Purpose: To assess the efficacy and safety of non-chemotherapy anticancer drugs (immunotherapy or targeted therapy) compared to best supportive care (BSC) or placebo for the treatment of advanced gastric cancer (GC). Methods: Systematic review of randomized controlled trials (RCTs) searching (May 2022) MEDLINE, EMBASE, CENTRAL, Epistemonikos, ClinicalTrials.gov, and PROSPERO. Certainty of evidence was evaluated following GRADE. Results: Six RCTs included. Targeted therapies likely result in a slight increase in overall survival (OS) (HR 0.84, 95% CI 0.75, 0.93; moderate certainty) and progression-free survival (PFS) (HR 0.52, 95% CI 0.43, 0.62; moderate certainty). Toxicity had a slightly increased risk (RR 1.19, 95% CI 0.95, 1.48; low certainty). Immunotherapy also showed a likely improvement in PFS (HR 0.60, 95% CI 0.49, 0.73; moderate certainty), while toxicity showed a likely higher risk (RR 2.72, 95% CI 1.24, 5.94; moderate certainty). However, benefits in survival translated to time gains of slightly over a month for OS and less than a month for PFS. No data were reported on performance status (PS), hospital admissions, or quality of life (QoL). Conclusions: Our study suggests some survival benefits with low toxicity from these treatments, but gains are marginal. Uncertainties persist regarding their impact on QoL and outcomes for patients with poor PS. Caution is advised in treatment selection for advanced GC patients, who should actively participate in decision-making. Future research should include diverse patient populations and assess patient-centered outcomes with consistent comparator groups for BSC. Trial Registration: The study protocol was registered in OSF (https://doi.org/10.17605/OSF.IO/7CHX6) on 2022–04-01.

Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are substantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chemotherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS patients treated with neoadjuvant chemotherapy. We analysed variants in genes involved in anthracycline metabolism (ABCB1, ABCC2, NQO1, CBR3, and SLC22A16) and in ifosfamide catabolism (ALDH1A1) in 79 treated patients. Two genes showed significant association after adjusted multivariate analysis: ABCC2 and ALDH1A1. In patients treated with anthracyclines, ABCC2 rs3740066 was associated with risk of febrile neutropenia (p = 0.031), and with decreased overall survival (OS) (p = 0.024). ABCC2 rs2273697 was associated with recurrence-free survival (RFS) (p = 0.024). In patients treated with ifosfamide, ALDH1A1 rs3764435 was associated with RFS (p = 0.046). Our pharmacogenetic study shows for the first time that variants in genes regulating the metabolism of neoadjuvant chemotherapy may be helpful to predict toxicity and survival benefit in high-risk STS treated with neoadjuvant chemotherapy. Further validation studies are needed to establish their clinical utility.

Purpose: Characterization of the management and outcomes of patients diagnosed with hepatocellular carcinoma (HCC) and treated with systemic therapy who were included in the Spanish gastrointestinal RETUD registry. Methods/patients: This is a retrospective, registry-based, non-interventional, multicenter study conducted in Spain (NCT06711211, retrospectively registered in Dec-2024). This cohort from the RETUD registry includes adult patients diagnosed with HCC and treated with systemic therapy between Jan-2017 and Feb-2024. Sociodemographic, clinical, therapeutic and survival data are analyzed descriptively. Results: Four hundred and sixty nine patients were included (median age: 65.8 years; 90.2% males; 98.1% Caucasian). At diagnosis, 51.8% presented a clinical stage of Barcelona Clinic Liver Cancer (BCLC)-C. At the start of systemic treatment, 34.5% and 30.3% of the patients showed extrahepatic spread of the disease and main portal vein invasion, respectively. The most frequently administered first-line systemic therapies were sorafenib (57.1%), atezolizumab/bevacizumab (27.7%) and lenvatinib (7.5%). More than a third of the cohort (37.1%) received locoregional treatment at any time (before, concurrent and/or after systemic treatment). Overall, the median progression-free survival (PFS) and overall survival (OS) were 5.1 and 9.8 months, respectively. Patients receiving atezolizumab/bevacizumab showed the longest PFS (10.6 months) and OS (14.0 months) of all treatment groups and a numerically higher objective response rate (ORR) compared to the overall population (31.0% vs 12.5%). Conclusions: This study offers valuable insights into the clinical characteristics, management, and outcomes of HCC patients in Spain in a real-world setting. Our results suggest potential benefits of immunotherapy-based combinations over other available alternatives, supporting findings from interventional and real-world studies.

