Publications by authors named "Shinichi Aishima"

236 Publications

Infiltration of CD1a-positive dendritic cells in advanced laryngeal cancer correlates with unfavorable outcomes post-laryngectomy.

BMC Cancer 2021 Aug 30;21(1):973. Epub 2021 Aug 30.

Department of Pathology & Microbiology, Saga University Faculty of Medicine, Saga, Japan.

Background: The prognosis of advanced laryngeal cancer is unfavorable despite advances in multidisciplinary therapy. Dendritic cells (DCs) play a central role in antitumor immunity. Tumor-infiltrating CD1a DCs have been reported to be associated with clinical outcomes in carcinomas of various organs, but the clinical impact of CD1a DCs in laryngeal cancer remains to be unequivocally established.

Methods: We retrospectively analyzed the cases of 57 patients with Stage III or IV laryngeal cancer who underwent a total laryngectomy. Immunohistochemistry detection of CD1a, S100 and CD8 was performed on representative resected specimens. CD1a DCs, S100 DCs and CD8 cytotoxic T-lymphocytes (CTLs) were evaluated, and the cases divided into high and low groups according to the cut-off of the median values for each of these 3 parameters.

Results: Compared to the CD1a-low group, the CD1a-high group had more advanced cases and showed significantly worse disease-specific survival (DSS) (P = 0.008) and overall survival (OS) (P = 0.032). The analyses of S100 DCs and CD8 CTLs revealed no significant impact on clinical outcomes. However, multivariate analysis revealed that infiltration of CD1a DCs was an independent unfavorable prognostic factor for both DSS (P = 0.009) and OS (P = 0.013).

Conclusions: Our results demonstrated that the infiltration of CD1a DCs was associated with unfavorable clinical outcomes in patients with advanced laryngeal cancer who underwent a total laryngectomy as the initial treatment.
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http://dx.doi.org/10.1186/s12885-021-08715-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406956PMC
August 2021

Effect of skin-capsular distance on controlled attenuation parameter for diagnosing liver steatosis in patients with nonalcoholic fatty liver disease.

Sci Rep 2021 Aug 2;11(1):15641. Epub 2021 Aug 2.

Liver Center, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

The effect of the skin-capsular distance (SCD) on the controlled attenuation parameter (CAP) for diagnosis of liver steatosis in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. The SCD was measured using B-mode ultrasound, and the CAP was measured using the M probe of FibroScan. According to the indications of the M probe, 113 patients with an SCD of ≤ 25 mm were included in the present study. The association between the SCD and CAP was investigated, and the diagnostic performance of the SCD-adjusted CAP was tested. The SCD showed the most significant positive correlation with the CAP (ρ = 0.329, p < 0.001). In the multiple regression analysis, the SCD and serum albumin concentration were associated with the CAP, independent of pathological liver steatosis. According to the multivariate analysis, two different formulas were developed to obtain the adjusted CAP using the SCD and serum albumin concentration as follows: adjusted CAP (dB/m) = CAP - (5.26 × SCD) and adjusted CAP (dB/m) = CAP - (5.35 × SCD) - (25.77 × serum albumin concentration). The area under the receiver operating characteristic curve for diagnosis of a steatosis score ≥ 2 of adjusted CAP was 0.678 and 0.684 respectively, which were significantly greater than the original CAP (0.621: p = 0.030 and p = 0.024). The SCD is associated with the CAP independent of liver steatosis. Adjustment of the CAP using the SCD improves the diagnostic performance of the CAP in NAFLD.
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http://dx.doi.org/10.1038/s41598-021-94970-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329228PMC
August 2021

Predictive value of cytokeratin-18 fragment levels for diagnosing steatohepatitis in patients with nonalcoholic fatty liver disease.

Eur J Gastroenterol Hepatol 2021 Jul 30. Epub 2021 Jul 30.

Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Hyogo Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Women's Medical University Medical Center East, Tokyo Liver Center, Saga University Hospital, Saga Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima Department of General Internal Medicine2, Kawasaki Medical School, Okayama Faculty of Nursing, Gifu Kyoritsu University, Gifu Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Kanagawa Department of Gastroenterology and Hepatology, Center for Digestive and Liver Diseases, Nara City Hospital, Nara Department of Diagnostic Pathology, Nara City Hospital, Nara Shiroishi Clinic of Internal Medicine, Hokkaido Department of Pathology & Microbiology, Faculty of Medicine, Saga University, Saga Center for Innovative Cancer Therapy, Kurume University Research, Kurume Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Aichi, Japan.

Objective: Several noninvasive markers have been developed to predict nonalcoholic steatohepatitis (NASH). We investigated the predictive value of the cytokeratin-18 fragment (CK18-F) level and FIB-4 index for diagnosing NASH in patients with nonalcoholic fatty liver disease (NAFLD).

Methods: A total of 246 patients histologically diagnosed with NASH (n = 185) or nonalcoholic fatty liver (n = 61) were enrolled. We analyzed weighted receiver operating characteristic (ROC) curves for the prediction of NASH and determined the relationship between the CK18-F level and the histological features of NASH. In addition, we investigated the predictive value of the combination of the CK18-F level and FIB-4 index for diagnosing NASH.

Results: The area under the ROC curve (AUROC) value of the CK18-F level was 0.77. With a CK18-F cutoff level of 260 U/L, the sensitivity and specificity for diagnosing NASH were 82.7 and 57.4%, respectively. Multiple comparisons showed that the CK18-F level did not differ among fibrosis stages but did significantly differ among hepatocyte ballooning grades. Overall, 95.7% (66/69) of patients with a FIB-4 index of ≥2.67 had NASH. In patients with a FIB-4 index of <2.67, the AUROC value of the CK18-F level for predicting NASH was 0.77 and a CK18-F cutoff level of 260 U/L resulted in a sensitivity and specificity of 82.4 and 56.9%.

Conclusions: The CK18-F level had a good predictive ability for diagnosing NASH in patients with NAFLD. Additionally, the combination of the CK18-F level and FIB-4 index accurately and noninvasively predicted NASH, even those with a low FIB-4 index.
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http://dx.doi.org/10.1097/MEG.0000000000002176DOI Listing
July 2021

Cytological Appearances of Ovarian Seromucinous Borderline Tumor in Ascites: Presentation of 2 Cases.

Acta Cytol 2021 20;65(5):440-447. Epub 2021 Jul 20.

Department of Pathology, Saga University Hospital, Saga, Japan.

