担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00535-020-01724-5

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記述言語：日本語   出版者・発行元：医学図書出版(株)  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41379-019-0405-7

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1053/j.gastro.2018.10.029

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Publishing Group  

DOI： 10.1038/s41556-018-0122-3

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その他リンク： http://orcid.org/0000-0002-1068-7024

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/ctg.2017.3

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1053/j.gastro.2013.10.045

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/gut.2007.129684

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1158/1078-0432.CCR-07-0111

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その他リンク： http://orcid.org/0000-0002-1068-7024

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/nm1294

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その他リンク： http://www.nature.com/articles/nm1294

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/1878-0261.70011

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report the rare case of severe cognitive disorder and ataxia caused by entrectinib in a patient with NTRK1 fusion gene-positive intrahepatic cholangiocarcinoma. The case was a 56-year-old woman after nine courses of GCS therapy. The patient experienced grade 1 muscle weakness on day 4 and grade 3, cognitive disorder on day 7 after receiving entrectinib, which led to hospitalization. The symptoms were reversible and tended to improve after withdrawal of entrectinib. It is crucial to increase awareness of TRKi-specific adverse events and their proper management.

DOI： 10.1007/s12328-024-02076-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by germline variants in the APC gene, leading to the development of numerous colorectal polyps and significantly increases the risk of colorectal cancer. A diagnosis is typically made using colonoscopy, and genetic testing can assist in patient surveillance and carrier identification. Recent advances include the use of whole-genome array comparative genomic hybridization (a-CGH), which provides better resolution of genetic imbalances. We aimed to explore the specific features of FAP patients with whole APC gene deletions using high-resolution a-CGH and to compare patient characteristics. Two polyposis patients with whole APC deletions were identified, and the lost genetic sizes ranged from 0.3–1.1 Mb. Nervous abnormalities were a characteristic symptom in a patient with a 1.1 Mb loss. A patient with an approximately 0.3 Mb loss, which included the entire APC gene, presented a polyposis phenotype without intellectual disability. The comparison of genetic losses, with or without intellectual disability, revealed 7 genetic changes. Consequently, EPB41L4A is a candidate gene associated with the neurogenic phenotype.

DOI： 10.1038/s41439-024-00301-z

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その他リンク： https://www.nature.com/articles/s41439-024-00301-z

担当区分：最終著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J02025&link_issn=&doc_id=20241105300004&doc_link_id=10.2958%2Fsuizo.39.316&url=https%3A%2F%2Fdoi.org%2F10.2958%2Fsuizo.39.316&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

担当区分：最終著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本胆道学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

Objective:

This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection.

Summary Background Data:

Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown.

Methods:

Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated.

Results:

These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways.

Conclusion:

Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.

DOI： 10.1097/sla.0000000000006444

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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担当区分：責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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担当区分：最終著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The molecular mechanisms underpinning the development of metachronous tumors in the remnant bile duct following surgical resection of primary biliary tract carcinomas (BTCs) are unknown. This study aimed to elucidate these mechanisms by evaluating the clinicopathologic features of BTCs, the alterations to 31 BTC-related genes on targeted sequencing, and the aberrant expression of p53, p16, SMAD4, ARID1A and β-catenin on immunohistochemistry. Twelve consecutive patients who underwent resection of metachronous BTCs following primary BTC resection with negative bile duct margins were enrolled. Among the 12 metachronous tumors, six exhibited anterograde growth in the lower portion and six exhibited retrograde growth in the upper portion of the biliary tree. Surgical resection of metachronous BTCs resulted in recurrence-free survival in seven, local recurrence in five, and death in two patients. Nine achieved 5-year overall survival after primary surgery. Molecular analyses revealed that recurrently altered genes were: TP53, SMAD4, CDKN2A, ELF3, ARID1A, GNAS, NF1, STK11, RNF43, KMT2D and ERBB3. Each of these was altered in at least three cases. A comparison of the molecular features between 12 paired primary and metachronous BTCs indicated that 10 (83%) metachronous tumors developed in clonal association with corresponding primary tumors either successionally or phylogenically. The remaining two (17%) developed distinctly. The successional tumors consisted of direct or evolved primary tumor clones that spread along the bile duct. The phylogenic tumors consisted of genetically unstable clones and conferred a poor prognosis. Metachronous tumors distinct from their primaries harbored fewer mutations than successional and phylogenic tumors. In conclusion, over 80% of metachronous BTCs that develop following primary BTC resection are probably molecularly associated with their primaries in either a successional or a phylogenetic manner. Comparison between the molecular features of a metachronous tumor and those of a preceding tumor may provide effective therapeutic clues for the treatment of metachronous BTC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

DOI： 10.1002/path.6265

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A young patient diagnosed with advanced colon cancer and liver metastasis was found to have familial adenomatous polyposis (FAP) through comprehensive genomic analysis. Whole-genome array comparative genomic hybridization (aCGH) revealed germline deletions at chromosome 5q22.1-22.2 encompassing the entire APC gene. The patient and her son exhibited mild intellectual disability without developmental delay. This case highlights the need for further exploration of the characteristics associated with whole APC deletions. aCGH is a valuable tool for studying FAP and provides a detailed analysis of large deletions.

DOI： 10.1038/s41439-024-00270-3

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Visualization of the pancreatobiliary junction is one of the challenges faced by endoscopic ultrasonography (EUS). The water-filling technique, which allows for the observation of the ampulla at a suitable distance by injecting water into the lumen of the duodenum, was used for this purpose. However, a new gel immersion technique has recently been introduced for visualizing the gastrointestinal tract. This study investigated the effectiveness of visualizing the pancreatobiliary junction in EUS by comparing both water filling and the new gel immersion technique in identical cases. METHODS: The study ran from June to December 2021. Ten images from each technique were retrospectively compared by three independent researchers. The primary result of the study was the number of images depicting the "Pancreatic and Biliary Ducts Penetrating the Duodenal Muscularis Propria" (defined as Excellent observation) in each technique. The secondary outcome was defined as gel immersion technique's safety and impact on duodenal lumen distension. RESULTS: Ten patients used the gel immersion technique. All patients underwent the water-filling technique first, followed by gel injection after the water was completely aspirated. The average number of pictures rated as "Excellent observation," which is the primary outcome, was significantly higher with the gel immersion technique than with water filling, and no adverse events were observed. The subanalysis revealed that both convex and radial echoendoscopes are equally effective at depicting the ampulla with the gel immersion technique. CONCLUSIONS: The ability to depict the pancreatobiliary junction using the gel immersion technique is superior to that of the water-filling method, which may allow for a more detailed assessment of the ampullary region with both radial and convex echoendoscopes. This can be a useful EUS technique for diagnosing pancreaticobiliary maljunction or periampullary tumors.

DOI： 10.1007/s00464-024-10762-6

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DOI： 10.1016/j.ejcskn.2024.100025

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

Objectives

The role of long noncoding RNAs (lncRNAs) in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Extracellular vesicle (EV)–encapsulated RNAs could be effective targets for liquid biopsy. We aimed to identify previously unknown EV-encapsulated lncRNAs in PDAC and establish highly accurate methods for isolating EVs.

