Resistance exercise in combination with aerobic exercise reduces the incidence of serious events in patients with liver cirrhosis: a meta-analysis of randomized controlled trials.

BACKGROUND: Exercise, particularly resistance exercise, is beneficial for sarcopenia in patients with liver cirrhosis. However, the effects of exercise on events remain unclear. We aimed to examine the effects of exercise on serious events in patients with liver cirrhosis using a meta-analysis of randomized controlled trials (RCTs). METHODS: A literature search was conducted in 2022. Eleven RCTs were selected for the meta-analysis (exercise group, n = 232; control group, n = 193). Serious events were defined as death or serious complications according to the original articles. A meta-analysis was performed using a random-effects model. The primary outcome was the incidence of serious events. RESULTS: In the 11 RCTs, the incidence of serious events was 5.6% (13/232) and 12.3% (24/193) in the exercise and control groups, respectively. However, a meta-analysis demonstrated no significant difference in the incidence of serious events between the two groups (risk difference [RD] - 0.03, 95% confidence intervals (CI) - 0.07 to 0.02). In a stratification analysis based on a combination of aerobic and resistance exercise, five RCTs (n = 185) were enrolled. The incidence of serious events was 6.25% (7/112) and 24.7% (18/73) in the combination exercise and control groups, respectively. A meta-analysis demonstrated a significant reduction in the incidence of serious events in the combination exercise group compared with the control group (RD - 0.12; 95% CI - 0.21 to - 0.03). CONCLUSIONS: Resistance exercise in combination with aerobic exercise reduces serious events in patients with liver cirrhosis. A combination of aerobic and resistance exercise may be beneficial to improve the prognosis of patients with liver cirrhosis.

Phase angle is related to physical function and quality of life in preoperative patients with lumbar spinal stenosis.

Lumbar spinal stenosis (LSS) can interfere with daily life and quality of life (QOL). Evaluating physical function and QOL and helping patients to improve is the focus of rehabilitation. Phase angle (PhA) assessment is widely used to measure body composition and is considered an indicator of physical function and QOL. This study investigated the relationship between PhA and physical function, physical activity, and QOL in patients with LSS. PhA, handgrip strength, walking speed, Timed Up and Go test (TUG), Life Space Assessment (LSA), Prognostic Nutritional Index (PNI), Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ), and EQ-5D were assessed and statistically analyzed. The study included 133 patients with LSS. Multiple regression analysis of PhA adjusted for age, sex, and body mass index (Model 1) and for Model 1 + PNI (Model 2) showed significant correlations (P < 0.05) with handgrip strength, walking speed, TUG, and LSA. Regarding QOL, PhA was significantly correlated (P < 0.05) with lumbar function in JOABPEQ. PhA was associated with physical function and QOL in patients with LSS and might be a new clinical indicator in this population.

High intramuscular adipose tissue content was a favorable prognostic factor in patients with advanced gastric cancer treated with nivolumab monotherapy.

BACKGROUND: Nivolumab extends the overall survival (OS) of patients with advanced gastric cancer (AGC). Intramuscular adipose tissue (IMAT) is associated with the prognosis of patients with various cancers. We investigated the effect of IMAT on OS in patients with AGC treated with nivolumab. METHODS: We enrolled patients with AGC treated with nivolumab (n = 58, 67 years old, men/women 40/18). The subjects were classified into long-term or short-term survival groups according to the median value. The IMAT was evaluated using computed tomography scans at the umbilical level. The decision tree algorithm was employed to reveal the profile associated with prognosis. RESULTS: In decision tree analysis, immune-related adverse events (irAEs) were the first divergence variable, and prolonged survival was observed in 100% of patients with irAEs (profile 1). However, long survival was observed in 38% of patients with no irAEs. Among these patients, IMAT was identified as the second divergence variable, and long survival was observed in 63% of patients with high IMAT (profile 2). In patients with low IMAT, only 21% showed prolonged survival (profile 3). Median OS was 717 days (95% confidence interval [CI], 223 to not reached) in profile 1, 245 days (95% CI, 126 to 252) in profile 2, and 132 days (95% CI, 69 to 163) in profile 3. CONCLUSION: Immune-related adverse events and high IMAT were favorable factors for OS in patients with AGC treated with nivolumab. Thus, along with irAEs, skeletal muscle quality is important in managing patients with AGC treated with nivolumab.

