Prophylactic tenofovir alafenamide for hepatitis B virus reactivation and reactivation-related hepatitis.

No prospective study on the efficacy of tenofovir alafenamide (TAF), a novel tenofovir prodrug, in preventing hepatitis B virus (HBV) reactivation has yet been reported. This multicenter prospective study enrolled HBV-carriers who received TAF to prevent HBV reactivation before antitumor or immunosuppressive therapy, and patients with resolved HBV infection who experienced HBV-reactivation and received TAF to prevent HBV reactivation-related hepatitis. The efficacy of prophylactic TAF in preventing HBV reactivation and HBV reactivation-related hepatitis was evaluated at 6 and 12 months after initiating TAF. Overall, 110 patients were administered TAF to prevent HBV reactivation or HBV reactivation-related hepatitis. Three patients died owing to primary disease, whereas one patient was transferred to another hospital within 6 months after initiating TAF. Seven patients died due to primary disease, and five patients were transferred to another hospital within 12 months after initiating TAF. Therefore, 106 and 94 (77 patients with HBV infection, 17 with previous-HBV infection) patients were evaluated at 6 and 12 months after initiating TAF, respectively. No patient experienced HBV reactivation, HBV reactivation-related hepatitis, or treatment discontinuation due to HBV reactivation or adverse events of TAF after 6 and 12 months. TAF could effectively prevent HBV reactivation and HBV reactivation-related hepatitis.

Impact of telephone follow-up on hepatocellular carcinoma patients receiving oral chemotherapy from an ambulatory-care setting.

INTRODUCTION: In recent years, most molecular target drugs have been administered orally, as prescribed at ambulatory services in hospitals and at patients' homes. Telephone follow-up is increasingly being used in clinical practice for patients needing additional support post-discharge and for the prevention of hospital readmissions. The purpose of this study was to clarify the clinical benefits of telephone follow-up while administering oral anticancer drugs. METHODS: This was a single-center, observational, retrospective study. We evaluated hepatocellular carcinoma patients who received sorafenib or lenvatinib between March 2010 and February 2018. The primary endpoint was the incidence of adverse events. RESULTS: From the total of 130 patients, 83 patients received telephone follow-up and 47 did not. The incidence of hand-foot skin reactions significantly reduced in patients with telephone follow-up (odds ratio (OR) 3.69, 95% confidence interval (CI) 1.16-11.8, p = 0.020). The median durations (ranges) of adherence to oral chemotherapy were 259 days (15-1730) for the telephone follow-up group and 121 days (14-1105) for the no-telephone follow-up group (p < 0.001). Moreover, the disease control rate was significantly higher in the telephone follow-up group (OR 2.52, 95% CI 1.15-5.53, p = 0.020). CONCLUSIONS: Remote interventions, such as telephone follow-up, are useful means of managing adverse events in patients receiving oral anticancer drugs and can lead to improved treatment results.

Very urgent endoscopic retrograde cholangiopancreatography is associated with early discharge in patients with non-severe acute cholangitis.

BACKGROUND: endoscopic retrograde cholangiopancreatography (ERCP) is a first-line procedure for biliary drainage in patients with acute cholangitis, and there are no studies focused on very urgent ERCP within several hours of hospital arrival. This study aimed to elucidate the use of very urgent ERCP for non-severe acute cholangitis. METHODS: this retrospective observational study included patients with non-severe acute cholangitis who underwent ERCP between April 2011 and June 2020 in our institution. Patients were stratified into three groups based on time to ERCP after hospital arrival: very urgent (≤ 3 hours), urgent (3-24 hours) and elective (> 24 hours). The primary outcome was length of hospital stay (LOS). RESULTS: the study cohort included 291 patients, 168 males (57.7 %), with a median age of 76 (interquartile range, 70-83) years. In all, 47, 196 and 48 patients underwent very urgent, urgent and elective ERCP, respectively. Median LOS in the very urgent, urgent, and elective groups was 12, 14, and 15 days, respectively (Kaplan-Meier method). A shorter LOS was associated with earlier ERCP (log-rank trend test, p = 0.04). The rates of readmission within 30 days of discharge and of adverse events were not significantly different among the three groups. By multivariate analysis, very urgent ERCP was associated with a significantly earlier discharge than urgent and elective ERCP (HR, 0.71, p = 0.04 and HR, 0.47, p < 0.01, respectively). In addition, age ≥ 75 years, pancreatitis, albumin ≤ 2.8 g/dL and two or more ERCP procedures were associated with a significantly longer LOS (HRs < 1, p < 0.05). CONCLUSIONS: very urgent ERCP for non-severe acute cholangitis was associated with early discharge.

