Faculty Bibliography

Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-beta) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-beta inhibition using the anti-TGF-beta antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-beta inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.

OBJECTIVE: To compare bariatric surgery versus intensive medical weight management (MWM) in patients with type 2 diabetes mellitus (T2DM) who do not meet current National Institutes of Health criteria for bariatric surgery and to assess whether the soluble form of receptor for advanced glycation end products (sRAGE) is a biomarker to identify patients most likely to benefit from surgery. BACKGROUND: There are few studies comparing surgery to MWM for patients with T2DM and BMI less than 35. METHODS: Fifty-seven patients with T2DM and BMI 30 to 35, who otherwise met the criteria for bariatric surgery were randomized to MWM versus surgery (bypass, sleeve or band, based on patient preference). The primary outcomes assessed at 6 months were change in homeostatic model of insulin resistance (HOMA-IR) and diabetes remission. Secondary outcomes included changes in HbA1c, weight, and sRAGE. RESULTS: The surgery group had improved HOMA-IR (-4.6 vs +1.6; P = 0.0004) and higher diabetes remission (65% vs 0%, P < 0.0001) than the MWM group at 6 months. Compared to MWM, the surgery group had lower HbA1c (6.2 vs 7.8, P = 0.002), lower fasting glucose (99.5 vs 157; P = 0.0068), and fewer T2DM medication requirements (20% vs 88%; P < 0.0001) at 6 months. The surgery group lost more weight (7. vs 1.0 BMI decrease, P < 0.0001). Higher baseline sRAGE was associated with better weight loss outcomes (r = -0.641; P = 0.046). There were no mortalities. CONCLUSIONS: Surgery was very effective short-term in patients with T2DM and BMI 30 to 35. Baseline sRAGE may predict patients most likely to benefit from surgery. These findings need to be confirmed with larger studies.ClinicalTrials.gov ID: NCT01423877.

OBJECTIVE:: To assess the impact of revisional surgery after laparoscopic adjustable gastric banding (LAGB) on weight loss at 12 and 24 months. BACKGROUND:: There is no uniform consensus as to the optimal procedure for patients requiring revision after LAGB. Few studies address the issue of weight loss after band salvage procedures, despite this being a critical factor in deciding which reoperative procedure to choose. METHODS:: A retrospective analysis was conducted of adult patients who underwent LAGB from January 1, 2001 to June 30, 2009 at a single institution. Patients who required revision for pouch-related problems including band slippage, pouch dilation, and hiatal hernia were studied. Demographic data, body mass index (BMI), percentage excess weight loss (% EWL), and operative details were recorded. Weights were recorded at 12 and 24 months after revision. These were compared with initial weight, weight before revision, and weight in patients who did not have a reoperation. RESULTS:: Of 3876 patients, 390 patients were included in analysis of weight outcomes after revision. The procedure-related mortality was 0%. Early (30-day) complications occurred in 0.5%, late complications (erosion) in 0.5%, and 29 patients (7.4%) required a second revision. For patients undergoing revision, the initial weight was 124.06 +/- 21.28 kg and BMI was 44.80 +/- 6.12 kg/m. At reoperation, weight was 89.18 +/- 20.51 kg, BMI was 32.25 +/- 6.50 kg/m and, %EWL was 54.13 +/- 21.80%. Twelve months postrevision, weight was 92.24 +/- 20.22 kg, BMI was 33.32 +/- 6.41 kg/m, and %EWL was 48.81 +/- 22.71%. Weight was 92.42 +/- 19.91 kg, BMI was 33.53 +/- 6.25 kg/m, and %EWL was 47.50 +/- 22.91% twenty-four months postrevision. CONCLUSIONS:: Reoperation for pouch-related problems after LAGB is safe and effective. Weight loss is maintained after reoperation.