A low-intensity 10-min resistance exercise program that ameliorated hepatic fibrosis indices and altered G-CSF/IP-10/PDGF-BB in a patient with nonalcoholic fatty liver disease: A case report.

We developed a low-intensity 10-min resistance exercise program for nonalcoholic fatty liver disease (NAFLD). We report a case of NAFLD with elevated hepatic fibrosis indices, which were improved by a 60-week daily exercise program. A 71-year-old female patient with NAFLD whose hepatic fibrosis stage corresponded to F2 was referred to our hospital. She performed the exercise once a day with no changes in other lifestyle habits and medications. The homeostasis model assessment-insulin resistance value and NAFLD-liver fat score, the Hepamet fibrosis score, and the enhanced liver fibrosis score decreased. The FIB-4 index and serum levels of Mac-2 binding protein glycosylation isomer decreased to the reference values. We investigated the changes in chemokines/cytokines. The serum granulocyte-colony stimulating factor level was increased, and serum interferon-gamma-induced protein-10 and platelet-derived growth factor-BB levels were decreased. Our program may be beneficial for improving hepatic fibrosis in patients with NAFLD.

Effects of a low-intensity resistance exercise program on serum miR-630, miR-5703, and Fractalkine/CX3CL1 expressions in subjects with No exercise habits: A preliminary study.

AIMS: Exercise is effective for the prevention of liver cancer. Exercise exerts biological effects through the regulation of microRNAs (miRNAs) and cytokines/myokines. We aimed to investigate the effects of low-intensity resistance exercise on serum miRNA and cytokine/myokine expressions in subjects with no exercise habits. METHODS: We enrolled seven male subjects with no exercise habits in this prospective before-after study. All subjects performed a low-intensity resistance exercise program (three metabolic equivalents, approximately 20 min/session). Serum miRNA expressions were evaluated using microarrays. We performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of differentially expressed miRNAs before and after exercise. Serum cytokine/myokine expressions were evaluated using a multiplex panel. RESULTS: All subjects completed the exercise program with no adverse events. In the microarray analysis, seven miRNAs showed a significant change between before and after exercise. Of these, microRNA (miR)-630 and miR-5703 showed a >1.5-fold increase (miR-630: 40.7 vs. 69.3 signal intensity, p = 0.0133; miR-5703: 30.7 vs. 55.9 signal intensity, p = 0.0051). KEGG pathway enrichment analysis showed that miR-630- and miR-5703-related genes were enriched in 37 and 5 pathways, including transforming growth factor-beta and Wnt signaling pathways, respectively. In the multiplex analysis, 12 cytokines/myokines showed significant alteration after exercise compared to before exercise. Of these, fractalkine/CX3CL1 showed the most significant up-regulation by exercise (94.5 vs. 109.1 pg/ml, p = 0.0017). CONCLUSIONS: A low-intensity resistance exercise program was associated with upregulation of serum miR-630, miR-5703, and fractalkine/CX3CL1 expressions in subjects with no exercise habits. Thus, even low-intensity exercise may alter miRNA and cytokine/myokine expressions in humans.

Risks of Muscle Atrophy in Patients with Malignant Lymphoma after Autologous Stem Cell Transplantation.