Background: Seromucinous borderline tumor (SMBT) is a rare neoplasm which was newly defined in the 2014 WHO classification. Although the clinical and histopathological characteristics of SMBT have been well described, its cytological characteristics have not. We recently experienced 2 cases of SMBT which were defined by cytological findings of ascites.

Case Presentation: Case 1 was a 65-year-old Japanese woman. Preoperative imaging studies revealed abundant ascites and a cystic tumor, with a solid component measuring 13 cm on the left ovary. Radical surgery was performed during the intraoperative diagnosis of ovarian borderline tumor, made by histological examinations of frozen tumor sections. The cytological smears of preoperatively and intraoperatively collected ascites showed many atypical cells resembling reactive mesothelial cells. Alcian-blue staining of cell block sections revealed intracytoplasmic mucin, and the results of immunohistochemistry were consistent with SMBT. The final pathological diagnosis of tumor was SMBT. Case 2 was a 28-year-old Japanese woman. Preoperative imaging studies revealed a small amount of ascites and cystic tumors with solid components in the bilateral ovaries. She initially underwent fertility preservation surgery. SMBT was suspected by cytological examination of smears of intraoperatively collected ascites and the findings of cell block. She underwent additional radical surgery based on a final pathological diagnosis of SMBT.

Conclusion: In our experience, the tumor cells of SMBT in ascites mimicked reactive mesothelial cells. The nuclear atypia of SMBTs was intermediate between that of reactive mesothelial cells and serous carcinoma. The immunohistochemistry and mucin staining using cell block were very helpful for facilitating the cytodiagnosis of SMBT.
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http://dx.doi.org/10.1159/000517313DOI Listing
September 2021

Prognostic implications of the coexisting precursor lesion types in invasive gallbladder cancer.

Hum Pathol 2021 Aug 11;114:44-53. Epub 2021 May 11.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. Electronic address:

Invasive gallbladder carcinoma (GBC) is preceded by two main types of precursor lesions: intracholecystic papillary-tubular neoplasms (ICPNs) and biliary intraepithelial neoplasias (BilINs). Invasive GBCs with an ICPN component have more favorable prognoses than those without an ICPN component. Some BilINs show a relatively exophytic papillary pattern but do not meet the ICPN criteria; at our institution, we call these papillary neoplasias. To clarify the clinical significance of papillary neoplasia, we herein examined 80 invasive GBCs and classified them into three groups based on the type of preinvasive lesions: those with ICPN (ICPN group, n = 35), those with papillary neoplasia (pap-neoplasia group, n = 13), and those without ICPN/papillary neoplasia (group without ICPN/pap-neoplasia, n = 32). We then compared the prognostic differences and characterized the tumors of each group by determining the immunohistochemical expressions of various biomarkers. The overall survival periods of the ICPN and pap-neoplasia groups were significantly longer than that of the group without ICPN/pap-neoplasia (P < 0.0001, P = 0.0036, respectively). Multivariate analysis revealed that lacking ICPN/papillary neoplasia was independently associated with poor prognosis (P = 0.0007), as were poor differentiation (P = 0.0395), presence of preoperative symptoms (P = 0.0488), and advanced stage (P = 0.0234). Invasive components of the ICPN and pap-neoplasia groups were characterized by higher expressions of p16 and p53 compared with those of the group without ICPN/pap-neoplasia. The prognoses of the invasive GBCs with either papillary neoplasia or ICPN were thus more favorable than those of the invasive GBCs without ICPN/pap-neoplasia. Invasive GBCs with exophytic papillary preinvasive lesions (ICPN and papillary neoplasia) may be biologically different from those without such lesions.
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http://dx.doi.org/10.1016/j.humpath.2021.05.001DOI Listing
August 2021

Hepatic stellate cell as a Mac-2-binding protein-producing cell in patients with liver fibrosis.

Hepatol Res 2021 Apr 20. Epub 2021 Apr 20.

Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Gunma University, Maebashi, Japan.

Background: Mac-2 binding protein (M2BP) glycosylated isomer (M2BPGi) is a serum marker of liver fibrosis; M2BPGi is a glycosylated form of M2BP. Hepatocytes and hepatic stellate cells (HSCs) have been studied to determine the source of M2BP. This study proposes to identify the origin of M2BP in fibrotic liver.

Methods: Using liver fibrosis tissue specimens from 15 patients with liver cancer, M2BP mRNA and M2BP were detected by in situ hybridization and immunohistochemistry, respectively. The expression levels of M2BP mRNA were evaluated with scores of 3, 2, and 1. Fluorescent in situ hybridization was carried out to evaluate the distribution of M2BP mRNA and the activated-HSC marker αSMA mRNA; multicolor fluorescent immunohistochemistry was used for protein localization of M2BP, αSMA, and CD68. The Kruskal-Wallis test analyzed the relationship between M2BP mRNA expression and existing serum fibrosis markers.

Results: M2BP mRNA was expressed in spindle-shaped cells along the fibrous septa and in the perisinusoidal area of the fibrotic liver. The HSC markers αSMA mRNA and M2BP mRNA were colocalized in the spindle-shaped cells; on the protein level, M2BP was expressed in Kupffer cells. M2BP mRNA expression was positively correlated with serum M2BPGi levels. Aspartate transaminase-to-platelet ratio index, Fibrosis-4, hyaluronic acid, and the 15-minute indocyanine green retention rate were significantly correlated with M2BP mRNA expression.

Conclusions: M2BP mRNA transcription in fibrotic liver was primarily observed in HSCs but not at the M2BP level, which suggests that HSCs might produce and introduce M2BP to Kupffer cells and serum.
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http://dx.doi.org/10.1111/hepr.13648DOI Listing
April 2021

A deep learning model to detect pancreatic ductal adenocarcinoma on endoscopic ultrasound-guided fine-needle biopsy.

Sci Rep 2021 Apr 19;11(1):8454. Epub 2021 Apr 19.

Department of Pathology, Kurume University School of Medicine, Kurume, 830-0011, Japan.

