Background/Objectives: Biliary tract cancers (BTCs), encompassing tumors of the bile ducts, gallbladder, or ampulla of Vater, are notoriously hard to manage, especially when surgery is off the table and standard chemotherapy provides only modest benefits. While emerging treatments such as immune checkpoint inhibitors have shown promise, mixed clinical trial results and varied study endpoints have left their true impact unclear. This concise review consolidates current evidence on combining chemotherapy with immunotherapy to clarify whether these regimens can significantly improve outcomes and steer more effective treatment strategies for BTCs. Methods: A comprehensive literature search was conducted across PubMed, Embase, Web of Science, and ClinicalTrials.gov for randomized controlled trials (RCTs) and prospective comparative studies published from January 2010 to December 2024. Fixed-effect meta-analyses (inverse-variance method) were used as the primary approach, with random-effects models (REML) performed as sensitivity analyses to confirm robustness were performed to calculate pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). Leave-one-out sensitivity analyses and Egger’s tests assessed result stability and publication bias. The review was conducted in accordance with PRISMA 2020 guidelines and registered in OSF. Results: Two RCTs (n = 1754; chemoimmunotherapy n = 874, chemotherapy n = 880) were included in the quantitative meta-analysis. Compared to chemotherapy alone, chemoimmunotherapy significantly reduced the risk of death by 20% (OS, HR = 0.80; 95% CI 0.72–0.89; I² = 0%) and the risk of disease progression or death by 19% (PFS, HR = 0.81; 95% CI 0.73–0.90; I² = 33.5%). Leave-one-out sensitivity analyses confirmed result stability. Egger’s tests showed no significant publication bias (OS p = 0.30; PFS p = 0.40). Two additional studies (IMbrave 151 and Monge 2022) lacking comparative survival data were qualitatively assessed. Conclusions: Chemoimmunotherapy significantly improves OS and PFS compared with chemotherapy alone in advanced BTC, with consistent findings across included trials. These results support the incorporation of chemoimmunotherapy as a first-line therapeutic strategy. Future research should prioritize biomarker-driven patient selection, evaluation of long-term clinical outcomes, and integration of targeted therapies with chemoimmunotherapy.

Background: Angiopoietin-like protein 4 (ANGPTL4) plays a crucial role in processes such as angiogenesis, inflammation, and metabolism. Despite numerous studies suggesting its involvement in cancer, a definitive role remains unclear. We introduce the first comprehensive meta-analysis and pan-cancer bioinformatics study on ANGPTL4, aiming to unravel its implications across various cancer types. Methods: Moderate-to high-quality observational studies were retrieved from PubMed, Scopus, and Embase. A meta-analysis was conducted using the R package “meta.” Survival analysis was performed using GEPIA2 and TIMER2.0. Immune infiltration, mutational burden, and drug resistance analyses was done via GSCAlite. Co-expression and gene set enrichment analyses (GSEA) were carried out using cBioportal and enrichr, respectively. Results: Increased ANGPTL4 expression was linked to worse tumor grade (OR = 1.51, P = 0.023), stage (OR = 2.42, P < 0.001), lymph node metastasis (OR = 1.76, P = 0.012), vascular invasion (OR = 2.16, P = 0.01), and lymphatic invasion (OR = 2.20, P < 0.001). Furthermore, ANGPTL4 expression was linked to worse OS (HR = 1.40, 95% CI: 1.29,1.50, P = 0.0001). Single gene level analysis revealed that ANGPTL4 upregulated epithelial-to-mesenchymal transition (EMT) in 23 different cancers. Immune infiltration varied between cancer types, but increased infiltration of cancer-associated fibroblasts was observed in most cancers. Mutation analysis revealed increased alterations in TP53 and CDKN2A in cohorts with ANGPTL4 alterations. GSEA of co-expressed genes revealed involvement in hypoxia, EMT, VEGF-A complex, TGF-B pathways, and extracellular matrix organization. Conclusions: ANGPTL4 plays a significant role in tumor progression via its positive regulation of EMT and angiogenesis, while possibly harboring a TGF-B dependent role in systemic metastasis. Therefore, ANGPTL4 is a suitable target for future drug development.

