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Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1–2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7–28·0) for the nivolumab group and 13·4 months (5·7–25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9–18·4) with nivolumab and 14·7 months (11·9–17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72–1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

Maintenance of liver function is important for better outcomes after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). The aim of this study was to examine the effects of oral branched-chain amino acid (BCAA) supplementation on liver function, intrahepatic recurrence rate, and incidence of complications after RFA for HCC. Patients with cirrhosis who underwent RFA were enrolled between August 2009 and April 2012, randomized to oral supplementation with Aminoleban EN (BCAA group) or diet alone (control group), and followed to determine changes in serum parameters and health status. Patients in the BCAA group were instructed to ingest a packet of Aminoleban EN twice daily. Levels of physical and mental stress were assessed using the Short Form-8 health survey. Oral BCAA and dietary interventions were initiated 2 wk before local therapy, and contrast-enhanced computed tomography was performed every 3 mo to assess recurrence. We evaluated 25 patients in the BCAA group and 26 in the control group. The median follow-up period was 3.9 y (736–1818 d). There were no significant differences between the two groups in basal characteristics. Complications were less frequent in the BCAA group (P = 0.03). Event-free survival was significantly higher in the BCAA group, whereas the intrahepatic recurrence rate was significantly lower (P = 0.04 and 0.036, respectively). A significant improvement in the Short Form-8 mental component score was observed in the BCAA group only (P < 0.01). Aminoleban EN may be beneficial for cirrhotic patients after RFA to relieve mental stress and reduce the risks for intrahepatic recurrence and complications. •To our knowledge, this is the first prospective trial to verify the benefits of early-stage branched-chain amino acid (BCAA) supplementation during therapy for liver cirrhosis.•After radiofrequency ablation, Aminoleban EN may be beneficial for relieving mental stress.•BCAA administration can have a long-term inhibiting effect on carcinogenesis and can improve event-free and overall survival.

Background Liver cancer is a serious global health problem and is associated with poor spiritual health. Bibliotherapy is beneficial in improving health outcomes in cancer patients, yet there is a lack of empirical evidence of its effect on the spiritual health of liver cancer patients in China. The study aimed to investigate the effects of bibliotherapy based on Chinese traditional culture on the spiritual health of patients with liver cancer in China. This study was approved by the Ethics Committee of Hunan Normal University School of Medicine and registered with the Chinese Clinical Trial Registry with the registration (No: 2021260), which registration in June 30th 2021. Methods A total of 60 patients with liver cancer were divided into the intervention group ( n  = 30) and the control group ( n  = 30) through WeChat. The intervention group received bibliotherapy therapy based on traditional Chinese culture, while the control group received routine care. Spiritual health was assessed using the Spiritual Attitude and Involvement List (SAIL) and compared before and after the intervention between the two groups. The chi-square test and t -test were used to analyze the intervention effects. Results The two groups were comparable in all baseline characteristics including the SAIL score. After 5 weeks of intervention, the score of SAIL increased significantly from 96.76 ± 15.08 to 106.93 ± 13.82 in the intervention group ( t  =  − 29.380, p  < 0.001), while no significant difference in SAIL score was observed in the control group (from 95.27 ± 16.40 to 95.31 ± 16.24, t  =  − 0.189, p  = 0.852). Similar patterns were also observed in its three dimensions of connecting with oneself, connecting with the environment, and connecting with transcendence. Conclusions Our study showed that bibliotherapy based on traditional Chinese culture using the WeChat platform can greatly improve the spiritual health of patients with liver cancer and has the potential to be widely applied to cancer patients to improve their well-being.

PurposeHepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths globally. Patients are often diagnosed with advanced disease, in which systemic and locoregional therapies are commonly used as first-line treatment. Such treatments can cause adverse events (AEs) that negatively affect quality of life (QoL), which is particularly undesirable where prognosis is poor. The aim of the present study was to evaluate the impact of common AEs on QoL in patients with HCC.MethodsData from the SARAH randomized controlled trial (RCT) were analyzed. Given the large number of distinct AEs that occurred in the trial, AEs were grouped as in the SARAH trial and prioritized using principal component analysis (PCA). Linear mixed-effects models were then applied with age, ECOG status, and AEs as predictors of the QoL change as measured with the EORTC Core Quality of Life Questionnaire (QLQ-C30).ResultsThe PCA resulted in the selection of 28 AEs for inclusion in the linear mixed-effects models. Of the 28 AEs, diarrhea, decreased appetite, abdominal pain, and palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) were significant drivers of reductions in QoL as measured using the QLQ-C30 global health status scale. Diarrhea, abdominal pain, and hand-foot syndrome were also significant drivers of reduced QoL outcomes.ConclusionThe present analysis showed that diarrhea, decreased appetite, abdominal pain, and palmar-plantar erythrodysesthesia were significantly associated with reduced QoL in patients with unresectable HCC. Reducing the incidence and/or severity of these AEs should therefore be a key focus when selecting the optimal treatments for these patients.Plain English summaryPatients with advanced liver cancer can have a poor prognosis, and preservation of quality of life is an important consideration when choosing appropriate treatments. The SARAH clinical study looked at two treatment options for primary liver cancer — sorafenib and selective internal radiation therapy or SIRT — and collected data on quality of life and how often patients experienced adverse events. Our study used these data to understand which adverse events may have had the largest effect on quality of life. We found that, no matter how severe, gastrointestinal disorders (such as diarrhea, vomiting, nausea, and anorexia) were associated with significant reductions in patient quality of life. We also found that severe constitutional symptoms (such as fever, fatigue, and weight loss) significantly reduced quality of life. The findings may be used to inform choices of treatments or to better prioritize the management of adverse events that cause the greatest reductions in quality of life.

