Publications by authors named "Masao Omata"

629 Publications

Pre-existing liver disease is associated with poor outcome in patients with SARS CoV2 infection; The APCOLIS Study (APASL COVID-19 Liver Injury Spectrum Study).

Hepatol Int 2020 Sep 4;14(5):690-700. Epub 2020 Jul 4.

Division of Hepatobiliary, Cipto Mangunkusuamo Hospital, University of Indonesia, Jakarta, Indonesia.

Background And Aims: COVID-19 is a dominant pulmonary disease, with multisystem involvement, depending upon comorbidities. Its profile in patients with pre-existing chronic liver disease (CLD) is largely unknown. We studied the liver injury patterns of SARS-Cov-2 in CLD patients, with or without cirrhosis.

Methods: Data was collected from 13 Asian countries on patients with CLD, known or newly diagnosed, with confirmed COVID-19.

Results: Altogether, 228 patients [185 CLD without cirrhosis and 43 with cirrhosis] were enrolled, with comorbidities in nearly 80%. Metabolism associated fatty liver disease (113, 61%) and viral etiology (26, 60%) were common. In CLD without cirrhosis, diabetes [57.7% vs 39.7%, OR = 2.1 (1.1-3.7), p = 0.01] and in cirrhotics, obesity, [64.3% vs. 17.2%, OR = 8.1 (1.9-38.8), p = 0.002] predisposed more to liver injury than those without these. Forty three percent of CLD without cirrhosis presented as acute liver injury and 20% cirrhotics presented with either acute-on-chronic liver failure [5 (11.6%)] or acute decompensation [4 (9%)]. Liver related complications increased (p < 0.05) with stage of liver disease; a Child-Turcotte Pugh score of 9 or more at presentation predicted high mortality [AUROC 0.94, HR = 19.2 (95 CI 2.3-163.3), p < 0.001, sensitivity 85.7% and specificity 94.4%). In decompensated cirrhotics, the liver injury was progressive in 57% patients, with 43% mortality. Rising bilirubin and AST/ALT ratio predicted mortality among cirrhosis patients.

Conclusions: SARS-Cov-2 infection causes significant liver injury in CLD patients, decompensating one fifth of cirrhosis, and worsening the clinical status of the already decompensated. The CLD patients with diabetes and obesity are more vulnerable and should be closely monitored.
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http://dx.doi.org/10.1007/s12072-020-10072-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334898PMC
September 2020

Squamous Cell Carcinoma of the Lung With Micropapillary Pattern.

J Thorac Oncol 2020 09 12;15(9):1541-1544. Epub 2020 Jun 12.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan.

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http://dx.doi.org/10.1016/j.jtho.2020.05.023DOI Listing
September 2020

Consolidated BRCA1/2 Variant Interpretation by MH BRCA Correlates with Predicted PARP Inhibitor Efficacy Association by MH Guide.

Int J Mol Sci 2020 May 29;21(11). Epub 2020 May 29.

Genome Analysis Center, Yamanashi Central Hospital, Kofu 400-8506, Japan.

variants are prognostic biomarkers for hereditary breast and/or ovarian cancer (HBOC) syndrome and predictive biomarkers for PARP inhibition. In this study, we benchmarked the classification of variants from patients with HBOC-related cancer using MH BRCA, a novel computational technology that combines the ACMG guidelines with expert-curated variant annotations. Evaluation of variants ( = 1040) taken from four HBOC studies showed strong concordance within the pathogenic (98.1%) subset. Comparison of MH BRCA's ACMG classification to ClinVar submitter content from ENIGMA, the international consortium of investigators on the clinical significance of variants, the ARUP laboratories, a clinical testing lab of the University of UTAH, and the German Cancer Consortium showed 99.98% concordance (4975 out of 4976 variants) in the pathogenic subset. In our patient cohort, refinement of patients with variants of unknown significance reduced the uncertainty of cancer-predisposing syndromes by 64.7% and identified three cases with potential family risk to HBOC due to a likely pathogenic variant p.V1653L (NM_007294.3:c.4957G > T; rs80357261). To assess whether classification results predict PARP inhibitor efficacy, contextualization with functional impact information on DNA repair activity were performed, using MH Guide. We found a strong correlation between treatment efficacy association and MH BRCA classifications. Importantly, low efficacy to PARP inhibition was predicted in 3.95% of pathogenic variants from four examined HBOC studies and our patient cohort, indicating the clinical relevance of the consolidated variant interpretation.
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http://dx.doi.org/10.3390/ijms21113895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312854PMC
May 2020

Genome analysis of peeling archival cytology samples detects driver mutations in lung cancer.

Cancer Med 2020 07 29;9(13):4501-4511. Epub 2020 Apr 29.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan.

Introductions: When tumor tissue samples are unavailable to search for actionable driver mutations, archival cytology samples can be useful. We investigate whether archival cytology samples can yield reliable genomic information compared to corresponding formalin-fixed paraffin-embedded (FFPE) tumor samples.

Patients And Methods: Pretreatment class V archival cytology samples with adequate tumor cells were selected from 172 lung cancer patients. The genomic profiles of the primary lung tumors have been analyzed through whole-exome regions of 53 genes. We compared the genomic profiles based on the oncogenicity and variant allele frequency (VAF) between the archival cytology and the corresponding primary tumors. We also analyzed the genomic profiles of serial cytological samples during the treatment of EGFR-TKI.

Results: A total of 43 patients were analyzed with the paired samples for DNA mutations and other three patients were analyzed for their fusion genes. A total of 672 mutations were detected. Of those, 106 mutations (15.8%) were shared with both samples. Sixty of seventy-seven (77.9%) shared mutations were oncogenic or likely oncogenic mutations with VAF ≧10%. As high as 90% (9/10) actionable driver mutations and ALK and ROS1 fusion genes were successfully detected from archival cytology samples. Sequential analysis revealed the dynamic changes in EGFR-TKI-resistant mutation (EGFR p.T790M) during the course of treatment.

