Publications by authors named "Tatsuya Yamashita"

184 Publications

Treatment patterns and medical costs after hepatectomy in real-world practice for patients with hepatocellular carcinoma in Japan.

Hepatol Res 2021 Jul 19. Epub 2021 Jul 19.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.

Aim: To examine the treatment patterns and medical costs in real-world practice among patients who received hepatectomy for hepatocellular carcinoma (HCC) in Japan.

Methods: Data of patients who underwent hepatectomy as an initial therapy for primary HCC were extracted from a Japanese medical claims database from April 2008 to December 2019. The types of additional treatments for recurrent HCC and medical costs for up to 3 years from the first hepatectomy were analyzed. The average cumulative cost per patient starting on the date of the first hepatectomy was calculated using the Kaplan-Meier sample-average method.

Results: Data from 2,342 patients (median age, 71 years) were analyzed. Overall, 35.6% of patients received at least one HCC treatment within 3 years of the first hepatectomy. The total average cumulative 3-year medical cost was JPY 4,993,300 (95% confidence interval [CI]: 4,804,100 to 5,220,500). Surgical procedures were the most costly components in the first month after hepatectomy, whereas the costs of drugs, which mainly included antiviral and antineoplastic medications, increased thereafter. Patients with advanced stage HCC, hepatitis C, or a higher Charlson Comorbidity Index at hepatectomy, or those who required additional treatment, especially with antineoplastic drugs for recurrent HCC, incurred higher medical costs.

Conclusions: Patients with HCC after hepatectomy experienced a large economic burden, which was more serious for those with advanced stage HCC, higher comorbidities, and hepatitis at baseline and for patients treated with antineoplastic drugs. A treatment selection that considers its medical cost burden would help to reduce some of these economic burdens. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/hepr.13701DOI Listing
July 2021

Dysbiotic gut microbiota in pancreatic cancer patients form correlation networks with the oral microbiota and prognostic factors.

Am J Cancer Res 2021 15;11(6):3163-3175. Epub 2021 Jun 15.

Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University 13-1 Takara-Machi, Kanazawa, Ishikawa, Japan.

Microbiota in the gut and oral cavities of pancreatic cancer (PC) patients differ from those of healthy persons, and bacteria in PC tissues are associated with patients' prognoses. However, the species-level relationship between a dysbiotic gut, oral and cancerous microbiota, and prognostic factors remains unknown. Whole-genome sequencing was performed with fecal DNA from 24 PC patients and 18 healthy persons (HD). Microbial taxonomies, metabolic pathways, and viral presence were determined. DNA was sequenced from saliva and PC tissues, and the association between the gut, oral, and cancer microbiota and prognostic factors in PC patients was analyzed. The PC microbiota were altered from those of the healthy microbiota in terms of microbial taxonomy, pathways and viral presence. Twenty-six species differed significantly between the PC and HD microbiota. Six fecal microbes, including , were associated with an increased hazard of death. In the co-occurrence network, microbes that were abundant in PC patients were plotted close together and formed clusters with prognosis-associated microbes, including . Multiple salivary microbes were present in the co-occurrence network. and were detected in the PC tissues and formed a network with the fecal and salivary microbes. The dysbiotic gut microbiota in the PC patients formed a complex network with the oral and cancerous microbiota, and gut microbes abundant in the PC patients were closely linked with poor prognostic factors in the network.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263681PMC
June 2021

Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: A Subgroup Analysis of Asian Patients in the Phase 3 KEYNOTE-240 Trial.

Liver Cancer 2021 Jun 27;10(3):275-284. Epub 2021 Apr 27.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Introduction: KEYNOTE-240 investigated the efficacy and safety of pembrolizumab plus best supportive care (BSC) in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC). Results for the subgroup of patients from Asia are described.

Methods: Adults with advanced HCC previously treated with sorafenib were randomized 2:1 to pembrolizumab or placebo plus BSC. Here, the Asian subgroup comprised patients enrolled in Hong Kong, Japan, Korea, the Philippines, Taiwan, and Thailand. Primary endpoints were progression-free survival (PFS) per blinded central imaging review and overall survival (OS). Secondary endpoints included objective response rate (ORR) per blinded central imaging review, duration of response (DOR), and safety.

Results: The Asian subgroup included 157 patients. As of January 2, 2019, the median follow-up in this subgroup was 13.8 months for pembrolizumab and 8.3 months for placebo. The median PFS was 2.8 months for pembrolizumab (95% confidence interval [CI] 2.6-4.1) versus 1.4 months (95% CI 1.4-2.4) for placebo (hazard ratio [HR] 0.48; 95% CI 0.32-0.70). The median OS was 13.8 months (95% CI 10.1-16.9) for pembrolizumab versus 8.3 months (95% CI 6.3-11.8) for placebo (HR 0.55; 95% CI 0.37-0.80). ORR was 20.6% (95% CI 13.4-29.5) for pembrolizumab versus 2.0% (95% CI 0.1-10.6) for placebo (difference: 18.5%; 95% CI 8.3-27.6). The median DOR was 8.6 and 2.8 months for pembrolizumab and placebo, respectively. Any grade treatment-related adverse events (TRAEs) occurred in 63 patients (58.9%) receiving pembrolizumab and 24 patients (48.0%) receiving placebo; 14 (13.1%) and 2 (4.0%) patients experienced grade 3-5 TRAEs, respectively. No treatment-related deaths occurred.

Conclusion: Pembrolizumab demonstrated antitumor activity and was well tolerated in the Asian subgroup of KEYNOTE-240. A trend toward greater benefit with pembrolizumab in the Asian subgroup was observed compared with the overall cohort, supporting further evaluation of pembrolizumab treatment in this population.
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http://dx.doi.org/10.1159/000515553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237794PMC
June 2021

Comparison of gemcitabine-based chemotherapies for advanced biliary tract cancers by renal function: an exploratory analysis of JCOG1113.

Sci Rep 2021 Jun 18;11(1):12885. Epub 2021 Jun 18.

Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan.

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504-0.937) in the low CCr group. Although the total number of incidences of all Grade 3-4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.
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http://dx.doi.org/10.1038/s41598-021-92166-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213853PMC
June 2021

Restorative effect of adipose tissue-derived stem cells on impaired hepatocytes through Notch signaling in non-alcoholic steatohepatitis mice.

