Department of Surgery
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Item Epstein–Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival(ScienceDirect, 2015-06) Ferrajoli, Alessandra; Ivan, Cristina; Ciccone, Maria; Shimizu, Masayoshi; Kita, Yoshiaki; Ohtsuka, Masahisha; D'Abundo, Lucilla; Qiang, Jun; Lerner, Susan; Nouraee, Nazila; Rabe, Kari G.; Rassenti, Laura Z.; Van Roosbroeck, Katrien; Manning, John T.; Yuan, Yuan; Zhang, Xinna; Shanafelt, Tait D.; Wierda, William G.; Sabbioni, Silvia; Tarrand, Jeffrey J.; Estrov, Zeev; Radovich, Milan; Liang, Han; Negrini, Massimo; Kipps, Thomas J.; Kay, Neil E.; Keating, Michael; Calin, George A.; Department of Surgery, IU School of MedicineAlthough numerous studies highlighted the role of Epstein–Barr Virus (EBV) in B-cell transformation, the involvement of EBV proteins or genome in the development of the most frequent adult leukemia, chronic lymphocytic leukemia (CLL), has not yet been defined. We hypothesized that EBV microRNAs contribute to progression of CLL and demonstrated the presence of EBV miRNAs in B-cells, in paraffin-embedded bone marrow biopsies and in the plasma of patients with CLL by using three different methods (small RNA-sequencing, quantitative reverse transcription PCR [q-RT-PCR] and miRNAs in situ hybridization [miRNA-ISH]). We found that EBV miRNA BHRF1-1 expression levels were significantly higher in the plasma of patients with CLL compared with healthy individuals (p < 0 · 0001). Notably, BHRF1-1 as well as BART4 expression were detected in the plasma of either seronegative or seropositive (anti-EBNA-1 IgG and EBV DNA tested) patients; similarly, miRNA-ISH stained positive in bone marrow specimens while LMP1 and EBER immunohistochemistry failed to detect viral proteins and RNA. We also found that BHRF1-1 plasma expression levels were positively associated with elevated beta-2-microglobulin levels and advanced Rai stages and observed a correlation between higher BHRF1-1 expression levels and shorter survival in two independent patients' cohorts. Furthermore, in the majority of CLL cases where BHRF1-1 was exogenously induced in primary malignant B cells the levels of TP53 were reduced. Our findings suggest that EBV may have a role in the process of disease progression in CLL and that miRNA RT-PCR and miRNAs ISH could represent additional methods to detect EBV miRNAs in patients with CLL.Item Blocking porcine sialoadhesin improves extracorporeal porcine liver xenoperfusion with human blood(Wiley, 2013-07) Waldman, Joshua P.; Vogel, Thomas; Burlak, Christopher; Coussios, Constantin; Dominguez, Javier; Friend, Peter; Rees, Michael A.; Surgery, School of MedicineBACKGROUND: Patients in fulminant hepatic failure currently do not have a temporary means of support while awaiting liver transplantation. A potential therapeutic approach for such patients is the use of extracorporeal perfusion with porcine livers as a form of "liver dialysis". During a 72-h extracorporeal perfusion of porcine livers with human blood, porcine Kupffer cells bind to and phagocytose human red blood cells (hRBC) causing the hematocrit to decrease to 2.5% of the original value. Our laboratory has identified porcine sialoadhesin expressed on Kupffer cells as the lectin responsible for binding N-acetylneuraminic acid on the surface of the hRBC. We evaluated whether blocking porcine sialoadhesin prevents the recognition and subsequent destruction of hRBCs seen during extracorporeal porcine liver xenoperfusion. METHODS: Ex vivo studies were performed using wild type pig livers perfused with isolated hRBCs for 72-h in the presence of an anti-porcine sialoadhesin antibody or isotype control. RESULTS: The addition of an anti-porcine sialoadhesin antibody to an extracorporeal porcine liver xenoperfusion model reduces the loss of hRBC over a 72-h period. Sustained liver function was demonstrated throughout the perfusion. CONCLUSIONS: This study illustrates the role of sialoadhesin in mediating the destruction of hRBCs in an extracorporeal porcine liver xenoperfusion model.Item Ultrasonography-Guided Identification With Methylene Blue Tattooing of the Ilioinguinal Nerve for Neurectomy for Chronic Pain: A Case Series(AMA, 2015-02) Eppstein, Andrew Curtiss; Munshi, Imtiaz A.; Sakamato, Bryan; Gwirtz, Kenneth; Department of Surgery, IU