Conclusion: Archival cytology sample with adequate tumor cells can yield genetic information compared to the primary tumors. If tumor tissue samples are unavailable, we can use archival cytology samples to search for actionable driver mutations.
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http://dx.doi.org/10.1002/cam4.3089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333826PMC
July 2020

Molecular Mechanisms: Connections between Nonalcoholic Fatty Liver Disease, Steatohepatitis and Hepatocellular Carcinoma.

Int J Mol Sci 2020 Feb 23;21(4). Epub 2020 Feb 23.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The patatin-like phospholipase-3 (PNPLA3) I148M sequence variant is one of the strongest genetic determinants of NAFLD/NASH. PNPLA3 is an independent risk factor for HCC among patients with NASH. The obesity epidemic is closely associated with the rising prevalence and severity of NAFLD/NASH. Furthermore, metabolic syndrome exacerbates the course of NAFLD/NASH. These factors are able to induce apoptosis and activate immune and inflammatory pathways, resulting in the development of hepatic fibrosis and NASH, leading to progression toward HCC. Small intestinal bacterial overgrowth (SIBO), destruction of the intestinal mucosa barrier function and a high-fat diet all seem to exacerbate the development of hepatic fibrosis and NASH, leading to HCC in patients with NAFLD/NASH. Thus, the intestinal microbiota may play a role in the development of NAFLD/NASH. In this review, we describe recent advances in our knowledge of the molecular mechanisms contributing to the development of hepatic fibrosis and HCC in patients with NAFLD/NASH.
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http://dx.doi.org/10.3390/ijms21041525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073210PMC
February 2020

Dual-molecular barcode sequencing detects rare variants in tumor and cell free DNA in plasma.

Sci Rep 2020 02 25;10(1):3391. Epub 2020 Feb 25.

Department of Gastroenterology, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, Japan.

Conventional next generation sequencing analysis has provided important insights into cancer genetics. However, the detection of rare (low allele fraction) variants remains difficult because of the error-prone nucleotide changes derived from sequencing/PCR errors. To eliminate the false-positive variants and detect genuine rare variants, sequencing technology combined with molecular barcodes will be useful. Here, we used the newly developed dual-molecular barcode technology (Ion AmpliSeq HD) to analyze somatic mutations in 24 samples (12 tumor tissues and 12 plasma) from 12 patients with biliary-pancreatic and non-small cell lung cancers. We compared the results between next generation sequencing analysis with or without molecular barcode technologies. The variant allele fraction (VAF) between non-molecular barcode and molecular barcode sequencing was correlated in plasma DNA (R = 0.956) and tumor (R = 0.935). Both methods successfully detected high VAF mutations, however, rare variants were only identified by molecular barcode sequencing and not by non-molecular barcode sequencing. Some of these rare variants in tumors were annotated as pathogenic, and therefore subclonal driver mutations could be observed. Furthermore, the very low VAF down to 0.17% were identified in cell free DNA in plasma. These results demonstrate that the dual molecular barcode sequencing technologies can sensitively detect rare somatic mutations, and will be important in the investigation of the clonal and subclonal architectures of tumor heterogeneity.
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http://dx.doi.org/10.1038/s41598-020-60361-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042261PMC
February 2020

Identification of Clonality through Genomic Profile Analysis in Multiple Lung Cancers.

J Clin Med 2020 Feb 20;9(2). Epub 2020 Feb 20.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

In cases of multiple lung cancers, individual tumors may represent either a primary lung cancer or both primary and metastatic lung cancers. In this study, we investigated the differences between clinical/histopathological and genomic diagnoses to determine whether they are primary or metastatic. 37 patients with multiple lung cancers were enrolled in this study. Tumor cells were selected from tissue samples using laser capture microdissection. DNA was extracted from those cells and subjected to targeted deep sequencing. In multicentric primary lung cancers, the driver mutation profile was mutually exclusive among the individual tumors, while it was consistent between metastasized tumors and the primary lesion. In 11 patients (29.7%), discrepancies were observed between genomic and clinical/histopathological diagnoses. For the lymph node metastatic lesions, the mutation profile was consistent with only one of the two primary lesions. In three of five cases with lymph node metastases, the lymph node metastatic route detected by genomic diagnosis differed from the clinical and/or pathological diagnoses. In conclusion, in patients with multiple primary lung cancers, cancer-specific mutations can serve as clonal markers, affording a more accurate understanding of the pathology of multiple lung cancers and their lymphatic metastases and thus improving both the treatment selection and outcome.
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http://dx.doi.org/10.3390/jcm9020573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074554PMC
February 2020

Rapid progressive lung cancers harbouring multiple clonal driver mutations with big bang evolution model.

Cancer Genet 2020 02 25;241:51-56. Epub 2019 Dec 25.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan; The University of Tokyo, Tokyo, Japan.

Introduction: Next-generation sequencing (NGS) of multiple metastases in an advanced cancer patient reveals the evolutional history of the tumor. The evolutionary model is clinically valuable because it reflects the future course of the tumorigenic process and prognosis of the patient.

Materials And Methods: We experienced two lung cancer patients whose clinical courses were abruptly deteriorating resulting in very poor prognosis. To investigate the evolutionary model of these patients, we performed targeted sequencing covering whole exons of 53 significantly mutated genes associated with lung cancer of multiple metastases by autopsy. We conducted PyClone analysis to infer subclonal archtecture of multi-lesional samples.

