Explore the vast range of titles available.

Introduction:Physical exercise is essential for maintaining functionality and independence in later life. However, the specific benefits of boxing as a form of exercise remain unclear. Objective: To describe the protocol of Boxe4Ageing, a program designed to compare the effects of boxing (BT) and multicomponent training (MT) on cognitive performance, brain activity, physical fitness, and fall risk in community-dwelling older adults in Portugal.Methodology: This quasi-experimental study protocol will include participants aged ≥60years, assigned to one of three groups: BT, MT, or a control group (CG). The exercise programs will run for 24 weeks, with twosessionsper week. CG participants will maintain their usual activities. Assessments will occur at baseline, mid-intervention (12 weeks), post-intervention (24 weeks), and after a 12-week detraining period. Results:Primary outcomes include cognition, brain activity, physical fitness, and fall risk; secondary outcomes are quality of life and exercise satisfaction. Discussion: If successful, this study could provide evidence supporting the inclusion of boxing in community health programs aimed at preventing falls, improving cognitive health, and enhancing physical fitness in older adults. It mayoffer a low-cost, accessible intervention with significant potential benefits for older adults.Trial Registration: ClinicalTrials.gov–Identifier NCT05826314, registered April 24, 2023. Introducción: El ejercicio físico es esencial para mantener la funcionalidad y la independencia en la edad avanzada. Sin embargo, los beneficios específicos del boxeo como forma de ejercicio siguen siendo poco claros.Objetivo: Describir el protocolo de Boxe4Ageing, un programa diseñado para comparar los efectos del entrenamiento de boxeo (BT) y el entrenamiento multicomponente (MT) sobre el rendimiento cognitivo, la actividad cerebral, la condición física y el riesgo de caídas en adultos mayores que viven en la comunidad en Portugal.Metodología: Este protocolo de estudio cuasi-experimental incluirá participantes de ≥60 años, asignados a uno de tres grupos: BT, MT o un grupo control (GC). Los programas de ejercicio se desarrollarán durante 24 semanas, con dos sesiones por semana. Los participantes del GC mantendrán sus actividades habituales. Las evaluaciones se realizarán al inicio, a mitad de la intervención (12 semanas), al finalizar la intervención (24 semanas) y después de un período de desentrenamiento de 12 semanas.Resultados: Los resultados primarios incluyen cognición, actividad cerebral, condición física y riesgo de caídas; los resultados secundarios son la calidad de vida y la satisfacción con el ejercicio.Discusión: Si tiene éxito, este estudio podría proporcionar evidencia que respalde la inclusión del boxeo en programas comunitarios de salud destinados a prevenir caídas, mejorar la salud cognitiva y aumentar la condición física en adultos mayores. Podría ofrecer una intervención de bajo costo, accesible y con beneficios potenciales significativos para esta población.Registro del ensayo: ClinicalTrials.gov –Identificador NCT05826314, registrado el 24 de abril de 2023.

The PANTHER classification system ( http://www.pantherdb.org ) is a comprehensive system that combines genomes, gene function classifications, pathways and statistical analysis tools to enable biologists to analyze large-scale genome-wide experimental data. The current system (PANTHER v.14.0) covers 131 complete genomes organized into gene families and subfamilies; evolutionary relationships between genes are represented in phylogenetic trees, multiple sequence alignments and statistical models (hidden Markov models (HMMs)). The families and subfamilies are annotated with Gene Ontology (GO) terms, and sequences are assigned to PANTHER pathways. A suite of tools has been built to allow users to browse and query gene functions and analyze large-scale experimental data with a number of statistical tests. PANTHER is widely used by bench scientists, bioinformaticians, computer scientists and systems biologists. Since the protocol for using this tool (v.8.0) was originally published in 2013, there have been substantial improvements and updates in the areas of data quality, data coverage, statistical algorithms and user experience. This Protocol Update provides detailed instructions on how to analyze genome-wide experimental data in the PANTHER classification system. Here the authors provide an update to their 2013 protocol for using the PANTHER classification system, detailing how to analyze genome-wide experimental data with the newest version of PANTHER (v.14.0), with improvements in the areas of data quality, data coverage, statistical algorithms and user experience.

