Acute kidney injury development is associated with mortality in Japanese patients with cirrhosis: impact of amino acid imbalance.

BACKGROUND: Acute kidney injury (AKI) is a serious complication of cirrhosis. This study analyzed the prognostic effect of AKI in patients with cirrhosis and its risk factors, particularly in relation to amino acid imbalance. METHODS: This retrospective study reviewed 808 inpatients with cirrhosis at two institutes in Gifu, Japan. AKI was diagnosed according to the recommendations of the International Club of Ascites. Amino acid imbalance was assessed by measuring serum branched-chain amino acid (BCAA) levels, tyrosine levels, and the BCAA-to-tyrosine ratio (BTR). Factors associated with mortality and AKI development were assessed using the Cox proportional hazards regression model with AKI as a time-dependent covariate and the Fine-Gray competing risk regression model, respectively. RESULTS: Of the 567 eligible patients without AKI at baseline, 27% developed AKI and 25% died during a median follow-up period of 4.7 years. Using a time-dependent covariate, AKI development (hazard ratio [HR], 6.25; 95% confidence interval [CI], 3.98-9.80; p < 0.001) was associated with mortality in patients with cirrhosis independent of potential covariates. In addition, alcohol-associated/-related liver disease, metabolic dysfunction-associated steatohepatitis, Child-Pugh score, and BTR (subdistribution HR 0.78; 95% CI 0.63-0.96; p = 0.022) were independently associated with AKI development in patients with cirrhosis. Similar results were obtained in the multivariate model that included BCAA and tyrosine levels instead of BTR. CONCLUSIONS: AKI is common and associated with mortality in Japanese patients with cirrhosis. An amino acid imbalance is strongly associated with the development of AKI in patients with cirrhosis.

Brief intervention for chronic liver disease patients with alcohol use disorder in a hepatology outpatient unit: Effects and limitations.

AIM: It is not uncommon to encounter outpatients in the hepatology department with harmful alcohol habits. When treating such chronic liver disease (CLD) patients, an adequate intervention method for harm reduction of alcohol use, such as brief intervention (BI) or BI and nalmefene, should be considered. This study aimed to elucidate the clinical effectiveness of BI for CLD patients affected by harmful alcohol use. METHODS: From June 2021 to 2023, 123 Japanese CLD outpatients (hepatitis B virus : hepatitis C virus : alcoholic liver disease : others = 32:18:42:31) with an Alcohol Use Disorders Identification Test (AUDIT) score of ≥8 at the initial interview and a repeat interview with AUDIT 9 months later were enrolled. Clinical features related to patient behavior following the initial AUDIT interview were retrospectively evaluated, and compared between patients without and with BI treatment. RESULTS: For the non-BI and BI groups, baseline AUDIT score (median 10 [interquartile range (IQR) 9-13] vs. 12 [IQR 10-17], p = 0.016) and relative change in AUDIT score (median 0 [IQR -3 to 2] vs. -3 [IQR -7 to 0], p < 0.01) showed significant differences, whereas there was no significant difference between the groups for AUDIT score at the time of the second interview (p = 0.156). Following BI, significant improvements were observed for items 1, 2, 3, 4, 5, 8, and 10 of AUDIT (each p < 0.05). CONCLUSION: Patients with an alcohol use disorder as well as those with alcohol dependency who received BI showed a significant decline in AUDIT score, although the score of the follow-up AUDIT indicated continued alcohol use disorder. In addition to BI, medication with nalmefene should be considered, based on individual factors.

Skeletal muscle atrophy is exacerbated by steatotic and fibrotic liver-derived TNF-α in senescence-accelerated mice.