A randomized multicenter phase II trial was conducted to assess the sequential treatment strategy using FOLFIRI.3 and gemcitabine alternately (Arm 2) compared to gemcitabine alone (Arm 1) in patients with metastatic non pre-treated pancreatic adenocarcinoma. The primary endpoint was the progression-free survival (PFS) rate at 6 months. It concludes that the sequential treatment strategy appears to be feasible and effective with a PFS rate of 43.5% in Arm 2 at 6 months (26.1% in Arm 1). This paper reports the results of the longitudinal analysis of the health-related quality of life (HRQoL) as a secondary endpoint of this study. HRQoL was evaluated using the EORTC QLQ-C30 at baseline and every two months until the end of the study or death. HRQoL deterioration-free survival (QFS) was defined as the time from randomization to a first significant deterioration as compared to the baseline score with no further significant improvement, or death. A propensity score was estimated comparing characteristics of partial and complete responders. Analyses were repeated with inverse probability weighting method using the propensity score. Multivariate Cox regression analyses were performed to identify independent factors influencing QFS. 98 patients were included between 2007 and 2011. Adjusting on the propensity score, patients of Arm 2 presented a longer QFS of Global Health Status (Hazard Ratio: 0.52 [0.31-0.85]), emotional functioning (0.35 [0.21-0.59]) and pain (0.50 [0.31-0.81]) than those of Arm 1. Patients of Arm 2 presented a better HRQoL with a longer QFS than those of Arm 1. Moreover, the propensity score method allows to take into account the missing data depending on patients' characteristics. Eudract N° 2006-005703-34. (Name of the Trial: FIRGEM).

Rehabilitation is considered a fundamental component of cancer treatment, especially for patients undergoing cancer surgery. In contrast to conventional rehabilitation education, digital rehabilitation has the potential to improve patients' access to postoperative rehabilitation programs. While digital health has rapidly emerged to aid patients with various diseases, their clinical efficacy in the recovery of patients with primary liver cancer (PLC) undergoing hepatectomy remains inadequately investigated. This study aims to evaluate whether a digital postoperative rehabilitation intervention is efficient in improving physical fitness, enhancing exercise adherence, and alleviating fatigue among patients with PLC after hepatectomy. A randomized controlled trial was undertaken across 2 university-affiliated hospitals in Eastern China. A total of 100 participants were enrolled in this study and were allocated randomly to either the digital health (intervention group, n=50) or the rehabilitation manual-based group (control group, n=50) at a 1:1 ratio. Patients were unblinded and prospectively followed for the intervention of 3 weeks. Outcome measures included physical fitness, exercise adherence, and status of fatigue. Overall, 91 out of 100 patients completed the research and were evaluated after 3 weeks of intervention. The digital health group showed better cardiopulmonary endurance than the control group. The mean difference in the change of 6-minute walk test distance from baseline between the groups was 70.21 (95% CI 0.730-82.869) m (P=.05). No statistically significant effects were found for grip strength, 5-repetition-sit-to-stand test time, and fatigue. The exercise adherence in the digital health group was higher than that in the control group (χ22=15.871, P<.001). The findings suggested that the implementation of digital health had a positive impact on recovery in exercise capacity after hepatectomy. In addition, rehabilitation exercise mode based on digital health has the potential to improve the exercise adherence of patients with PLC compared to conventional manual-based rehabilitation guidance.

Objective: Comprehensive studies are scarce with regard to the quality of life (QOL) of hepatocellular carcinoma (HCC) patients after transcatheter arterial chemoembolization (TACE) and/or radiofrequency ablation (RFA) treatment. The purpose of this study was to examine the impact of TACE alone and that of the TACE followed by RFA (TACE-RFA) on QOL in HCC patients. Methods: QOL was measured using the Functional Assessment of Cancer Therapy-General (FACT-G) (Version 4.0) questionnaire, translated into Chinese, as a measure of QOL among Chinese HCC patients. Prospectively, 83 patients in both TACE group (n = 40) and TACE-RFA group (n = 43) completed the questionnaire at baseline and 3 months after treatment, respectively. Results: The TACE-RFA group resulted in a significantly higher total QOL score, socio-family well-being score, and functional well-being score than that of TACE group, 3 months after respective treatment. Liver function, tumor recurrence and complication, age, income were the most important factors affecting the QOL of HCC patients after treatment. The logistic regression analyses showed that Child-Pugh Class and tumor recurrence after treatment were independent predictors of post-treatment QOL scores of HCC patients. Conclusions: The overall QOL of HCC patients in TACE-RFA group was maintained at a relatively higher level than that of TACE group. TACE followed by RFA appeared to be more favorable than TACE alone with respect to QOL.