BACKGROUND: This study was designed to examine the characteristics of pedestrian and bicyclist collisions with motor vehicles within New York City's high-density hub. The primary objectives were to map crash locations and to identify hot spots within these injury clusters. The secondary objective was to quantify differences in injury severity based on road type and user behaviors. METHODS: Between December 2008 and June 2011, data were prospectively collected from pedestrians and bicyclists struck by motor vehicles and brought to Bellevue Hospital, a Level 1 trauma center in New York City. Behaviors by cohort (i.e., crossing patterns for pedestrians, riding patterns for bicyclists), Injury Severity Score (ISS), and collision locations were extracted from the database. Analyses of mean ISS were performed using a Student's t test with a p < 0.05 considered significant. Geomaps were created to identify clusters or "hot spots," where higher volumes of crashes occurred over time. Spatial analysis was performed to demonstrate whether these were random events. RESULTS: A total of 1,457 patients (1,075 pedestrians and 382 bicyclists) were enrolled. Collision locations were known for 97.5%. Of the injured pedestrians, those crossing avenues (n = 277) had higher ISSs than those crossing streets (n = 522) (p = 0.01) and were more likely to die (p = 0.002). Pedestrians crossing midblock (n = 185) had higher mean ISSs than those crossing with the signal in the crosswalk (n = 320) (8.12 vs. 5.01, p < 0.001). Based on density mapping, hot spots of pedestrian collisions were detected in midtown Manhattan, while hot spots for bicyclists were detected at bridge and tunnel portals. Spatial analysis indicates that these are not random events (p < 0.05). CONCLUSION: Pedestrians injured on avenues sustained more serious injuries than those injured on narrower streets. A better understanding of collision locations and features may allow for tailored injury prevention strategies. Trauma centers serve an important role in public health surveillance within their local communities. LEVEL OF EVIDENCE: Epidemiologic study, level III.

BACKGROUND: When surgeons decide to become surgeons has important implications. If the decision is made prior to or early in medical school, surgical education can be more focused on surgical diseases and resident skills. METHODS: To determine when surgeons - compared with their nonsurgical colleagues - decide on their medical path, residents in surgery, internal medicine, obstetrics and gynecology, pediatrics, psychiatry, and emergency medicine were surveyed. Timing of residency choice, demographic data, personal goals, and reason for residency choice were queried. RESULTS: A total of 234 residents responded (53 surgical residents). Sixty-two percent of surgeons reported that they were "fairly certain" of surgery before medical school, 13% decided during their preclinical years, and 25% decided during their clerkship years. This compares with an aggregate 40%, 7%, and 54%, respectively, for the other 5 residency specialties. These differences were statistically significant (P = .001). When the 234 residents were asked about their primary motivation for choosing their field, 51% pointed to expected job satisfaction and 44% to intellectual curiosity, and only 3% mentioned lifestyle, prestige, or income. CONCLUSIONS: General surgery residents decide on surgery earlier than residents in other programs. This may be advantageous, resulting in fast-tracking of these medical students in acquiring surgical knowledge, undertaking surgical research, and early identification for surgical residency programs. Surgical training in the era of the 80-hour work week could be enhanced if medical students bring much deeper knowledge of surgery to their first day of residency.

Background. Uterine leiomyosarcoma (LMS) is a rare diagnosis, which is seldom cured when it recurs with metastatic disease. We evaluated patients who present with first time recurrence treated surgically to determine prognostic factors associated with long-term survival. Methods. Over a 16-year period, 41 patients were operated on for recurrent uterine sarcoma. Data examined included patient age, date of initial diagnosis, tumor histology, grade at the initial diagnosis, cytopathology changes in tumor activity from the initial diagnosis, residual tumor after all operations, use of adjuvant therapy, dates and sites of all recurrences, and disease status at last followup. Results. 24 patients were operated for first recurrence of metastatic uterine LMS. Complete tumor resection with histologic negative margins was achieved in 16 (67%) patients. Overall survival was significantly affected by the FIGO stage at the time of the initial diagnosis, the ability to obtain complete tumor resection at the time of surgery for first time recurrent disease, single tumor recurrence, and recurrence greater than 12 months from the time of the initial diagnosis. Median disease-free survival was 14 months and overall survival was 27 months. Conclusion. Our findings suggest that stage 1 at the time of initial diagnosis, recurrence greater than 12 months, isolated tumor recurrence, and the ability to remove ability to perform complete tumor resection at the time of the first recurrence can afford improved survival in selected patientsat the time of the first recurrence can afford improved survival in selected patients.