Stem Cell Res 2021 Jul 6;54:102425. Epub 2021 Jun 6.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan. Electronic address:

Adipose tissue-derived stem cells (ADSCs) have been suggested as a novel treatment for non-alcoholic steatohepatitis (NASH); however, the mechanisms underlying their therapeutic effect remain poorly understood. In this study, we aimed to investigate the association of Notch signaling, which is crucial for cellular proliferation and differentiation in ADSC-mediated treatment of NASH. Flow cytometry analysis of ADSCs showed that they expressed the Notch ligands JAG1, DLL1, and DLL4. The expression of genes associated with the Notch signaling pathway was attenuated in hepatocytes of NASH model mice. We further observed ADSC-mediated activation of Notch signaling in these hepatocytes in addition to an increase in proliferating cell nuclear antigen cells and a decrease in TdT-mediated dUTP-biotin nick end labeling apoptotic cells. Co-culture of palmitic acid-induced steatotic hepatocytes and ADSCs resulted in the activation of Notch signaling and reduction of apoptosis of steatotic hepatocytes. Moreover, inhibition of Notch signaling by a γ-secretase inhibitor and knockdown of Notch ligands using siRNA attenuated the anti-apoptotic effect of co-cultured ADSCs in vitro. Our findings show that the Notch signaling pathway is involved in the inhibition of apoptosis and restoration of cellular proliferation of hepatocytes from NASH mice following ADSC treatment.
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http://dx.doi.org/10.1016/j.scr.2021.102425DOI Listing
July 2021

Clinical trial of autologous adipose tissue-derived regenerative (stem) cells therapy for exploration of its safety and efficacy.

Regen Ther 2021 Dec 21;18:97-101. Epub 2021 May 21.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.

Introduction: Liver cirrhosis is the ultimate condition of chronic liver diseases. Non-alcoholic steatohepatitis and fatty liver diseases are emerging in association with metabolic syndrome largely due to excess nutrition. Stromal cells of adipose tissue are enriched mesenchymal stem cells which are pluripotent and immunomodulatory, which are expected to be applied for repairing/regenerative therapy of the impaired organs.

Methods: We conducted the multi-institutional clinical trial (Japanese UMIN Clinical Trial Registry: UMIN000022601) of cell therapy using freshly isolated autologous adipose tissue-derived regenerative (stem) cells (ADRCs), which are obtained by the investigational trial device, adipose tissue dissociation device, for liver cirrhosis patients due to non-alcoholic steatohepatitis or fatty liver disease, to exploratory assess efficacy as well as safety of this trial. We completed treatment and 24 weeks follow-up for 7 patients.

Results: We observed that 6 out of 7 patients' serum albumin concentration was improved. As for prothrombin activity, 5 out of 7 patients showed improvement. No trial-related adverse events, which were serious or non-serious, was observed. Besides, no malfunction of the investigational trial device was encountered.

Conclusion: Thus, treatment with autologous ADRCs obtained with the investigational trial device in steatohepatitis-related cirrhosis was confirmed to be safely conductible and potentially promising for the retaining or improving the impaired hepatic reserve.
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http://dx.doi.org/10.1016/j.reth.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165289PMC
December 2021

Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial.

Lancet Gastroenterol Hepatol 2021 Aug 2;6(8):649-658. Epub 2021 Jun 2.

FSBSI N N Blokhin Russian Cancer Research Center, Moscow, Russia.

Background: Hepatocellular carcinoma is the third-leading cause of cancer-related death worldwide. Preservation of health-related quality of life (HRQOL) during treatment is an important therapeutic goal. The aim of this study was to evaluate the effect of treatment with lenvatinib versus sorafenib on HRQOL.

Methods: REFLECT was a previously published multicentre, randomised, open-label, non-inferiority phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment for unresectable hepatocellular carcinoma. Eligible patients were aged 18 years or older with unresectable hepatocellular carcinoma and one or more measurable target lesion per modified Response Evaluation Criteria in Solid Tumors criteria, Barcelona Clinic Liver Cancer stage B or C categorisation, Child-Pugh class A, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or lower, and adequate organ function. Patients were randomly assigned (1:1) via an interactive voice-web response system; stratification factors for treatment allocation included region; macroscopic portal vein invasion, extrahepatic spread, or both; ECOG performance status; and bodyweight. Patient-reported outcomes (PROs), collected at baseline, on day 1 of each subsequent cycle, and at the end of treatment, were evaluated in post-hoc analyses of secondary and exploratory endpoints in the analysis population, which was the subpopulation of patients with a PRO assessment at baseline. A linear mixed-effects model evaluated change from baseline in PROs, including European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and hepatocellular carcinoma-specific QLQ-HCC18 scales (both secondary endpoints of the REFLECT trial). Time-to-definitive-deterioration analyses were done based on established thresholds for minimum differences for worsening in PROs. Responder analyses explored associations between HRQOL and clinical response. This study is registered with ClinicalTrials.gov, NCT01761266.

Findings: Of 954 eligible patients randomly assigned to lenvatinib (n=478) or sorafenib (n=476) between March 14, 2013, and July 30, 2015, 931 patients (n=468 for lenvatinib; n=463 for sorafenib) were included in this analysis. Baseline PRO scores reflected impaired HRQOL and functioning and considerable symptom burden relative to full HRQOL. Differences in overall mean change from baseline estimates in most PRO scales generally favoured the lenvatinib over the sorafenib group, although the differences were not nominally statistically or clinically significant. Patients treated with lenvatinib experienced nominally statistically significant delays in definitive, meaningful deterioration on the QLQ-C30 fatigue (hazard ratio [HR] 0·83, 95% CI 0·69-0·99), pain (0·80, 0·66-0·96), and diarrhoea (0·52, 0·42-0·65) domains versus patients treated with sorafenib. Significant differences in time to definitive deterioration were not observed for other QLQ-C30 domains, and there was no difference in time to definitive deterioration on the global health status/QOL score (0·89, 0·73-1·09). For most PRO scales, differences in overall mean change from baseline estimates favoured responders versus non-responders. Across all scales, HRs for time to definitive deterioration were in favour of responders; median time to definitive deterioration for responders exceeded those for non-responders by a range of 4·8 to 14·6 months.

Interpretation: HRQOL for patients undergoing treatment for unresectable hepatocellular carcinoma is an important therapeutic consideration. The evidence of HRQOL benefits in clinically relevant domains support the use of lenvatinib compared with sorafenib to delay functional deterioration in advanced hepatocellular carcinoma.