Summary Very few patients with liver metastases from colorectal cancer can be cured. We have investigated whether a treatment to slow the growth of liver metastases, hepatic-artery infusion of floxuridine, improves palliation in this setting. In a randomised study of 100 patients, we compared quality of life and survival in patients who received hepatic-artery infusion of floxuridine and in those who received conventional symptom palliation. 95% of control patient survival time was spent with normal quality-of-life scores, which suggests that the aim of treatment should be to prolong normal-quality survival rather than merely to sustain quality of life. There was a significant prolongation (p=0·03) in overall survival in floxuridine-treated patients compared with controls (median 405 vs 226 days). There were similar significant prolongations in normal-quality (ie, normal symptom scores) survival for physical symptoms (p=0·04), anxiety (p=0·04), and depression (p=0·04). This survival benefit was associated with significant reductions in metastasis size on computed tomography (p=0·001) and in serum carcinoembryonic antigen concentration (p=0·006) in floxuridine-treated patients. There was no evidence of treatment-related hepatotoxicity as assessed by serum aspartate aminotransferase and bilirubin measurements. This is the first demonstration that survival can be prolonged with normal quality of life in patients with colorectal liver metastases. We conclude that hepatic-artery floxuridine infusion can be recommended for suitable patients.

Background Collaborative care interventions to treat depression have begun to be tested in settings outside of primary care. However, few studies have expanded the collaborative care model to other settings and targeted comorbid physical symptoms of depression. Purpose The aims of this report were to: (1) describe the design and methods of a trial testing the efficacy of a stepped collaborative care intervention designed to manage cancer-related symptoms and improve overall quality of life in patients diagnosed with hepatobiliary carcinoma; and (2) share the lessons learned during the design, implementation, and evaluation of the trial. Methods The trial was a phase III randomized controlled trial testing the efficacy of a stepped collaborative care intervention to reduce depression, pain, and fatigue in patients diagnosed with advanced cancer. The intervention was compared to an enhanced usual care arm. The primary outcomes included the Center for Epidemiological Studies-Depression scale, Brief Pain Inventory, and Functional Assessment of Cancer Therapy (FACT)-Fatigue, and the FACT-Hepatobiliary. Sociodemographic and disease-specific characteristics were recorded from the medical record; Natural Killer cells and cytokines that are associated with these symptoms and with disease progression were assayed from serum. Results  and  Discussion The issues addressed include: (1) development of collaborative care in the context of oncology (e.g., timing of the intervention, tailoring of the intervention, ethical issues regarding randomization of patients, and changes in medical treatment over the course of the study); (2) use of a website by chronically ill populations (e.g., design and access to the website, development of the website and intervention, ethical issues associated with website development, website usage, and unanticipated costs associated with website development); (3) evaluation of the efficacy of intervention (e.g., patient preferences, proxy raters, changes in medical treatment, and inclusion of biomarkers as endpoints); and (4) analyses and interpretation of the intervention (e.g., confounding factors, dose and active ingredients, and risks and benefits of collaborative care interventions in chronically ill patients). Limitations The limitations to the study, although not fully realized at this time as the trial is ongoing, include: (1) heterogeneity of the diagnoses and treatments of participants; and (2) inclusion of caregivers as proxy raters but not as participants in the intervention. Conclusions Collaborative care interventions to manage multiple symptoms in a tertiary cancer center are feasible. However, researchers designing and implementing interventions that are web-based, target multiple symptoms, and for oncology patients may benefit from previous experiences.

Aims To investigate the impact of varying levels of chronic stress on the disease-free survival (DFS) and overall survival (OS) of patients with hepatocellular carcinoma (HCC) following curative treatment and establish a comprehensive evaluation index for chronic stress. Methods Ninety HCC patients who underwent curative treatment were assessed for chronic stress using hair cortisol concentration, Stress Score, and the Perceived Stress Scale (PSS-10). The optimal cut-off values for these markers were statistically determined, and correlations among them were analyzed to create the Chronic Stress Index (CSI), which classified patients into high or low chronic stress groups. DFS and OS were compared between the groups. Additionally, a systematic review of literatures on the effects of chronic stress and cancer recurrence was conducted. Results The optimal cut–off values of the Stress Score, PSS-10, and hair cortisol concentration were 15.30, 50.00 and 19.70 pg/mg, respectively. Patients with a CSI score of 3 to 4 were classified into the low chronic stress state (LCSS) group, whereas those scoring 5 to 6 were classified into the high chronic stress state (HCSS) group. Patients in the HCSS group had significantly reduced DFS ( P  < 0.001) and OS ( P  = 0.033) compared to the LCSS group. The systematic review identified only three clinical trials on chronic stress and cancer recurrence. Conclusion High chronic stress levels are associated with shorter DFS and OS in HCC patients. The CSI classification effectively categorized the chronic stress state, providing a novel tool for clinical evaluation.