Histopathological diagnosis of pancreatic ductal adenocarcinoma (PDAC) on endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) specimens has become the mainstay of preoperative pathological diagnosis. However, on EUS-FNB specimens, accurate histopathological evaluation is difficult due to low specimen volume with isolated cancer cells and high contamination of blood, inflammatory and digestive tract cells. In this study, we performed annotations for training sets by expert pancreatic pathologists and trained a deep learning model to assess PDAC on EUS-FNB of the pancreas in histopathological whole-slide images. We obtained a high receiver operator curve area under the curve of 0.984, accuracy of 0.9417, sensitivity of 0.9302 and specificity of 0.9706. Our model was able to accurately detect difficult cases of isolated and low volume cancer cells. If adopted as a supportive system in routine diagnosis of pancreatic EUS-FNB specimens, our model has the potential to aid pathologists diagnose difficult cases.
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http://dx.doi.org/10.1038/s41598-021-87748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055968PMC
April 2021

Gut microbiota composition associated with hepatic fibrosis in non-obese patients with non-alcoholic fatty liver disease.

J Gastroenterol Hepatol 2021 Aug 29;36(8):2275-2284. Epub 2021 Mar 29.

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

Background And Aim: Gut microbiota composition is associated with the pathogenesis of non-alcoholic fatty liver disease. However, the association between gut microbiota composition and non-alcoholic fatty liver disease in non-obese patients remains unclear. We compared clinical parameters and gut microbiota profiles of healthy controls and non-obese and obese patients with non-alcoholic fatty liver disease.

Methods: We examined the clinical parameters and gut microbiota profiles by 16S rRNA sequences and short-chain fatty acid levels in fecal samples from 51 non-obese patients with non-alcoholic fatty liver disease (body mass index <25 kg/m ) and 51 obese patients with non-alcoholic fatty liver disease (body mass index ≥30 kg/m ) who underwent pathological examination and 87 controls at five hospitals in Japan.

Results: Although no significant differences between the non-obese and other groups were observed in alpha diversity, a significant difference was found in beta diversity. We observed a significant decrease in serum alanine aminotransferase levels, Eubacterium population, and butyric acid levels in non-obese patients with non-alcoholic fatty liver disease compared with those in obese patients with non-alcoholic fatty liver disease. A significant negative correlation was found between the stage of hepatic fibrosis and Eubacterium abundance in non-obese patients with non-alcoholic fatty liver disease.

Conclusions: The decrease in the abundance of Eubacterium that produces butyric acid may play an important role in the development of non-alcoholic fatty liver disease in non-obese individuals. This study was registered at the University Hospital Medical Information Network clinical trial registration system (UMIN000020917).
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http://dx.doi.org/10.1111/jgh.15487DOI Listing
August 2021

Unclassified hepatocellular adenoma with beta-catenin mutation: a case report.

Surg Case Rep 2021 Feb 12;7(1):46. Epub 2021 Feb 12.

Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Gunma University, 22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan.

Background: Hepatocellular adenoma (HCA) subtypes are considered as risk factors for malignant transformation; thus, an accurate diagnosis is important. We report a case of resected HCA previously diagnosed as unclassified HCA using immunohistochemistry, subsequently discovered to harbor a mutation in exon 3 of the beta (β)-catenin gene using deoxyribonucleic acid (DNA) sequencing.

Case Presentation: The patient was a 26-year-old woman who was referred to our hospital because of a 150-mm tumor in the right lobe of the liver. Considering the possibility of malignancy, we performed right lobe hepatectomy. Based on the histopathological and immunohistochemical findings, the tumor was diagnosed as an unclassified HCA. Next, we performed sequencing of DNA isolated from the tumor and identified a mutation in exon 3 of β-catenin, suggesting that the tumor contained an activating mutation of the β-catenin gene.

Conclusion: β-Catenin mutations in HCA cannot be detected by immunohistochemistry alone, and molecular analysis is required to accurately diagnose and evaluate its prognosis.
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http://dx.doi.org/10.1186/s40792-021-01131-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881073PMC
February 2021

Direct Comparison of US and MR Elastography for Staging Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

Clin Gastroenterol Hepatol 2020 Dec 17. Epub 2020 Dec 17.

Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address:

Background & Aims: As alternatives to the expensive liver biopsy for assessing liver fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD), we directly compared the diagnostic abilities of magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE), and two-dimensional shear wave elastography (2D-SWE).

Methods: Overall, 231 patients with biopsy-proven NAFLD were included. Intra- and inter-observer reproducibility was analyzed using intraclass correlation coefficient in a sub-group of 70 participants, in whom liver stiffness measurement (LSM) was performed by an elastography expert and an ultrasound expert who was an elastography trainee on the same day.

Results: Valid LSMs were obtained for 227, 220, 204, and 201 patients using MRE, VCTE, 2D-SWE, and all three modalities combined, respectively. Although the area under the curve did not differ between the modalities for detecting stage ≥1, ≥2, and ≥3 liver fibrosis, it was higher for MRE than VCTE and 2D-SWE for stage 4. Sex was a significant predictor of discordance between VCTE and liver fibrosis stage. Skin-capsule distance and the ratio of the interquartile range of liver stiffness to the median were significantly associated with discordance between 2D-SWE and liver fibrosis stage. However, no factors were associated with discordance between MRE and liver fibrosis stage. Intra- and inter-observer reproducibility in detecting liver fibrosis was higher for MRE than VCTE and 2D-SWE.

Conclusions: MRE, VCTE, and 2D-SWE demonstrated excellent diagnostic accuracy in detecting liver fibrosis in patients with NAFLD. MRE demonstrated the highest diagnostic accuracy for stage 4 detection and intra- and inter-observer reproducibility. UMIN Clinical Trials Registry No. UMIN000031491.
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http://dx.doi.org/10.1016/j.cgh.2020.12.016DOI Listing
December 2020

Histopathological findings of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

J Med Ultrason (2001) 2020 Oct 2;47(4):549-554. Epub 2020 Nov 2.

Department of Pathology, School of Medicine, Kurume University, Kurume, Japan.

Nonalcoholic fatty liver disease (NAFLD) is based on the concept of pathological morphology as well as clinical findings, and is broadly categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The differential diagnosis between NAFL and NASH is important because NASH has the potential to progress to cirrhosis and hepatocellular carcinoma. NAFL is simple hepatic steatosis without hepatocellular injury, while NASH is characterized by macrovesicular steatosis, inflammation, and ballooning hepatocytes with a predominantly centrilobular (zone 3) distribution. Liver biopsy is a useful test for diagnosing NAFLD, but it is invasive. Therefore, various noninvasive methods including diagnostic imaging have been developed in recent years. To verify their usefulness, it is necessary to clarify in detail how the pathological findings are reflected in the image findings as imaging and histopathological findings are closely related. We describe the main histological features of NAFLD, i.e., steatosis, inflammation, ballooning hepatocytes, Mallory-Denk bodies, and fibrosis, as well as the evolutional process to liver cirrhosis.
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http://dx.doi.org/10.1007/s10396-020-01061-3DOI Listing
October 2020

Immunohistochemical analysis of the aggregation of CD1a-positive dendritic cells in resected specimens and its association with surgical outcomes for patients with gallbladder cancer.

