Body Mass Index and Oncologic Outcomes after Esophagectomy

ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS These data suggest that IAP is a local immunomodulating factor, perhaps regulating LPS-TLR4 interaction between commensal microflora and intestinal epithelium.

28.16. Differential Expression and Function of Urea Transporters in Rat and Human Colon. D. Collins,1 A. Hogan,1 D. C. Winter,1 A. W. Baird,2 G. S. Stewart2; 1St Vincent’s University Hospital, Dublin, Ireland; 2University College Dublin, Dublin, Ireland Gastrointestinal urea transporters play a significant role in urea nitrogen salvaging (UNS) processes between mammalian hosts and gut bacteria. In regions of high bacterial populations (proximal colon), urea is secreted into the colonic lumen and used as a nutrient source by commensal bacteria. Although urea transporters are expressed in human colon, their functional relevance remains to be elucidated. The aim of this study was to investigate expression and function of the facilitative urea transporter UT-B in rat and human colon. Immunoblot analysis demonstrated expression of a 35 kDa glycosylated UT-B protein in colonic mucosa with significantly higher expression in right colon compared to left (P < 0.01, N ¼ 3). This glycosylated UT-B protein was predominantly located in plasma membrane-enriched samples (P < 0.001, N ¼ 6). Urea flux studies performed in rat and human colon mounted in Ussing chambers demonstrated higher urea flux in right compared to left colon(P < 0.05, N ¼ 6). In addition, bi-directional urea flux in right colonic specimens was sensitive to the urea transporter inhibitor, 1,3, dimethylurea (DMU) (P < 0.05,N ¼ 6). This study demonstrates differential expression and function of UTB transporters in rat and human colon suggesting that urea transport is an important process in the symbiotic relationship between gut commensal bacteria and their mammalian hosts.

28.17. The Humoral Response after Laparoscopic versus Open Colorectal Surgery - A Meta-Analysis. T. Sammour, A. Kahokehr, A. G. Hill; University of Auckland, Auckland, New Zealand Background: The local and systemic humoral response after colorectal surgery is thought to affect post-operative recovery. Despite a number of trials comparing this response between laparoscopic and open surgery, results are conflicting. We aimed to systematically review the results from randomised controlled clinical trials comparing the humoral response after laparoscopic versus open colorectal surgery. Methods: A high-sensitivity search was conducted independently by two of the authors with no language restriction. Studies were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), Cochrane Library, Medline (January 1966 to January 2009), PubMed (1950 to January 2009) and Embase (1947 to January 2009). Relevant meeting abstracts and reference lists were manually searched. Data analysis was performed using Review Manager Version 5.0. Results: Thirteen randomised controlled trials were included. Meta-analysis demonstrated a significantly higher serum IL-6 on day 1 after open colorectal resection for neoplasia (n ¼ 97) compared with laparoscopic resection (n ¼ 76, p ¼ 0.0008) without significant heterogeneity. Data for plasma IL-6 were heterogeneous, with no apparent difference between groups. No other significant differences were identified, and there were not enough data on local peritoneal humoral factors to allow meta-analysis. Conclusion: Open colorectal resection for neoplasia is associated with higher post-operative serum levels of IL-6 on day 1 than equivalent laparoscopic surgery. The aetiology and clinical significance of this finding is uncertain, and further studies are required to elucidate any differences in the local humoral response which may be more clinically relevant in surgery for this indication.