BACKGROUND AND AIM: Although liver diseases, including non-alcoholic steatohepatitis, are associated with skeletal muscle atrophy, the mechanism behind their association has not been fully elucidated. In this study, the effects of aging and non-alcoholic steatohepatitis on the skeletal muscle, and the interaction between the liver and muscle were investigated using a diet-induced non-alcoholic steatohepatitis model in senescence-accelerated mice. METHODS: A total of four groups of senescence-accelerated mice and the control mice were fed either a non-alcoholic steatohepatitis-inducing or control diet, and their livers and skeletal muscles were removed for examinations. RESULTS: In the senescence-accelerated/non-alcoholic steatohepatitis group, serum level of alanine aminotransferase was markedly elevated and histopathology of non-alcoholic steatohepatitis was significant. Skeletal muscles were also markedly atrophied. The expression of the ubiquitin ligase Murf1 in the muscle was significantly increased with muscle atrophy, while that of Tnfa was not significantly different. In contrast, the hepatic Tnfa expression and serum TNF-α levels were significantly increased in the senescence-accelerated/non-alcoholic steatohepatitis group. These results suggest that liver-derived TNF-α might promote muscle atrophy associated with steatohepatitis and aging through Murf-1. The metabolomic analysis of skeletal muscle indicated higher spermidine and lower tryptophan levels in the steatohepatitis-diet group. CONCLUSIONS: The findings of this study revealed an aspect of liver-muscle interaction, which might be important in developing treatments for sarcopenia associated with liver diseases.

Nupr1 deficiency downregulates HtrA1, enhances SMAD1 signaling, and suppresses age-related bone loss in male mice.

Nuclear protein 1 (NUPR1) is a stress-induced protein activated by various stresses, such as inflammation and oxidative stress. We previously reported that Nupr1 deficiency increased bone volume by enhancing bone formation in 11-week-old mice. Analysis of differentially expressed genes between wild-type (WT) and Nupr1-knockout (Nupr1-KO) osteocytes revealed that high temperature requirement A 1 (HTRA1), a serine protease implicated in osteogenesis and transforming growth factor-ß signaling was markedly downregulated in Nupr1-KO osteocytes. Nupr1 deficiency also markedly reduced HtrA1 expression, but enhanced SMAD1 signaling in in vitro-cultured primary osteoblasts. In contrast, Nupr1 overexpression enhanced HtrA1 expression in osteoblasts, suggesting that Nupr1 regulates HtrA1 expression, thereby suppressing osteoblastogenesis. Since HtrA1 is also involved in cellular senescence and age-related diseases, we analyzed aging-related bone loss in Nupr1-KO mice. Significant spine trabecular bone loss was noted in WT male and female mice during 6-19 months of age, whereas aging-related trabecular bone loss was attenuated, especially in Nupr1-KO male mice. Moreover, cellular senescence-related markers were upregulated in the osteocytes of 6-19-month-old WT male mice but markedly downregulated in the osteocytes of 19-month-old Nupr1-KO male mice. Oxidative stress-induced cellular senescence stimulated Nupr1 and HtrA1 expression in in vitro-cultured primary osteoblasts, and Nupr1 overexpression enhanced p16ink4a expression in osteoblasts. Finally, NUPR1 expression in osteocytes isolated from the bones of patients with osteoarthritis was correlated with age. Collectively, these results indicate that Nupr1 regulates HtrA1-mediated osteoblast differentiation and senescence. Our findings unveil a novel Nupr1/HtrA1 axis, which may play pivotal roles in bone formation and age-related bone loss.

Effects of Rifaximin on Circulating Albumin Structures and Serum Ammonia Levels in Patients with Liver Cirrhosis: A Preliminary Study.

Circulating albumin structures, including their oxidized and reduced forms, are involved in hepatic encephalopathy (HE) development. However, the effects of rifaximin, a key drug in HE treatment, on the circulating albumin structure in patients with liver cirrhosis remain unclear. In this multicenter prospective study, eight patients with hyperammonemia (≥80 µg/dL) were enrolled. The circulating albumin structure was evaluated using the ratio of oxidized albumin (human nonmercaptalbumin, HNA). Patients were administered 400 mg rifaximin 3 times/day for 3 months, and laboratory data were assessed at baseline and during observation. Among the eight patients, three were men; the median age and body mass index were 70 years and 26.4 kg/m2, respectively. The median HNA and serum ammonia levels at baseline were 41% and 143 µg/dL, respectively. After rifaximin therapy, HNA showed a decreasing tendency (median; from 41% to 36%, p = 0.321), but serum albumin levels showed no significant change (from 3.5 g/dL to 3.5 g/dL, p = 1.00); serum ammonia levels significantly reduced (median: 143 µg/dL to 76 µg/dL, p = 0.015). Thus, rifaximin reduces serum ammonia levels and may improve circulating albumin structure in patients with cirrhosis. Further large-scale studies are required to confirm these preliminary results.

