記述言語：英語   掲載種別：研究論文（学術雑誌）  

Abnormalities of the AT-rich interaction domain 1A (ARID1A) occur in cancer tissues and precursors or premalignant lesions in various organs. To investigate the significance of ARID1A abnormalities in the early phase of cancer development in the stomach, we screened for ARID1A loss and p53 overexpression in glands in non-neoplastic gastric mucosa using immunohistochemistry. We tested 230 tissue blocks of 77 patients with gastric carcinoma, and in 10% of non-neoplastic mucosa we detected ARID1A-lost and in 3.7% p53-overexpressed foci. Loss of ARID1A expression occurred in the scales of several glands, which were morphologically characterized as authentic, pseudo-pyloric, or intestinal metaplastic glands devoid of dysplastic changes. In contrast, p53-overexpressed foci were detected in dysplastic intestinal metaplasia. In early gastric cancer cases (n = 46), ARID1A-lost foci were frequent in samples of patients with Epstein-Barr virus-associated gastric carcinoma (p = 0.037). Ultra-deep DNA sequencing of ARID1A-lost foci revealed frameshift and nonsense mutations in ARID1A. Mapping abnormal glands in the entire resected stomach of the three selected patients demonstrated that ARID1A-lost foci clustered with p53 abnormal glands. ARID1A-lost epithelial cells may develop clonal growth through the pathway, different from p53-abnormal intestinal metaplasia, and require one or more events to develop into an overt carcinoma, such as EBV infection.

DOI： 10.1111/pin.13320

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To overcome the increasing burden on pathologists in diagnosing gastric biopsies, we developed an artificial intelligence-based system for the pathological diagnosis of gastric biopsies (AI-G), which is expected to work well in daily clinical practice in multiple institutes. The multistage semantic segmentation for pathology (MSP) method utilizes the distribution of feature values extracted from patches of whole-slide images (WSI) like pathologists' "low-power view" information of microscopy. The training dataset included WSIs of 4511 gastric biopsy tissues from 984 patients. In tissue-level validation, MSP AI-G showed better accuracy (91.0%) than that of conventional patch-based AI-G (PB AI-G) (89.8%). Importantly, MSP AI-G unanimously achieved higher accuracy rates (0.946 ± 0.023) than PB AI-G (0.861 ± 0.078) in tissue-level analysis, when applied to the cohorts of 10 different institutes (3450 samples of 1772 patients in all institutes, 198-555 samples of 143-206 patients in each institute). MSP AI-G had high diagnostic accuracy and robustness in multi-institutions. When pathologists selectively review specimens in which pathologist's diagnosis and AI prediction are discordant, the requirement of a secondary review process is significantly less compared with reviewing all specimens by another pathologist.

DOI： 10.1111/cas.15514

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The histological growth pattern of liver metastases (desmoplastic, pushing, and replacement patterns) at the tumor-liver parenchymal interface is a prognostic factor in patients with colorectal cancer. However, data regarding its association with the primary tumor characteristics and molecular alterations are limited. This study evaluated the histological growth pattern in 136 cases of colorectal cancer liver metastases without preoperative treatment, comparing it with the clinicopathological features of the primary tumor. Liver metastasis exhibiting predominantly non-desmoplastic pattern (<50%), observed in 74 cases (54%), was associated with hepatic vein invasion (P = 0.025), worse recurrence-free survival (P < 0.001) and overall survival (P = 0.008). In multivariate analyses, multiple tumors (P < 0.001) and non-desmoplastic patterns (P = 0.009) were associated with worse recurrence-free survival, and tumor size (P = 0.025) and non-desmoplastic pattern (P = 0.025) were associated with worse overall survival. In 88 patients with available primary tumor tissue slides, non-desmoplastic pattern in the liver metastasis was associated with high-grade tumor budding (P = 0.002), high-grade poorly differentiated cluster (P = 0.021), absence of mucinous histology (P = 0.016), and aberrant p53 expression (complete loss or overexpression; P  0.001) of the primary colorectal cancer. In conclusion, the histological growth pattern in liver metastasis was a strong and independent prognostic factor for colorectal cancer. Our observations highlight the significant associations between histological growth patterns in liver metastases and histopathological features of the primary tumor, especially invasive front morphology and p53 aberration.

DOI： 10.1016/j.humpath.2022.02.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The prevalence of Helicobacter pylori infection and chronic atrophic gastritis is decreasing in Japan, which has led to a decline in the incidence of gastric cancer. However, there are various subtypes of gastric cancer that arise from the background mucosa without H. pylori infection, and their histological characteristics are distinct from those of gastric cancer with chronic atrophic gastritis. SUMMARY: In this review, after a brief overview of conventional gastric carcinoma with H. pylori infection, including its molecular classification, histological characteristics of gastric cancer after eradicating H. pylori are described. The clinicopathological characteristics of gastric cancer independent of H. pylori infection are then explained. Autoimmune gastritis (type A gastritis) increases the risk of gastric adenocarcinoma and neuroendocrine tumors. Gastric carcinoma without H. pylori infection has various histological subtypes, including fundic gland-type adenocarcinoma (oxyntic gland adenoma), foveolar-type adenocarcinoma/adenoma, signet ring cell carcinoma, and adenocarcinoma of the esophagogastric junction. In addition, some familial gastric cancer syndromes, including hereditary diffuse gastric cancer, familial adenomatous polyposis, and gastric adenocarcinoma and proximal polyposis of the stomach, are also discussed. Key Messages: Although the incidence of gastric cancer will decrease in the near future, the diversity of gastric cancer pathology will be enhanced because H. pylori-negative gastric cancer will have a significant impact on the clinical practice guidelines for gastric cancer. Gastroenterologists and pathologists should be aware of the morphological diversity of H. pylori-negative gastric cancer, and attention should be paid to the status of the background gastric mucosa while examining gastric cancer.

DOI： 10.1159/000519337

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記述言語：英語  

DOI： 10.1111/pin.13162

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct molecular subtype of gastric cancer characterized by viral infection and cellular abnormalities, including loss of AT-rich interaction domain 1A (ARID1A) expression (lost ARID1A). To evaluate the significance of lost ARID1A in the development of EBVaGC, we performed in situ hybridization of EBV-encoded RNA (EBER) and immunohistochemistry of ARID1A in the non-neoplastic gastric mucosa and intramucosal cancer tissue of EBVaGC with in vitro infection analysis of ARID1A-knockdown and -knockout gastric cells. Screening of EBER by in situ hybridization revealed a frequency of approximately 0.2% EBER-positive epithelial cells in non-neoplastic gastric mucosa tissue samples. Six small foci of EBV-infected epithelial cells showed two types of histology: degenerated (n = 3) and metaplastic (n = 3) epithelial cells. ARID1A was lost in the former type. In intramucosal EBVaGC, there were ARID1A-lost (n = 5) and -preserved tumors (n = 7), suggesting that ARID1A-lost carcinomas are derived from ARID1A-lost precursor cells in the non-neoplastic mucosa. Lost ARID1A was also observed in non-neoplastic mucosa adjacent to an ARID1A-lost EBVaGC. In vitro experiments using siRNA knockdown and the CRISPR/Cas9-knockout system demonstrated that transient reduction or permanent loss of ARID1A expression markedly increased the efficiency of EBV infection to stomach epithelial cells. Taken together, lost ARID1A plays a role in initiating EBV-driven carcinogenesis in stomach epithelial cells, which develop to a distinct subtype of EBVaGC within the proper mucosal layer. Lost ARID1A is one of the constituents of virus-host interactions in the carcinogenesis of EBVaGC.

DOI： 10.1371/journal.pone.0256440

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Gastric neuroendocrine carcinoma (NEC) is a rare and aggressive subtype with a poor prognosis. We aim to investigate expression profiles of HER2 and programmed death ligand 1 (PD-L1) in gastric NEC to test the potential applicability of drugs targeting these molecules. METHODS AND RESULTS: Expression levels of HER2 and PD-L1 were evaluated in 25 gastric NECs, including 10 pure NECs and 15 mixed adenocarcinoma-NECs, and a combined positive score (CPS) was used to evaluate PD-L1 expression. The correlations of expression levels with both clinicopathological features and the expression of p53, retinoblastoma protein (Rb) and mismatch repair proteins were also analysed. Eighteen of the 25 (72%) cases showed a PD-L1 CPS of ≥ 1, which was previously shown to be associated with response to pembrolizumab. Positive nodal metastasis and low tumour-infiltrating lymphocyte (TIL) levels at the invasive margin were significantly associated with a PD-L1 CPS of < 1. The NEC component was HER2-negative in all cases, whereas HER2 positivity was observed in the adenocarcinoma component of six of 15 (40%) mixed adenocarcinoma-NECs. Mismatch repair deficiency, a mutant pattern of p53 expression and loss of Rb expression were observed in four (16%), 17 (68%) and nine (36%) cases, respectively, although these alterations were not associated with the PD-L1 CPS or other clinicopathological characteristics. CONCLUSIONS: HER2 is unlikely to be an effective target in gastric NEC owing to the lack of HER2 expression, whereas the PD-1/PD-L1 pathway is a potential therapeutic target for gastric NEC because of the relatively high prevalence of a PD-L1 CPS of ≥ 1 in this subtype.

DOI： 10.1111/his.14230

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gastric cancer (GC) is one of the most common and life-threatening malignancies. The course of disease and tumor aggressiveness vary among GCs, although how early fate is determined and by what factors remains elusive. To solve this question, we collected 43 gastric intramucosal neoplasias (GINs), comprising dysplasia/intraepithelial neoplasia (D/IEN; a premalignant lesion) and minute GC (miGC; ≤10 mm) of intestinal histotype and performed targeted deep DNA sequencing of 67 GC-related genes derived from large-scale data. Gastric D/IEN was classified into low or high grade (LG-D/IEN or HG-D/IEN). The most frequent mutations in D/IENs included APC (19/25; 76%), ARID2 (6/25; 24%) and MUC6 (5/25; 20%). All LG-D/IENs had APC mutation (12/12) and APC hotspot mutations affecting R1450 and E1554 were noted in both LG-D/IEN and HG-D/IEN. ARID2 mutation always co-occurred with APC mutation, whose tumor variant allele frequency (TVAF) was higher than that of ARID2 in D/IEN. APC and TP53 mutations were mutually exclusive in D/IEN (p = 0.031 [main cohort], p = 0.025 [expanding cohort]) and TP53-mutated D/IEN was exclusively HG-D/IEN (4/4). TP53 mutations were highly recurrent (11/14; 79%) in MLH1-positive miGCs and were detected even in two microscopic lesions measuring 1 and 3 mm, respectively. Furthermore, TVAF analyses suggested that TP53 mutation is the initial event in the TP53-mutated miGCs. In contrast, TP53 mutation was absent (0/4) in MLH1-negative small intramucosal carcinoma (8-24 mm). Advanced GC data suggested that early mutations (APC and TP53) may affect the potential of cancerous progression from D/IEN. This study revealed somatic mutational landscape and initial mutations of GINs, and we report for the first time that TP53 mutations precede other mutations in intestinal-type GC. Our results also indicate that molecular subtyping based on APC/TP53 mutations would be a high-priority approach for determining and predicting the malignant potential of GIN, including D/IEN. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/path.5208

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC), one of four major gastric cancer types, consists of clonal growth of EBV-infected epithelial cells. However, the significance of viral loads in each tumor cell has not been evaluated. EBV-DNA is stably maintained in episomal form in the nucleus of each cancer cell. To estimate EBV copy number per genome (EBV-CN), qPCR of viral EBNA1 and host GAPDH, standardized by Namalwa DNA (one copy/genome), was applied to the formalin-fixed paraffin embedded (FFPE) surgically resected EBVaGC specimens (n = 43) and EBVaGC cell lines (SNU-719 and NCC-24). In surgical specimens, the cancer cell ratio (CCR) was determined with image analysis, and EBV-CN was obtained by adjusting qPCR value with CCR. Fluorescent in situ hybridization (FISH) was also applied to the FFPE sections using the whole EBV-genome as a probe. In surgical specimens, EBV-CN obtained by qPCR/CCR was between 1.2 and 185 copies with a median of 9.9. EBV-CN of SNU-719 and NCC-24 was 42.0 and 1.1, respectively. A linear correlation was observed with qPCR/CCR data up to 20 copies/genome (40 signals/nucleus), the limit of FISH analysis. In addition, substantial variation in the number of EBV foci was observed. Based on qPCR/CCR, high EBV-CN (>10 copies) correlated with PD-L1 expression in cancer cells (P = 0.015), but not with other pathological indicators. Furthermore, EBVaGC with high EBV-CN showed worse disease-specific survival (P = 0.041). Our findings suggest that cancer cell viral loads may contribute to expression of the immune checkpoint molecule and promotion of cancer progression in EBVaGC.

DOI： 10.1371/journal.pone.0211358

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Extranodal NK/T cell lymphoma, nasal type (ENKL) developed in a patient with intestinal Epstein-Barr virus (EBV)-positive T/NK-cell lymphoproliferative disorder (LPD). The patient was a 46-year-old Chinese man who complained of diarrhea and abdominal pain without immune-deficiency. Endoscopy demonstrated ileum ulcers like Crohn's disease, without histological granulomas. His symptoms continued waxing and waning for 3 years until he developed overt lymphoma (ENKL) in the nasal cavity. The ileum lesions exacerbated into a large deep ulcer, and the biopsy specimens from the ileum, including the one 3 years ago, showed infiltration of small lymphocytes containing many EBV-positive T/NK cells without atypia. Thus, the patient illness of intestine was revealed as intestinal EBV-positive T/NK-cell LPD, which might be closely associated with development of ENKL in this patient. In cases of inflammatory bowel disease without typical clinical courses and histological findings, check-up of EBV in the biopsy might help correct diagnosis.

DOI： 10.1016/j.prp.2018.05.022

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) frequently harbors dense lymphocytic infiltration, suggesting a specific microenvironment allowing coexistence with tumor immunity. CD47, which mediates the "do not eat me" signal in innate immunity, is also important in adaptive anti-tumor immunity. We investigated the significance of CD47 in EBVaGC compared with EBV-negative gastric cancer and the correlation with various immune cells. By immunohistochemistry of CD47, high, low, and negative expression was observed in 24, 63, and 12% of EBVaGC (n = 41), while 11, 49, and 39% of EBV-negative gastric cancer (n = 262), respectively, indicating that high expression of CD47 in cancer cells was significantly frequent and increased in EBVaGC (P = 0.043). In contrast to EBV-negative gastric carcinoma in which no significant correlation was observed between CD47 and survival, high expression of CD47 correlated significantly with worse disease-specific survival (P = 0.011) and overall survival (P = 0.013) in EBVaGC. To further clarify the role of CD47 expression in EBVaGC, digital image analysis of immune cell infiltration revealed that high CD47 expression was correlated with a lower ratio of CD8+/Foxp3+ T cells (P = 0.021), a sensitive indicator of tumor immunity. Thus, CD47 lowers anti-tumor immunity in EBVaGC by finely tuning profile of infiltrating T cells, suggesting that CD47 is an additional target for cancer immunotherapy against this virus-driven gastric cancer.

DOI： 10.1007/s00428-018-2332-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer cells use PD-L1 to evade antitumor immunity through interaction with programmed cell death protein 1 (PD-1) on T cells. Recent whole-genome sequence studies revealed frequent gene amplification of PD-L1 in Epstein-Barr virus-associated gastric cancer (EBVaGC). To investigate the significance of PD-L1 in cancer cells and their microenvironment in EBVaGC, we studied PD-L1 expression by analysis of the public database and immunohistochemistry with fluorescent in situ hybridization (FISH) of the PD-L1 gene. Analysis of the database from The Cancer Genome Atlas also disclosed high expression of PD-L1 in EBVaGC compared with other molecular subtypes of GC. Expression of PD-L1 was frequently detected in cancer cells of EBVaGC (33/96; 34%), with infiltration of PD-L1+ immune cells in its stroma (43/96; 45%). Both expression of PD-L1 in cancer cells and PD-L1+ immune cell infiltration in EBVaGC were significantly correlated with diffuse histology according to Lauren's classification and tumor invasion (pT1b or more). As a prognostic indicator, PD-L1 expression in cancer cells correlated with poor outcomes in both overall survival and disease-specific survival (P=0.0498, 0.007). PD-L1-positive cancers had dense infiltration of PD-L1+ immune cells as well as CD8+ and PD-1+ cells in EBVaGC. FISH analysis of representative samples of the tumor demonstrated gene amplification of PD-L1 in 11% of cases. PD-L1-amplified cells corresponded to PD-L1-positive cells showing high-intensity immunohistochemical staining among cancer cells showing weak or moderate intensities. Taken together, PD-L1 expression in cancer cells and their microenvironment may contribute to the progression of EBVaGC, and gene amplification occurs as clonal evolution during progression. This specific subtype of GC infected with EBV is potentially a good candidate for immunotherapy targeting of the PD-L1/PD-1 axis.

DOI： 10.1038/modpathol.2016.202

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記述言語：日本語   出版者・発行元：(株)文光堂  

病理解剖1052例の病理解剖報告書を対象に、「突然」のキー・ワードで検索を行い症例を抽出した。得られた症例について臨床推定死因、病理解剖診断、死後CT画像による診断を検討した。その結果、突然死は全症例中40例(3.8%)であった。生前の臨床診断と剖検診断の一致は20例(50%)、死因が生前不明・解剖で判明または生前診断と解剖診断が不一致は計13例(32.5%)、剖検を行っても死因が不明であったのは7例(17.5%)であった。急変した場所(院内か院外)、急変までの期間(10日以上か10日未満)では一致率に差はなかった。急変後に画像検索(CT等)が行われた症例、また消化器疾患や脳疾患を有する症例は全例とも生前の臨床診断と剖検診断が一致した。死後CTは8例で行われ、うち3例は死後CTのみでは死因推定が困難で、剖検で死因が判明した。以上、突然死の死因の不一致率は過去の報告における不一致率と同程度であり、突然死で特に不一致率が高いわけではなかった。突然死であるか否かに関わらず、病理解剖は重要であると考えられた。

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担当区分：筆頭著者   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）  

Recent studies suggest that CD204-positive (CD204(+)) M2-type tumor-associated macrophages (TAMs) are associated with the aggressive behavior of various cancers. However, the clinicopathologic significance of tumor-infiltrating CD204(+) macrophages and their correlation with Epstein-Barr virus (EBV) in gastric cancer is unclear. Tissue microarrays were constructed from 119 surgically resected gastric cancer specimens (86 EBV-negative and 28 EBV-positive cases). After immunohistochemistry of CD204, the density of CD204(+) cells was calculated using image analysis software, and associations between CD204 and clinicopathologic factors including patient survival were examined. High CD204(+) cell density was significantly associated with several adverse prognostic factors, including older age (P = .008), advanced tumor depth (P < .001), lymph node metastasis (P < .001), presence of venous invasion (P < .001), and lymphatic invasion (P = .03). Low CD204(+) cell density was significantly associated with EBV infection. Advanced tumor depth and presence of lymph node metastasis were significantly associated with high CD204(+) cell density in both EBV-positive and EBV-negative subgroups. High CD204(+) cell density was significantly associated with shorter cancer-specific survival (P = .0015). In conclusion, a high density of CD204(+) TAMs was associated with the aggressive behavior and worse survival of gastric cancer. Low density of CD204(+) TAMs was associated with infection of EBV, which may explain the favorable outcome of EBV-associated gastric carcinoma. Our results suggest that a specific immune microenvironment may be associated with the biological behavior of gastric cancer and that EBV-associated gastric carcinoma is distinctive from other gastric carcinomas in tumor immunity.