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28.18. Body Mass Index and Oncologic Outcomes after Esophagectomy. M. Melis,1 K. L. Meredith,2 J. M. McLoughlin,3 J. M. Weber,2 E. M. Siegel,2 S. Hoffe,2 K. K. Turaga,2 G. Dittrick,2 E. M. Dean,2 R. C. Karl2; 1New York University and the VA NYHHS, New York, NY; 2Moffitt Cancer Center, Tampa, FL; 3Medical College of Georgia, Augusta, GA Introduction: The aim of this study was to determine the influence of elevated body mass index on outcomes after esophagectomy for cancer. Methods: From our comprehensive esophageal cancer database consisting of 510 patients we identified 166 obese (BMI  30), 176 overweight (BMI 25-29) and 148 normal-weight (BMI 20-24) patients that underwent esophagectomy. Malnourished patients (BMI of < 20) were excluded. Cumulative survival was calculated by the Kaplan and Meier method; differences in survival times between groups were analyzed by log rank method. The study end-points were overall and recurrence-free survivals. Results: The patient group consists of 420 men and 70 women with a mean age at time of surgery of 64 years (range 28-86). The categories of patients (obese, overweight, and normal-weight) were similar in terms of demographics and co-morbidities, with the exception of a younger age (62.5 vs. 66.2 vs 65.3 years, p ¼ 0.002), and a higher incidence of diabetes (23.5% vs. 11.4% vs 10.1%, p ¼ 0.001) and hiatal hernia (28.3% vs. 14.8% vs. 20.3%, p ¼ 0.01) for obese patients. More patients with BMI > 24 were found with adenocarcinoma, compared to the normal-weight group (90.8% vs. 90.9% vs. 82.5%, p ¼ 0.03). Despite similar pre-operative stage, obese patients were less likely to receive neoadjuvant treatment (47.6% vs. 54.5% vs 66.2%, p ¼ 0.004). Response to neoadjuvant treatment, type of surgery performed, extent of lymphadenectomy, rate of R0 resections, peri-operative complications, and

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ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS

administration of adjuvant chemotherapy were not influenced by BMI. At a median follow-up of 21 months, 5-year overall and recurrence-free survivals were significantly better in obese patients (respectively 51%, 45%, 33%, p 0.01 and 51%, 44%, 33%, p 0.01, see Figure 1). Conclusions: In our experience patients with higher BMI, despite lower chances of receiving combined modality treatment, had improved overall and disease-free survivals. This data suggest a biologic effect of obesity on esophageal cancer survival.

28.19. The Resistance if Esophageal Cancer Cells to Bile Salt Insult Is Associated with Manganese Superoxide Dismutase. S. C. Schiffman, Y. Li, X. Li, R. C. Martin, IV; University of Louisville, Louisville, KY Introduction: Bile acid exposure is implicated as an etiologic agent in the carcinogenic initiation and progression of normal esophageal epithelial cells to Barrett’s metaplastic cells and to esophageal adenocarcinoma (EAC). It is speculated that normal squamous epithelium is replaced by metaplastic columnar cells, which are resistant to bile exposure. This study attempted to analyze the impact of bile acid exposure on normal esophageal cells, Barrett’s metaplastic cells, esophageal adenocarcinoma cells and esophageal squamous carcinoma cells. We also sought to determine if cellular resistance to bile salts is related to manganese superoxide dismutase (MnSOD). Methods: The normal esophageal epithelial cells (Het 1A), Barrett’s metaplastic cells (BAR-T), esophageal adenocarcinoma cells (OE 19) and esophageal squamous carcinoma cells (OC 3) were seeded 1 x10^5 cells per well. They were exposed to specific bile acids of sodium choleate (A), sodium deoxycholate (B), sodium glycocholate (C), sodium taurocholate (D) and a mixture of all 4 reagents (E) at concentrations ranging from 0.05 mM to 0.8 mM and incubated 4-24 hours. MTT incorporation assay was performed and absorbance was measured with spectrophotometry. OD values were normalized to reference cell control number and growth percentage was determined. MnSOD expression and MnSOD enzymatic activity were evaluated using Western Blot. Results: In Het 1A cells, bile salt concentrations at 0.8 mM and 0.4 mM significantly inhibited growth. At 0.8 mM, sodium choleate (16% of control cell growth), sodium deoxycholate (17%), sodium glycocholate (27%), sodium taurocholate (26%) and mixture of all 4 reagents (17%) significantly inhibited cell growth. At 0.4 mM, sodium choleate (22%), sodium deoxycholate (49%), sodium glycocholate (57%), sodium taurocholate (35%) and mixture (26%) deceased cell growth significantly. Cell growth was only moderately inhibited (6376%) at concentrations less than 0.2 mM. Het 1A cells appear to be most sensitive to sodium choleate and the mixture of the 4 reagents. The effect on growth was not additive when cells were exposed to a mixture of the 4 bile salt reagents, but rather reflected the growth percentage of the strongest reagent (sodium choleate). OC 3 cells grew very well at every concentration despite bile salt insult. OE19 cells were resistant to bile salts and had equivocal growth at all concentrations. OC3 cells appeared to be more resistant to insult than OE 19 cells (Table). On statistical analysis, there was significant difference (p < 0.05) in growth between the cell lines at every concentration except 0.2 mM of mixture (p ¼ 0.052) and 0.4 mM sodium glycocholate (p ¼ 0.069). (Table). On Western Blot, MnSOD expression decreased after treatment with bile acids. However, MnSOD expression was increased in cells which were pretreated with MnSOD prior to bile acid exposure. Conclusions: OC 3 cells are the most resistant to bile salt reagents, whereas Het 1A cells are the least. This resistance may be related to an increase in MnSOD expression.

