Background: The endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and... Show moreBackground: The endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and provides direction towards more effective and less toxic adjuvant treatment strategies for women with endometrial cancer. Primary objective(s): The RAINBO program of clinical trials will investigate four molecular class-directed adjuvant treatment strategies following surgical resection to either increase cure rates through the addition of novel targeted therapies or safely reduce toxicity and improve quality of life through treatment de-escalation. Study hypothesis: Molecular-directed adjuvant treatment strategies will improve clinical outcomes and reduce toxicity of unwarranted therapies in women with endometrial cancer. The overarching and translational research RAINBO program will advance knowledge of predictive and prognostic (bio)markers that will improve prognostication and treatment allocation. Trial design: The RAINBO program is a platform of four international clinical trials and an overarching research program. The randomized phase III p53abn-RED trial for women with invasive stage I-III p53abn endometrial cancer compares adjuvant chemoradiation followed by olaparib for 2 years with adjuvant chemoradiation alone. The randomized phase III MMRd-GREEN trial for women with stage II (with lymphovascular space invasion (LVSI)) or stage III mismatch repair-deficient (MMRd) endometrial cancer compares adjuvant radiotherapy with concurrent and adjuvant durvalumab for 1 year to radiotherapy alone. The randomized phase III NSMP-ORANGE trial is a treatment de-escalation trial for women with estrogen receptor positive stage II (with LVSI) or stage III no specific molecular profile (NSMP) endometrial cancer comparing radiotherapy followed by progestin for 2 years to adjuvant chemoradiation. The POLEmut-BLUE trial is a phase II trial in which the safety of de-escalation of adjuvant therapy is investigated for women with stage I-III POLEmut endometrial cancer: no adjuvant therapy for lower-risk disease and no adjuvant therapy or radiotherapy alone for higher-risk disease. The overarching RAINBO program will combine data and tumor material of all participants to perform translational research and evaluate molecular class-based adjuvant therapy in terms of efficacy, toxicity, quality of life, and cost-utility. Major inclusion/exclusion criteria: Inclusion criteria include a histologically confirmed diagnosis of endometrial cancer treated by hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel lymph node biopsy, with no macroscopic residual disease after surgery and no distant metastases, and molecular classification according to the WHO 2020 algorithm. Primary endpoint(s): Recurrence-free survival at 3 years in the p53abn-RED, MMRd-GREEN, and NSMP-ORANGE trials and pelvic recurrence at 3 years in the POLEmut-BLUE trial. Sample size: The p53abn-RED trial will include 554 patients, the MMRd-GREEN trial 316, the NSMP-ORANGE trial 600, and the POLEmut-BLUE trial 145 (120 for lower-risk disease and approximately 25 for higher-risk disease). The overarching research program will pool the four sub-trials resulting in a total sample size of around 1600. Estimated dates for completing accrual and presenting results: The four clinical trials will have different completion dates; main results are expected from 2028. Show less
Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in... Show moreAims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1 beta can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.[GRAPHICS]. Show less
