyses. Classification based on the spatial dynamics of T- and B-cell responses (refined immunosubtype) was developed, and its clinicopathologic significance was analyzed.nnRESULTS: We found that stem-like CD4 and CD8 T cells were mainly observed in T-cell aggregates and T-cell zone of tertiary lymphoid structure (TLS). The differentiation of T follicular helper cells was associated with the development of TLS, whereas the differentiation of CXCL13-expressing CD4 TCXCL13 cells with a phenotype resembling T peripheral helper cells was associated with the development of the lymphoplasmacytic microenvironment. The refined immunosubtype could predict clinical outcomes of resectable HCC after surgery and unresectable HCC after Atezo + Bev therapy. The immune microenvironment of metastatic lesions tended to reflect those of primary lesions.nnCONCLUSIONS: We revealed the spatial dynamics of T- and B-cell responses in HCC, which is closely associated with the clinical outcome after surgical resection or Atezo + Bev therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37543670,

title = {A comprehensive appraisal of HER2 heterogeneity in HER2-amplified and HER2-low colorectal cancer},

author = {Taiki Hashimoto and Daisuke Takayanagi and Junpei Yonemaru and Tomoaki Naka and Kengo Nagashima and Erika Machida and Takashi Kohno and Yasushi Yatabe and Yukihide Kanemitsu and Ryuji Hamamoto and Atsuo Takashima and Kouya Shiraishi and Shigeki Sekine},

doi = {10.1038/s41416-023-02382-z},

issn = {1532-1827},

year  = {2023},

date = {2023-10-01},

journal = {Br J Cancer},

volume = {129},

number = {7},

pages = {1176--1183},

abstract = {BACKGROUND: This study aimed to elucidate the clinicopathological and molecular features of HER2-amplified and HER2-low colorectal cancers (CRCs). We also characterised HER2 expression statuses in CRCs focusing on their intratumoral heterogeneity and alterations in metastatic lesions to establish practical HER2 status assessment.nnMETHODS: We evaluated 1009 CRCs for HER2 expression and HER2 amplification by immunohistochemistry and FISH, respectively, and correlated the results to clinicopathological and molecular data. For HER2-positive tumours, HER2 expression in metastatic lesions was also assessed.nnRESULTS: Twenty-five HER2-amplified (2.5%) and 46 HER2-low tumours (4.6%) were identified. HER2-amplified tumours consistently lacked a mucinous component and HER2-low tumours tended to be in the right colon, but no other clinicopathological features were noted. KRAS, NRAS or BRAF mutations were detected in only two HER2-amplified tumours (8%), whereas 23 HER2-low tumours (50%) had one of these mutations. Most HER2-amplified and HER2-low tumours showed a homogeneous or mosaic HER2 expression pattern and a clustered heterogeneous expression pattern was rather rare. HER2 expression was maintained in most metastatic lesions in both HER2-amplified (93%) and HER2-low tumours (81%).nnCONCLUSIONS: These results suggest that biopsy-based assessment of primary lesions is appropriate for the identification of CRC patients eligible for systemic HER2-targeted therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37300323,

title = {Tumor steatosis and glutamine synthetase expression in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy},

author = {Yutaka Kurebayashi and Hanako Tsujikawa and Katsutoshi Sugimoto and Daisuke Yunaiyama and Yoichi Araki and Kazuhiro Saito and Hiroshi Takahashi and Tatsuya Kakegawa and Takuya Wada and Yusuke Tomita and Masakazu Abe and Yu Yoshimasu and Hirohito Takeuchi and Taiki Hirata and Kentaro Sakamaki and Kazuhiro Kakimi and Toshitaka Nagao and Takao Itoi and Michiie Sakamoto},

doi = {10.1111/hepr.13933},

issn = {1386-6346},

year  = {2023},

date = {2023-10-01},

journal = {Hepatol Res},

volume = {53},

number = {10},

pages = {1008--1020},

abstract = {AIM: The anti-programmed death-ligand 1 antibody atezolizumab and vascular endothelial growth factor-neutralizing antibody bevacizumab in combination (Atezo + Bev) have become the first-line therapy in advanced hepatocellular carcinoma (HCC). Distinct types of tumor immune microenvironment (TIME) and their associations with specific molecular subclasses and driver gene mutations have been identified in HCC; however, these insights are mainly based on surgically resected early-stage tumors. The current study aimed to reveal the biology and TIME of advanced HCC and their significance in predicting clinical outcomes of Atezo + Bev therapy.nnMETHODS: Thirty-three patients with advanced HCC who were scheduled for treatment with Atezo + Bev therapy were included in this study. Pretreatment tumor biopsy, pre- and posttreatment diffusion-weighted magnetic resonance imaging (MRI) with nine b values (0-1500 s/mm ), and other clinicopathologic factors were analyzed.nnRESULTS: Compared with resectable HCC, advanced HCC was characterized by higher proliferative activity, a higher frequency of Wnt/β-catenin-activated HCC, and lower lymphocytic infiltration. Prognostically, two metabolism-related factors, histopathologically determined tumor steatosis and/or glutamine synthetase (GS) expression, and MRI-determined tumor steatosis, were the most significant prognostic indicators for progression-free survival (PFS) and overall survival after Atezo + Bev therapy. Furthermore, changes in the pre- and posttreatment true diffusion coefficients on MRI, which might reflect changes in TIME after treatment, were significantly associated with better PFS.nnCONCLUSIONS: The biology and TIME of HCC were strikingly different in advanced HCC compared with those of surgically resected HCC. Two metabolism-related factors, pathologically determined tumor steatosis and/or GS expression, and MRI-determined tumor steatosis, were found to be the most significant prognostic indicators for Atezo + Bev therapy in advanced HCC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36517953,

title = {Immunovascular microenvironment in relation to prognostic heterogeneity of WNT/β-catenin-activated hepatocellular carcinoma},

author = {Kosuke Matsuda and Yutaka Kurebayashi and Yohei Masugi and Ken Yamazaki and Akihisa Ueno and Hanako Tsujikawa and Hidenori Ojima and Minoru Kitago and Osamu Itano and Masahiro Shinoda and Yuta Abe and Michiie Sakamoto},

doi = {10.1111/hepr.13869},

issn = {1386-6346},

year  = {2023},

date = {2023-04-01},

journal = {Hepatol Res},

volume = {53},

number = {4},

pages = {344--356},

abstract = {AIM: WNT/β-catenin-activated hepatocellular carcinoma (W/B subclass HCC) is considered a molecularly homogeneous entity and has been linked to resistance to immunotherapy. However, recent studies have indicated possible heterogeneity in the immunovascular microenvironment in this subclass. We set out to test the hypothesis that specific immunovascular features might stratify W/B subclass HCCs into tumors having distinct aggressive natures.nnMETHODS: In this study, we analyzed 352 resected HCCs including 78 immunohistochemically defined W/B subclass HCCs. The density of tumor-infiltrating CD3 T cells and the area ratio of vessels encapsulating tumor clusters (VETC) were calculated on tissue specimens. The gene expressions of angiogenic factors were measured by quantitative reverse transcription-polymerase chain reaction. Disease-free survival (DFS) was assessed using multivariable Cox regression analyses.nnRESULTS: The T-cell density of W/B subclass HCCs was regionally heterogenous within tumor tissues, and focally reduced T-cell density was observed in areas with VETC. VETC-positivity (defined as VETC area ratio greater than 1%) was inversely associated with T-cell infiltration in both W/B subclass and non-W/B subclass HCCs. Fibroblast growth factor 2 (FGF2) gene expression was higher in W/B subclass than in non-W/B subclass HCCs. The VETC-positivity and low T-cell density correlated with increased expression of FGF2 in W/B subclass HCCs. Additionally, VETC-positive HCCs showed significantly shorter DFS in W/B subclass HCCs.nnCONCLUSIONS: In conclusion, the immune and vascular microenvironments are interrelated and are also correlated with clinicopathological heterogeneity in W/B subclass HCC. These results could inform clinical practice and translational research on the development of therapeutic stratification of HCCs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35968980,

title = {Sporadic and Familial Adenomatous Polyposis-associated Foveolar-type Adenoma of the Stomach},

author = {Tomoaki Naka and Taiki Hashimoto and Hourin Cho and Noriko Tanabe and Teruhiko Yoshida and Yasushi Yatabe and Takaki Yoshikawa and Seiichiro Abe and Shigeki Sekine},

doi = {10.1097/PAS.0000000000001949},

issn = {1532-0979},

year  = {2023},

date = {2023-01-01},

journal = {Am J Surg Pathol},

volume = {47},

number = {1},

pages = {91--101},

abstract = {Gastric foveolar-type adenoma (FA) is a rare benign neoplasm occurring either sporadically or in patients with familial adenomatous polyposis (FAP). However, the molecular features of FA and the relationship between sporadic and syndromic lesions remain unclear. In this study, we performed clinicopathological, immunohistochemical, and genetic analyses of 18 sporadic and 30 FAP-associated FAs. Most sporadic and FAP-associated FAs were located in the upper or middle third of the stomach, on a background of fundic gland mucosa. Most lesions were low-grade, but 3 lesions had a high-grade component. Sporadic FAs included 2 morphologically distinct subtypes, that is, flat and raspberry-like FAs, which we distinguished based on the endoscopic features. Seven lesions were regarded as flat FAs, appearing as large, slightly elevated lesions and measuring 11 to 87 mm in size. Conversely, 10 raspberry-like FAs were small bright-red polyps, measuring 2 to 8 mm in size. FAP-associated FAs, particularly larger lesions, exhibited morphologic features resembling flat FAs but varied significantly in size (2 to 103 mm). Mutation analysis identified APC and KRAS mutations in all flat FAs but never in raspberry-like FAs. Remarkably, somatic APC and KRAS mutations were also detected in 19 (63%) and 27 (90%) of FAP-associated FAs, respectively. This indicates that they are genetically equivalent to sporadic, flat FAs. This study showed that sporadic FA includes at least 2 morphologically and genetically distinct subtypes: flat and raspberry-like FA. Furthermore, flat FA represents a sporadic counterpart of FAP-associated FA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35715628,