Transl Oncol 2021 Jan 24;14(1):100923. Epub 2020 Oct 24.

Department of Pathology, Saga University Hospital, Nabeshima 5-1-1, Saga 849-8501, Japan; Department of Pathology & Microbiology, Saga University Faculty of Medicine, Saga, Japan.

Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis. Antigen-presenting dendritic cells (DCs) play a central role in antitumor immunity. DCs expressing CD1a (CD1a-DCs) are considered immature DCs. The aim of this study was to evaluate the clinical impact of CD1a-DC infiltration into GBC tissue. Seventy-five patients with GBC (excluding non-invasive and intramucosal cancer) were enrolled. Immunohistochemistry for CD1a, S100 and CD8 was performed using representative surgically resected specimens. The cases were divided into a high CD1a-DC group (27 cases, 36%) and low CD1a-DC group (48 cases, 64%) according to the degree of CD1a-DC infiltration/aggregation. The high CD1a-DC group contained fewer patients with distant metastasis (P = 0.039) and more patients given postoperative chemotherapy (P = 0.038). The high CD1a-DC group had significantly longer overall survival (P = 0.001) and disease-specific survival (P = 0.002) than the low CD1a-DC group. In contrast, S100-DC and CD8+ tumor-infiltrating lymphocyte statuses were without effect on OS or DSS. The results of multivariate analyses indicated that the degree of infiltration/aggregation of CD1a-DCs was an independent prognostic factor associated with a favorable prognosis after surgery.
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http://dx.doi.org/10.1016/j.tranon.2020.100923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590585PMC
January 2021

Decrease in fasting insulin secretory function correlates with significant liver fibrosis in Japanese non-alcoholic fatty liver disease patients.

JGH Open 2020 Oct 9;4(5):929-936. Epub 2020 Jun 9.

Liver Center Saga University Hospital Saga Japan.

Background And Aim: Non-alcoholic fatty liver disease (NAFLD) is typically associated with metabolic syndrome and diabetes, and insulin resistance is involved in its pathogenesis. However, the relationship between insulin secretion and NAFLD is unclear. We aimed to characterize the relationship between fasting insulin secretory function (ISF), evaluated using the homeostatic model assessment-beta cell function (HOMA-β) and the severity of fibrosis during NAFLD.

Methods: A-β was calculated in 188 patients with biopsy-confirmed NAFLD, and the correlations between Log HOMA-β and clinical parameters, including hepatic fibrosis, were calculated.

Results: Log HOMA-β was significantly lower in NAFLD patients with significant fibrosis (stages 2-4) than in those in the early stages (stages 0-1) (median [interquartile range]) (2.1 [1.9-2.4] 2.0 [1.8-2.2], = 0.04). The prevalence of significant fibrosis decreased with increasing Log HOMA-β: it was 59.2% in participants with low ISF (Log HOMA-β < 1.85), 43.6% in those with intermediate ISF (1.85 ≤ Log HOMA-β < 2.25), and 68.0% in those with high ISF (Log HOMA-β ≥ 2.25). Patients with lower Log HOMA-β had lower current body mass index (BMI), BMI at 20 years of age, and peak lifetime BMI than patients with intermediate or high Log HOMA-β.

Conclusions: Fasting ISF decreased alongside the development of liver fibrosis in NAFLD, suggesting that an impaired β cell function has a characteristic finding of significant liver fibrosis in relatively nonobese Japanese patients.
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http://dx.doi.org/10.1002/jgh3.12367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578285PMC
October 2020

Guidance for diagnosing autoimmune pancreatitis with biopsy tissues.

Pathol Int 2020 Oct 6;70(10):699-711. Epub 2020 Aug 6.

Kansai Medical University Kouri Hospital, Osaka, Japan.

The biopsy-based diagnosis of autoimmune pancreatitis (AIP) is difficult but is becoming imperative for pathologists due to the increased amount of endoscopic ultrasound-guided biopsy tissue. To cope with this challenge, we propose guidance for the biopsy diagnosis of type 1 AIP. This guidance is for pathologists and comprises three main parts. The first part includes basic issues on tissue acquisition, staining, and final diagnosis, and is intended for gastroenterologists as well. The second part is a practical guide for diagnosing type 1 AIP based on the AIP clinical diagnostic criteria 2018. Inconsistent histological findings, tips for evaluating IgG4 immunostaining and key histological features including the ductal lesion and others are explained. Storiform fibrosis and obliterative phlebitis are diagnostic hallmarks but are sometimes equivocal. Storiform fibrosis is defined as spindle-shaped cells, inflammatory cells and fine collagen fibers forming a flowing arrangement. Obliterative phlebitis is defined as fibrous venous obliteration with inflammatory cells. Examples of each are provided. The third part describes the differentiation of AIP from pancreatic ductal adenocarcinoma (PDAC), focusing on histological features of acinar-ductal metaplasia in AIP, which is an important mimicker of PDAC. This guidance will help standardize pathology reports of pancreatic biopsies for diagnosing type 1 AIP.
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http://dx.doi.org/10.1111/pin.12994DOI Listing
October 2020

Discordant pathological diagnosis of non-alcoholic fatty liver disease: A prospective multicenter study.

JGH Open 2020 Jun 17;4(3):497-502. Epub 2019 Dec 17.

Liver Center Saga University Hospital Saga Japan.

Background: Liver biopsy has been the standard procedure for diagnosing and evaluating the severity of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, interobserver discordance remains a critical issue in its pathological diagnosis.

Methods And Results: We examined the concordance rates of pathological scoring and diagnosis between pathologists at individual institutions (local diagnosis) and two central pathologists specialized in liver pathology (central diagnosis). A total of 150 patients with NAFLD underwent prospective liver biopsies. NAFLD activity score (NAS) and fibrosis stage were evaluated, and NASH was determined according to Matteoni's classification. NAS, scores for all NAS components, and fibrosis stage were diagnosed at a lower degree by central compared with local diagnosis. NASH was diagnosed in 34% of the patients according to central pathologists compared with 54% according to local pathologists ( < 0.001). The concordance rates for NAS, steatosis, inflammation, ballooning, fibrosis, and NASH diagnosis were 26.7, 62.7, 51.3, 48.7, 43.3, and 50.7%, respectively. The correlation coefficient between local and central diagnoses was the lowest for the scoring of ballooning ( = 0.218).