School of MedicineChronic ilioinguinal pain is a common but morbid complication of inguinal herniorrhaphy for 12% to 62% of patients.1 Although pharmacologic options exist (such as nerve blocks), long-term pain relief is inferior to surgical neurectomy.2,3 We present our experience in ilioinguinal neurectomy with preoperative ultrasonography-guided identification and perineural injection of methylene blue to tattoo the nerve.Item Clinical Assessment and Management Examination—Outpatient (CAMEO): Its Validity and Use in a Surgical Milestones Paradigm(Elsevier, 2015-01) Wilson, Adam B.; Choi, Jennifer N.; Torbeck, Laura J.; Mellinger, John D.; Dunnington, Gary L.; Williams, Reed G.; Department of Surgery, IU School of MedicineObjectives Clinical Assessment and Management Examination—Outpatient (CAMEO) is a metric for evaluating the clinical performance of surgery residents. The aim of this study was to investigate the measurement characteristics of CAMEO and propose how it might be used as an evaluation tool within the general surgery milestones project. Design A total of 117 CAMEO evaluations were gathered and used for analysis. Internal consistency reliability was estimated, and item characteristics were explored. A Kruskal-Wallis procedure was performed to discern how well the instrument discriminated between training levels. An exploratory factor analysis was also conducted to understand the dimensionality of the evaluation. Setting CAMEO evaluations were collected from 2 departments of surgery geographically located in the Midwestern United States. Combined, the participating academic institutions graduate approximately 18 general surgery residents per year. Participants In this retrospective data analysis, the number of evaluations per resident ranged from 1 to 7, and evaluations were collected from 2006 to 2013. For the purpose of data analysis, residents were classified as interns (postgraduate year 1 [PGY1]), juniors (PGY2-3), or seniors (PGY4-5). Results CAMEO scores were found to have high internal consistency (Cronbach’s α = 0.96), and all items were highly correlated (≥0.86) to composite CAMEO scores. Scores discriminated between senior residents (PGY4-5) and lower level residents (PGY1-3). Per an exploratory factor analysis, CAMEO was revealed to measure a single dimension of “clinical competence.” Conclusions The findings of this research aligned with related literature and verified that CAMEO scores have desirable measurement properties, making CAMEO an attractive resource for evaluating the clinical performance of surgery residents.Item Ranking Surgical Residency Programs: Reputation Survey or Outcomes Measures?(Elsevier, 2015-11) Wilson, Adam B.; Torbeck, Laura J.; Dunnington, Gary L.; Department of Surgery, IU School of MedicineObjective The release of general surgery residency program rankings by Doximity and U.S. News & World Report accentuates the need to define and establish measurable standards of program quality. This study evaluated the extent to which program rankings based solely on peer nominations correlated with familiar program outcomes measures. Design Publicly available data were collected for all 254 general surgery residency programs. To generate a rudimentary outcomes-based program ranking, surgery programs were rank-ordered according to an average percentile rank that was calculated using board pass rates and the prevalence of alumni publications. A Kendall τ-b rank correlation computed the linear association between program rankings based on reputation alone and those derived from outcomes measures to validate whether reputation was a reasonable surrogate for globally judging program quality. Results For the 218 programs with complete data eligible for analysis, the mean board pass rate was 72% with a standard deviation of 14%. A total of 60 programs were placed in the 75th percentile or above for the number of publications authored by program alumni. The correlational analysis reported a significant correlation of 0.428, indicating only a moderate association between programs ranked by outcomes measures and those ranked according to reputation. Seventeen programs that were ranked in the top 30 according to reputation were also ranked in the top 30 based on outcomes measures. Conclusions This study suggests that reputation alone