DOI： 10.1016/j.humpath.2016.06.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is characterized by prominent intratumoral lymphocyte infiltration, with some infiltration by other types of inflammatory cells, such as neutrophils. In this study, the significance of tumor-associated neutrophils (TANs) and cytotoxic T lymphocytes (CTLs) was investigated in EBVaGC. CD66b-positive TANs and CD8-positive CTLs in surgically resected EBVaGC tissues were evaluated by immunohistochemistry and digital imaging analysis. Cut-off values were determined with receiver operating characteristic curve analyses. Forty-two of 77 cases (55 %) had some infiltration of TANs (CD66b-positive areas >0.5 %, TAN(+)) and 35 (45 %) had scant infiltration (TAN(-)). Thirty-five cases (45 %) had more CTLs (CD8-positive area >18 %, CTL-high) and 42 (55 %) had fewer (CTL-low). There was no correlation between CD66b- and CD8-positive areas in the tumor (P = 0.453). TAN(+) correlated with intestinal-type histology (P = 0.048) and low frequency of lymph node metastasis (P = 0.023), while CTL-low with upper location (P = 0.030) and advanced invasion depth (pT2 or greater) (P = 0.006). Disease-specific survival was not significantly correlated with TANs or CTLs. Multivariate logistic regression analysis revealed TAN(-) to be independently associated with lymph node metastasis (P = 0.036). None of the cases of TAN(+) early EBVaGC with submucosal invasion showed lymph node metastasis (95 % confidence interval 0-13.3 %). When compared with 24 EBV-negative gastric carcinomas, EBVaGC had significantly more CTLs (P < 0.001), while there was no difference in the number of TANs. TANs in EBVaGC may suppress lymph node metastasis, and absence of TANs might suggest careful follow-up or additional therapy in cases of post-endoscopic resection.

DOI： 10.1007/s00428-016-1915-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct subtype of gastric carcinoma, consisting of clonal growth of EBV-infected epithelial cells. Its unique characteristics have been demonstrated by epidemiological, clinical and pathological studies using in situ hybridization for EBV-encoded small RNAs. An oncogenic process for EBVaGC has also been revealed. EBV uses various host-cell machineries, including cell division machinery to propagate clonal virus genomes, DNA-methylation machinery to epigenetically control infected cells, and microRNA and exosome machineries to modify the behavior and microenvironment of infected cells. Recent comprehensive molecular analyses from The Cancer Genome Atlas project demonstrate that EBVaGC is a representative molecular subtype that is distinct from microsatellite unstable, genomically stable and chromosome unstable subtypes. In addition to having the highest level of DNA methylation in CpG islands of promoter regions, EBVaGC harbors particular gene alterations, including a high frequency of mutations in PIK3CA and ARID1A, mutation in BCOR, and amplification of PD-L1 and PD-L2. Although currently undetermined, the virus might use the altered cellular functions that are induced by these somatic mutations. Further investigation of virus-driven oncogenesis will enable hitherto unknown functions of stomach epithelial cell machineries to be elucidated, which may reveal potential therapeutic targets for EBVaGC.

DOI： 10.1159/000434683

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AT-rich interactive domain 1A (ARID1A) is a subunit of the Switch/Sucrose non-fermentable (SWI/SNF) chromatin remodeling complex. Recently, genome-wide whole exome sequencing revealed frequent mutations of ARID1A in hepatocellular carcinoma, but clinicopathological significance of ARID1A alteration has not been clarified yet. In this study, expression of ARID1A was investigated immunohistochemically in 290 cases of hepatocellular carcinomas. In the evaluation of tissue microarrays, cases of ARID1A alteration (63 total cases, 21.7%) consisted of 11 (3.8%) cases showing loss of expression and 52 (17.9%) with weak expression. Alteration of ARID1A was correlated with larger tumor size (P=0.034) and well or moderate differentiation of tumor histology (P=0.035). There was no significant correlation with age, sex, cirrhosis, TNM stage, tumor size, number of tumors, vascular invasion, patient survival, HBV infection, HCV infection, heavy use of alcohol, nor diabetes mellitus. EBER in situ hybridization was negative in all 11 cases with loss of ARID1A. Altered expression of ARID1A was inversely correlated with nuclear expression of p53 (P=0.018) or beta-catenin (P=0.025). There was some heterogeneity of ARID1A alteration within each case, and immunohistochemistry of the whole sections demonstrated that four of 11 cases with loss of ARID1A in TMA analysis showed localized positive area within the tumor. Alteration of ARID1A may accelerate tumor growth in a subset of hepatocellular carcinoma, and this pathway may be distinct from p53 and beta-catenin pathways.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary tumor thrombotic microangiopathy is a rare but lethal complication in cancer-bearing patients, particularly those with gastric cancer. It is characterized by cancer cell emboli with marked intimal proliferation. In the present study, we tried to elucidate the pathogenesis of pulmonary tumor thrombotic microangiopathy, notably angiogenic factors specific for cancer cells lodged in pulmonary arteries. An autopsy series of gastric cancer (51 cases) was reviewed for pulmonary tumor thrombotic microangiopathy and pulmonary tumor cell emboli without intimal proliferation. Pathological and immunohistochemical characteristics were compared between two groups. In eight cases in muscular pulmonary arteries, tumor thrombotic microangiopathy was noted, and in three cases pulmonary tumor emboli without intimal proliferation was noted. Histological features of pulmonary tumor thrombotic microangiopathy included small nests or single cancer cells accompanied by intimal proliferation, whereas in pulmonary tumor emboli large cell nests prevailed. By immunohistochemistry, in pulmonary tumor thrombotic microangiopathy, cancer cells expressed platelet-derived growth factor-A (7/8 cases) and vascular endothelial growth factor-C (8/8) more frequently than in pulmonary tumor emboli (0/3 and 1/3; P = 0.02 and P = 0.055, respectively). Expression of tissue factor, vascular endothelial growth factor-A and -D, osteopontin, fibroblast growth factor-2, and platelet-derived growth factor-B was similar in both groups. Platelet-derived growth factor-A and vascular endothelial growth factor-C might induce intimal proliferation in pulmonary arteries and contribute to the development of pulmonary tumor thrombotic microangiopathy.

DOI： 10.1007/s00428-013-1403-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The AT-rich interactive domain 1A gene (ARID1A), which encodes one of the subunits in the Switch/Sucrose Nonfermentable chromatin remodeling complex, carries mutations and is responsible for loss of protein expression in gastric carcinoma, particularly with Epstein-Barr virus (EBV) infection and a microsatellite instability-high phenotype. We used immunohistochemistry to investigate the significance of ARID1A loss in 857 gastric carcinoma cases, including 67 EBV(+) and 136 MLH1-lost gastric carcinomas (corresponding to a microsatellite instability-high phenotype). Loss of ARID1A expression was significantly more frequent in EBV(+) (23/67; 34 %) and MLH1-lost (40/136; 29 %) gastric carcinomas than in EBV(-)MLH1-preserved (32/657; 5 %) gastric carcinomas (P < 0.01). Loss of ARID1A correlated with larger tumor size, advanced invasion depth, lymph node metastasis, and poor prognosis in EBV(-)MLH1-preserved gastric carcinoma. A correlation was found only with tumor size and diffuse-type histology in MLH1-lost gastric carcinoma, but no correlation was observed in EBV(+) gastric carcinoma. Loss of ARID1A expression in EBV(+) gastric carcinoma was highly frequent in the early stage of gastric carcinoma, although EBV infection did not cause downregulation of ARID1A: EBV-positive nasopharyngeal carcinomas (n = 8) and lymphomas (n = 15) failed to show loss of ARID1A, and EBV infection did not cause loss of ARID1A in gastric carcinoma cell lines. Taken together, loss of ARID1A may be an early change in carcinogenesis and may precede EBV infection in gastric epithelial cells, while loss of ARID1A promotes cancer progression in gastric cancer cells without EBV infection or loss of MLH1 expression. Loss of ARID1A has different and pathway-dependent roles in gastric carcinoma.

DOI： 10.1007/s00428-012-1303-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

IgG4-related sclerosing disease is a rare disease characterized by fibrosis and lymphoplasmacytic infiltration in various organs. Here, we report a rare case of IgG4-related fibrosis that presented as a unilateral ureteral mass in a 39-year-old man who presented with abdominal pain. Left hydronephrosis and a mass measuring 3 × 1.1 cm in the lower portion of the left ureter were found. As a ureteral malignancy could not be ruled out, the left ureter was resected partially. Pathologically, severe fibrosis and infiltration of plasma cells, lymphocytes, and eosinophils were found. No malignancy was found. Immunohistochemically, most of the plasma cells were IgG4-positive. The serum IgG4 level was also elevated (233 mg/dl). The histological characteristics were similar to those of retroperitoneal fibrosis, inflammatory pseudotumor, or idiopathic segmental ureteritis. It is important to consider IgG4-related sclerosing disease in the differential diagnosis of a unilateral ureteral mass.

DOI： 10.1016/j.prp.2011.08.003

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記述言語：日本語   出版者・発行元：(一社)日本病理学会  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J03623&link_issn=&doc_id=20100525290011&doc_link_id=%2Fcd9jjodp%2F2010%2F002702%2F011%2F0140-0143%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcd9jjodp%2F2010%2F002702%2F011%2F0140-0143%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Infective endocarditis (IE) is a life-threatening disease characterized by various systemic complications, including neurological manifestations. Although subarachnoid hemorrhage (SAH) is a rare complication of IE, particularly in the absence of aneurysms, the underlying pathophysiological mechanisms remain poorly understood. We report a rare autopsy of a man in his 50s who suddenly died without medical intervention. Postmortem imaging and autopsy showed bilateral convexal SAH (cSAH). Histological examination confirmed IE with gram-positive bacterial colonies in the mitral valve and septic embolization in several organs. In the subarachnoid hemorrhage, gram-positive bacterial colonies and multiple vessels with intense neutrophilic infiltration were observed. These findings provide rare pathological evidence that cSAH can be caused by septic emboli-induced vascular destruction, independent of aneurysmal rupture. This case highlights the need for clinicians and forensic pathologists to consider IE in unexplained deaths with elevated inflammatory marker levels and SAH, even when no cerebral aneurysms are detected. Prompt diagnosis and treatment could be lifesaving in similar cases. To the best of our knowledge, this is an exceptionally rare case report documenting histological confirmation of non-aneurysmal SAH secondary to IE in a forensic autopsy.

DOI： 10.1016/j.jflm.2026.103189

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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/s10014-025-00525-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We aimed to investigate early postmortem changes of the healthy pancreas longitudinally across antemortem computed tomography (AMCT) to postmortem computed tomography (PMCT). MATERIALS AND METHODS: This study included adult patients who were treated and died at a university hospital and underwent unenhanced AMCT within seven months before death, and PMCT within 24 hours after death. Included subjects had undergone pathological autopsy between 2013 and 2020 and were proven to have a healthy pancreas on autopsy. The pancreatic parenchyma on images was segmented using CT-value threshold-assisted initial contouring followed by manual slice-by-slice refinement. Their volume, density, and histogram-based distribution parameters (skewness and kurtosis) of the voxel-wise pancreatic density distribution within the segmented pancreas region of interest were measured using an image analyzer on unenhanced AMCT and PMCT. The values were compared statistically. RESULTS: A total of 38 participants were included in the study (male/female, 23/15; mean age, 64.1±15.1 (SD) years). The pancreatic density on AMCT (31.2 ± 8.7 HU) decreased significantly on PMCT (26.6 ± 8.1 HU). Similarly, the pancreatic volume on AMCT (63.8 ± 23.2 ml) significantly reduced on PMCT (56.8 ± 22.6 ml). Histogram skewness of the voxel-wise pancreatic density distribution significantly increased from AMCT to PMCT, whereas histogram kurtosis of this density distribution exhibited a non-significant difference. CONCLUSION: Pancreatic density and volume significantly decrease in early postmortem. These findings provide a basis for interpreting normal postmortem pancreatic imaging.

DOI： 10.7759/cureus.101444

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Inflammatory blood markers and tumor-infiltrating lymphocytes (TILs) are associated with the prognosis of various cancers. However, reports on their value as prognostic markers in soft tissue undifferentiated pleomorphic sarcoma (UPS) are limited. We aimed to clarify the predictive value of these markers for the prognosis of patients with UPS, focusing on resectable tumors of the extremities and trunk. METHODS: This retrospective analysis included data from 103 patients with localized UPS in the extremities and trunk. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and systemic inflammatory response index (SIRI) were calculated, and the median values were determined as cut-off values. Immunohistochemical staining of CD8 + TILs was also performed. Disease-specific overall survival (DOS) and distant metastasis-free survival (DMFS) rates were analyzed using the Kaplan-Meier method, and prognostic factors were identified using the Cox proportional hazards model. RESULTS: Among the inflammatory blood markers, SIRI was found to be a sensitive prognostic factor, and a high SIRI was associated with worse DOS (P = 0.16) and DMFS (P = 0.09). Although CD8 + TILs were not associated with DOS (P = 0.67), high CD8 + TILs correlated with improved DMFS (P = 0.20). Only tumor size > 10 cm was significantly associated with worse DMFS (P = 0.02) in the univariate analysis, while inflammatory blood markers and CD8 + TIL showed no correlation. The combination of SIRI and CD8 + TILs revealed that high CD8 + TILs in tumor tissue could improve DMFS (P = 0.04) and DOS (P = 0.15) in patients with high SIRI compared to those with low CD8 + TILs and high SIRI. CONCLUSIONS: In patients with localized UPS, CD8 + TILs infiltration into the tumor tissue could improve the prognosis of patients with high SIRI.

DOI： 10.1186/s12885-025-15182-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

p53 is one of the most important tumour suppressors exerting antitumour effects primarily via apoptosis. TP53 mutations are common in gastric tumorigenesis; however, nearly half of the gastric cancers (GCs) remain wildtype TP53 (TP53_WT). We investigated epigenetic/genetic profiles of GCs and the carcinogenic mechanisms underlying GCs with TP53_WT. Comprehensive DNA methylation analysis revealed four DNA methylation epigenotypes (MEs) in GCs, namely, high ME (HME), extremely HME (E-HME), low ME (LME), and extremely LME (E-LME). E-HME matched Epstein-Barr virus (EBV)-positive GC (E-HME/EBV). HME can be further categorised into MLH1-deficient (HME_MLH1(-)) and -proficient cases. The Cancer Genome Atlas data confirmed that HME_MLH1(-)/microsatellite instability (MSI) and E-HME/EBV cases significantly retained TP53_WT and had higher MDM2 expression levels than other MEs. We hypothesised that apoptosis pathways in TP53_WT GC may be suppressed post-transcriptionally by activated MDM2. Short hairpin RNA-mediated MDM2 knockdown and the p53-MDM2 inhibitors, nutlin-3 and RG7388, induced apoptosis in TP53_WT GC cells, indicating that activated MDM2 suppressed p53 protein levels and thereby attenuated the downstream p53 pathway activation, which was restored upon MDM2 knockdown or inhibitor treatment. Collectively, DNA-hypermethylated GC cases, HME_MLH1(-)/MSI and E-HME/EBV, follow a unique carcinogenic pathway to evade apoptosis in the absence of TP53 mutation, potentially making them responsive to therapeutic strategies that function primarily through the p53 pathway. © 2025 The Pathological Society of Great Britain and Ireland.

DOI： 10.1002/path.6480

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記述言語：英語  

DOI： 10.1161/CIRCULATIONAHA.124.073093

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Artificial intelligence for rare pathological lesion detection faces dual challenges: expert annotation scarcity and domain shifts across institutions. Using multi-institutional kidney biopsies from 22 hospitals with 3 scanner types (NDPI, VSI, SVS), we demonstrate that model performance decreases dramatically across domains, with up to 70.3% reduction in detection precision for rare lesions such as crescents and segmental sclerosis (comprising only 2-3% of annotations). We present an approach integrating semi-supervised learning with residual CycleGAN-based domain adaptation, reducing mean Fréchet inception distance between institutions from 55.9 to 20.2 while preserving diagnostic morphology. We identified context-dependent optimal strategies: semi-supervised learning with 50% confidence threshold excelled in same-hospital scenarios (15.2-17.7% improvement for rare lesions), while our combined GAN-Semi-Supervised approach demonstrated superior performance in cross-scanner scenarios between NDPI and VSI formats (up to 63.4% improvement for crescents). This methodology enables robust performance across diverse healthcare settings with minimal expert annotation.