Conclusion: Concordance rates among pathologists for the evaluation of NAFLD are currently poor, and simple and reliable diagnostic and evaluation criteria are urgently needed to improve the clinical management of NAFLD patients.
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http://dx.doi.org/10.1002/jgh3.12289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273711PMC
June 2020

Metabolomic/lipidomic-based analysis of plasma to diagnose hepatocellular ballooning in patients with non-alcoholic fatty liver disease: A multicenter study.

Hepatol Res 2020 Aug 15;50(8):955-965. Epub 2020 Jul 15.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Aim: Liver biopsy is still required for the diagnosis of hepatocellular ballooning and inflammation, which are important histological features of non-alcoholic steatohepatitis. We undertook this multicenter, cross-sectional study to identify novel blood markers for the diagnosis of hepatocellular ballooning.

Methods: We enrolled 176 patients, of whom 132 were proven by liver biopsy as having non-alcoholic fatty liver disease (NAFLD) and classified as non-ballooning (ballooning grade 0) (n = 83) or ballooning (ballooning grade 1 and 2) (n = 49) by a central pathology review. We carried out gas chromatography-mass spectrometry, hydrophilic interaction liquid chromatography tandem mass spectrometry, and lipidomics with plasma.

Results: As correlates of hepatocellular ballooning, among the clinical parameters, serum type IV collagen 7S correlated most significantly with the ballooning grade (correlation coefficient [CC] = 0.463; P < 0.001). Among the metabolic/lipidomic markers, phosphatidylcholine (PC) (aa-44:8) correlated most significantly with the ballooning grade (CC = 0.394; P < 0.001). The area under the receiver operating characteristic curve of type IV collagen 7S, choline, and lysophosphatidylethanolamine (LPE) (e-18:2), was 0.846 (95% confidence interval, 0.772-0.919).

Conclusions: Plasma levels of PC were positively correlated, and those of lysophosphatidylcholine and LPE were negatively correlated with hepatocellular ballooning in NAFLD patients. These non-invasive metabolic/lipidomic-based plasma tests might be useful to distinguish between cases of NAFLD with and without hepatocellular ballooning.
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http://dx.doi.org/10.1111/hepr.13528DOI Listing
August 2020

Unclassified hepatocellular adenoma with histological brown pigment deposition and serum PIVKA-II level elevation: a case report.

Surg Case Rep 2020 May 7;6(1):94. Epub 2020 May 7.

Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Gunma University, 3-39-22 Showamachi, Maebashi, Gunma, 371-8511, Japan.

Background: Hepatocellular adenoma (HCA) is conventionally considered a rare benign liver tumor, but advanced studies have revealed that HCA is heterogeneous, and may include a type that is prone to malignant transformations. Differentiation between well-differentiated hepatocellular carcinoma and focal nodular hyperplasia is necessary to diagnose hepatocellular adenoma through imaging; however, the tumor marker of hepatocellular carcinoma, protein induced by vitamin K absence, or antagonist II (PIVKA-II), is rarely positive in hepatocellular adenoma.

Case Presentation: A 44-year-old woman presented to our hospital with complaints of loss of appetite and weight loss. Multidetector row computed tomography revealed a liver tumor (diameter, 80 mm) that was enhanced in the arterial phase. Her serum PIVKA-II level was very high (3327 mAU/mL). Based on the enlargement of the mass and the results of the diagnostic imaging, hepatocellular adenoma or hepatocellular carcinoma was suspected, and we considered the possibility of a malignant transformation due to the high level of serum PIVKA-II; thus, we performed hepatectomy. Histological examination showed brown pigment deposition in the hepatocytes, which was determined to be lipofuscin granules. Based on immunohistochemical findings, the diagnosis was unclassified hepatocellular adenoma. Immunohistochemical examinations revealed that the adenoma cells in the tumor were positive for PIVKA-II. Her serum PIVKA-II level returned to normal after the resection.

Conclusions: We present a case of unclassified hepatocellular adenoma with brown pigment deposition and elevation of serum PIVKA-II level. For the differentiation of liver tumors with high levels of PIVKA-II and hypervascular mass, hepatocellular adenoma should be considered.
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http://dx.doi.org/10.1186/s40792-020-00853-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205962PMC
May 2020

Diagnostic accuracy of FibroScan-AST score to identify non-alcoholic steatohepatitis with significant activity and fibrosis in Japanese patients with non-alcoholic fatty liver disease: Comparison between M and XL probes.

Hepatol Res 2020 Jul 13;50(7):831-839. Epub 2020 May 13.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Aim: Recently, FibroScan-AST (FAST) score was reported to be effective for identifying non-alcoholic steatohepatitis (NASH) with significant activity and fibrosis in non-alcoholic fatty liver disease (NAFLD). The aim of this study was to confirm the diagnostic accuracy of FAST score of Japanese patients and compare the cut-off values and diagnostic accuracy between the FibroScan M and XL probes.

Methods: Eighty-two and 84 patients were included the verification and validation sets, respectively. All patients were diagnosed with NAFLD by biopsy by two central expert pathologists. Liver stiffness measurements and controlled attenuation parameter were carried out, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis.

Results: No significant difference existed in FAST score between the M and XL probes (0.489 vs. 0.483, P = 0.187). No significant difference existed in the area under the ROC between the two probes (M, 0.7598; XL, 0.7614; P = 0.958). According to the Youden index, the cut-off value using the M probe was 0.57 with 68.2% sensitivity and 78.3% specificity. For the XL probe, the cut-off value was 0.56 with 68.2% sensitivity and 73.3% specificity. To obtain sensitivity and specificity values higher than 90%, cut-off values of 0.35 and 0.66 were chosen for the M probe and 0.32 and 0.63 were chosen for the XL probe.

Conclusions: There was no significant difference in diagnostic accuracy of FAST score between the FibroScan M and XL probes. The FAST score can be used to identify NASH with significant risk in Japanese patients regardless of probe selection.
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http://dx.doi.org/10.1111/hepr.13508DOI Listing
July 2020

Clinicopathological characteristics of combined hepatocellular cholangiocarcinoma from the viewpoint of patient prognosis after hepatic resection: High rate of early recurrence and its predictors.