Materials and Methods

Extracellular vesicles were isolated using existing and newly developed methods, namely, PEViA-UC and PEViA-IP, from serum samples of 20 patients with PDAC, 22 patients with intraductal papillary mucinous neoplasms, and 21 healthy individuals. Extracellular vesicle lncRNA expression was analyzed using digital PCR.

Results

Gene expression analysis using cDNA microarray revealed a highly expressed lncRNA, HEVEPA, in serum EVs from patients with PDAC. We established PEViA-UC and PEViA-IP using PEViA reagent, ultracentrifugation, and immunoprecipitation. Although detection of EV-encapsulated HEVEPA using existing methods is challenging, PEViA-UC and PEViA-IP detected EV HEVEPA, which was highly expressed in patients with PDAC compared with non-PDAC patients. The detection sensitivity for discriminating PDAC from non-PDAC using the combination of HEVEPA and HULC, which are highly expressed lncRNAs in PDAC, and carbohydrate antigen 19-9 (CA19-9), was higher than that of HEVEPA, HULC, or CA19-9 alone.

Conclusions

Extracellular vesicle lncRNAs isolated using PEViA-IP and CA19-9 together could be effective targets in liquid biopsy for PDAC diagnosis.

DOI： 10.1097/mpa.0000000000002315

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.job.2024.01.007

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Multiple myeloma (MM), a neoplasm of plasma cells (PCs), is a highly heterogeneous disease with multifocal dissemination throughout the body. Minimal residual disease (MRD) detected using PCs in bone marrow (BM) is important for MM management; however, frequent invasive examinations impose a significant burden on patients. METHODS: Analysis using plasma cell-free DNA (cfDNA) might represent an alternative tool for disease monitoring. In this study, we observed the disease status in a patient with MM by examining the KRAS mutation allele frequency (MAF) in plasma cfDNA using digital PCR. RESULTS: During treatment, the MAF was correlated with serum immunoglobulin A and free light chain-kappa levels. After the second autologous peripheral blood stem cell transplantation, the KRAS MAF became immediately positive after confirming MRD negativity using PCs from BM. Shortly thereafter, the patient experienced clinical relapse primarily involving bone lesions. CONCLUSION: Mutant KRAS monitoring in cfDNA using serial blood collection might reflect the disease status more accurately than invasive BM examinations, especially in patients with MM whose primary lesions have extra-BM locations. It could also help predict treatment responses and outcomes.

DOI： 10.1016/j.cca.2023.117590

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.modpat.2023.100358

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1245/s10434-023-13451-1

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担当区分：最終著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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担当区分：最終著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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担当区分：最終著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Comprehensive genomic profiling (CGP) tests have been covered by public insurance in Japan for patients with advanced solid tumors who have completed or are completing standard treatments or do not have them. Therefore, genotype-matched drug candidates are often unapproved or off-label, and improving clinical trial access is critical, involving the appropriate timing of CGP tests. To address this issue, we analyzed the previous treatment data for 441 patients from an observational study on CGP tests discussed by the expert panel at Hokkaido University Hospital between August 2019 and May 2021. The median number of previous treatment lines was two; three or more lines accounted for 49%. Information on genotype-matched therapies was provided to 277 (63%). Genotype-matched clinical trials were ineligible because of an excess number of previous treatment lines or use of specific agents were found in 66 (15%) patients, with the highest proportion in breast and prostate cancers. Many patients met the exclusion criteria of one to two or more treatment lines across cancer types. In addition, previous use of specific agents was a frequent exclusion criterion for breast, prostate, colorectal, and ovarian cancers. The patients with tumor types with a low median number (two or fewer) of previous treatment lines, including most rare cancers, primary unknown cancers, and pancreatic cancers, had significantly fewer ineligible clinical trials. The earlier timing of CGP tests may improve access to genotype-matched clinical trials, with their proportion varying by cancer type. Each relevant society needs to advocate the desirable timing of CGP testing nationwide.

DOI： 10.1111/cas.15837

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.7759/cureus.37656

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担当区分：責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Background

Low-grade papillary Schneiderian carcinoma (LGPSC) is a relatively new entity of the sinonasal tract and is characterized by a bland morphology simulating sinonasal papilloma, invasive growth pattern with pushing borders, and aggressive clinical behavior with multiple recurrences and metastatic potential. Recently, DEK::AFF2 fusions were identified in LGPSC. However, some LPGSCs lack DEK::AFF2 fusion, and the molecular features of these tumors have not been clarified.

Case presentation

A 69-year-old man presented with a discharge of pus from his left cheek. Computed tomography revealed a mass involving the left maxillary sinus, ethmoid sinus, and nasal cavity with the destruction of the orbital wall. The biopsy specimens showed that the tumor had a predominantly exophytic, papillary growth and did not have an apparent stromal invasion. The tumor was composed of multilayered epithelium that showed bland morphology with a round to polygonal shape, abundant eosinophilic cytoplasm, and uniform nuclei. Dense neutrophilic infiltrates were focally present. Immunohistochemically, CK5/6 was strongly and diffusely positive, and p16 was negative. p63 was mainly positive in the basal layer, and EMA was predominantly expressed in the outermost cell layer. DNA-based targeted sequencing showed TP53 R175H mutation, whereas neither EGFR nor KRAS mutation was identified. Reverse transcription polymerase chain reaction and fluorescence in situ hybridization revealed no DEK::AFF2 fusion.

Conclusions

We describe the first case of TP53-mutant LGPSC and review the literature. LGPSC is a genetically heterogeneous entity, and the recognition of this rare entity and comprehensive assessment of clinicopathological and molecular findings are crucial for the correct pathological diagnosis and clinical management.

DOI： 10.1186/s13000-023-01334-8

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その他リンク： https://link.springer.com/article/10.1186/s13000-023-01334-8/fulltext.html

担当区分：最終著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jmoldx.2023.02.007

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00428-023-03524-7

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その他リンク： https://link.springer.com/article/10.1007/s00428-023-03524-7/fulltext.html

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Baishideng Publishing Group Inc.  