Survival benefit of l-carnitine supplementation in patients with cirrhosis.

BACKGROUND: l-Carnitine supplementation is effective in improving muscle cramps, hyperammonemia, and hepatic encephalopathy in patients with cirrhosis. However, limited evidence is available on the effect of l-carnitine supplementation on the survival of patients with cirrhosis. METHODS: In this retrospective study, 674 patients with cirrhosis admitted to Gifu University Hospital or Chuno Kosei Hospital between October 2011 and December 2018 were enrolled. l-carnitine supplementation was defined as the use of l-carnitine for >30 consecutive days during the follow-up period. Propensity score matching was applied to create comparable groups between l-carnitine-treated and untreated patients. Mortality was evaluated using the Cox proportional hazards model. RESULTS: Among the patients, 93 were excluded. Of the remaining 581 patients, 71 (12%) received l-carnitine supplementation. Propensity matching identified 189 patients (63 l-carnitine-treated and 126 untreated patients) with comparable baseline characteristics in both groups. Of the matched patients, 33 (52%) l-carnitine-treated and 74 (59%) untreated patients died during the median follow-up period of 36.3 months. Overall survival was significantly higher in l-carnitine-treated patients than in untreated patients (hazard ratio [HR], 0.66; 95% CI, 0.43-0.99). A subgroup analysis showed that the survival benefit of l-carnitine supplementation was prominent in patients with Child-Pugh Class B or C (HR, 0.39; 95% CI, 0.23-0.68), serum albumin levels ≤3.5 g/dl (HR, 0.59; 95% CI, 0.37-0.95), and ammonia levels ≥90 mcg/dl (HR, 0.50; 95% CI, 0.26-0.97), and in those without sarcopenia (HR, 0.56; 95% CI, 0.35-0.90). CONCLUSION: l-Carnitine supplementation may improve survival in patients with cirrhosis.

Leukemia/lymphoma-related factor (LRF) or osteoclast zinc finger protein (OCZF) overexpression promotes osteoclast survival by increasing Bcl-xl mRNA: A novel regulatory mechanism mediated by the RNA binding protein SAM68.

RANKL induces NFATc1, a key transcriptional factor to induce osteoclast-specific genes such as cathepsin K, whereas transcriptional control of osteoclast survival is not fully understood. Leukemia/lymphoma-related factor (LRF) in mouse and osteoclast zinc finger protein (OCZF) in rat are zinc finger and BTB domain-containing protein (zBTB) family of transcriptional regulators, and are critical regulators of hematopoiesis. We have previously shown that differentiation and survival were enhanced in osteoclasts from OCZF-Transgenic (Tg) mice. In the present study, we show a possible mechanism of osteoclast survival regulated by LRF/OCZF and the role of OCZF overexpression in pathological bone loss. In the in vitro cultures, LRF was highly colocalized with NFATc1 in cells of early stage in osteoclastogenesis, but only LRF expression persisted after differentiation into mature osteoclasts. LRF expression was further enhanced in resorbing osteoclasts formed on dentin slices. Osteoclast survival inhibitor such as alendronate, a bisphosphonate reduced LRF expression. Micro CT evaluation revealed that femurs of OCZF-Tg mice showed significantly lower bone volume compared to that of WT mice. Furthermore, OCZF overexpression markedly promoted bone loss in ovariectomy-induced osteolytic mouse model. The expression of anti-apoptotic Bcl-xl mRNA, which is formed by alternative splicing, was enhanced in the cultures in which osteoclasts are formed from OCZF-Tg mice. In contrast, the expression of pro-apoptotic Bcl-xs mRNA was lost in the culture derived from OCZF-Tg mice. We found that the expression levels of RNA binding splicing regulator, Src substrate associated in mitosis of 68 kDa (Sam68) protein were markedly decreased in OCZF-Tg mice-derived osteoclasts. In addition, shRNA-mediated knockdown of Sam68 expression increased the expression of Bcl-xl mRNA, suggesting that SAM68 regulates the expression of Bcl-xl. These results indicate that OCZF overexpression reduces protein levels of Sam68, thereby promotes osteoclast survival, and suggest that LRF/OCZF is a promising target for regulating pathological bone loss.