Results: The NGS analysis revealed both patients harboring multiple clonal driver mutations. In Case.1, KRAS Q61H, KEAP1 G333C, STK11 K312*, RBM10 Q320* and MGA I1429V and in Case.2, TP53 R337L, TP53 Q192*, PTEN W274C, RB1 P29fs and CREBBP P696L with high allele fraction were detected in all lesions. These mutations were clustered and occupied major population across multi-lesional tumor samples. Our data suggested their lung cancers progressed with punctuated and big bang evolutional model.

Conclusion: We should pay attention to clinical course of lung cancer patients harboring multiple clonal driver mutations in their primary lesions. Their punctuated and big bang evolutionary process could develop systemic clinically undetectable metastases with an unexpected speed.
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http://dx.doi.org/10.1016/j.cancergen.2019.12.006DOI Listing
February 2020

Multi-regional sequencing reveals clonal and polyclonal seeding from primary tumor to metastases in advanced gastric cancer.

J Gastroenterol 2020 May 7;55(5):553-564. Epub 2020 Jan 7.

Department of Gastroenterology, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.

Background: Tumor metastases to lymph nodes and distant organs are associated with worse prognosis in gastric cancer. However, little is known about the genetic profiles, subclonal architecture, and evolutional processes across primary tumors and metastases.

Methods: We analyzed the genetic alterations of 106 multiregional samples including primary tumors, lymph node metastases, and visceral metastases from 10 patients with advanced gastric cancer. Histologically different portions were obtained by laser-capture microdissection. We reconstructed the subclonal architectures and inferred the primary to lymph or visceral metastatic seeding patterns.

Results: The different histological portions in primary tumors had common mutations, suggesting common ancestral tumor origins transformed into distinct histological types. In almost all cases, TP53 mutations were identified as clonal mutations across primary tumors and metastases. Subclonal reconstruction and phylogenetic analysis showed primary tumors were classified into monoclonal or polyclonal tumors. All monoclonal primary tumors disseminated as metastases with the same tumor composition (100%, 26/26 samples). In contrast, polyclonal primary tumors mainly spread as metastases by way of polyclonal seeding (84%: 37/44 samples).

Conclusions: Clonal mutations were maintained at both the primary and metastatic sites and genetic divergence of these was low. These findings shed light on the genetic basis of primary tumor dissemination and metastatic processes in advanced gastric cancer.
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http://dx.doi.org/10.1007/s00535-019-01659-6DOI Listing
May 2020

Liver diseases in the Asia-Pacific region: a Lancet Gastroenterology & Hepatology Commission.

Lancet Gastroenterol Hepatol 2020 02 15;5(2):167-228. Epub 2019 Dec 15.

Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Taipei, Taiwan.

The Asia-Pacific region is home to more than half of the global population and accounted for 62·6% of global deaths due to liver diseases in 2015. 54·3% of global deaths due to cirrhosis, 72·7% of global deaths due to hepatocellular carcinoma, and more than two-thirds of the global burden of acute viral hepatitis occurred in this region in 2015. Chronic hepatitis B virus (HBV) infection caused more than half of the deaths due to cirrhosis in the region, followed by alcohol consumption (20·8%), non-alcoholic fatty liver disease (NAFLD; 12·1%), and chronic infection with hepatitis C virus (HCV; 15·7%). In 2015, HBV accounted for about half the cases of hepatocellular carcinoma in the region. Preventive strategies for viral hepatitis-related liver disease include increasing access to clean drinking water and sanitation. HBV vaccination programmes for neonates have been implemented by all countries, although birth-dose coverage is extremely suboptimal in some. Availability of screening tests for blood and tissue, donor recall policies, and harm reduction strategies are in their initial stages in most countries. Many governments have put HBV and HCV drugs on their essential medicines lists and the availability of generic versions of these drugs has reduced costs. Efforts to eliminate viral hepatitis as a public health threat, together with the rapid increase in per-capita alcohol consumption in countries and the epidemic of obesity, are expected to change the spectrum of liver diseases in the Asia-Pacific region in the near future. The increasing burden of alcohol-related liver diseases can be contained through government policies to limit consumption and promote less harmful patterns of alcohol use, which are in place in some countries but need to be enforced more strictly. Steps are needed to control obesity and NAFLD, including policies to promote healthy lifestyles and regulate the food industry. Inadequate infrastructure and insufficient health-care personnel trained in liver diseases are issues that also need to be addressed in the Asia-Pacific region. The policy response of most governments to liver diseases has thus far been inadequate and poorly funded. There must be a renewed focus on prevention, early detection, timely referral, and research into the best means to introduce and improve health interventions to reduce the burden of liver diseases in the Asia-Pacific region.
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http://dx.doi.org/10.1016/S2468-1253(19)30342-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164809PMC
February 2020

A case with hepatic portal vein gas who required delayed elective surgery.

Int J Surg Case Rep 2019 6;65:233-237. Epub 2019 Nov 6.

Internal Medicine, Yamanashi Prefectural Central Hospital, Japan.

Introduction: Hepatic portal venous gas (HPVG) is believed to be an indication for emergent surgery because it is associated with high mortality rate. However, the recent increase in the use of modern abdominal computed tomography (CT) has resulted in the detection of HPVG in more benign conditions. Therefore, the decision-making process whether we chose emergent surgery or conservative treatment without surgery is important for the patients with HPVG.

Case Presentation: An 84-year-old male was referred to our hospital due to the sudden onset of abdominal pain and massive hepatic portal vein gas on emergent CT. The Acute Physiology and Chronic Health Evaluation (APACHE) II Score was calculated as 17; slightly elevated comparing with the other cases who were successfully treated without surgery. Although the PHVG was remained at follow up CT on the next day after the onset, the symptoms were improved. We selected conservative treatment without emergent surgery and he discharged on 9 day after the onset. However, he was suffered from right lower abdominal pain and vomiting and admitted our hospital on 23th day. He developed ischemic intestinal stenosis and underwent a surgery of partial resection of ileum.