DOI： 10.4251/wjgo.v15.i1.186

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.modpat.2023.100102

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Life-threatening cytomegalovirus infection (CMVI) has been reported even in patients with malignant lymphoma (ML) who have not received hematopoietic stem cell transplantation (w/o HSCT) but had been treated with chemotherapy or radiotherapy. However, the CMVI incidence and risk factors (RFs) in patients with ML w/o HSCT have not been fully elucidated. This study aimed to evaluate the clinical aspects, including incidence and RFs, of CMVI in patients with ML w/o HSCT. METHODS: We retrospectively reviewed all patients with ML who received chemotherapy or radiotherapy in our department from 2005 to 2013. The overall survival (OS), incidence and RFs of CMVI, and other characteristics of patients with CMVI were analyzed. RESULTS: Overall, 236 patients with ML w/o HSCT were evaluated. Of these, 5.5% (13/236) developed CMVI; 54% (7/13) received steroid pretreatment before primary therapy (PT) for ML; and 62% (8/13) received > 2 therapeutic regimens for ML. The OS curve of patients with CMVI was significantly worse than that of patients without CMVI (p < 0.0001, log-rank test). A univariate analysis identified B symptoms (p = 0.00321), serum albumin < 3.5 g/dL (p = 0.0007837), C-reactive protein level > the upper limit of normal (p = 0.0006962), steroid pretreatment before PT for ML (p = 0.0004262), > 2 therapeutic regimens for ML (p = 0.0000818), T cell lymphoma (p = 0.006406), and non-complete remission (p = 0.02311) as RFs for CMVI. A multivariate analysis identified steroid pretreatment before PT for ML [odds ratio (OR): 4.71 (95% confidence interval [CI]: 1.06-21.0); p = 0.0419] and > 2 therapeutic regimens for ML [OR: 9.25 (95% CI: 2.33-36.8); p = 0.00159] as independent RFs for CMVI in patients with ML w/o HSCT. CONCLUSIONS: Attention should be paid to CMVI development in patients with ML w/o HSCT pretreated with steroids or who had multiple therapeutic regimens.

DOI： 10.1186/s12885-022-10008-5

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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担当区分：責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1245/s10434-022-11735-6

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background and study aims  Recent advances in cancer treatment have involved the clinical application of immune checkpoint inhibitors (ICIs) for various type of cancers. The adverse events associated with ICIs are generally referred to as immune-related adverse events (irAEs). Gastrointestinal irAEs are a major disorder, but gastritis is not frequently observed. The aims of this study were to elucidate the clinical, endoscopic, and histological characteristics of irAE gastritis. Patients and methods  Information on patients treated with ICIs were collected from a single institute over 3 years. IrAE gastritis was identified based on the clinical course and endoscopic and histopathological findings. Of the 359 patients treated with ICIs, four cases of irAE gastritis were identified in clinical records from the endoscopy unit. The endoscopic and histopathological findings were analyzed, and further immunohistochemical studies with immune subtype markers and programmed cell death ligand-1 (PD-L1) antibody were conducted. Results  Among four patients with irAE gastritis, the remarkable endoscopic characteristics were network-pattern erosion, erythematous and edematous mucosa with thick purulent discharge, and fragile mucosa. Corresponding histological features were fibrinopurulent exudate, severe inflammatory cell infiltration, and epithalaxia, respectively. The PD-L1 expression rate was ≥ 1 % in the gastric tissue of all patients with gastritis. These patients were treated with prednisolone (PSL) and their symptoms improved within a few days to 2 weeks. Conclusions  IrAE gastritis were characterized by specific endoscopic findings. The appropriate endoscopic diagnosis may lead to effective treatment with PSL.

DOI： 10.1055/a-1839-4303

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.gie.2022.02.009

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Posttransplant lymphoproliferative disease (PTLD) is a critical complication of hematopoietic stem cell transplantation (HSCT). PTLD is classified into early and late-onset PTLDs. In post-HSCT patients, late-onset PTLD is rare, particularly PTLD after HSCT for Epstein-Barr virus (EBV)-related lymphoproliferative disease. Here, we report the case of a patient diagnosed with late-onset EBV-related hemophagocytic lymphohistiocytosis (HLH), that of PTLD, after HSCT for chronic active EBV infection (CAEBV), that of EBV related lymphoproliferative disease, probably because of EBV reactivation. PATIENT CONCERNS AND DIAGNOSIS: A 22-year-old woman with abdominal fullness visited our hospital. Blood examination showed pancytopenia with atypical lymphocytes, liver dysfunction, and elevated lactate dehydrogenase level. In contrast, bone marrow aspiration showed slight hemophagocytosis with increased natural-killer cells (NK cells). As serum antibodies against EBV were atypical, we calculated the EBV-DNA level in peripheral blood and this level was significantly high. EBV was infected with NK cells, and EBV's monoclonality in NK cells was confirmed. Thus, the patient was diagnosed with CAEBV. INTERVENTIONS AND OUTCOMES: The patient received chemotherapy and cord blood cell transplantation (CBT); CAEBV was well controlled. Approximately 6years from CBT for CAEBV, she visited our hospital because of fever. Blood examination revealed pancytopenia with atypical lymphocytes, liver dysfunction, and elevated lactate dehydrogenase level. In contrast, bone marrow aspiration showed hemophagocytosis with increased B and T cell counts without increased NK cell count. Additionally, serum antibody titers against EBV were atypical, and the EBV-DNA level in the peripheral blood was high. EBV was infected with only B cells, and EBV's monoclonality was confirmed. A more detailed analysis indicated that EBV-specific cytotoxic T lymphocytes were inactive. Therefore, she was diagnosed with late-onset EBV-related HLH. She received extensive treatment, but EBV-related HLH did not improve. Finally, she died about 3 weeks after diagnosis. CONCLUSION: PTLD, including HLH, is a life-threatening complication after transplantation, including HSCT. To our knowledge, this is the first case of late-onset EBV-related HLH after CBT for CAEBV. Late-onset PTLD has an indolent clinical course, but our patient's disease course was extremely aggressive. Therefore, late-onset EBV-related PTLD may be life-threatening.

DOI： 10.1097/MD.0000000000029055

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The profile of the human small intestinal microbiota remains to be uncovered primarily due to sampling difficulties. Ileostomy provides the intestinal luminal contents as ileostomy effluents (IE) that offer opportunity for performing extensive analyses of nutrients, gastrointestinal fluids, metabolites, and microbiome. In the present study, we evaluated changes in the microbiome, pH, and bacterial short-chain fatty acids (SCFAs) in IE obtained from patients who had undergone ileostomy following surgical resection of colon cancer and inflammatory bowel disease (IBD). We enrolled 11 patients who varied in the duration of ileostomy from 3 days to >5 years after surgery and had no inflammation in the small intestine. The analyses suggested that IE from patients previously having IBD had less diversity and greater intraday and interday fluctuations, and increased pH and decreased levels of propionic acid and acetic acid than those in IE from patients previously having cancer. Furthermore, correlation analysis suggested a possible effect of the intestinal microbiome on luminal pH, presumably via SCFA production. The present study suggested that inflammation in the colon may induce long-term dysbiosis in the small intestine even after removal of diseased parts of the colon. Moreover, pharmaceutical-grade Japanese traditional medicine daikenchuto (TU-100) was found to have beneficial effects on postoperative bowel dysfunction and the human small intestinal microbiota. Taken together, these results suggest the necessity of a direct remedy for dysbiosis and the treatment of gastrointestinal lesions to achieve favorable outcomes for chronic gastrointestinal disorders.

