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Background and Aim: Metachronous gastric cancer (GC) frequently occurs in patients who have undergone endoscopic resection (ER) for GC. We evaluated the risk for development of metachronous GC following ER for GC based on genetic polymorphisms for alcohol dehydrogenase‐1B (ADH1B) and aldehyde dehydrogenase‐2 (ALDH2), as well as alcohol consumption and smoking habits. Methods: We studied 77 patients who underwent ER for GC (median follow‐up of 84 months). Genotyping of ADH1B/ALDH2 was performed using saliva sampling. Histories of alcohol consumption and smoking before and after ER and Helicobacter pylori eradication were documented. Results: Multivariate analyses revealed that homozygous slow‐metabolizing ADH1B (hazard ratio [HR] = 2.38, P < 0.13), heavy smoking (HR = 2.36, P < 0.09), and cigarette smoking after ER (HR = 2.47, P < 0.10) were not independently associated with the risk of secondary GC development. We analyzed the cessation status of the 38 patients who were classified as heavy smokers before ER based on their smoking habits after the ER and divided them into a cessation group (n = 27, non‐smokers after ER) and a non‐cessation group (n = 11). Cumulative incidence curves of secondary GC in the cessation and non‐cessation groups revealed 5‐year incidence rates of 19.0% and 45.0%, respectively (P = 0.02). Conclusion: Continued cigarette smoking, at a high level, may be an important risk factor for the development of metachronous GC. Advice for smoking cessation should be given. [ABSTRACT FROM AUTHOR]

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. Lay Summary: Hepatitis B virus (HBV) reactivation during antitumor or immunosuppressive therapy could be fatal. Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir with high efficacy and safety for hepatitis B infection. Nonetheless, there exist no prospective studies on the efficacy of TAF prophylaxis for the prevention of HBV reactivation. This prospective multicenter study is the first to show the high efficacy of TAF prophylaxis for the prevention of HBV reactivation. [ABSTRACT FROM AUTHOR]

Progressive liver fibrosis after anti-HCV treatment is a risk factor for HCC. Angiopoietin-2 (Ang2) is associated with non-regression of liver fibrosis after direct-acting antiviral (DAA). This study evaluated the predictive value of serum Ang2 levels for HCC occurrence or recurrence after DAA administration. In this retrospective study, 310 HCV-infected patients treated with DAAs in 2014–2020 were screened and evaluated for HCC occurrence or recurrence every three–six months. Multivariate Cox regression analysis revealed that age ≥ 75 years (HR: 2.92, 95% CI: 1.34–6.33; p = 0.007) and baseline Ang2 level ≥ 464 pg/mL (HR: 2.75, 95% CI: 1.18–6.37; p = 0.019) were significantly associated with HCC occurrence after DAA therapy. A high or low risk of HCC after DAA therapy could be distinguished by the combination of age and baseline Ang2 level. The cumulative incidences of de-novo HCC at two and four years were 0.8% and 3.8% in the low-risk group and 22.6% and 27.1% in the high-risk group, respectively. Baseline Ang2 level ≥ 402 pg/mL was significantly associated with HCC recurrence in patients who achieved sustained virological response with DAAs (HR: 3.68). In conclusion, serum Ang2 levels can predict HCC occurrence and recurrence after successful HCV eradication by DAAs. [ABSTRACT FROM AUTHOR]

