358 Background: In resectable GAC/GEJAC, MSI status is associated with better survival and potential lack of benefit from chemotherapy. Given the high responsiveness of MSI tumors to immunotherapy, neoadjuvant or definitive dual CTLA-4/PD(L)-1 inhibition may allow omission of chemotherapy or surgery. Methods: INFINITY is a multicentre, single-arm, multi-cohort phase II trial (NCT04817826) investigating the activity and safety of tremelimumab+durvalumab as neoadjuvant (Cohort 1) or definitive (Cohort 2) treatment for MSI, mismatch repair deficient (dMMR) and EBV-negative resectable GAC/GEJAC. In Cohort 1, patients (pts) received a 12-week treatment with single high dose tremelimumab 300 mg and durvalumab 1500 mg q4 weeks (T300/D) for 3 cycles followed by surgery. The primary endpoint was pCR rate (ypT0N0) with negative ctDNA after T300/D. Secondary endpoints: disease-free survival, overall survival, quality of life. Exploratory: correlation of pCR with clinical variables, PDL-1 CPS assessed by IHC 22C3, tumor mutational burden (TMB) by Foundation One, liquid biopsies and other biomarkers. Cohort 2 investigates non operative management after same treatment regimen. Results: Overall, 18 pts with MSI/dMMR resectable cT2-4 any N GAC/GEJAC were recruited in Cohort 1. One withdrew consent and 2 achieved a complete clinical-pathological response at radiology and endoscopy (ongoing) and refused surgery. Among 15 evaluable patients, 1 had disease progression and 14 underwent resection. pCR rate was 60% (9/15) and major-complete pathological response (<10% viable cells) was 80%. All pts with pCR had negative ctDNA status pre-surgery. pCR rate was 1/6 (17%) in T4 vs 8/9 (89%) in T2-3 tumors (p=0.011), whereas no correlation was found with baseline N status. PDL-1 CPS was not associated with outcomes and TMB had a non-significant trend of correlation with pCR (median TMB 26 in non-pCR vs 40 in pCR group, p=0.2). Grade≥3 immune-related AEs occurred in 3 pts of safety population (n=18): colitis, pneumonitis, liver toxicity, all resolved with high dose steroids and did not impair surgery. Two pts died after surgery for other reasons than disease or AEs, whereas no disease relapses were observed in remaining pts. QoL and additional translational analyses on RNA-seq, digital spatial profiling and ctDNA monitoring will be presented. Conclusions: Pre-operative T300/D for 3 months was safe and provided promising proof of efficacy in MSI, dMMR GAC/GEJAC pts. These results open the way to investigate NOM in pts with clinical, pathological and molecular (ctDNA minimal residual disease) complete response after T300/D. Enrollment in Cohort 2 has started after IDMC evaluation and protocol. amendment to include only pts with cT2-3 tumors confirmed at staging laparoscopy. Clinical trial information: NCT04817826 .
Iron deficiency anemia (IDA) is the most common nutritional deficiency in children. Most children with IDA are treated with oral iron preparations. However, intravenous (IV) iron is an alternative for children with severe IDA who have difficulty in adhering to or absorbing oral iron. We sought to describe the safety and effectiveness of IV iron sucrose for treatment of IDA in children. Pharmacy records of children who received IV iron sucrose at a children's hospital between 2004 and 2014 were reviewed. Laboratory markers of anemia and iron studies were obtained and preinfusion and postinfusion values were compared. Records were also reviewed for adverse reactions. A total of 142 patients received IV iron sucrose over 10 years. The mean age was 11 years, 9 months. One patient of 142 developed cough and wheezing during the infusion. No other adverse events were found. IV iron sucrose resulted in a statistically significant and clinically meaningful increase in hemoglobin, mean corpuscular volume, serum iron, ferritin, and % iron saturation, with a corresponding decrease in total iron binding capacity. The use of IV iron sucrose in pediatric patients with IDA is safe and leads to a moderate increase in hemoglobin and substantial improvement in iron studies.