DOI： 10.1016/j.gene.2022.146266

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The RNA exosome is a multi-subunit ribonuclease complex that is evolutionally conserved and the major cellular machinery for the surveillance, processing, degradation, and turnover of diverse RNAs essential for cell viability. Here we performed integrated genomic and clinicopathological analyses of 27 RNA exosome components across 32 tumor types using The Cancer Genome Atlas PanCancer Atlas Studies' datasets. We discovered that the EXOSC4 gene, which encodes a barrel component of the RNA exosome, was amplified across multiple cancer types. We further found that EXOSC4 alteration is associated with a poor prognosis of pancreatic cancer patients. Moreover, we demonstrated that EXOSC4 is required for the survival of pancreatic cancer cells. EXOSC4 also repressed BIK expression and destabilized SESN2 mRNA by promoting its degradation. Furthermore, knockdown of BIK and SESN2 could partially rescue pancreatic cells from the reduction in cell viability caused by EXOSC4 knockdown. Our study provides evidence for EXOSC4-mediated regulation of BIK and SESN2 mRNA in the survival of pancreatic tumor cells.

DOI： 10.3390/ijms23010496

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Chemotherapy for advanced gastric cancer is recommended in the guidelines; however, later-line treatment remains controversial. Since immune checkpoint inhibitors have been used for the treatment of various malignancies, trials have been performed for gastric cancer. A phase 3 trial indicated the survival benefit of nivolumab monotherapy for gastric cancer patients treated with prior chemotherapy regimens. PATIENTS AND METHODS: A regional cohort study was undertaken to determine the real-world data of nivolumab treatment for patients with advanced or recurrent gastric cancer. The patients were enrolled for 2 years from October 2017 to October 2019 and were prospectively followed for 1 year to examine the overall survival (OS). The patient characteristics were analyzed in a multivariate analysis and a nomogram to predict the probability of survival was generated. RESULTS: In total, 70 patients who received nivolumab as ≥third-line chemotherapy were included in the Asahikawa Gastric Cancer Cohort. The median OS was 7.5 (95% CI, 4.8-10.2) months and the response rate was 18.6%. Diffuse type classification, bone metastasis, high neutrophil/lymphocyte ratio, and high CRP were associated with poor OS/prognosis in the multivariate analysis. A nomogram was developed based on these clinical parameters and the concordance index was 0.80 (95% CI, 0.68-0.91). The responders were aged and were frequently diagnosed with intestinal type gastric cancer, including patients with a HER2-positive status (27.3%) or microsatellite instability-high (27.3%) status. CONCLUSIONS: The regional cohort study of nivolumab monotherapy for gastric cancer patients revealed prognostic factors and a nomogram was developed that could predict the probability of survival.

DOI： 10.1002/cam4.4461

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Characterization of the genomic landscape of biliary tract cancer (BTC) may lead to applying genotype-matched therapy for patients with this disease. Evidence that comprehensive cancer genomic profiling (CGP) guides genotype-matched therapy to improve clinical outcomes is building. However, the significance of CGP in patients with BTC remains unclarified in clinical practice. Therefore, the purposes of this study were to assess the utility of CGP and identify associations between clinical outcomes and genomic alterations in patients with BTC. In this prospective analysis, detection rates for actionable genomic alterations and access rates for genotype-matched therapy were analyzed in 72 patients with advanced BTC who had undergone commercial CGP. Cox regression analyses assessed relationships between overall survival and genomic alterations detected with CGP. The most common genomic alterations detected were TP53 (41, 56.9%), followed by CDKN2A/B (24, 33.3%/20, 27.8%), and KRAS (20, 27.8%). Actionable genomic alterations were identified in 58.3% (42/72) of patients. Detection rates for FGFR2 fusions, IDH1 mutations, and BRAF V600E were low in this cohort. Eight (11.1%) patients received genotype-matched therapy. For patients with intrahepatic cholangiocarcinoma (ICC), CDKN2A/B loss was associated with shorter overall survival. These real-world data demonstrate that CGP can identify therapeutic options in patients with advanced BTC. CDKN2A/B loss was identified as a poor prognostic factor in patients with ICC. Thus, this study provides a rationale for considering CGP in planning therapeutic strategies for advanced BTC.

DOI： 10.3389/fonc.2022.988527

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Neuroendocrine carcinoma (NEC) of the esophagogastric junction (EGJ) is a rare disease with no established treatments. Herein, we describe a case of recurrent squamous cell carcinoma (SCC) after achieving complete response to chemotherapy against NEC of the EGJ. A 67-year-old man was referred to our hospital because of epigastric discomfort. Computed tomography imaging and esophagogastroduodenoscopy revealed ulcerated tumors at the EGJ. Endoscopic biopsy revealed small tumor cells with a high nuclear/cytoplasmic ratio, suggesting small-cell NEC. Immunohistochemistry (IHC) analysis showed tumor cells with an MIB-1 index of 80%. The patient achieved complete response after 10 cycles of chemotherapy. Follow-up endoscopic examination revealed small red-colored mucosal lesions in the center of the cicatrized primary lesion. Re-biopsy detected cancer cells harboring large eosinophilic cytoplasm with keratinization and no evidence of NEC components. IHC of the cells were cytokeratin 5/6-positive and p53-negative. The tumor persisted without evidence of metastases after chemoradiotherapy, and total gastrectomy with lymph node dissection was performed. Pathological assessment of the resected specimens revealed SCC, without evidence of NEC. The patient survived without a recurrence for &amp;gt;3 years after the initial presentation. Somatic mutation profiles of the primary NEC and recurrent SCC were analyzed by targeted amplicon sequencing covering common cancer-related mutations. Both tumors possessed <italic>TP53</italic> Q192X mutation, whereas <italic>SMAD4</italic> S517T was found only in SCC, suggesting that both tumor components originated from a founder clone with a stop-gain mutation in <italic>TP53</italic>. The somatic mutation profile of the tumors indicated that that loss of heterozygosity (LOH) at the <italic>TP53</italic> gene might have occurred during the differentiation of the founder clone into NEC, while a <italic>SMAD4</italic> mutation might have contributed to SCC development, indicating branching and subclonal evolution from common founder clone to both NEC and SCC. The mutation assessments provided valuable information to better understand the clonal evolution of metachronous cancers.

DOI： 10.3389/fgene.2021.608324

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本膵臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for the pathogenesis of cHCC-CCA, the cells might originate from transformed hepatocytes that undergo ductular transdifferentiation or dedifferentiation. We previously demonstrated that concomitant introduction of mutant HRASV12 (HRAS) and Myc into mouse hepatocytes induced dedifferentiated tumors that expressed fetal/neonatal liver genes and proteins. Here, we examine whether the phenotype of HRAS- or HRAS/Myc-induced tumors might be affected by the disruption of the Trp53 gene, which has been shown to induce biliary differentiation in mouse liver tumors. Hepatocyte-derived liver tumors were induced in heterozygous and homozygous p53-knockout (KO) mice by hydrodynamic tail vein injection of HRAS- or Myc-containing transposon cassette plasmids, which were modified by deleting loxP sites, with a transposase-expressing plasmid. The HRAS-induced and HRAS/Myc-induced tumors in the wild-type mice demonstrated histological features of HCC, whereas the phenotype of the tumors generated in the p53-KO mice was consistent with cHCC-CCA. The expression of fetal/neonatal liver proteins, including delta-like 1, was detected in the HRAS/Myc-induced but not in the HRAS-induced cHCC-CCA tissues. The dedifferentiation in the HRAS/Myc-induced tumors was more marked in the homozygous p53-KO mice than in the heterozygous p53-KO mice and was associated with activation of Myc and YAP and suppression of ERK phosphorylation. Our results suggest that the loss of p53 promotes ductular differentiation of hepatocyte-derived tumor cells through either transdifferentiation or Myc-mediated dedifferentiation.