OBJECTIVE: Muscle atrophy is associated with autologous stem cell transplantation (ASCT)-related outcomes in patients with malignant lymphoma (ML). However, the impact of ASCT on muscle mass remains unclear in patients with ML. The aims of this study were to investigate changes in muscle mass and risk profiles for muscle atrophy after ASCT. METHOD: We enrolled 40 patients with refractory ML (age 58 [20-74] years, female/male 16/24, body mass index (BMI) 21.1 kg/m2 [17.1-29.6]). Psoas muscle mass was assessed using the psoas muscle index (PMI) before and after ASCT. STATISTICAL ANALYSIS USED: Independent factors associated with a severe decrease rate of change in PMI were evaluated by decision-tree analysis, respectively. RESULTS: PMI was significantly decreased after ASCT (4.61 vs. 4.55 cm2/m2; P=0.0425). According to the decision-tree analysis, the regimen was selected as the initial split. The rates of change in PMI were -5.57% and -3.97% for patients administered MCEC and LEED, respectively. In patients who were administered LEED, the second branching factor was BMI. In patients with BMI < 20.3 kg/m2, the rate of change in PMI was -7.16%. On the other hand, the rate of change in PMI was 4.05% for patients with BMI ≥ 20.3 kg/m2. CONCLUSION: We demonstrated that muscle mass decreased after ASCT in patients with ML. Patients who received MCEC and patients with low BMI were at risk for a decrease in muscle mass.

Prevalence and profiles of ramucirumab-associated severe ascites in patients with hepatocellular carcinoma.

Severe ascites is an adverse event of ramucirumab (RAM), a second-line treatment for hepatocellular carcinoma (HCC). Ascites can be associated with various factors, including nutritional status and muscle quality. The aim of the present study was to investigate the prevalence and profiles of RAM-associated severe ascites in patients with HCC. This retrospective study enrolled 14 consecutive patients with HCC treated with RAM (median age, 72 years; Barcelona Clinic Liver Cancer stage B/C, 6/8). Nutritional status and muscle quality were evaluated using the controlling nutritional status (CONUT) score and intramuscular adipose tissue (IMAT) content, respectively. Factors associated with severe ascites were evaluated using decision-tree analysis. The median progression-free survival (PFS) time was 2.1 months, and the overall objective response and disease control rates were 14 and 50%, respectively. Severe ascites developed in 57.1% of the patients, and the median onset was 37.5 days (range, 14-61 days) after initiation of RAM treatment. In the decision-tree analysis, the CONUT score and IMAT content were the first and second splitting variables for the development of severe ascites. In patients with a CONUT score ≥5 and IMAT <-0.54, the prevalence of severe ascites was 80 and 100%, respectively. A high incidence of severe ascites was observed in patients treated with RAM. A CONUT score ≥5 and an IMAT <-0.54 were associated with severe ascites. Thus, caution must be taken for severe ascites in patients with HCC treated with RAM, in particular patients with malnutrition and fat infiltration in muscle.

Effects of In-Hospital Exercise on Frailty in Patients with Hepatocellular Carcinoma.

Frailty including physical inactivity is associated with the survival of patients with hepatocellular carcinoma (HCC). We aimed to investigate the effects of in-hospital exercise on frailty in patients with HCC. This was a multi-center observational study. Patients with HCC were classified into exercise (n = 114) and non-exercise (n = 67) groups. The exercise group was treated with a mixture of aerobic and resistance exercises (20-40 min/day, median four days). Frailty was assessed using the liver frailty index (LFI). Factors for changes in LFI were examined by multivariate and decision-tree analyses. The factors were also examined after propensity score matching. During hospitalization, LFI was significantly improved in the exercise group compared to the non-exercise group (ΔLFI -0.17 vs. -0.02, p = 0.0119). In multivariate analysis, exercise (odds ratio (OR) 2.38, 95% confidence interval (CI) 1.240-4.570, p = 0.0091) and females (OR 2.09; 95%CI, 1.062-4.109; p = 0.0328) were identified as independent factors for the improvement of LFI. In the decision-tree analysis, exercise was identified as an initial classifier associated with the improvement of LFI. Similar findings were also seen in the propensity score matching analyses. We demonstrated that in-hospital exercise improved frailty in patients with HCC. Thus, in-hospital exercise may be beneficial for improving physical function in patients with HCC.

Effects of In-Hospital Physical Therapy on Activities of Daily Living in Patients with Hepatocellular Carcinoma.