Little is known about the spectrum of mitochondrial DNA (mtDNA) mutations across pediatric malignancies. In this study, we analyzed matched tumor and normal whole genome sequencing data from 616 pediatric patients with hematopoietic malignancies, solid tumors, and brain tumors. We identified 391 mtDNA mutations in 284 tumors including 45 loss-of-function mutations, which clustered at four statistically significant hotspots in MT-COX3, MT-ND4, and MT-ND5, and at a mutation hotspot in MT-tRNA-MET. A skewed ratio (4.83) of nonsynonymous versus synonymous (dN/dS) mtDNA mutations with high statistical significance was identified on the basis of Monte Carlo simula-tions in the tumors. In comparison, opposite ratios of 0.44 and 0.93 were observed in 616 matched normal tissues and in 249 blood samples from children without cancer, respectively. mtDNA mutations varied by cancer type and mtDNA haplogroup. Collectively, these results suggest that deleterious mtDNA mutations play a role in the development and progression of pediatric cancers.Significance: This pan-cancer mtDNA study establishes the landscape of germline and tumor mtDNA mutations and identifies hotspots of tumor mtDNA mutations to pinpoint key mitochondrial functions in pediatric malignancies.
ImportanceThere are few studies assessing the association of tumor mutational burden (TMB) and clinical outcomes in a large cohort of patients with diverse advanced cancers.ObjectiveTo clinically validate a TMB biomarker from a next-generation sequencing targeted gene panel assay.Design, Setting, and ParticipantsA prespecified cohort study using the deidentified clinicogenomic Tempus database of patients sequenced between 2018 and 2022, which contained retrospective, observational data originating from 300 cancer sites including 199 community sites and 101 academic sites. Patients with advanced solid tumors across 8 cancer types and more than 20 histologies, sequenced with Tempus xT who were treated with immune checkpoint inhibitors (ICIs) in the first-line or second-line setting were included. Data were analyzed from September 2018 to August 2022.ExposureTreatment with US Food and Drug Administration (FDA)–approved antiprogrammed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) ICI and/or in combination with a cytotoxic T-lymphocyte-associated protein-4 ICI.Main Outcomes and MeasuresThe primary outcome was the association of tumor mutational burden (TMB) binary category (high [≥10 mut/mb] vs low) with overall survival (OS) in patients treated with ICIs. Secondary outcomes were progression-free survival (PFS), and time to progression (TTP).ResultsIn the evaluable cohort of 674 patients, the median (IQR) age was 69.4 (28.6-89.8) years, 271 patients (40.2%) were female, and 435 patients (64.5%) were White. The most common advanced cancers were non–small cell lung cancer (330 patients [49.0%]), followed by bladder cancer (148 patients [22.0%]), and head and neck squamous cell carcinoma (96 patients [14.8%]). Median (IQR) follow-up was 7.2 (3.2-14.1) months. High TMB (TMB-H) cancers (206 patients [30.6%]) were significantly associated with longer OS than low TMB (TMB-L) cancers (hazard ratio [HR], 0.72; upper confidence bound [UCB], 0.91; P = .01). In a prospective subset of 403 patients treated with ICIs after TMB testing, TMB-H cancers (135 patients [33.5%]) were significantly associated with longer OS (HR, 0.61; UCB, 0.84; P = .005), PFS (HR, 0.62; UCB, 0.82; P = .003), and TTP (HR, 0.67; UCB, 0.92; P = .02) than TMB-L cancers. An overall survival benefit was seen regardless of the type of ICI used (pembrolizumab, 339 patients; HR, 0.67; UCB, 0.94; P = .03), other ICIs (64 patients; HR, 0.37; UCB, 0.85; P = .03), and after adjusting for PD-L1 and microsatellite stability status (403 patients; HR = 0.67; UCB, 0.92; P = .02).Conclusions and RelevanceIn this cohort study of patients with advanced solid tumors treated with ICIs in diverse clinics, TMB-H cancers were significantly associated with improved clinical outcomes compared with TMB-L cancers.
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