Efficacy and safety of direct oral anticoagulants in the pediatric population: a systematic review and a meta-analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) represent a cornerstone of adult venous thromboembolism (VTE) treatment. Recently, randomized controlled trials (RCTs) investigating DOACs in pediatrics have been performed. OBJECTIVES: To evaluate the efficacy and safety of DOACs in the pediatric population. METHODS: We systematically searched MEDLINE (PubMed), EMBASE, and ClinicalTrials.gov from initiation up to August 20, 2022, for RCTs comparing DOACs to standard of care (SOC) in patients aged <18 years according to PRISMA guidelines (PROSPERO registration CRD42022353870). The primary analysis was performed according to the anticoagulation intensity and clinical setting (ie, prophylaxis in cardiac disease or treatment in VTE). Efficacy outcomes were all-cause mortality and VTE. Safety outcomes were major bleeding (MB), clinically relevant non-MB, any bleeding, serious adverse events, and discontinuation due to adverse events (AEs). RESULTS: Seven RCTs were included in the systematic review and 6 in the meta-analysis (3 prophylaxis in cardiac disease and 3 treatment in VTE). DOACs showed a significant reduction of VTE recurrence for treatment (odds ratio [OR] = 0.42; 95% CI, 0.19-0.94) and a nonsignificant reduction in VTE occurrence in prophylaxis (OR = 0.22; 95% CI, 0.03-1.55). No differences were observed for any bleeding, serious AEs, and MB in prophylaxis. Nonsignificant trends were observed for clinically relevant non-MB, MB in treatment, and discontinuation due to AE in prophylaxis. We found a significant increase in discontinuation due to AE in treatment. CONCLUSIONS: DOAC treatment seems to reduce VTE compared with SOC without major safety issues in the pediatric population, whereas DOAC prophylaxis seems at least comparable to SOC.

Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients.

The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often respond to immune-checkpoint blockade. We previously reported that the treatment of colorectal cancer preclinical models with temozolomide (TMZ) leads to MMR deficiency, increased tumor mutational burden (TMB), and sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-methylguanine-DNA-methyltransferase (MGMT)-deficient, MMR-proficient, RAS-mutant mCRC patients received priming therapy with TMZ. Analysis of tissue biopsies and circulating tumor DNA (ctDNA) revealed the emergence of a distinct mutational signature and increased TMB after TMZ treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes, and the p.T1219I MSH6 variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A subset of patients whose tumors displayed the MSH6 mutation, the TMZ mutational signature, and increased TMB achieved disease stabilization upon pembrolizumab treatment. SIGNIFICANCE: MMR-proficient mCRCs are unresponsive to immunotherapy. We provide the proof of concept that inactivation of MMR genes can be achieved pharmacologically with TMZ and molecularly monitored in the tissue and blood of patients with mCRC. This strategy deserves additional evaluation in mCRC patients whose tumors are no longer responsive to standard-of-care treatments. See related commentary by Willis and Overman, p. 1612. This article is highlighted in the In This Issue feature, p. 1599.