Background: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease marked by airway inflammation and obstruction. Ensifentrine is a novel inhaled PDE3 and PDE4 inhibitor with both bronchodilator and anti-inflammatory effects. Objectives: Comprehensively review the available evidence on ensifentrine and its potential role in COPD management. Design: Systematic review and meta-analysis with trial sequential analysis of randomized clinical trials. Data sources and methods: We systematically searched PubMed, Scopus, ScienceDirect, Cochrane Library, and Medline for clinical trials published between 2018 and August 2024 that evaluated the safety and efficacy of ensifentrine in patients with COPD. We assessed study quality using the RoB 2 tool and conducted the meta-analysis with the “meta” package in R (version 4.3.2), using the mean difference with a 95% confidence interval to evaluate changes in outcomes. Results: Five studies met the predefined inclusion criteria with 2519 participants. At week 12, the pooled analysis indicated that forced expiratory volume in 1 s (FEV ₁ ) and trough FEV ₁ were significantly increased in the ensifentrine group (mean difference (MD): 91.32; 95% CI: 69.63 to 113.01) and (MD: 40.90; 95% CI: 19.65 to 62.15), respectively. At week 24, the pooled analysis indicated that the evaluating respiratory symptoms total score was significantly decreased in the ensifentrine group (MD: −0.81; 95% CI: −1.36 to −0.27), transition dyspnea index score was significantly increased in the ensifentrine group (MD: 0.96; 95% CI: 0.62 to 1.29), no significant difference was observed in rescue medication use (MD: −0.30; 95% CI: −0.60 to 0.00), and no significant difference was observed in St. George’s Respiratory Questionnaire total score (MD: −1.46; 95% CI: −3.22 to 0.30). Based on subgroup analysis, higher doses were associated with more favorable results. Conclusion: In conclusion, owing to its dual effects, ensifentrine has a significant impact on improving pulmonary function and quality of life with minimal side effects. Promising results are expected if implied by synergizing with other drugs, however, more studies are needed to study the long-term effect on disease progression. Trial registration: The study protocol was published via PROSPERO: International Prospective Register of Systematic Reviews (#CRD42024570799).

Background: Pancreatic adenocarcinoma (PAAD) is an aggressive subtype of pancreatic cancer that is estimated to have a 5-year overall survival rate of only 13%. Most patients present with advanced disease with unpredictable outcomes. The identification of prognostic biomarkers is important to accurately stratify these patients. Methods: We investigated the molecular and survival-related role of ENHO in PAAD by analyzing TGCA mRNA and miRNA data. Survival analysis was conducted using TIMER2.0, “survival”, and “survminer”. Gene set enrichment analysis was conducted using enrichr, while miRNA-mRNA interactions were identified using “multiMiR”. Immune infiltration was assessed using CIBERSORT ABS and ImmuCellAI. Results: We observed that ENHO was strikingly downregulated in PAAD tissues (p = 3.68 × 10⁻⁶⁸), and patients with higher ENHO levels enjoyed significantly better overall survival (HR = 0.597; 95% CI: 0.419–0.852; p < 0.01). Pathway analysis showed that genes co-upregulated with ENHO were enriched for insulin secretion and ion channel activity, whereas those co-downregulated were related to epithelial–mesenchymal transition and extracellular matrix remodeling. Higher ENHO also tracked with increased CD8⁺ T-cell infiltration and correlated positively with PDCD1 and LAG3 but negatively with B7-H3, CD70, and NT5E. Conclusions: Our results point to a protective role for ENHO in pancreatic adenocarcinoma.