Conclusions: The clinical finding of this case showing subtle differences from cases who were successfully treated without surgery. We hope this report will help physician's decision-making process for HPVG.
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http://dx.doi.org/10.1016/j.ijscr.2019.10.085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864318PMC
November 2019

Microsatellite instability status is determined by targeted sequencing with MSIcall in 25 cancer types.

Clin Chim Acta 2020 Mar 13;502:207-213. Epub 2019 Nov 13.

Department of Gastroenterology, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, Japan; The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.

Background: Microsatellite instability (MSI) occurs in solid tumors and is a predictive biomarker for remarkable response to immune checkpoint inhibitors. Detection of MSI status has been conventionally conducted by PCR-electrophoresis-based assay (MSI-PCR) and immunohistochemistry (IHC) of mismatch repair proteins. However, these approaches require visual confirmation and involve some difficulties in determining MSI statuses from equivocal results.

Methods: We performed amplicon-based targeted sequencing of 76 microsatellite loci (MSI-NGS) in 184 formalin-fixed paraffin-embedded (FFPE) tumor tissues and baseline control samples. A bioinformatics tool, MSIcall, was used to calculate the quantitative values based on the aligned sequence reads and evaluated MSI status. Furthermore, we examined the concordance between the results from MSI-NGS and MSI-PCR/IHC. Diagnostic accuracy, sensitivity, and specificity were estimated by receiver operating characteristic (ROC) curve analysis. For validation cohort, we studied additional 50 tumor samples to determine the MSI status.

Results: Of 184 tumor samples, MSI-PCR and IHC analysis classified 161 tumors as MSS/pMMR and 23 as MSI-H/dMMR. Using MSI-NGS combined with MSIcall, we predicted MSI status with high accuracy (98.9%), specificity (91.3%), and sensitivity (100%) in 25 types of cancers. This method achieved an area under the ROC curve (AUC) value of 0.9986. Furthermore, we achieved the 100% concordant results using additional 50 samples for validation.

Conclusion: We demonstrated newly developed MSI-NGS with MSIcall accurately determines the MSI status of FFPE tumor tissues thorough sequencing of tumor samples alone without patient-matched normal controls. This approach can be applied to all types of solid tumors to determine responders to immune-oncology therapy.
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http://dx.doi.org/10.1016/j.cca.2019.11.002DOI Listing
March 2020

Accurate detection of KRAS, NRAS and BRAF mutations in metastatic colorectal cancers by bridged nucleic acid-clamp real-time PCR.

BMC Med Genomics 2019 11 11;12(1):162. Epub 2019 Nov 11.

Department of Gastroenterology, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, Japan.

Background: Patients with metastatic colorectal cancer can benefit from anti-EGFR therapy, such as cetuximab and panitumumab. However, colorectal cancers harboring constitutive activating mutations in KRAS, NRAS and BRAF genes are not responsive to anti-EGFR therapy. To select patients for appropriate treatment, genetic testing of these three genes is routinely performed.

Methods: We applied bridged nucleic acid-clamp real-time PCR (BNA-clamp PCR) to detect somatic hotspot mutations in KRAS, NRAS and BRAF. PCR products from BNA-clamp PCR were subsequently analyzed Sanger sequencing. We then compared results with those from the PCR-reverse sequence-specific oligonucleotide probe (PCR-rSSO) method, which has been used as in vitro diagnostic test in Japan. To validate the mutation status, we also performed next generation sequencing using all samples.

Results: In 50 formalin-fixed paraffin-embedded tissues, KRAS mutations were detected at frequencies of 50% (25/50) and 52% (26/50) by PCR-rSSO and BNA-clamp PCR with Sanger sequencing, respectively, and NRAS mutations were detected at 12% (6/50) and 12% (6/50) by PCR-rSSO and BNA-clamp PCR with Sanger sequencing, respectively. The concordance rate for detection of KRAS and NRAS mutations between the two was 94% (47/50). However, there were three discordant results. We validated these three discordant and 47 concordant results by next generation sequencing. All mutations identified by BNA-clamp PCR with Sanger sequencing were also identified by next generation sequencing. BNA-clamp PCR detected BRAF mutations in 6% (3/50) of tumor samples.

Conclusions: Our results indicate that BNA-clamp PCR with Sanger sequencing detects somatic mutations in KRAS, NRAS and BRAF with high accuracy.
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http://dx.doi.org/10.1186/s12920-019-0610-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849194PMC
November 2019

Rapidly declining trend of signet ring cell cancer of the stomach may parallel the infection rate of Helicobacter pylori.

BMC Gastroenterol 2019 Nov 8;19(1):178. Epub 2019 Nov 8.

Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan.

Background: Studies indicate that gastric cancer (GC) incidence has decreased, whereas signet ring cell carcinoma (SRC) incidence has increased. However, recent trends in GC incidence are unclear. We used our hospital cancer registry to evaluate the changes in the incidence of GC, SRC, and non-SRC (NSRC) over time in comparison to changes in the H. pylori infection rates over time.

Methods: We identified 2532 patients with GC enrolled in our registry between January 2007 and December 2018 and statistically analyzed SRC and NSRC incidence. The H. pylori infection rate in patients with SRC was determined by serum anti-H. pylori antibody testing, urea breath test, biopsy specimen culture, and immunohistochemical analysis (IHC) of gastric tissue. Additionally, genomic detection of H. pylori was performed in SRCs by extracting DNA from formalin-fixed paraffin-embedded gastric tissue and targeting 16S ribosomal RNA of H. pylori.