Funding: Eisai and Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S2468-1253(21)00110-2DOI Listing
August 2021

The dorsal hippocampus is required for the formation of long-term duration memories in rats.

Eur J Neurosci 2021 Jul 21;54(2):4595-4608. Epub 2021 Jun 21.

Graduate School of Psychology, Doshisha University, Kyotanabe, Japan.

Interval timing-the perception of durations mainly in seconds or minutes-is a ubiquitous behavior in organisms. Animal studies have suggested that the hippocampus plays an essential role in duration memory; however, the memory processes involved are unclear. To clarify the role of the dorsal hippocampus in the acquisition of long-term duration memories, we adapted the "time-shift paradigm" to a peak-interval procedure. After a sufficient number of training with an initial target duration (20 s), the rats underwent "shift sessions" with a new target duration (40 s) under a muscimol (0.5 µg per side) infusion into the bilateral dorsal hippocampus. The memory of the new target duration was then tested in drug-free "probe sessions," including trials in which no lever presses were reinforced. In the probe sessions, the mean response rate distribution of the muscimol group was located leftward to the control group, but these two response rate distributions were superimposed on the standardized time axis, suggesting a scalar property. In the session-by-session analysis, the mean peak time (an index of timing accuracy) of the muscimol group was lower than that of the control group in the probe sessions, but not in the shift sessions. These findings suggest that the dorsal hippocampus is required for the formation of long-term duration memories within the range of interval timing.
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http://dx.doi.org/10.1111/ejn.15328DOI Listing
July 2021

Impact of hepatitis C virus on survival in patients undergoing resection of intrahepatic cholangiocarcinoma: Report of a Japanese nationwide survey.

Hepatol Res 2021 May 26. Epub 2021 May 26.

Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.

Aim: We reviewed the data of a nationwide follow-up survey to determine the impact of hepatitis C virus (HCV) infection on the outcomes of hepatectomy for mass-forming (MF) type, and combined mass-forming and periductal infiltrating (MF + PI) type intrahepatic cholangiocarcinoma (ICC).

Methods: In total, 956 patients with ICC who underwent curative hepatic resection were included in this cohort study, and patients were classified according to virus status. Patients were classified according to virus status as follows: HCV-related ICC (n = 138, 14.4%), hepatitis B virus (HBV)-related ICC (n = 43, 4.5%) and non-virus-related ICC (n = 775, 81.1%). To control for variables, we used 1:1 propensity score-matching to compare outcomes after surgery between HCV-related (n = 102) and non-virus-related ICC cases (n = 102).

Results: We successfully matched HCV-related and non-virus-related ICC cases with similar liver function and tumor characteristics. Patients with HCV-related ICC had significantly shorter recurrence-free survival (hazard ratio 0.62, 95% confidence interval 0.42-0.92, p = 0.016) and overall survival (hazard ratio: 0.57, 95% confidence interval: 0.37-0.88, p = 0.011) than patients with non-virus-related ICC. Cox proportional hazard analysis showed that HCV-related ICC offered a worse prognosis than non-virus-related ICC.

Conclusions: HCV infection increases the risk of recurrence and worsens overall survival in patients after curative resection for MF and combined MF + PI type ICC.
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http://dx.doi.org/10.1111/hepr.13676DOI Listing
May 2021

[The paradigm shifts in the treatment of the intermediate stage hepatocellular carcinoma].

Nihon Shokakibyo Gakkai Zasshi 2021 ;118(5):407-417

Department of Gastroenterology, Kanazawa University Hospital.

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http://dx.doi.org/10.11405/nisshoshi.118.407DOI Listing
May 2021

BMP9-ID1 signaling promotes EpCAM-positive cancer stem cell properties in hepatocellular carcinoma.

Mol Oncol 2021 Apr 9. Epub 2021 Apr 9.

Department of Gastroenterology, Kanazawa University Hospital, Japan.

The malignant nature of hepatocellular carcinoma (HCC) is closely related to the presence of cancer stem cells (CSCs). Bone morphologic protein 9 (BMP9), a member of the transforming growth factor-beta (TGF-β) superfamily, was recently reported to be involved in liver diseases including cancer. We aimed to elucidate the role of BMP9 signaling in HCC-CSC properties and to assess the therapeutic effect of BMP receptor inhibitors in HCC. We have identified that high BMP9 expression in tumor tissues or serum from patients with HCC leads to poorer outcome. BMP9 promoted CSC properties in epithelial cell adhesion molecule (EpCAM)-positive HCC subtype via enhancing inhibitor of DNA-binding protein 1 (ID1) expression in vitro. Additionally, ID1 knockdown significantly repressed BMP9-promoted HCC-CSC properties by suppressing Wnt/β-catenin signaling. Interestingly, cells treated with BMP receptor inhibitors K02288 and LDN-212854 blocked HCC-CSC activation by inhibiting BMP9-ID1 signaling, in contrast to cells treated with the TGF-β receptor inhibitor galunisertib. Treatment with LDN-212854 suppressed HCC tumor growth by repressing ID1 and EpCAM in vivo. Our study demonstrates the pivotal role of BMP9-ID1 signaling in promoting HCC-CSC properties and the therapeutic potential of BMP receptor inhibitors in treating EpCAM-positive HCC. Therefore, targeting BMP9-ID1 signaling could offer novel therapeutic options for patients with malignant HCC.
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http://dx.doi.org/10.1002/1878-0261.12963DOI Listing
April 2021

CX3CL1-CX3CR1 Signaling Deficiency Exacerbates Obesity-induced Inflammation and Insulin Resistance in Male Mice.

Endocrinology 2021 Jun;162(6)

Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan.