Antibodies targeting the immune checkpoint molecules PD-1, PD-L1 and CTLA-4, administered alone or in combination with chemotherapy, are the standard of care in most patients with metastatic non-small-cell lung cancers. When given before curative surgery, tumor responses and improved event-free survival are achieved. New antibody combinations may be more efficacious and tolerable. In an ongoing, open-label phase 2 study, 60 biomarker-unselected, treatment-naive patients with resectable non-small-cell lung cancer were randomized to receive two preoperative doses of nivolumab (anti-PD-1) with or without relatlimab (anti-LAG-3) antibody therapy. The primary study endpoint was the feasibility of surgery within 43 days, which was met by all patients. Curative resection was achieved in 95% of patients. Secondary endpoints included pathological and radiographic response rates, pathologically complete resection rates, disease-free and overall survival rates, and safety. Major pathological (≤10% viable tumor cells) and objective radiographic responses were achieved in 27% and 10% (nivolumab) and in 30% and 27% (nivolumab and relatlimab) of patients, respectively. In 100% (nivolumab) and 90% (nivolumab and relatlimab) of patients, tumors and lymph nodes were pathologically completely resected. With 12 months median duration of follow-up, disease-free survival and overall survival rates at 12 months were 89% and 93% (nivolumab), and 93% and 100% (nivolumab and relatlimab). Both treatments were safe with grade ≥3 treatment-emergent adverse events reported in 10% and 13% of patients per study arm. Exploratory analyses provided insights into biological processes triggered by preoperative immunotherapy. This study establishes the feasibility and safety of dual targeting of PD-1 and LAG-3 before lung cancer surgery. ClinicalTrials.gov Indentifier: NCT04205552 . In an open-label phase 2 trial, patients with non-small-cell lung cancer received neoadjuvant anti-PD-1 with or without anti-LAG-3, showing that curative intent surgery after combined blockade of PD-1 and LAG-3 is feasible, and leads to preliminary clinical responses.

Background Treatment of patients with non-metastatic, locally advanced rectal cancer (LARC) includes pre-operative chemoradiation, total mesorectal excision (TME) and post-operative adjuvant chemotherapy. This trimodality treatment provides local tumor control in most patients; but almost one-third ultimately die from distant metastasis. Most survivors experience significant impairment in quality of life (QoL), due primarily to removal of the rectum. A current challenge lies in identifying patients who could safely undergo rectal preservation without sacrificing survival benefit and QoL. Methods/Design This multi-institutional, phase II study investigates the efficacy of total neoadjuvant therapy (TNT) and selective non-operative management (NOM) in LARC. Patients with MRI-staged Stage II or III rectal cancer amenable to TME will be randomized to receive FOLFOX/CAPEOX: a) before induction neoadjuvant chemotherapy (INCT); or b) after consolidation neoadjuvant chemotherapy (CNCT), with 5-FU or capecitabine-based chemoradiation. Patients in both arms will be re-staged after completing all neoadjuvant therapy. Those with residual tumor at the primary site will undergo TME. Patients with clinical complete response (cCR) will receive non-operative management (NOM). NOM patients will be followed every 3 months for 2 years, and every 6 months thereafter. TME patients will be followed according to NCCN guidelines. All will be followed for at least 5 years from the date of surgery or—in patients treated with NOM—the last day of treatment. Discussion The studies published thus far on the safety of NOM in LARC have compared survival between select groups of patients with a cCR after NOM, to patients with a pathologic complete response (pCR) after TME. The current study compares 3-year disease-free survival (DFS) in an entire population of patients with LARC, including those with cCR and those with pCR. We will compare the two arms of the study with respect to organ preservation at 3 years, treatment compliance, adverse events and surgical complications. We will measure QoL in both groups. We will analyze molecular indications that may lead to more individually tailored treatments in the future. This will be the first NOM trial utilizing a regression schema for response assessment in a prospective fashion. Trial registration NCT02008656

Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n  = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n  = 130); and paclitaxel with cisplatin (TP group; n  = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1–32.0, P  < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7–18.1, P  = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 . In a randomized phase 3 trial, neoadjuvant anti-PD-1 plus either paclitaxel and cisplatin or nab-paclitaxel and cisplatin elicited a significantly superior pathological complete response rate versus neoadjuvant paclitaxel and cisplatin alone in patients with resectable locally advanced esophageal squamous cell carcinoma.