Results: Overall, 211 patients had SRC (8.3%). Compared with patients with NSRC, those with SRC were younger (P <  0.001) and more likely to be female (P <  0.001). Time series analysis using an autoregressive integrated moving average model revealed a significant decrease in SRC (P <  0.001) incidence; NSRC incidence showed no decline. There was no difference in H. pylori infection prevalence between the SRC and NSRC groups. IHC and genomic methods detected H. pylori in 30 of 37 (81.1%) SRCs.

Conclusions: Reduction in H. pylori infection prevalence may be associated with the decrease in the incidence of SRC, which was higher than that of NSRC.
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http://dx.doi.org/10.1186/s12876-019-1094-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842265PMC
November 2019

PD-L1 Expression and Tumor-Infiltrating Lymphocytes in Thymic Epithelial Neoplasms.

J Clin Med 2019 Nov 1;8(11). Epub 2019 Nov 1.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Thymic epithelial tumors (TETs) are rare malignant mediastinal tumors that are difficult to diagnose and treat. The programmed death 1 (PD-1) receptor and its ligand (PD-L1) are expressed in various malignant tumors and have emerged as potential immunotherapeutic targets. However, the immunobiology of TETs is poorly understood. We evaluated PD-L1 expression and the presence of tumor-infiltrating lymphocytes (CD8 and CD3 expression) in surgical TET specimens from 39 patients via immunohistochemistry and determined their relation to clinicopathological parameters. Cases with membranous reactivity of the PD-L1 antibody in ≥1% of tumor cells were considered positive. Positive PD-L1 expression was observed in 53.9% of cases. Histologically, PD-L1 expression was positive in 2/6 type A, 2/6 type AB, 3/9 type B1, 4/4 type B2, 5/6 type B3, and 5/8 type C TET cases. Thus, the number of cases with PD-L1 expression and the percent expression of PD-L1 were significantly higher in more aggressive thymomas (type B2 or B3). CD3+ and CD8+ tumor-infiltrating lymphocytes were diffusely and abundantly distributed in all cases. These data suggest that a PD-1/PD-L1 blockade is a promising treatment for TETs, with more beneficial treatment effects for aggressive thymomas such as type B2 or B3.
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http://dx.doi.org/10.3390/jcm8111833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912585PMC
November 2019

APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation.

Hepatol Int 2019 Nov 20;13(6):649-661. Epub 2019 Sep 20.

Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan.

In the direct-acting antiviral (DAA) era for hepatitis C virus (HCV) infection, sustained virological response (SVR) is very high, but close attention must be paid to the possible occurrence of hepatocellular carcinoma (HCC) and reactivation of hepatitis B virus (HBV) in patients with co-infection who achieved SVR in short term. HCC occurrence was more often observed in patients with previous HCC history. We found occurrence of HCC in 178 (29.6%) of 602 patients with previous HCC history (15.4 months mean follow-up post-DAA initiation) but, in contrast, in only 604 (1.3%) of 45,870 patients without previous HCC history (18.2 months mean follow-up). Thus, in these guidelines, we recommend the following: in patients with previous HCC history, surveillance at 4-month intervals for HCC by ultrasonography (US) and tumor markers should be performed. In patients without previous HCC history, surveillance at 6- to 12-month intervals for HCC including US is recommended until the long-term DAA treatment effects, especially for the resolution of liver fibrosis, are confirmed. This guideline also includes recommendations on how to follow-up patients who have been infected with both HCV and HBV. When HCV was eradicated in these HBsAg-positive patients or patients with previous HBV infection (anti-HBc and/or anti-HBs-positive), it was shown that HBV reactivation or HBV DNA reappearance was observed in 67 (41.4%) of 162 or 12 (0.9%) of 1317, respectively. For these co-infected patients, careful attention should be paid to HBV reactivation for 24 weeks post-treatment.
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http://dx.doi.org/10.1007/s12072-019-09988-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861433PMC
November 2019

Genomic profile of urine has high diagnostic sensitivity compared to cytology in non-invasive urothelial bladder cancer.

Cancer Sci 2019 Oct 10;110(10):3235-3243. Epub 2019 Aug 10.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan.

Cytology is widely conducted for diagnosis of urothelial bladder cancer; however, its sensitivity is still low. Recent studies show that liquid biopsies can reflect tumor genomic profiles. We aim to investigate whether plasma or urine is more suitable for detecting tumor-derived DNA in patients with early-stage urothelial bladder cancer. Targeted sequencing of 71 genes was carried out using a total of 150 samples including primary tumor, urine supernatant, urine precipitation, plasma and buffy coat from 25 patients with bladder cancer and five patients with cystitis and benign tumor. We compared mutation profiles between each sample, identified tumor-identical mutations and compared tumor diagnostic sensitivities between urine and conventional cytology. We identified a total of 168 somatic mutations in primary tumor. In liquid biopsies, tumor-identical mutations were found at 53% (89/168) in urine supernatant, 48% (81/168) in urine precipitation and 2% (3/168) in plasma. The high variant allele fraction of urine was significantly related to worse clinical indicators such as tumor invasion and cytological examination. Although conventional cytology detected tumor cells in only 22% of non-invasive tumor, tumor diagnostic sensitivity increased to 67% and 78% using urine supernatant and precipitation, respectively. Urine is an ideal liquid biopsy for detecting tumor-derived DNA and more precisely reflects tumor mutational profiles than plasma. Genomic analysis of urine is clinically useful for diagnosis of superficial bladder cancer at early stage.
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http://dx.doi.org/10.1111/cas.14155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778642PMC
October 2019

Clinical Implications of Noncoding Indels in the Surfactant-Encoding Genes in Lung Cancer.