Impact of Controlling nutritional status (CONUT) in patients with unresectable advanced pancreatic cancer receiving multi-agent chemotherapy: A single center, retrospective cohort study.

Controlling nutritional status (CONUT) calculated using the serum albumin concentration, total lymphocyte count, and total cholesterol, was developed as a screening tool for the early detection of undernutrition. In addition, CONUT has been reported to be a prognostic predictor of various malignancies. AIM: To investigate the impact of CONUT in patients with advanced pancreatic cancer (APC). METHODS: Between June 2014 and October 2020, 110 consecutive patients with APC who received multi-agent chemotherapy were retrospectively reviewed. Patients were classified into four categories (normal, 1; light, 2; moderate, 3; severe, 4) based on CONUT. Progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Thirty-nine (35.4%), 63 (57.2%), and 8 (7.2%) patients had CONUT 1, 2, and 3, respectively, but no patients for CONUT 4. The baseline characteristics did not differ significantly between CONUT classifications. In the multivariate analyses, the presence of metastasis (hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.22-3.52), CONUT 2 (HR, 2.15; 95% CI, 1.32-3.54), and CONUT 3 (HR, 9.18; 95% CI, 2.67-23.50) were independent risk factors for PFS. The presence of metastasis (HR, 1.76; 95% CI, 1.04-3.07), CONUT 2 (HR, 1.92; 95% CI, 1.16-3.24), and CONUT 3 (HR, 10.71; 95% CI, 3.87-27.63) were also independent risk factors for OS. A median OS in CONUT 1, 2, and 3 were 20, 14.5, and 3.5 months (CONUT 1 vs. CONUT 2, p = 0.02; CONUT 1 vs. CONUT 3, p < 0.01; CONUT 2 vs. CONUT 3, p < 0.01), respectively. CONCLUSION: CONUT could be a predictor of prognosis for survival in patients with APC.

Handgrip strength stratifies the risk of covert and overt hepatic encephalopathy in patients with cirrhosis.

BACKGROUND: Handgrip strength (HGS) is a simple and convenient method to assess nutrition status in patients with cirrhosis. This retrospective study aimed to investigate the utility of HGS for predicting patients with covert hepatic encephalopathy (CHE) and patients at high risk of overt hepatic encephalopathy (OHE). METHODS: We reviewed 963 patients with cirrhosis and consequently enrolled eligible 270 patients. HGS was measured using a digital grip dynamometer. CHE was diagnosed using a computer-aided neuropsychiatric test. Factors associated with CHE were estimated using the logistic regression model. Predictors associated with OHE occurrence were analyzed using the Fine-Gray competing risk regression model. RESULTS: Of the 270 eligible patients, reduced HGS was observed in 102 (38%), reduced muscle mass in 107 (40%), and CHE in 53 (20%). Multivariate analysis showed that serum ammonia levels (odds ratio [OR], 2.23; 95% CI, 1.14-4.36; P = 0.014) and reduced HGS (OR, 3.68; 95% CI, 1.93-7.03; P < 0.001) were independently associated with CHE. During the median follow-up period of 24.5 months, 43 (16%) patients experienced OHE. After adjusting for possible confounding factors, multivariate analysis showed that reduced HGS (subdistribution hazard ratio, 2.36; 95% CI, 1.27-4.38; P = 0.007) was a significant predictor in the development of OHE. CONCLUSION: Patients with reduced HGS had a higher prevalence of CHE and a higher risk for OHE occurrence than those with normal HGS. The measurement of HGS could be a simple bedside modality to stratify the patients' risk for CHE and OHE.

Olmesartan-associated sprue-like enteropathy diagnosed by capsule endoscopy and double balloon endoscopy.

