Browsing by Author "Kays, Joshua K."
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Item Approach to wild-type gastrointestinal stromal tumors(AME Publishing Company, 2018-11-15) Kays, Joshua K.; Sohn, Jeffrey D.; Kim, Bradford J.; Goze, Katherine; Koniaris, Leonidas G.; Surgery, School of MedicineGastrointestinal stromal tumors (GISTs) arise from the intestinal pacemaker cells of Cajal. Wild-type gastrointestinal stromal tumors (WT-GIST) are a unique and uncommon subtype of GISTs that lack activating mutations in the tyrosine kinase c-KIT or platelet derived growth factor receptor alpha (PDGFRA) receptors. The lack of these growth-stimulating mutations renders tyrosine kinase receptor inhibitors, such as imatinib mesylate, relatively ineffective against these tumors. WT-GIST arises most commonly due to underlying alternate proliferative signals associated with germ-line, genetic mutations. WT-GIST frequently arises in patients with BRAF mutations, Carney’s Triad or neurofibromatosis type-1 (NF-1). All patients with WT-GIST require a careful examination for germ-line mutations and very close observation for recurrent tumors. Surgery remains a mainstay therapy for these patients. This review aims to discuss the most recent data available on the diagnosis and treatment of WT-GIST.Item Biliary Bypass with Laparoscopic Choledochoduodenostomy(Springer, 2018-05) Kays, Joshua K.; Koniaris, Leonidas G.; Milgrom, Daniel P.; Nakeep, Attila; Surgery, School of MedicineLaparoscopic choledochoduodenostomy (LCDD) is employed to treat many benign biliary diseases when endoscopic or percutaneous techniques are not feasible. We describe our technique for LCDD, which utilizes common bile duct transection and an end-to-side biliary-enteric anastomosis. This procedure includes the following elements: isolation and transection of the common bile duct, mobilization of the duodenum (Kocher maneuver), inspection of the common bile duct, and end-to-side biliary-enteric anastomosis. Key details and pitfalls are discussed. Over a 5-year period, LCDD was performed on 18 patients. Indications included intractable abdominal pain (10) and choledocholithiasis (8). The majority of patients, 83%, tolerated the operation well with no complications. There was one postoperative intra-abdominal abscess and two anastomotic strictures, one in the immediate postoperative period and the other 9 months after the operation. The median length of stay was 4 days (IQR 3.0–5.3), and there was minimal blood loss. Based on our experience, LCDD with transection and end-to-side biliary-enteric anastomosis is a safe and effective biliary bypass technique.Item The Combination of Low Skeletal Muscle Mass and High Tumor Interleukin-6 Associates with Decreased Survival in Clear Cell Renal Cell Carcinoma(MDPI, 2020-06-17) Kays, Joshua K.; Koniaris, Leonidas G.; Cooper, Caleb A.; Pili, Roberto; Jiang, Guanglong; Liu, Yunlong; Zimmers, Teresa A.; Medical and Molecular Genetics, School of MedicineClear cell renal carcinoma (ccRCC) is frequently associated with cachexia which is itself associated with decreased survival and quality of life. We examined relationships among body phenotype, tumor gene expression, and survival. Demographic, clinical, computed tomography (CT) scans and tumor RNASeq for 217 ccRCC patients were acquired from the Cancer Imaging Archive and The Cancer Genome Atlas (TCGA). Skeletal muscle and fat masses measured from CT scans and tumor cytokine gene expression were compared with survival by univariate and multivariate analysis. Patients in the lowest skeletal muscle mass (SKM) quartile had significantly shorter overall survival versus the top three SKM quartiles. Patients who fell into the lowest quartiles for visceral adipose mass (VAT) and subcutaneous adipose mass (SCAT) also demonstrated significantly shorter overall survival. Multiple tumor cytokines correlated with mortality, most strongly interleukin-6 (IL-6); high IL-6 expression was associated with significantly decreased survival. The combination of low SKM/high IL-6 was associated with significantly lower overall survival compared to high SKM/low IL-6 expression (26.1 months vs. not reached; p < 0.001) and an increased risk of mortality (HR = 5.95; 95% CI = 2.86–12.38). In conclusion, tumor cytokine expression, body composition, and survival are closely related, with low SKM/high IL-6 expression portending worse prognosis in ccRCC.Item Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform(MDPI, 2020-12-15) Narasimhan, Ashok; Shahda, Safi; Kays, Joshua K.; Perkins, Susan M.; Cheng, Lijun; Schloss, Katheryn N. H.; Schloss, Daniel E. I.; Koniaris, Leonidas G.; Zimmers, Teresa A.; Surgery, School of MedicinePatients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; however, no such markers are in use. Via Somascan, we measured ~1300 plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of >5% cancer weight loss (FC ≥ |1.5|, p ≤ 0.05). Six were common for cancer stage (Up: GDF15, TIMP1, IL1RL1; Down: CCL22, APP, CLEC1B). Four were common for local/cachexia (C1R, PRKCG, ELANE, SOST: all oppositely regulated) and four for metastatic/cachexia (SERPINA6, PDGFRA, PRSS2, PRSS1: all consistently changed), suggesting that stage and cachexia status might be molecularly separable. We found 71 proteins that correlated with cachexia severity via weight loss grade, weight loss, skeletal muscle index and radiodensity (r ≥ |0.50|, p ≤ 0.05), including some known cachexia mediators/markers (LEP, MSTN, ALB) as well as novel proteins (e.g., LYVE1, C7, F2). Pathway, correlation, and upstream regulator analyses identified known (e.g., IL6, proteosome, mitochondrial dysfunction) and novel (e.g., Wnt signaling, NK cells) mechanisms. Overall, this study affords a basis for validation and provides insights into the processes underpinning cancer cachexia.Item The impact of members of the Society of University Surgeons on the scholarship of American surgery(Elsevier, 2016-07) Valsangkar, Nakul P.; Kays, Joshua K.; Feliciano, David V.; Martin, Paul J.; Parett, Jordan S.; Joshi, Mugdha M.; Zimmers, Teresa A.; Koniaris, Leonidas G.; Department of Surgery, IU School of MedicineBackground A core objective of the Society of University Surgeons (SUS) is research focused: to “advance the art and science of surgery through original investigation.” This study sought to determine the current impact of the SUS on academic surgical productivity. Methods Individual faculty data for numbers of publications, citations, and National Institute of Health (NIH) funding history were collected for 4,015 surgical faculty at the top 55 NIH-funded departments of surgery using SCOPUS and the NIH Research Portfolio Online Reporting Tools. SUS membership was determined from membership registry data. Results Overall, 502 surgical faculty (12.5%) were SUS members with 92.7% holding positions of associate or full professor (versus 59% of nonmembers). Median publications (P) and citations (C) among SUS members were P: 112, C: 2,460 versus P: 29, C: 467 for nonmembers (P < .001). Academic productivity was considerably higher by rank for SUS members than for nonmembers: associate professors (P: 61 vs 36, C: 1,199 vs 591, P < .001) and full professors (P: 141 vs 81, C: 3,537 vs 1,856, P < .001). Among full professors, SUS members had much higher rates of NIH funding than did nonmembers (52.6% vs 26%, P < .05) and specifically for R01, P01, and U01 awards (37% vs 17.7%, P < .01). SUS members were 2 times more likely to serve in divisional leadership or chair positions (23.5% vs 10.2%, P < .05). Conclusion SUS society members are a highly productive academic group. These data support the premise that the SUS is meeting its research mission and identify its members as very academically productive contributors to research and scholarship in American surgery and medicine.Item Integrating therapies for surgical adult soft tissue sarcoma patients(AME Publishing Company, 2018-11-02) Milgrom, Daniel P.; Sehdev, Amikar; Kays, Joshua K.; Koniaris, Leonidas G.; Surgery, School of MedicineSarcomas are an uncommon group of over 50 different individual histological malignancies arising from mesenchymal (non-epithelial or connective) tissues. Overall, they constitute 1% of human malignancies with an annual incidence rate of fewer than 5 patients per million. Sarcoma may arise from any mesenchymal cell lineages including fat, muscle, or other connective tissues. Due to the rarity of these groups of malignancies, many subtypes were, and still today, are managed as a single entity. This review focused on soft tissue sarcomas with an emphasis on how to integrate therapies for patients with this rare disorder. The role for surgical resection in cure and palliation as well as the relative benefits of adjuvant therapies such as chemotherapy and radiation therapy are discussed.Item Postoperative renal impairment is associated with increased length of stay for incisional hernia repair after liver transplantation(Elsevier, 2019-10-01) Butler, James R.; O'Brien, Daniel C.; Kays, Joshua K.; Ridlen, Kyle; Kubal, Chandrashekhar A.; Ekser, Burcin; Timsina, Lava; Fridell, Jonathan A.; Mangus, Richard S.; Powelson, John A.; Surgery, School of MedicineBackground Incisional hernia repair is the most common procedure after orthotopic liver transplantation. Although enhanced recovery protocols are increasingly employed, the post–orthotopic liver transplantation patient may not benefit from all aspects of these models. The aim of the present study is to assess which perioperative interventions and patient factors affect hospital length of stay in a cohort of post–orthotopic liver transplantation patients undergoing incisional hernia repair. Methods We conducted a retrospective review of a series of adult patients undergoing incisional hernia repair after orthotopic liver transplantation. The primary endpoint was length of stay. Results were stratified by demographic, intraoperative, and postoperative variables. Results Eleven percent (172/1523) of patients who received orthotopic liver transplantation during the study period underwent subsequent incisional hernia repair. Median length of