28.20. The Synergistic Effects of the Somatostatin Analog Pasireotide (SOM230) and Raf-1 Pathway Activation in Human Carcinoid Cancer Cells. S. N. Pinchot, R. Davis, M. Kunnimalaiyaan, H. Chen; University of Wisconsin, Madison, WI Background: Gastrointestinal (GI) carcinoids are rare neuroendocrine (NE) tumors characterized by the production of bioactive hormones such as 5-hydroxytryptamine and chromogranin A. Besides surgery, there are limited curative and palliative treatments available. We have previously demonstrated that combined therapy with octreotide, a naturally occurring somatostatin analog which is effective in managing symptoms in patients with the malignant carcinoid syndrome, and Raf-1 pathway activation results in synergistic growth inhibition without synergistic effects on NE hormone production. In the present study, we investigate the synergistic effects of the recently developed long-acting somatostatin analog, pasireotide (SOM 230), and Raf-1 pathway activation. Methods: Human gastrointestinal carcinoid tumor cells stably transduced with an estradiol-inducible Raf-1 construct (BON-Raf) were treated with 1mM b-estradiol to activate the Raf-1 signaling pathway, while an equivalent dose of ethanol, solvent for the b-estradiol, was used to treat control cells. Raf-1 activated cells and control cells were subsequently treated with up to 50mM of the long-acting somatostatin analog, pasireotide (SOM230). Western analysis was used to demonstrate activation of the Raf-1 pathway by phosphorylation of ERK1/2 and to measure the NE tumor markers CgA and human achaete-scute complex-like 1 (ASCL1). Cancer cell proliferation was measured by the MTT assay. Results: b-estradiol treatment resulted in phosphorylation of ERK1/2 in BON-Raf cells, indicating activation of the Raf-1 signaling pathway. Importantly, treatment of human carcinoid cells with SOM230 alone resulted in a nearly 50% growth inhibition inhibition by MTT assay; however, the combination of Raf-1 activation and SOM230 treatment did not lead to synergistic growth inhibition of BON cells. Similarly, induction of Raf-1 led to a marked reduction in NE tumor markers, but no additional effects on NE hormone levels were noted with the combination of Raf-1 activation and SOM230 treatment. Conclusions: SOM230, a recently developed long-acting somatostatin analog, demonstrates significant growth inhibition of human GI carcinoid cells in vitro; however, the combination of SOM230 and Raf-1 activation does not lead to synergistic growth inhibition. Interestingly, this study-the second in a series of studies evaluation the relative synergistic potencies of somatostatin analogs and Raf-1 activation-shows that SOM230 alone is more effective than the current standard therapy, octreotide, in reducing cancer cell proliferation in vitro. However, while combination therapy with octreotide and Raf-1 pathway activation demonstrated synergy with respect to growth inhibition in vitro, combination therapy with SOM230 and Raf-1 activation did not demonstrate this same synergy.

ONCOLOGY 7: MELANOMA/BREAST/ ENDOCRINE 29.1. Grading of Ductal and Lobular Carcinoma, with Emphasis on Differences of Surgically Relevant Tumor Size. M. S. Wachtel, A. Halldorsson, S. Dissanaike; Texas Tech University School of Medicine, Lubbock, TX Objective. Evaluated were differences between lobular carcinoma and grades of ductal carcinoma. Methods. SEER data were obtained from women diagnosed with invasive lobular (n ¼ 12,301), grade I (n ¼ 13,783), grade II (n ¼ 41,881) and grade III ductal carcinoma (n ¼ 42,724) between 1988 and 1999, all with known TNM stages, none T0 or M1, none with extra-axillary lymph node metastases, all with surgical extirpation describable as either mastectomy or resection less than mastectomy, all above age 20, none diagnosed at autopsy. Multinomial regression was used. Explanatory variables