Cancers (Basel) 2019 Apr 17;11(4). Epub 2019 Apr 17.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Lung cancer arises from the accumulation of genetic mutations, usually in exons. A recent study identified indel mutations in the noncoding region of surfactant-encoding genes in lung adenocarcinoma cases. In this study, we recruited 94 patients with 113 lung cancers (88 adenocarcinomas, 16 squamous cell carcinomas, and nine other histologies) who had undergone surgery in our department. A cancer panel was designed in-house for analyzing the noncoding regions, and targeted sequencing was performed. Indels in the noncoding region of surfactant-encoding genes were identified in 29/113 (25.7%) cases and represent the precise cell of origin for the lung cancer, irrespective of histological type and/or disease stage. In clinical practice, these indels may be used as clonal markers in patients with multiple cancers and to determine the origin of cancer of unknown primary site.
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http://dx.doi.org/10.3390/cancers11040552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520783PMC
April 2019

Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review.

Int J Mol Sci 2019 Mar 18;20(6). Epub 2019 Mar 18.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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http://dx.doi.org/10.3390/ijms20061358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470669PMC
March 2019

Validation of Tokyo Guideline 2013 as Treatment of Acute Cholecystitis by Real World Data.

Dig Dis 2019 7;37(4):303-308. Epub 2019 Feb 7.

Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Yamanashi, Japan.

Background: The Tokyo Guidelines (TG; 2013) indicated that emergency cholecystectomy is an important early treatment option for acute cholecystitis; however, surgical intervention is not necessarily indicated in patients with advanced age. We evaluated percutaneous transhepatic gallbladder aspiration (PTGBA), percutaneous transhepatic gallbladder drainage (PTGBD), and the administration of antibiotics alone as treatment options for acute -cholecystitis.

Methods: From January 2010 to December 2017, 159 patients with acute cholecystitis were treated at our institution. The data from these patients were retrospectively analyzed.

Results: Of these 159 cases, 109 underwent PTGBA, 28 underwent PTGBD, and 22 were administered antibiotics alone. None of the 159 patients needed urgent (early) cholecystectomy, and all patients were discharged without mortality. PTGBA was unsuccessful in only 6 of 109 patients; PTGBD was performed in these 6 cases. Long-term follow-up was conducted in all cases. Of the 159 patients, 146 had gallbladder stones initially, while 13 had none at the time of presentation. Of these 146 patients with gallbladder stones, 84 underwent elective cholecystectomy, while 62 did not. Of the 84 patients who underwent elective cholecystectomy, 2 developed choledocholithiasis; of the 62 patients who did not undergo elective cholecystectomy, 5 developed choledocholithiasis and 2 developed acute cholecystitis. The incidences of choledocholithiasis and acute cholecystitis did not significantly differ between the 2 groups (p = 0.06).

Conclusions: Despite the recommendations in the TG (2013), emergency cholecystectomy was not needed in any of the present patients with acute cholecystitis. Acute cholecystitis can be successfully treated with -PTGBA or PTGBD, which are simple procedures with good short- and long-term safety. These procedures are highly recommended for patients with acute cholecystitis, especially in the elderly population.
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http://dx.doi.org/10.1159/000496738DOI Listing
May 2019

Deficiency of mismatch repair genes is less frequently observed in signet ring cell compared with non-signet ring cell gastric cancer.

Med Oncol 2019 Jan 29;36(3):23. Epub 2019 Jan 29.

Genome Analysis Center, Yamanashi Central Hospital, 1-1-1, Fujimi, Kofu, Yamanashi, Japan.

Signet ring cell (SRC) gastric cancer at advanced stage has poor prognosis. While a recent study reported nearly one-third of SRC cases contain tumors with deficient mismatch repair (MMR) genes, other studies in SRC have been inconclusive. To re-analyze the results, we performed immunohistochemical staining of MLH1, MSH2, MSH6 and PMS2 proteins in 38 SRC gastric tumors compared with 109 non-SRC (NSRC) tumors from 94 patients. In contrast to the previous study, all SRC gastric tumors normally expressed MMR proteins, whereas 22 of 109 of NSRC (20%) showed deficient MMR proteins. To reinforce our results, we referred to the Cancer Genome Atlas (TCGA) genomic database and found that only 6 (6%) of 99 samples with diffuse gastric tumors showed deficient MMR, whereas 64 (21%) of 304 in intestinal gastric tumors showed deficient MMR. Our results as well as the TCGA database indicated that MMR genes are infrequently inactivated in SRC gastric cancer. These findings indicate that SRC patients may not be the best candidates for immuno-oncology therapy.
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http://dx.doi.org/10.1007/s12032-019-1246-4DOI Listing
January 2019

The efficacy and safety of lenvatinib for advanced hepatocellular carcinoma in a real-world setting.

Hepatol Int 2019 Mar 22;13(2):199-204. Epub 2019 Jan 22.

Department of Gastroenterology, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu, 400-8506, Yamanashi, Japan.

Background/purpose: Lenvatinib (an inhibitor of vascular endothelial growth factor (GF) receptors 1-3, fibroblast GF receptors 1-4, platelet-derived GF receptor α, rearranged during transfection, and stem cell factor receptor) was non-inferior to sorafenib in a phase 3 (REFLECT) trial of advanced hepatocellular carcinoma. This study examined the efficacy and safety of lenvatinib in a real-world setting.

Methods: This was a retrospective, multicenter, observational study. Inclusion and exclusion criteria were based on the phase 3 trial, and participants were observed for at least 12 weeks. Therapeutic effect was determined using the modified Response Evaluation Criteria In Solid Tumors (m-RECIST) at the 8th week. Patients received oral lenvatinib 12 mg/day (body weight > 60 kg) or 8 mg/day (body weight < 60 kg). Dose interruptions followed by reductions for lenvatinib-related toxicities were permitted. Grades of adverse events (AEs) complied with the Common Terminology Criteria for Adverse Events version 4.0.

