Segovia, Diana

PURPOSE Detection of molecular residual disease using circulating tumor DNA (ctDNA) may enable postoperative risk stratification and guide adjuvant therapy. We evaluated the prognostic value of a tissue-free, epigenomic ctDNA assay in patients with stage III colon cancer (CC) enrolled in a phase III adjuvant chemotherapy trial. METHODS Plasma samples were collected after surgery and before adjuvant infusional fluorouracil, leucovorin, and oxaliplatin alone or combined with cetuximab. ctDNA was analyzed using a tissue-free assay; in ctDNA-positive patients, tumor fraction (TF) was quantified and genotyping was performed with a 739-gene panel. Associations with disease-free survival (DFS), time to recurrence (TTR), and overall survival (OS) were assessed using multivariable Cox models adjusted for covariates. RESULTS Among 2,260 evaluable patients, 461 (20.4%) were ctDNA-positive with significantly higher detection in advanced T-/N-stage, high-grade, obstruction/perforation, and BRAF V600E tumors. At a median follow-up of 6.1 years, ctDNA positivity was independently associated with shorter TTR (hazard ratio [HR], 5.96 [95% CI, 5.11 to 6.96]), DFS (HR, 5.03 [95% CI, 4.36 to 5.81]), and OS (HR, 4.45 [95% CI, 3.76 to 5.27]; all P < .0001). The 5-year DFS was 27.7% (95% CI, 23.8 to 32.2) v 77.1% (95% CI, 75.1 to 79.1) in ctDNA-positive versus ctDNA-negative patients, and adverse prognostic impact was greater in lower T/N stage, low-risk, and dMMR subsets (interaction P = .0012-.041). Among ctDNA-positive patients, TF was nearly double in those who recurred or died ( P = .0002) and stratified patients for TTR, DFS, and OS (all adjusted P < .002). Genotyping identified mutations in FLT1 (OR, 8.99) and PREX2 (OR, 7.73) genes that were most strongly associated with recurrence ( P < .03). CONCLUSION Evaluation of ctDNA in resected stage III CC using a tissue-free assay provided robust and independent prognostic value. Higher ctDNA burden, dMMR, and specific mutations defined poor prognostic groups among ctDNA-positive patients.

Abstract Background Optimal treatment for resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma remains unclear due to limited head-to-head comparisons among chemotherapy and chemoradiation regimens. This network meta-analysis aimed to determine the relative efficacy of available multimodality treatment regimens in these patients. Methods MEDLINE, EMBASE, Scopus, Web of Science, and CENTRAL were searched till September 20, 2024. Phase 3 randomized trials evaluating perioperative/neoadjuvant systemic therapy ± radiation in resectable gastric/GEJ adenocarcinoma were included. Primary outcomes were disease-free survival (DFS) and overall survival (OS). Frequentist network meta-analysis was conducted to compare hazard ratios (HRs) and 95% confidence intervals (CIs). Results Fifteen trials (8072 patients) were analyzed. pFLOT (perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel) ranked highest for DFS in the overall population (P-score 91%), achieving significant improvements compared to surgery alone (HR 0.48, 95% CI, 0.38-0.60) and nCROSS (neoadjuvant paclitaxel, carboplatin, and radiotherapy) (0.67, 0.56-0.81). For OS, nPLF + nCRT(EP) (neoadjuvant cisplatin, leucovorin, and fluorouracil for induction, followed by etoposide, cisplatin, and radiotherapy) (P-score 90%) and pFLOT (P-score 87%) were the top regimens. pFLOT significantly outperformed surgery alone (0.57, 0.45-0.72) and nCROSS (0.73, 0.60-0.89). Based on the limited data available, adding neoadjuvant chemoradiation to pFLOT provided no additional OS (1.14, 0.76-1.72) or DFS (1.22, 0.83-1.82) benefit. Similarly, adding pembrolizumab to perioperative chemotherapy (cisplatin and fluorouracil/capecitabine) was not superior to pFLOT (DFS: 1.10, 0.71-1.69; OS: 1.09, 0.69-1.72). Conclusions pFLOT demonstrated superior efficacy in resectable gastric/GEJ adenocarcinoma, outperforming surgery alone, nCROSS, and alternative perioperative regimens. The additive role of immunotherapy requires further investigation to optimize patient selection and outcomes.

OBJECTIVE Patients with autosomal dominant polycystic kidney disease (ADPKD) have been identified to have a significantly increased risk of developing intracranial aneurysms (IAs). These patients are diagnosed at younger ages and are also at increased risk for IA rupture. The objective of this systematic review and meta-analysis was to identify risk factors associated with IA detection during screening of asymptomatic ADPKD patients. METHODS The authors searched for studies reporting the prevalence of IA among patients with ADPKD screened using MRA, CTA, or DSA on PubMed, Embase, Google Scholar, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov prior to August 2023 by using individualized standardized search strategies. Eligibility of all retrieved studies was assessed according to the PRISMA guidelines. Risk of bias of the included observational studies was assessed using the Newcastle-Ottawa Scale. Meta-analysis was performed using a random-effects model. RESULTS Twenty-four observational studies involving 5907 patients with ADPKD were identified for quantitative analysis. The authors observed an overall prevalence of IA of 12.6%. They identified several risk factors for IA with statistically significantly increased odds for unruptured IA (UIA) detection, including female sex (18 studies, OR 1.63, 95% CI 1.37–1.94, I 2 = 0%), family history of either IA or subarachnoid hemorrhage (SAH) (12 studies, OR 2.17, 95% CI 1.68–2.81, I 2 = 0%), family history of SAH (3 studies, OR 2.67, 95% CI 1.25–5.71, I 2 = 66.0%), stage 3 or greater chronic kidney disease (CKD) (4 studies, OR 2.55, 95% CI 1.84–3.54, I 2 = 0%), and hypertension (13 studies, OR 1.41, 95% CI 1.04–1.91, I 2 = 34%). Age > 45 years, family history of ADPKD, smoking status, and presence of liver cysts did not reach statistical significance as risk factors during this meta-analysis. CONCLUSIONS The results of the authors’ meta-analysis suggest increased risk of UIA detection in screening of ADPKD patients who are female, have a family history of IA or SAH, have hypertension, or have moderate or more severe CKD. Given the increased prevalence of IA in ADPKD patients with these risk factors, these patients may stand to benefit from screening for IA early in treatment or at time of diagnosis, even if neurologically asymptomatic.