title = {Clinicopathological and molecular characteristics of RSPO fusion-positive colorectal cancer},

author = {Taiki Hashimoto and Daisuke Takayanagi and Junpei Yonemaru and Tomoaki Naka and Kengo Nagashima and Yasushi Yatabe and Dai Shida and Ryuji Hamamoto and Sam O Kleeman and Simon J Leedham and Timothy Maughan and Atsuo Takashima and Kouya Shiraishi and Shigeki Sekine},

doi = {10.1038/s41416-022-01880-w},

issn = {1532-1827},

year  = {2022},

date = {2022-10-01},

journal = {Br J Cancer},

volume = {127},

number = {6},

pages = {1043--1050},

abstract = {BACKGROUND: RSPO fusions that lead to WNT pathway activation are potential therapeutic targets in colorectal cancer (CRC), but their clinicopathological significance remains unclear.nnMETHODS: We screened 1019 CRCs for RSPO fusions using multiplex reverse transcription-PCR. The RSPO fusion-positive tumours were subjected to whole-exome sequencing (WES).nnRESULTS: Our analysis identified 29 CRCs with RSPO fusions (2.8%), consisting of five with an EIF3E-RSPO2 fusion and 24 with PTPRK-RSPO3 fusions. The patients were 17 women and 12 men. Thirteen tumours (45%) were right-sided. Histologically, approximately half of the tumours (13/29, 45%) had a focal or extensive mucinous component that was significantly more frequent than the RSPO fusion-negative tumours (13%; P = 8.1 × 10). Four tumours (14%) were mismatch repair-deficient. WES identified KRAS, BRAF, and NRAS mutations in a total of 27 tumours (93%). In contrast, pathogenic mutations in major WNT pathway genes, such as APC, CTNNB1 and RNF43, were absent. RSPO fusion status did not have a statistically significant influence on the overall or recurrence-free survival. These clinicopathological and genetic features were also confirmed in a pooled analysis of previous studies.nnCONCLUSION: RSPO fusion-positive CRCs constitute a rare subgroup of CRCs with several characteristic clinicopathological and genetic features.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35188590,

title = {Activating KRAS and GNAS mutations in heterotopic submucosal glands of the stomach},

author = {Hourin Cho and Taiki Hashimoto and Tomoaki Naka and Yasushi Yatabe and Ichiro Oda and Yutaka Saito and Takaki Yoshikawa and Shigeki Sekine},

doi = {10.1007/s00535-022-01863-x},

issn = {1435-5922},

year  = {2022},

date = {2022-05-01},

journal = {J Gastroenterol},

volume = {57},

number = {5},

pages = {333--343},

abstract = {BACKGROUND: The heterotopic submucosal gland (HSG) is a common incidental finding in gastrectomy specimens. The majority of HSGs are small incidental lesions, which are also known as gastritis cystica profunda. However, larger lesions may appear as an inverted growth of well-organized mucosa referred to as gastric inverted polyps.nnMETHODS: To determine whether genetic alterations are involved in HSG development, we analyzed 63 gastric HSG lesions using targeted next-generation sequencing and immunohistochemistry.nnRESULTS: Histologically, HSG lesions consistently had areas of pyloric gland differentiation with variable extent of foveolar differentiation. Although the background mucosa showed intestinal metaplasia in most cases (98%), intestinal-type epithelium was seen in only one HSG lesion (2%). Sequencing analysis identified activating KRAS, BRAF, CTNNB1, and GNAS mutations in 34 (54%), 1 (2%), 1 (2%), and 7 (11%) lesions, respectively. HSG lesions harboring a KRAS mutation were more likely to present extensive foveolar differentiation (P = 0.013) and absence of parietal cells (P = 0.0081). Five HSG lesions had a dysplastic component, and concordant genetic alterations were detected between the non-dysplastic and dysplastic areas of two lesions that were successfully analyzed. Immunohistochemical staining demonstrated diffuse expression of mutant KRAS protein in lesions with the most common genetic alteration, KRAS G12D.nnCONCLUSIONS: Our study demonstrated that a major proportion of HSGs were proliferative lesions associated with oncogenic mutations, with more than half of lesions harboring activating KRAS mutations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34657298,

title = {Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments},

author = {Yutaka Kurebayashi and Kosuke Matsuda and Akihisa Ueno and Hanako Tsujikawa and Ken Yamazaki and Yohei Masugi and Wit Thun Kwa and Kathryn Effendi and Yasushi Hasegawa and Hiroshi Yagi and Yuta Abe and Minoru Kitago and Hidenori Ojima and Michiie Sakamoto},

doi = {10.1002/hep.32201},

issn = {1527-3350},

year  = {2022},

date = {2022-05-01},

journal = {Hepatology},

volume = {75},

number = {5},

pages = {1139--1153},

abstract = {BACKGROUND AND AIMS: Immune cells and tumor vessels constitute important elements in tumor tissue; however, their detailed relationship in human tumors, including HCC, is still largely unknown. Consequently, we expanded our previous study on the immune microenvironment of HCC and analyzed the relationship among the immune microenvironment, inflammatory/angiostatic factor expression, angiogenic factor expression, and tumor vessel findings, including vessels encapsulating tumor clusters (VETC) and macrotrabecular-massive (MTM) patterns.nnAPPROACH AND RESULTS: We classified HCC into four distinct immunovascular subtypes (immune-high/angiostatic [IH/AS], immune-mid/angio-mid [IM/AM], immune-low/angiogenic [IL/AG], and immune-low/angio-low [IL/AL]). IH/AS, IM/AM, and IL/AG subtypes were associated with decreasing lymphocytic infiltration and increasing angiogenic factor expression and VETC/MTM positivity, reflecting their reciprocal interaction in the tumor microenvironment of HCC. IL/AG subtype was further characterized by CTNNB1 mutation and activation of Wnt/β-catenin pathway. IL/AL subtype was not associated with increased lymphocyte infiltration or angiogenic factor expression. Prognostically, IH/AS subtype and VETC/MTM positivity were independently significant in two independent cohorts. Increased angiogenic factor expression was not necessarily associated with VETC/MTM positivity and poor prognosis, especially when inflammatory/angiostatic milieu coexisted around tumor vessels. These results may provide insights on the therapeutic effects of immunotherapy, antiangiogenic therapies, and their combinations. The potential of evaluating the immunovascular microenvironment in predicting the clinical effect of these therapies in nonresectable HCC needs to be analyzed in the future study.nnCONCLUSIONS: HCC can be classified into four distinct immunovascular subtypes (IH/AS, IM/AM, IL/AG, and IL/AL) that reflect the reciprocal interaction between the antitumor immune microenvironment and tumor angiogenesis. In addition to its clinicopathological significance, immunovascular classification may also provide pathological insights on the therapeutic effect of immunotherapy, antiangiogenic therapy, and their combination.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35961696,

title = {Liver cancer risk-predictive molecular biomarkers specific to clinico-epidemiological contexts},

author = {Naoto Kubota and Naoto Fujiwara and Yujin Hoshida},

doi = {10.1016/bs.acr.2022.01.005},

issn = {2162-5557},

year  = {2022},

date = {2022-01-01},

journal = {Adv Cancer Res},

volume = {156},

pages = {1--37},

abstract = {Hepatocellular carcinoma (HCC) risk prediction is increasingly important because of the low annual HCC incidence in patients with the rapidly emerging non-alcoholic fatty liver disease or cured HCV infection. To date, numerous clinical HCC risk biomarkers and scores have been reported in literature. However, heterogeneity in clinico-epidemiological context, e.g., liver disease etiology, patient race/ethnicity, regional environmental exposure, and lifestyle-related factors, obscure their real clinical utility and applicability. Proper characterization of these factors will help refine HCC risk prediction according to certain clinical context/scenarios and contribute to improved early HCC detection. Molecular factors underlying the clinical heterogeneity encompass various features in host genetics, hepatic and systemic molecular dysregulations, and cross-organ interactions, which may serve as clinical-context-specific biomarkers and/or therapeutic targets. Toward the goal to enable individual-risk-based HCC screening by incorporating the HCC risk biomarkers/scores, their assessment in patient with well-defined clinical context/scenario is critical to gauge their real value and to maximize benefit of the tailored patient management for substantial improvement of the poor HCC prognosis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34514550,

title = {APC mutations are common in adenomas but infrequent in adenocarcinomas of the non-ampullary duodenum},

author = {Kenichi Ishizu and Taiki Hashimoto and Tomoaki Naka and Yasushi Yatabe and Motohiro Kojima and Takeshi Kuwata and Satoru Nonaka and Ichiro Oda and Minoru Esaki and Masashi Kudo and Naoto Gotohda and Teruhiko Yoshida and Takaki Yoshikawa and Shigeki Sekine},

doi = {10.1007/s00535-021-01823-x},

issn = {1435-5922},

year  = {2021},

date = {2021-11-01},

journal = {J Gastroenterol},

volume = {56},

number = {11},

pages = {988--998},

abstract = {BACKGROUND: Recent studies highlighted the clinicopathological heterogeneity of non-ampullary duodenal adenomas and adenocarcinomas, but the detailed process of the malignant transformation remains unclear.nnMETHODS: We analyzed 144 adenomas and 54 adenocarcinomas of the non-ampullary duodenum for immunohistochemical phenotypes, genetic alterations, and mismatch repair (MMR) status to probe their histogenetic relationship.nnRESULTS: The median ages of patients with adenoma and adenocarcinoma were the same (66 years). Adenomas were histologically classified as intestinal-type adenoma (n = 124), pyloric gland adenoma (PGA, n = 10), gastric-type adenoma, not otherwise specified (n = 9), and foveolar-type adenoma (n = 1). Protein-truncating APC mutations were highly frequent in adenomas (85%), with the highest prevalence in intestinal-type adenomas (89%), but rare in adenocarcinomas (9%; P = 2.1 × 10). Close associations between phenotypic marker expression and genetic alterations were observed in adenomas, but not in adenocarcinomas, excluding the common association between GNAS mutations and MUC5AC expression. MMR deficiency was more frequent in adenocarcinomas (20%) than in adenomas (1%; P = 2.6 × 10). One MMR-deficient adenoma and three MMR-deficient adenocarcinomas occurred in patients with Lynch syndrome. Additionally, three other patients with an MMR-deficient adenocarcinoma fulfilled the revised Bethesda criteria.nnCONCLUSION: The discrepant APC mutation frequency between adenomas and adenocarcinomas suggests that APC-mutated adenomas, which constitute the large majority of non-ampullary duodenal adenomas, are less prone to malignant transformation. Non-ampullary duodenal adenocarcinomas frequently exhibit MMR deficiency and should be subject to MMR testing to determine appropriate clinical management, including the identification of patients with Lynch syndrome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34147970,