Early response and safety of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in patients who do not meet IMbrave150 eligibility criteria.

AIM: A clinical trial (IMbrave150) indicated the efficacy and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma (HCC). In this study, we evaluated this therapeutic combination in a real-world setting, with a focus on patients who did not meet the IMbrave150 eligibility criteria. METHODS: In this multicenter study, patients with unresectable HCC treated with atezolizumab plus bevacizumab between October 2020 and May 2021 were screened. In patients who did not meet IMbrave150 eligibility criteria, treatment responses and safety at 6 and 12 weeks were evaluated. RESULTS: Atezolizumab plus bevacizumab was initiated in 64 patients, including 46 patients (71.9%) who did not meet IMbrave150 eligibility criteria. Most of these patients had a history of systemic therapy (44/46). The objective response rate and disease control rate observed using Response Evaluation Criteria in Solid Tumors 1.1 were 5.2% and 82.8% at 6 weeks and 10.0% and 84.0% at 12 weeks, respectively; these rates were similar between patients who met and did not meet the IMbrave150 criteria. Ten patients experienced progressive disease (PD) at 6 weeks. Portal vein tumor thrombosis was significantly associated with PD (p = 0.039); none of the 15 patients with hepatitis B virus-related HCC experienced PD (p = 0.050). The most common adverse events of grade 3 or higher were aspartate aminotransferase elevation (n = 8, 13.8%) and the safety profile was similar between patients who met and did not meet the IMbrave150 criteria. CONCLUSION: Most patients treated with atezolizumab plus bevacizumab did not meet the IMbrave150 criteria; however, the combination therapy showed good safety and efficacy at the early treatment phase.

IFN-λ3 as a host immune response in acute hepatitis E virus infection.

BACKGROUND AND AIM: Hepatitis E virus (HEV) is mainly transmitted orally, either waterborne or zoonotic foodborne. Intestinal viruses such as rotavirus are known to induce type III interferon (IFN) in the gastrointestinal (GI) tract where type III IFN dominantly functions in comparison with type I IFN. Therefore, the aim of this study is to investigate the significance of type III IFN (IFN-λ3) in acute hepatitis E. METHODS: IFN-λ3 and HEV RNA levels in the sera of patients with acute HEV infection and in the supernatant of HEV-inoculated cells were measured, using an in-house high-sensitivity method and reverse transcription-polymerase chain reaction, respectively. RESULTS: High serum IFN-λ3 levels were found in the early phase of acute HEV infection, which normalized after resolution. Interestingly, serum IFN-λ3 levels correlated well with serum HEV RNA titers in the same sera, both of which showed the peak before the robust increase of transaminases. In vitro experiments demonstrated that HEV replicated well in the cells with little IFN-λ3 induction (Caco-2, A549) and recombinant IFN-λ3 inhibited HEV replication in a dose-dependent manner. In contrast, in HT-29 cells, a colon cancer cell line, HEV poorly replicated and induced IFN-λ3 in a titer-dependent manner. CONCLUSIONS: These clinical and experimental observations suggest that HEV induced IFN-λ3 as a host innate immune response, which may play a protective role against HEV.

Lenvatinib in patients with unresectable hepatocellular carcinoma who do not meet the REFLECT trial eligibility criteria.

AIM: This study aimed to determine the efficacy and safety of lenvatinib for patients with unresectable hepatocellular carcinoma (HCC) who did not meet REFLECT eligibility criteria (phase 3 clinical trial). METHODS: In this multicenter retrospective study, patients with unresectable HCC treated with lenvatinib between 2018 and 2019 and had adequate clinical data were included. Objective response rate, progression-free-survival (PFS) and safety were evaluated according to meeting or not meeting the REFLECT eligibility criteria and according to the criteria of the REFLECT trial. RESULTS: Of the 105 patients included, 61% (64 of 105) did not meet the REFLECT eligibility criteria. Safety and median PFS of lenvatinib were similar between the patients who did and those who did not meet the criteria. Among the patients who did not meet the criteria, 28, 27, 14, six, seven and five had a history of tyrosine kinase inhibitor (TKI) treatment, Child-Pugh score B, HCC in ≥50% of the liver, reduced platelet count, bile duct invasion and main portal vein invasion, respectively. The efficacy and safety of lenvatinib for patients with or without Child-Pugh-score B or HCC in ≥50% of the liver were similar. Although treatment outcome was not significantly different, patients with TKI treatment history tended to have longer median PFS, whereas those with main portal vein invasion tended to have shorter median PFS. CONCLUSION: Lenvatinib was effective for patients who did not meet the REFLECT inclusion criteria. However, the treatment outcome may vary according to several factors, such as a history of TKI treatment and tumor invasion.

