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Item Acute aortic syndrome(AME Publishing Company, 2016-05) Corvera, Joel S.; Department of Surgery, IU School of MedicineAcute aortic syndrome (AAS) is a term used to describe a constellation of life-threatening aortic diseases that have similar presentation, but appear to have distinct demographic, clinical, pathological and survival characteristics. Many believe that the three major entities that comprise AAS: aortic dissection (AD), intramural hematoma (IMH) and penetrating aortic ulcer (PAU), make up a spectrum of aortic disease in which one entity may evolve into or coexist with another. Much of the confusion in accurately classifying an AAS is that they present with similar symptoms: typically acute onset of severe chest or back pain, and may have similar radiographic features, since the disease entities all involve injury or disruption of the medial layer of the aortic wall. The accurate diagnosis of an AAS is often made at operation. This manuscript will attempt to clarify the similarities and differences between AD, IMH and PAU of the ascending aorta and describe the challenges in distinguishing them from one another.Item Acute Febrile Neutrophilic Dermatosis after Deep Inferior Epigastric Perforator Flap Breast Reconstruction(KoreaMed Synapse, 2016-09) Chu, Michael W.; Cook, Julia A.; Hazen, Alexes; Department of Surgery, IU School of MedicineItem Adipocytes enhance murine pancreatic cancer growth via a hepatocyte growth factor (HGF)-mediated mechanism(Elsevier, 2016-04) Ziegler, Kathryn M.; Considine, Robert V.; True, Eben; Swartz-Basile, Deborah A.; Pitt, Henry A.; Zyromski, Nicholas J.; Department of Surgery, IU School of MedicineINTRODUCTION: Obesity accelerates the development and progression of pancreatic cancer, though the mechanisms underlying this association are unclear. Adipocytes are biologically active, producing factors such as hepatocyte growth factor (HGF) that may influence tumor progression. We therefore sought to test the hypothesis that adipocyte-secreted factors including HGF accelerate pancreatic cancer cell proliferation. MATERIAL AND METHODS: Murine pancreatic cancer cells (Pan02 and TGP-47) were grown in a) conditioned medium (CM) from murine F442A preadipocytes, b) HGF-knockdown preadipocyte CM, c) recombinant murine HGF at increasing doses, and d) CM plus HGF-receptor (c-met) inhibitor. Cell proliferation was measured using the MTT assay. ANOVA and t-test were applied; p < 0.05 considered significant. RESULTS: Wild-type preadipocyte CM accelerated Pan02 and TGP-47 cell proliferation relative to control (59 ± 12% and 34 ± 12%, p < 0.01, respectively). Knockdown of preadipocyte HGF resulted in attenuated proliferation vs. wild type CM in Pan02 cells (35 ± 5% vs. 68 ± 14% greater than control; p < 0.05), but proliferation in TGP-47 cells remained unchanged. Recombinant HGF dose-dependently increased Pan02, but not TGP-47, proliferation (p < 0.05). Inhibition of HGF receptor, c-met, resulted in attenuated proliferation versus control in Pan02 cells, but not TGP-47 cells. CONCLUSIONS: These experiments demonstrate that adipocyte-derived factors accelerate murine pancreatic cancer proliferation. In the case of Pan02 cells, HGF is responsible, in part, for this proliferation.Item Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2(Elsevier, 2016-02-18) Redis, Roxana S.; Vela, Luz E.; Lu, Weiqin; de Oliveira, Juliana Ferreira; Ivan, Cristina; Rodriguez-Aguayo, Cristian; Adamoski, Douglas; Pasculli, Barbara; Taguchi, Ayumu; Chen, Yunyun; Fernandez, Agustin F.; Valledor, Luis; Van Roosbroeck, Katrien; Chang, Samuel; Shah, Maitri; Kinnebrew, Garrett; Han, Leng; Atlasi, Yaser; Cheung, Lawrence H.; Huang, Gilbert Yuanjay; Monroig, Paloma; Ramirez, Marc S.; Ivkovic, Tina Catela; Van, Long; Ling, Hui; Gafà, Roberta; Kapitanovic, Sanja; Lanza, Giovanni; Bankson, James A.; Huang, Peng; Lai, Stephan Y.; Bast, Robert C.; Rosenblum, Michael G.; Radovich, Milan; Ivan, Mircea; Bartholomeusz, Geoffrey; Liang, Han; Fraga, Mario F.; Widger, William R.; Hanash, Samir; Berindan-Neagoe, Ioana; Lopez-Berestein, Gabriel; Ambrosio, Andre