Simple Summary: The IMbrave150 trial led to the approval of atezolizumab and bevacizumab for the treatment of unresectable hepatocellular carcinoma (HCC). We performed a retrospective multicenter study including 115 patients with unresectable HCC treated with atezolizumab and bevacizumab, revealing that the combination of atezolizumab and bevacizumab is equally effective for patients meeting the IMbrave150 trial eligibility criteria and for patients not meeting these criteria, generally due to a history of systemic therapy, platelet counts < 75 × 109/L, Child-Pugh B, and 2+ proteinuria. However, liver functional reserve should be carefully monitored in patients not meeting the IMbrave150 trial eligibility criteria. The IMbrave150 trial demonstrated the high efficacy and safety of atezolizumab and bevacizumab for unresectable hepatocellular carcinoma (HCC). In this multicenter study, the efficacy of this combination and its effect on liver functional reserve were evaluated in patients not meeting the eligibility criteria of IMbrave150. Of 115 patients with unresectable HCC treated with atezolizumab and bevacizumab between October 2020 and January 2022, 72 did not meet the eligibility criteria of IMbrave150, most frequently due to a history of systemic therapy (60/72), platelet counts < 75 × 109/L (7/72), Child-Pugh B (9/72), and 2+ proteinuria (8/72). Atezolizumab and bevacizumab therapy was equally effective for patients who did or did not meet the eligibility criteria (PFS, 6.5 vs. 6.9 months, p = 0.765), consistent with subgroup analyses of histories of systemic therapy, platelet counts, Child-Pugh, and proteinuria. Baseline ALBI scores were worse in patients who did not meet the criteria than in those who did and significantly worsened after treatment initiation in patients not meeting the criteria (baseline vs. 12 weeks; 2.35 ± 0.43 vs. −2.18 ± 0.54; p = 0.007). Accordingly, atezolizumab plus bevacizumab was effective for patients not meeting the eligibility criteria of IMbrave150, although careful monitoring for changes in liver functional reserve is needed. [ABSTRACT FROM AUTHOR]

For long-term treatment of hepatitis B virus (HBV) infection, switching from tenofovir-disoproxil-fumarate (TDF) to tenofovir-alafenamide (TAF) may prevent renal dysfunction and bone loss. However, the precise effects of this switch on the blood lipid profile remain to be clarified. This is an important issue as TDF is known to have effects on both low- and high-density lipids. Therefore, our retrospective multi-center study aimed to evaluate the effects of switching from TDF to TAF on the lipid profile of patients with HBV infection. Samples were obtained prior to the switch from TDF to TAF and at 6–12 months after TAF initiation. In some cases, additional samples obtained pre- and post-TDF administration were available for analysis. Serum cholesterol levels, including oxidized-low-density lipoprotein (LDL) and non-high-density lipoprotein-cholesterol (HDL-c), and the rate of dyslipidemia, according to the NCEP-ATP III lipid risk classification, were analyzed. The data from 69 patients were analyzed, including 33 patients with pre- and post-TDF-initiation serum samples. Total cholesterol (T-chol), HDL-c, LDL-c, non-HDL-c, and oxidized LDL levels increased significantly after switching to TAF. With regard to sequential changes pre- to post-TAF, TDF was associated with significantly lower serum T-chol, HDL-c, and oxidized LDL-c levels, with T-chol, HDL-c, LDL-c, and oxidized LDL-c levels increasing significantly after the switch. The switch from TDF to TAF was also associated with an increase in the rate of dyslipidemia, from 33% to 39%, with an increase in the rate of severe dyslipidemia of 1.4% and 5.8%, based on T-chol and LDL-c levels. Of note, no cases of severe dyslipidemia were detected pre-TAF treatment. As oxidized LDL-c and non-HDL-c are strongly associated with atherosclerosis development, careful monitoring of lipid is needed after switching from TDF to TAF in this clinical population. [ABSTRACT FROM AUTHOR]