The CX3CL1-CX3CR1 system plays an important role in disease progression by regulating inflammation both positively and negatively. We reported previously that C-C chemokine receptors 2 and 5 promote obesity-associated adipose tissue inflammation and insulin resistance. Here, we demonstrate that CX3CL1-CX3CR1 signaling is involved in adipose tissue inflammation and insulin resistance in obese mice via adipose tissue macrophage recruitment and M1/M2 polarization. Cx3cl1 expression was persistently decreased in the epididymal white adipose tissue (eWAT) of high-fat diet-induced obese (DIO) mice, despite increased expression of other chemokines. Interestingly, in Cx3cr1-/- mice, glucose tolerance, insulin resistance, and hepatic steatosis induced by DIO or leptin deficiency were exacerbated. CX3CL1-CX3CR1 signaling deficiency resulted in reduced M2-polarized macrophage migration and an M1-dominant shift of macrophages within eWAT. Furthermore, transplantation of Cx3cr1-/- bone marrow was sufficient to impair glucose tolerance, insulin sensitivity, and regulation of M1/M2 status. Moreover, Cx3cl1 administration in vivo led to the attenuation of glucose intolerance and insulin resistance. Thus, therapy targeting the CX3CL1-CX3CR1 system may be beneficial in the treatment of type 2 diabetes by regulating M1/M2 macrophages.
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http://dx.doi.org/10.1210/endocr/bqab064DOI Listing
June 2021

The characteristics of the immune cell profiles in peripheral blood in cholangiocarcinoma patients.

Hepatol Int 2021 Jun 22;15(3):695-706. Epub 2021 Mar 22.

Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, 920-8641, Japan.

Background: Immune related cells are known to be closely related to the therapeutic effects and prognoses of cancer patients. In this study, we analyzed immune cell profiles (ICP) of cholangiocarcinoma patients (CCA).

Methods: To measure the frequency of immune cells, peripheral blood mononuclear cells of 41 CCA and 10 healthy volunteers (HV) were analyzed by FACS.

Results: There were significant differences between CCA and HV in ICP, and these differences were a consequence of tumor-bearing status, because many items in ICP before surgery were restored to levels in HV after surgery. Therefore, these changes were specifically attributable to cholangiocarcinoma, and we examined if they can function as biomarkers for therapeutic effects and prognoses. A shorter overall survival was associated with a lower frequency of helper T cells (HT) (p = 0.001), a higher frequency of effector regulatory T cells (eTregs) (p = 0.008), and a lower frequency of CD80 + eTregs (p = 0.024) in the best supportive care group, with a lower frequency of CD25 + naïve Tregs (nTregs) (p = 0.005) in the chemotherapy group, and with a lower frequency of OX40 + HT (p = 0.022), CD25 + CD8 + T cells (p = 0.017), and OX40 + CD8 + T cells (p = 0.032) in the surgery group. The recurrence factors were a higher frequency of CD4 + T cells (p = 0.009), CCR6 + nTregs (p = 0.014), and CXCR3 + nTregs (p = 0.012), and a lower frequency of PD-1 + HT (p = 0.006), OX40 + HT (p = 0.004), CD8 + T cells (p = 0.001), and CTLA-4 + CD8 + T cells (p = 0.036).

Conclusions: The ICP in CCA are specifically attributable to cholangiocarcinoma, and may be biomarkers for therapeutic effects and prognoses.
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http://dx.doi.org/10.1007/s12072-021-10177-8DOI Listing
June 2021

Ramucirumab in patients with advanced hepatocellular carcinoma and elevated α-fetoprotein: Outcomes by treatment-emergent ascites.

Hepatol Res 2021 Jun 4;51(6):715-721. Epub 2021 May 4.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

Aim: The REACH and REACH-2 trials investigated ramucirumab versus placebo in patients with advanced hepatocellular carcinoma (HCC). Ascites is common in HCC and is associated with poorer outcomes. This exploratory, pooled meta-analysis of patients with baseline α-fetoprotein (AFP) ≥400 ng/ml investigated outcomes by treatment-emergent (TE) ascites in REACH and REACH-2.

Methods: A pooled meta-analysis of independent patient data for participants (N = 542) with baseline AFP ≥400 ng/ml (stratified by study) from REACH and REACH-2 was carried out. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier estimator, and OS further assessed by Cox models. The effect of TE ascites on OS was evaluated by multivariate Cox models.

Results: Treatment-emergent ascites developed in 66 patients (20.9%) in the ramucirumab group and 33 patients (14.8%) in the placebo group. When adjusted for treatment duration, the incidence rates per 100 patient-years of any grade TE ascites were 59.1 and 71.9 for the ramucirumab and placebo groups, respectively, and the incidence of grade ≥3 TE ascites were 13.4 and 19.6, respectively. Treatment-emergent ascites was associated with TE hypoalbuminemia (odds ratio 4.9; 95% confidence interval 2.5-9.3), but not TE proteinuria or hypertension. One patient discontinued ramucirumab treatment due to TE ascites. Ramucirumab treatment improved OS and PFS compared with placebo, irrespective of TE ascites.

Conclusions: When adjusted for treatment duration, the incidence of TE ascites was no higher in patients who received ramucirumab than in those who received placebo. Ramucirumab was well tolerated and provided a survival benefit irrespective of the development of TE ascites.
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http://dx.doi.org/10.1111/hepr.13638DOI Listing
June 2021

Alcohol Intake Is Associated With Elevated Serum Levels of Selenium and Selenoprotein P in Humans.

Front Nutr 2021 22;8:633703. Epub 2021 Feb 22.

Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

Selenoprotein P is a hepatokine with antioxidative properties that eliminate a physiologic burst of reactive oxygen species required for intracellular signal transduction. Serum levels of selenoprotein P are elevated during aging and in people with type 2 diabetes, non-alcoholic fatty liver disease, and hepatitis C. However, how serum levels of full-length selenoprotein P are regulated largely remains unknown, especially in the general population. To understand the significance of serum selenoprotein P levels in the general population, we evaluated intrinsic and environmental factors associated with serum levels of full-length selenoprotein P in 1,183 subjects participating in the Shika-health checkup cohort. Serum levels of selenium were positively correlated with liver enzymes and alcohol intake and negatively correlated with body mass index. Serum levels of selenoprotein P were positively correlated with age, liver enzymes, and alcohol intake. In multiple regression analyses, alcohol intake was positively correlated with serum levels of both selenium and selenoprotein P independently of age, gender, liver enzymes, and fatty liver on ultrasonography. In conclusion, alcohol intake is associated with elevated serum levels of selenium and selenoprotein P independently of liver enzyme levels and liver fat in the general population. Moderate alcohol intake may exert beneficial or harmful effects on health, at least partly by upregulating selenoprotein P. These findings increase our understanding of alcohol-mediated redox regulation and form the basis for the adoption of appropriate drinking guidelines.
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http://dx.doi.org/10.3389/fnut.2021.633703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937717PMC
February 2021

Serum Laminin γ2 Monomer as a Diagnostic and Predictive Biomarker for Hepatocellular Carcinoma.