Hepatol Res 2020 Jul 12;50(7):863-870. Epub 2020 May 12.

Kyushu Study Group of Liver Surgery, Nagasaki, Japan.

Aim: Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a very rare subtype of primary liver carcinoma; therefore, its clinicopathological characteristics have not yet been elucidated in detail. The aim of the study was to reveal the clinicopathological characteristics and prognostic factors of cHCC-CCA after hepatic resection (HR) METHODS: A total of 124 patients who underwent curative HR for cHCC-CCA between 2000 and 2016 were enrolled in this multi-institutional study conducted by the Kyushu Study Group of Liver Surgery. Clinicopathological analysis was performed from the viewpoint of patient prognosis.

Results: A total of 62 patients (50%) had early recurrence within 1.5 years after HR, including 36 patients (58%) with extrahepatic recurrence. In contrast, just four patients (3%) had late recurrence occurring >3 years after HR. The independent predictors of early recurrence were as follows: des-gamma carboxyprothrombin >40 mAU/mL (odds ratio 26.2, P = 0.0117), carbohydrate antigen 19-9>37 IU/l (odds ratio 18.0, P = 0.0200), and poorly differentiated HCC or CCA (odds ratio 11.2, P = 0.0259).

Conclusions: Half of the patients with cHCC-CCA had early recurrence after HR. Preoperative elevation of des-gamma carboxyprothrombin or carbohydrate antigen 19-9 and the existence of poorly differentiated components of HCC or CCA in resected specimens are predictors of its early recurrence.
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http://dx.doi.org/10.1111/hepr.13507DOI Listing
July 2020

Accumulation of Astrocytic Aquaporin 4 and Aquaporin 1 in Prion Protein Plaques.

J Neuropathol Exp Neurol 2020 04;79(4):419-429

Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Gerstmann-Sträussler-Scheinker (GSS) disease with P102L mutation and familial Creutzfeldt-Jakob disease (CJD) with V180I mutation are 2 major hereditary prion diseases in Japan. GSS and some familial CJD [V180I] exhibit characteristic prion protein (PrP) plaques. Overexpression of the astrocytic water channel proteins aquaporin (AQP) 1 and AQP4 was recently reported in sporadic CJD. To clarify the pathological characteristics of AQP1 and AQP4 in prion disease patient brains with plaque-type deposition, we investigated 5 patients with GSS, 2 patients with CJD [V180I], and 2 age-matched control cases without neurological diseases using immunohistochemistry and double immunofluorescence methods. We demonstrated that there is the intense expression of AQP1 and AQP4 around prion plaques, especially in distal astrocytic processes deep inside these plaques. Similar results have been reported in the senile plaques and ghost tangles of Alzheimer disease brains and a protective role of AQP4 in which AQP4 is redistributed toward the plaques and works as a barrier against the deleterious effects of these plaques has been suggested. Our results, which show a similar clustering of AQPs around PrP plaques, therefore support the possibility that AQPs also have a protective role in plaque formation in prion diseases.
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http://dx.doi.org/10.1093/jnen/nlaa010DOI Listing
April 2020

Accuracy of the Enhanced Liver Fibrosis test, and combination of the Enhanced Liver Fibrosis and non-invasive tests for the diagnosis of advanced liver fibrosis in patients with non-alcoholic fatty liver disease.

Hepatol Res 2020 Jun 25;50(6):682-692. Epub 2020 Mar 25.

Liver Center, Saga University Hospital, Saga, Japan.

Aim: The Enhanced Liver Fibrosis (ELF) test comprises a logarithmic algorithm combining three serum markers of hepatic extracellular matrix metabolism. We aimed to evaluate the performance of ELF for the diagnosis of liver fibrosis and to compare it with that of liver stiffness measurement (LSM) by FibroScan in non-alcoholic fatty liver disease.

Methods: ELF cut-off values for the diagnosis of advanced fibrosis were obtained using receiver operating characteristic analysis in patients with biopsy-confirmed non-alcoholic fatty liver disease (training set; n = 200). Diagnostic performance was analyzed in the training set and in a validation set (n = 166), and compared with that of LSM in the FibroScan cohort (n = 224).

Results: The area under receiver operating characteristic curve was 0.81 for the diagnosis of advanced fibrosis, and the ELF cut-off values were 9.34 with 90.4% sensitivity and 10.83 with 90.6% specificity in the training set, and 89.8% sensitivity and 85.5% specificity in the validation set. There was no significant difference in the area under the receiver operating characteristic curve between ELF and LSM (0.812 and 0.839). A combination of ELF (cut-off 10.83) and LSM (cut-off 11.45) increased the specificity to 97.9% and the positive predictive value, versus ELF alone. Sequential use of the Fibrosis-4 index (cut-off 2.67) and ELF (cut-off 9.34) increased the sensitivity to 95.9%.

Conclusions: ELF can identify advanced liver fibrosis in non-alcoholic fatty liver disease, and its diagnostic accuracy is comparable to that of FibroScan. According to the clinical setting, combinations or sequential procedures using other non-invasive tests complement the diagnostic performance of ELF for the identification of advanced fibrosis.
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http://dx.doi.org/10.1111/hepr.13495DOI Listing
June 2020

Fairly rare small-diameter hepatocellular carcinoma with right adrenal gland metastasis having an inferior vena cava tumor thrombus: a case report.

Surg Case Rep 2019 Nov 6;5(1):170. Epub 2019 Nov 6.

Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Background: Hepatocellular carcinoma (HCC) may lead to extrahepatic metastasis (EHM). Most patients with EHM had either intrahepatic stage III or IVA tumor at the site of metastases. Herein, we present the case of a fairly rare 1.5-cm small-diameter HCC with right adrenal gland tumor having an inferior vena cava (IVC) tumor thrombus.