Sprue-like enteropathy associated with olmesartan is characterized by villous atrophy in the duodenum. We report the case of an 81-year-old woman diagnosed with olmesartan-associated sprue-like enteropathy with no villous atrophy in the duodenum. The patient had been taking olmesartan for 10 years and complained of diarrhea and weight loss. Despite undergoing general treatment for 2 months, her symptoms showed no improvement. Gastrointestinal endoscopy and pathological findings showed no villous atrophy in the duodenum. However, villous atrophy was observed in the small intestine by capsule endoscopy. Pathological biopsy with double balloon endoscopy provided a definitive diagnosis. Diarrhea improved with the discontinuation of olmesartan and weight increased within a week of withdrawal. After the improvement of clinical symptoms, both endoscopic and pathological findings of villous atrophy in small intestine showed improvement.

Usefulness of the Stroop Test in Diagnosing Minimal Hepatic Encephalopathy and Predicting Overt Hepatic Encephalopathy.

Minimal hepatic encephalopathy (MHE) adversely affects the clinical outcomes of patients with liver cirrhosis. This prospective study aimed to evaluate the utility of the Stroop test in the diagnosis of MHE and prediction of overt hepatic encephalopathy (OHE) in Japanese patients with cirrhosis. We enrolled 152 patients who underwent the Stroop test between November 2018 and February 2020. MHE was diagnosed using a combination of neuropsychological tests as the gold standard. The enrolled patients were followed up prospectively until the occurrence of OHE or August 2020. The optimal cutoff value of the Stroop test measurements was determined by receiver operating characteristic (ROC) curve analysis, and its predictive ability was assessed using the area under the ROC curve (AUC). Among the 139 eligible patients, 50 (36%) were diagnosed with MHE. The OffTime+OnTime cutoff value of 218.3 seconds had the best discriminative ability for MHE diagnosis, with an AUC of 0.77, a sensitivity of 74%, and a specificity of 75%. During a median follow-up of 10.8 months, 6 (4%) patients developed OHE. The OffTime+OnTime cutoff value of 305.6 seconds had the highest predictive ability for OHE, with an AUC of 0.79, a sensitivity of 67%, and a specificity of 92%. This value predicted OHE occurrence independent of liver functional reserve and prior OHE (hazard ratio, 19.8; P = 0.003). These two cutoff values remained statistically significant even when patients with prior OHE were excluded from the analysis. Conclusion: The Stroop test was useful for diagnosing patients with MHE and predicting OHE in Japanese patients with cirrhosis.

Utility of the SARC-F Questionnaire for Sarcopenia Screening in Patients with Chronic Liver Disease: A Multicenter Cross-Sectional Study in Japan.

Diagnosing sarcopenia is challenging. This multicenter cross-sectional study aimed to evaluate the utility of the SARC-F score system for identifying sarcopenia in patients with chronic liver disease (CLD). We enrolled 717 patients from five participating centers who completed the SARC-F between November 2019 and March 2021. Sarcopenia was diagnosed based on the Japan Society of Hepatology Working Group on Sarcopenia in Liver Disease Consensus. Muscle strength was estimated using a grip dynamometer, and muscle mass was assessed using computed tomography or bioelectrical impedance analysis. The association between SARC-F and sarcopenia was analyzed using a logistic regression model. The optimal SARC-F cutoff value for identifying sarcopenia was determined using receiver operating characteristic (ROC) curve analysis. Of the 676 eligible patients, 15% were diagnosed with sarcopenia. The SARC-F distribution was 0 points in 63% of patients, 1 point in 17%, 2 points in 7%, 3 points in 4%, and ≥4 points in 8%. The SARC-F items of "Strength" (odds ratio (OR), 1.98; 95% confidence interval (CI), 1.03-3.80) and "Falls" (OR, 2.44; 95% CI, 1.48-4.03) were significantly associated with sarcopenia. The SARC-F value of 1 point showed a higher discriminative ability for identifying sarcopenia than the 4 points that are conventionally used (p < 0.001), with an area under the ROC curve of 0.68, sensitivity of 0.65, specificity of 0.68, positive predictive value of 0.27, and negative predictive value of 0.92. SARC-F is useful for identifying patients with CLD who are at risk of sarcopenia.

Reduced handgrip strength predicts poorer survival in chronic liver diseases: A large multicenter study in Japan.