title = {A comparison of cost-effectiveness between offering antidepressant-CBT combinations first or second, for moderate to severe depression in Japan},

author = {Yoshihide Yamada and Riku Miyahara and Masataka Wada and Akira Ninomiya and Teppei Kosugi and Masaru Mimura and Mitsuhiro Sado},

doi = {10.1016/j.jad.2021.05.095},

issn = {1573-2517},

year  = {2021},

date = {2021-09-01},

journal = {J Affect Disord},

volume = {292},

pages = {574--582},

abstract = {BACKGROUND: It is not clear which method is more cost-effective: To initially provide all depressed patients with combination therapy (COMB; i.e. cognitive behavioural therapy plus pharmacotherapy), followed by antidepressant treatment (AD) for those still in depression; or, to first provide AD for all patients, followed by COMB for non-remission patients. The aim is to investigate whether a COMB-first strategy would be more cost-effective than an AD-first strategy, in treating depression.nnMETHODS: A Markov model was developed to perform the analysis. The primary outcome was the incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) at 104 weeks. Probabilistic sensitivity analysis and scenario analysis were performed, to investigate the uncertainty associated with the clinical parameters and the impact of CBT's cost on the results, respectively.nnRESULTS: The ICER per QALY at 104 week, was JPY 591,822 (USD 5,725) for moderate depression and JPY 499,487 (USD 4,832) for severe one. The scenario analysis revealed the ICER became JPY 1,147,518 (USD 11,101) for moderate and JPY 968,484 (USD 9,369) for severe when the CBT cost was set as JPY 14,400 (USD 139)(i.e. GBP 96: the unit cost of CBT in UK), which is well below the threshold recommended by NICE (i.e. GBP 20,000-30,000).nnLIMITATIONS: This is a model-based analysis which was conducted from the health insurance perspective. Then, the analysis from the societal perspective would generate different results.nnCONCLUSIONS: The results suggest that a COMB-first strategy would be more cost effective than an AD-first strategy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33574087,

title = {Rapid Depletion of Intratumoral Regulatory T Cells Induces Synchronized CD8 T- and NK-cell Activation and IFNγ-Dependent Tumor Vessel Regression},

author = {Yutaka Kurebayashi and Colleen P Olkowski and Kelly C Lane and Olga V Vasalatiy and Biying C Xu and Ryuhei Okada and Aki Furusawa and Peter L Choyke and Hisataka Kobayashi and Noriko Sato},

doi = {10.1158/0008-5472.CAN-20-2673},

issn = {1538-7445},

year  = {2021},

date = {2021-06-01},

journal = {Cancer Res},

volume = {81},

number = {11},

pages = {3092--3104},

abstract = {Regulatory T cells (Tregs) are known to inhibit antitumor immunity, yet the specific mechanism by which intratumoral Tregs promote tumor growth remains unclear. To better understand the roles of intratumoral Tregs, we selectively depleted tumor-infiltrating Tregs using anti-CD25-F(ab') near-infrared photoimmunotherapy. Depletion of tumor-infiltrating Tregs induced transient but synchronized IFNγ expression in CD8 T and natural killer (NK) cells. Despite the small fraction of CD8 T and NK cells contained within examined tumors, IFNγ produced by these CD8 T and NK cells led to efficient and rapid tumor vessel regression, intratumoral ischemia, and tumor necrosis/apoptosis and growth suppression. IFNγ receptor expression on vascular endothelial cells was required for these effects. Similar findings were observed in the early phase of systemic Treg depletion in tumor-bearing  mice; combination with IL15 therapy further inhibited tumor growth and achieved increased complete regression. These results indicate the pivotal roles of intratumoral Tregs in maintaining tumor vessels and tumor growth by suppressing CD8 T and NK cells from producing IFNγ, providing insight into the mechanism of Treg-targeting therapies. SIGNIFICANCE: Intratumoral Treg depletion induces synchronized intratumoral CD8 T- and NK-cell activation, IFNγ-dependent tumor vessel regression, and ischemic tumor necrosis/apoptosis, indicating the roles of intratumoral Tregs to support the tumor vasculature. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/3092/F1.large.jpg.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33631044,

title = {NTRK fusion-positive colorectal cancer in Japanese population},

author = {Junpei Yonemaru and Taiki Hashimoto and Daisuke Takayanagi and Tomoaki Naka and Yasushi Yatabe and Yukihide Kanemitsu and Kouya Shiraishi and Shigeki Sekine},

doi = {10.1111/pin.13082},

issn = {1440-1827},

year  = {2021},

date = {2021-05-01},

journal = {Pathol Int},

volume = {71},

number = {5},

pages = {355--359},

abstract = {ALK, ROS1 and NTRK fusions are involved in the tumorigenesis of various organs, including colorectal cancer. This study aims to clarify the prevalence of these fusions in colorectal cancer in the Japanese population. Immunohistochemical analysis of 1012 specimens of colorectal cancer revealed two NTRK-positive cases (0.2%) whereas no ALK- or ROS1-positive cases were identified. Reverse transcription polymerase chain reaction (RT-PCR) detected an LMNA-NTRK1 fusion in a case of adenosquamous carcinoma and a TPM3-NTRK1 fusion in a case of tubular adenocarcinoma. Both NTRK1 fusion-positive cases lacked activating mutations in KRAS and BRAF and were mismatch repair-deficient with loss of MLH1 and PMS2 expression and MLH1 promoter methylation. Our results show that receptor tyrosine kinase fusions are rare but present in colorectal cancers in Japanese patients, with a prevalence similar to that reported in other countries.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32573056,

title = {Immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: Relationship with histopathological and molecular classifications},

author = {Yutaka Kurebayashi and Naoto Kubota and Michiie Sakamoto},

doi = {10.1111/hepr.13539},

issn = {1386-6346},

year  = {2021},

date = {2021-01-01},

journal = {Hepatol Res},

volume = {51},

number = {1},

pages = {5--18},

abstract = {Tumor tissue is composed of tumor cells and tumor stroma. Tumor stroma contains various immune cells and non-immune stromal cells, forming a complex tumor microenvironment which plays pivotal roles in regulating tumor growth. Recent successes in immunotherapies against tumors, including immune checkpoint inhibitors, have further raised interests in the immune microenvironment of liver carcinoma. The immune microenvironment of tumors is formed because of interactions among tumor cells, immune cells and non-immune stromal cells, including fibroblasts and endothelial cells. Different patterns of immune microenvironment are observed among different tumor subtypes, and their clinicopathological significance and intertumor/intratumor heterogeneity are being intensively studied. Here, we review the immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma, focusing on its histopathological appearance, clinicopathological significance, and relationship with histological and molecular classifications. Understanding the comprehensive histopathological picture of a tumor immune microenvironment, in addition to molecular and genetic approaches, will further potentiate the effort for precision medicine in the era of tumor-targeting immunotherapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32415517,

title = {Sporadic pyloric gland adenoma associated with a large fundic gland polyp: genetic evidence for stepwise progression},

author = {Satoru Nonaka and Taiki Hashimoto and Ichiro Oda and Shigeki Sekine},

doi = {10.1007/s10120-020-01082-4},

issn = {1436-3305},

year  = {2020},

date = {2020-11-01},

journal = {Gastric Cancer},

volume = {23},

number = {6},

pages = {1102--1106},

abstract = {Pyloric gland adenoma (PGA) is an uncommon variant of gastric adenoma exhibiting pyloric gland/mucous neck cell differentiation. We present a sporadic PGA associated with a large fundic gland polyp (FGP) in a woman in her 40 s without Helicobacter pylori infection. The polyp, measuring 25 mm in size, was located in the middle gastric body and was removed by endoscopic submucosal dissection. Histological examination revealed three morphologically distinct components: FGP, FGP with large cysts, and PGA. A genetic analysis identified a truncating APC mutation in all the three components, supporting their histogenetic relationship. Additionally, a GNAS mutation was detected in two components, FGP with large cysts and PGA, whereas a KRAS mutation was exclusively found in the PGA component. Thus, despite the unusual presentation, the PGA component harbored prototypical genetic alterations. The differential genetic alterations observed in the three components imply that they represent stepwise progression from FGP to PGA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33256232,