L.B.; Dias, Sandra M Gomes; Calin, George A.; Department of Surgery, IU School of MedicineAltered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68). The CCAT2 interaction with the CFIm complex fine-tunes the alternative splicing of Glutaminase (GLS) by selecting the poly(A) site in intron 14 of the precursor mRNA. These findings uncover a complex, allele-specific regulatory mechanism of cancer metabolism orchestrated by the two alleles of a long ncRNA.Item An Alternative Technique for Immediate Direct-to-Implant Breast Reconstruction-A Case Series(Wolters Kluwer, 2016-07-22) Downs, Ronald K.; Hedges, Kellee; Department of Surgery, IU School of MedicineBACKGROUND: The practice of breast reconstruction continues to evolve with the introduction of new technologies. The authors describe a unique approach allowing immediate direct-to-implant reconstruction that can be performed on an outpatient basis. METHODS: After a nipple-sparing mastectomy, acellular dermal matrix (ADM)-covered implants are placed in a prepectoral position in an immediate reconstruction. Assessment of results was performed via a retrospective review of demographic and procedural data. RESULTS: Forty-five patients (79 breasts), mean age 46.8 years, were treated with direct-to-implant reconstruction using ADM-wrapped implants placed above the muscle with mean follow-up of 23.1 months (median 22 mo). Mean body mass index was 24.3, and 15 patients (33.3%) were current or former smokers. Twenty-seven patients (60%) had prior breast surgery with 22 (49%) exposed to chemotherapy and 34 (76%) radiation. Procedure time averaged 155 minutes and hospital length of stay averaged 0.6 days. Complications included flap necrosis in 22 cases (28%), seroma in 12 (15%), infection in 8 (10%), rippling in 28 (35%), and contracture in 8 (10%). In 14 breasts (18%), postoperative wound complications (flap necrosis or infection) led to implant loss. CONCLUSIONS: The availability of ADM and cohesive gel implants has allowed us to perform above-the-muscle implant breast reconstruction in reduced time and often on an outpatient basis. Complication rates were comparable to expected results of standard expander-to-implant, staged breast reconstruction. This technique is a viable option delivering clinically and aesthetically acceptable results in select patients.Item Analysis of Cases inWhich a Biopsy Specimen Is Positive and an Excised Lesion Is Negative for Nonmelanoma Skin Cancer(JAMA, 2016-05) Han, Jane; Nosrati, Naveed N.; Soleimani, Tahereh; Munshi, Imtiaz A.; Flores, Roberto L.; Tholpady, Sunil S.; Department of Surgery, IU School of MedicineNonmelanoma skin cancers (NMSCs), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), are the most common types of cancer with the fastest-growing treatment costs in the United States.1 Standard treatment requires biopsy for histologic confirmation, followed by excision. Oftentimes, no residual carcinoma is detected, implying spontaneous clearance at rates reported to vary from 24% to 76%.2- 5 These types of lesions have been investigated by others2- 5 and are not fully understood. Our study aims to determine the lesion and patient characteristics that would most strongly predict a histologically negative result for an excised lesion after a biopsy specimen had positive margins.Item Artery-Only Ear Replantation in a Child: A Case Report With Daily Photographic Documentation(Open Science Company, 2016-12-28) Mendenhall, Shaun D.; Sawyer, Justin D.; Adkinson, Joshua M.; Department of Surgery, IU School of MedicineObjective: Ear replantation poses a significant technical challenge even for the skilled microsurgeon. Many ear amputations result from avulsion and thus have damaged and often diminutive vessels with a paucity of veins. Artery-only replantation is an option for ear salvage, but little is published on the clinical course and appearance after this procedure. Methods: A subtotal ear replantation was performed on a 10-year-old boy without a venous anastomosis. Leech therapy was used to manage venous congestion postoperatively, and daily photography was performed to document the clinical course. Results: Postoperative