DOI： 10.1038/s41746-025-02160-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: It has been suggested that chemoradiotherapy may cause fibrosis of the internal anal sphincter, resulting in sclerosis. However, no report has quantitatively investigated this relationship by using real-time tissue elastography. OBJECTIVE: To clarify the relationship between fibrosis and elasticity of the internal anal sphincter in patients undergoing surgery for lower rectal cancer with or without preoperative chemoradiotherapy from a histological perspective. DESIGN: A single-center, prospective cohort study. SETTINGS: The surgical and pathological departments in a tertiary referral university hospital. PATIENTS: Eighteen patients with rectal cancer who underwent abdominoperineal resection between May 2019 and May 2022 were included in the study. MAIN OUTCOME MEASURES: Real-time tissue elastography was performed before surgery to measure internal anal sphincter hardness as "elasticity" (hardest (0) to softest (255); decreased elasticity indicated sclerotic changes). Internal anal sphincter fibrosis was evaluated using Masson's trichrome and Elastica van Gieson staining. We evaluated internal anal sphincter elasticity after preoperative chemoradiotherapy and preoperatively in patients who did not undergo preoperative chemoradiotherapy and analyzed the correlation with the percentage of internal anal sphincter fibrosis in the resected specimens. RESULTS: Of the 18 patients, 10 underwent preoperative chemoradiotherapy. A significantly higher percentage of internal anal sphincter fibrosis was observed in the chemoradiotherapy group. Post-chemoradiotherapy elasticity was significantly lower in patients undergoing chemoradiotherapy compared to pre-chemoradiotherapy elasticity and that in patients not undergoing chemoradiotherapy. The analysis of the correlation between internal anal sphincter elasticity and fibrosis showed that elasticity decreased as the percentage of fibrosis increased. LIMITATIONS: This study was conducted at a single institution, and the number of cases was small. The radiation dose to the anal canal may have differed depending on the location of the tumor, which may have affected internal anal sphincter elasticity. CONCLUSIONS: Internal anal sphincter elasticity may reflect tissue sclerosis associated with fibrosis caused by chemoradiotherapy.

DOI： 10.1007/s00384-025-05026-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently developed pathology foundation models, pretrained on large-scale pathology datasets, have demonstrated excellent performance in various downstream tasks. This study evaluated the utility of pathology foundation models combined with multiple instance learning (MIL) for kidney pathology analysis. We used 242 hematoxylin and eosin-stained whole slide images (WSIs) from the Kidney Precision Medicine Project (KPMP) and Japan-Pathology Artificial Intelligence Diagnostics Project databases as the development cohort, comprising 47 healthy controls, 35 acute interstitial nephritis, and 160 diabetic kidney disease (DKD) slides. External validation was performed using 83 WSIs from the University of Tokyo Hospital. Pretrained pathology foundation models were utilized as patch encoders and compared with ImageNet-pretrained ResNet50. Using the extracted patch features, we trained MIL models to classify diagnoses. In internal validation, all foundation models outperformed ResNet50, achieving area under the receiver operating characteristic curve (AUROC) over 0.980. In external validation, the performance of ResNet50 markedly dropped, which was in contrast to all foundation models. Visualization of attention heatmaps confirmed that foundation models accurately recognized diagnostically relevant structures. In overt proteinuria (albuminuria ≥ 300 mg/gCre or proteinuria ≥ 1000 mg/gCre) prediction task, foundation models also outperformed ResNet50. We successfully integrated pathology foundation models with MIL to achieve robust diagnostic performance.

DOI： 10.1038/s41598-025-19297-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This study presents a prospective experimental analysis aimed to investigate the enzymatic interactions that cause histologic changes in the vascular wall to help prevent bleeding complications after pancreatic surgery. Severe hemorrhage can result from the accumulation of pancreatic juice and digestive fluids around vascular stumps. However, the specific digestive enzymes and their interactions that cause histologic damage to vascular walls remain unclear. METHODS: Histopathologic changes in porcine arterial and venous walls were examined 48 hours after exposure to enzymatic solutions and human pancreatic juice, with or without a mixture of other digestive fluids obtained from 4 patients undergoing pancreatoduodenectomy. Moreover, the protective effect of a protease inhibitor added to active pancreatic juice against histopathologic damage was evaluated. RESULTS: Thinning of the arterial walls, with degeneration of smooth muscle nuclei and muscle/collagen fibers in the media, was significant after exposure to trypsin or chymotrypsin, and, among human digestive fluids, only after exposure to pancreatic juice mixed with intestinal fluid. Venous walls were more vulnerable to proteases and digestive fluids. Histopathological changes in the arterial wall were prevented when 10 units of nafamostat mesylate (protease inhibitor) were added to the pancreatic juice mixed with intestinal fluid. CONCLUSION: The activation of pancreatic proteases through mixing with intestinal fluids is a major factor causing histologic damage to the arterial media, leading to aneurysm formation and rupture of the vascular wall. Developing methods for the localized and continuous administration of protease inhibitors around vascular stumps could reduce life-threatening bleeding complications after pancreatic surgery.

DOI： 10.1016/j.surg.2025.109591

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Postmortem computed tomography (PMCT) typically reveals blood clots and sedimentation in cardiac and vascular structures. We examined the associations between these postmortem findings and antemortem clinical and laboratory parameters in in-hospital death. MATERIAL AND METHODS: This prospective study included 114 non-traumatic in-hospital deaths where PMCT was performed within 24 h postmortem. Two radiologists evaluated high-density areas in the right and left atria, pulmonary artery, and thoracic aorta, and classified them as blood clots or gravitational sedimentation. The clinical and laboratory data from the week before death were analyzed using univariate and multivariate logistic regression. RESULTS: Interobserver agreement was excellent for all anatomical sites (κ = 0.87-0.91). Blood clot or blood sedimentation were observed in 34-53% of cases across different locations. Per univariate analysis, non-pneumonic infections, positive blood cultures, and elevated coagulation parameters (prothrombin time-international normalized ratio, activated partial thromboplastin time) were associated with gravitational sedimentation. In contrast, solid malignancies and higher values of hematologic parameters (platelet count, red blood cells, hemoglobin, neutrophil percentage) were associated with blood clot formation (all p < .05). Per multivariate analysis, non-pneumonic infections maintained strong associations with gravitational sedimentation across all sites (p < .05), while higher platelet counts independently predicted blood clot formation in the right atrium, left atrium, and thoracic aorta (p < .05). CONCLUSION: Postmortem gravitational sedimentation was associated with non-pneumonic infections, whereas clot formation correlated with higher platelet counts. These findings provide objective criteria for interpreting PMCT findings and may aid in evaluating patients' antemortem clinical status, particularly when clinical information is limited.

DOI： 10.1007/s11604-025-01797-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

SETD1A is a member of the KMT2 histone H3K4 methyltransferase family of mammalian proteins. Aberrant SETD1A expression is associated with a poor prognosis in patients with gastric cancer (GC). We found that the catalytic domain of SETD1A is nonessential for GC cell proliferation, whereas the non-catalytic FLOS domain is essential. The loss of SETD1A commonly reduces the expression of E2F target genes in GC cell lines from the three independent molecular subtypes. A pooled CRISPR screen and cDNA rescue experiment showed that TAF6 acts downstream of SETD1A's non-catalytic function, which is essential for GC cell proliferation. Both SETD1A and TAF6 are required for G1/S cell cycle progression in GC cells. The mRNA expression of E2F4 highly correlated with both the SETD1A and TAF6 expression in patients with GC. Notably, E2F4 supported the expression of TAF6 but not that of SETD1A, suggesting that E2F4 serves as a coregulator of SETD1A, which is involved in regulating TAF6. These results demonstrate that the non-canonical roles of SETD1A and its downstream pathways are crucial for cell cycle progression in GC.

DOI： 10.1038/s41419-025-07976-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Histological analysis of kidney biopsies is crucial in diagnosing kidney diseases and predicting clinical outcomes. Recently developed pathology foundation models, pretrained on large-scale pathology datasets, have demonstrated excellent performance in various downstream applications. This study evaluated the utility of pathology foundation models combined with multiple instance learning (MIL) for kidney pathology analysis. METHODS: We used 242 hematoxylin and eosin (H&E)-stained whole slide images (WSIs) from the Kidney Precision Medicine Project (KPMP) and Japan-Pathology Artificial Intelligence Diagnostics Project (JP-AID) databases as the development cohort, comprising 47 healthy controls, 35 acute interstitial nephritis, and 160 diabetic kidney disease (DKD) slides. External validation was performed using 83 WSIs from the University of Tokyo Hospital (UT dataset). Diagnoses were based on adjudicated diagnoses (KPMP) or expert pathologists-derived diagnoses (JP-AID and UT). Pretrained pathology foundation models were utilized as patch encoders and compared with ImageNet-pretrained ResNet50. RESULTS: In internal validation, all foundation models outperformed ResNet50, achieving area under the receiver operating characteristic curve (AUROC) over 0.980. In external validation, the performance of ResNet50 markedly dropped (AUROC = 0.768), whereas all foundation models maintained higher performance (AUROC over 0.800). Visualization with attention heatmaps confirmed that foundation models accurately recognized diagnostically relevant structures. Additionally, foundation models outperformed ResNet50 in predicting severe proteinuria among DKD cases from KPMP dataset. CONCLUSION: We successfully integrated pathology foundation models with MIL to achieve robust diagnostic performance, even when trained on a relatively small dataset, highlighting their potential for real-world clinical applications. Key words: artificial intelligence, renal pathology, foundation model, multiple instance learning.

DOI： 10.1101/2025.06.03.25328845

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

An ileal conduit is the most commonly used urinary diversion following radical cystectomy. Malignancy of the ileal conduit rarely occurs, and Paget disease has not been reported in the peristomal skin of an ileal conduit. Herein, we describe a case of extramammary Paget disease in the peristomal skin of an ileal conduit. A 61-year-old male patient had undergone total pelvic exenteration along with ileostomy and ileal conduit diversion for colorectal cancer 30 years previously. The patient presented with a large skin ulcer around the ileal conduit in his right lower abdomen. The lesion, including the distal end of the ileal conduit, was excised based on a preoperative mapping biopsy, and the skin defect measuring 9 cm × 20 cm around the ileal conduit was simultaneously reconstructed with a pedicled anterolateral thigh flap transfer. The immunohistochemical study of the specimen revealed intraepidermal dysplastic glandular epithelial cells that were positive for CK7 and CK20 but negative for GCDFP15, suggesting that the Paget cells originated from internal malignancy. One year after the surgery, there was no recurrence of the cancer and no evidence of other malignancy. This case showed a rare presentation of secondary extramammary Paget disease in the peristomal skin of the ileal conduit. A pedicled perforator flap transfer was successfully used to immediately reconstruct a large peristomal skin defect after wide local excision.

DOI： 10.1097/GOX.0000000000006793

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: This study evaluates the diagnostic performance of a large language model (LLM) in determining causes of death by comparing three different information sources. METHODS: A total of 150 consecutive adult in-hospital cadavers underwent postmortem CT and pathological autopsy (2009-2013). The diagnostic accuracy of Claude 3.5 Sonnet (Anthropic, San Francisco, California) was evaluated in determining both underlying and immediate causes of death using three different information sources (clinical history alone, postmortem CT findings alone as documented by radiologists in their reports, and their integration). For each case, the LLM provided a primary diagnosis and two differential diagnoses. The autopsy result was used as the reference standard to assess accuracy. RESULTS: For underlying causes, the integration of both sources achieved significantly higher accuracy (78.0%) compared with the clinical history alone (69.3%) or the CT findings alone (42.0%) (p<0.001). When considering either primary or differential diagnoses, the accuracy reached 84.7% with integrated sources, 78.0% with clinical history alone, and 58.7% with CT findings alone. For immediate causes, the integrated approach showed higher accuracy in the primary diagnosis (61.3%) than the clinical history alone (52.0%) and CT findings alone (46.7%) (p<0.001). Disease-specific diagnostic accuracy analyses revealed marked variations, with hematologic malignancies showing the most significant differences among information sources (clinical history: 78.9%, CT findings alone: 36.8%, integrated analysis: 85.7%; p=0.003). CONCLUSION: Integrating postmortem CT findings with clinical history enhances LLM-based cause-of-death determination accuracy, demonstrating the value of multiple information sources while highlighting opportunities for disease-specific diagnostic optimization.

DOI： 10.7759/cureus.83721

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Fibrillary glomerulonephritis (FGN) is a rare form of immune complex-mediated primary glomerular disease frequently coexisting with malignancies or autoimmune diseases. The kidney prognosis is extremely poor, with approximately 50% of patients progressing to end-stage kidney disease within 2-4 years after diagnosis. However, no established treatment currently exists. CASE PRESENTATION: Here we describe a rare case of FGN diagnosed in a patient progressing from monoclonal gammopathy to multiple myeloma. The histopathological findings of the kidney biopsy were consistent with classical FGN and revealed no evidence of myeloma cast nephropathy. Albumin-dominant, Bence Jones protein-negative proteinuria further supported this diagnosis. The patient was successfully treated with anti-myeloma chemotherapies including autologous stem cell transplant, resulting in significant improvement in kidney function. CONCLUSION: Based on our experience, secondary FGN associated with plasma cell neoplasms may represent a rare entity that responds favorably to anti-myeloma therapies. Initial investigations to rule out coexistent plasma cell neoplasms are crucial for the optimal management of FGN patients.

DOI： 10.1159/000545498

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/CIRCHEARTFAILURE.124.012047

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Membranous nephropathy (MN) is a common cause of adult-onset nephrotic syndrome. It is also known as a minor but established renal manifestation of Immunoglobulin G4-related disease (IgG4-RD). Previous reports suggest that MN can also be an initial manifestation of IgG4-RD, all of which are phospholipase A2 receptor (PLA2R)-negative MN. We describe a case of PLA2R-positive MN that subsequently developed other manifestations of IgG4-RD. A 60-year-old male with nephrotic syndrome was diagnosed as primary MN with positive staining for PLA2R on the initial renal biopsy, which remained in partial remission with supportive therapy using angiotensin II receptor blocker (ARB) without steroid. About 1 year later, a renal mass was detected during an annual checkup, and contrast-enhanced computed tomography revealed low-density masses in bilateral kidneys and the head of the pancreas. The findings of endoscopic biopsy of the pancreatic mass were consistent with autoimmune pancreatitis (AIP) and the second renal biopsy showed the findings of MN with tubulointerstitial nephritis, both of which led to a diagnosis of IgG4-RD. The second renal biopsy also showed positive PLA2R. The patient received oral glucocorticoid therapy for IgG4-RD, which improved IgG4-related AIP and renal masses and also resulted in complete remission of MN. To our knowledge, this is the first reported case of PLA2R-positive MN with subsequent development of IgG4-RD. It is sometimes difficult to determine whether PLA2R-positive MN occurring with IgG4-RD is primary MN or secondary MN associated with IgG4-RD. The possibility of developing IgG4-RD should be considered even when preceding MN is PLA2R-positive, suggesting of primary MN.

DOI： 10.1007/s13730-024-00941-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tiopronin is a key drug used to treat cystinuria. A 41-year-old Japanese woman with cystinuria presented with eyelid edema and weight gain after the administration of tiopronin. Her serum albumin was 1.8 g/dL and her urinary protein level was 5.5 g/gCre. After cessation of tiopronin, she achieved remission of nephrotic syndrome (NS). Secondary NS due to tiopronin was evident based on the clinical course and laboratory values. A kidney biopsy showed membranous nephropathy (MN), and an immunofluorescence analysis revealed strong deposition of immunoglobulin G4 (IgG4). However, a previous case report of tiopronin-induced MN showed staining for IgG1 and IgG3. This case report suggests a novel etiology for tiopronin-induced MN.

DOI： 10.2169/internalmedicine.4047-24

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: This study evaluates the diagnostic performance of the latest large language models (LLMs), GPT-4o (OpenAI, San Francisco, CA, USA) and Claude 3 Opus (Anthropic, San Francisco, CA, USA), in determining causes of death from medical histories and postmortem CT findings. METHODS: We included 100 adult cases whose postmortem CT scans were diagnosable for the causes of death using the gold standard of autopsy results. Their medical histories and postmortem CT findings were compiled, and clinical and imaging diagnoses of both the underlying and immediate causes of death, as well as their personal information, were carefully separated from the database to be shown to the LLMs. Both GPT-4o and Claude 3 Opus generated the top three differential diagnoses for each of the underlying or immediate causes of death based on the following three prompts: 1) medical history only; 2) postmortem CT findings only; and 3) both medical history and postmortem CT findings. The diagnostic performance of the LLMs was compared using McNemar's test. RESULTS: For the underlying cause of death, GPT-4o achieved primary diagnostic accuracy rates of 78%, 72%, and 78%, while Claude 3 Opus achieved 72%, 56%, and 75% for prompts 1, 2, and 3, respectively. Including any of the top three differential diagnoses, GPT-4o's accuracy rates were 92%, 90%, and 92%, while Claude 3 Opus's rates were 93%, 69%, and 93% for prompts 1, 2, and 3, respectively. For the immediate cause of death, GPT-4o's primary diagnostic accuracy rates were 55%, 58%, and 62%, while Claude 3 Opus's rates were 60%, 62%, and 63% for prompts 1,2, and 3, respectively. For any of the top three differential diagnoses, GPT-4o's accuracy rates were 88% for prompt 1 and 91% for prompts 2 and 3, whereas Claude 3 Opus's rates were 92% for all three prompts. Significant differences between the models were observed for prompt two in diagnosing the underlying cause of death (p = 0.03 and <0.01 for the primary and top three differential diagnoses, respectively). CONCLUSION: Both GPT-4o and Claude 3 Opus demonstrated relatively high performance in diagnosing both the underlying and immediate causes of death using medical histories and postmortem CT findings.

DOI： 10.7759/cureus.67306

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure. METHODS: Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes. RESULTS: Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction-induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload. CONCLUSIONS: Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure.

DOI： 10.1161/CIRCULATIONAHA.123.064719

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Lymphocytic myocarditis (LM) is primarily triggered by various factors including viral infections and subsequent immune responses. While rare, some patients with LM experience recurrence with a life-threatening fulminant form. Although combining steroids and immunosuppressants, such as azathioprine and mycophenolate mofetil, has demonstrated favourable outcomes in patients with LM, their efficacy is limited to the chronic phase. Indeed, various immunosuppressants have been used for LM with fulminant manifestation; however, their evidence remains lacking. In our case series, two patients with LM experienced fulminant relapses during steroid tapering, and another presented persistent cardiac enzymes elevation despite steroid therapies. Consequently, we initiated calcineurin inhibitors alongside steroids, resulting in well-controlled clinical courses without further recurrence of LM and significant adverse effects. Our cases suggest calcineurin inhibitors as therapeutic options for managing steroid-resistant LM with fulminant relapse.