Case Presentation: A 75-year-old man had a 1.5-cm hepatocellular carcinoma (HCC) in segment 8 of the liver and a 3.0-cm right adrenal gland tumor with inferior vena cava (IVC) tumor thrombus. He underwent partial hepatectomy, right adrenalectomy, and IVC tumor thrombectomy. Tumor resection was successful, but the tumor progressed rapidly, and the patient died 8 months after the operation. Immunohistochemical staining revealed that both HCC cells and adrenal tumor cells were positive for HCC markers Glypican-3 and alpha-fetoprotein. In terms of adrenal carcinoma markers vimentin and Melan-A, vimentin was negative in the HCC and adrenal tumor, and Melan-A was negative in the HCC. In adrenal tumor, slight positivity of Melan-A was observed, but the intensity of staining was clearly weak compared with that in normal adrenal glands. CD133, one of the stem cell markers, was positive in both HCC and adrenal tumor cells. Next-generation amplicon sequencing analyses were performed using DNA derived from the HCC, adrenal tumor, and normal liver tissue. After exome data analyses for representative HCC-related genes as TERT, CTNNB1, TP53, and ARID2, TP53 mutation (exon3: c.G351 T: p.R117S) was found in both HCC cells and adrenal tumor cells. Conversely, no significant mutations in other genes were observed. These pathological findings and sequencing results showed that the adrenal tumor might be an adrenal metastasis of HCC in spite of small primary tumor size.

Conclusions: This case suggests that the right adrenal tumor was a metastasis of HCC. Immunohistochemical staining and gene mutation analyses using NGS are very useful in differentiating the tumor origin.
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http://dx.doi.org/10.1186/s40792-019-0705-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834821PMC
November 2019

Accuracy of liver stiffness measurement and controlled attenuation parameter using FibroScan M/XL probes to diagnose liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease: a multicenter prospective study.

J Gastroenterol 2020 Apr 25;55(4):428-440. Epub 2019 Oct 25.

Liver Center, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

Background: Few studies have evaluated both liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD) using both FibroScan M and XL probes. This study was performed to investigate the accuracy of both FibroScan probes to diagnose liver fibrosis and steatosis in patients with NAFLD.

Methods: We prospectively enrolled 137 consecutive patients with clinically suspected NAFLD in our joint-research facilities. Liver biopsies, liver stiffness measurements (LSMs), and controlled attenuation parameter (CAP) measurements were performed, and 122 patients with NAFLD diagnosed pathologically by central pathologists were included in the final analysis.

Results: Reliable LSM results were obtained in 85.2% (M) and 89.3% (XL) of patients, and CAP was reliable in 90.2% (M) and 90.2% (XL). The median LSM was significantly lower with the XL than M probe, and CAP was significantly higher with the XL than M probe. The optimal cut-off values for diagnosing the fibrosis stage were lower for LSM with the XL than M probe (stage ≥ 2, 6.7 vs. 7.0; stage ≥ 3, 8.2 vs. 10.8; stage 4, 14.3 vs. 16.8, respectively), whereas those of CAP were higher for the XL than M probe (score of ≥ 2, 273 vs. 267; score of 3, 302 vs. 286, respectively). There were no significant differences in accuracy of the LSM and CAP between the probes.

Conclusions: Liver fibrosis and steatosis could be equally evaluated with FibroScan M and XL probes in patients with NAFLD. There was no significant difference in diagnostic accuracy between the two probes using probe-specific cut-off values.
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http://dx.doi.org/10.1007/s00535-019-01635-0DOI Listing
April 2020

[Pathology of metastatic liver tumors].

Authors:
Shinichi Aishima

Nihon Shokakibyo Gakkai Zasshi 2019;116(9):697-701

Department of Pathology & Microbiology, Faculty of Medicine, Saga University.

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http://dx.doi.org/10.11405/nisshoshi.116.697DOI Listing
January 2019

Frequent Detection of Pituitary-Derived PrPres in Human Prion Diseases.

J Neuropathol Exp Neurol 2019 10;78(10):922-929

Department of Neuropathology, Graduate School of Medical Sciences.

Human prion diseases including sporadic Creutzfeldt-Jakob disease (sCJD), inherited prion diseases, and acquired human prion diseases are lethal neurodegenerative diseases. One of the major sources of iatrogenic Creutzfeldt-Jakob disease was human growth hormone (hGH-iCJD) derived from contaminated cadaveric pituitaries. The incidence of hGH-iCJD has decreased since changing from growth hormone extracted from human cadaveric pituitaries to recombinant pituitary hormones. However, extensive analysis on the localization and detecting of abnormal prion protein in the pituitary gland are limited. In this study, we examined 9 autopsied brains and pituitary glands from 6 patients with prion disease (3 Gerstmann-Sträussler-Scheinker disease, 2 sCJD, and 1 dura mater graft-associated CJD) and 3 individuals with nonprion diseases. Western blot analysis of pituitary samples demonstrated unique glycoforms of normal cellular prion protein with molecular weights of 30-40 kDa, which was higher than the typical 25-35 kDa prion protein in brains. Proteomic analysis also revealed prion protein approximately the molecular weight of 40 kDa in pituitary samples. Moreover, proteinase K-resistant Prion protein was frequently detected in pituitary samples of the prion diseases. Immunohistochemistry for Prion protein revealed mosaic cellular distribution preferentially in growth hormone- or prolactin-producing cells.
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http://dx.doi.org/10.1093/jnen/nlz075DOI Listing
October 2019

Decreased cytokeratin 7 expression correlates with the progression of cervical squamous cell carcinoma and poor patient outcomes.

J Obstet Gynaecol Res 2019 Nov 9;45(11):2228-2236. Epub 2019 Sep 9.

Department of Pathology & Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Aim: To identify potential biomarkers for tumor progression and patient outcomes in cervical squamous cell carcinoma.

Methods: We examined the expressions of CK7 and CK17 as potential markers of the squamo-columnar junction, and podoplanin as a basal cell marker using surgical and biopsy samples of patients in grade 3 cervical intraepithelial neoplasia (n = 30), operable invasive carcinoma (OP group, n = 53) and inoperable invasive carcinoma before radiotherapy and/or chemotherapy (RC group, n = 76).

Results: The positive rates of CK7 and podoplanin in invasive carcinoma were significantly lower than those in grade 3 cervical intraepithelial neoplasia (P = 0.001, P < 0.0001). The positive rates of CK7 and podoplanin in the RC group were significantly lower than those in the OP group (P < 0.0001, P = 0.04), while CK17 expression showed significantly higher positivity in the RC group than in the OP group (P < 0.0001). Negative CK7 expression showed a potential impact on overall survival in early-stage patients. In the RC group, the prevalence of cases with post-therapeutic residual carcinoma cells was higher in the CK7-negative group than in the positive group (P = 0.003). We found that decreased expression of CK7 could be a prognostic factor in early-stage cervical cancer patients.