venous congestion was successfully managed with leech therapy. Four days after the replantation, arterial thrombosis occurred that required a take back and salvage with an interposition vein graft for arterial repair. Native venous drainage and arterial revascularization from skin edges were evident by postoperative day 12, and leeches were discontinued on day 14. The patient required debridement of the posterior ear and superior helix necrotic skin, with burying of the upper portion of the ear in a superior auricular skin flap. The ear was subsequently released from the head, and the exposed portions were covered successfully with a full-thickness skin graft. Conclusions: While arterial and venous anastomoses should always be attempted, arterial-only ear replantation can provide excellent results when venous congestion is properly managed. Daily photography can be a useful tool to monitor subtle skin color changes that may indicate native venous drainage and arterial revascularization.Item Assessment of muscle mass and strength in mice(SpringerNature, 2015-08-19) Bonetto, Andrea; Andersson, Daniel C.; Waning, David L.; Department of Surgery, IU School of MedicineMuscle weakness is an important phenotype of many diseases that is linked to impaired locomotion and increased mortality. The force that a muscle can generate is determined predominantly by muscle size, fiber type and the excitation-contraction coupling process. Here we describe methods for the histological assessment of whole muscle to determine fiber cross-sectional area and fiber type, determination of changes in myocyte size using C2C12 cells, in vivo functional tests and measurement of contractility in dissected whole muscles. The extensor digitorum longus and soleus muscles are ideally suited for whole-muscle contractility, and dissection of these muscles is described.Item Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models(Impact Journals, 2016-07-26) Awasthi, Niranjan; Scire, Emily; Monahan, Sheena; Grojean, Meghan; Zhang, Eric; Schwarz, Margaret A.; Schwarz, Roderich E.; Department of Surgery, IU School of MedicineNab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm3 in controls, 42.4 mm3 after nab-paclitaxel (p = 0.002), 93.3 mm3 after BMS-754807 (p = 0.01) and 1.9 mm3 after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm3 in controls, 23.1 mm3 after nab-paclitaxel (p = 0.002), 118.2 mm3 after BMS-754807 (p = 0.02) and -87.4 mm3 (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy.Item Automated pancreatic cyst screening using natural language processing: a new tool in the early detection of pancreatic cancer(Elsevier, 2015-05) Roch, Alexandra M.; Mehrabi, Saeed; Krishnan, Anand; Schmidt, Heidi E.; Kesterson, Joseph; Beesley, Chris; Dexter, Paul R.; Palakal, Matthew; Schmidt, C. Max; Department of Surgery, IU School of MedicineINTRODUCTION: As many as 3% of computed tomography (CT) scans detect pancreatic cysts. Because pancreatic cysts are incidental, ubiquitous and poorly understood, follow-up is often not performed. Pancreatic cysts may have a significant malignant potential and their identification represents a 'window of opportunity' for the early detection of pancreatic cancer. The purpose of this study was to implement an automated Natural Language Processing (NLP)-based pancreatic cyst identification system. METHOD: A multidisciplinary team was assembled. NLP-based identification algorithms were developed based on key words commonly used by physicians to describe pancreatic cysts and programmed for automated search of electronic medical records. A pilot study was conducted prospectively in a single institution. RESULTS: From March to September 2013, 566,233 reports belonging to 50,669 patients were analysed. The mean number of patients reported with a pancreatic cyst was 88/month (range 78-98). The mean sensitivity and specificity were 99.9% and 98.8%, respectively. CONCLUSION: NLP is an effective tool to automatically identify patients with pancreatic cysts based on electronic medical records (EMR). This highly accurate system can help capture patients 'at-risk' of pancreatic cancer in a registry.