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Browsing by Author "Beane, Joal D."
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Item Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC)(BMJ, 2019-06) Lo, Winifred; Zhu, Bin; Sabesan, Arvind; Wu, Ho-Hsiang; Powers, Astin; Sorber, Rebecca A.; Ravichandran, Sarangan; Chen, Ina; McDuffie, Lucas A.; Quadri, Humair S.; Beane, Joal D.; Calzone, Kathleen; Miettinen, Markku M.; Hewitt, Stephen M.; Koh, Christopher; Heller, Theo; Wacholder, Sholom; Rudloff, Udo; Surgery, School of MedicineINTRODUCTION: Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC. METHODS: One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age). RESULTS: Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants. CONCLUSION: Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.Item Is American College of Surgeons NSQIP organ space infection a surrogate for pancreatic fistula?(Elsevier, 2014-12) Parikh, Janak Atul; Beane, Joal D.; Kilbane, E. Molly; Milgrom, Daniel P.; Pitt, Henry A.; Department of Surgery, IU School of MedicineBACKGROUND: In the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP), pancreatic fistula has not been monitored, although organ space infection (OSI) data are collected. Therefore, the purpose of this analysis was to determine the relationship between ACS NSQIP organ space infection and pancreatic fistulas. STUDY DESIGN: From 2007 to 2011, 976 pancreatic resection patients were monitored via ACS NSQIP at our institution. From this database, 250 patients were randomly chosen for further analysis. Four patients were excluded because they underwent total pancreatectomy. Data on OSI were gathered prospectively. Data on pancreatic fistulas and other intra-abdominal complications were determined retrospectively. RESULTS: Organ space infections (OSIs) were documented in 22 patients (8.9%). Grades B (n = 26) and C (n = 5) pancreatic fistulas occurred in 31 patients (12.4%); grade A fistulas were observed in 38 patients (15.2%). Bile leaks and gastrointestinal (GI) anastomotic leaks each developed in 5 (2.0%) patients. Only 17 of 31 grade B and C pancreatic fistulas (55%), and none of 38 grade A fistulas were classified as OSIs in ACS NSQIP. In addition, only 2 of 5 bile leaks (40%) and 2 of 5 GI anastomotic leaks (40%) were OSIs. Moreover, 3 OSIs were due to bacterial peritonitis, a chyle leak, and an ischemic bowel. CONCLUSIONS: This analysis suggests that the sensitivity (55%) and specificity (45%) of organ space infection (OSI) in ACS NSQIP are too low for OSI to be a surrogate for grade B and C pancreatic fistulas. We concluded that procedure-specific variables will be required for ACS NSQIP to improve outcomes after pancreatectomy.Item Vascular challenges from pancreatoduodenectomy in the setting of coeliac artery stenosis(BMJ Publishing Group, 2017-03-16) Beane, Joal D.; Schwarz, Roderich E.; Surgery, School of MedicineCoeliac artery stenosis due to median arcuate ligament compression or atherosclerotic disease is a frequently unrecognised challenge to recovery after pancreatoduodenectomy. The described case illustrates management with intraoperative superior mesenteric artery to hepatic artery bypass graft that led to haemorrhagic challenges postoperatively but ultimately a good recovery. Aspects of preoperative diagnosis, preoperative intervention and intraoperative management options are reviewed. Surgeons need to possess these tools to prevent complications from coeliac artery stenosis when pancreatoduodenectomy is required.