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Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

BACKGROUND: The high morbidity and mortality rates of pancreaticoduodenectomy are mainly associated with pancreaticojejunal anastomosis, the most fragile and susceptible to complications such as clinically relevant postoperative pancreatic fistula. AIMS: The alternative fistula risk score and the first postoperative day drain fluid amylase are predictors of the occurrence of clinically relevant postoperative pancreatic fistula. No consensus has been reached on which of the scores is a better predictor; moreover, their combined predictive power remains unclear. To the best of our knowledge, this association had not yet been studied. METHODS: This study assessed the predictive effect of alternative fistula risk score and/or drain fluid amylase on clinically relevant postoperative pancreatic fistula in a retrospective cohort of 58 patients following pancreaticoduodenectomy. The Shapiro-Wilk and Mann-Whitney tests were applied for assessing the distribution of the samples and for comparing the medians, respectively. The receiver operating characteristics curve and the confusion matrix were used to analyze the predictive models. RESULTS: The alternative fistula risk score values were not statistically different between patients in the clinically relevant postoperative pancreatic fistula and non- clinically relevant postoperative pancreatic fistula groups (Mann-Whitney U test 59.5, p=0.12). The drain fluid amylase values were statistically different between clinically relevant postoperative pancreatic fistula and non- clinically relevant postoperative pancreatic fistula groups (Mann-Whitney U test 27, p=0.004). The alternative fistula risk score and drain fluid amylase were independently less predictive for clinically relevant postoperative pancreatic fistula, compared to combined alternative fistula risk score + drain fluid amylase. CONCLUSION: The combined model involving alternative fistula risk score >20% + drain fluid amylase=5,000 U/L was the most effective predictor of clinically relevant postoperative pancreatic fistula occurrence following pancreaticoduodenectomy. RESUMO RACIONAL: A alta morbimortalidade da pancreaticoduodenectomia está associada, principalmente, à anastomose pancreatojejunal, a mais frágil e suscetível a complicações como a fístula pancreática pós-operatória clinicamente relevante (clinically relevant postoperative pancreatic fistula - CR-POPF). OBJETIVOS: O escore alternativo de risco de fístula (alternative fistula risk score) e os níveis de amilase do fluido de drenagem no primeiro dia pós-operatório (first postoperative day drain fluid) são preditores da ocorrência de fístula pancreática pós-operatória clinicamente relevante. Nenhum consenso foi alcançado sobre qual das pontuações é um melhor preditor; além disso, seu poder preditivo combinado permanece obscuro. Até onde sabemos, essa associação ainda não havia sido estudada. MÉTODOS: Este estudo avaliou o efeito preditivo do escore alternativo de risco de fístula e/ou do fluido de drenagem no primeiro dia pós-operatório em uma coorte retrospectiva de 58 pacientes após pancreaticoduodenectomia. Os testes de Shapiro-Wilk e Mann-Whitney foram aplicados para avaliar a distribuição das amostras e para comparar as medianas, respectivamente. A curva de características operacionais do receptor e a matriz de confusão foram utilizadas para analisar os modelos preditivos. RESULTADOS: Os valores do escore alternativo de risco de fístula não foram estatisticamente diferentes entre os pacientes dos grupos fístula pancreática pós-operatória clinicamente relevante e não- fístula pancreática pós-operatória clinicamente relevante (teste U de Mann-Whitney 59,5, p=0,12). Os valores de fluido de drenagem no primeiro dia pós-operatório foram estatisticamente diferentes entre os grupos fístula pancreática pós-operatória clinicamente relevante e não- fístula pancreática pós-operatória clinicamente relevante (teste U de Mann-Whitney 27, p=0,004). O escore alternativo de risco de fístula e fluido de drenagem no primeiro dia pós-operatório foram independentemente menos preditivos para fístula pancreática pós-operatória clinicamente relevante, em comparação com escore alternativo de risco de fístula + fluido de drenagem no primeiro dia pós-operatório combinados. CONCLUSÕES: O modelo combinado envolvendo escore alternativo de risco de fístula>20% + fluido de drenagem no primeiro dia pós-operatório=5.000 U/L foi o preditor mais eficaz da ocorrência de fístula pancreática pós-operatória clinicamente relevante após pancreaticoduodenectomia.