AIM: Sarcopenia has a high prevalence and can be an adverse predictor in patients with chronic liver diseases (CLDs). We sought to assess the prevalence of sarcopenia and its prognostic significance in patients with CLDs at multiple centers in Japan. METHODS: In this retrospective study, we collated the data of 1624 patients with CLDs (976 men). The diagnosis of sarcopenia was determined by the sarcopenia assessment criteria of the Japan Society of Hepatology. Predictors of mortality were identified using univariate and multivariate analyses. RESULTS: Muscle weakness and skeletal muscle loss occurred in 33.5% and 29.3% of all subjects, respectively, while sarcopenia occurred in 13.9% of all patients. Patients with sarcopenia had a poorer prognosis among all patients, patients with hepatocellular carcinoma (HCC), and those without HCC by log-rank test. The multivariate Cox proportional hazards model identified female gender (hazard ratio [HR], 0.59; p = 0.03), alcoholic liver disease (HR, 4.25; p < 0.01), presence of HCC (HR, 6.77; p < 0.01), Child-Pugh classes A (HR, 1.42; p < 0.05), B (HR, 2.70; p < 0.01), and C (HR, 6.30; p < 0.01), and muscle weakness (HR, 2.24; p < 0.01) as significant adverse predictors. The cut-off values of handgrip strength (HGS) for prognosis determined by maximally selected rank statistics were calculated as 27.8 kg for men and 18.8 kg for women. CONCLUSION: Reduced HGS in patients with CLD was an independent adverse predictor of mortality, with cut-off values of 27.8 kg for men and 18.8 kg for women.

Increased Visceral Adipose Tissue and Hyperinsulinemia Raise the Risk for Recurrence of Non-B Non-C Hepatocellular Carcinoma after Curative Treatment.

We investigated the factors affecting recurrence-free survival in patients with non-B non-C hepatocellular carcinoma (HCC) who received curative treatment. Decision-tree analysis was performed in 72 curative cases of non-B non-C HCC to extract the risk factors for recurrence. The reliability of the extracted risk factors was evaluated using the Kaplan-Meier method and the Cox proportional hazards model. The decision-tree analysis extracted three factors-visceral adipose tissue (VAT) index (VATI; <71 and ≥71 cm2/m2), which was the cross-sectional areas of VAT on the computed tomographic image at the umbilical level, normalized by the square of the height, fasting immunoreactive insulin (FIRI; <5.5 and ≥5.5 µU/mL), and alpha-fetoprotein (AFP; <11 and ≥11 ng/mL). The Cox proportional hazards model showed that VATI (hazard ratio (HR): 2.556, 95% confidence interval (CI): 1.191-5.486, p = 0.016), FIRI (HR: 3.149, 95% CI: 1.156-8.575, p = 0.025), and AFP (HR: 3.362, 95% CI: 1.550-7.288, p = 0.002) were all independent risk factors for HCC recurrence. Non-B non-C HCC patients with a higher VATI (≥71 cm2/m2) or higher FIRI (≥5.5 µU/mL) and AFP (≥11 ng/mL) if VATI was <71 cm2/m2 are prone to recurrence after curative treatment.

Recurrent hepatogastric fistula during lenvatinib therapy for advanced hepatocellular carcinoma managed by over-the-scope clip closure: a case report.

Objective: Lenvatinib is an oral multitarget tyrosine kinase inhibitor (mTKI) and is recommended for patients with advanced hepatocellular carcinoma (HCC) with Child-Pugh A liver function, who are not amenable to surgical resection, locoregional treatment, or transcatheter arterial chemoembolization. Hepatogastric fistula is a rare complication with a poor prognosis in patients with HCC. Previous reports on fistula formation during mTKI therapy for HCC were all associated with sorafenib. Here, we report the first case of recurrent hepatogastric fistula during lenvatinib therapy for advanced HCC managed using an over-the-scope clip (OTSC). Patient: We present the case of a 73-year-old man with alcoholic liver cirrhosis who was treated for multiple HCC for 7 years. HCC was treated using repetitive transcatheter arterial chemoembolization, radiofrequency ablation, and sorafenib. Owing to disease progression, lenvatinib treatment was started. During lenvatinib treatment, recurrent hepatogastric fistulas developed. An OTSC was useful for fistula closure and prevention of recurrence. Results: The major cause of fistula formation is considered to be the direct invasion of HCC; however, HCC treatment might also be a contributing factor in our case. In addition, OTSC was useful for fistula closure. Conclusion: Clinicians should be aware of the fatal complications during HCC treatment.