Activities of daily living (ADL) are frequently impaired in patients with hepatocellular carcinoma (HCC). In this retrospective study, we aimed to investigate the effects of physical therapy on ADLs in patients with HCC during hospitalization for cancer treatment. Nineteen patients with HCC were enrolled. During hospitalization, patients performed a combination of resistance training, stretching, and aerobic exercise (20-60 min/day). ADLs were assessed using the functional independence measure (FIM). Changes in FIM were evaluated by before-after analysis. No significant difference was seen in Child-Pugh class before and after physical therapy. The bilateral knee extension strength and chair stand test were significantly increased after physical therapy compared with before physical therapy (p = 0.001 and p = 0.008, respectively). The total FIM score was significantly increased after physical therapy compared with that before physical therapy (p = 0.0156). Among the 18 indexes of FIM, the stairs index was significantly improved after physical therapy compared with that before physical therapy (5.9 vs. 6.4 points, p = 0.0241). We demonstrated that physical therapy improved muscle strength without worsening liver function. Furthermore, physical therapy improved FIM, especially in the stairs index, in patients with HCC. Thus, physical therapy may be beneficial in patients with HCC during cancer treatment.

Profiles Combining Muscle Atrophy and Neutrophil-to-Lymphocyte Ratio Are Associated with Prognosis of Patients with Stage IV Gastric Cancer.

We aimed to investigate the impact of muscle atrophy and the neutrophil-to-lymphocyte ratio (NLR), a sub-clinical biomarker of inflammation and nutrition, on the prognosis of patients with unresectable advanced gastric cancer. We retrospectively enrolled 109 patients with stage IV gastric cancer (median age 69 years; female/male 22%/78%; median observational period 261 days). Independent factors and profiles for overall survival (OS) were determined by Cox regression analysis and decision-tree analysis, respectively. OS was calculated using the Kaplan-Meier method. The prevalence of muscle atrophy was 82.6% and the median NLR was 3.15. In Cox regression analysis, none of factors were identified as an independent factor for survival. The decision-tree analysis revealed that the most favorable prognostic profile was non-muscle atrophy (OS rate 36.8%). The most unfavorable prognostic profile was the combination of muscle atrophy and high NLR (OS rate 19.6%). The OS rate was significantly lower in patients with muscle atrophy and high NLR than in patients with non-muscle atrophy (1-year survival rate 28.5% vs. 54.7%; log-rank test p = 0.0014). In conclusion, "muscle atrophy and high NLR" was a prognostic profile for patients with stage IV gastric cancer. Thus, the assessment of muscle mass, subclinical inflammation, and malnutrition may be important for the management of patients with stage IV gastric cancer.

Impact of Decorin on the Physical Function and Prognosis of Patients with Hepatocellular Carcinoma.

The outcome of patients with hepatocellular carcinoma (HCC) is still poor. Decorin is a small leucine-rich proteoglycan, which exerts antiproliferative and antiangiogenic properties in vitro. We aimed to investigate the associations of decorin with physical function and prognosis in patients with HCC. We enrolled 65 patients with HCC treated with transcatheter arterial chemoembolization (median age, 75 years; female/male, 25/40). Serum decorin levels were measured using enzyme-linked immunosorbent assays; patients were classified into the High or Low decorin groups by median levels. Associations of decorin with physical function and prognosis were evaluated by multivariate correlation and Cox regression analyses, respectively. Age and skeletal muscle indices were not significantly different between the High and Low decorin groups. In the High decorin group, the 6-min walking distance was significantly longer than the Low decorin group and was significantly correlated with serum decorin levels (r = 0.2927, p = 0.0353). In multivariate analysis, the High decorin group was independently associated with overall survival (hazard ratio 2.808, 95% confidence interval 1.016-8.018, p = 0.0498). In the High decorin group, overall survival rate was significantly higher than in the Low decorin group (median 732 days vs. 463 days, p = 0.010). In conclusion, decorin may be associated with physical function and prognosis in patients with HCC.

Impact of cancer rehabilitation on the prognosis of patients with hepatocellular carcinoma.

