Hereditary Cancer Program (ProCanHe): 21-years of experience at a referral registry in Argentina

Registries in South America were initiated in the early 90´s with thehelp of Henry T. Lynch. The Programa de Cancer Hereditario (Pro.Can.He), is a multidisciplinary program established in 1996 at theHospital Italiano, Argentina. The aim of the study is to update our 21-year experience to determine the applicability of genetic testshighlighting the most informative molecular findings in relation toLynch syndrome mostly.Materials and methods: Families undergoing genetic testing aftergenetic counselling between1996-2018 were included. Data were obtainedfrom a prospective IRB approved database. Clinicalepidemiologicaland molecular variables were analysed. Genetic testswere carried out after a genetic counselling session and obtainingthe informed consent of the patient.Molecular testingUntil 2015, the search for variants was carried out by PCR and Sangersequencing of exons and adjacent intronic regions of MLH1 andMSH2. Then, sequencing of MLH1/MSH2/MSH6/PMS2/EPCAM geneswas performed by NGS and large rearrangements were detected byMLPA. The variants were classified according to international databases.Variants with uncertain or unreported clinical significancewere analysed In-silico using the PolyPhen, SIFT and/or Human Splicingfinder 3.0 software.ResultsA total of 83 families (49 fulfilled Amsterdam Criteria [AC] and 34 BethesdaCriteria [BC]) were analysed. Pathogenic variants were foundin 26 out of 83 (31.3%) families, been 23 pathogenic and 3 likelypathogenic.Splice site and large rearrangements represented 19.2% (5/26) and11.5% (3/26) of the variants.23% (6/26) of them were originally describedin this series and 1 was a founding mutation from Piedmont,Italy. Affected genes include MSH2, MLH1, MSH6 and PMS2 (12, 11, 2and 1 cases respectively). Mutation detection rates in AC and BT familieswere 48.9% (N=24) and 5.9% (N=2), p<0.01. Among AC families,those with identified mutation had a lower median age of cancer onset and higher incidence of extra-CCR cancer than those withoutidentified mutations. Additionally, we have also studied other genesin patients with different clinical conditions included in the registry.We identified mutations in APC, MUTYH, BMPR1A, SMAD4, CDH1,BRCA1-2, CHEK2.ConclusionThe multidisciplinary approach and the international collaborationsallowed the correct implementation of the genetic tests. To ourknowledge, this study is the first Characterization of AC families accordingto genetic tests in South America. This allowed the identificationof AC families with different ages of onset and prevalence ofextra-CRC cancers, as well as several significant variant not previouslyreported in international databases.Fil: Piñero, Tamara Alejandra. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Herrando, Ignacio. Hospital Italiano; ArgentinaFil: Kalfayan, Pablo Germán. Hospital Italiano; ArgentinaFil: Gonzales, M.. Hospital Italiano; ArgentinaFil: Ferro, A.. Hospital Italiano; ArgentinaFil: Santino, Juan Pablo. Hospital Italiano; ArgentinaFil: Cajal, R.. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Falconi, D.. Hospital Italiano; ArgentinaFil: Guerrero, Gisella. Hospital Italiano; ArgentinaFil: Verzura, A.. Hospital Italiano; ArgentinaFil: Riggi, Maria. Hospital Italiano; ArgentinaFil: Church, James. No especifíca;Fil: Peltomäki, P.. No especifíca;Fil: Martins, Alexandra. No especifíca;Fil: Pavicic, Walter Hernan. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Dominguez, M.. University of Oslo; NoruegaFil: Vaccaro, C.. Hospital Italiano; ArgentinaThe 3rd European Hereditary Tumour Group MeetingNiceFranciaEuropean Hereditary Tumour Group Meetin

International Validation of the Immunoscore Biopsy in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy

PURPOSE: No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&amp;W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (IS ) was recently suggested in a preliminary study. METHODS: This international validation study included 249 patients with clinical complete response (cCR) managed by W&amp;W strategy. Intratumoral CD3+ and CD8+ T cells were quantified on pretreatment rectal biopsies by digital pathology and converted to IS . The primary end point was time to recurrence (TTR; the time from the end of neoadjuvant treatment to the date of local regrowth or distant metastasis). Associations between IS and outcomes were analyzed by stratified Cox regression adjusted for confounders. Immune status of tumor-draining lymph nodes (n = 161) of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery was investigated by 3'RNA-Seq and immunofluorescence. RESULTS: Recurrence-free rates at 5 years were 91.3% (82.4%-100.0%), 62.5% (53.2%-73.3%), and 53.1% (42.4%-66.5%) with IS High, IS Intermediate, and IS Low, respectively (hazard ratio [HR; Low High], 6.51; 95% CI, 1.99 to 21.28; log-rank = .0004). IS was also significantly associated with disease-free survival (log-rank = .0002), and predicted both local regrowth and distant metastasis. In multivariate analysis, IS was independent of patient age, sex, tumor location, cT stage (T, primary tumor; c, clinical), cN stage (N, regional lymph node; c, clinical), and was the strongest predictor for TTR (HR [IS High Low], 6.93; 95% CI, 2.08 to 23.15; = .0017). The addition of IS to a clinical-based model significantly improved the prediction of recurrence. Finally, B-cell proliferation and memory in draining lymph nodes was evidenced in the draining lymph nodes of patients with cCR. CONCLUSION: The IS is validated as a biomarker to predict both local regrowth and distant metastasis, with a gradual scaling of the risk of pejorative outcome

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)