does not fully capture a representative snapshot of a program’s quality. Rather, the use of multiple quantifiable indicators and attributes unique to programs ought to be given more consideration when assigning ranks to denote program quality. It is advised that the interpretation and subsequent use of program rankings be met with caution until further studies can rigorously demonstrate best practices for awarding program standings.Item TFAP2C Expression in Breast Cancer - Correlation with Overall Survival Beyond 10 Years of Initial Diagnosis(Springer, 2015-08) Perkins, Susan M.; Bales, Casey; Vladislav, Tudor; Althouse, Sandra; Miller, Kathy D.; Sandusky, George; Badve, Sunil; Nakshatri, Harikrishna; Department of Surgery, IU School of MedicineRecurrence and death in a significant number of patients with ERα-positive breast cancer occurs 10–20 years after diagnosis. Prognostic markers for late events have been more elusive. TFAP2C (AP2γ) regulates the expression of ERα, the ERα pioneer factors FOXA1 and GATA3, and controls ERα-dependent transcription. The purpose of this investigation is to determine the long-term prognostic value of TFAP2C. A tissue microarray (TMA) consisting of breast tumors from 451 patients with median follow-up time of 10.3 years was created and tested for the expression of TFAP2C by immunohistochemistry. Wilcoxon Rank-Sum and Kruskal–Wallis tests were used to determine if TFAP2C H-scores correlate with other tumor markers. Cox proportional hazards regression models were used to determine whether TFAP2C H-scores and other tumor markers were related to overall and disease-free survival in univariate and multivariable models. TFPAC2 overexpression did not impact overall survival during the first 10 years after diagnosis, but was associated with a shorter survival after 10 years (HR 3.40, 95 % CI 1.58, 7.30; p value = 0.002). This late divergence persisted in ER-positive (HR 2.86, 95 % CI 1.29, 6.36; p value = 0.01) and endocrine therapy-positive subgroups (HR 4.19, 95 % CI 1.72, 10.23; p value = 0.002). For the ER+ and endocrine therapy subgroup, the HR was 3.82 (95 % CI 1.53, 9.50; p value = 0.004). TFAP2C H-scores were not correlated with other tumor markers or related to disease-free survival. In this hypothesis-generating study, we show that higher TFAP2C scores correlate with poor overall survival after 10 years of diagnosis in ERα-positive and endocrine therapy-treated subgroups.Item Detection of Hepatocellular Carcinoma in Hepatitis C Patients: Biomarker Discovery by LC-MS(Elsevier, 2014-09-01) Bowers, Jeremiah; Hughes, Emma; Skill, Nicholas; Maluccio, Mary; Raftery, Daniel; Department of Surgery, IU School of MedicineHepatocellular carcinoma (HCC) accounts for most cases of liver cancer worldwide; contraction of hepatitis C (HCV) is considered a major risk factor for liver cancer even when individuals have not developed formal cirrhosis. Global, untargeted metabolic profiling methods were applied to serum samples from patients with either HCV alone or HCC (with underlying HCV). The main objective of the study was to identify metabolite based biomarkers associated with cancer risk, with the long term goal of ultimately improving early detection and prognosis. Serum global metabolite profiles from patients with HCC (n=37) and HCV (n=21) were obtained using high performance liquid chromatography-mass spectrometry (HPLC-MS) methods. The selection of statistically significant metabolites for partial least-squares discriminant analysis (PLS-DA) model creation based on biological and statistical significance was contrasted to that of a traditional approach utilizing p-values alone. A PLS-DA model created using the former approach resulted in a model with 92% sensitivity, 95% specificity, and an AUROC of 0.93. A series of PLS-DA models iteratively utilizing three to seven metabolites that were altered significantly (p<0.05) and sufficiently (FC≤0.7 or FC≥1.3) showed the best performance using p-values alone, the PLS-DA model was capable of generating 73% sensitivity, 95% specificity, and an AUROC of 0.92. Metabolic profiles derived from LC-MS readily distinguish patients with HCC and HCV from those with HCV only. Differences in the metabolic profiles between highrisk individuals and HCC indicate the possibility of identifying the early development