Background and Aim: The mechanism underlying carcinogenesis and the genomic features of superficial non‐ampullary duodenal epithelial tumors (SNADETs) have not been elucidated in detail. In this study, we examined the genomic features of incipient SNADETs, such as small lesions resected via endoscopic treatment, using next‐generation sequencing (NGS). Methods: Twenty consecutive patients who underwent endoscopic treatment for SNADETs of less than 20 mm between January and December 2017 were enrolled. Targeted genomic sequencing was performed through NGS using a panel of 160 cancer‐related genes. Furthermore, the alteration/mutation frequencies in SNADETs were examined. Results: The maximum size of the SNADETs examined in this study was 12 mm in diameter. Five SNADETs were classified as low‐grade dysplasia (LGD) tumors, while 14 SNADETs were classified as high‐grade dysplasia tumors. Only one carcinoma in situ was detected. NGS data for 16 samples were obtained. APC alterations were detected in 81% of samples (13/16). KRAS, BRAF, and TP53 alterations were detected in 25% (4/16), 18.8% (3/16), and 6.3% (1/16) of cases, respectively. Conclusion: We detected APC alterations in most small SNADETs resected via endoscopic treatment, from LGD to carcinoma samples. Even in SNADETs classified as small LGD exhibited KRAS and BRAF alterations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Entecavir and tenofovir–disoproxil–fumarate are first-line nucleos(t)ide analogs (NA) for treatment of hepatitis B virus (HBV) infections; however, their long-term administration can impact extrahepatic organs. Herein, we sought to examine the effect of NA on lipid metabolism while also characterizing the associated mechanism. Methods: A retrospective study was performed on HBV patients administered entecavir or tenofovir–disoproxil–fumarate. Patient clinical information, as well as their preserved serum samples obtained at baseline and 6–12 months after treatment initiation, were analyzed. A 1:1 propensity score matching was applied to the assignment of tenofovir–disoproxil–fumarate or entecavir treatment. Changes in serum cholesterol, including oxidized-LDL, were analyzed. Subsequently, in vitro analysis elucidated the mechanism associated with the effect of NAs on lipid metabolism. Results: Administration of tenofovir–disoproxil–fumarate, not entecavir, to chronic HBV patients, decreased serum cholesterol levels, including non-HDL and oxidized-LDL, which are strongly associated with arteriosclerosis. In vitro analysis revealed that tenofovir–disoproxil–fumarate reduced supernatant cholesterol, and upregulated the scavenger receptor, CD36, in hepatocytes. Meanwhile, silencing of hepatic CD36 increased supernatant cholesterol and negated the cholesterol-reducing effect of tenofovir–disoproxil–fumarate in HepG2-cells. Reporter, microarray, and RT-PCR analyses further revealed that tenofovir–disoproxil–fumarate treatment activates PPAR-α-mediated signaling, and upregulates PPAR-α target genes, including CPT1 and CD36. Alternatively, silencing of PPAR-α reversed the effects of tenofovir–disoproxil–fumarate on CD36. Conclusions: Tenofovir–disoproxil–fumarate modulates lipid metabolism by upregulating hepatic CD36 via PPAR-α activation. Since dyslipidemia could be associated with arteriosclerosis and hepatocarcinogenesis, these discoveries provide novel insights into anti-HBV therapies, as well as the associated extrahepatic effects of NA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To elucidate the long‐term outcomes of permanent endoscopic biliary stenting (EBS) and risk factors for recurrent biliary obstruction (RBO) in high‐risk or elderly patients with common bile duct (CBD) stones. Methods: The electronic database of Hakodate Municipal Hospital was searched to identify elderly or high‐risk patients with CBD stones who had undergone permanent EBS using a plastic stent without stone removal and were followed up between April 2011 and May 2019, with no further intervention until symptoms occurred. Results: We analyzed a total of 47 patients, of whom 19 (40.4%) were men, with a median age of 86 years (interquartile range 80‐90 years). RBO and death without biliary disease occurred in 14 (29.8%) and 19 (40.4%) patients, respectively. The cumulative RBO rates at 20, 40, and 60 months were 22.1%, 31.8%, and 35.5%, respectively. The median time to RBO was 13.0 and 38.0 months in the group with CBD stone ≥15 mm and 11‐14 mm in diameter, respectively. The cumulative RBO incidence rate in the group with CBD stone ≤10 mm in diameter did not reach 50%. The cumulative RBO incidence rates were significantly different among the three groups based on the CBD stone diameter (competing risk analysis, P < 0.01). Multivariate analysis showed that an increase in CBD stone diameter predicted the increased risk of RBO (hazard ratio 1.26, P = 0.01). Conclusions: Permanent EBS is a feasible option for high‐risk patients with small CBD stones. [ABSTRACT FROM AUTHOR]