Entecavir treatment of hepatitis B virus-infected patients with severe renal impairment and those on hemodialysis.

AIM: Entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) are first-line nucleos(t)ide analogues for hepatitis B virus (HBV)-infected patients. However, consecutive TDF treatment causes renal dysfunction, and the safety and efficacy of TAF have not been established in severe renal dysfunction patients, including hemodialysis patients. The efficacy and safety of ETV in these populations has not been clarified. The study aimed to clarify this. METHODS: In this retrospective multicenter study, between 2006 and 2018, a total of 567 HBV-infected patients treated with ETV monotherapy were screened. Patients were included if >20 years old, treated with ETV monotherapy for >1 year, and had proper clinical information. The efficacy of ETV and changes in renal function were evaluated according to renal function. RESULTS: A total of 273 patients were included: 9.2% (25/273), 1.8% (5/273), and 3.7% (10/273) had chronic kidney disease (CKD) stage G3, CKD stage G4/5, and were on hemodialysis, respectively. Overall, 84.2%, 94.0%, and 96.2% of patients experienced serum HBV-DNA disappearance at 1, 2, and 3 years, respectively, after treatment initiation. In patients with CKD stage G3-5, estimated glomerular filtration rate tended to restore with time, which was in contrast to patients without renal dysfunction. The rate of disappearance in serum HBV-DNA, alanine transaminase normalization, and virological breakthrough was similar between patients with or without renal dysfunction. ETV showed high efficacy for all 10 hemodialysis patients without virological breakthrough. CONCLUSIONS: Entecavir for HBV-infected patients with severe renal dysfunction, including hemodialysis patients, is highly effective and does not affect renal function.

Safety and efficacy of sofosbuvir and ribavirin for genotype 2 hepatitis C Japanese patients with renal dysfunction.

AIM: The safety and efficacy of sofosbuvir (SOF) and ribavirin (RBV) have not been well clarified in patients with renal dysfunction because clinical trials have not included such patients. We evaluated the safety and efficacy of SOF and RBV for genotype 2 hepatitis C virus (HCV)-infected patients with renal dysfunction. METHODS: The study included genotype 2 HCV-infected patients who received SOF and RBV between July 2014 and May 2017. The sustained virologic response (SVR) after the treatment and safety during the therapy were evaluated according to renal function. RESULTS: A total of 231 patients were included in this study. The median age was 62 years old, and 45.9% (106/231) were men. Of the 231 patients, 191 (82.8%) and 40 (17.2%) were classified as having chronic kidney disease (CKD) stages G1/2 and G3, respectively. The overall SVR rate was 97% (224/231). The SVR rates in patients with CKD stages G1, 2, G3a, and G3b were 98.1%, 98.6%, 87.9%, and 100%, respectively, and this therapy was tolerated. Multivariate analysis indicated that renal dysfunction was significantly associated with a non-SVR (odds ratio, 6.963; 95% confidence interval, 1.494-32.41; P = 0.013). The patients with renal dysfunction were older, had advanced liver fibrosis, lower baseline platelet and hemoglobin levels, and a higher rate of RBV dose reduction. CONCLUSIONS: Sofosbuvir and RBV therapy is highly effective and safe for genotype 2 HCV-infected Japanese patients. However, attention should be paid to baseline renal function when SOF- and RBV-containing regimens are used for patients with renal dysfunction.

Add-on effects of fluvastatin in simeprevir/pegylated-interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study.

BACKGROUND: The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated-interferon (Peg-IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct-acting antiviral-containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add-on treatment in Peg-IFN and RBV combination therapy for HCV-infected patients significantly improved the sustained virologic response (SVR), but the add-on effect of FLV on SMV combination therapy is not well understood. METHODS: This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b-infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12 weeks of SMV/Peg-IFN/RBV followed by 12 weeks of Peg-IFN/RBV with or without 24 weeks of FLV. The SVR rate and adverse events were compared between the two groups. RESULTS: Thirty-one patients were allocated to the FLV add-on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis-4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end-of-treatment response rates, SVR rates at 24 weeks after treatment, and safety profiles were also similar between the two groups. CONCLUSIONS: This prospective, randomized, multicenter study indicated that FLV had no add-on effect when given with SMV/Peg-IFN/RBV combination therapy for genotype 1b HCV-infected patients.