Results: All 16 patients included in this study had prior treatment history, and a median 3.9 years had passed since the first treatment. Fatigue, hypertension, and proteinuria were the most frequent AEs, and were higher than Grade 2. AEs could be controlled by appropriate dose reduction, interruption, and symptomatic treatment according to the protocol. In the m-RECIST evaluation at the 8th week, 0, 6, 8, and 1 patients had achieved complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 40%.

Conclusion: Lenvatinib treatment could be accomplished with safety and good response in a real-world setting.
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http://dx.doi.org/10.1007/s12072-019-09929-4DOI Listing
March 2019

Molecular subtype switching in early-stage gastric cancers with multiple occurrences.

J Gastroenterol 2019 Aug 21;54(8):674-686. Epub 2019 Jan 21.

Department of Gastroenterology, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, Japan.

Background: Multiple gastric cancers at the same time (synchronous) or recurrence after 1 year (metachronous) are frequently encountered. Since their genetic profiles were not well elucidated, we molecularly subtyped the genetic events of synchronous and metachronous early-stage gastric cancers.

Methods: We studied mismatch repair (MMR) genes in 84 tumors from 31 patients (15 synchronous and 16 metachronous) by immunohistochemistry. We performed microsatellite instability analysis and targeted sequencing of 58 significantly mutated genes (SMGs) in 35 tumors from thirteen patients. Genomic data from TCGA were used for comparisons with advanced-stage cancers.

Results: Among the 31 patients, at least one deficient-MMR (dMMR) tumor was observed in eight (26%). Of eight patients, seven showed a mixture of proficient-MMR (pMMR) and dMMR tumors. The one case with only dMMR had six recurrent tumors within 2 years. To further subtype, we sequenced 58 SMGs in 35 samples (25 pMMR and 10 dMMR) from thirteen patients. In 35 samples, 163 mutations were identified, but none matched in almost cases, strongly indicating different clonal origins, whether synchronous or metachronous occurrences. Of the 25 pMMR cases, 1 belonged to Epstein-Barr virus (EBV), 24 belonged to chromosomal instability (CIN) subtypes. Of the thirteen cases, repetitive CIN, a mixture of CIN and MSI, a mixture of CIN and EBV, and repetitive MSI were observed in nine (70%), two (15%), one (8%) and one (8%), respectively.

Conclusions: Despite multiple tumors occurring in the same patient simultaneously or several years apart, clonal origin was totally different. 'Switching' or 'mixing' of dMMR and pMMR, EBV or CIN occurred, which had clinical relevance with regard to immunotherapy.
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http://dx.doi.org/10.1007/s00535-019-01547-zDOI Listing
August 2019

Durable response by olaparib for a Japanese patient with primary peritoneal cancer with multiple brain metastases: A case report.

J Obstet Gynaecol Res 2019 Mar 22;45(3):743-747. Epub 2018 Nov 22.

Genome Analysis Center, Yamanashi Prefectural Central Hospital, Yamanashi, Japan.

Brain metastases (BM) from epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) are extremely rare, accounting for 1-2.5% of all cases. Although therapeutic options, such as surgery, irradiation and chemotherapy are proven to yield survival benefit, the overall prognosis of these patients remains unsatisfactory. Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, olaparib is useful for patients with recurrent EOC or PPC. However, reports suggesting the efficacy of PARP inhibitors for patients with EOC or PPC with BM are limited. We report the case of a 58-year-old Japanese woman with recurrent PPC with multiple BM. After obtaining informed consent from the patient, we performed BRCA testing that detected a deleterious BRCA 1 mutation. At that time, olaparib was not yet approved in Japan, we learned about the compassionate use program of olaparib called Managed Access Program (MAP). Of note, we have established a system to enroll patients in MAP. After olaparib treatment, the patient exhibited a considerable decrease of BMs. Eighteen months since the initiation of olaparib treatment, the patient has reported no evidence of disease progression. Olaparib maintenance treatment could be effective for Japanese patients with PPC and multiple BMs.
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http://dx.doi.org/10.1111/jog.13851DOI Listing
March 2019

APASL clinical practice recommendation: how to treat HCV-infected patients with renal impairment?

Hepatol Int 2019 Mar 11;13(2):103-109. Epub 2018 Dec 11.

Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan.

Chronic hepatitis C virus (HCV) infection is common among patients with chronic kidney disease (CKD) and those on hemodialysis due to nosocomial infections and past blood transfusions. While a majority of HCV-infected patients with end-stage renal disease are asymptomatic, some may ultimately experience decompensated liver diseases and hepatocellular carcinoma. Administration of a combination of elbasvir/grazoprevir for 12 weeks leads to high sustained virologic response (SVR) rates in patients with HCV genotypes (GTs) 1a, 1b or 4 and stage 4 or 5 CKD. Furthermore, a combination of glecaprevir/pibrentasvir for 8-16 weeks also results in high SVR rates in patients with all HCV GTs and stage 4 or 5 CKD. However, these regimens are contraindicated in the presence of advanced decompensated cirrhosis. Although sofosbuvir and/or ribavirin are not generally recommended for HCV-infected patients with severe renal impairment, sofosbuvir-based regimens may be appropriate for those with mild renal impairment. To eliminate HCV worldwide, HCV-infected patients with renal impairment should be treated with interferon-free therapies.
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http://dx.doi.org/10.1007/s12072-018-9915-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418053PMC
March 2019

Genomic Characteristics of Invasive Mucinous Adenocarcinomas of the Lung and Potential Therapeutic Targets of B7-H3.

