The endoscopic management armamentarium of gastrointestinal disruptions including perforations, leaks, and fistulas has slowly but steadily broadened in recent years. Previously limited to surgical or conservative medical management, innovations in advanced endoscopic techniques like natural orifice transluminal endoscopic surgery (NOTES) have paved the path towards development of endoscopic closure techniques. Early recognition of a gastrointestinal defect is the most important independent variable in determining successful endoscopic closure and patient outcome. Some devices including through the scope clips and stents have been well studied for other indications and have produced encouraging results in closure of gastrointestinal perforations, leaks and fistulas. Over the scope clips, endoscopic sutures, vacuum therapy, glue, and cardiac device occluders are other alternative techniques that can be employed for successful endoscopic closure.
Background Recent evidence suggests a rising incidence of cancer in younger individuals. Herein, we report the epidemiologic, pathologic, and molecular characteristics of a patient cohort with early-onset pancreas cancer (EOPC). Methods Institutional databases were queried for demographics, treatment history, genomic results and outcomes. Overall survival (OS) from date of diagnosis was estimated using Kaplan-Meier method. Results Four hundred and fifty patients with EOPC were identified at Memorial Sloan Kettering between 2008 and 2018. Median OS was 16.3 months (95% confidence interval [CI] = 14.6 to 17.7 months) in the entire cohort and 11.3 months (95% CI = 10.2 to 12.2 months) for patients with stage IV disease at diagnosis. One hundred and thirty-two (29.3% of the cohort) underwent somatic testing; 21 of 132 (15.9%) had RAS wild-type cancers with identification of several actionable alterations, including ETV6-NTRK3, TPR-NTRK1, SCLA5-NRG1 and ATP1B1-NRG1 fusions, IDH1 R132C mutation, and mismatch repair deficiency. One hundred and thirty-eight (30.7% of the cohort) underwent germline testing; 44 of 138 (31.9%) had a pathogenic germline variant (PGV) and 27.5% harbored alterations in cancer susceptibility genes. Of patients seen between 2015 and 2018, 30 of 193 (15.5%) had a pathogenic germline variant. Among 138 who underwent germline testing, those with a PGV had a reduced all-cause mortality compared to patients without a PGV controlling for stage and year of diagnosis (hazard ratio = 0.42, 95%CI = 0.26 to 0.69). Conclusions PGVs are present in a substantial minority of patients with EOPC. Actionable somatic alterations were identified frequently in EOPC, enriched in the RAS wild-type subgroup. These observations underpin the recent guidelines for universal germline testing and somatic profiling in pancreatic ductal adenocarcinoma.
Context: Pancreatic cancer (PDAC) is one of the most challenging cancers to treat with modest recent improvements in survival from new systemic therapies. There is growing interest in individualized therapy underpinned by somatic and germline genomic alterations. Objective: A systematic review of data on therapies targeting somatic and germline alterations, and their downstream pathways in PDAC. Method: A systematic literature search was conducted using PRISMA guidelines to include relevant results published after January 1, 2008. Results: A total of 71 relevant studies were included. We identified 36 studies targeting the KRAS-pathway, the most common being with MEK-inhibitor therapy. Twenty-two studies were identified that evaluated platinum-based chemotherapy and PARP inhibitors in patients with deleterious mutations in DNA damage repair genes and have shown encouraging results.
Stem cells generate great interest because they hold the promise for treatment of various incurable diseases. Several distinct stem cell populations have been identified in each organ, including the skin. As the skin is the largest organ in the body and is easily accessible, cutaneous stem cells have raised significant hopes for being a rich source of easily available multipotent stem cells. Genetic alterations and mutations in stem cells are being proposed as initiation step in multiple cancers. Small populations of oncogenic stem cells termed as cancer stem cells or tumour-initiating cells have been identified in multiple tumours, including squamous cell carcinomas, and melanomas that can sustain tumour growth, underlie its malignant behaviour and initiate distant metastases. These cells are controlled and regulated by the same pathways that are also responsible for maintenance and differentiation of normal stem cells. Developing a targeted therapy against the oncogenic stem cells and dysregulated members of the signalling pathways may be the key to understanding and treating skin cancers like melanomas, for which we still do not have an effective treatment.
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