title = {Clinical and Molecular Prediction of Hepatocellular Carcinoma Risk},

author = {Naoto Kubota and Naoto Fujiwara and Yujin Hoshida},

doi = {10.3390/jcm9123843},

issn = {2077-0383},

year  = {2020},

date = {2020-11-01},

journal = {J Clin Med},

volume = {9},

number = {12},

abstract = {Prediction of hepatocellular carcinoma (HCC) risk becomes increasingly important with recently emerging HCC-predisposing conditions, namely non-alcoholic fatty liver disease and cured hepatitis C virus infection. These etiologies are accompanied with a relatively low HCC incidence rate (~1% per year or less), while affecting a large patient population. Hepatitis B virus infection remains a major HCC risk factor, but a majority of the patients are now on antiviral therapy, which substantially lowers, but does not eliminate, HCC risk. Thus, it is critically important to identify a small subset of patients who have elevated likelihood of developing HCC, to optimize the allocation of limited HCC screening resources to those who need it most and enable cost-effective early HCC diagnosis to prolong patient survival. To date, numerous clinical-variable-based HCC risk scores have been developed for specific clinical contexts defined by liver disease etiology, severity, and other factors. In parallel, various molecular features have been reported as potential HCC risk biomarkers, utilizing both tissue and body-fluid specimens. Deep-learning-based risk modeling is an emerging strategy. Although none of them has been widely incorporated in clinical care of liver disease patients yet, some have been undergoing the process of validation and clinical development. In this review, these risk scores and biomarker candidates are overviewed, and strategic issues in their validation and clinical translation are discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32384323,

title = {Clinicopathologic and Molecular Characteristics of Familial Adenomatous Polyposis-associated Traditional Serrated Adenoma},

author = {Takuma Okamura and Taiki Hashimoto and Tomoaki Naka and Teruhiko Yoshida and Noriko Tanabe and Reiko Ogawa and Masayoshi Yamada and Yutaka Saito and Yasushi Yatabe and Shigeki Sekine},

doi = {10.1097/PAS.0000000000001502},

issn = {1532-0979},

year  = {2020},

date = {2020-09-01},

journal = {Am J Surg Pathol},

volume = {44},

number = {9},

pages = {1282--1289},

abstract = {Colorectal carcinogenesis in familial adenomatous polyposis (FAP) follows a conventional adenoma-carcinoma sequence. However, previous studies have also reported the occurrence of traditional serrated adenomas (TSAs) in patients with FAP. In the present study, we analyzed the clinicopathologic and molecular features of 37 TSAs from 21 FAP patients. Histologically, the majority of FAP-associated TSAs showed typical cytology and slit-like serration; however, ectopic crypt formation was infrequent. Next-generation sequencing and Sanger sequencing identified KRAS and BRAF V600E mutations in 18 (49%) and 14 (38%) TSAs, respectively. Somatic APC mutations were detected in 26 lesions (84% of analyzed cases). Three lesions had BRAF non-V600E mutations, and 2 of them had a concurrent KRAS mutation. Seven TSAs (19%) were associated with a precursor polyp, 6 with a hyperplastic polyp, and 1 with a sessile serrated lesion, and all of them showed the BRAF V600E mutation. Additional sequencing analysis of 4 TSAs with a precursor polyp showed that the BRAF V600E mutation was shared between the TSA and precursor components, but APC mutations were exclusive to the TSA component in all the analyzed lesions. None of the lesions showed the high CpG island methylation phenotype. These results indicate that FAP-associated TSAs frequently have KRAS or BRAF mutations, similar to sporadic cases, and second-hit somatic APC mutations are commonly involved in their tumorigenesis as in other FAP-associated tumors. Although progression to adenocarcinoma is likely rare, tumorigenesis via the serrated pathway occurs in patients with FAP.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32052185,

title = {Clinicopathological and molecular correlations in traditional serrated adenoma},

author = {Shigeki Sekine and Satoshi Yamashita and Masayoshi Yamada and Taiki Hashimoto and Reiko Ogawa and Hiroshi Yoshida and Hirokazu Taniguchi and Motohiro Kojima and Toshikazu Ushijima and Yutaka Saito},

doi = {10.1007/s00535-020-01673-z},

issn = {1435-5922},

year  = {2020},

date = {2020-04-01},

journal = {J Gastroenterol},

volume = {55},

number = {4},

pages = {418--427},

abstract = {BACKGROUND: Traditional serrated adenoma (TSA) is the least common type of colorectal serrated polyp, which exhibits considerable morphological and molecular diversity.nnMETHODS: We examined the spectra of alterations in MAPK and WNT pathway genes and their relationship with clinicopathological features in 128 TSAs.nnRESULTS: Sequencing analyses identified BRAF V600E, BRAF non-V600E, KRAS, and NRAS mutations in 77, 3, 45, and 1 lesion, respectively. Collectively, 124 lesions (97%) had mutations in MAPK pathway genes. Alterations in WNT pathway genes were identified in 107 lesions (84%), including RSPO fusions/overexpression, RNF43 mutations, ZNRF3 mutations, APC mutations, and CTNNB1 mutations in 47, 45, 2, 13, and 2 lesions, respectively. Ten lesions (8%) harbored GNAS mutations. There was significant interdependence between the altered MAPK and WNT pathway genes. RSPO fusions/overexpression was significantly associated with KRAS mutations (31/47, 66%), whereas most RNF43 mutations coexisted with the BRAF V600E mutation (40/45, 89%). Histologically, extensive slit-like serration was more common in lesions with the BRAF V600E mutation (71%) and those with RNF43 mutations (87%). Prominent ectopic crypt formation was more prevalent in lesions with RSPO fusions/overexpression (58%) and those with GNAS mutations (100%).nnCONCLUSIONS: Our observations indicate that TSAs mostly harbor various combinations of concurrent WNT and MAPK gene alterations. The associations between genetic and morphological features suggest that the histological diversity of TSA reflects the underlying molecular heterogeneity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31930673,

title = {Clinicopathological features of hepatocellular carcinoma with fatty change: Tumors with macrovesicular steatosis have better prognosis and aberrant expression patterns of perilipin and adipophilin},

author = {Naoto Kubota and Hidenori Ojima and Mami Hatano and Ken Yamazaki and Yohei Masugi and Hanako Tsujikawa and Yoko Fujii-Nishimura and Akihisa Ueno and Yutaka Kurebayashi and Masahiro Shinoda and Minoru Kitago and Yuta Abe and Yuko Kitagawa and Michiie Sakamoto},

doi = {10.1111/pin.12889},

issn = {1440-1827},

year  = {2020},

date = {2020-04-01},

journal = {Pathol Int},

volume = {70},

number = {4},

pages = {199--209},

abstract = {The clinicopathological characteristics of steatosis in hepatocellular carcinoma (HCC) remain unclear. Here, we elucidate the features of macrovesicular steatosis (MaS) and microvesicular steatosis (MiS) in HCC and their relationships with background liver steatosis. A total of 165 HCC lesions were classified as MaS-HCC, MiS-HCC, or conventional HCC (cHCC) according to the cutoff value of 30% MaS or MiS in tumor cells. We analyzed the clinicopathological differences among these groups. MaS-HCC had less portal vein invasion, a higher proportion of HCC with intratumoral fibrosis, and a lower cumulative risk of recurrence than MiS-HCC or cHCC. Moreover, both MaS-HCC and MiS-HCC had lower incidences of hepatitis virus infection and higher levels of HbA1c than cHCC. Background liver steatosis was also higher in MaS-HCC than in cHCC. Immunohistochemical expression of perilipin (Plin1) and adipophilin (ADRP), major proteins expressed on lipid droplet membranes, revealed that almost all lipid droplets in HCC were Plin1 negative, whereas those in background liver were positive. In contrast, ADRP was expressed on lipid droplets in both HCC and background liver. We concluded that MaS-HCC and MiS-HCC were associated with metabolic abnormalities but exhibited different biologic behaviors. Furthermore, lipid droplets in HCC were pathophysiologically different from those in background liver.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31209633,

title = {Identification of a novel PRR15L-RSPO2 fusion transcript in a sigmoid colon cancer derived from superficially serrated adenoma},

author = {Yasuhiko Mizuguchi and Taku Sakamoto and Taiki Hashimoto and Shunsuke Tsukamoto and Satoru Iwasa and Yutaka Saito and Shigeki Sekine},

doi = {10.1007/s00428-019-02604-x},

issn = {1432-2307},

year  = {2019},

date = {2019-11-01},

journal = {Virchows Arch},

volume = {475},

number = {5},

pages = {659--663},

abstract = {Superficially serrated adenoma (SuSA) is a recently proposed subtype of colorectal serrated lesion. We here report a sigmoid colon cancer derived from SuSA, which exhibited aggressive clinical behavior. Endoscopically, the tumor appeared as a superficial elevated lesion with a large nodule. Histological examination of the surgically resected material showed tubular adenocarcinoma associated with SuSA. Although tumor invasion was limited to the submucosal layer, lymph node and extranodal metastases were detected. The patient subsequently developed peritoneal metastases and died 15 months after surgery. Molecular analyses identified a KRAS mutation and a novel PRR15L-RSPO2 fusion, which retains the entire coding region of RSPO2, in both SuSA and adenocarcinoma components. The present study demonstrates the malignant potential of SuSA and expands the spectrum of RSPO fusions in colorectal neoplasms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30916365,

title = {EIF3E-RSPO2 and PIEZO1-RSPO2 fusions in colorectal traditional serrated adenoma},

author = {Taiki Hashimoto and Reiko Ogawa and Hiroshi Yoshida and Hirokazu Taniguchi and Motohiro Kojima and Yutaka Saito and Shigeki Sekine},

doi = {10.1111/his.13867},

issn = {1365-2559},

year  = {2019},

date = {2019-08-01},

journal = {Histopathology},

volume = {75},

number = {2},

pages = {266--273},

abstract = {AIMS: Traditional serrated adenoma (TSA) is an uncommon type of colorectal serrated polyp. RSPO fusions, which potentiate WNT signalling, are common and characteristic genetic alterations in TSA. The aim of this study was to further characterise the prevalence and variation of RSPO fusions in TSA.nnMETHODS AND RESULTS: Quantitative polymerase chain reaction (PCR) analysis of 99 TSAs revealed overexpression of RSPO2 and RSPO3 in six and 29 lesions, respectively. Reverse transcription PCR identified previously reported PTPRK-RSPO3 fusion transcripts in all 29 TSAs with RSPO3 overexpression, confirming that PTPRK-RSPO3 is the predominant RSPO fusion in TSAs. Among the six lesions with RSPO2 overexpression, two overexpressed full-length RSPO2. An EIF3E-RSPO2 fusion, which is a known recurrent RSPO fusion in colorectal cancer, was detected in three lesions. In addition, rapid amplification of cDNA ends identified a novel PIEZO1-RSPO2 fusion in one TSA. All of the four TSAs with RSPO2 fusions concurrently had KRAS mutations and showed the classic histological features.nnCONCLUSIONS: The present study identified EIF3E-RSPO2 and PIEZO1-RSPO2 in TSAs. Our observations expand the spectrum of RSPO fusions in TSAs, and suggest that TSAs are precursors of colorectal cancers with these RSPO2 fusions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31145701,