Hepatology 2021 Feb 20. Epub 2021 Feb 20.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.

Backgrounds And Aims: Structural dynamics of basement membrane components are still to be elucidated in the process of hepatocarcinogenesis. We evaluated the characteristics of HCC expressing laminin γ2 monomer (LG2m), a basement membrane component not detected in normal tissues, for HCC diagnosis. We further determined whether elevated serum LG2m is a risk factor for HCC development in patients with chronic hepatitis C (CHC).

Approach And Results: In HCC cell lines, LG2m was expressed in alpha-fetoprotein (AFP)-negative, CD90-positive cells characterized by highly metastatic natures. Using 14 cell lines and 258 HCC microarray data, we identified that LG2m gene signature was associated with Hoshida's S1/Boyault's G3 molecular subclasses with poor prognosis, which could not be recognized by AFP. Serum LG2m was assessed in 24 healthy donors, 133 chronic liver disease patients, and 142 HCC patients, and sensitivity and specificity of LG2m testing for HCC diagnosis were 62.9% and 70.5%, respectively (cutoff, 30 pg/mL). We evaluated the consequence of LG2m elevation in two independent HCC cohorts (n = 47 and n = 81), and LG2m-high HCC showed poor prognosis with later development of distant organ metastasis (cutoff, 60 pg/mL). LG2m was slightly elevated in a subset of CHC patients, and Kaplan-Meier analysis indicated a high incidence of HCC (n = 70). For validation, we enrolled 399 CHC patients with sustained virological response (SVR) as a multicenter, prospective study, and serum LG2m elevation correlated with a high incidence of HCC in the CHC patients with SVR (P < 0.0001).

Conclusions: LG2m is a predictive biomarker for the development of metastatic HCC. Elevated serum LG2m is an HCC risk in CHC patients who have achieved SVR.
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http://dx.doi.org/10.1002/hep.31758DOI Listing
February 2021

Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab.

Br J Cancer 2021 Apr 3;124(8):1388-1397. Epub 2021 Feb 3.

Kindai University, Osaka, Japan.

Background: Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).

Methods: Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.

Results: Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6-12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354-0.574; p < 0.0001).

Conclusions: AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.

Clinical Trial Registration: ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).
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http://dx.doi.org/10.1038/s41416-021-01260-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039038PMC
April 2021

Effect of ramucirumab on ALBI grade in patients with advanced HCC: Results from REACH and REACH-2.

JHEP Rep 2021 Apr 13;3(2):100215. Epub 2020 Nov 13.

Massachusetts General Hospital Cancer Center, Harvard Medical Center, Boston, MA, USA.

Background & Aims: The albumin-bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with ramucirumab or placebo using the ALBI score in patients with advanced HCC.

Methods: Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive ramucirumab 8 mg/kg or placebo every 2 weeks. Data were analysed by trial and as a meta-analysis of individual patient-level data (pooled population) from REACH (alpha-fetoprotein ≥400 ng/ml) and REACH-2. Patients from REACH with Child-Pugh class B were analysed as a separate cohort. The ALBI grades and scores were calculated at baseline and before each treatment cycle.

Results: Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 1; hazard ratio [HR]: 1.38 [1.13-1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445-0.824]) and ALBI grade 2 (HR 0.814 [0.630-1.051]).

Conclusions: Compared with placebo, ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade.

Lay Summary: Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide. Prognosis is affected by many clinical factors including liver function both before and during anticancer treatment. Here we have used a validated approach to assess liver function using 2 laboratory parameters, serum albumin and bilirubin (ALBI), both before and during treatment with ramucirumab in 2 phase III placebo-controlled studies. We confirm the practicality of using this more simplistic approach in assessing liver function prior to and during anticancer therapy, and demonstrate ramucirumab did not impair liver function when compared with placebo.
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http://dx.doi.org/10.1016/j.jhepr.2020.100215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772786PMC
April 2021

Safety and efficacy of sorafenib followed by regorafenib or lenvatinib in patients with hepatocellular carcinoma.

Hepatol Res 2021 Feb 4;51(2):190-200. Epub 2020 Dec 4.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.

Aim: Sequential administration of sorafenib followed by regorafenib or lenvatinib is effective against advanced hepatocellular carcinoma (HCC). In this study, we compared the safety profiles and anti-tumor effects of sequential sorafenib and regorafenib or lenvatinib therapy in patients with HCC.

Methods: We investigated adverse events, treatment responses and dose intensities in patients with HCC who were consecutively treated with sorafenib followed by regorafenib or lenvatinib at the individual level.

Results: Each group included 20 patients. The safety profiles of regorafenib and sorafenib were similar. The severity of hypophosphatemia, palmar-plantar erythrodysesthesia syndrome, and decreased neutrophil counts associated with regorafenib or sorafenib was similar in 12 patients. Conversely, the incidences and grades of adverse events differed between sorafenib and lenvatinib treatment. The anti-tumor effects of regorafenib and lenvatinib compared with sorafenib were significantly different for each patient. The response to treatment and progression-free survival were comparable for regorafenib and lenvatinib. The median relative dose intensities during the first 56 days of regorafenib and lenvatinib treatment were 83.6 and 80.0%, respectively.

Conclusions: Similar adverse events were experienced by patients during consecutive treatment with sorafenib and regorafenib, which was not observed during treatment with sorafenib and lenvatinib. The obtained safety profile of sorafenib provided meaningful insights for selecting sequential therapy for patients with advanced HCC.
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http://dx.doi.org/10.1111/hepr.13588DOI Listing
February 2021

Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis.

J Immunother Cancer 2020 11;8(2)

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan

Background: Pancreatic ductular adenocarcinoma (PDAC) is among the most dreadful of malignancies, in part due to the lack of efficacious chemotherapy. Immune checkpoint inhibitors, including anti-programmed cell death 1 (anti-PD-1) antibodies, are novel promising forms of systemic immunotherapy. In the current study, we assessed whether gemcitabine (GEM) combined with anti-PD-1 antibody treatment was efficacious as immunochemotherapy for advanced PDAC using a murine model of liver metastasis.