of liver cancer in at risk patients. The use of biological significance as a selection process prior to PLSDA modeling may offer improved probabilities for translation of newly discovered biomarkers to clinical application.Item Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing(Springer, 2014-01) Radovich, Milan; Clare, Susan E.; Atale, Rutuja; Pardo, Ivanesa; Hancock, Bradley A.; Solzak, Jeffrey P.; Kassem, Nawal; Mathieson, Theresa; V. Storniolo, Anna Maria; Rufenbarger, Connie; Lillemoe, Heather A.; Blosser, Rachel J.; Choi, Mi Ran; Sauder, Candice A.; Doxey, Diane; Henry, Jill E.; Hilligoss, Eric E.; Sakarya, Onur; Hyland, Fiona C.; Hickenbotham, Matthew; Zhu, Jin; Glasscock, Jarret; Badve, Sunil; Ivan, Mircea; Liu, Yunlong; Sledge, George W.; Schneider, Bryan P.; Department of Surgery, IU School of MedicineTriple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.Item Protecting Ideas: Ethical and Legal Considerations when a Grant’s Principal Investigator Changes(Springer, 2015-07) Koniaris, Leonidas G.; Coombs, Mary I.; Meslin, Eric M.; Zimmers, Teresa A.; Department of Surgery, IU School of MedicineEthical issues related the responsible conduct of research involve questions concerning the rights and obligations of investigators to propose, design, implement, and publish research. When a principal investigator (PI) transfers institutions during a grant cycle, financial and recognition issues need to be addressed to preserve all parties’ obligations and best interests in a mutually beneficial way. Although grants often transfer with the PI, sometimes they do not. Maintaining a grant at an institution after the PI leaves does not negate the grantee institution’s obligation to recognize the PI’s original ideas, contributions, and potential rights to some forms of expression and compensation. Issues include maintaining a role for the PI in determining how to take credit for, share and publish results that involve his or her original ideas. Ascribing proper credit can become a thorny issue. This paper provides a framework for addressing situations and disagreements that may occur when a new PI continues the work after the original PI transfers. Included are suggestions for proactively developing institutional mechanisms that address such issues. Considerations include how to develop solutions that comply with the responsible conduct of research, equitably resolve claims regarding reporting of results, and avoid the possibility of plagiarism.Item Ethnicity-dependent and -independent heterogeneity in healthy normal breast hierarchy impacts tumor characterization(Nature Publishing Group, 2015-08-27) Nakshatri, Harikrishna; Anjanappa, Manjushree; Bhat-Nakshatri, Poornima; Department of Surgery, IU School of MedicineRecent reports of widespread genetic variation affecting regulation of gene expression raise the possibility of significant inter-individual differences in stem-progenitor-mature cell hierarchy in adult organs. This has not been explored because of paucity of methods to quantitatively assess subpopulation of normal epithelial cells on individual basis. We report the remarkable inter-individual differences in differentiation capabilities as documented by phenotypic heterogeneity in stem-progenitor-mature cell hierarchy of the normal breast. Ethnicity and genetic predisposition are partly responsible for this heterogeneity, evidenced by the finding that CD44+/CD24- and PROCR+/EpCAM- multi-potent stem cells were elevated significantly in African American women compared with Caucasians. ALDEFLUOR+ luminal stem/progenitor cells were lower in BRCA1-mutation carriers compared with cells from healthy donors (p = 0.0014). Moreover, tumor and adjoining-normal breast cells of the same patients showed distinct CD49f+/EpCAM+ progenitor, CD271+/EpCAM- basal, and ALDEFLUOR+ cell profiles. These inter-individual differences in the rate of differentiation in the normal breast may contribute to a substantial proportion of transcriptome, epigenome, and signaling pathway alterations and consequently has the potential to spuriously magnify the extent of documented tumor-specific gene expression. Therefore, comparative analysis of phenotypically defined subpopulations of normal and tumor cells on an individual basis may be required to identify cancer-specific aberrations.