title = {Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma},

author = {Shigeki Sekine and Tohru Kiyono and Eijitsu Ryo and Reiko Ogawa and Susumu Wakai and Hitoshi Ichikawa and Koyu Suzuki and Satoru Arai and Koji Tsuta and Mitsuaki Ishida and Yuko Sasajima and Naoki Goshima and Naoya Yamazaki and Taisuke Mori},

doi = {10.1172/JCI126185},

issn = {1558-8238},

year  = {2019},

date = {2019-05-01},

journal = {J Clin Invest},

volume = {129},

number = {9},

pages = {3827--3832},

abstract = {Poroma is a benign skin tumor exhibiting terminal sweat gland duct differentiation. The present study aimed to explore the potential role of gene fusions in the tumorigenesis of poromas. RNA sequencing and reverse transcription PCR identified highly recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poromas (92/104 lesions, 88.5%) and their rare malignant counterpart, porocarcinomas (7/11 lesions, 63.6%). A WWTR1-NUTM1 fusion was identified in a single lesion of poroma. Fluorescent in-situ hybridization confirmed genomic rearrangements involving these genetic loci. Immunohistochemical staining could readily identify the YAP1 fusion products as nuclear expression of the N-terminal portion of YAP1 with a lack of the C-terminal portion. YAP1 and WWTR1, also known as YAP and TAZ, respectively, encode paralogous transcriptional activators of TEAD, which are negatively regulated by the Hippo signaling pathway. The YAP1 and WWTR1 fusions strongly transactivated a TEAD reporter and promoted anchorage-independent growth, confirming their tumorigenic roles. Our results demonstrate the frequent presence of transforming YAP1 fusions in poromas and porocarcinomas and suggest YAP1/TEAD-dependent transcription as a candidate therapeutic target against porocarcinoma.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30425335,

title = {RHOA mutations and CLDN18-ARHGAP fusions in intestinal-type adenocarcinoma with anastomosing glands of the stomach},

author = {Taiki Hashimoto and Reiko Ogawa and Tzu-Yin Tang and Hiroshi Yoshida and Hirokazu Taniguchi and Hitoshi Katai and Ichiro Oda and Shigeki Sekine},

doi = {10.1038/s41379-018-0181-9},

issn = {1530-0285},

year  = {2019},

date = {2019-04-01},

journal = {Mod Pathol},

volume = {32},

number = {4},

pages = {568--575},

abstract = {A subtype of intestinal-type adenocarcinoma of the stomach, characterized by low-grade cytological atypia and anastomosing glands, has been described in several reports under different names. One of the remarkable features of these lesions, herein referred to as intestinal-type adenocarcinoma with anastomosing glands, is the frequent association of poorly differentiated adenocarcinoma components. Here we analyzed 44 intestinal-type adenocarcinomas with anastomosing glands focusing on the molecular abnormalities that are common in diffuse-type gastric cancers. Next-generation sequencing identified RHOA and CDH1 mutations in 22 (50%) and one lesion (2%), respectively. Reverse transcription-PCR detected CLDN18-ARHGAP fusions in three lesions (7%). Immunohistochemically, none of the lesions showed abnormal p53 expression patterns whereas focal and diffuse loss of ARID1A was observed in four and one lesion, respectively. Examination of 37 lesions of dysplasia and 26 usual-type intramucosal adenocarcinomas identified one RHOA mutation in adenocarcinoma and no CLDN18-ARHGAP fusions, indicating that these genetic alterations are highly specific to intestinal-type adenocarcinomas with anastomosing glands among differentiated-type intramucosal neoplasms. The present study showed that intestinal-type adenocarcinoma with anastomosing glands represents a genetically distinct group of tumors with the frequent presence of RHOA mutations and CLDN18-ARHGAP fusions, which are thought to be specific to diffuse-type gastric cancers.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30179900,

title = {Acquisition of WNT Pathway Gene Alterations Coincides With the Transition From Precursor Polyps to Traditional Serrated Adenomas},

author = {Taiki Hashimoto and Reiko Ogawa and Hiroshi Yoshida and Hirokazu Taniguchi and Motohiro Kojima and Yutaka Saito and Shigeki Sekine},

doi = {10.1097/PAS.0000000000001149},

issn = {1532-0979},

year  = {2019},

date = {2019-01-01},

journal = {Am J Surg Pathol},

volume = {43},

number = {1},

pages = {132--139},

abstract = {Colorectal traditional serrated adenomas (TSAs) are often associated with precursor polyps, including hyperplastic polyps and sessile serrated adenoma/polyps. To elucidate the molecular mechanisms involved in the progression from precursor polyps to TSAs, the present study analyzed 15 precursor polyp-associated TSAs harboring WNT pathway gene mutations. Laser microdissection-based sequencing analysis showed that BRAF or KRAS mutations were shared between TSA and precursor polyps in all lesions. In contrast, the statuses of WNT pathway gene mutations were different between the 2 components. In 8 lesions, RNF43, APC, or CTNNB1 mutations, were exclusively present in TSA. RNF43 mutations were shared between the TSA and precursor components in 3 lesions; however, they were heterozygous in the precursor polyps whereas homozygous in the TSA. In 4 lesions with PTPRK-RSPO3 fusions, RNA in situ hybridization demonstrated that overexpression of RSPO3, reflecting PTPRK-RSPO3 fusion transcripts, was restricted to TSA components. Consistent with the results of the genetic and in situ hybridization analyses, nuclear β-catenin accumulation and MYC overexpression were restricted to the TSA component in 13 and 12 lesions, respectively. These findings indicate that the WNT pathway gene alterations are acquired during the progression from the precursor polyps to TSAs and that the activation of the WNT pathway plays a critical role in the development of TSA rather than their progression to high-grade lesions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29789649,

title = {Superficially serrated adenoma: a proposal for a novel subtype of colorectal serrated lesion},

author = {Taiki Hashimoto and Yusaku Tanaka and Reiko Ogawa and Taisuke Mori and Hiroshi Yoshida and Hirokazu Taniguchi and Nobuyoshi Hiraoka and Motohiro Kojima and Yasuhiro Oono and Yutaka Saito and Shigeki Sekine},

doi = {10.1038/s41379-018-0069-8},

issn = {1530-0285},

year  = {2018},

date = {2018-10-01},

journal = {Mod Pathol},

volume = {31},

number = {10},

pages = {1588--1598},

abstract = {We describe a series of colorectal polyps characterized by mixed adenomatous and serrated features, herein referred to as superficially serrated adenomas. Twenty superficially serrated adenomas were obtained from 11 female and 9 male patients aged 62-87 years. Most lesions endoscopically appeared as small sessile polyps, but larger lesions were plaque-like (2-20 mm; median, 5 mm). Eighteen lesions (90%) were located in the sigmoid colon or rectum. They consisted primarily of straight, adenomatous glands but showed serration confined to the superficial layer. Immunohistochemistry revealed CK20 expression in the upper layer. Proliferating cells, determined by their expression of Ki-67, were localized to the middle to bottom layers. Genetic analyses identified KRAS mutations in 19 lesions and a BRAF mutation in one lesion. Furthermore, RSPO fusions and/or overexpression were observed in 18 lesions and truncating APC mutations were observed in the two remaining lesions. Consistent with the presence of WNT pathway gene alterations, all superficially serrated adenomas showed focal or diffuse nuclear β-catenin accumulation. Since concurrent KRAS mutations and RSPO fusions are reportedly common in traditional serrated adenomas, we reviewed 129 traditional serrated adenomas and found 15 lesions (12%) that were associated with superficially serrated adenoma components. Remarkably, all but one superficially serrated adenoma-associated traditional serrated adenoma exhibited concurrent KRAS mutations and RSPO fusions/overexpression. The present study suggests that superficially serrated adenoma is a morphologically and molecularly distinct type of colorectal serrated polyp that is histogenetically related to traditional serrated adenoma.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29920740,

title = {Reappraisal of the genetic heterogeneity of sessile serrated adenoma/polyp},

author = {Hourin Cho and Taiki Hashimoto and Hiroshi Yoshida and Hirokazu Taniguchi and Reiko Ogawa and Taisuke Mori and Nobuyoshi Hiraoka and Yutaka Saito and Shigeki Sekine},

doi = {10.1111/his.13688},

issn = {1365-2559},

year  = {2018},

date = {2018-10-01},

journal = {Histopathology},

volume = {73},

number = {4},

pages = {672--680},

abstract = {AIMS: Sessile serrated adenoma/polyp (SSA/P) is regarded as a genetically homogeneous entity, with most lesions harbouring the BRAF V600E mutation. The present study aimed to reappraise the genetic heterogeneity of SSA/Ps and its clinicopathological significance.nnMETHODS AND RESULTS: We performed next-generation sequencing of 272 SSA/Ps without dysplasia and evaluated morphological and molecular features associated with the respective genotypes. BRAF V600E, BRAF non-V600E, KRAS and NRAS mutations were found in 223 (82.0%), three (1.2%), 28 (10.3%) and one lesion (0.4%), respectively. Notably, all lesions with BRAF non-V600E mutations had either KRAS or NRAS mutations concurrently. Twenty SSA/Ps (7.4%) were negative for these mutations. KRAS-mutated SSA/Ps were located more often in the distal colon (42%) compared to those with the BRAF V600E mutation (14%). Histologically, minimally serrated crypts and goblet cell-rich crypts were more common in KRAS-mutated and mutation-negative SSA/Ps. However, in most instances, SSA/Ps lacking the BRAF V600E mutation were indistinguishable morphologically from those with the BRAF V600E mutation. MUC5AC and MUC6 expression was common regardless of the mutation status, but more extensive in SSA/Ps with the BRAF V600E mutation. CpG island methylator phenotype-high was more frequent in SSA/Ps with the BRAF V600E mutation (60%), followed by mutation-negative SSA/Ps (40%) and KRAS-mutated SSA/Ps (16%).nnCONCLUSIONS: The present study confirmed the common presence of the BRAF V600E mutation in SSA/Ps, but also demonstrated a degree of molecular heterogeneity of SSA/Ps. SSA/Ps with and without the BRAF V600E mutation showed slightly different but overlapping histological and molecular features.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29603348,