Skeletal Muscle Depletion: A Risk Factor for Pneumonia following Gastric Endoscopic Submucosal Dissection in Elderly Patients.

INTRODUCTION: Endoscopic submucosal dissection (ESD) is an effective treatment for gastric neoplasms in elderly patients; however, it involves several adverse events, including pneumonia. This study aimed to investigate whether skeletal muscle depletion (SMD) was associated with the development of pneumonia in elderly patients who underwent gastric ESD. METHODS: This retrospective observational cohort study included 157 patients (≥80 years) who had undergone gastric ESD. The skeletal muscle cross-sectional area was measured by CT, and the value of the third lumbar vertebra skeletal muscle index (L3 SMI) was evaluated. The SMD was defined as an L3 SMI value ≤38.0 cm2/m2 for women and ≤42.0 cm2/m2 for men. Pneumonia was also diagnosed using CT to identify all included patients. RESULTS: Among 157 patients, 66 (42.0%) showed SMD. In the SMD group, the incidence of pneumonia was 21.2%, whereas it was 7.7% in the non-SMD group (p = 0.018). The longest hospitalization duration was 19 days. Antibiotics were administered in 61.9% of the patients. Procedure time was not significantly different between the groups (72 ± 54 min vs. 62 ± 44 min, p = 0.201). On multivariate analysis, SMD was an independent risk factor for the development of pneumonia (odds ratio = 3.16, 95% confidence interval, 1.18-8.50, p = 0.023). CONCLUSIONS: SMD was not a rare entity in patients aged ≥80 years with gastric neoplasms. SMD was a significant risk factor for pneumonia related to gastric ESD in elderly patients.

Zinc deficiency predicts overt hepatic encephalopathy and mortality in liver cirrhosis patients with minimal hepatic encephalopathy.

AIM: Minimal hepatic encephalopathy (MHE) is associated with poor outcomes and the development of overt hepatic encephalopathy (OHE) in patients with liver cirrhosis (LC). Zinc plays a key role in the detoxification of ammonia, a risk factor of hepatic encephalopathy. This study aimed to investigate whether zinc deficiency predicts OHE occurrence and mortality in LC patients with MHE. METHOD: This retrospective study included 100 LC patients with MHE. MHE was diagnosed using a computer-aided neuropsychiatric test. Predictors associated with the development of OHE were analyzed using the Fine-Gray competing risk regression model. Cox proportional hazards regression analysis was carried out to evaluate the risk factors of mortality. Survival rates were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Of the 100 LC patients with MHE, 41% had zinc deficiency (<60 µg/dl). Zinc deficiency was observed more frequently in the patients with reduced liver function reserve. During the median follow-up period of 9.9 months, 16% of the patients with MHE developed OHE. The patients with zinc deficiency had a higher risk of OHE than those without zinc deficiency (p = 0.03). Zinc deficiency was also associated with poor survival (p = 0.004). Multivariate analyses showed that zinc predicts the development of OHE (subdistribution hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.92-0.99; p = 0.008) and mortality (HR, 0.96; 95% CI, 0.93-0.99; p = 0.02), independently of liver function reserves. CONCLUSION: Zinc deficiency is likely to be a predictor of both OHE development and mortality in LC patients with MHE.

The impact of sarcopenia and decrease in skeletal muscle mass in patients with advanced pancreatic cancer during FOLFIRINOX therapy.