DOI： 10.1111/cas.14996

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/OBJECTIVES: Decrease in skeletal muscle mass and function is associated with a poor prognosis following surgical resection of pancreatic ductal adenocarcinomas (PDAs). This study evaluated whether skeletal muscle mass decrease affects PDA outcomes. METHODS: Data of 112 patients with advanced and unresectable PDA who underwent chemotherapy in a single institution were retrospectively analyzed. Information on age, sex, hematological investigations, including systemic inflammation-based markers and nutritional assessment biomarkers, and imaging parameters of skeletal muscle mass and visceral adipose tissue were retrieved from the patients' medical records. The efficiency of the Cox, Weibull, and standardized exponential models were compared using hazard ratios and the Akaike Information Criterion (AIC). RESULTS: Results from the Weibull, Cox, and standardized exponential model analyses indicated that low skeletal muscle mass, Eastern Cooperative Oncology Group performance status (PS), and the requirement of biliary drainage were associated with the highest risk of death, followed by carcinoembryonic antigen (CEA) levels and the presence of ascites. The AIC value from the four significant parameters was lowest for the Weibull-exponential distribution (222.3) than that of the Cox (653.7) and standardized exponential models (265.7). We developed a model for estimating the 1-year survival probability using the Weibull-exponential distribution. CONCLUSIONS: Low-skeletal muscle index, PS, requirement of biliary drainage, CEA levels, and presence of ascites are independent factors for predicting poor patient survival after chemotherapy. Improved survival modeling using a parametric approach may accurately predict the outcome of patients with advanced-stage PDA.

DOI： 10.1016/j.pan.2021.03.002

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担当区分：責任著者   記述言語：日本語   出版者・発行元：(一社)日本膵臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy (NAC/NACRT) for resectable/borderline resectable pancreatic cancers was recently performed to improve clinical outcomes and led to good results, although it remains controversial whether NAC/NACRT is beneficial for resectable pancreatic cancer. A few recent studies revealed longer patency and lower cost related to the stent occlusion of a metal stent than those of a plastic stent during NAC/NACRT. It also remains controversial which type of self-expandable metal stent (SEMS) is the most suitable for patients with resectable/borderline resectable pancreatic cancer during NAC/NACRT: an uncovered SEMS (USEMS), a fully covered SEMS (FCSEMS) or a partially covered SEMS (PCSEMS). So far, two randomised controlled trials indicated that a USEMS and an FCSEMS were similar in preoperative stent dysfunction and adverse event rate. Thus, we aimed to verify the non-inferiority of a PCSEMS to a USEMS in this multicentre randomised controlled trial. METHODS AND ANALYSIS: We designed a multicentre randomised controlled trial, for which we will recruit 100 patients with resectable/borderline resectable pancreatic cancer and distal biliary obstruction scheduled for NAC/NACRT from 13 high-volume institutions. Patients will be randomly allocated to the PCSEMS group or USEMS group. The primary outcome measure is the preoperative biliary event rate. Data will be analysed after completion of the study. We will calculate the 95% CIs of the incidence of preoperative biliary events in each group and analyse whether the difference between them is within the non-inferiority margin (10%). ETHICS AND DISSEMINATION: This study has been approved by the institutional review board of Hokkaido University Hospital. The results will be submitted for presentation at an international medical conference and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000041737; jRCT1012200002.

DOI： 10.1136/bmjopen-2020-045698

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gastric cancer is a heterogenous disease with different phenotypes, genotypes, and clinical outcomes, including sensitivity to treatments and prognoses. Recent medical advances have enabled the classification of this heterogenous disease into several groups and the consequent analysis of their clinicopathological characteristics. Gastric cancer associated with Epstein-Barr virus (EBV) and microsatellite-unstable tumors are considered to be the two major subtypes as they are clearly defined by well-established methodologies, such as in situ hybridization and polymerase chain reaction-based analyses, respectively. However, discrepancies in the histological diagnosis of gastric neoplasms remain problematic, and international harmonization should be performed to improve our understanding of gastric carcinogenesis. We re-evaluated Japanese cases of early gastric cancer according to the current World Health Organization (WHO) criteria and classified them into genomic subtypes based on microsatellite instability (MSI) and EBV positivity to determine the initial genetic events in gastric carcinogenesis. A total of 113 Japanese early gastric cancers (including low- and high-grade dysplasias) treated with endoscopic resection over 5 years were archived in our hospital. A histological re-evaluation according to the WHO criteria revealed 54 adenocarcinomas, which were divided into 6 EBV-positive (11.1%), 7 MSI-high (MSI-H, 13.0%), and 41 microsatellite stable cases (75.9%). MSI-H adenocarcinoma was confirmed by an immunohistochemistry assay of mismatch repair proteins. Programmed death-ligand 1 immunostaining with two antibodies (E1L3N and SP263) was positive in tumor cells of one MSI-H adenocarcinoma case (1/7, 14.3%). The proportion of stained cells was higher with clone SP263 than with E1L3N. Histologically, EBV-positive carcinomas were poorly differentiated (83.8%), and MSI-H cancers were frequent in well to moderately differentiated adenocarcinoma (85.7%), indicating that the EBV-positive subtype presented with high-grade morphology even when an early lesion. Our study indicates that the WHO criteria are useful for subdividing Japanese early gastric cancers, and this subdivision may be useful for comparative analysis of precursor lesions and early carcinoma.

DOI： 10.1002/cjp2.209

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pancreatic cancer currently has no subtypes that inform clinical decisions; hence, there exists an opportunity to rearrange the morphological and molecular taxonomy that guides a better understanding of tumor characteristics. Nonetheless, accumulating studies to date have revealed the large-duct type variant, a unique subtype of pancreatic ductal adenocarcinoma (PDA) with cystic features. This subtype often radiographically mimics intraductal papillary mucinous neoplasms (IPMNs) and involves multiple small cysts occasionally associated with solid masses. The "bunch-of-grapes" sign, an imaging characteristic of IPMNs, is absent in large-duct PDA. Large-duct PDA defines the mucin profile, and genetic alterations are useful in distinguishing large-duct PDA from IPMNs. Histologically, neoplastic ducts measure over 0.5 mm, forming large ductal elements. Similar to classic PDAs, this subtype is frequently accompanied by perineural invasion and abundant desmoplastic reactions, and KRAS mutations in codon 12 are nearly ubiquitous. Despite such morphological similarities with IPMNs, the prognosis of large-duct PDA is equivalent to that of classic PDA. Differential diagnosis is therefore essential.