title = {Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification},

author = {Yutaka Kurebayashi and Hidenori Ojima and Hanako Tsujikawa and Naoto Kubota and Junki Maehara and Yuta Abe and Minoru Kitago and Masahiro Shinoda and Yuko Kitagawa and Michiie Sakamoto},

doi = {10.1002/hep.29904},

issn = {1527-3350},

year  = {2018},

date = {2018-09-01},

journal = {Hepatology},

volume = {68},

number = {3},

pages = {1025--1041},

abstract = {Immune cells constitute an important element of tumor tissue. Accumulating evidence indicates their clinicopathological significance in predicting prognosis and therapeutic efficacy. Nonetheless, the combinations of immune cells forming the immune microenvironment and their association with histological findings remain largely unknown. Moreover, it is unclear which immune cells or immune microenvironments are the most prognostically significant. Here, we comprehensively analyzed the immune microenvironment and its intratumor heterogeneity in 919 regions of 158 hepatocellular carcinomas (HCCs), and the results were compared with the corresponding histological and prognostic data. Consequently, we classified the immune microenvironment of HCC into three distinct immunosubtypes: Immune-high, Immune-mid, and Immune-low. The Immune-high subtype was characterized by increased B-/plasma-cell and T cell infiltration, and the Immune-high subtype and B-cell infiltration were identified as independent positive prognostic factors. Varying degrees of intratumor heterogeneity of the immune microenvironment were observed, some of which reflected the multistep nature of HCC carcinogenesis. However, the predominant pattern of immunosubtype and immune cell infiltration of each tumor was prognostically important. Of note, the Immune-high subtype was associated with poorly differentiated HCC, cytokeratin 19 (CK19) , and/or Sal-like protein 4 (SALL4) high-grade HCC, and Hoshida's S1/Boyault's G2 subclasses. Furthermore, patients with high-grade HCC of the predominant Immune-high subtype had significantly better prognosis. These results provide a rationale for evaluating the immune microenvironment in addition to the usual histological/molecular classification of HCC.nnCONCLUSION: The immune microenvironment of HCC can be classified into three immunosubtypes (Immune-high, Immune-mid, and Immune-low) with additional prognostic impact on histological and molecular classification of HCC. (Hepatology 2018).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28543708,

title = {Comprehensive characterization of RSPO fusions in colorectal traditional serrated adenomas},

author = {Shigeki Sekine and Reiko Ogawa and Taiki Hashimoto and Kojima Motohiro and Hiroshi Yoshida and Hirokazu Taniguchi and Yutaka Saito and Ohno Yasuhiro and Atsushi Ochiai and Nobuyoshi Hiraoka},

doi = {10.1111/his.13265},

issn = {1365-2559},

year  = {2017},

date = {2017-10-01},

journal = {Histopathology},

volume = {71},

number = {4},

pages = {601--609},

abstract = {AIMS: Traditional serrated adenoma (TSA) is a rare but distinct type of colorectal polyp. Our previous study showed that PTPRK-RSPO3 fusions are frequent and characteristic genetic alterations in TSAs. This study aimed to characterize comprehensively the prevalence and variability of RSPO fusions in colorectal TSAs.nnMETHODS AND RESULTS: We examined RSPO expression and explored novel RSPO fusions in 129 TSAs, including 66 lesions analysed previously for WNT pathway gene mutations. Quantitative polymerase chain reaction (qPCR) analyses identified three and 43 TSAs overexpressing RSPO2 and RSPO3, respectively, whereas the expression of RSPO1 and RSPO4 was marginal or undetectable in all cases. RSPO overexpression was always mutually exclusive with other WNT pathway gene mutations. Known PTPRK-RSPO3 fusions were detected in 37 TSAs, all but one of which overexpressed RSPO3. In addition, rapid amplification of cDNA ends revealed three novel RSPO fusion transcripts, an NRIP1-RSPO2 fusion and two PTPRK-RSPO3 fusion isoforms, in six TSAs. Overall, 43 TSAs had RSPO fusions (33%), whereas four TSAs (3%) overexpressed RSPO in the absence of RSPO fusions. TSAs with RSPO fusions showed several clinicopathological features, including distal localization (P = 0.0063), larger size (P = 0.0055), prominent ectopic crypt foci (P = 8.4 × 10 ), association of a high-grade component (P = 1.1 × 10 ), and the presence of KRAS mutations (P = 4.5 × 10 ).nnCONCLUSIONS: The present study identified RSPO fusion transcripts, including three novel transcripts, in one-third of colorectal TSAs and showed that PTPRK-RSPO3 fusions were the predominant cause of RSPO overexpression in colorectal TSA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28614199,

title = {WNT Pathway Gene Mutations Are Associated With the Presence of Dysplasia in Colorectal Sessile Serrated Adenoma/Polyps},

author = {Taiki Hashimoto and Satoshi Yamashita and Hiroshi Yoshida and Hirokazu Taniguchi and Toshikazu Ushijima and Tesshi Yamada and Yutaka Saito and Atsushi Ochiai and Shigeki Sekine and Nobuyoshi Hiraoka},

doi = {10.1097/PAS.0000000000000877},

issn = {1532-0979},

year  = {2017},

date = {2017-09-01},

journal = {Am J Surg Pathol},

volume = {41},

number = {9},

pages = {1188--1197},

abstract = {Sessile serrated adenoma/polyps (SSA/Ps) are believed to be the major precursor of serrated pathway-derived colorectal carcinomas. To better characterize the process of progression from SSA/Ps to carcinomas, we analyzed 46 SSA/Ps with dysplasia and 45 SSA/Ps without dysplasia using targeted next-generation sequencing and immunohistochemistry. Among the WNT pathway genes analyzed, protein-truncating mutations of RNF43, APC, and ZNRF3 were identified in 23 (50%), 4 (9%), and 3 (7%) SSA/Ps with dysplasia, respectively. In contrast, SSA/Ps without dysplasia rarely had WNT pathway gene mutations, except for 3 lesions with RNF43 mutations (7%). None of the SSA/Ps had CTNNB1 mutations or RSPO fusions. Thus, WNT pathway gene mutations were more common in SSA/Ps with dysplasia than in SSA/Ps without dysplasia (P=3.0×10). Consistently, nuclear β-catenin accumulation and MYC overexpression, indicative of active WNT signaling, were present in most of the SSA/Ps with dysplasia, but were rare in those without dysplasia. BRAF (86%) or KRAS mutations (7%) were identified in the majority of SSA/Ps, regardless of the presence or absence of dysplasia. MLH1 expression was lost in 14 SSA/Ps with dysplasia (30%). The majority of MLH1-deficient SSA/Ps with dysplasia had RNF43 mutations (86%), most of which were frameshift mutations involving mononucleotide repeats. In contrast, MLH1-retained lesions had less frequent RNF43 mutations with no hot spots (34%), and 4 had APC mutations (13%). These results suggest that WNT pathway gene mutations are involved in the development of dysplasia in SSA/Ps and that MLH1-deficient and MLH1-retained SSA/Ps with dysplasia exhibit distinct mutation profiles of WNT pathway genes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28548127,

title = {Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis},

author = {Shigeki Sekine and Taisuke Mori and Reiko Ogawa and Masahiro Tanaka and Hiroshi Yoshida and Hirokazu Taniguchi and Takeshi Nakajima and Kokichi Sugano and Teruhiko Yoshida and Mamoru Kato and Eisaku Furukawa and Atsushi Ochiai and Nobuyoshi Hiraoka},

doi = {10.1038/modpathol.2017.39},

issn = {1530-0285},

year  = {2017},

date = {2017-08-01},

journal = {Mod Pathol},

volume = {30},

number = {8},

pages = {1144--1151},

abstract = {Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. MMR deficiency is a ubiquitous feature of Lynch syndrome-associated colorectal adenocarcinomas; however, it remains unclear when the MMR-deficient phenotype is acquired during tumorigenesis. To probe this issue, the present study examined genetic alterations and MMR statuses in Lynch syndrome-associated colorectal adenomas and adenocarcinomas, in comparison with sporadic adenomas. Among the Lynch syndrome-associated colorectal tumors, 68 of 86 adenomas (79%) and all adenocarcinomas were MMR-deficient, whereas all the sporadic adenomas were MMR-proficient, as determined by microsatellite instability testing and immunohistochemistry for MMR proteins. Sequencing analyses identified APC or CTNNB1 mutations in the majority of sporadic adenomas (58/84, 69%) and MMR-proficient Lynch syndrome-associated adenomas (13/18, 72%). However, MMR-deficient Lynch syndrome-associated adenomas had less APC or CTNNB1 mutations (25/68, 37%) and frequent frameshift RNF43 mutations involving mononucleotide repeats (45/68, 66%). Furthermore, frameshift mutations affecting repeat sequences constituted 14 of 26 APC mutations (54%) in MMR-deficient adenomas whereas these frameshift mutations were rare in MMR-proficient adenomas in patients with Lynch syndrome (1/12, 8%) and in sporadic adenomas (3/52, 6%). Lynch syndrome-associated adenocarcinomas exhibited mutation profiles similar to those of MMR-deficient adenomas. Considering that WNT pathway activation sufficiently drives colorectal adenoma formation, the distinct mutation profiles of WNT pathway genes in Lynch syndrome-associated adenomas suggest that MMR deficiency commonly precedes adenoma formation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27896849,