DOI： 10.1002/ehf2.14896

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Enhancer cis-regulatory elements play critical roles in gene regulation at many stages of cell growth. Enhancers in cancer cells also regulate the transcription of oncogenes. In this study, we performed a comprehensive analysis of long-range chromatin interactions, histone modifications, chromatin accessibility and expression in two gastric cancer (GC) cell lines compared to normal gastric epithelial cells. We found that GC-specific enhancers marked by histone modifications can activate a population of genes, including some oncogenes, by interacting with their proximal promoters. In addition, motif analysis of enhancer-promoter interacting enhancers showed that GC-specific transcription factors are enriched. Among them, we found that MYB is crucial for GC cell growth and activated by the enhancer with an enhancer-promoter loop and TCF7 upregulation. Clinical GC samples showed epigenetic activation of enhancers at the MYB locus and significant upregulation of TCF7 and MYB, regardless of molecular GC subtype and clinicopathological factors. Single-cell RNA sequencing of gastric mucosa with intestinal metaplasia showed high expression of TCF7 and MYB in intestinal stem cells. When we inactivated the loop-forming enhancer at the MYB locus using CRISPR interference (dCas9-KRAB), GC cell growth was significantly inhibited. In conclusion, we identified MYB as an oncogene activated by a loop-forming enhancer and contributing to GC cell growth.

DOI： 10.1093/narcan/zcae020

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Public Library of Science (PLoS)  

High viral titers of infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been detected in human corpses long after death. However, little is known about the kinetics of infectious SARS-CoV-2 in corpses. In this case series study, we investigated the postmortem kinetics of infectious SARS-CoV-2 in human corpses by collecting nasopharyngeal swab samples at multiple time points from six SARS-CoV-2-infected patients after their death. SARS-CoV-2 RNA was detected by quantitative reverse transcription-polymerase chain reaction from nasopharyngeal swab samples collected from all six deceased patients. A viral culture showed the presence of infectious virus in one deceased patient up to 12 days after death. Notably, this patient had a shorter time from symptom onset to death than the other patients, and autopsy samples showed pathological findings consistent with viral replication in the upper respiratory tract. Therefore, this patient died during the viral shedding phase, and the amount of infectious virus in the corpse did not decrease over time up to the date of autopsy (12 days after death). The findings of this study indicate that the persistence of SARS-CoV-2 in corpses can vary among individuals and may be associated with the stage of the disease at the time of death. These important results complement many previously reported findings on the infectivity of SARS-CoV-2 at postmortem.

DOI： 10.1371/journal.pone.0287068

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study aimed to establish the diagnostic criteria for upper gastrointestinal bleeding (UGIB) using postmortem computed tomography (PMCT). This case-control study enrolled 27 consecutive patients with autopsy-proven UGIB and 170 of the 566 patients without UGIB who died in a university hospital in Japan after treatment and underwent both noncontrast PMCT and conventional autopsy between 2009 and 2020. Patients were randomly allocated to two groups: derivation and validation sets. Imaging findings of the upper gastrointestinal contents, including CT values, were recorded and evaluated for their power to diagnose UGIB in the derivation set and validated in the validation set. In the derivation set, the mean CT value of the upper gastrointestinal contents was 48.2 Hounsfield units (HU) and 22.8 HU in cases with and without UGIB. The optimal cutoff CT value for diagnosing UGIB was ≥27.7 HU derived from the receiver operating characteristic curve analysis (sensitivity, 91.7%; specificity, 81.2%; area under the curve, 0.898). In the validation set, the sensitivity and specificity in diagnosing UGIB for the CT cutoff value of ≥27.7 HU were 84.6% and 77.6%, respectively. In addition to the CT value of ≥27.7 HU, PMCT findings of solid-natured gastrointestinal content and intra/peri-content bubbles ≥4 mm, extracted from the derivation set, increased the specificity for UGIB (96.5% and 98.8%, respectively) but decreased the sensitivity (61.5% and 38.5%, respectively) in the validation set. In diagnosing UGIB on noncontrast PMCT, the cutoff CT value of ≥27.7 HU and solid gastrointestinal content were valid and reproducible diagnostic criteria.

DOI： 10.1371/journal.pone.0304993

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The stomach is an important digestive organ with various biological functions. However, because of the complexity of its cellular and glandular composition, its precise cellular biology has yet to be elucidated. In this study, we conducted single-cell RNA sequencing (scRNA-seq) and subcellular-level spatial transcriptomics analysis of the human stomach and constructed the largest dataset to date: a stomach encyclopedia. This dataset consists of approximately 380,000 cells from scRNA-seq and the spatial transcriptome, enabling integrated analyses of transcriptional and spatial information of gastric and metaplastic cells. This analysis identified LEFTY1 as an uncharacterized stem cell marker, which was confirmed through lineage tracing analysis. A wide variety of cell-cell interactions between epithelial and stromal cells, including PDGFRA+BMP4+WNT5A+ fibroblasts, was highlighted in the developmental switch of intestinal metaplasia. Our extensive dataset will function as a fundamental resource in investigations of the stomach, including studies of development, aging, and carcinogenesis.

DOI： 10.1016/j.celrep.2023.113236

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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.ebiom.2023.104844

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Cancer cells evade apoptosis in colorectal cancer (CRC); however, overlap between apoptosis and poor prognosis marker proteins in the invasive front of tumors has not been reported. Here, we aimed to clarify the relationship between apoptosis, apoptosis-related protein expression, and prognosis in the central and invasive front regions of CRC using tissue microarrays. PATIENTS AND METHODS: Data of 207 patients with pathological stage 3 CRC, who underwent radical surgery between October 2010 and November 2014, were retrospectively reviewed. We assessed apoptosis using M30 CytoDEATH, CD163, and p53 immunostaining in tumor sections in the center and invasive front using tissue microarrays and correlated the results with the survival outcomes. RESULTS: M30 CytoDEATH staining was negative; 134 cases (64.7%) were apoptosis-negative in the center and 103 (49.8%) were apoptosis-negative at the invasive front. CD163 positivity was observed in 16 cases (7.8%) in the center and in 36 cases (17.6%) at the invasive front; p53 positivity was observed in 33 (15.9%) and 64 (30.9%) cases in the center and invasive front, respectively. CD163 and p53 expression was not associated with survival outcomes; however, the apoptosis-negative group at the invasive front had significantly poorer survival outcomes (overall survival: p=0.044, relapse-free survival: p=0.001). We identified cases with a poor prognosis by combining apoptosis and CD163 expression. CONCLUSION: A lower apoptosis percentage at the invasive front is associated with a poorer prognosis. CRC cases with a poor prognosis can be identified by evaluating apoptosis and CD163 expression in the invasive front.

DOI： 10.21873/anticanres.16581

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyloidosis is triggered by the truncation of amyloid precursor proteins, causing organ damages. While previous studies found the truncation of amyloid A (AA) and amyloid transthyretin (ATTR) occurs in C- and N-terminal, respectively, the detailed mechanism of the fibril formation remains unclear. Liquid chromatography mass spectrometry is usually applied for a qualitative purpose, and thus quantification of tryptic peptide residue is difficult. We therefore employed a mass spectrometry-based quantification by isotope-labeled cell-free (MS-QBIC) to analyze the truncation processes in amyloid fibrillogenesis of AA and ATTR using the formalin-fixed paraffin-embedded tissues of autopsy cases. In this study, the process of transthyretin from an 'early fibril state' consisting of full-length ATTR to a 'mature ATTR amyloid fibril' with a truncated low-amyloidogenic segment has been mathematically revealed. The amount of full-length ATTR was nine times higher than in mature fibers. Large cohort studies using MS-QBIC may shed light on the clinical significance of amyloid fibrils.

DOI： 10.1007/s00428-023-03591-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Minimally invasive autopsy (MIA) is an alternative to full autopsy for collection of tissue samples from patient's bodies, using an instrument such as a biopsy needle. MIA has been conducted in many cases of coronavirus disease 2019 (COVID-19) and contributed to elucidation of the pathogenesis of the disease. However, most of these cases were hospital deaths, and there are few reports on the application of MIA in out-of-hospital deaths with varying extent of postmortem changes. In this study, MIA and autopsy were both performed in 15 COVID-19 cases 2-30 days after death, including 11 out-of-hospital deaths. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome detection by reverse transcriptase quantitative polymerase chain reaction using MIA samples was mostly consistent with that using autopsy samples, especially for lung tissue, even in out-of-hospital cases. MIA had high sensitivity and specificity (> 0.80). Histological examination of lung tissue obtained by MIA showed characteristics of COVID-19 pneumonia, with 91% agreement with autopsy samples, and localization of SARS-CoV-2 protein in lung tissue was indicated by immunohistochemistry, with 75% agreement. These results suggest that MIA is applicable to out-of-hospital deaths of COVID-19 with a variety of postmortem changes, especially when autopsy is not available.

DOI： 10.7883/yoken.JJID.2023.140

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Postmortem computed tomography (CT) is an essential tool for investigating the causes of death. Postmortem CT has characteristic imaging findings and should not be interpreted in the same manner as clinical antemortem images. In analyzing the cause of death in in-hospital death cases using postmortem images, it is crucial to understand early postmortem and post-resuscitation changes. In addition, it is essential to understand the limitations of diagnosing the cause of death or significant pathology relating to death on non-contrast-enhanced postmortem CT. In Japan, there has also been social demand to establish a system for postmortem imaging at the time of death. To facilitate such a system, clinical radiologists should be prepared to interpret postmortem images and assess the cause of death. This review article provides comprehensive information regarding unenhanced postmortem CT for in-hospital death cases in daily clinical practice in Japan.

DOI： 10.1007/s11604-023-01443-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

An 84-year-old man developed a membranoproliferative glomerulonephritis pattern of injury, and the most likely cause detected during a workup was monoclonal IgG-λ in the urine and serum. Predominant IgG and λ light chain deposition was confirmed only by immunofluorescence using formalin-fixed, paraffin-embedded tissue and not by immunohistochemistry. A smaller and non-linear dynamic range of immunohistochemistry makes it less quantitative than immunofluorescence staining and may explain why immunohistochemistry failed to detect the light chain restriction. This case suggests that immunohistochemistry may not serve as a substitute for immunofluorescence on formalin-fixed, paraffin-embedded tissue in detecting masked monoclonal immunoglobulin deposits, although further research is warranted.

DOI： 10.2169/internalmedicine.1117-22

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The prolonged presence of infectious SARS-CoV-2 in deceased patients with COVID-19 has been reported. However, infectious virus titers have not been determined. Such information is important for public health, death investigation, and handling corpses. The aim of this study was to assess the level of SARS-CoV-2 infectivity in the corpses of patients with COVID-19. METHODS: We collected 11 nasopharyngeal swabs and 19 lung tissue specimens from 11 autopsy cases with COVID-19 in 2021. We then investigated the viral genomic copy number by real-time reverse transcription-polymerase chain reaction and infectious titers by cell culture and virus isolation. RESULTS: Infectious virus was present in six of 11 (55%) cases, four of 11 (36%) nasopharyngeal swabs, and nine of 19 (47%) lung specimens. The virus titers ranged from 6.00E + 01 plaque-forming units/ml to 2.09E + 06 plaque-forming units/g. In all cases in which an infectious virus was found, the time from death to discovery was within 1 day and the longest postmortem interval was 13 days. CONCLUSION: The corpses of patients with COVID-19 may have high titers of infectious virus after a long postmortem interval (up to 13 days). Therefore, appropriate infection control measures must be taken when handling corpses.

DOI： 10.1016/j.ijid.2023.01.046

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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 among the most common malignancies worldwide, characterized by geographical, epidemiological and histological heterogeneity. Here, we report an extensive, multiancestral landscape of driver events in gastric cancer, involving 1,335 cases. Seventy-seven significantly mutated genes (SMGs) were identified, including ARHGAP5 and TRIM49C. We also identified subtype-specific drivers, including PIGR and SOX9, which were enriched in the diffuse subtype of the disease. SMGs also varied according to Epstein-Barr virus infection status and ancestry. Non-protein-truncating CDH1 mutations, which are characterized by in-frame splicing alterations, targeted localized extracellular domains and uniquely occurred in sporadic diffuse-type cases. In patients with gastric cancer with East Asian ancestry, our data suggested a link between alcohol consumption or metabolism and the development of RHOA mutations. Moreover, mutations with potential roles in immune evasion were identified. Overall, these data provide comprehensive insights into the molecular landscape of gastric cancer across various subtypes and ancestries.

DOI： 10.1038/s41588-023-01333-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

During the coronavirus disease 2019 (COVID-19) pandemic, autopsies have provided valuable insights into the pathogenesis of COVID-19. The precise effect of this pandemic on autopsy procedures in Japan, especially in instances unrelated to COVID-19, has not yet been established. Therefore, we conducted a questionnaire survey from December 2020 to January 2021 regarding the status of pathological autopsy practices in Japan during the first year of the COVID-19 pandemic. The questionnaire was sent to 678 medical facilities with pathologists, of which 227 responded. In cases where a confirmed diagnosis of COVID-19 was not made at the time of autopsy, many facilities counted them as suspected COVID-19 cases if pneumonia was suspected clinically. At around half of the sites, autopsies were prohibited for suspected COVID-19 cases. In addition, the number of autopsies of non-COVID-19 cases during the pandemic period was also investigated, and a significant decrease was observed compared with the incidence in the pre-pandemic period. The COVID-19 pandemic has affected not only the autopsies of COVID-19 cases but also the entire practice of pathological autopsies. It is necessary to establish a system that supports the implementation of pathological autopsy practices during the pandemic of an emerging infectious disease.

DOI： 10.1111/pin.13306

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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  

The prognosis of gastric cancer (GC) is significantly affected by distant metastases and postoperative recurrences. Bone metastasis is one of the worst prognostic metastases in GC; however, its molecular mechanisms and predictive biomarkers remain elusive. In prostate and breast cancers, it has been reported that overexpression of Cadherin 11 (CDH11), a mesenchymal cell-cell contact factor, is known to be correlated with bone metastasis. Overexpression of CDH11 mRNA in bulk GC tissues has also been reported to be associated with a worse prognosis. However, a more precise evaluation of CDH11 expression in GC cells is necessary to establish a robust link between CDH11 and metastatic features of GC. We performed immunohistochemical analysis of CDH11 expression in 342 GC cases, of which specimens were obtained at the time of surgery, with a special focus on its aberrant membranous expression in GC cells. The correlations between aberrant CDH11 expression and distant metastases and the prognosis of GC cases were statistically investigated. Approximately half of the GC cases investigated showed aberrant expression of CDH11 in the GC cells of primary lesions. Aberrant CDH11 expression was statistically associated with bone metastasis of GCs. Moreover, metastases to the liver and distant lymph nodes were also statistically correlated with CDH11 expression. Aberrant CDH11 expression in GC cells in primary tumor lesions was shown to be a predictive biomarker of distant metastases in GC. GCs with CDH11 expression require preventive clinical attention for the detection of metastatic lesions.

DOI： 10.1016/j.prp.2022.154294

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Microsatellite instability (MSI) is a major carcinogenic pathway with prognostic and predictive implications. The validity of PCR-based MSI testing is well established in colorectal cancer; however, the data is limited in non-colorectal gastrointestinal cancers. The aim of this study is to clarify the detailed MSI profiles of non-colorectal gastrointestinal cancers and to investigate the differences from those of colorectal cancers. METHODS AND RESULTS: MSI testing was performed using paired tumour/normal tissues of 123 mismatch repair-deficient cancers detected by immunohistochemistry including 80 non-colorectal cancers (8 esophagogastric junction (EGJ), 57 gastric, and 15 small intestine) and 43 colorectal cancers. Fragment size analysis revealed that the mean nucleotide shifts of five markers (Promega panel) were the highest in the stomach (6.4), followed by colorectum (5.7), small intestine (5.0), and EGJ cancers (mean, 4.0; p = 0.015, vs. stomach). All cases showed ≥ 1 nucleotide shift in ≥ 2 markers and were considered as MSI-high. However, when the cutoff was set to ≥ 3 nucleotide shifts in ≥ 2 markers, 3 EGJ (37.5%), 2 small intestine (13.3%), and 2 gastric (3.5%) cancers showed false-negative results. In addition, cases with isolated loss of MSH6 or PMS2 showed smaller nucleotide shifts than those in others. CONCLUSIONS: MSI testing is applicable to non-colorectal gastrointestinal cancers; however, a subset of them can yield false-negative results due to subtle nucleotide shift in multiple markers. Analysis of paired tumour/normal tissues and careful interpretation is necessary to avoid false-negative results and ensure appropriate treatment.

DOI： 10.1111/his.14830

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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  

This study was designed to examine the antemortem factors affecting cerebrospinal fluid (CSF) Hounsfield Units (HU) on postmortem computed tomography (PMCT) compared to the antemortem CT (AMCT). Fifty-five participants without brain lesions who died at a university hospital and underwent AMCT, PMCT, and an autopsy were enrolled. We recorded age, sex, time after death, the CSF HU on AMCT and PMCT at multiple measuring points, 4-point-scale brain atrophy grade on AMCT, and the cella media index. We tested the effects of CSF HU factors observed on PMCT. No significant differences were observed between CSF HUs at any of the PMCT measurement points. The average CSF HU on PMCT was positively correlated with the natural logarithm of the time after death (Pearson's correlation coefficient, 0.81; p < 0.001). No other factors showed correlative relationships. Up until approximately 12 h after death, the CSF HU on PMCT depended only on the time since death.

DOI： 10.1016/j.jflm.2022.102461

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer-derived antibodies exhibited acidic pH-selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.

DOI： 10.1111/cas.15596

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Gastric adenocarcinoma of fundic-gland type (GA-FG) is a gastric malignancy with little relation to Helicobacter pylori. Clinical characteristics of GA-FG have been established, but molecular mechanisms leading to tumorigenesis have not yet been elucidated. METHODS: We subjected three GA-FG tumors-normal mucosa pairs to microarray analysis. Network analysis was performed for the top 30 up-regulated gene transcripts, followed by immunohistochemical staining to confirm the gene expression analysis results. AGS and NUGC4 cells were transfected with the gene-encoding NK2 homeobox 1/thyroid transcription factor 1 (NKX2-1/TTF-1) to evaluate transcriptional changes in its target genes. RESULTS: Comprehensive gene expression analysis identified 1410 up-regulated and 1395 down-regulated gene probes with ≥ two-fold difference in expression. Among the top 30 up-regulated genes in GA-FG, we identified transcription factor NKX2-1/TTF-1, a master regulator of lung/thyroid differentiation, together with surfactant protein B (SFTPB), SFTPC, and secretoglobin family 3A member 2(SCGB3A2), which are regulated by NKX2-1/TTF-1. Immunohistochemical analysis of 16 GA-FG specimens demonstrated significantly higher NKX2-1/TTF-1 and SFTPB levels, as compared to that in adjacent normal mucosa (P < 0.05), while SCGB3A2 levels did not differ (P = 0.341). Transduction of NKX2-1/TTF-1 into AGS and NUGC4 cells induced transactivation of SFTPB and SFTPC, indicating that NKX2-1/TTF-1 can function as normally in gastric cells as it can in the lung cells. CONCLUSIONS: Our first transcriptome analysis of GA-FG indicates significant expression of NKX2-1/TTF1 in GA-FG. Immunohistochemistry and cell biology show ectopic expression and normal transactivation ability of NKX2-1/TTF-1, suggesting that it plays an essential role in GA-FG development.