DOI： 10.3748/wjg.v27.i23.3262

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is categorized into four distinct types: the gastric, intestinal, pancreatobiliary, and oncocytic. Each type is associated with specific clinicopathological features. We aimed to uncover the molecular mechanisms underlying the development of these types of IPMN. METHODS: We obtained 103 lesions of various types, including 49 gastric, 26 intestinal, 22 pancreatobiliary, and 6 oncocytic lesions, from 43 IPMNs, including 36 with multiple types. Comparative analysis was performed by targeted sequencing of 37 genes in different lesion types within each pancreas. RESULTS: Gastric-type low-grade lesions were observed in all 36 tumors with multiple types, with 245 mutations identified across all samples. The average number of mutations was significantly different between different lesion grades and types: 1.88 for low-grade lesions, 2.77 for high-grade lesions, and 2.38 for invasive lesions (p = 0.0067); and 1.96 for gastric-type lesion, 2.92 for intestinal-type lesion, 2.73 for pancreatobiliary-type lesion, and 2.17 for oncocytic-type lesion (p = 0.0163). Tracing of mutations between lesions containing multiple types in the same pancreas suggested three developmental pathways, denoted as "progressive", "divergent", and "independent". The progressive and divergent pathways indicate an ancestral lesion that was mostly gastric-type and low-grade may progress or diversify into lesions of other types and/or higher grades. The independent pathway suggests that some high-grade lesions of any type may develop independently. CONCLUSION: These findings suggest that gastric-type low-grade lesions have a risk of progression into high-grade lesions of other types. Therefore, low-grade gastric-type IPMNs should be under constant surveillance.

DOI： 10.1007/s00535-021-01783-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is effective in treating both naïve and T790M-mutated EGFR-TKI-resistant non-small cell lung cancer patients. The EGFR C797S mutation is the major osimertinib resistance mechanism. The present study monitored the EGFR C797S mutation during osimertinib treatment in Japanese patients using droplet digital PCR (ddPCR). In our first cohort, C797S detection was validated with tumor specimens and/or plasma samples from 26 patients using ddPCR with custom-designed probes detecting and discriminating T790M and C797S in cis and trans positions. In our second cohort, 18 patients with EGFR-T790M who were going to start osimertinib were analyzed using ddPCR by collecting the plasma samples every month from the beginning of the course of osimertinib. In the first cohort, C797S was detected in 15.4% of patients. C797S and T790M in cis and trans positions were distinguished using ddPCR. In the second cohort, serial cfDNA evaluation revealed that the rate of EGFR mutation changes with disease state. Increases of EGFR mutation were detected, including C797S several months before the diagnosis of disease progression. As with the first cohort, C797S and T790M in cis and trans position were distinguished by ddPCR at disease progression. Coincidentally, in the first cohort, next generation sequencing detected NRAS Q61K mutation and the resistance with NRAS Q61K mutation was overcome by trametinib. In the second cohort, serial cfDNA analysis was useful for evaluating bone oligo-progression and local radiation therapy.

DOI： 10.1111/cas.14879

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Triple-negative breast cancer (TNBC) has a poorer prognosis than other breast cancer subtypes; therefore, identifying markers of early recurrence is important. The present study aimed to establish a liquid biopsy protocol for droplet digital PCR-based detection of frequently mutated genes in patients with TNBC. Tumor DNA from 36 patients with TNBC who relapsed within 2 years after surgical resection was retrospectively analyzed. Somatic mutational profiles were evaluated using targeted sequencing to identify frequently mutated genes and genes associated with molecularly targeted therapies. The association between genetic alterations and associated protein phosphorylation was investigated using immunohistochemical analysis. Recurrent hot spot mutations in the plasma were monitored over time. Mutation-specific probes were used to successfully detect mutations in the blood samples of patients who were positive for PIK3CA H1047R and AKT1 E17K mutations. Somatic mutations in AKT1 (14.9%) and PIK3CA (25.5%) were frequently identified in the data. Robust phosphorylation of AKT and S6RP was more common in tumors with PIK3CA H1047R and AKT1 E17K mutational background than in tumors with wild-type PIK3CA and AKT1. In conclusion, the present study evaluated a high-sensitivity detection system for frequently mutated genes that was also applicable for cell-free DNA. The PI3K/AKT pathway was revealed to be activated in patients harboring PIK3CA H1047R and AKT1 E17K mutations; therefore, the PI3K/AKT pathway may be a promising candidate for targeted therapy in these patients.

DOI： 10.3892/ol.2021.12681

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1053/j.gastro.2021.04.049

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII). Hematological malignancies, especially lymphoid malignancies, are known to be underlying causes of AHA; however, thus far, there is no report of AHA associated with Epstein-Barr-virus-associated T/natural killer-cell lymphoproliferative disease (EBV-T/NK-LPD). Here, we present a case of AHA that developed during treatment for EBV-T/NK-LPD. HISTORY: A 69-year-old man visited our hospital because of general fatigue. Blood examination showed pancytopenia, and computed tomography revealed whole-body lymphadenopathy, but there were no findings indicating hematological malignancy from bone marrow aspiration and cervical lymph node biopsy. The level of EBV DNA in peripheral blood was extremely high, and he was diagnosed with EBV-T/NK-LPD. EBV-T/NK-LPD improved with prednisolone (PSL) administration. Seventeen months after starting treatment, the patient complained of back and right leg pain. At that time, he had been treated with low-dose PSL, and EBV-T/NK-LPD was well controlled. Imaging revealed hematoma of the right iliopsoas muscle. Prolonged activated partial thromboplastin time (APTT) was the only abnormal finding in a screening coagulation test. FVIII coagulant activity was below detection limit, and FVIII inhibitor level was increased. From these results, he was diagnosed with AHA.A higher dose of PSL was administered, and, after 1 month of treatment, FVIII activity gradually increased, and FVIII inhibitor level became undetectable. APTT also normalized, and complete remission was achieved and maintained for 13 months with low-dose PSL. During treatment, EBV-T/NK-LPD was well controlled. CONCLUSION: It is speculated that proliferating lymphocytes interfere with normal immune functions and that abnormal autoantibodies are produced from those lymphocytes in patients with LPD. Therefore, we speculate that EBV-infected and proliferating monoclonal NK cells might have modulated the immune system and produced autoantibodies against FVIII, thus causing AHA in this patient with EBV-T/NK-LPD.