BACKGROUND: Flexion-extension radiographs are often used to assess for removal of the cervical collar in the setting of trauma. The objective of this study was to evaluate their adequacy. We hypothesized that a significant proportion is inadequate. METHODS: This was a retrospective review of C-spine clearance at a level 1 trauma center. A trauma-trained radiologist interpreted all flexion-extension radiographs for adequacy. Studies performed within 7 days of injury were considered acute. RESULTS: Three hundred fifty-five flexion-extension radiographs were examined. Ninety-five percent% of these studies were inadequate (51% because of the inability to visualize the top of T1, whereas 44% had less than 30 degrees of angulation from neutral). Two hundred ten studies were performed acutely; of these, 97% were inadequate. When performed 7 days or longer from injury, 91% were inadequate. CONCLUSIONS: Injury to the C-spine may harbor significant consequences; therefore, its proper evaluation is critical. The majority of flexion-extension films are inadequate. As such, they should not be included in the algorithm for removal of the cervical collar. If used, adequacy must be verified and supplemental radiographic studies obtained as indicated.

BACKGROUND: While the efficacy of helmet use in the prevention of head injury is well described, helmet use as it relates to bicyclists' behaviors and hospital resource use following injury is less defined. The objective of this study was to compare the demographics, behaviors, hospital workups, and outcomes of bicyclists based on helmet use. METHODS: This study was a subset analysis of a 2.5-year prospective cohort study of vulnerable roadway users conducted at Bellevue Hospital Center, a New York City Level 1 trauma center. All bicyclists with known helmet status were included. Demographics, insurance type, traffic law compliance, alcohol use, Glasgow Coma Scale (GCS) score, initial imaging studies, Abbreviated Injury Scale (AIS) score, Injury Severity Score (ISS), admission status, length of stay, disposition, and mortality were assessed. Information was obtained primarily from patients; witnesses and first responders provided additional information. RESULTS: Of 374 patients, 113 (30.2%) were wearing helmets. White bicyclists were more likely to wear helmets; black bicyclists were less likely (p = 0.037). Patients with private insurance were more likely to wear helmets, those with Medicaid or no insurance were less likely (p = 0.027). Helmeted bicyclists were more likely to ride with the flow of traffic (97.2%) and within bike lanes (83.7%) (p < 0.001 and p = 0.013, respectively). Nonhelmeted bicyclists were more likely to ride against traffic flow (p = 0.003). There were no statistically significant differences in mean GCS score, AIS score, and mean ISS for helmeted versus nonhelmeted bicyclists. Nonhelmeted patients were more likely to have head computed tomographic scans (p = 0.049) and to be admitted (p = 0.030). CONCLUSION: Helmet use is an indicator of safe riding practices, although most injured bicyclists do not wear them. In this study, helmet use was associated with lower likelihood of head CTs and admission, leading to less hospital resource use. Injured riders failing to wear helmets should be targeted for educational programs. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of cleaved caspase-3 and BCL-xL and downregulation of cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHC class II, ICAM-1, B7-1, and B7-2 but increased their production of selected proinflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacity to activate allogeneic as well as Ag-restricted CD4(+) and CD8(+) T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune phenotype and IFN-gamma production. Because endoplasmic reticulum (ER) stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAPK and Akt signaling. Further, lowering ER stress by 4-phenylbutyrate mitigated the enhanced immune stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.