stay was 5 days (range 2–50). The strongest predictor of length of stay was postoperative renal function. Despite liberal intraoperative administration of volume (median 642 mL/h) and brisk intraoperative urine output (median 72 mL/h), postoperative acute kidney injury occurred in 48% of patients. Those that developed acute kidney injury received less intraoperative volume (6 vs 8.5 mL/kg/h; P = .031) and the severity of postoperative renal injury was inversely related to the amount intraoperative volume given. Conclusions In patients undergoing incisional hernia repair after orthotopic liver transplantation, postoperative renal function is frequently impaired. Although many aspects of current ERAS protocols may be applied to post-transplant patients, restrictive intraoperative fluid administration strategies should be employed with caution given a high propensity for the development of post-operative acute kidney injury in this complex population.Item Profiling of Adipose and Skeletal Muscle in Human Pancreatic Cancer Cachexia Reveals Distinct Gene Profiles with Convergent Pathways(MDPI, 2021-04-20) Narasimhan, Ashok; Zhong, Xiaoling; Au, Ernie P.; Ceppa, Eugene P.; Nakeeb, Atilla; House, Michael G.; Zyromski, Nicholas J.; Schmidt, C. Max; Schloss, Katheryn N. H.; Schloss, Daniel E. I.; Liu, Yunlong; Jiang, Guanglong; Hancock, Bradley A.; Radovich, Milan; Kays, Joshua K.; Shahda, Safi; Couch, Marion E.; Koniaris, Leonidas G.; Zimmers, Teresa A.; Surgery, School of MedicineThe vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n = 11) and patients with PDAC (n = 24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.Item Role for targeted resection in the multidisciplinary treatment of metastatic gastrointestinal stromal tumor(AME Publishing Company, 2019-04-29) Kim, Bradford J.; Milgrom, Daniel P.; Feizpour, Cyrus; Kays, Joshua K.; Koniaris, Leonidas G.; Surgery, School of MedicineThe management of advanced gastrointestinal stromal tumors (GISTs) has evolved in the modern era due to the discovery of c-kit mutations and the development of tyrosine kinase inhibitors (TKIs). Until the advent of TKIs such as imatinib, the median survival reported for patients with advanced GIST was 19 months. Although surgery is the treatment of choice for resectable primary GIST, its role in cases of recurrence and metastasis remains to be unclear. This review outlines the potential beneficial role of repeat surgical resection in the multidisciplinary treatment of advanced GIST in the era of TKIs.Item Sarcopenia is a Significant Predictor of Mortality After Abdominal Aortic Aneurysm Repair(JCSM, 2018) Kays, Joshua K.; Liang, Tiffany W.; Zimmers, Teresa A.; Milgrom, Daniel P.; Abduljabar, Hamzah; Young, Andrew; Kim, Bradford J.; Bell, Teresa M.; Fajardo, Andres; Murphy, Michael P.; Koniaris, Leonidas G.; Surgery, School of MedicineAims Repair of abdominal aortic aneurysms (AAA) decreases the incidence of rupture and death. In cancer patients, sarcopenia has been associated with increased surgical complications and mortality. The impact of sarcopenia on survival after AAA repair has yet to be described. Methods and Results Patient demographic, laboratory, body composition measurements and survival data were obtained from patients undergoing AAA repair at the Indiana University medical campus over a 5-year period. Univariate and multivariate analyses were performed to identify factors associated with overall survival. Overall, 58.2% presented with sarcopenia. Sarcopenic patients were older (71.8±8.3 versus 66.8±8.1 years; p<0.001), had lower body mass index (BMI) (26.3±5.2 versus 31.5±5.9 kg/m2; p<0.001), higher rates of myosteatosis (84.4% versus 52.%; p<0.001), greater AAA diameter (60.6±14.0 versus 57.8±11.7 mm; p=0.016), higher Charlson Comorbidity Index (CCI) (32.3% versus 25.1% ≥6; p=0.034), and increased rates of rupture (8.2% versus 3.8%; p=0.047). Sarcopenic and nonsarcopenic patients had no difference in 30-day morbidity (8.5% versus 8.5%; p=0.991) or mortality (3.7% versus 0.9%; p=0.07). Univariate analysis demonstrated age, sarcopenia, myosteatosis, CCI, and BMI to be associated with long-term survival. There was no correlation between BMI and sarcopenia. Both sarcopenia and myosteatosis resulted in decreased one-, three-, and five-year survivals compared to their counterparts. On multivariate analysis sarcopenia is independently associated with survival, conferring a 1.6-fold increase in death (p=0.04). The combination of sarcopenia plus myosteatosis doubled the risk of death compared to sarcopenia alone. Conclusions This is the first study to demonstrate that over half of all patients undergoing AAA repair are sarcopenic, a condition associated with increased mortality. Sarcopenia with myosteatosis is associated with double the mortality of sarcopenia alone. CT scan, but not BMI, accurately identifies sarcopenia and myosteatosis. Defining the mechanisms through which sarcopenia contributes to late death after AAA repair is critical to developing novel interventions that may improve survival in this high risk population.