Sarcopenia is a prognostic factor for patients with hepatocellular carcinoma (HCC). Cancer rehabilitation (CR) improves patients' physical function and muscle mass. We investigated the effects of CR on the prognosis of patients with HCC. The present study was a prospective observational study, which analyzed 152 patients with HCC who underwent transcatheter arterial chemoembolization (TACE) between 2013 and 2016. Patients were classified into the CR (n=85) and control (n=67) groups. The effects of CR on muscle mass were evaluated by changes in the skeletal muscle index (SMI) before and after TACE. Independent factors associated with survival were evaluated by Cox regression analysis. Kaplan-Meier analysis was used to compare the survival rate between the CR and control groups. The difference in survival rate between the two groups was also examined after propensity score matching. SMI was significantly increased in the CR group compared with the control group. In Cox regression analysis, independent factors associated with survival were CR and Child-Pugh class A (estimate 1.760, 95% CI 0.914-3.226, P=0.001; estimate 1.602, 95% CI 0.426-2.998, P=0.0129). The survival rate was significantly higher in the CR group than in the control group (median 552 vs. 424 days; P=0.0359). The survival rate was also significantly higher in the CR group than that in the control group after propensity score matching (median 529 vs. 369 days; P=0.0332). CR was associated with prolonged survival in patients with HCC who underwent TACE. Patients with cancer are recommended to maintain physical activity even during cancer treatment.

Clinical utility of the Liver Frailty Index for predicting muscle atrophy in chronic liver disease patients with hepatocellular carcinoma.

AIM: Muscle atrophy is a prognostic factor for patients with chronic liver disease (CLD) and hepatocellular carcinoma (HCC). The Liver Frailty Index (LFI) is a simple physical function test; however, an association between LFI and muscle mass remains unclear. We aimed to investigate the utility of LFI for predicting muscle atrophy in CLD patients with HCC. METHODS: We enrolled 138 CLD patients with HCC (aged 77 years, female/male 34.8%/65.2%). Muscle mass was assessed by skeletal muscle index, and patients were classified into the muscle atrophy group (n = 109) or the non-muscle atrophy group (n = 29). Physical frailty was assessed by LFI. The optimal cut-off value of LFI for predicting muscle atrophy was identified by receiver operating characteristic analysis. RESULTS: In the muscle atrophy group, the prevalence of pre-frail/frail was significantly higher than the non-muscle atrophy group (87.2% vs. 58.6%, P = 0.0005). In the logistic regression analysis, being female and pre-frail/frail were identified as independent factors associated with muscle atrophy (pre-frail/frail; OR 3.601, 95% CI 1.381-9.400, P = 0.0088). In patients with normal grip strength, 71.1% of patients were pre-frail/frail, in which 82.8% of patients showed muscle atrophy. Receiver operating characteristic statistics provided an area under the curve of 0.74, and an LFI cut-off value of 2.94 for predicting muscle atrophy (sensitivity 88.06%, specificity 52.17%, accuracy 77.91%). CONCLUSIONS: We showed that pre-frail/frail was an independent factor for muscle atrophy in CLD patients with HCC. Furthermore, LFI predicted muscle atrophy with high sensitivity, even in patients with normal grip strength. Thus, LFI might be a useful screening tool for muscle atrophy in CLD patients with HCC.

Slow walking speed overlapped with low handgrip strength in chronic liver disease patients with hepatocellular carcinoma.

AIM: Walking speed and grip strength are parameters of muscle function; however, evaluating walking speed is not always available in clinical practice. We aimed to investigate the impact of walking speed on the evaluation of muscle dysfunction in chronic liver disease (CLD) patients with hepatocellular carcinoma (HCC). METHODS: We enrolled 107 consecutive CLD patients with HCC in this study (age 76 years [range 60-92 years]; female/male 39/68; body mass index 22.9 [range 20.0-25.3]; chronic hepatitis/liver cirrhosis 25/82). Muscle dysfunction was evaluated using the Asian Working Group for Sarcopenia criteria (grip strength or walking speed) and the Japan Society of Hepatology criteria (grip strength). A correlation between walking speed and skeletal muscle index was evaluated. Independent factors for slow walking speed were evaluated using a logistic regression analysis. RESULTS: There was no significant correlation between walking speed and skeletal muscle index (r = 0.14, P = 0.16). For both the Asian Working Group for Sarcopenia and Japan Society of Hepatology criteria, 33.6% of all patients were classified as having muscle dysfunction. All patients with slow walking speed (4.7% of all patients) also showed low handgrip strength. The logistic regression analysis identified grip strength as an independent factor for slow walking speed (OR 0.65; 95% CI 0.432-0.838; P = 0.008). CONCLUSIONS: No difference was seen in the prevalence of muscle dysfunction between the Asian Working Group for Sarcopenia and Japan Society of Hepatology criteria in CLD patients with HCC. Furthermore, all patients with slow walking speed also showed low handgrip strength. Thus, for the evaluation of muscle dysfunction, grip strength might be a suitable proxy for walking speed in CLD patients with HCC.