Purpose: To develop and internally validate the PANTHEIA-SIRI prognostic model, which integrates log-transformed systemic inflammation response index (SIRI) with clinical predictors, to estimate overall survival (OS) in metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line chemotherapy. Methods: We used data from the multicenter PANTHEIA-SEOM registry. OS was defined from chemotherapy start. The model was fitted as a Weibull accelerated failure time model in the survival-analysis population with multiple imputation. Predictors were log-transformed baseline SIRI, modeled with restricted cubic splines, ECOG, tumor burden, chemotherapy regimen, and anorexia-cachexia syndrome. Internal validation used a separate, non-overlapping cohort from the same registry; the centers contributing to each cohort are listed in a supplementary annex. TRIPOD was followed. Discrimination was assessed with Harrell´s C-index and calibration with IPCW Brier scores and IPA. Results: The derivation cohort comprised 672 patients with SIRI data (593 analyzed for survival) across 22 Spanish hospitals (2015–2025); 80.1% had died after a median OS of 9.9 months. The imputation-pooled derivation C-index was 0.654 (95% CI, 0.627–0.681); optimism-corrected, 0.629. Internal validation used 62 separate patients from the same registry; 96.8% had died after a median OS of 9.2 months. The validation C-index was 0.603 (95% CI, 0.518–0.687). Calibration was adequate at 6 and 12 months. Conclusions: The PANTHEIA-SIRI model provides individualized OS estimates in mPDAC with routine clinical predictors. Its open-access calculator ( https://pantheia-siri.shinyapps.io/calc/ ) may support prognostic communication, treatment-intensity selection, and supportive-care planning. Routine clinical implementation will require further validation in larger, fully independent cohorts.

Molecular factors influencing prognosis in leiomyosarcomas (LMS) remain poorly understood. Given that LMS arise from smooth muscle and that the dystrophin gene (DMD) has been suggested as a tumor suppressor in this tumor type, this study investigated dystrophin expression and somatic mutations in DMD, and dystrophin–glycoprotein complex (DGC) and dysferlin (DYSF) coding genes as prognostic biomarkers in LMS. Seventy-seven patients with LMS were retrospectively included in the study. Dystrophin expression was evaluated by immunohistochemistry. The presence of DMD point mutations were determined using next-generation sequencing (NGS), and DMD copy-number variants were assessed by multiplex ligation-dependent probe amplification (MLPA) technique. Low dystrophin expression was observed in 66% of tumors and showed a nominal association with tumor grade, with 76% of grade 3, 58% of grade 2, and 33% of grade 1 tumors showing low dystrophin expression (p = 0.046). Dystrophin expression was not associated with overall survival (OS), nor with recurrence-free survival (RFS) in localized cases or progression-free survival (PFS) in metastatic cases. However, dystrophin expression was significantly associated with shorter OS (p = 0.006) and RFS (p = 0.003) in patients with localized grade 2 tumors. Mutations in DMD, DGC-coding genes and DYSF were identified in 59% of tumors, but no significant associations were found with pathological, molecular, or survival data. Loss of dystrophin expression was common in LMS tumors and was associated with high-grade tumors in our cohort. Nonetheless, the role of dystrophin as a prognostic biomarker of survival was only observed in patients with localized grade 2 tumors in this exploratory, hypothesis-generating study, and therefore needs further validation.