DOI： 10.1097/MD.0000000000025518

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

An 83-year-old man without specific symptoms was referred to our hospital for further evaluation and treatment of apparent double primary tumors of the cystic duct and common bile duct. Computed tomography showed contrast-enhanced solid tumors in the cystic duct and common bile duct. Magnetic resonance imaging showed that the bile duct tumor was isointense on T1-weighted images and had low intensity on T2-weighted images. In addition, the bile duct tumor showed high intensity on diffusion-weighted images. Endoscopic ultrasonography revealed the tumor of the common bile duct and endoscopic retrograde cholangiopancreatography demonstrated a filling defect in the bile duct. The cystic duct was not identified on endoscopic ultrasonography or endoscopic retrograde cholangiopancreatography. Transpapillary biopsy of the bile duct tumor showed adenocarcinoma. The patient was diagnosed with double primary tumors of the cystic duct and the common bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy. Microscopic examination with molecular profiling of the tumors revealed a high-grade noninvasive intracholecystic papillary neoplasm of the cystic duct extending into the common bile duct and forming a tubulopapillary neoplasm with invasion of the common bile duct.

DOI： 10.1007/s12328-020-01311-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We previously showed that Lactobacillus brevis-derived polyphosphate (poly P) exerts a curative effect on intestinal inflammation. However, whether or not poly P improves the inflammation and injury of distant organs remains unclear. AIMS: We aimed to investigate the change in the intestinal microbiome and to evaluate the protective effect of poly P on injuries in a cerulein-induced acute pancreatitis (AP) mouse. METHODS: Poly P was orally administered to BALB/C mice every day for 24 days, and then mice were intraperitoneally injected with cerulein. Before cerulein injection, stool samples were collected and analyzed by 16S rRNA gene sequencing. Mice were sacrificed at 24 h after the last cerulein injection; subsequently, the serum, pancreas, and colon were collected. RESULTS: The microbial profile differed markedly between poly P and control group. Notably, the levels of beneficial bacteria, including Alistipes and Candidatus_Saccharimonas, were significantly increased, while those of the virulent bacteria Desulfovibrio were decreased in the poly P group. The elevations of the serum amylase and lipase levels by cerulein treatment were suppressed by the pre-administration of poly P for 24 days, but not for 7 days. The numbers of cells MPO-positive by immunohistology were decreased and the levels of MCP-1 significantly reduced in the AP + Poly P group. An immunofluorescence analysis showed that the ZO-1 and occludin in the colon was strongly augmented in the epithelial cell membrane layer in the AP + Poly P group. CONCLUSIONS: Poly P attenuates AP through both modification of the intestinal microbiome and enhancement of the intestinal barrier integrity.

DOI： 10.1007/s10620-020-06747-9

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記述言語：英語  

Myeloid sarcoma (MS), which involves extramedullary lesions, is classified as a unique subtype of acute myeloid leukemia (AML). At present, no standard treatments for MS have been established. The patient was an 89-year-old man with myelodysplastic syndrome-excess blast-2 (MDS-EB-2) with a 2-year history of intermittent treatment with azacitidine (AZA) during a 4-year history of MDS. He developed painful cutaneous tumors 8 months after the second discontinuation of AZA. They were refractory for antibiotics and topical tacrolimus hydrate. A tumor biopsy was performed, and the histological findings of the tumor lesion showed a proliferation of tumor cells that were positive for myeloperoxidase and CD68 and negative for CD4 and CD123. The patient was diagnosed with MDS-associated MS. MDS-EB-2 quickly progressed to AML with the appearance of peripheral blood blasts and 25% bone marrow blasts. Monotherapy with reduced-dose AZA (37.5 mg/m2 for 7 days, every 4-6 weeks) was restarted, and the MS quickly disappeared. The patient's MS was successfully treated with 16 cycles of AZA treatment over a 22-month period. There have been 10 reported cases in which MS was successfully treated with AZA. Among the 10 cases, the patient in the present case was the oldest. Treatment with reduced-dose AZA should be considered as a therapeutic option for MS in elderly patients with MDS, especially patients who are ineligible for intensive chemotherapy.

DOI： 10.1155/2021/6640597

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Non-coding RNAs (ncRNAs), or RNA molecules that do not code for proteins, are generally categorized as either small or long ncRNA (lncRNA) and are involved in the pathogenesis of several diseases including many cancers. Identification of a large number of ncRNAs could help to elucidate previously unknown mechanisms in phenotype regulation. Some ncRNAs are encapsulated by extracellular vesicles (EVs) and transferred to recipient cells to regulate cellular processes, including epigenetic and post-transcriptional regulations. Recent studies have uncovered novel molecular mechanisms and functions of lncRNAs in pancreatic ductal adenocarcinoma (PDAC), one of the most intractable cancers that is highly invasive and metastatic. As the epithelial-mesenchymal transition (EMT) triggers tumor cell invasion and migration, clarification of the roles of lncRNA in EMT and tumor cell stemness would be critical for improving diagnostic and therapeutic approaches in metastatic cancers. This review provides an overview of relevant studies on lncRNA and its involvement with EMT in PDAC. Emerging knowledge offers evidence for the dysregulated expression of lncRNAs and essential insights into the potential contribution of both lncRNAs and EVs in the pathogenesis of PDAC. Future directions and new clinical applications for PDAC are also discussed.

DOI： 10.3389/fmolb.2021.717890

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Pancreatoblastoma is a rare malignant epithelial neoplasm of the pancreas that mainly occurs in children and involves abnormalities in the WNT/β-catenin pathway, such as CTNNB1 mutation. However, the molecular abnormalities in adult pancreatoblastoma are not well known. Case Presentation: An elderly man, who underwent elective distal pancreatectomy and splenectomy, was referred to our hospital with a mass in the tail of the pancreas. Histologically, the lesion revealed proliferation of clear, basophilic, and cartilaginous tumor cells with lymphatic metastasis. Each of the morphologically distinct tumor components showed different immunohistochemical patterns, indicating heterogeneous differentiation, including epithelial (both acinar and ductal), mesenchymal, and neuroendocrine differentiation. All tumor components showed nuclear expression of β-catenin and cyclin D1. Per next-generation sequencing (NGS), the clear and basophilic tumor cells shared mutations in APC, GRM8, LAMP1, and AKA9. Among the mutations, APC, c.1816_1817insA showed the highest frequency in both cell types, indicating that APC mutation was a driver mutation of the tumor. A diagnosis of PB was rendered. Summary: In conclusion, the clear and basophilic cells of the tumor were supposedly derived from the same clone and subsequently acquired additional mutations. This is the first report of clonal evolution in pancreatoblastoma.