Background: Despite recent advances in the treatment of multiple myeloma (MM), the disease remains incurable. Agents targeting the programmed death-1 (PD-1) axis have become key treatments for many cancers; however, monotherapies with PD-1/PD-L-1 inhibitors (PD-1i) have shown a limited efficacy in MM patients. We conducted a meta-analysis to evaluate the safety and efficacy of PD-1i in combination with standard of care (SOC) therapies for MM. Methods: A systematic search identified phase II and III randomized clinical trials involving MM patients treated with PD-1i, using terms such as “Relapsed Multiple Myeloma” and “PD-1 inhibitors.” The search included trials published in English after 2016 using the PubMed, CINAHL, and Cochrane databases. Data were analyzed using RStudio v4.4.2, with survival data assessed using Kaplan–Meier methods and Cox proportional hazards analysis. Results: Our search yielded 19 total trials, of which 5 (representing 889 unique patients) met the criteria for inclusion. A total of 488 patients received PD-1i + SOC, and 401 received SOC alone. The median progression-free survival (PFS) was 6.26 months for the PD-1i + SOC group and 7.34 months for the SOC alone group (HR, 1.2; 95% CI: 0.95–1.41; p = 0.14). The median overall survival (OS) was 22.49 months for PD-1i + SOC compared to 24.38 months for SOC alone (HR, 1.11; 95% CI: 0.87–1.42, p = 0.36). The PD-1i group showed a higher incidence of all-grade pneumonia (RR = 1.44, 95% CI: 1.03–2.02, p = 0.03), grade ≥ 3 neutropenia (RR = 1.36, 95% CI: 1.00–1.85, p = 0.05), immune-mediated adverse events (RR = 10.1, 95% CI: 0.38–271.1, p = 0.17), and grade ≥ 3 irAEs (RR = 9.59, 95% CI: 0.62–148.8, p = 0.11). Conclusion: This analysis highlights the limited efficacy and increased toxicity of adding PD-1i to SOC in MM patients. Further research is needed to explore whether targeting the PD-1/PD-L1 axis in combination with novel therapies can safely enhance the therapeutic efficacy in MM patients.

Background and Aims: Oral squamous cell carcinoma (OSCC) is the predominant form of head and neck squamous cell carcinoma (HNSCC), accounting for most cancer‐related deaths due to metastasis and recurrence. COX‐2, an inflammatory biomarker encoded by prostaglandin‐endoperoxide synthase 2 (PTGS2) gene, has been shown to play a significant role in the prognosis of OSCC. Herein, we performed this meta‐analysis to evaluate COX‐2 as a potential therapeutic target in OSCC. Methods: PubMed, Embase, Web of Science, and Scopus databases were searched from inception to April 2024, to identify studies with Immunohistochemistry (IHC)‐based quantification that measure the clinicopathological features and prognostic significance of COX‐2 in OSCC. The role of COX‐2 expression in OSCC was evaluated by pooled hazard ratios (HRs), odd ratios (ORs) and 95% confidence intervals (CIs). The meta‐analysis was performed using the Review Manager (RevMan) version 5.4.1. Results: Ten studies were included in this review. High expression of COX‐2 was significantly associated with poor prognosis, with overall survival and progression‐free survival in patients with OSCC indicated by the pooled HR (HR 1.49, 95% Cl: 1.06–2.10) and (HR: 1.86, 95% CI: 1.21–2.87), respectively. Also, high COX‐2 expression was significantly associated with advanced T stage (T3/T4) and TNM stage (ll/lV), as shown by the pooled OR (OR: 2.91, 95% Cl: 1.52–5.55) and (OR: 2.68, 95% CI: 1.43–5.02), respectively. However, there was no significant association between lymph node metastasis and high expression of COX‐2 (pooled OR: 2.16, 95% Cl: 0.71–6.57). Conclusion: In conclusion, the present evidence suggests a role of COX‐2 overexpression as a prognostic biomarker and in targeted therapy of OSCC patients. Further studies on the role of COX‐2 expression might provide a more profound insight into the mechanism of carcinogenesis in OSCC.