Methods: The murine model of PDAC liver metastasis was established by intrasplenically injecting the murine pancreatic cancer cell line PAN02 into immunocompetent C57BL/6J mice. The mice were treated with an anti-PD-1 antibody, GEM, or a combination of GEM plus anti-PD-1 antibody, and compared with no treatment (control); liver metastases, immune cell infiltration, gene expression, immune cell response phenotypes, and overall survival were investigated.

Results: In the metastatic tumor tissues of mice treated with GEM plus anti-PD-1 antibody, we observed the increased infiltration of Th1 lymphocytes and M1 macrophages. Gene expression profile analysis of peripheral blood cells obtained from mice treated with GEM plus anti-PD-1 antibody clearly highlighted T cell and innate immune signaling pathways. Survival of PDAC liver metastasis mice was significantly prolonged by the combination therapy (median survival, 66 days) when compared with that of GEM alone treatment (median survival, 56 days). Expanded lymphocytes, which were isolated from the splenocytes of PDAC liver metastasis mice treated with GEM plus anti-PD-1 antibody, had an increased number of M1 macrophages.

Conclusion: The combination of anti-PD-1 antibody immunotherapy with GEM was beneficial to treat a murine model of PDAC liver metastasis by enhancing the immune response mediated by Th1 lymphocytes and M1 macrophages and was associated with CD8+ T cells.
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http://dx.doi.org/10.1136/jitc-2020-001367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668383PMC
November 2020

Hepatic Arterial Infusion Chemotherapy versus Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2020 Sep 24;9(5):583-595. Epub 2020 Jul 24.

Yamanashi Prefectural Central Hospital, Kofu, Japan.

Background: Prior to the approval of sorafenib, hepatic arterial infusion chemotherapy (HAIC) was offered to patients with advanced hepatocellular carcinoma (HCC) in East Asia, particularly Japan. According to the Japanese guidelines, HAIC is recommended as one of the treatment options in patients without extrahepatic metastasis (EHM).

Methods: The present cohort study compared the use of HAIC and sorafenib on outcomes of patients with advanced HCC. Consecutive patients with advanced HCC who received HAIC or sorafenib as a first-line systemic therapy were enrolled from 10 Japanese institutions. The primary outcomes were overall survival (OS) in patients with macrovascular invasion (MVI), but without EHM, and OS in patients without both MVI and EHM.

Results: Between 2009 and 2016, 2,006 patients were enrolled (541 HAIC patients, 1,465 sorafenib patients). After propensity score matching, the OS of patients with MVI but without EHM was significantly longer in the HAIC group compared with the sorafenib group (10.1 vs. 9.1 months for the HAIC and sorafenib groups, respectively; = 170 for each group; hazard ratio [HR] 0.668; 95% confidence interval [95% CI] 0.475-0.935; = 0.018). There was no significant difference in OS between patients without both MVI and EHM (12.2 vs. 15.4 months for the HAIC and sorafenib groups, respectively; = 76 in each cohort after propensity score matching; HR 1.227; 95% CI 0.699-2.155; = 0.475).

Conclusion: HAIC is a potential front-line treatment choice in a subpopulation of patients with advanced HCC with MVI but without EHM.
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http://dx.doi.org/10.1159/000508724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548914PMC
September 2020

Clinical features and diagnostic imaging of cholangiolocellular carcinoma compared with other primary liver cancers: a surgical perspective.

Technol Cancer Res Treat 2020 Jan-Dec;19:1533033820948141

General and Digestive Surgery, 12857Kanazawa Medical University, Kahoku, Ishikawa, Japan.

Background And Objectives: Although cholangiolocellular carcinoma is considered a combined hepatocellular and cholangiocarcinoma, we feel that this classification is not appropriate. Therefore, we compared the diagnostic imaging findings, surgical prognosis, and pathological features of cholangiolocellular carcinoma with those of other combined hepatocellular and cholangiocarcinoma subtypes, hepatocellular carcinoma, and cholangiocarcinoma.

Methods: The study patients included 7 with classical type combined hepatocellular and cholangiocarcinoma; 8 with stem cell feature, intermediate type combined hepatocellular and cholangiocarcinoma; 13 with cholangiolocellular carcinoma; 58 with cholangiocarcinoma; and 359 with hepatocellular carcinoma. All patients underwent hepatectomy or living-related donor liver transplantation from 2001 to 2014.

Results: cholangiolocellular carcinoma could be distinguished from hepatocellular carcinom, other combined hepatocellular and cholangiocarcinoma subtypes, and cholangiocarcinoma by the presence of intratumoral Glisson's pedicle, hepatic vein penetration, and tumor-staining pattern on angiography-assisted CT. Cholangiolocellular carcinoma was associated with a significantly lower SUV-max than that of cholangiocarcinoma on FDG-PET. Hepatocellular carcinoma, classical type, and cholangiolocellular carcinoma had significantly better prognoses than stem cell feature, intermediate type and cholangiocarcinoma. A cholangiocarcinoma component was detected in cholangiolocellular carcinoma that progressed to the hepatic hilum, and the cholangiocarcinoma component was found in perineural invasion and lymph node metastases.

Conclusions: From the viewpoint of surgeon, cholangiolocellular carcinoma should be classified as a good-prognosis subtype of biliary tract carcinoma because of its tendency to differentiate into cholangiocarcinoma during its progression, and its distinctive imaging and few recurrence rates different from other combined hepatocellular and cholangiocarcinoma subtypes.
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http://dx.doi.org/10.1177/1533033820948141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592326PMC
October 2020

Effect of adoptive T-cell immunotherapy on immunological parameters and prognosis in patients with advanced pancreatic cancer.

Cytotherapy 2021 Feb 6;23(2):137-145. Epub 2020 Sep 6.

Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.

Background Aims: Immunotherapy is effective for many types of cancer, but its benefits in advanced pancreatic cancer, which has a poor prognosis, are not well established. In this study, the authors examined the effects of adoptive T-cell immunotherapy (ATI) on immune cell profiles and prognosis in patients with unresectable advanced pancreatic cancer.

Methods: Seventy-seven patients with unresectable advanced pancreatic cancer were treated with six cycles of αβ T cells alone or in combination with chemotherapy or chemoradiation. Immune cell profiles in peripheral blood samples obtained before and after treatment were comprehensively evaluated by flow cytometry. Furthermore, associations between changes in immune cell frequencies and prognosis were determined.