title = {Cytoplasmic MSH2 immunoreactivity in a patient with Lynch syndrome with an EPCAM-MSH2 fusion},

author = {Shigeki Sekine and Reiko Ogawa and Shinya Saito and Mineko Ushiama and Dai Shida and Takeshi Nakajima and Hirokazu Taniguchi and Nobuyoshi Hiraoka and Teruhiko Yoshida and Kokichi Sugano},

doi = {10.1111/his.13104},

issn = {1365-2559},

year  = {2017},

date = {2017-03-01},

journal = {Histopathology},

volume = {70},

number = {4},

pages = {664--669},

abstract = {AIMS: Immunohistochemistry for mismatch repair (MMR) proteins is being increasingly used to examine MMR status in tumours. The aim of the present article was to report the case of a colon cancer patient with Lynch syndrome who showed unusual cytoplasmic MMR protein localization.nnMETHODS AND RESULTS: Histologically, the colon cancer was diagnosed as medullary carcinoma associated with prominent tumour-infiltrating lymphocytes and a Crohn's-like reaction. Immunohistochemistry revealed cytoplasmic and nuclear expression of MSH2 in non-neoplastic cells, and exclusively cytoplasmic expression in tumour cells. MSH6 expression was nuclear in non-neoplastic cells, but was lost in tumour cells. Nuclear expression of MLH1 and PMS2 was retained in both non-neoplastic and tumour cells. The tumour was microsatellite instability-high, which is indicative of defective MMR function. A subsequent germline mutation analysis identified a genomic deletion spanning the 3' region of EPCAM and the 5' region of MSH2, resulting in an in-frame fusion of EPCAM and MSH2.nnCONCLUSIONS: The unusual cytoplasmic immunoreactivity of MSH2 was considered to be attributable to the non-functional EPCAM-MSH2 fusion product. The present case illustrates that not only loss of expression, but also abnormal localization, of MMR proteins is indicative of a defective MMR system.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27697523,

title = {TGF-β-induced phosphorylation of Akt and Foxo transcription factors negatively regulates induced regulatory T cell differentiation},

author = {Yutaka Kurebayashi and Yukiko Baba and Akiko Minowa and Niken Adiba Nadya and Miyuki Azuma and Akihiko Yoshimura and Shigeo Koyasu and Shigenori Nagai},

doi = {10.1016/j.bbrc.2016.09.153},

issn = {1090-2104},

year  = {2016},

date = {2016-11-01},

journal = {Biochem Biophys Res Commun},

volume = {480},

number = {1},

pages = {114--119},

abstract = {Transforming growth factor-β (TGF-β) is a pivotal cytokine in the differentiation of regulatory T cells, and Foxo transcription factors positively regulate this process. On the other hand, the function of Foxo transcription factors is negatively regulated by PI3K/Akt signaling, which is activated by TGF-β in many types of cells; yet the role of TGF-β in Akt activity and its downstream substrates in CD4 T cells, including Foxo transcription factors, remains to be determined. Herein, we demonstrate that TGF-β selectively induces Akt phosphorylation at Ser473 but not at Thr308 in a class I PI3K-dependent manner in CD4 T cells, resulting in the phosphorylation and inhibition of Foxo transcription factors and negatively regulating the differentiation of induced regulatory T cells (iTregs). These observations reveal a novel negative regulatory mechanism involving Akt and Foxo transcription factors induced by TGF-β in the iTreg differentiation process.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26826556,

title = {Mismatch repair deficiency in Lynch syndrome-associated colorectal adenomas is more prevalent in older patients},

author = {Masahiro Tanaka and Takeshi Nakajima and Kokichi Sugano and Teruhiko Yoshida and Hirokazu Taniguchi and Yukihide Kanemitsu and Masato Nagino and Shigeki Sekine},

doi = {10.1111/his.12941},

issn = {1365-2559},

year  = {2016},

date = {2016-08-01},

journal = {Histopathology},

volume = {69},

number = {2},

pages = {322--328},

abstract = {AIMS: The aim of this study was to examine the expression of mismatch repair (MMR) proteins in Lynch syndrome (LS)-associated colorectal adenomas and to evaluate their relationship with clinicopathological variables and potential utility in LS screening.nnMETHODS AND RESULTS: We performed immunohistochemistry for MLH1, PMS2, MSH2 and MSH6 in 134 adenomas obtained from 26 genetically confirmed LS patients. MMR deficiency, as determined by loss of any MMR protein, was observed in 113 adenomas (84%). All the MMR-deficient adenomas exhibited homogeneous loss of MMR proteins, which reflected underlying germline mutations. MMR deficiency was more frequent in adenomas obtained from older patients (aged ≥60 years; 81 of 86, 94%), with larger tumour size (>5 mm; 71 of 73, 97%) and with high-grade dysplasia (50 of 51, 98%). Multivariate analyses indicated that increased age and larger tumour size were associated independently with MMR deficiency.nnCONCLUSIONS: This study shows that MMR deficiency is associated significantly with increased age, in addition to two previously reported factors-larger size and high-grade dysplasia. When adenomas are analysed during LS screening, high sensitivity is expected if the adenomas are associated with any of these three factors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26924569,

title = {Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma},

author = {Shigeki Sekine and Satoshi Yamashita and Taro Tanabe and Taiki Hashimoto and Hiroshi Yoshida and Hirokazu Taniguchi and Motohiro Kojima and Kazuya Shinmura and Yutaka Saito and Nobuyoshi Hiraoka and Toshikazu Ushijima and Atsushi Ochiai},

doi = {10.1002/path.4709},

issn = {1096-9896},

year  = {2016},

date = {2016-06-01},

journal = {J Pathol},

volume = {239},

number = {2},

pages = {133--138},

abstract = {The molecular mechanisms underlying the serrated pathway of colorectal tumourigenesis, particularly those related to traditional serrated adenomas (TSAs), are still poorly understood. In this study, we analysed genetic alterations in 188 colorectal polyps, including hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), TSAs, tubular adenomas, and tubulovillous adenomas by using targeted next-generation sequencing and reverse transcription-PCR. Our analyses showed that most TSAs (71%) contained genetic alterations in WNT pathway components. In particular, PTPRK-RSPO3 fusions (31%) and RNF43 mutations (24%) were frequently and almost exclusively observed in TSAs. Consistent with the WNT pathway activation, immunohistochemical analysis showed diffuse and focal nuclear accumulation of β-catenin in 53% and 30% of TSAs, respectively. APC mutations were observed in tubular and tubulovillous adenomas and in a subset of TSAs. BRAF mutations were exclusively and frequently encountered in serrated lesions. KRAS mutations were observed in all types of polyps, but were most commonly encountered in tubulovillous adenomas and TSAs. This study has demonstrated that TSAs frequently harbour genetic alterations that lead to WNT pathway activation, in addition to BRAF and KRAS mutations. In particular, PTPRK-RSPO3 fusions and RNF43 mutations were found to be characteristic genetic features of TSAs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26787825,

title = {Comprehensive Immune Profiling of Lung Adenocarcinomas Reveals Four Immunosubtypes with Plasma Cell Subtype a Negative Indicator},

author = {Yutaka Kurebayashi and Katsura Emoto and Yuichiro Hayashi and Ikuo Kamiyama and Takashi Ohtsuka and Hisao Asamura and Michiie Sakamoto},

doi = {10.1158/2326-6066.CIR-15-0214},

issn = {2326-6074},

year  = {2016},

date = {2016-03-01},

journal = {Cancer Immunol Res},

volume = {4},

number = {3},

pages = {234--247},

abstract = {Neoplastic cancer cells and cancer stroma (including infiltrating immune cells) determine the biology and prognosis of cancer. Various types of adaptive and innate immune cells are known to infiltrate the cancer stroma. However, the patterns and spatial distribution of immune cell infiltration as well as its association with tumor histology remain poorly understood. To address these issues, we comprehensively analyzed the infiltrating immune cells present in lung adenocarcinoma. The principal types of both adaptive and innate infiltrating immune cells were immunohistochemically evaluated in the predominant histologic components of 111 lung adenocarcinomas. The same analysis was also carried out on 143 samples of histologic subtypes making up more than 20% of tumors. As a result, plasma cells and B cells with interfollicular distribution were almost exclusively observed in invasive histologic subtypes, while an increased number of mast cells were observed in noninvasive histologic subtypes. Cluster analysis revealed four distinct immunosubtypes (CD8, mast cell, macrophage/dendritic cell, and plasma cell subtypes) based on the infiltrating immune cell profiles. These immunosubtypes correlated with histologic subtypes, and univariate and multivariate analyses identified the plasma cell subtype as an independent negative prognostic factor. These plasma cells may be one of the major producers of the immunosuppressive cytokine IL35 in cancer stroma.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25936647,

title = {Excellent prognosis following endoscopic resection of patients with rectal neuroendocrine tumors despite the frequent presence of lymphovascular invasion},

author = {Masau Sekiguchi and Shigeki Sekine and Taku Sakamoto and Yosuke Otake and Takeshi Nakajima and Takahisa Matsuda and Hirokazu Taniguchi and Ryoji Kushima and Yuichiro Ohe and Yutaka Saito},