DOI： 10.1007/s10120-022-01334-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 55-year-old woman showed progressive renal dysfunction after unilateral deceased-donor lung transplantation for lymphangioleiomyomatosis. A kidney biopsy showed a striped pattern of interstitial fibrosis, suggesting calcineurin inhibitor toxicity, and zebra body accumulation was found predominantly in the podocytes, characteristics of Fabry disease. Nevertheless, she had no extra-renal symptoms of the disease, and gene testing identified no known mutation or exon deletion. Our case report and literature review suggest that this atypical lysosomal inclusion may be phospholipidosis induced by sertraline. Potential underlying etiologies linking zebra body deposits may be not only hereditary but also drug-induced phospholipidosis.

DOI： 10.2169/internalmedicine.0882-22

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Infection with certain viruses is an important cause of cancer. The Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium recently analyzed the whole-genome sequencing (WGS) data from 2656 cases across 21 cancer types, and indicated that Epstein-Barr virus (EBV) is detected in many different cancer cases at a higher frequency than previously reported. However, whether EBV-positive cancer cases detected by WGS-based screening correspond to those detected by conventional histopathological techniques is still unclear. In this study, to elucidate the involvement of EBV in various cancers, we reanalyzed the WGS data of the PCAWG cohort combined with the analysis of clinical samples of gastric and pancreatic cancer in our cohort. Based on EBV copy number in each case, we classified tumors into three subgroups: EBV-High, EBV-Low, and EBV-Negative. The EBV-High subgroup was found to be EBV-positive in the cancer cells themselves, whereas the EBV-Low subgroup was EBV-positive in the surrounding lymphocytes. Further, the EBV-Low subgroup showed a significantly worse prognosis for both gastric cancer and across cancer types. In summary, we classified tumors based on EBV copy number and found a unique cancer subgroup, EBV-positive in the surrounding lymphocytes, which was associated with a poor prognosis.

DOI： 10.1002/cam4.4967

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Efficient molecular targeting therapies for most gastric cancers (GCs) are currently lacking, despite GC being one of the most frequent and often devastating malignancies worldwide. Thus, identification of novel therapeutic targets for GC is in high demand. Recent advancements of high-throughput nucleic acid synthesis methods combined with next-generation sequencing (NGS) platforms have made it feasible to conduct functional genomics screening using large-scale pooled lentiviral libraries aimed at discovering novel cancer therapeutic targets. In this study, we performed NGS-based functional genomics screening for human GC cell lines using an originally constructed 6,399 shRNA library targeting all 2,096 human metabolism genes. Our screening identified aspartyl-tRNA synthetase (DARS) as a possible candidate for a therapeutic target for GC. In-house tissue microarrays containing 346 cases of GC combined with public datasets showed that patients with high expression levels of DARS protein exhibited more advanced clinicopathological parameters and a worse prognosis, specifically among diffuse-type GC patients. Both in vitro and in vivo experiments concretely evidenced that DARS inhibition achieved robust growth suppression of GC cells. Moreover, RNA-sequencing of GC cell lines under shRNA-mediated DARS knockdown suggested that DARS inhibition exerts its effect through the inactivation of multiple p-ERK pathways. This MAPK-related growth suppression by DARS inhibition would also be applicable to other cancers; thus, it is warranted to investigate the expression and clinical significance of DARS in a wide spectrum of malignancies. Taken together, NGS-based high-throughput pooled lentiviral screening showed DARS as a novel prognostic marker and a promising therapeutic target for GC. This article is protected by copyright. All rights reserved.

DOI： 10.1002/path.5980

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure.

DOI： 10.1038/s41467-022-30630-y

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出版者・発行元：Cold Spring Harbor Laboratory  

Abstract

The stomach is an important digestive organ with a variety of biological functions. However, due to the complexity of its cellular and glandular composition, the precise cellular biology has yet to be elucidated. In this study, we conducted single-cell RNA sequence analysis of the human stomach and constructed a 137,610-cell dataset, the largest cell atlas reported to date. By integrating this single-cell analysis with spatial cellular distribution analysis, we were able to clarify novel aspects of the developmental and tissue homeostatic ecosystems in the human stomach. We identified LEFTY1+ as a potential stem cell marker in both gastric and intestinal metaplastic glands. We also revealed skewed distribution patterns for PDGFRA+BMP4+WNT5A+ fibroblasts that play pivotal roles in, or even precede, the phenotypic changes from gastric to metaplastic mucosa. Our extensive dataset will function as a fundamental resource in investigations of the stomach, including studies on development, aging, and carcinogenesis.

DOI： 10.1101/2022.05.22.493006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Understanding the tumor microenvironment (TME) and anti-tumor immune responses in gastric cancer are required for precision immune-oncology. Taking advantage of next-generation sequencing technology, the feasibility and reliability of transcriptome-based TME analysis were investigated. TME of 30 surgically resected gastric cancer tissues was analyzed by RNA-Seq, immunohistochemistry (IHC) and flow cytometry (FCM). RNA-Seq of bulk gastric cancer tissues was computationally analyzed to evaluate TME. Computationally analyzed immune cell composition was validated by comparison with cell densities established by IHC and FCM from the same tumor tissue. Immune cell infiltration and cellular function were also validated with IHC and FCM. Cell proliferation and cell death in the tumor as assessed by RNA-Seq and IHC were compared. Computational tools and gene set analysis for quantifying CD8+ T cells, regulatory T cells and B cells, T cell infiltration and functional status, and cell proliferation and cell death status yielded an excellent correlation with IHC and FCM data. Using these validated transcriptome-based analyses, the immunological status of gastric cancer could be classified into immune-rich and immune-poor subtypes. Transcriptome-based TME analysis is feasible and is valuable for further understanding the immunological status of gastric cancer.

DOI： 10.1038/s41598-022-12610-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study assessed the effect of magnifying endoscopy with narrow-band imaging (M-NBI) on the endoscopic differential diagnosis between intramucosal gastric carcinomas and adenomas with matched characteristics. Associations between magnified endoscopic findings and pathological high-grade cellular and architectural atypia were also investigated. In total, the records of 50 adenomas and 50 intramucosal well-differentiated adenocarcinomas matched by tumor size (≥ 20 mm or < 20 mm), shape (depression or non-depression), and color (red or non-red) were extracted. Fourteen endoscopists diagnosed adenoma or cancer in the 100 cases with conventional white light imaging (C-WLI), then did the same with C-WLI + M-NBI.The cancer diagnostic sensitivity, specificity, and accuracy were assessed. The sensitivity of C-WLI + M-NBI for cancer diagnosis was 79.9% compared to 71.6% with C-WLI (p < 0.001). There were no significant differences in specificity (40.1% vs. 36.3%, p = 0.296) and accuracy (55.9% vs. 58.1%, p = 0.163). High-grade cytological or architectural atypia was diagnosed more often with irregular microvascular pattern (IMVP) or microsurface pattern (IMSP), respectively, than the low-grade forms. In conclusion, IMVP and IMSP correlate with high-grade cytological and architectural atypia. M-NBI is useful in differentiating intramucosal carcinoma from adenoma and can reduce underdiagnosis of cancer.

DOI： 10.1038/s41598-022-12315-0

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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.fri.2022.200497

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) without lateral lymph node (LLN) dissection is widely performed for lower advanced rectal cancer. However, it is unclear whether residual cancer cells in the LLNs undergo apoptosis, disappear, or regrow if unresected. METHODS: Overall, 293 consecutive patients with T3/4 rectal cancer who underwent CRT followed by radical surgery between September 2003 and December 2018 were retrospectively reviewed. We assessed apoptosis of the residual primary tumor, mesorectum lymph nodes (MLN), and LLN using M30 cytoDEATH immunostaining and evaluated the degree of apoptosis. The difference in the prognosis of the lateral lymph node metastasis positive (LLNM +) and lateral lymph node metastasis negative (LLNM-) groups was assessed. RESULTS: There were 31 patients (10.6%) who were diagnosed with a complete response by hematoxylin and eosin (HE) staining. The residual cancer cells showed complete apoptosis in the primary lesion in 28 patients, in the metastatic MLN in only two patients, and in the metastatic LLN in one patient. The LLNM + group had a significantly poorer distant recurrence, recurrence-free survival, and overall survival than the LLNM- group. CONCLUSION: The majority of the residual cancer tissue in LNs observed by HE staining was found to be non-apoptotic. If LLN metastasis is suspected on pretreatment imaging, performing LLN dissection together with TME should be considered.

DOI： 10.1007/s00384-021-04085-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Serum amyloid A (SAA) is an acute phase protein, which undergoes structural changes and deposits in the extracellular matrix, causing organ damage. Systemic AA amyloidosis is a relatively common amyloid subtype among the more than 30 amyloid subtypes, but the mechanism of amyloid fibril formation remains unclear. In this study, we investigated the tissue distribution of SAA derived peptides in formalin-fixed paraffin embedded (FFPE) specimens of human myocardium with amyloidosis using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). In the whole SAA protein, four trypsin-digested peptides in the range of SAA2-67 were visualized and the N-terminal peptide; SAA2-15, was selectively localized in the Congo red-positive region. The C-terminal peptides; SAA47-62, SAA48-62, and SAA63-67 were detected not only in the Congo red-positive region but also in the surrounding negative region. Our results demonstrate that the N-terminal SAA2-15 plays a critical role in the formation of AA amyloid fibril, as previously reported. Roles of the C-terminal peptides require further investigation.

DOI： 10.1371/journal.pone.0275993

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Prediction of tissue origin of esophagogastric junction (EGJ) adenocarcinomas can be important for therapeutic decision, but no molecular marker is available. Here, we aimed to develop such a marker taking advantage of tissue-specific profiles of DNA methylation. METHODS: DNA methylation profiles of gastric adenocarcinomas (GACs) were obtained by an Infinium HumanMethylation450 BeadChip array, and those of esophageal adenocarcinoma (EACs) were obtained from the TCGA database. DNA from formalin-fixed paraffin-embedded (FFPE) samples was analyzed by bisulfite pyrosequencing. RESULTS: In the screening set, 51 of 145,841 CpG sites in CpG islands were methylated at significantly higher levels in 30 GACs compared to those in 30 EACs. Among them, SLC46A3 and cg09177106 were unmethylated in all the 30 EACs. Predictive powers of these two markers were successfully confirmed in an independent validation set (18 GACs and 18 EACs) (SLC46A3, sensitivity = 77.8%, specificity = 100%; cg09177106, sensitivity = 83.3%, specificity = 94.4%), and could be applied to FFPE samples (37 GACs and 18 EACs) (SLC46A3, P = 0.0001; cg09177106, P = 0.0028). On the other hand, EAC-specific markers informative in the FFPE samples could not be isolated. Using these GAC-specific markers, nine of 46 (19.6%) TCGA EGJ adenocarcinomas were predicted to be GACs. CONCLUSIONS: Two GAC-specific markers, SLC46A3 and cg09177106, had a high specificity for identifying the tissue origin of EGJ adenocarcinoma.

DOI： 10.1007/s10120-021-01252-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Overlap syndrome refers to a group of conditions that have clinical features of more than one well-characterised rheumatic disease and meet the respective classification criteria. There are no typical renal histological findings in overlap syndrome. When patients with overlap syndrome develop renal dysfunction, various potential causes, including lupus nephritis (LN), renal crisis by systemic sclerosis, interstitial nephritis, and so on, need to be distinguished. Here, we report a 44-year-old woman with overlap syndrome involving systemic lupus erythematosus (SLE), diffuse cutaneous systemic scleroderma, and Sjogren's syndrome, who was also positive for anti-mitochondrial M2 antibody. She developed glomerular haematuria, proteinuria, and increase in creatinine appeared gradually. Suspecting LN, renal biopsy was performed. However, in the interstitium, mild infiltration of lymphocytes and plasma cells and very partial fibrosis were observed. Immunofluorescence microscopy revealed predominant mesangial immunoglobulin M, C3, and λ light chain staining. Overall, LN was not diagnosed based on these findings. Renal dysfunction was normalised by glucocorticoid treatment for 3 months. This case suggests the importance of a renal diagnosis based on renal pathological findings, especially in a case of overlap syndrome including SLE.

DOI： 10.1093/mrcr/rxab017

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記述言語：英語  

Endometrial stromal sarcoma is a rare uterine mesenchymal neoplasm, and extrauterine endometrial stromal sarcoma is even rarer, with a limited number of case reports. In the present report, we present a case of low-grade extrauterine endometrial stromal sarcoma originating from the mesentery in a 49-year-old woman, without endometrial stromal sarcoma in the uterus or evidence of endometriosis. The tumor was diagnosed using recombination of the JAZF1 gene by fluorescence in situ hybridization. Computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose positron emission tomography/computed tomography showed a 13 cm, primarily polycystic, mass containing a contrast-enhancing solid component with restricted diffusion and mild 18F-fluorodeoxyglucose uptake. A large cystic component may be a characteristic feature of extrauterine endometrial stromal sarcoma, given the low pressure from the surrounding tissues.

DOI： 10.1016/j.radcr.2021.06.063

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Schwannomas are neoplasms that typically arise from the myelin sheath of peripheral nerves and rarely originate within the brain parenchyma. Some case reports present schwannomas arising from the brainstem, but regrowth of the tumor and the efficacy of postoperative irradiation have not been examined. In addition, the genetic background of schwannomas arising from the brainstem has not been investigated. CASE PRESENTATION: A 21-year-old male presented with diplopia, dysphagia, and left-sided hemiparesis, dysesthesia, and ataxia. Intracranial imaging showed a heterogeneous mass with a cystic lesion in the pontomedullary junction. Since the tumor caused obstructive hydrocephalus, the patient underwent subtotal tumor resection. A histopathologic evaluation aided a diagnosis of brainstem intraparenchymal schwannoma. Gradual postoperative mass regrowth was recognized. Three-dimensional conformal radiotherapy was performed on the residual mass and surgical cavity. No tumor regrowth was observed 4 years after surgery. To investigate the genetic background of the tumor, target sequences for 36 genes, including NF2, SMARCB1, and LZTR1, and microsatellite analysis for loss of 22q did not show any somatic variants or 22q loss. CONCLUSIONS: We suggest that brainstem schwannomas might differ from conventional schwannomas in their genetic background.

DOI： 10.1186/s12920-021-01049-z

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記述言語：英語  

Postmortem computed tomography (CT) is currently a well-known procedure and helps in postmortem investigations. In this case report, we report a unique postmortem CT finding: delayed cerebral enhancement associated with the antemortem infusion of contrast medium. A 72-year-old female lost consciousness at a restaurant and was taken to a hospital in an ambulance. Despite resuscitation efforts, she died of hypoxic-ischemic encephalopathy caused by cardiac arrest. About 6 h before her death, she underwent enhanced antemortem CT of the head. No abnormal enhancement was observed in the cerebral parenchyma. Then, 11 h after her death, she underwent unenhanced postmortem CT, which showed bilateral hyperdense caudate nucleus and putamina, due to residual iodinated contrast medium, in addition to other characteristic findings of hypoxic-ischemic encephalopathy. The mechanism underlying this phenomenon could be the destruction of the blood-brain barrier, and/or selective vulnerability, due to hypoxic-ischemic changes in the gray matter. Enhancement of basal ganglia on postmortem CT due to antemortem infusion of iodinated contrast medium might suggest hypoxic-ischemic encephalopathy, which should be noted in postmortem CT interpretations.

DOI： 10.1016/j.radcr.2021.04.065

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) had clinical success in the treatment of non-small cell lung carcinoma (NSCLC). An effect of this drug on kidney has not been clarified and the occurrence of glomerulonephritis related to EGFR-TKI has rarely been reported. We present the case of a 71-year-old man with NSCLC who developed proteinuria and microscopic hematuria with the rise in a titer of MPO-ANCA, when 2 years and 3 months passed since the initiation of erlotinib, one of oral EGFR-TKI. Two serial biopsies support that ANCA-associated vasculitis may have been modified by the persistent use of erlotinib. We initiated intravenous pulse therapy with methylprednisolone followed by oral prednisone. The proteinuria has decreased and serum CRP was normalized. However, the serum creatinine level and hematuria did not change during the treatment period. While EGFR inhibition is implicated in protective control for glomerulonephritis, it may exacerbate vasculitis. Close monitoring of the kidney function and urinary findings is required during the use of EGFR inhibitors, such as erlotinib, because it may cause renal adverse events.

DOI： 10.1007/s13730-021-00632-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Streptococcal toxic shock syndrome (STSS) is a severe infection most commonly caused by group A streptococcus. It is clinically characterized by rapidly progressive multiple organ failure and septic shock. This report presents four fatal cases associated with STSS. In two cases (cases 2 and 3), the portals of entry may be ulcer and mucosa at the surgical site; the initial symptoms in these cases included fever. In the other cases, the portal of entry was unknown; the initial symptom was pain. In two cases (cases 1 and 3), malpractice was suspected before autopsy. At autopsy, blood culture was positive for group A streptococcus in all of the present cases. Although C-reactive protein levels were increased, procalcitonin levels were not markedly elevated. This is the first report of autopsy cases associated with STSS in which postmortem computed tomography was performed; the swelling of muscles and increased concentrations of peripheral subcutaneous tissue without gas may be characteristic findings. Histology revealed extensive bacterial colonies and necrosis with mild neutrophilic reaction in two cases (cases 3 and 4), and hemophagocytosis in two cases (cases 1 and 4). It is essential to perform appropriate examinations and make a proper diagnosis because STSS still has a high fatality rate and medical malpractice is often suspected. In addition, it is important to evaluate STSS again for the reduction of the fatal cases associated with STSS.