Background and Aim: Lenvatinib has been recently approved as a first‐line systematic therapy for patients with advanced hepatocellular carcinoma (HCC) based on the results of the phase 3 clinical trial REFLECT. This trial excluded patients with a history of systemic chemotherapy, bile duct invasion, and Child‐Pugh grade B. We aimed to investigate the efficacy and safety of lenvatinib for these patients and in the real‐world setting. Methods: Among patients who were administered lenvatinib for advanced HCC between April and October 2018 in Hokkaido University Hospital and related hospitals, we evaluated those who were followed for more than 2 months and whose treatment response was evaluated via dynamic computed tomography at baseline and 2 months after treatment initiation. Meanwhile, patients were excluded if they had decompensated liver cirrhosis, were followed up less than 2 months, or were not evaluated at 2 months. Patients were also stratified according to compliance with the REFLECT inclusion criteria for further analysis. Results: A total of 41 patients were included; more than 50% did not meet the REFLECT inclusion criteria. In total, 5 (12.2%), 20 (48.8%), 12 (29.3%), and 4 (9.3%) showed complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 61.2%. The objective response rate and disease control rate were similar between patients who did and did not meet the REFLECT inclusion criteria. Moreover, the safety profile was also similar between the two patient groups. Conclusion: Lenvatinib showed high early response rate and tolerability in patients with advanced HCC. Favorable outcomes were similarly observed in patients who did not meet the REFLECT inclusion criteria. [ABSTRACT FROM AUTHOR]

A Mössbauer spectroscopy study of the iron-based superconductor KxFe2−ySe2, with two superconducting phases of SC1 and a pressure induced SC2 was performed under pressure. This compound consists of two separated phases of major magnetic (non-superconducting) and minor superconducting components. The internal magnetic field of the major magnetic component decreased at the SC2 phase and disappeared around 15 GPa, while that of the minor non-magnetic component maintained its intensity up to 14.9 GPa. Multiple internal magnetic fields were introduced for improved fits to the spectra of the magnetic component at the SC2 phase, suggesting the importance of the electron–electron correlation in the emergence of the SC2 phase. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Heart failure with preserved ejection fraction (HFpEF) is now recognized as a geriatric syndrome with multifactorial pathophysiology and clinical heterogeneity rather than a solely left ventricular diastolic dysfunction. Because the pathophysiology of HFpEF is suggested to differ by age, this study compared the clinical characteristics and prognostic factors between HFpEF patients aged 65 to 84 years and those aged 85 years or older. DESIGN: Retrospective cohort study. SETTING: The Tokyo CCU Network including 73 hospitals in Tokyo, Japan. PARTICIPANTS: Individuals aged 65 years or older with HFpEF (N = 4305). MEASUREMENTS: Very old patients were defined as those aged 85 years or older. Potential risk factors for in‐hospital mortality were selected by univariate analyses, and those with a P value <.10 were used in multivariate Cox regression analysis with forward selection (likelihood ratio) to identify significant factors. RESULTS: Prevalence of hypertension was significantly higher in very old patients, whereas prevalence of coronary artery disease, diabetes mellitus, hyperlipidemia, and smoking was significantly higher in patients aged 65 to 84 years. In very old patients, low systolic blood pressure (hazard ratio [HR] =.988), high serum creatinine level (HR = 1.34), and coexisting chronic obstructive pulmonary disease (COPD; HR = 2.01) were identified as independent risk factors for in‐hospital mortality. In contrast, low systolic blood pressure (HR =.987) and low body mass index (HR =.935) were identified as independent risk factors in patients aged 65 to 84 years. CONCLUSION: Significant differences were observed in the clinical characteristics and prognostic factors for in‐hospital mortality between HFpEF patients aged 65 to 84 and those 85 years and older. Of note, coexisting COPD was associated with significantly lower survival rate only in patients aged 85 years and older, suggesting the prognostic impact of concomitant pulmonary disease in HFpEF may increase with age. These results have implications for future research and management of older HFpEF patients. J Am Geriatr Soc 00:1–6, 2019. J Am Geriatr Soc 67:2123–2128, 2019 [ABSTRACT FROM AUTHOR]