doi = {10.1007/s00535-015-1079-7},

issn = {1435-5922},

year  = {2015},

date = {2015-12-01},

journal = {J Gastroenterol},

volume = {50},

number = {12},

pages = {1184--1189},

abstract = {BACKGROUND: Endoscopic resection (ER) has been increasingly used for the treatment of rectal neuroendocrine tumors (NETs); however, only limited data are available on its long-term outcomes. This study analyzed the long-term outcomes of rectal NETs treated by ER and characterized potential risk factors for metastasis in these cases, with emphasis on lymphovascular invasion.nnMETHODS: We retrospectively analyzed the clinicopathological features and outcomes of 86 patients with 90 rectal NETs who had been treated by ER. Lymphovascular invasion was reevaluated using elastic-staining and double-staining immunohistochemistry.nnRESULTS: En bloc resection with tumor-free margins was achieved in 87 lesions (96.7%). The median tumor size was 5 mm (range 2-13), and all the lesions were confined to the submucosal layer. The Ki-67 index was less than 3% in all the lesions, which were therefore classified as NET G1. Elastic-staining and double-staining immunohistochemistry revealed the presence of lymphatic and venous invasion in 23 (25.6%) and 35 lesions (36.7%), respectively. Collectively, lymphatic and/or vascular invasion was identified in 42 lesions (46.7%). All cases were followed up without additional surgery, and no metastasis or recurrence was detected during the median follow-up period of 67.5 months.nnCONCLUSIONS: This study showed an excellent long-term prognosis following ER of patients with rectal NETs, confirming that ER is a valid treatment option for small rectal NETs. The present study also revealed highly prevalent lymphovascular invasion even in minute rectal NETs; this observation raises a question regarding its significance as a risk factor for metastasis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25832318,

title = {Familial adenomatous polyposis-associated and sporadic pyloric gland adenomas of the upper gastrointestinal tract share common genetic features},

author = {Taiki Hashimoto and Reiko Ogawa and Akiko Matsubara and Hirokazu Taniguchi and Kokichi Sugano and Mineko Ushiama and Teruhiko Yoshida and Yae Kanai and Shigeki Sekine},

doi = {10.1111/his.12705},

issn = {1365-2559},

year  = {2015},

date = {2015-11-01},

journal = {Histopathology},

volume = {67},

number = {5},

pages = {689--698},

abstract = {AIMS: Familial adenomatous polyposis (FAP) is a hereditary cancer predisposition syndrome caused by a germline APC mutation. A recent study showed the enrichment of pyloric gland adenomas (PGAs) of the stomach, in addition to fundic gland polyps (FGPs) and foveolar-type adenomas (FAs), in patients with FAP. In the present study, we analysed the genetic alterations in these FAP-associated gastric lesions.nnMETHODS AND RESULTS: Mutational statuses of GNAS and KRAS, which are frequently mutated in sporadic PGAs, as well as those of APC, were examined in PGAs, FAs and FGPs in patients with FAP using Sanger sequencing. Our analysis identified GNAS mutations in five of six PGAs (83%), but in none of the three FAs or the 40 FGPs examined. KRAS mutations were identified in four PGAs (67%), one FA (33%) and one FGP (3%). Somatic truncating APC mutations were found in all PGAs (100%), two FAs (67%) and 14 FGPs (47%). We additionally analysed sporadic PGAs of the stomach and duodenum and identified truncating APC mutations in 11 of 25 lesions (44%).nnCONCLUSIONS: FAP-associated and sporadic PGAs not only show similar morphologies, but also share common genetic aberrations, including mutations of GNAS, KRAS and APC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26355235,

title = {TERT promoter mutations are frequent and show association with MED12 mutations in phyllodes tumors of the breast},

author = {Masayuki Yoshida and Reiko Ogawa and Hiroshi Yoshida and Akiko Maeshima and Yae Kanai and Takayuki Kinoshita and Nobuyoshi Hiraoka and Shigeki Sekine},

doi = {10.1038/bjc.2015.326},

issn = {1532-1827},

year  = {2015},

date = {2015-10-01},

journal = {Br J Cancer},

volume = {113},

number = {8},

pages = {1244--1248},

abstract = {BACKGROUND: Phyllodes tumors are rare fibroepithelial neoplasms of the breast, which carry the potential risk of local recurrence and metastasis. Phyllodes tumors share several histological features with fibroadenomas, and no widely accepted markers for distinguishing these lesions have been identified.nnMETHODS: We analyzed molecular abnormalities related to telomere elongation in tumors, including TERT promoter mutations, as well as loss of expression of ATRX and DAXX, in a total of 104 phyllodes tumors and fibroadenomas.nnRESULTS: Sequencing analyses showed that TERT promoter mutations were frequent in phyllodes tumors (30/46, 65%), but rare in fibroadenomas (4/58, 7%). Among phyllodes tumors, the mutations were more frequent in borderline tumors (13/15, 87%), but were also common in benign (9/18, 50%) and malignant tumors (8/13, 62%). Remarkably, all but one TERT promoter-mutated tumor also contained MED12 mutations, indicating that these mutations are strongly associated (P=8.4 × 10(-6)). Expression of ATRX and DAXX, as evaluated by immunohistochemistry, was retained in all tumors.nnCONCLUSIONS: Our observations suggest a critical role of TERT promoter mutations, in cooperation with MED12 mutations, in the development of phyllodes tumors. Because TERT promoter mutations are rare among fibroadenomas, their detection may be of potential use in discriminating between phyllodes tumors and fibroadenomas.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25839987,

title = {Frequent MED12 mutations in phyllodes tumours of the breast},

author = {M Yoshida and S Sekine and R Ogawa and H Yoshida and A Maeshima and Y Kanai and T Kinoshita and A Ochiai},

doi = {10.1038/bjc.2015.116},

issn = {1532-1827},

year  = {2015},

date = {2015-05-01},

journal = {Br J Cancer},

volume = {112},

number = {10},

pages = {1703--1708},

abstract = {BACKGROUND: Phyllodes tumours are rare fibroepithelial tumours of the breast, that include benign, borderline, and malignant lesions. Although the molecular basis of phyllodes tumours largely remains unknown, a recent exome study identified MED12 mutations as a sole recurrent genetic alteration in fibroadenoma, a common benign fibroepithelial tumour that shares some histological features with the phyllodes tumour.nnMETHODS: Forty-six phyllodes tumours and 58 fibroadenomas of the breast were analysed for MED12 mutations by using Sanger sequencing.nnRESULTS: MED12 mutations were identified in 37 out of the 46 phyllodes tumours (80%). The prevalence of MED12 mutations was similar among benign (15/18, 83%), borderline (12/15, 80%), and malignant tumours (10/13, 77%). MED12 mutations were also identified in 36 of the 58 fibroadenomas (62%). The mutations were frequent among intracanalicular-type (24/32, 75%) and complex-type lesions (4/6, 67%), but were significantly less common among the pericanalicular-type lesions (8/20, 40%). A microdissection-based analysis showed that MED12 mutations were confined to the stromal components in both phyllodes tumours and fibroadenomas.nnCONCLUSIONS: MED12 mutations were frequent among the phyllodes tumours of the breast, regardless of the tumour grade. Phyllodes tumours and fibroadenomas share, at least in part, a common genetic background.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25717252,

title = {ARID1A expression in gastric adenocarcinoma: clinicopathological significance and correlation with DNA mismatch repair status},

author = {Ryo Inada and Shigeki Sekine and Hirokazu Taniguchi and Hitoshi Tsuda and Hitoshi Katai and Toshiyoshi Fujiwara and Ryoji Kushima},

doi = {10.3748/wjg.v21.i7.2159},

issn = {2219-2840},

year  = {2015},

date = {2015-02-01},

journal = {World J Gastroenterol},

volume = {21},

number = {7},

pages = {2159--2168},

abstract = {AIM: To analyze the mismatch repair (MMR) status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.nnMETHODS: We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas. The results were further correlated with clinicopathological variables.nnRESULTS: The loss of any MMR protein expression, indicative of MMR deficiency, was observed in 38 cases (7.8%) and was significantly associated with an older age (68.6±9.2 vs 60.4±11.7, P<0.001), a female sex (55.3% vs 31.3%, P=0.004), an antral location (44.7% vs 25.7%, P=0.021), and a differentiated histology (57.9% vs 39.7%, P=0.023). Abnormal ARID1A expression, including reduced or loss of ARID1A expression, was observed in 109 cases (22.3%) and was significantly correlated with lymphatic invasion (80.7% vs 69.5%, P=0.022) and lymph node metastasis (83.5% vs 73.7%, P=0.042). The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency (47.4% vs 20.2%, P<0.001). A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor (HR=1.36, 95%CI: 1.01-1.84; P=0.040).nnCONCLUSION: Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion, lymph node metastasis, poor prognosis, and MMR deficiency in gastric adenocarcinomas.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24329753,

title = {Consistent absence of HER2 expression, regardless of HER2 amplification status, in neuroendocrine carcinomas of the stomach},

author = {Michihiro Ishida and Shigeki Sekine and Hirokazu Taniguchi and Takeo Fukagawa and Hitoshi Katai and Ryoji Kushima},

doi = {10.1111/his.12348},

issn = {1365-2559},

year  = {2014},

date = {2014-06-01},

journal = {Histopathology},

volume = {64},

number = {7},

pages = {1027--1031},

abstract = {AIMS: To determine HER2 amplification status and HER2 overexpression status in neuroendocrine carcinomas (NECs) of the stomach.nnMETHODS AND RESULTS: We analysed 51 gastric NECs, including 15 pure NECs and 36 NECs associated with adenocarcinoma and/or dysplasia, for HER2 amplification by dual-colour chromogenic in-situ hybridization, and for HER2 expression by immunohistochemistry. HER2 amplification was observed in three NECs (6%) and in seven (19%) cases of adenocarcinoma/dysplasia associated with NEC. Immunohistochemically, all of the NECs, including those showing HER2 amplification, lacked HER2 expression. On the other hand, positive and equivocal HER2 overexpression was observed in three (8%) and six (17%) cases of adenocarcinoma/dysplasia associated with NEC, respectively.nnCONCLUSIONS: HER2 expression is consistently absent in gastric NECs, regardless of HER2 amplification status or association with HER2-positive adenocarcinoma/dysplasia components. Accordingly, HER2 is unlikely to be a valid therapeutic target in gastric NECs. Also, the absence of HER2 expression in NECs could be one of the causes of intratumoral heterogeneity of HER2 expression in gastric cancers.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}