DOI： 10.1016/j.legalmed.2021.101851

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記述言語：英語  

INTRODUCTION AND IMPORTANCE: Colorectal surveillance via colonoscopy in patients with Lynch syndrome reduces the mortality of colorectal cancer. On the other hand, it is unclear whether surveillance for other malignancies, including small bowel cancer, is beneficial. We report a patient with Lynch syndrome who developed ileal cancer after surgery for ascending colon cancer. CASE PRESENTATION: A 47-year-old man visited our hospital for a check-up for positive fecal occult blood. He was diagnosed with ascending colon cancer and met the clinical criteria for the diagnosis of Lynch syndrome based on his past and family history. The Bethesda markers demonstrated high-frequent microsatellite instability. Laparoscopy-assisted right hemicolectomy was performed. He received follow-up colonoscopy the next year, which revealed ileal cancer near the anastomosis. He underwent resection of the second cancer via a laparoscopic approach, and has been free from recurrence for five years. CLINICAL DISCUSSION: Small bowel cancer has a dismal prognosis because a high percentage of patients were diagnosed at advanced stages. The diagnosis of metachronous ileal cancer by the first follow-up colonoscopy after surgery for ascending colon cancer offered a long disease-free survival in our patient. CONCLUSION: The clinical course suggested the importance of inspecting the small bowel in Lynch syndrome patients, especially when colorectal cancer is diagnosed.

DOI： 10.1016/j.ijscr.2021.105714

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To investigate the changes in ascites attenuation between antemortem (AMCT) and postmortem computed tomography (PMCT) analyses of the same subjects. METHODS: Thirty-five subjects who underwent unenhanced or enhanced AMCT within 7 days before death, unenhanced PMCT, and autopsy were evaluated. In each subject, ascites attenuation was measured at similar sites on AMCT and PMCT. Attenuation changes were evaluated in 42 unenhanced AMCT/PMCT site pairs (23 subjects) and 20 enhanced AMCT/PMCT site pairs (12 subjects). Factors contributing to CT attenuation changes were also assessed, including the time interval between AMCT and PMCT, serum albumin level, estimated glomerular filtration rate, and ascites volume. RESULTS: Significantly elevated CT attenuation was observed between enhanced AMCT and PMCT (12.2 ± 6.3 vs. 18.7 ± 10.4 Hounsfield units; paired t-test, p = 0.006), but not between unenhanced AMCT and PMCT (13.5 ± 8.9 vs. 13.4 ± 9.3; p = 0.554). A significant inverse association was observed between the degree of CT attenuation change and the time interval between enhanced AMCT and PMCT (Spearman's rank correlation coefficient, r = -0.56, p = 0.01). CONCLUSIONS: We confirmed an elevated level of ascites attenuation on PMCT relative to AMCT in subjects who underwent enhanced AMCT shortly before death.

DOI： 10.1016/j.forsciint.2021.110727

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Glisson invasion by CLM is associated with a risk of margin-positive resection, leading to poor long-term outcomes after hepatectomy. This study was performed to evaluate the efficacy of intraoperative ultrasonography (IOUS) for the diagnosis of Glisson's capsule invasion by colorectal liver metastasis (CLM). METHODS: This prospective study involved 50 consecutive patients undergoing hepatectomy for CLM. Preoperatively, all patients had undergone gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI). During hepatectomy, a contrast agent (perflubutane) was intravenously injected and Glisson invasion was estimated based on three characteristic findings: a tumor thrombus, peripheral dilatation, and border irregularity/caliber change. The diagnostic abilities of the preoperative and intraoperative imaging studies were evaluated based on pathological examinations of resected specimens. RESULTS: Among 187 CLMs resected, pathological examinations proved Glisson invasion in 24 tumors (13%). IOUS revealed a tumor thrombus in 3 tumors (1.6%), peripheral dilatation in 4 (2.1%), and border irregularity and/or caliber change in 24 (12.8%). The sensitivity and specificity of IOUS with any of the above three findings for diagnosis of Glisson invasion was 79% and 96%, respectively, while preoperative EOB-MRI detected Glisson invasion in only four tumors (sensitivity/specificity, 17%/100%). The cutoff value of caliber change for diagnosis of Glisson invasion was set at 140% by receiver operating characteristic analysis. The R0 resection rates were not significantly different between patients with (82%) and without (85%) Glisson invasion. CONCLUSIONS: Identification of characteristic findings (tumor thrombus, peripheral dilatation, and border irregularity/caliber change) by contrast-enhanced IOUS is useful for the prediction of Glisson invasion by CLM.

DOI： 10.1007/s00268-020-05883-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is characterized by the infiltration of lymphocytes and a unique tumor microenvironment. Exosomes from cancer cells are essential for intercellular communication. The aims of this study were to investigate the secretion of EBVaGC exosomes and their physiological effect on dendritic cell maturation in vitro and to characterize dendritic cells (DCs) in EBVaGC in vivo. Western blotting analysis of CD63 and CD81 of exosomes from EBV-infected gastric cancer cell lines indicated an increase in exosome secretion. The fraction of monocyte-derived DCs positive for the maturation marker CD86 was significantly suppressed when incubated with exosomes from EBV-infected gastric cancer cell lines. Immunohistochemical analysis of GC tissues expressing DC markers (S100, Langerin, CD1a, CD83, CD86, and BDCA-2) indicated that the density of DCs was generally higher in EBVaGC than in EBV-negative GC, although the numbers of CD83- and CD86-positive DCs were decreased in the group with high numbers of CD1a-positive DCs. A low number of CD83-positive DCs was marginally correlated with worse prognosis of EBVaGC in patients. EBVaGC is a tumor with abundant DCs, including immature and mature DCs. Moreover, the maturation of DCs is suppressed by exosomes from EBV-infected epithelial cells.

DOI： 10.3390/microorganisms8111776

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Despite the accumulating evidences of the significance of humoral cancer immunity, its molecular mechanisms have largely remained elusive. Here we show that B-cell repertoire sequencing of 102 clinical gastric cancers and molecular biological analyses unexpectedly reveal that the major humoral cancer antigens are not case-specific neo-antigens but are rather commonly identified as ribonucleoproteins (RNPs) in the focal adhesion complex. These common antigens are shared as autoantigens with multiple autoimmune diseases, suggesting a direct molecular link between cancer- and auto-immunity on the focal adhesion RNP complex. This complex is partially exposed to the outside of cancer cell surfaces, which directly evokes humoral immunity and enables functional bindings of antibodies to cancer cell surfaces in physiological conditions. These findings shed light on humoral cancer immunity in that it commonly targets cellular components fundamental for cytoskeletal integrity and cell movement, pointing to a novel modality of immunotherapy using humoral immunological reactions to cancers.

DOI： 10.1038/s42003-020-01305-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background Gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI is superior to CT in the detection of colorectal liver metastases (CRLMs) smaller than 10 mm. However, few studies have used MRI findings to predict patients' long-term prognosis. Purpose To investigate the relationship between Gd-EOB-DTPA-enhanced MRI findings in the liver parenchyma peripheral to CRLM and both pathologic vessel invasion and long-term prognosis. Materials and Methods This retrospective study included patients who underwent Gd-EOB-DTPA-enhanced MRI before curative surgery for CRLM, without neoadjuvant chemotherapy, between July 2008 and June 2015. Early enhancement, reduced Gd-EOB-DTPA uptake, and bile duct dilatation peripheral to the CRLM at MRI were evaluated by three abdominal radiologists. All tumor specimens were reevaluated for the presence or absence of portal vein, hepatic vein, and bile duct invasion. Predictors of recurrence-free survival (RFS) and overall survival (OS) after surgery were identified with Cox proportional hazard model with the Bayesian information criterion. Previously reported prognosticators were selected for multivariable analyses. The median follow-up period was 60 months (range, 9-127 months). Results Overall, 106 patients (mean age, 65 years ± 12 [standard deviation]; 68 men) with 148 CRLMs were evaluated. Bile duct dilatation peripheral to the tumor was associated with pathologic portal vein invasion (sensitivity, 12 of 50 [24%]; specificity, 89 of 98 [91%]; P = .02), bile duct invasion (sensitivity, eight of 19 [42%]; specificity, 116 of 129 [90%]; P = .001), poor RFS (P = .03; hazard ratio [HR] = 2.4 [95% confidence interval {CI}: 1.3, 4.2]), and poor OS (P = .01; HR = 2.4 [95% CI: 1.2, 4.9]). For RFS and OS, early enhancement and reduced Gd-EOB-DTPA uptake peripheral to the CRLM were eliminated by means of variable selection in the multivariable analysis, but the combination of these findings with bile duct dilatation provided a predictor of poor OS (P = .001; HR = 3.3 [95% CI: 1.6, 6.8]). Conclusion MRI signal intensity changes peripheral to the colorectal liver metastasis were predictors of long-term prognosis after curative surgery without neoadjuvant chemotherapy. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Bashir in this issue.

DOI： 10.1148/radiol.2020202367

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Esophagectomy with extended lymph node (LN) dissection is a standard treatment for resectable esophageal cancer to prevent recurrence, but severe, potentially life-threatening postoperative complications are still important issues. Accurate diagnosis of LN metastases would enable the decision to dissect or leave the LNs in regions with high risk of complications. Advancements in intraoperative gamma probe and radioactivity detectors have made intraoperative navigation surgery possible using a radiotracer as a marker. F-FDG is one such candidate markers, and the diagnostic power of FDG through counting the radioactivity close to each LN should be elucidated. MATERIALS AND METHODS: In 20 patients, 1073 LNs including 38 metastatic LNs were prospectively investigated. Preoperative FDG PET was performed on the same day before esophagectomy and visually surveyed in each LN station to identify abnormal uptake. The FDG radioactivity of each individual dissected LN was measured by a well-type counter, and the pathological diagnosis was compared with LN radioactivity on a one-by-one basis and with the preoperative FDG PET findings for each LN station. RESULTS: Lymph node station-based analysis showed a sensitivity and specificity of 28.6% and 96.7%, respectively. One-by-one LN-based analysis using a cutoff value obtained from the receiver operating characteristic curve showed a sensitivity and specificity of 94.7% and 78.7%, respectively, demonstrating higher accuracy compared with the use of LN weight or the shortest diameter. CONCLUSIONS: The FDG uptake by each LN is a potentially useful marker for navigation surgery in esophageal cancer and has higher accuracy than LN weight or diameter.

DOI： 10.1097/RLU.0000000000003224

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.fri.2020.200375

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In this study, we compared the postmortem computed tomography (PMCT) findings among nonpathological lungs, lungs with bacterial pneumonia, and lungs with pulmonary edema in patients following non-traumatic in-hospital death. We studied 104 consecutive adult patients (208 lungs) who died in our tertiary care hospital and underwent PMCT and pathological autopsy (both within 2.5 days after death), and were pathologically diagnosed with nonpathological lungs, bacterial pneumonia, and pulmonary edema. Thirteen pulmonary features were assessed on the CT scans. We also examined the association between the time elapsed since death and the pulmonary findings. We observed increased lung opacities with horizontal plane formation, diffuse opacities, diffuse bronchovascular bundle thickening, symmetric opacities to the contralateral lung, and decreased segmental opacities with time elapsed since death (Cochran-Armitage test for trend). Multiple logistic regression revealed that the presence of opacities without horizontal plane formation or centrilobular opacities, and the absence of diffuse bronchovascular bundle thickening were associated with histopathological pneumonia, whereas the presence of opacities with horizontal plane formation, diffuse opacities, and interlobular septal thickening were associated with histopathological pulmonary edema. In conclusion, specific pulmonary PMCT findings increased with time elapsed since death, and some lung findings may facilitate the diagnosis of bacterial pneumonia and pulmonary edema.

DOI： 10.1016/j.legalmed.2020.101716

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To evaluate the utility of unenhanced postmortem computed tomography (PMCT) for the investigation of in-hospital nontraumatic death in children up to 3 years of age.This study included the cadavers of children who died from intrinsic diseases before 3 years of age. The major underlying disease and the main organ-disease systems associated with the immediate causes of death were determined by clinical evaluation, PMCT, and autopsy, which were used as a reference standard. The rates of concordance between the former two methods and autopsy were calculated for all cases.In total, 22 cadavers (12 male and 10 female; mean age, 6.1 ± 8.2 months) were included. The rates of concordance between clinical evaluation/PMCT and autopsy for diagnosis of the major underlying disease and main organ-disease systems associated with the immediate causes of death were 100%/36% (P = .0015) and 59%/41% (P = .37), respectively. In cases where the respiratory system was associated with the immediate cause of death, PMCT showed greater diagnostic sensitivity (90%) than did clinical evaluation (20%). In contrast, the diagnostic sensitivity of PMCT was lower than that of clinical evaluation in cases involving disorders of the cardiac system and multiple organ systems (0% vs 100% for both).The findings of this study suggest that the use of unenhanced PMCT with clinical evaluation can result in improved detection of the immediate cause of death in select cases of in-hospital nontraumatic death before 3 years of age.

DOI： 10.1097/MD.0000000000020130

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Germline and environmental effects on the development of gastric cancers (GC) and their ethnic differences have been poorly understood. Here, we performed genomic-scale trans-ethnic analysis of 531 GCs (319 Asian and 212 non-Asians). There was one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, almost all of which were attributable to alcohol intake behavior, smoking habit, and Asian-specific defective ALDH2 allele. Alcohol-related GCs have low mutation burden and characteristic immunological profiles. In addition, we found frequent (7.4%) germline CDH1 variants among Japanese GCs, most of which were attributed to a few recurrent single-nucleotide variants shared by Japanese and Koreans, suggesting the existence of common ancestral events among East Asians. Specifically, approximately one-fifth of diffuse-type GCs were attributable to the combination of alcohol intake and defective ALDH2 allele or to CDH1 variants. These results revealed uncharacterized impacts of germline variants and lifestyles in the high incidence areas.

DOI： 10.1126/sciadv.aav9778

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Immune checkpoint inhibitors (CPIs), including pembrolizumab, are becoming common oncological treatments. CPIs have been associated with a significant risk of developing immune-related adverse events (irAEs), such as nephritis and interstitial nephritis. However, the occurrence of glomerulonephritis has only rarely been reported. We herein present the case of a 75-year-old woman with non-small cell lung carcinoma (NSCLC) who developed proteinuria and microscopic hematuria during treatment with pembrolizumab. Renal biopsy revealed tubulointerstitial nephritis and IgA nephropathy. Considering that a urinalysis showed no abnormality before treatment, the condition might have been induced by pembrolizumab. In this report, we focus on the correct diagnosis and management of renal irAEs, which remain controversial.

DOI： 10.2169/internalmedicine.3928-19

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記述言語：英語  

• Relative apical sparing of LS is useful for diagnosis of CA. • Amyloid protein was greater in the basal than apical wall in a patient with ATTR-CA. • Differences in amyloid load may contribute to the apical sparing phenomenon.

DOI： 10.1016/j.case.2019.09.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Thirty years have passed since a possible association of Epstein-Barr virus (EBV) with gastric carcinoma was reported. We now know EBV-associated gastric carcinoma to be a specific subtype of gastric carcinoma. Global epigenetic methylation and counteraction of the antitumour microenvironment are two major characteristics of this subtype of gastric carcinoma. Recent development of therapeutic modalities for gastric carcinoma, such as endoscopic mucosal dissection and immune checkpoint inhibitor therapy, has made the presence of EBV infection a biomarker for the treatment of gastric carcinoma. This review presents a portrait of EBV-associated gastric carcinoma from initiation to maturity that we define as the 'gastritis-infection-cancer sequence', followed by its molecular abnormalities and interactions with immune checkpoint molecules and the microenvironment. EBV non-coding RNAs (microRNA and circular RNA) and exosomes derived from EBV-infected cells that were previously behind the scenes are now recognized for their roles in EBV-associated gastric carcinoma. The virus utilizes cellular machinery skilfully to control infected cells and their microenvironment. We should thus strive to understand virus-host interactions more fully in the following years to overcome this virus-driven subtype of gastric carcinoma.

DOI： 10.1007/s00428-019-02724-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The aim of this study was to clarify whether a cancer stem cell marker could be an indicator of post-operative peritoneal recurrence of colon cancer. METHODS: Expression of four putative markers (CD133, CD44 variant 6, aldehyde dehydrogenase-1 and leucine-rich repeating G-protein-coupled receptor-5 (LGR5)) was evaluated immunohistochemically in primary tumour samples from 292 patients who underwent curative resection for non-metastasised pT4 colon cancer at the University of Tokyo Hospital between 1997 and 2015. RESULTS: Peritoneal recurrence was significantly higher in LGR5-negative cases (5-year cumulative incidence: 27.5% vs. 14.4%, p = 0.037). Multivariable analysis confirmed that negative LGR5 expression was an independent risk factor for peritoneal recurrence (hazard ratio (HR) 2.79, p = 0.005) in addition to poor differentiation, positive lymph node metastasis, preoperative carcinoembryonic antigen > 5 ng/mL and anastomotic leakage. The addition of LGR5 significantly improved the predictive value of the multivariable model (net reclassification improvement: 0.186, p = 0.028: integrated discrimination improvement: 0.047, p = 0.008). CONCLUSIONS: Negative LGR5 expression was a significant predictor of peritoneal recurrence in patients with pT4 colon cancer. Therefore, LGR5 might be a promising biomarker to identify patients at high risk of post-operative peritoneal metastasis.

DOI： 10.1038/s41416-019-0442-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We have developed an activatable red fluorescence probe for dipeptidylpeptidase-IV (DPP-IV) by precisely controlling the photoinduced electron transfer (PeT) process of a red fluorescent scaffold, SiR600. The developed probe exhibited an extremely low background signal and showed significant fluorescence activation upon reaction with DPP-IV, enabling sensitive detection of esophageal cancer in clinical specimens from cancer patients.

DOI： 10.1021/acs.bioconjchem.9b00198

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer immunotherapy with immune checkpoint inhibitors (CPIs) and interleukin-2 (IL-2) has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune system activation. Here, we addressed this need by targeting both the CPI antibodies anti-cytotoxic T lymphocyte antigen 4 antibody (αCTLA4) + anti-programmed death ligand 1 antibody (αPD-L1) and the cytokine IL-2 to tumors via conjugation (for the antibodies) or recombinant fusion (for the cytokine) to a collagen-binding domain (CBD) derived from the blood protein von Willebrand factor (VWF) A3 domain, harnessing the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature. We show that intravenously administered CBD protein accumulated mainly in tumors. CBD conjugation or fusion decreases the systemic toxicity of both αCTLA4 + αPD-L1 combination therapy and IL-2, for example, eliminating hepatotoxicity with the CPI molecules and ameliorating pulmonary edema with IL-2. Both CBD-CPI and CBD-IL-2 suppressed tumor growth compared to their unmodified forms in multiple murine cancer models, and both CBD-CPI and CBD-IL-2 increased tumor-infiltrating CD8+ T cells. In an orthotopic breast cancer model, combination treatment with CPI and IL-2 eradicated tumors in 9 of 13 animals with the CBD-modified drugs, whereas it did so in only 1 of 13 animals with the unmodified drugs. Thus, the A3 domain of VWF can be used to improve safety and efficacy of systemically administered tumor drugs with high translational promise.