Conclusion: This result may provide strategies and suggestions for new treatment options and follow-up practices in managing patients with cervical cancer.
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http://dx.doi.org/10.1111/jog.14108DOI Listing
November 2019

A unique autopsy case of ascending aortic dissection caused by giant cell arteritis without drug therapy.

Pathol Int 2019 Oct 11;69(10):614-618. Epub 2019 Aug 11.

Departments of Pathology & Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Giant cell arteritis is a granulomatous inflammation of large and medium-sized arteries, occurring predominantly in older women. In this case, a 76-year-old woman was hospitalized for examination because of a high C-reactive protein (CRP) level, but nothing remarkable was found on thoracicoabdominal computed tomography (CT) or head magnetic resonanse imaging (MRI). On the 46th day from the first visit, she died suddenly due to cardiac tamponade. On pathological autopsy, we found the cause of death to be acute aortic dissection (Stanford type A) due to giant cell arteritis occurred in the ascending aorta. Histologically, granulomatous vasculitis with giant cells was recognized in the ascending aorta, thoracic descending aorta and abdominal aorta and their branches. Interestingly, similar granulomatous vasculitis was also found in the medium and small vessels of other plural organs, including the heart, liver, uterine corpus, and its appendages. To our knowledge, giant cell arteritis with multiple-organ granulomatous changes has not been reported before. We herein reported a unique autopsy case of giant cell arteritis in a patient not treated with medication.
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http://dx.doi.org/10.1111/pin.12845DOI Listing
October 2019

CXCL12 expression in intrahepatic cholangiocarcinoma is associated with metastasis and poor prognosis.

Cancer Sci 2019 Oct 13;110(10):3197-3203. Epub 2019 Aug 13.

Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan.

Intrahepatic cholangiocarcinoma is a rare malignant biliary neoplasm that causes a poor prognosis even after curative hepatectomy. Liver metastasis is the major recurrence pattern of intrahepatic cholangiocarcinoma; therefore, the prevention of liver metastasis is a desirable objective. The aim of this study is to identify gene(s) related to liver metastasis of intrahepatic cholangiocarcinoma and to examine the inhibitory effects on metastasis of intrahepatic cholangiocarcinoma by controlling such gene(s). We collected 3 pairs of intrahepatic cholangiocarcinoma frozen samples, and 36 pairs (primary and metastatic lesions) of intrahepatic cholangiocarcinoma formalin-fixed paraffin-embedded samples, from patients who underwent surgical resection at hospitals related to the Kyushu Study Group of Liver Surgery between 2002 and 2016. We carried out cDNA microarray analyses and immunohistochemistry to identify candidate genes, and evaluated one of them as a therapeutic target using human cholangiocarcinoma cell lines. We identified 4 genes related to liver metastasis using cDNA microarray, and found that CXCL12 was the only gene whose expression was significantly higher in liver metastasis than in primary intrahepatic cholangiocarcinoma by immunohistochemistry (P = .003). In prognosis, patients in the high CXCL12 group showed a significantly poor prognosis in disease-free (P < .0001) and overall survival (P = .0004). By knockdown of CXCL12, we could significantly suppress the invasive and migratory capabilities of 2 human cholangiocarcinoma cell lines. Therefore, CXCL12 might be associated with metastasis and poor prognosis in intrahepatic cholangiocarcinoma.
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http://dx.doi.org/10.1111/cas.14151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778649PMC
October 2019

Primary mucoepidermoid carcinoma of the liver with CRTC1-MAML2 fusion: a case report.

Diagn Pathol 2019 Jul 27;14(1):84. Epub 2019 Jul 27.

Department of Anatomic Pathology Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.

Background: CRTC1-MAML2 fusion is often detected in low- or intermediate-grade salivary mucoepidermoid carcinoma (MEC), and it is associated with a favorable clinical course. Primary MEC of the liver is an extremely rare, aggressive tumor, and no study has investigated CRTC1-MAML2 fusion.

Case Presentation: A 79-year-old Japanese female presented with an approx. 5-cm hepatic mass lesion. We surgically resected the lesion under the clinical diagnosis of intrahepatic cholangiocarcinoma. The histological and immunohistochemical findings were consistent with high-grade MEC, consisting of squamoid, mucin-producing, and intermediate tumor cells. Our RT-PCR analysis revealed the presence of CRTC1-MAML2 fusion. This fusion gene was further confirmed by direct sequencing. The patient is still alive almost 10 years after the surgery.

Conclusion: This is the first case report of primary MEC of the liver with CRTC1-MAML2 fusion, with long survival. The present case has significant implications for the entity of primary MEC of the liver which should be distinguished from adenosquamous carcinoma.
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http://dx.doi.org/10.1186/s13000-019-0863-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661078PMC
July 2019

IFN-γ Promotes Epithelial-Mesenchymal Transition and the Expression of PD-L1 in Pancreatic Cancer.

J Surg Res 2019 08 27;240:115-123. Epub 2019 Mar 27.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Tumor immune reactions not only provide host defense but also accelerate tumor immune escape and phenotype switching. Here, we examined the association of programmed cell death ligand 1 (PD-L1) expression with epithelial-mesenchymal transition (EMT)-associated markers in pancreatic ductal adenocarcinoma (PDA) within the context of the tumor microenvironment.

Materials And Methods: PDA samples from 36 patients were analyzed for PD-L1, vimentin, E-cadherin, and Snail expressions and for PDA cell and immune cell infiltration. PD-L1 expression and EMT in PDA cell lines under conditions of altering interferon gamma (IFN-γ) signals were also assessed.

Results: Immunohistochemistry revealed a significant correlation between vimentin and PD-L1 expression, whereas double staining showed them to be simultaneously expressed by PDA cells. Positive vimentin expression was associated with the infiltration of a lower number of CD8 T cells and a higher number of FoxP3 cells and poor patient prognosis (P = 0.03). PDA tumor cells promoted PD-L1 expression and EMT under the presence of IFN-γ, which was inhibited by the signal transducer and activator of transcription (STAT)1 small interfering RNA.

Conclusions: Strong correlations were observed between PD-L1 expression, EMT, and the immunosuppressive tumor microenvironment. Targeting STAT1 combined with PD-1/PD-L1 immunotherapy may improve outcomes for patients with PDA.
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http://dx.doi.org/10.1016/j.jss.2019.02.038DOI Listing
August 2019
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