First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%. EMPOWER-Lung 3 ( NCT03409614 ), a double-blind, placebo-controlled, phase 3 study, examined cemiplimab plus platinum-doublet chemotherapy as first-line treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this study, 466 patients with stage III/IV aNSCLC without EGFR , ALK or ROS1 genomic tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg ( n  = 312) or placebo ( n  = 154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary endpoint was OS. The trial was stopped early per recommendation of the independent data monitoring committee, based on meeting preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval (CI), 15.5–not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9–16.1) with placebo plus chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53–0.93; P  = 0.014). Grade ≥3 adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both monotherapy and in combination with chemotherapy for both squamous and non-squamous histologies. Results from EMPOWER-Lung 3 demonstrate increased overall survival with cemiplimab plus platinum-doublet chemotherapy compared to cemiplimab as first-line treatment in patients with advanced non-small cell lung cancer, irrespective of PD-L1 expression.

First-line systemic therapeutic options for advanced esophageal squamous cell carcinoma (ESCC) are limited. In this multicenter, double-blind phase 3 trial, a total of 551 patients with previously untreated, locally advanced or metastatic ESCC and PD-L1 combined positive score of ≥1 were randomized (2:1) to receive serplulimab (an anti-PD-1 antibody; 3 mg/kg) or placebo (on day 1), plus cisplatin (50 mg/m 2 ) (on day 1) and continuous infusion of 5-fluorouracil (1,200 mg/m 2 ) (on days 1 and 2), once every 2 weeks. The study met the primary endpoints. At the prespecified final analysis of progression-free survival (PFS) assessed by the blinded independent radiological review committee, serplulimab plus chemotherapy significantly improved PFS compared with placebo plus chemotherapy (median PFS of 5.8 months and 5.3 months, respectively; hazard ratio, 0.60; 95% confidence interval, 0.48–0.75; P  < 0.0001). At the prespecified interim analysis of overall survival (OS), serplulimab plus chemotherapy also significantly prolonged OS compared with placebo plus chemotherapy (median OS of 15.3 months and 11.8 months, respectively; hazard ratio, 0.68; 95% confidence interval, 0.53–0.87; P  = 0.0020). Grade 3 or higher treatment-related adverse events occurred in 201 (53%) and 81 (48%) patients in the serplulimab plus chemotherapy group and the placebo plus chemotherapy group, respectively. Serplulimab plus chemotherapy administered every 2 weeks significantly improved PFS and OS in patients with previously untreated, PD-L1-positive advanced ESCC, with a manageable safety profile. This study is registered with ClinicalTrials.gov ( NCT03958890 ). The combination of anti-PD-1 treatment with cisplatin and 5-fluorouracil in patients with previously untreated, PD-L1-positive esophageal squamous cell carcinoma improved progression-free survival and overall survival.

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n  = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n  = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P  = 0.003), higher overall response rate (44.0% versus 13.0%, P  = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P  = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8 + T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 . In a randomized phase 2 trial comparing anti-PD-1 plus anti-VEGF plus an HDAC inhibitor versus anti-PD-1 plus an HDAC inhibitor in patients with MSS/pMMR colorectal cancer, the triplet combination led to significantly better 18-week progression-free survival.

