A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

Measuring the global mechanical properties of the human thorax: Costo-vertebral articulation.

Biomechanical simulation of the human thorax, e.g. for 3D-printed rib implant optimisation, requires an accurate knowledge of the associated articulation and tissue stiffness. The present study is focusing on determining the stiffness of the costo-vertebral articulations. Specimens of rib segments including the adjacent thoracic vertebrae and ligaments were obtained from two human post-mortem bodies at four different rib levels. The rib samples were loaded with a tensile force in the local longitudinal, sagittal and transverse direction and the resulting displacement was continuously measured. The moment-angle response of the rib articulations was also determined by applying a load at the rib end in the cranial - caudal direction and measuring the resulting displacement. The torsional load response of the costo-vertebral articulations at an applied moment between -0.1 Nm and 0.1 Nm corresponded to a median range of motion of 13.2° (6.4° to 20.9°). An almost uniform stiffness was measured in all tensile loading directions. The median displacement at the defined force of 28 N was 1.41 mm in the longitudinal, 1.55 mm in the sagittal, and 1.08 mm in the transverse direction. The measured moment-angle response of the costo-vertebral articulation is in line with the data from literature. On the contrary, larger displacements in longitudinal, sagittal and transverse directions were measured compared to the values found in literature.

Efficacy and safety of atezolizumab/bevacizumab in patients with HCC after prior systemic therapy: A global, observational study.

BACKGROUND: Since the introduction of the combination treatment of anti-programmed death-ligand 1 antibody atezolizumab and anti-VEGF antibody bevacizumab (AB), median overall survival in HCC has drastically improved. However, evidence on the efficacy and safety of the novel treatment standard in patients with prior exposure to systemic treatment is scarce. The aim of this global, multicenter, observational study was to evaluate the efficacy and safety of AB in patients after previous systemic therapy. METHODS: We screened our global, multicenter, prospectively maintained registry database for patients who received any systemic therapy before AB. The primary end point was overall survival; secondary end points were time-to-progression, progression-free survival, objective response rate, and safety (rate and severity of adverse events). RESULTS: Among 493 patients who received AB for unresectable HCC, 61 patients received prior systemic therapy and were included in this analysis. The median age of the study population was 66 years, with 91.8% males. Predominant risk factors for HCC were viral hepatitis (59%) and alcohol (23%). Overall survival for AB was 16.2 (95% CI, 14.5-17.9) months, time-to-progression and progression-free survival were 4.1 (95% CI, 1.5-6.6) and 3.1 (95% CI, 1.1-5.1) months, respectively. The objective response rate was 38.2% (7.3% with complete and 30.9% with partial response). Overall survival was not influenced by treatment line (2nd vs. >2nd) or previous systemic treatment modality (tyrosine kinase inhibitors vs. immune checkpoint inhibitors). Treatment-related adverse events of all grades according to Common Terminology Criteria for Adverse Events were documented in 42.6% of patients, with only 13.1% of grade ≥3, including one death. CONCLUSION: In this observational study, AB emerges as a safe and efficacious treatment option in patients with HCC previously treated with other systemic therapy.

Perioperative Insulin Regimens in Patients With Insulin-Treated Type 2 Diabetes Mellitus Hospitalized for a Short Time for Minor Eye Surgery.

BACKGROUND: Elective surgery in patients with insulin-treated type 2 diabetes mellitus (T2D) and the admission period in the hospital, comprise a distinctive and challenging situation for physicians, nurses, as well as for the patients themselves. There is a lack of widely accepted evidence-based and standardized approach of care in regard to perioperative management of patients with insulin-treated T2D. METHODS: The main purpose of this proof-of-concept study was to investigate whether a standardized insulin and meal regimen on the day of surgery leads to a better management of diabetes in terms of blood glucose (BG) levels. Two different insulin and meal regimens-group A with half of insulin dose given with a standardized postoperative meal and group B with a custom preoperative breakfast and full insulin dose-were compared with Group C with routine care (no meal and no insulin injection on the day of surgery). Each group consisted of 12 to 15 patients. BG measurements were performed pre- and immediately postoperatively, before meals and at bedtime. RESULTS: Both standardized and well-defined insulin and meal regimens resulted in better average BG levels in the perioperative period, especially in the morning after the surgery. CONCLUSIONS: In this study, we observed that a standardized perioperative insulin regimen efficiently lowered postoperative BG levels. Providing a custom breakfast and a full insulin dose resulted in lower postoperative BG levels. These approaches were not associated with an increase in hypoglycemic events. Physicians and nursing staff gave positive feedback to the structured and well-defined approaches.