DOI： 10.1126/scitranslmed.aau3259

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Colorectal cancers with microsatellite instability-high (MSI-H) status, due to mismatch repair deficiency, are associated with poor patient outcomes after relapse. We aimed to identify novel therapeutic targets for them. EXPERIMENTAL DESIGN: We performed MSI analyses of over 2,800 surgically resected colorectal tumors obtained from consecutive patients treated in Japan from 1998 through June 2016. Whole-exome sequencing, transcriptome sequencing, and methylation analyses were performed on 149 of 162 tumors showing MSI in BAT25 and BAT26 loci. We analyzed patient survival times using Bonferroni-adjusted log-rank tests. RESULTS: Sporadic MSI-H colorectal cancers with promoter methylation of MLH1 (called MM) had a clinicopathological profile that was distinct from that of colorectal cancers of patients with germline mutations (Lynch syndrome, LS-associated) or somatic, Lynch-like mutations in mismatch repair genes. MM tumors had more insertions and deletions and more recurrent mutations in BRAF and RNF43 than LS-associated or Lynch-like MSI-H tumors. Eleven fusion kinases were exclusively detected in MM MSI-H colorectal cancers lacking oncogenic KRAS/BRAF missense mutations and were associated with worse post-relapse prognosis. We developed a simple method to identify MM tumors and applied it to a validation cohort of 28 MSI-H colorectal cancers, identifying 16 MM tumors and 2 fusion kinases. CONCLUSIONS: We discovered that fusion kinases are frequently observed among sporadic MM MSI-H colorectal cancers. The new method to identify MM tumors enables us to straightforwardly group MSI-H patients into candidates of LS or fusion kinase carriers.

DOI： 10.1158/1078-0432.CCR-18-1574

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掲載種別：研究論文（学術雑誌）  

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その他リンク： https://dblp.uni-trier.de/db/journals/corr/corr1910.html#abs-1910-04473

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Factors associated with efficacy and safety of cold snare polypectomy (CSP) are not well established. The aim is to elucidate the predictors of R0 resection and immediate bleeding of CSP. METHODS: We retrospectively reviewed a database of patients who underwent CSP for subcentimetric polyps at the University of Tokyo Hospital in Japan. Using the data regarding the characteristics of patients and polyps, such as location, size, and macroscopic appearance; use of narrow band imaging with magnification (NBI-M); and endoscopists' experience, we revealed the predictive factors associated with R0 resection and immediate post-CSP bleeding by univariate and multivariate analyses. RESULTS: In total, 399 polyps, in 200 patients without antithrombotics, were removed. Failure of tissue retrieval was noted in 4% of resected lesions. There was no intramucosal carcinoma observed. The overall rate of R0 resection was 46%. Multivariate analysis elucidated that the observation of the polyp with NBI-M was an independent predictor associated with R0 resection (odds ratio [OR] 1.90; p = 0.024). Although immediate post-CSP bleeding occurred in 19 polyps (4.8%), no delayed bleeding or perforation was observed. Multivariate analysis revealed protruded lesion as an independent risk factor for immediate bleeding (OR 3.54; p = 0.018). CONCLUSIONS: A higher rate of R0 resection with CSP can be achieved by performing colonoscopy with NBI-M, than with white-light imaging. Macroscopic protruding appearance of a polyp is a risk factor for immediate bleeding.

DOI： 10.1371/journal.pone.0213281

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記述言語：英語  

DOI： 10.1007/s00277-018-3286-9

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記述言語：英語  

DOI： 10.1007/s00277-018-3248-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The objective of this study was to investigate the incidence and clinical significance of intratumoral fat deposition in colorectal liver metastases (CLMs) after preoperative chemotherapy using dual-echo gradient-recalled echo MRI. MATERIALS AND METHODS: Our institutional review board approved this retrospective radiographic study and waived the requirement for informed patient consent. Fifty-nine patients (33 men, 26 women; median age, 62 years old) who underwent preoperative MRI and curative hepatic resection for colorectal liver metastases after chemotherapy were selected. Twenty patients also underwent MRI before chemotherapy. On dual-echo gradient-recalled echo MR images, intratumoral fat deposition and fat signal fraction at the densest areas of fat deposition in colorectal liver metastases were evaluated. Predictors of overall survival and intratumoral fat deposition after chemotherapy were identified by multivariate analyses. RESULTS: Before and after chemotherapy, 0 (0%) and 32 (54%) of the patients exhibited intratumoral fat deposition, respectively. Independent predictors of poor overall survival were presence of five or more CLMs (p < 0.001), fat signal fraction of 12% or more (p = 0.01), age of 65 years or older (p = 0.02), and tumor response classified as progressive or stable disease by the Response Evaluation Criteria in Solid Tumors 1.1 (p = 0.049). Predictors of tumor fat signal fraction being 12% or greater after chemotherapy were largest tumor size of 5 cm or more (p = 0.005), tumor calcification (p = 0.008), and history of cetuximab or panitumumab administration (p = 0.04). CONCLUSION: CLMs after preoperative chemotherapy frequently exhibit intratumoral fat deposition.

DOI： 10.2214/AJR.17.18814

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Understanding the genetic background of a tumor is important to better stratify patient prognosis and select optimal treatment. For colorectal liver metastases (CLM), however, clinically available biomarkers remain limited. METHODS: After a comprehensive sequencing of 578 cancer-related genes in 10 patients exhibiting very good/poor responses to chemotherapy, the A5.1 variant of the MICA gene was selected as a potential biomarker for CLM. The clinical relevance of MICA A5.1 was then investigated in 58 patients who underwent CLM resection after chemotherapy. RESULTS: The A5.1 variant was observed in 16 (27.6%) patients examined using direct DNA sequencing, and a very high concordance rate (56/58, 96.6%) for the MICA variant was confirmed between tumor tissues and normal liver parenchyma. A multivariate analysis of 38 patients with no history of treatment with anti-EGFR antibodies confirmed that MICA A5.1 was significantly correlated with an optimal CT morphologic response (OR 11.67; 95% CI 2.08-65.60; p = 0.005) and tended to be correlated with a tumor viability of < 20% after chemotherapy (OR 5.91; 95% CI 0.97-36.02; p = 0.054). MICA A5.1 was also associated with a decreased risk of progression after CLM resection. CONCLUSION: The MICA A5.1 polymorphism was associated with a better CT morphologic response to chemotherapy and a reduced risk of relapse after CLM resection. Given the high concordance rate in MICA variants between normal liver tissue and CLM, the genetic background of the host could be a new biomarker for CLM.

DOI： 10.1159/000490411

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Postmortem computed tomography (PMCT) of the brain has an important role in detection of subarachnoid hemorrhage (SAH), which has a high mortality rate. However, a phenomenon known as "pseudo-SAH," or high-attenuation areas along the cisterns mimicking SAH, may be seen on CT. The aim of this study was to evaluate the diagnostic accuracy of brain PMCT for SAH and to identify the characteristics of pseudo-SAH. Findings on PMCT (sulcal effacement, asymmetry, maximum thickness of SAH signs, presence of acute/subacute intraventricular/intraparenchymal hemorrhage) and clinical history (left ventricular assist device [LVAD] implantation, anticoagulation therapy/coagulation disorder, global ischemia) were compared between subjects with true SAH and those with pseudo-SAH. Twenty eight of 128 enrolled subjects had positive signs of SAH on PMCT, 20 (71.4%) had SAH on autopsy, and 8 (28.6%) did not. The sensitivity, specificity, positive predictive value, and negative predictive value of SAH signs seen on PMCT were 95.2, 94.6, 71.4, and 99.3%, respectively. Asymmetry of SAH signs and acute/subacute intraventricular and intraparenchymal hemorrhage were significantly more common in true SAH cases than in pseudo-SAH cases. The maximum thickness of SAH signs was significantly greater in true SAH cases. A history of LVAD implantation, anticoagulation therapy, and/or a coagulation disorder were more common in true SAH cases but not significantly so. A history of global ischemia was significantly more common in pseudo-SAH cases. If signs of SAH are observed on PMCT, it is important to look for other signs on PMCT and carefully review the clinical history to avoid a diagnostic error.

DOI： 10.1007/s00414-017-1651-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Adenocarcinoma with lepidic growth pattern presents as a ground glass nodule (GGN) on high resolution computed tomography (CT), whereas peripheral pulmonary squamous cell carcinoma (SCC) usually presents as a solid nodule. We herein report a rare case of pulmonary SCC extending along the alveolar lumen representing as a GGN on a CT scan in a patient with pneumoconiosis. CASE PRESENTATION: A 77-year-old man with pneumoconiosis was found to have a gradually enlarging GGN in the right lower lobe of the lung on CT. An adenocarcinoma of the lung was suspected. The GGN was successfully resected by thoracoscopic segmentectomy. Pathological examination of the resected specimen was pathologically diagnosed as a stage IA SCC extending along the alveolar lumen. The patient had no evidence of recurrence 19 months after surgery. CONCLUSIONS: SCC should be included in the differential diagnosis of peripherally located GGNs, especially in patients at high risk of SCC of the lung such as those with pneumoconiosis.

DOI： 10.1186/s40792-017-0384-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A potentially favorable effect of chemotherapy on the incidence of micrometastases has been reported in patients with colorectal liver metastases (CLMs); however, the actual influence of chemotherapy on the distribution of micrometastases and surgical curability remains unclear. METHOD: The clinical impact of preoperative chemotherapy on the incidence and distribution of micrometastases was assessed in 191 patients with 357 CLM nodules. Potential radiologic measures for predicting the extent of microscopic cancer spread and surgical curability were then sought among the size-based and non-size-based radiologic response criteria. RESULTS: Multivariate analysis estimated a reduced incidence of micrometastases in patients receiving preoperative chemotherapy (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.26-0.76, p = 0.003). Furthermore, the addition of biologic agents to the preoperative chemotherapy regimen was correlated with a reduced incidence of microscopic cancer spread beyond a width of 1 mm from the margin of the main tumor (OR 0.28, 95% CI 0.11-0.74, p = 0.010 for bevacizumab; and OR 0.29, 95% CI 0.09-0.99, p = 0.048 for anti-epidermal growth factor receptor antibody). Receiver operating characteristic analyses revealed that the computed tomography (CT) morphologic response showed a moderate predictive power for the distribution of micrometastases, with an area under the curve of 0.687, while size-based response criteria were not reliable for estimating the extent of microscopic cancer spread. CONCLUSION: Notwithstanding the potential selection of patients after preoperative chemotherapy, the incidence and distribution of micrometastases may be reduced by preoperative chemotherapy. CT morphologic response may be a reliable predictor of both the degree of microscopic cancer spread and the curability of surgery.

DOI： 10.1245/s10434-017-5845-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A primitive cell-like gene expression signature is associated with aggressive phenotypes of various cancers. We assessed the expression of phenotypic markers characterizing primitive cells and its correlation with clinicopathologic and molecular characteristics in gastric cancer. Immunohistochemical analysis of a panel of primitive phenotypic markers, including embryonic stem cell markers (OCT4, NANOG, SALL4, CLDN6, and LIN28) and known oncofetal proteins (AFP and GPC3), was performed using tissue microarray on 386 gastric cancers. On the basis of the expression profiles, the 386 tumors were clustered into 3 groups: group 1 (primitive phenotype, n=93): AFP, CLDN6, GPC3, or diffuse SALL4 positive; group 2 (SALL4-focal, n=56): only focal SALL4 positive; and group 3 (negative, n=237): all markers negative. Groups 1 and 2 predominantly consisted of intestinal-type adenocarcinoma, including 13 fetal gut-like adenocarcinomas exclusively in group 1. Group 1 was significantly associated with higher T-stage, presence of vascular invasion and nodal metastasis when compared with groups 2 and 3. Group 1 was associated with patients' poor prognosis and was an independent risk factor for disease-free survival. Group 1 showed frequent TP53 overexpression and little association with Epstein-Barr virus or mismatch repair deficiency. Further analysis of the Cancer Genome Atlas data set validated our observations and revealed that tumors with primitive phenotypes were mostly classified as "chromosomal instability" in the Cancer Genome Atlas' molecular classification. We identified gastric cancer with primitive enterocyte phenotypes as an aggressive subgroup of intestinal-type/chromosomal instability gastric cancer. Therapeutic strategies targeting primitive markers, such as GPC3, CLDN6, and SALL4, are highly promising.

DOI： 10.1097/PAS.0000000000000869

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Radiation-associated colon cancer is a rare clinical entity. We herein describe the case of a patient with radiation-associated colon cancer who had undergone low anterior resection for rectal cancer following preoperative radiotherapy. Certain characteristics of radiation-associated colon cancer are highlighted. The patient was a 48-year-old man who had undergone low anterior resection for rectal cancer following preoperative radiotherapy at a total dose of 50 Gy, at the age of 29 years. When the patient presented at the University of Tokyo Hospital, 19 years after the surgery, he complained of severe anal pain and frequent defecation. Colonoscopy revealed two flat tumors in the sigmoid colon, located 10 cm to the oral side of the anastomosis site, which were diagnosed as well-differentiated adenocarcinomas. In addition, colonoscopy identified five flat polyps near the tumors, which were resected endoscopically. Computed tomography and magnetic resonance imaging revealed a mass in the sigmoid colon and no evidence of distant metastasis. Laparoscopic-assisted intersphincteric resection of the rectum and sigmoid colon with diverting ileostomy was performed. There were no specific postoperative complications and the patient was discharged from the hospital on the 20th postoperative day. On pathological examination, the resected rectum and sigmoid colon contained two separate tumors and six flat polyps. The two tumors were diagnosed as well-differentiated adenocarcinomas with invasion of the subserosa and submucosa, respectively. A total of 17 regional lymph nodes without metastasis were resected. The six flat polyps were diagnosed as tubular adenomas. We herein present a case of a radiation-associated colon cancer in a patient who had undergone low anterior resection for rectal cancer following preoperative radiotherapy 19 years prior. Colonoscopic surveillance of radiation-associated colon cancer may be indicated for rectal cancer patients treated with preoperative radiotherapy, particularly for those with long-standing radiation-induced colitis.

DOI： 10.3892/mco.2017.1252

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

As postmortem imaging has gained prominence as a supplement to traditional autopsy, it is important to understand the normal postmortem changes to enable the accurate evaluation of postmortem imaging. No studies have evaluated the postmortem changes in cardiothoracic ratio (CTR) compared with antemortem images in the same subjects. We studied 147 consecutive subjects who underwent antemortem and postmortem CT, and autopsy. Postmortem CT was performed <23h after death and was followed by autopsy. The subjects were divided into three groups: normal heart, old myocardial infarction, and CPR-treated hearts. CTR was compared between antemortem and postmortem CT using paired t tests, which revealed that the CTR was greater on postmortem CT than on antemortem CT in all groups (mean CTR: 0.53±0.06vs. 0.50±0.06, respectively; P<0.01). Sex, age, time elapsed since death, and the causes of death were examined as potential confounding factors for the postmortem changes in CTR, but no significant associations were found. Receiver-operating characteristic (ROC) curves were used to determine CTR values for cardiomegaly, which was defined according to the autopsy weight of the heart. The area under the ROC curve was 0.71 (95% confidence interval 0.63-0.79). The CTR threshold of 0.54 identified cardiomegaly with the greatest accuracy, compared with the general threshold of 0.50. In conclusion, the CT-determined CTR increases after death, irrespective of the heart's condition. We should be cautious of overdiagnosis of cardiomegaly on postmortem CT, and new criteria for interpreting cardiomegaly on postmortem CTR are needed.

DOI： 10.1016/j.legalmed.2016.12.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We present the first ever report on a colonic mucocele observed at the distal stump of a transverse loop colostomy caused by neoplasia. A 37-year-old female consulted us because of abdominal pain and vomiting caused by cystic lesions in the upper left abdominal quadrant. A preoperative checkup revealed no sign of neoplastic lesions; however, tumor resection was performed because of the symptoms. The tumor was a mucocele of the distal stump of the transverse colon with obstruction interposed between the mucocele and stoma. Pathological diagnosis was low-grade adenoma; however, it appeared like low-grade mucinous neoplasia of the appendix rather than a normal colonic adenoma. The neoplasia existed in the transitional segment between obstruction and dilatation. As this is the first case of colonic mucocele caused by mucinous neoplasia, no definite consensus for diagnosis and treatment exists. With reference to low-grade mucinous neoplasia, we propose that complete surgical resection be performed for diagnosis and a favorable outcome.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients with gastric cancer typically face gastrectomies even when few or no nodal metastases are reported. Current procedures poorly predict lymphatic metastases; thus, evaluation of target molecules expressed on cancer cell membranes is necessary for in vivo detection. However, marker development is limited by the intratumoral heterogeneity of gastric cancer cells. In this study, multiple gene expression arrays of 42 systemic normal tissue samples and 56 gastric cancer samples were used to investigate two adhesion molecules, cadherin 17 (CDH17) and claudin 18 (CLDN18), which are intestinal and gastric markers, respectively. Expression of CDH17 and CLDN18 was partially redundant, but overlapped in 50 of 56 cases (89.3%). Tissue microarrays constructed using primary lesions and nodal metastases of 106 advanced gastric cancers revealed CDH17 and CLDN18 expression in 98 positive cases of 106 (92%). Hierarchical clustering classified gastric cancers into three subgroups, CDH17(++)/CLDN18(+/-), CDH17(++)/CLDN18(++) or CDH17(+)/CLDN18(+), and CDH17(-)/CLDN18(++/+/-). Whole tissue sections displayed strong, homogeneous staining for CDH17 and CLDN18. Together, these results indicate that CDH17 and CLDN18 are useful target molecules; moreover, their coupling can aid in the comprehensive detection and localization of gastric cancer metastases in vivo to overcome challenges associated with intratumoral heterogeneity.