Results: ATI prolonged survival to 18.7 months compared with previous estimates of 6.2-11.1 months for patients treated with chemotherapy alone. ATI decreased CD3+CD4+CD8- T cell frequency in peripheral blood and increased CD3+CD4-CD8+ T cell frequency. An increase in CD3+ T cells and CD3+TCRγδ- T cells in peripheral blood after treatment was associated with a good prognosis.

Conclusions: ATI altered the immune profile in peripheral blood, including CD3+CD4-CD8+ T cells, and improved prognosis in pancreatic cancer.
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http://dx.doi.org/10.1016/j.jcyt.2020.08.001DOI Listing
February 2021

Investigation of Thrombosis Volume, Anticoagulants, and Recurrence Factors in Portal Vein Thrombosis with Cirrhosis.

Life (Basel) 2020 Sep 4;10(9). Epub 2020 Sep 4.

Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan.

This retrospective study investigated factors influencing the portal vein thrombosis (PVT) volume and recurrence in 52 cirrhosis patients with PVT from November 2008 to September 2018. All patients were treated with danaparoid sodium with or without additional antithrombin III. Blood platelet counts significantly correlated with the PVT volume (r = 0.17; < 0.01). Computed tomography confirmed recurrence as PVT aggravation was reported in 43 patients, with ≥50% PVT volume reduction following anticoagulation therapy. In 43 patients, recurrence significantly correlated with the pretreatment PVT volume ( = 0.019). Factors influencing recurrence included a Child-Pugh score >8 ( = 0.049) and fibrosis index ≤7.0 based on four factors (FIB-4) ( = 0.048). Moreover, the relationship between recurrence and correlating factors showed that 15 patients who received warfarin experienced recurrence more often when Child-Pugh scores were >8 ( = 0.023), regardless of maintenance treatment. For patients who did not receive warfarin, a PVT volume ≥3.0 mL significantly influenced recurrence ( = 0.039). Therefore, the platelet count influences the PVT volume. The pretreatment PVT volume correlated with recurrence after anticoagulation therapy. According to the Kaplan-Meier curve, risk factors for PVT recurrence after anticoagulation therapy included Child-Pugh scores >8 and FIB-4 ≤7.0. Therefore, the FIB-4 is a unique factor that shows trends opposing other liver function markers.
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http://dx.doi.org/10.3390/life10090177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555202PMC
September 2020

Direct-Acting Antiviral Agents Reduce the Risk of Malignant Transformation of Hepatobiliary Phase-Hypointense Nodule without Arterial Phase Hyperenhancement to Hepatocellular Carcinoma on Gd-EOB-DPTA-Enhanced Imaging in the Hepatitis C Virus-Infected Liver.

Liver Cancer 2020 Jun 7;9(3):261-274. Epub 2020 Jan 7.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.

Background And Aims: Hepatobiliary phase-hypointense nodules without arterial phase hyperenhancement (HHNs without APHE) on gadolinium-ethoxybenzyl-diethylenetriamine-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) are considered to be dysplastic nodules or early hepatocellular carcinoma (HCC) and have high risk of undergoing malignant transformation and progression to hypervascular HCC. The aim of this study was to evaluate the clinical outcome of HHNs without APHE diagnosed by Gd-EOB-DTPA-enhanced MRI before the eradication of HCV by direct-acting antiviral agents (DAAs).

Methods: We retrospectively investigated 221 consecutive patients with HCV infection who were treated with DAAs. Thirty patients with 65 HHNs without APHE were enrolled in a sustained virologic response (SVR) cohort and 22 with 43 HHNs without APHE who did not receive DAAs or had failed HCV eradication therapy were enrolled in a non-SVR cohort. Fifty-seven percent of patients in the SVR group and 64% of those in the non-SVR group had a history of HCC. The primary endpoint of this study was the development of hypervascular HCC from HHNs without APHE detected on imaging. The cumulative incidence and relative risk of progression to hypervascular HCC in relation to clinical characteristics were compared between the two cohorts.

Results: The 2-year cumulative incidence of progression to hypervascular HCC was 8.5 and 21.9% in the SVR and non-SVR cohorts, respectively. There was a significant reduction in progression of HHNs without APHE to HCC after the eradication of HCV ( = 0.022, log-rank test). Multivariate Cox regression analysis identified hyperintensity on T2-weighted images (relative risk 14.699, < 0.001) and achieving SVR (relative risk 0.290, = 0.043) as independent factors associated with the risk of HCC. During follow-up, 6 (9.2%) of the HHNs without APHE in the SVR cohort became undetectable on hepatocyte-phase images.

Conclusions: Eradication of HCV by DAAs could reduce the hypervascularization rate of HHNs without APHE, and some of these nodules disappeared.
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http://dx.doi.org/10.1159/000504889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325122PMC
June 2020

Intake of ω-6 Polyunsaturated Fatty Acid-Rich Vegetable Oils and Risk of Lifestyle Diseases.

Adv Nutr 2020 11;11(6):1489-1509

Gastroenterology.

Although excessive consumption of deep-fried foods is regarded as 1 of the most important epidemiological factors of lifestyle diseases such as Alzheimer's disease, type 2 diabetes, and obesity, the exact mechanism remains unknown. This review aims to discuss whether heated cooking oil-derived peroxidation products cause cell degeneration/death for the occurrence of lifestyle diseases. Deep-fried foods cooked in ω-6 PUFA-rich vegetable oils such as rapeseed (canola), soybean, sunflower, and corn oils, already contain or intrinsically generate "hydroxynonenal" by peroxidation. As demonstrated previously, hydroxynonenal promotes carbonylation of heat-shock protein 70.1 (Hsp70.1), with the resultant impaired ability of cells to recycle damaged proteins and stabilize the lysosomal membrane. Until now, the implication of lysosomal/autophagy failure due to the daily consumption of ω-6 PUFA-rich vegetable oils in the progression of cell degeneration/death has not been reported. Since the "calpain-cathepsin hypothesis" was formulated as a cause of ischemic neuronal death in 1998, its relevance to Alzheimer's neuronal death has been suggested with particular attention to hydroxynonenal. However, its relevance to cell death of the hypothalamus, liver, and pancreas, especially related to appetite/energy control, is unknown. The hypothalamus senses information from both adipocyte-derived leptin and circulating free fatty acids. Concentrations of circulating fatty acid and its oxidized form, especially hydroxynonenal, are increased in obese and/or aged subjects. As overactivation of the fatty acid receptor G-protein coupled receptor 40 (GPR40) in response to excessive or oxidized fatty acids in these subjects may lead to the disruption of Ca2+ homeostasis, it should be evaluated whether GPR40 overactivation contributes to diverse cell death. Here, we describe the molecular implication of ω-6 PUFA-rich vegetable oil-derived hydroxynonenal in lysosomal destabilization leading to cell death. By oxidizing Hsp70.1, both the dietary PUFA- (exogenous) and the membrane phospholipid- (intrinsic) peroxidation product "hydroxynonenal," when combined, may play crucial roles in the occurrence of diverse lifestyle diseases including Alzheimer's disease.
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http://dx.doi.org/10.1093/advances/nmaa072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666899PMC
November 2020

Tumor lysis syndrome in a patient with metastatic melanoma treated with nivolumab.