Cancers (Basel) 2018 Nov 30;10(12). Epub 2018 Nov 30.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Pulmonary invasive mucinous adenocarcinoma (IMA) is considered a variant of lung adenocarcinomas based on the current World Health Organization classification of lung tumors. However, the molecular mechanism driving IMA development and progression is not well understood. Thus, we surveyed the genomic characteristics of IMA in association with immune-checkpoint expression to investigate new potential therapeutic strategies. Tumor cells were collected from surgical specimens of primary IMA, and sequenced to survey 53 genes associated with lung cancer. The mutational profiles thus obtained were compared in silico to conventional adenocarcinomas and other histologic carcinomas, thereby establishing the genomic clustering of lung cancers. Immunostaining was also performed to compare expression of programmed death ligand 1 (PD-L1) and B7-H3 in IMA and conventional adenocarcinomas. Mutations in Kirsten rat sarcoma viral oncogene homolog () were detected in 75% of IMAs, but in only 11.6% of conventional adenocarcinomas. On the other hand, the frequency of mutations in epidermal growth factor receptor () and tumor protein p53 ) genes was 5% and 10%, respectively, in the former, but 48.8% and 34.9%, respectively, in the latter. Clustering of all 78 lung cancers indicated that IMA is distinct from conventional adenocarcinoma or squamous cell carcinoma. Strikingly, expression of PD-L1 in ≥1% of cells was observed in only 6.1% of IMAs, but in 59.7% of conventional adenocarcinomas. Finally, 42.4% and 19.4% of IMAs and conventional adenocarcinomas, respectively, tested positive for B7-H3. Although currently classified as a variant of lung adenocarcinoma, it is also reasonable to consider IMA as fundamentally distinct, based on mutation profiles and genetic clustering as well as immune-checkpoint status. The immunohistochemistry data suggest that B7-H3 may be a new and promising therapeutic target for immune checkpoint therapy.
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http://dx.doi.org/10.3390/cancers10120478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316015PMC
November 2018

Relationship between formalin reagent and success rate of targeted sequencing analysis using formalin fixed paraffin embedded tissues.

Clin Chim Acta 2019 Jan 3;488:129-134. Epub 2018 Nov 3.

Genome Analysis Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi 400-8506, Japan; The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, Japan.

Background: Tumor genetic alterations are determined to aid in selecting therapy and predicting prognosis. In routine clinical practice, targeted sequencing analysis is performed using formalin-fixed paraffin embedded (FFPE) tissues. However, successful genetic analysis remains challenging because FFPE DNA is fragmented during the sample preparation process.

Methods: Real-time PCR was performed to assess DNA quality and quantities. Targeted sequencing was performed using FFPE tissues fixed with different types of formalin.

Results: DNA was less fragmented from samples fixed in low formalin concentration (10% vs. 20%) and neutral buffered conditions (neutral buffered vs. non-neutral). DNA fragmentation increased over the fixation time. In a preliminary test study, we compared fixation using 10% neutral buffered formalin (n = 180) and 20% formalin (n = 26). The success rate of targeted analysis was higher using 10% neutral formalin (98.3%; 177/180) compared with 20% formalin (34.6%; 9/26). In a validation study with additional formalin-fixed paraffin embedded tissues fixed with 10% neutral buffered formalin (n = 860), we reproduced these results and achieved a high success rate for targeted sequencing analysis (98.4%; 846/860).

Conclusion: Our data show that 10% neutral buffered formalin is recommended for fixation of formalin-fixed paraffin embedded samples to achieve high success rate of targeted sequencing analysis.
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http://dx.doi.org/10.1016/j.cca.2018.11.002DOI Listing
January 2019

Prediction of the very early occurrence of HCC right after DAA therapy for HCV infection.

Hepatol Int 2018 Nov 21;12(6):523-530. Epub 2018 Sep 21.

Department of Gastroenterology, Yamanashi Central Hospital, Kofu, Yamanashi, Japan.

Background: Although direct-acting antiviral (DAA) developments make most of hepatitis C virus (HCV) infection curable, some HCV patients develop hepatocellular carcinoma (HCC) after curative treatment of HCV. There is much dispute whether the rapid clearance of the virus enhances the HCC development. In advance of the dispute, we should make clear the characteristics of the patients with very early occurrence and recurrence of HCC after DAA therapy because it was still unclear.

Methods: We prospectively followed consecutive patients with HCV who had received sofosbuvir (SOF)-based treatment at two hospitals. The baseline characteristics, laboratory data, and liver imaging findings were acquired. We evaluated the rate of HCC occurrence and recurrence within 1-year after DAA therapy and analyzed the associated factors of very early HCC occurrence and recurrence right after SOF therapy.

Results: Between July 2013 and October 2016, we studied two cohorts with HCV infection that received SOF therapy. 402 and 462 patients in Yamanashi Central Hospital and Chiba University Hospital were included in this analysis, respectively. The SVR12 rates of genotypes 1 and 2 were 98.9% (561/567) and 96.0% (285/297), respectively. 41 patients developed HCC within 1 year after SOF therapy. The cumulative HCC occurrence and recurrence rate after SOF therapy was 5.0%. The common associated factor of 1-year HCC occurrence and recurrence in all cohorts was the existence of imaging "dysplastic nodule".

Conclusions: SOF regimens for HCV also have very high rates of SVR 12 in the post-market distribution. The appearance of imaging "dysplastic nodule" was an associated factor of 1-year HCC occurrence and recurrence. To investigate existence of "dysplastic nodule" by imaging surveillance before DAA treatment is useful to detect high-risk patients of very early HCC occurrence and recurrence and it should be performed.
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http://dx.doi.org/10.1007/s12072-018-9895-5DOI Listing
November 2018
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