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The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.
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INTRODUCTION: Abdominal desmoid tumors are locally aggressive tumors that develop in familial adenomatous polyposis (FAP) patients, within the mesentery or abdominal wall. The understanding and implications of the treatment regimens are evolving. AIM: To assess the course, treatment, and outcomes of FAP and non-FAP abdominal desmoids and their related genetic alterations. METHODS: Retrospective cohort study. Demographics, tumor characteristics, oncological and surgical history, complications, genetic-testing, and mortality data were retrieved from two tertiary referral centers. RESULTS: Sixty-two patients were identified (46 FAP and 16 non-FAP). Thirty-eight patients (61.3%) underwent surgical procedures (12 urgent and 26 elective). Out of 33 tumor resections, 39.4% recurred. Hormonal therapy, COX-inhibitors, chemotherapy, imatinib, and sorafenib were used in 35 (56.4%), 30 (48.4%), 18 (29.1%), 7 (11.3%), and 8 (12.9%) of patients, respectively, with a 2 year progression-free survival of 67.8%, 57.7%, 38.4%, and 28.5%, respectively. Forty-one patients (66.1%) suffered complications: bowel obstruction (30.6%), hyperalimentation (14.5%), ureteral obstruction (12.9%), perforation (11.3%), abscess formation (3.2%), and spinal cord compression (3.2%). Non-FAP patients carried pathogenic mutations in CHEK2, BLM, ERCC5, MSH6, and PALB2. CONCLUSIONS: Abdominal desmoids are mostly FAP-related and are associated with severe outcomes. We also report a group of non-FAP abdominal desmoids, which includes patients with additional cancer-related gene alterations. This interesting group should be further explored.
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BACKGROUND: There is growing concern regarding the impact of adolescent obesity on adult health. The objective of this study was to evaluate the association between body mass index (BMI) in late adolescence and the incidence of pancreatic cancer during adulthood. METHODS: The authors analyzed a cohort of 1087,358 Israeli Jewish men and 707,212 Jewish women who underwent a compulsory physical examination between ages 16 and 19 years from 1967 to 2002. Pancreatic cancer incidence through December 31, 2012 was identified by linkage to the national cancer registry. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for pancreatic cancer according to the US Centers for Disease Control and Prevention (CDC) BMI percentiles at baseline. RESULTS: Over a median 23 year follow-up, 551 incident cases of pancreatic cancer cases occurred (423 men; 128 women). Compared with normal weight (5th to-<85th percentile), obesity (≥95th percentile) was associated with an increased risk of cancer among both men (HR, 3.67; 95% confidence interval [CI], 2.52-5.34) and women (HR, 4.07; 95% CI, 1.78-9.29). Among men, compared with low-normal BMI (≥5th to <25th percentile), high-normal BMI (≥75th to <85th percentile) and overweight (85th to 95th percentile) also were associated with a higher risk for cancer(high-normal BMI: HR, 1.49; 95% CI, 1.05-2.13; overweight: HR, 1.97; 95% CI, 1.39-2.80). The estimated population-attributable fraction because of overweight and obesity was 10.9% (95% CI, 6.1%-15.6%). CONCLUSIONS: Men and women who were obese or overweight as adolescents are at an increased risk for subsequent pancreatic cancer.