[A Case of Unknown Primary Carcinoma with Dermatomyositis].

A 50-year-old woman was diagnosed with dermatomyositis at the department of neurology in our hospital; she then received steroid pulse therapy. A positron emission computed tomography(PET-CT)revealed swollen lymph nodes near the aorta and in the left inguinal region. She presented at our institution for examination to determine the cause of her lymphadenopathy, but the primary site of the carcinoma was unknown. A histopathological examination of the lymph node specimen obtained using endoscopic ultrasonography-guided fine-needle aspiration(EUS-FNA)revealed a moderately to poorly differentiated adenocarcinoma. The patient underwent lymphadenectomy. After the surgery, a new lymph node metastasis appeared in the lower abdomen. We initiated a combination treatment with chemotherapy and radiotherapy. The patient died because of disease progression 31 months after her first visit.

[A case of mixed adenoneuroendocrine carcinoma of the distal bile duct].

We diagnosed distal cholangiocarcinoma in a 76-year-old woman who was then treated by subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination revealed a well-differentiated tubular adenocarcinoma on the side of the bile duct, and a neuroendocrine carcinoma in an area outside the bile duct where the tumor had infiltrated. Immunohistochemical staining identified homology between cytokeratins and MUC, indicating a similar origin. This report discusses problems associated with diagnosis and treatment by summarizing 22 patients who underwent curative resection and subsequently had a confirmed prognosis.

Efficacy and prognosis of antiviral therapy on hepatitis C following treatment of lymphoma in HCV-positive diffuse large-cell lymphoma.

The purpose of this study is to study the usefulness of post-remission antiviral therapy in cases of HCV-RNA-positive diffuse large-cell lymphoma. Antiviral therapy against HCV was performed after remission using CHOP or CHOP-like chemotherapy in combination with rituximab in five successive cases of HCV-RNA-positive diffuse large-cell lymphoma. The control groups consisted of a group of HCV-RNA-positive diffuse large-cell lymphoma cases prior to this trial (control 1), and a group of cases that tested negative for HIV, HCV, and HBV (control 2). All the cases were in remission at the time of initial treatment. There were no significant differences between the three groups in terms of age, sex, treatment, stage, or International Prognosis Index (IPI). When HCV antiviral therapy was performed after treatment for diffuse large-cell lymphoma, we observed no recurrence or deaths, and the 2-year overall survival and progression-free survival rates were significantly greater than those in the control 1 group (P = 0.0246). It is possible that a better prognosis can be achieved by performing HCV antiviral therapy after achieving remission in cases of HCV-RNA-positive diffuse large-cell lymphoma through the use of R-CHOP or similar treatments.

Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus-infected patients with renal impairment.

AIM: Hepatitis C virus (HCV) infection is a risk factor for end-stage renal disease, renal graft failure, and hemodialysis patient mortality. However, the efficacy of direct-acting antiviral therapy for HCV-infected patients with renal impairment is unclear. Additionally, the promising NS5B inhibitor sofosbuvir has not been recommended for patients with severe renal impairment. In this prospective, multicenter study, we evaluated the efficacy and safety of daclatasvir and asunaprevir combination therapy, with a focus on patients with renal impairment. METHODS: The study included 322 genotype 1 HCV-infected patients who received daclatasvir and asunaprevir combination therapy. The safety and sustained virological response was examined at 12 weeks after the end of treatment and safety was evaluated according to renal function. RESULTS: Of 322 patients, 5% (16/322) and 2.5% (8/322) had chronic kidney disease stage G3b (estimated glomerular filtration rate [eGFR], 30-44 mL/min/1.73 m2 ) and stage G4/5 (eGFR, 15-29/<15 mL/min/1.73 m2 ), respectively. Baseline presence of the NS5A resistance-associated variant, previous simeprevir treatment, and HCV RNA titers, which were predictors of a sustained viral response, were similar between patients with eGFR <45 mL/min/1.73 m2 and eGFR >45 mL/min/1.73 m2 . Notably, the 12-week sustained viral response rate was comparable in patients with eGFR <45 mL/min/1.73 m2 (100%, 24/24) and those with eGFR >45 mL/min/1.73 m2 (88.9%, 265/298; P = 0.07). Treatment discontinuation rates and adverse events, including alanine aminotransferase elevation, anemia, and renal disorders, were similar between the two groups. CONCLUSION: Daclatasvir and asunaprevir combination therapy for patients with renal dysfunction was highly effective and safe.