Effects of in-hospital exercise on sarcopenia in hepatoma patients who underwent transcatheter arterial chemoembolization.

BACKGROUND AND AIM: Sarcopenia is a prognostic factor in hepatocellular carcinoma (HCC) patients. HCC patients who underwent transcatheter arterial chemoembolization (TACE) are at a risk of muscle atrophy. We aimed to investigate the effects of in-hospital exercise on muscle mass and factors associated with muscle hypertrophy in HCC patients who underwent TACE. METHODS: We enrolled 209 HCC patients who underwent TACE. Patients were classified into either an exercise (n = 102) or control (n = 107) group. In the exercise group, patients were treated with in-hospital exercise (median 2.5 metabolic equivalents/20-40 min/day). The effects of exercise on muscle mass were evaluated by changes in skeletal muscle index (ΔSMI) between before and after TACE. Factors associated with an increase in SMI were analyzed by logistic regression and decision-tree analyses. RESULTS: There was no significant difference in serum albumin and bilirubin levels between the two groups. ΔSMI was significantly higher in the exercise group than in the control group (0.28 cm2 /m2 vs -1.11 cm2 /m2 , P = 0.0029). In the logistic regression analysis, exercise was an independent factor for an increase in SMI (hazard ratio 2.13; 95% confidence interval 1.215-3.846; P = 0.0085). Moreover, the decision-tree analysis showed that exercise was the initial divergence variable for an increase in SMI (the ratio of increased SMI: 53% in the exercise group vs 36% in the control group). CONCLUSIONS: In-hospital exercises increased muscle mass in HCC patients who underwent TACE. In addition, exercise was an independent factor for muscle hypertrophy. Thus, in-hospital exercise may prevent sarcopenia in HCC patients who underwent TACE.

Effects of in-hospital exercise on liver function, physical ability, and muscle mass during treatment of hepatoma in patients with chronic liver disease.

AIMS: Sarcopenia and physical disability assessed by a 6-min walking test (6MWT) are associated with poor prognosis of patients with chronic liver disease (CLD). However, CLD patients with hepatocellular carcinoma (HCC) mostly rest in bed during hospitalization. We aimed to investigate the effects of therapeutic exercise on liver function, 6MWT, and skeletal muscle mass during HCC treatment in patients with CLD. METHODS: We enrolled 54 CLD patients with HCC (median age, 76 years). During hospitalization, patients performed a combination of stretching, strength training, balance practice, and endurance training (2.5-4 metabolic equivalents/20 min/day). Primary outcomes were changes from admission to discharge in Child-Pugh class, 6MWT, and skeletal muscle mass. Furthermore, factors associated with skeletal muscle atrophy were analyzed by a decision-tree analysis. RESULTS: Exercise did not worsen the Child-Pugh class. On discharge, the 6MWT ambulation distance was maintained, and heart rate variability during the 6MWT was significantly improved compared to that on admission (area under the curve 50.3 vs. 39.0 arbitrary units; P = 0.0027). Although skeletal muscle mass was significantly reduced (20.6 kg vs. 20.0 kg, P = 0.0301), branched-chain amino acid (BCAA) treatment was identified as the most distinguishable factor for minimizing muscle mass atrophy (-1.1 kg vs. -0.5 kg/hospitalization). CONCLUSIONS: Therapeutic exercise improved physical ability without worsening liver function during hospitalization for HCC treatment in CLD patients. Although exercise did not completely prevent skeletal muscle atrophy, BCAA treatment minimized the skeletal muscle atrophy. Thus, exercise with BCAA treatment may be important for the management of CLD patients with HCC.