DOI： 10.3389/fonc.2021.725290

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00384-020-03657-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/mgg3.1348

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記述言語：日本語   出版者・発行元：(一社)日本膵臓学会  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J02025&link_issn=&doc_id=20200907320008&doc_link_id=%2Fcq0pancr%2F2020%2F003504%2F009%2F0302-0312%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcq0pancr%2F2020%2F003504%2F009%2F0302-0312%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

It is challenging to secure a cytopathologic diagnosis using minute amounts of tumor fluids and tissue fragments. Hence, we developed a rapid, accurate, low-cost method for detecting tumor cell-derived DNA from limited amounts of specimens and samples with a low tumor cellularity, to detect KRAS mutations in pancreatic ductal carcinomas (PDA) using digital PCR (dPCR). The core invention is based on the suspension of tumor samples in pure water, which causes an osmotic burst; the crude suspension could be directly subjected to emulsion PCR in the platform. We examined the feasibility of this process using needle aspirates from surgically resected pancreatic tumor specimens (n = 12). We successfully amplified and detected mutant KRAS in 11 of 12 tumor samples harboring the mutation; the positive mutation frequency was as low as 0.8%. We used residual specimens from fine-needle aspiration/biopsy and needle flush processes (n = 10) for method validation. In 9 of 10 oncogenic KRAS pancreatic tumor samples, the "water-burst" method resulted in a positive mutation call. We describe a dPCR-based, super-sensitive screening protocol for determining KRAS mutation availability using tiny needle aspirates from PDAs processed using simple steps. This method might enable pathologists to secure a more accurate, minimally invasive diagnosis using minute tissue fragments.

DOI： 10.1038/s41598-020-69221-6

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その他リンク： http://www.nature.com/articles/s41598-020-69221-6

掲載種別：研究論文（学術雑誌）  

DOI： 10.1101/gad.335166.119

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00428-020-02806-8

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担当区分：責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

DOI： 10.3389/fonc.2020.00728

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/path.5398

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/MD.0000000000020564

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担当区分：責任著者   記述言語：英語  

Background and study aims  Needle tract seeding during endoscopic ultrasound fine-needle biopsy (EUS-FNB) remains a concern. We investigated whether such seeding occurred in a patient with pancreatic ductal adenocarcinoma (PDA). Patient and methods  Surgically resected and EUS-FNB-derived specimens were genotyped to determine if a gastric wall tumor that emerged 3 years after curative resection of an early-stage PDA was clonally related to the original tumor. Results  The gastric tumor histologically resembled the primary PDA; the lesions also shared KRAS , SMAD4 , and RNF43 mutations. Genotyping of the preoperative EUS-FNB specimen, in which cancer was not detected, nevertheless revealed mutations that were identical to those in the resected primary and recurrent tumors. While the primary PDA had a low frequency of mutant SMAD4 , such mutations were highly prevalent in both the EUS-FNB and recurrent tumor specimens. Conclusions  The genetic lineages of sampled tissues from our patient revealed that needle tract seeding may have incidentally occurred when a subset of neoplastic cells within a heterogeneous tumor ( i. e. , an aggressive clone) was targeted during EUS-FNB.

DOI： 10.1055/a-1034-7700

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fonc.2019.01375

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ejro.2019.05.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/molecules24061106

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12029-018-0078-3

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1073/pnas.1901765116

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00428-019-02592-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1159/000495289

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background  Despite advances in the diagnosis of pancreatic ductal adenocarcinoma (PDA), histological evaluation of small and poorly defined masses in the pancreas is uncomfortable and unsafe. Methods  We herein report a case of early stage PDA, in which multiple KRAS mutations were detected in the pancreatic juice preoperatively. A small hypoechoic area adjacent to the portal vein was detected through endoscopic ultrasound in the pancreatic body. KRAS mutations were evaluated using plasma, and the pancreatic juice by digital PCR. Results  Pancreatic duct biopsy and pancreatic juice cytology were performed with no evidence of malignancy; however, KRAS mutations, KRAS G12V and G12D, were detected in the pancreatic juice. Histological assessment of the resected specimen demonstrated a solid tumor with desmoplastic reaction accompanied by carcinoma in situ in the main pancreatic duct where KRAS G12V mutation was identified. More detailed analysis demonstrated KRAS G12D mutation in the cluster of low grade pancreatic intraepithelial neoplasia, implying that the lesion developed independently. Conclusions  Our study indicates the potential of "endoscopic liquid biopsy" to capture the driver gene for PDA diagnosis.

DOI： 10.1055/a-0721-1747

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5217/ir.2018.16.3.416

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd.  

DOI： 10.1186/s13099-018-0251-z

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd.  

DOI： 10.1186/s12885-018-4006-5

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12885-018-5031-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/1878-0261.12110

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MD.0000000000004316

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1158/0008-5472.CAN-16-0810

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1158/2159-8290.CD-15-1442

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MPA.0000000000000556

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.55.7466

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5114/PJP.2016.61449

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/cjp2.8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MPA.0000000000000036

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-013-1423-8

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語  

DOI： 10.1083/jcb.201307066

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1253/circj.CJ-12-0897

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3164/jcbn.12-06

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00384-012-1416-8

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1471-230X-12-75

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpgi.00047.2011

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語  

DOI： 10.1111/j.1443-1661.2011.01188.x

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語  

DOI： 10.1055/s-0031-1291502

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00384-011-1311-8

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1440-1746.2011.07012.x

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-012-1017-x

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語  

AuthorAnti-microbial peptides are essential for the intestinal innate immunity that protects the intestinal epithelia from attacks by foreign pathogens. Human β-defensin (HBD) is one of the pivotal anti-microbial peptides that are expressed in the colonic epithelia. This study investigated the effect and the signaling mechanism of inducible β-defensin HBD2 by an essential amino acid, isoleucine (Ile) in colonic epithelial cells. Here we examined the expression level of HBD2 on induction of Ile in epithelial cells, and checked this pathway. HBD2 mRNA was induced by co-incubation with IL-1α and Ile in Caco2 cells, but not by Ile alone. An inhibitor of either ERK or Gi, a subunit of G-proteins, reduced the in- duction of HBD2 mRNA by Ile. The treatment with Ile also increased the intracellular calcium ion concentration, thus suggesting that the GPCR and ERK signaling pathway mediate the effects of Ile. These results indicate that an essential amino acid, Ile, enhances the expression of an inducible β-defensin, namely HBD2, by IL-1α through the activation of GPCRs and ERK signaling pathway. The administration of Ile may therefore represent a possible option to safely treat intestinal inflammation.

DOI： 10.4236/fns.2012.34077

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ibd.21597

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/s-0030-1256510

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語  

DOI： 10.1136/gut.2009.205526

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MPA.0b013e31820d1a03

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語  

DOI： 10.1136/gut.2009.186650D

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-011-0786-y

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/bcr.01.2011.3775

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ Publishing Group  

DOI： 10.1136/bcr.07.2010.3169

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/bcr.08.2010.3251

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ibd.21253

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ Publishing Group  

DOI： 10.1136/bcr.05.2010.3023

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1158/0008-5472.CAN-10-0412

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.11405/nisshoshi.107.784

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.canep.2010.01.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12328-009-0126-4

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その他リンク： http://orcid.org/0000-0002-1068-7024

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0008824

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MPA.0b013e3181b91cd0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1159/000231982

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/bcr.06.2009.2048

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記述言語：英語  

DOI： 10.1007/s12328-009-0116-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語  

DOI： 10.1016/j.surg.2009.03.018

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ijc.24032

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1053/j.gastro.2008.06.034

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1349-7006.2008.00795.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1677/ERC-07-0194

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.11405/nisshoshi.105.725

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DOI： 10.11405/nisshoshi.105.93

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