Background The standard treatment for localized/locally advanced gastroesophageal adenocarcinoma (GEA) is radical surgery and peri-operative FLOT treatment (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel), but around half patients still experience disease relapse. In gastrointestinal cancers, the presence of circulating tumor DNA (ctDNA) after surgery is associated with a high risk of relapse, and the lack of ctDNA clearance after post-operative treatment is strongly associated with early relapse. Therefore, liquid biopsy may guide the selection of patients with micrometastatic disease after preoperative chemotherapy and surgery for non-cross resistant regimens in the post-operative setting. Trastuzumab deruxtecan (T-DXd) is approved in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma after failure of at least one prior trastuzumab-based regimen. The DESTINY-Gastric01 and 02 trials showed remarkable activity and efficacy of T-DXd, thus supporting the investigation of this agent in early-stage disease to increase the chance of achieving disease eradication. Finally, the DESTINY-Gastric03 trial showed the safety profile and feasibility, with preliminary promising activity results of the combination of T-DXd with a fluoropyrimidine. Trial design TRINITY is an ongoing multicentre, randomized, open-label, interventional phase II study which will enroll approximately 46 patients with HER2-positive GEA, treated with pre-operative FLOT and radical surgery, and with the persistence of minimal residual disease detected by the Signatera™ assay in a liquid biopsy collected between 2 and 6 weeks after surgery. The trial is designed with an observational phase enrolling patients with HER2-positive GEA eligible for standard treatment with peri-operative FLOT and surgery. Eligible patients will be randomized on a 1:1 basis to the experimental treatment arm consisting of adjuvant T-DXd (6.4 mg/kg IV on day 1) plus either capecitabine (1000 mg/sqm BID orally on days 1–14) or 5-fluorouracil (600 mg/sqm continuous IV infusion on days 1–5) Q3 W for 6 cycles, or to the control arm with standard post-operative FLOT (at the same dose used during the last pre-operative cycle) for 4 cycles. Patients non-eligible for the interventional trial will continue the standard therapy and follow-up in the frame of the observational phase with collection of exploratory longitudinal liquid biopsies. The primary objective is ctDNA clearance at 1 year after randomization. Considering alpha- and beta-errors of 0.10 and 0.20 and hypothesizing a ctDNA clearance of 10% and 35% in the control and experimental arm, respectively, 23 patients per arm are required to prove the superiority of the experimental strategy. Secondary endpoints include disease-free survival, overall survival, metastases-free survival, patient-reported outcomes and safety. The trial also represents a translational platform, including extensive analysis of circulating, tissue, and immune biomarkers as exploratory endpoints. Enrollment is active and ongoing. Trial registration TRINITY is registered at ClinicalTrials.gov (NCT06253650).

Background Glioblastoma, IDH wildtype is the most common primary malignant brain tumor in adults. Despite best available treatment, prognosis remains poor. Current standard therapy consists of surgical tumor removal followed by radiotherapy and chemotherapy with the alkylating agent temozolomide. Antisecretory factor (AF), an endogenous protein, may potentiate the effect of temozolomide and alleviate cerebral edema. Salovum® is an egg-yolk powder enriched for AF and is classified as a medical food in the European Union. Salovum® has shown preliminary clinical effect on glioblastoma in a recent pilot study. Here, we aim to assess if add-on Salovum® to temozolomide therapy can improve outcomes in patients with newly diagnosed glioblastoma. Methods This is a multi-center, double-blinded, randomized, placebo-controlled phase II-III clinical trial to investigate superiority of Salovum® over placebo as add-on treatment for glioblastoma during concomitant and adjuvant temozolomide therapy. Patients with newly diagnosed glioblastoma that are planned for temozolomide treatment are screened for eligibility and randomized to receive Salovum® ( n  = 150) or placebo ( n  = 150). An interim analysis will be performed after 80 included patients to guide whether to continue or terminate. Primary endpoint is 12-month overall survival. Secondary outcome is 24-month overall survival. Discussion This study will likely produce high-grade evidence to support or reject Salovum® as add-on treatment for glioblastoma. Trial registration ClinicalTrials.gov NCT05669820 . Registered on January 3, 2023.