Association between the body mass index and the clinical findings in patients with acute heart failure: evaluation of the obesity paradox in patients with severely decompensated acute heart failure.

Obesity is known to be associated with the development of heart failure (HF). However, the relationship between the body mass index (BMI) and acute HF (AHF) remains to be elucidated. Eight hundred and eight AHF patients were enrolled in this study. The patients were assigned to four groups according to their BMI values: severely thin (n = 11, BMI <16), normal/underweight (n = 579, 16 ≤ BMI <25), overweight (n = 178, 25 ≤ BMI <30) and obese (n = 40, BMI ≥30). The patients in the severely thin group were more likely to be female, have systolic blood pressure (SBP) <100 mmHg and have valvular disease than normal/underweight patients. The patients in the overweight group were significantly younger than those in the normal/underweight, and those in the overweight group were more likely to have SBP ≥140 mmHg and hypertensive heart disease and less likely to have valvular disease than the patients in the normal/underweight group. The prognosis, including all-cause death, was significantly poorer among patients who were severely thin than those who were normal/underweight, overweight and significantly better among those who were overweight than those who were normal/underweight, severely thin and obese patients. A multivariate Cox regression model identified that severely thin [HR: 3.372, 95% confidence interval (CI) 1.362-8.351] and overweight (HR: 0.615, 95% CI 0.391-0.966) were independent predictors of 910-day mortality as the reference of normal/underweight. Overweight patients tended to have SBP ≥140 mmHg and be relatively young, while severely thin patients tended to have SBP <100 mmHg and be female. These factors were associated with a better prognosis of overweight patients and adverse outcomes in severely thin patients. These factors may contribute to the "obesity paradox" in severely decompensated AHF patients.

Are atherosclerotic risk factors associated with a poor prognosis in patients with hyperuricemic acute heart failure? The evaluation of the causal dependence of acute heart failure and hyperuricemia.

Atherosclerosis induces the elevation of uric acid (UA), and an elevated UA level is well known to lead to a poor prognosis in patients with acute heart failure (AHF). However, the prognostic value of atherosclerotic risk factors in hyperuricemic AHF patients remains to be elucidated. The data from 928 patients who were admitted to the intensive care unit (ICU) at Nippon Medical School Chiba Hokusoh Hospital between January 2001 and December 2014, and whose serum UA levels were measured were screened. A total of 394 AHF patients with hyperuricemia were enrolled in this study. The patients were assigned to a low-risk group (≤1 atherosclerosis risk factor) and a high-risk group (≥2 atherosclerosis risk factors) according to their number of risk factors. The patients in the low-risk group were more likely to have dilated cardiomyopathy, clinical scenario 3 than those in the high-risk group. The serum total bilirubin, blood urea nitrogen, C-reactive protein, and brain-type natriuretic peptide levels were significantly higher in the low-risk group than the high-risk group (p < 0.001, p = 0.005, p = 0.003, and p = 0.008, respectively). A multivariate Cox regression model revealed that the number of risk factors (number = 1, HR (hazard ratio) 0.243, 95 % CI 0.096-0.618, p = 0.003; number = 2, HR 0.253, 95 % CI 0.108-0.593, p = 0.002; number ≥3, HR 0.209, 95 % CI 0.093-0.472, p < 0.001), eGFR (per 1.0 mmol/l increase) (HR 0.977, 95 % CI 0.961-0.994, p = 0.007), and serum UA level (per 1 mg/dl increase) (HR 1.270, 95 % CI 1.123-1.435, p < 0.001) was an independent predictor of 1-year mortality. The prognosis, including all-cause death and HF events, was significantly poorer among the low-risk patients than among the high-risk patients. Atherosclerotic risk factors were not associated with a poor prognosis in patients with hyperuricemic AHF.

Autopsy of invasive ductal pancreatic carcinoma that transformed into a tumor producing granulocyte colony-stimulating factor.

A 64-year-old woman was diagnosed with unresectable pancreatic cancer and underwent chemotherapy. However, the number of leukocytes significantly increased as the disease progressed. Serum G-CSF values also increased, and she eventually died on day 511 after diagnosis. Immediately after autopsy, immunohistochemical staining with an anti-G-CSF monoclonal antibody was positive in the poorly differentiated adenocarcinoma area of the primary pancreatic cancer and liver metastatic foci, but negative in the well-differentiated tubular adenocarcinoma part of the primary pancreatic cancer. During de-differentiation, invasive pancreatic ductal carcinoma appeared to have changed to a tumor that produced G-CSF.