DOI： 10.18632/oncotarget.11638

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The purpose of this study was to evaluate the usefulness of brain postmortem computed tomography (PMCT) findings for the detection of global hypoxia or hypoperfusion leading to hypoxic-ischemic encephalopathy (HIE) prior to death. Cadavers of individuals who died from non-traumatic causes were subjected to PMCT and pathological autopsy. Cases with an episode of cardiopulmonary arrest, hypoxia, or hypoperfusion that required intensive respiratory management at least 24 h before death and exhibited findings of HIE in conventional autopsy (HIE group, n = 6) were compared with those without such episodes prior to death (control group; overall, n = 37; age-matched, n = 8) with regard to four parameters: (1) width of the central sulcus (CS), (2) attenuation difference at the basal ganglia (BG) level, (3) attenuation difference between cerebral gray matter (GM) and cerebral white matter (WM), and (4) attenuation difference between cerebellar GM and cerebral GM. The results revealed significant differences in the width of the CS (P < 0.001), attenuation difference at the BG level (P < 0.001), and attenuation difference between cerebral GM and cerebral WM (P = 0.009) between the HIE group and the overall control group. When the age-matched control group and the HIE group were compared, there was a significant difference in the width of the CS (P = 0.026) and attenuation difference at the BG level (P < 0.001). Our results suggest that effacement of the sulcus of the cerebral hemisphere and the loss of contrast at the BG level on brain PMCT indicate the existence of HIE prior to death.

DOI： 10.1007/s12024-016-9787-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare idiopathic disorder that occurs in women of childbearing age, and consists of a diffuse proliferation of abnormal smooth muscle cells along the thoracic and abdominal lymphogenous route. CASE PRESENTATION: We experienced a case of a 47-yo woman with recent history of systemic lupus erythematosus (SLE) diagnosed with endometrial cancer, initially suspected to have metastasized to pelvic and para-aortic lymph nodes based on preoperative diagnostic imaging. Subsequent pathological diagnosis revealed stage IB endometrial cancer without evidence of lymph node involvement. Instead, enlarged pelvic and para-aortic lymph nodes were found to be due to extrapulmonary LAM, from a primary lesion found inside the uterine myometrium. SLE improved after surgery. CONCLUSION: This is the first reported case of comorbid endometrial cancer, SLE, and aggressive LAM metastasizing to regional lymph nodes, and strengthens the clinical evidence for a common role of mTOR pathway hyperactivity and estrogen responsiveness in the pathophysiology of metastasizing lesions of the genital tract.

DOI： 10.1186/s12885-016-2413-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The purpose of this study is to compare the postmortem changes in computed tomography (CT) findings between normal spleen, splenic infarct, and splenic tumor infiltration. METHODS: The institutional review board approved this study, and informed consent was obtained from the next of kin. We studied 63 consecutive subjects who underwent antemortem CT, postmortem CT, and autopsy between February 2012 and December 2013. Postmortem CT was performed within 1678 min after death and was followed by pathological studies. The subjects were divided into three groups based on the pathological findings: normal, splenic infarct, and splenic tumor infiltration. The volume and attenuation of the spleen were compared between antemortem and postmortem CT using paired t tests. Gender, age, time elapsed since death, and the causes of death were examined as potential confounding factors of the postmortem changes in volume and attenuation. RESULTS: In all groups, the spleen decreased in volume and attenuation increased on postmortem CT compared with antemortem CT. The postmortem changes in spleen volume and attenuation were not significantly associated with sex, age, time elapsed since death, or causes of death. CONCLUSIONS: Spleen volume decreased and attenuation increased on postmortem CT compared with antemortem CT in subjects with a normal spleen, splenic infarct, or splenic tumor infiltration. These results should caution us against underestimating the significance of splenomegaly on postmortem CT, misinterpreting reduced splenic volume as the presence of hypovolemic or distributive shock in the subject while alive, and confusing postmortem splenic hyperattenuation with diseases characterized by this finding.

DOI： 10.1007/s00414-016-1337-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Early detection of esophageal squamous cell carcinoma (ESCC) is an important prognosticator, but is difficult to achieve by conventional endoscopy. Conventional lugol chromoendoscopy and equipment-based image-enhanced endoscopy, such as narrow-band imaging (NBI), have various practical limitations. Since fluorescence-based visualization is considered a promising approach, we aimed to develop an activatable fluorescence probe to visualize ESCCs. First, based on the fact that various aminopeptidase activities are elevated in cancer, we screened freshly resected specimens from patients with a series of aminopeptidase-activatable fluorescence probes. The results indicated that dipeptidylpeptidase IV (DPP-IV) is specifically activated in ESCCs, and would be a suitable molecular target for detection of esophageal cancer. Therefore, we designed, synthesized and characterized a series of DPP-IV-activatable fluorescence probes. When the selected probe was topically sprayed onto endoscopic submucosal dissection (ESD) or surgical specimens, tumors were visualized within 5 min, and when the probe was sprayed on biopsy samples, the sensitivity, specificity and accuracy reached 96.9%, 85.7% and 90.5%. We believe that DPP-IV-targeted activatable fluorescence probes are practically translatable as convenient tools for clinical application to enable rapid and accurate diagnosis of early esophageal cancer during endoscopic or surgical procedures.

DOI： 10.1038/srep26399

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: CD133 is a transmembrane protein that is proposed to be a stem cell marker of colorectal cancer (CRC); however, the correlation between CD133 expression and survival of CRC patients with liver metastasis has not been fully examined. METHODS: CD133 expression was evaluated immunohistochemically, both in primary tumors and synchronous liver metastases of 88 consecutive CRC patients, as well as recurrent lesions in the remnant liver of 27 of these 88 patients. The relationship between CD133 expression and clinicopathological characteristics, recurrence-free survival, and overall survival (OS) was analyzed. RESULTS: CD133 expression in liver metastases (mCD133) was detected in 50 of 88 patients (56.8 %), and had significant correlation with CD133 expression in primary lesions (pCD133) (p < 0.001). CD133 expression in liver recurrent lesions (recCD133) also had a significant correlation with mCD133 (p < 0.001). mCD133+ patients had significantly longer disease-free survival (p = 0.043) and OS (p = 0.014) than mCD133- patients. In addition, mCD133+ patients had a significantly lower rate of extrahepatic recurrence (p < 0.001). CONCLUSIONS: Patients without CD133 expression in liver metastasis had significantly shorter survival, perhaps because mCD133- patients had a significantly higher rate of extrahepatic recurrence.

DOI： 10.1245/s10434-016-5099-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high-methylation CRC. The methylation levels of six Group-1 and 14 Group-2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group-1 and Group-2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high-methylation CRC. But TSA showed low-methylation levels of Group-1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high-methylation CRC. High-methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p < 0.0001) and insertion/deletions (p = 0.002). MLH1-methylated SSA/P showed lower methylation level of MLH1 compared with high-methylation CRC, and rarely accompanied silencing of MLH1 expression. The mutation frequencies were not different between MLH1-methylated and MLH1-unmethylated SSA/P, suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype. Mutations of mismatch repair genes, e.g., MSH3 and MSH6, and genes in PI3K, WNT, TGF-β and BMP signaling (but not in TP53 signaling) were significantly involved in high-methylation CRC compared with adenoma, suggesting importance of abrogation of these genes in serrated pathway.

DOI： 10.1002/ijc.29903

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Gastric cancer exhibits various degrees of fluorine F-18 fluorodeoxyglucose ((18)F-FDG) uptake on positron emission tomography/computed tomography (PET/CT). We evaluated the relationship between (18)F-FDG uptake and the presence/absence of metastasis in individual lymph nodes (LN) on a one-to-one basis. METHODS: We analyzed 21 patients with gastric cancer. We injected (18)F-FDG intravenously in the morning, and gastrectomy with LN dissection was performed in the afternoon of the same day. Radiation doses were measured at each LN using a well-type counter, and we then compared (18)F-FDG uptake, the shortest diameter, and pathological examination results for each LN. RESULTS: In our study, 906 LNs were analyzed, including 115 metastatic LNs. Metastatic LNs showed significantly higher (18)F-FDG uptake (P < 0.0001), and were significantly enlarged (P < 0.0001). The receiver operating characteristics (ROC) curve had a larger area under the curve (0.71) for (18)F-FDG uptake than for the shortest LN diameter (0.60). Considering histology, the ROC curve for intestinal type adenocarcinoma had a larger area under the curve than that for diffuse type (0.75 vs 0.61). CONCLUSIONS: F-FDG uptake is potentially a more useful variable than LN diameter for discriminating between LN with and without metastasis, especially in intestinal type gastric cancer cases.

DOI： 10.1186/s12957-015-0743-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The computed tomography (CT) morphology after chemotherapy is reportedly correlated with the histopathologic response to chemotherapy and a better surgical outcome in patients with colorectal liver metastases (CLM). However, the true prognostic advantage of CT morphology remains uncertain. METHODS: The prognostic advantage of CT morphology was validated in 86 patients who underwent surgical resection for CLM after undergoing a 5-fluorouracil-based chemotherapy regimen with or without bevacizumab. RESULTS: An optimal morphologic response was observed in 18 (22.8%) patients, and a strong correlation between the CT morphology and tumor viability was confirmed (P < 0.001). A multivariate analysis revealed that bevacizumab (odds ratio [OR], 6.8; P = 0.03) and chemotherapy cycles ≥6 (OR, 3.6; P = 0.04) were associated with an optimal morphologic response. Overall survival (OS) and recurrence-free survival (RFS) were also predicted by CT morphology with a higher sensitivity. Particularly, a group 1 morphology was associated with a higher OS rate (3-year OS 100%) and RFS rate (3-year RFS, 57.0%), and a multivariate analysis confirmed that group 2 and group 3 tumor morphology was a significant predictive factor for tumor recurrence (hazard ratio [HR], 2.5; P = 0.03 and HR, 3.2; P < 0.01, respectively). CONCLUSION: The CT morphology of CLM predicts tumor viability and long-term surgical outcomes after chemotherapy.

DOI： 10.1007/s11605-015-2836-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3348/kjr.2015.16.4.798

Web of Science

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We aimed to confirm whether postmortem adrenal volumetric changes occur by measuring adrenal volumes on computed tomography (CT). Fifty-five adrenal glands from 28 subjects who died were included. All subjects underwent antemortem CT (AMCT) and postmortem CT (PMCT) within 94-1,191 min after death, followed by conventional autopsy. CT volumetry was performed using freely-available software. Differences between AMCT and PMCT adrenal volumes were evaluated statistically along with differences in the degree of volume change, elapsed time to PMCT, and presence of underlying malignant disease. The mean volume of the right adrenal gland decreased from 3.8 cm(3) on AMCT to 2.6 cm(3) on PMCT (P < 0.001); the left adrenal gland decreased from 4.2 cm(3) on AMCT to 3.1 cm(3) on PMCT (P < 0.001). Conventional autopsy revealed decreased intracellular lipid components in portions of the adrenal glands. No correlation between the adrenal gland reduction rate and the elapsed time from AMCT to death or from death to PMCT was observed (P = 0.99 and 0.79; P = 0.28 and 0.59 for the right and left adrenal glands, respectively). Significant differences in both the bilateral adrenal gland reduction rates and underlying malignant disease were found for the left adrenal gland (P = 0.015), but not for the right (P = 0.74). Adrenal volume reduction was observed on PMCT compared to AMCT. This highlights the need to further elucidate the mechanism of adrenal shrinkage during the agonal stage and after death. This may be explained by pathological findings of intracellular lipid depletion.

DOI： 10.1007/s11547-014-0449-1

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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.clbc.2014.10.008

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記述言語：英語  

DOI： 10.1007/s00277-014-2202-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The purpose of this study was to evaluate the brain by postmortem computed tomography (PMCT) versus antemortem computed tomography (AMCT) using brains from the same patients. We studied 36 nontraumatic subjects who underwent AMCT, PMCT, and pathological autopsy in our hospital between April 2009 and December 2013. PMCT was performed within 20 h after death, followed by pathological autopsy including the brain. Autopsy confirmed the absence of intracranial disorders that might be related to the cause of death or might affect measurements in our study. Width of the third ventricle, width of the central sulcus, and attenuation in gray matter (GM) and white matter (WM) from the same area of the basal ganglia, centrum semiovale, and high convexity were statistically compared between AMCT and PMCT. Both the width of the third ventricle and the central sulcus were significantly shorter in PMCT than in AMCT (P < 0.0001). GM attenuation increased after death at the level of the centrum semiovale and high convexity, but the differences were not statistically significant considering the differences in attenuation among the different computed tomography scanners. WM attenuation significantly increased after death at all levels (P<0.0001). The differences were larger than the differences in scanners. GM/WM ratio of attenuation was significantly lower by PMCT than by AMCT at all levels (P<0.0001). PMCT showed an increase in WM attenuation, loss of GM-WM differentiation, and brain swelling, evidenced by a decrease in the size of ventricles and sulci.

DOI： 10.1371/journal.pone.0143848

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary hypertension (PH) induced by pulmonary tumor thrombotic microangiopathy (PTTM) can be fatal because its rapid progression confounds diagnosis, and it is difficult to control with therapy. Here we describe a woman with symptomatic PTTM-PH accompanying gastric cancer that was suspected from perfusion scintigraphy. PTTM-PH was diagnosed by gastroesophageal endoscopy and lung biopsy after partial control of PH using the platelet-derived growth factor (PDGF) receptor (PDGFR) tyrosine kinase inhibitor, imatinib. Treatment with sildenafil and ambrisentan further decreased PH, and she underwent total gastrectomy followed by adjuvant TS-1 chemotherapy. PH did not recur before her death from metastasis. Postmortem histopathology showed recanalized pulmonary arteries where the embolized cancer masses disappeared. PDGF-A, -B, and PDGFR-α, β expression was detected in cancer cells and proliferating pulmonary vascular endothelial cells. Thus, PTTM-PH was successfully controlled using a combination of imatinib, drugs to treat pulmonary arterial hypertension, and cancer management.

DOI： 10.1536/ihj.14-220

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To evaluate radiographic features of endotracheal/endobronchial fluid in the airway (FA) observed on postmortem computed tomography (PMCT). We studied 164 subjects who died at our hospital between April 2009 and September 2012. Fluid in the airway was considered positive when fluid was identified in the lumen of 1 of the 2 main bronchi in continuity with a segmental bronchus. Pleural effusion and atelectasis/consolidation of the lung lower lobes were also evaluated. Fluid in the airway was observed in 60 (71%) of 84 subjects with unilateral or bilateral pleural effusion, and in 44 (55%) of 80 subjects without pleural effusion (P = 0.029). Of the latter, 41 (93%) had atelectasis/consolidation of the lower lung lobes. Among subjects without pleural effusion, average times after death to PMCT of subjects with and without FA were 501 and 314 minutes, respectively (P = 0.01). Time-course analysis showed that cases with FA on PMCT largely correlated with time after death (R = 0.7966). Fluid in the airway is frequently observed on PMCT in subjects with pleural effusion or atelectasis/consolidation of the lung. No FA in subjects without pleural effusion correlated to shorter times after death. In addition, FA frequency on PMCT increased over time after death.

DOI： 10.1097/PAF.0000000000000083

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: We evaluated the postmortem changes of striated muscle by comparing computed tomography (CT) images obtained postmortem and antemortem in the same patients. MATERIALS AND METHODS: We studied 33 consecutive patients who underwent antemortem CT, postmortem CT, and pathological autopsy in our tertiary care hospital between April 2009 and December 2010. Postmortem CT was performed within 20 h after death and was followed by pathological autopsy. Pathological autopsy confirmed the absence of muscular diseases such as amyotrophic lateral sclerosis, muscular dystrophy, myositis, and myasthenia, in all of the patients. The CT attenuation values of four cardiac muscle sites (anterior wall of the left ventricle, left ventricular free wall, posterior wall of the left ventricle, and the ventricular septum) and two skeletal muscle sites (the pectoralis major muscle and the erector spinae muscle) were compared between antemortem and postmortem CT using paired t test. RESULTS: Striated muscle had significantly greater attenuation on postmortem CT than on antemortem CT (P<0.001) in all six tissue sites. No significant association was found between postmortem change in the CT attenuation of striated muscle and gender, age, or elapsed time since death. CONCLUSION: This is the first longitudinal study to show hyperattenuation of striated muscle on postmortem CT images compared with antemortem CT images in the same patients.

DOI： 10.1371/journal.pone.0111457

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

It has been suggested that ubiquitin-conjugating enzyme E2C (UBE2C, also known as UBCH10) represents a promising cancer biomarker. However, the clinicopathological or prognostic significance as well as the functions of UBE2C in bladder cancer are largely unknown. To investigate the significance of UBE2C expression in bladder cancer, immunohistochemical analysis was performed using a tissue microarray. UBE2C positivity was observed in 51 of 82 (62%) bladder urothelial carcinoma cases treated with radical cystectomy. In contrast, UBE2C was negative in all of the non-neoplastic urothelium examined. UBE2C positivity was significantly associated with higher tumor stage (p=0.0061) and presence of lymphovascular invasion (p=0.0045). In addition, UBE2C positivity was significantly associated with shorter cancer-specific survival after cystectomy (log rank p=0.0017; multivariate hazard ratio, 2.49; 95% confidence interval, 1.09-5.71). Small interfering RNA-mediated suppression of UBE2C in UM-UC-3 bladder cancer cells inhibited cell proliferation in vitro. Taken together, our results suggest that UBE2C is a novel prognostic biomarker as well as a potential therapeutic target in bladder cancer.

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総ページ数：223p   記述言語：日本語  

CiNii Books

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総ページ数：viii, 90p   担当ページ：78-83   記述言語：日本語  

CiNii Books

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総ページ数：243p   担当ページ：65-68   記述言語：日本語  

CiNii Books

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総ページ数：209p   記述言語：日本語  

CiNii Books

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総ページ数：xiii, 77p   記述言語：日本語  

CiNii Books

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記述言語：日本語   出版者・発行元：アニムス編集委員会  

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記述言語：日本語   出版者・発行元：(株)文光堂  

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記述言語：日本語   出版者・発行元：(株)医学書院  

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記述言語：日本語   出版者・発行元：(株)文光堂  

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記述言語：日本語   出版者・発行元：(株)医学書院  

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記述言語：日本語   出版者・発行元：(株)東京医学社  

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記述言語：日本語   出版者・発行元：(株)日本メディカルセンター  

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記述言語：日本語   出版者・発行元：(株)文光堂  

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記述言語：日本語   出版者・発行元：(株)メディカルドゥ  

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開催年月日： 2023年11月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

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開催年月日： 2023年2月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

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開催年月日： 2021年11月

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開催年月日： 2021年11月

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開催年月日： 2021年4月

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開催年月日： 2020年7月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2020年7月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2020年1月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2018年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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