Sarcopenia, defined as decrease in skeletal muscle mass (SMM) and strength, might be associated with reduced survival. We investigated the impact of sarcopenia and decrease in SMM in patients with advanced pancreatic cancer during FOLFIRINOX (FX) therapy. Consecutive sixty-nine patients who received FX were evaluated. Skeletal muscle index (SMI) (cm2/m2) was used to evaluate SMM. The cut-off value of sarcopenia was defined as SMI <42 for males and <38 for females, based on the Asian Working Group for sarcopenia criteria. Sarcopenia was diagnosed in thirty-three (48 %) subjects. Comparison of baseline characteristics of the two groups (sarcopenia group: non-sarcopenia group) showed a significant difference in sex, tumour size and BMI. There was no significant difference in the incidence of adverse events with grades 3-5 and progression-free survival (PFS) during FX between the two groups (PFS 8·1 and 8·8 months; P = 0·88). On the multivariate analysis, progressive disease at the first follow-up computed tomography (hazard ratio (HR) 3·87, 95 % CI 1·53, 9·67), decreased SMI ≥ 7·9 % in 2 months (HR 4·02, 95 % CI 1·87, 8·97) and carcinoembryonic antigen ≥ 4·6 (HR 2·52, 95 % CI 1·10, 6·11) were significant risk factors associated with poor overall survival (OS), but sarcopenia at diagnosis was not. OS in patients with decreased SMI of ≥7·9 % and <7·9 % were 10·9 and 21·0 months (P < 0·01), respectively. In conclusion, decrease in SMM within 2 months after the initiation of chemotherapy had significantly shorter OS, although sarcopenia at diagnosis did not affect OS. Therefore, it might be important to maintain SMM during chemotherapy for a better prognosis.

Development of diffuse large B-cell lymphoma after sofosbuvir-ledipasvir treatment for chronic hepatitis C: A case report and literature review.

Recently, treatments for chronic hepatitis C virus (HCV) infection have significantly improved by the development of direct-acting antiviral agents (DAAs) and almost all patients with HCV can complete antiviral treatment without apparent adverse events. Malignant lymphoma, particularly B-cell non-Hodgkin's lymphoma, is one of the extrahepatic manifestations associated with chronic HCV infection. The effectiveness of anti-HCV therapy with DAAs for B-cell non-Hodgkin's lymphoma has been demonstrated in recent reports, whereas late-onset B-cell non-Hodgkin's lymphoma after HCV eradication with DAAs has occasionally been reported. In the present study, a 77-year-old man with chronic hepatitis C and intermediate liver cancer risk received sofosbuvir-ledipasvir treatment for 12 weeks. Two months following the end of antiviral therapy, he had achieved sustained virologic response for 8 weeks. However, the patient occasionally found swelling of the right cervical lymph nodes without any subjective symptoms. Lymph node biopsy revealed diffuse large B-cell lymphoma and whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography showed increased FDG uptake in the right cervical, right submandibular, mediastinal and mesenteric lymph nodes. The patient received six courses of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy and achieved complete response at 8 months after chemotherapy initiation. Thus, the development of lymphoid malignancies may arise, even after HCV eradication with DAAs. Therefore, clinicians should be aware of such risks during and after antiviral treatment with DAAs.

Rapid Depletion of Subcutaneous Adipose Tissue during Sorafenib Treatment Predicts Poor Survival in Patients with Hepatocellular Carcinoma.

The aim of this study was to assess the annualized changes in body composition, including skeletal muscle, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) before, during, and after sorafenib treatment in patients with hepatocellular carcinoma (HCC). This retrospective study evaluated 61 HCC patients treated with sorafenib. Annualized changes (Δ; cm2/m2/year) in skeletal muscle index (SMI), SAT index (SATI), and VAT index (VATI), which were defined as the cross-sectional areas (cm2) of those areas on computed tomography normalized by the square of one's height (m2), before (pre), during (during), and after (post) sorafenib treatment, were calculated. Patients within the 20th percentile cutoffs for these indices were classified into the rapid depletion group and the effects of these values on survival were analyzed using the Kaplan-Meier analysis and Cox proportional-hazards model. Annualized depletion rates of SMI (ΔSMIpre: -3.5, ΔSMIduring: -3.5, ΔSMIpost: -8.0) and VATI (ΔVATIpre: -3.2, ΔVATIduring: -2.8, ΔVATIpost: -15.1) accelerated after the cancellation of sorafenib, whereas that of SATI (ΔSATIpre: -4.8, ΔSATIduring; -7.6, ΔSATIpost; -8.0) had already accelerated during sorafenib treatment. Patients with rapid depletion of ΔSATIduring experienced significantly worse survival rates (p < 0.001), and it was an independent predictor of survival (p = 0.009), together with therapeutic effect (p < 0.001). Rapid depletion of SAT during sorafenib treatment can be used to predict survival in patients with HCC.