Clin J Gastroenterol 2020 Oct 27;13(5):935-939. Epub 2020 Jun 27.

Department of Gastroenterology, Kanazawa University Hospital, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan.

A 79-year-old man with metastatic melanoma of the right maxillary sinus and multiple liver metastases received a single dose of nivolumab. Eight days later, he experienced impaired consciousness, accompanied by abnormal laboratory and electrocardiographic findings. He was therefore diagnosed with tumor lysis syndrome (TLS). Laboratory and electrocardiographic findings improved immediately after continuous hemodiafiltration; however, he died 22 days after receiving nivolumab. Autopsy revealed massive tumor necrosis in the liver. There are few case reports of TLS associated with immune checkpoint inhibitors, indicating that we should be prepared to manage especially in a patient with liver involvement of high tumor burden.
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http://dx.doi.org/10.1007/s12328-020-01164-xDOI Listing
October 2020

Effects of adaptive immune cell therapy on the immune cell profile in patients with advanced gastric cancer.

Cancer Med 2020 07 11;9(14):4907-4917. Epub 2020 Jun 11.

Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa City, Japan.

Background: Immunotherapy for cancer patients has been the subject of attention in recent years. In this study, we investigated whether αβT-cell therapy causes changes in the host's immune cell profile, and if so, the effect of these changes on prognosis.

Methods: Peripheral blood mononuclear cells (PBMCs) from 30 gastric cancer patients who had completed one course of αβT-cell therapy were analyzed. The peripheral blood immune cell profile was established using PBMCs by counting the frequency of CD4+ helper T cells, CD8+ killer T cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells and measuring the expression of their surface markers. The changes after treatment and their association with response to treatment were investigated.

Results: Immune cell profiles changed greatly after treatment. The frequency of CD4+ helper T cells decreased, but that of CD8+ killer T cells increased. The frequency of programmed cell death 1 (PD-1)+ effector Tregs increased significantly, but only in the non-progressive disease (non-PD) group, in which it was significantly higher compared with the PD group. Patients in whom the frequency of PD-1+ effector Tregs increased had a significantly better prognosis than those in whom it decreased.

Conclusion: Our results suggested that αβT-cell therapy changes the host's immune cell profile, and an increase in PD-1+ effector Tregs may help improve prognosis.
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http://dx.doi.org/10.1002/cam4.3152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367616PMC
July 2020

Upregulation of the Long Non-Coding RNA HULC by Hepatitis C Virus and its Regulation of Viral Replication.

J Infect Dis 2020 Jun 9. Epub 2020 Jun 9.

Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Takara-machi, Kanazawa, Ishikawa, Japan.

Background: Many long non-coding RNAs (lncRNAs) have important roles in biological processes. The lncRNA HULC was found to be upregulated in human hepatoma tissues. HULC is thought to be involved in multiple steps of hepatoma development and progression; however, the relationship between HULC and hepatitis C virus (HCV) infection, which is a leading cause of hepatoma, remains unclear.

Methods: We examined the effect of HCV replication on HULC expression and the underlying mechanism using cell culture systems. Subsequently, we tested the effect of HULC suppression and overexpression on HCV replication. Finally, we examined the impact of HCV eradication on HULC expression using human liver tissue and blood samples.

Results: HCV replication increased HULC expression in cell cultures. A promoter assay showed that an HCV nonstructural protein, NS5A, increased HULC transcription. HULC suppression inhibited HCV replication; conversely, its overexpression enhanced HCV replication. These effects on HCV replication seemed to occur by the modification of HCV translation. Measurements from human liver and blood samples showed that HCV eradication significantly reduced HULC levels in the liver and blood.

Conclusions: HCV infection increases HULC expression in vitro and in vivo. HULC modulates HCV replication through an HCV internal ribosome entry site-directed translation step.
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http://dx.doi.org/10.1093/infdis/jiaa325DOI Listing
June 2020

Safety and Long-Term Outcome of Intratumoral Injection of OK432-Stimulated Dendritic Cells for Hepatocellular Carcinomas After Radiofrequency Ablation.

Transl Oncol 2020 Jul 12;13(7):100777. Epub 2020 May 12.

Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.

Dendritic cell (DC)-based immunotherapies are believed to help eradicate residual tumor cells, including hepatocellular carcinoma (HCC). Here, we assessed the safety and clinical response to OK432-stimulated monocyte-derived DCs (MoDCs) in treating HCC after radiofrequency ablation (RFA). MoDCs were derived from 30 HCC patients in the presence of interleukin-4 and granulocyte-macrophage colony stimulating factor for 5 days and then cultured for 2 more days in the medium (basic protocol) or stimulated with OK432. On day 7, DCs were harvested and percutaneously injected into HCC tumors after RFA. We observed no grade 3 or 4 National Cancer Institute Common Toxicity Criteria adverse events. Kaplan-Meier analysis indicated that patients treated with RFA + OK432-stimulated DCs transfer had longer recurrence-free survival than those treated with RFA + basic-protocol DCs (median: 24.8 vs 13.0 months; P = .003). RFA with DC infusion can enhance various tumor-associated antigen (TAA)-specific T-cell responses. Additionally, the 5-year RFS rate for patients with significantly increased TAA-specific T-cell responses was much higher than for other patients (50.0% vs. 7.7%; P = .030). Our study provides useful information for development of HCC immunotherapies (trial registration: UMIN000001701).
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http://dx.doi.org/10.1016/j.tranon.2020.100777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226894PMC
July 2020
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