Peter T. Yu

Silencing of RON Receptor Signaling Promotes Apoptosis and Gemcitabine Sensitivity in Pancreatic Cancers

The RON receptor tyrosine kinase is overexpressed in premalignant pancreatic intraepithelial neoplasia (PanIN) and in the majority of pancreatic cancers. In pancreatic cells, RON is an important K-Ras effector and RON ligand can enhance migration/invasion and apoptotic resistance. However, the pathobiological significance of RON overexpression in pancreatic cancers has yet to be fully established. In this study, we demonstrate that RON signaling mediates a unique transcriptional program that is conserved between cultured cells derived from murine PanIN or human pancreatic cancer cells grown as subcutaneous tumor xenografts. In both systems, RON signaling regulates expression of genes implicated in cancer-cell survival, including Bcl-2 and the transcription factors signal transducer and activator of transcription 3 (STAT 3) and c-Jun. shRNA-mediated silencing of RON in pancreatic cancer xenografts inhibited their growth, primarily by increasing susceptibility to apoptosis and by sensitizing them to gemcitabine treatment. Escape from RON silencing was associated with re-expression of RON and/or expression of phosphorylated forms of the related c-Met or epidermal growth factor receptors. These findings indicate that RON signaling mediates cell survival and in vivo resistance to gemcitabine in pancreatic cancer, and they reveal mechanisms through which pancreatic cancer cells may circumvent RON-directed therapies.

IGF1-R signals through the RON receptor to mediate pancreatic cancer cell migration

The RON receptor tyrosine kinase (RTK) is overexpressed in the majority of pancreatic cancers, yet its role in pancreatic cancer cell biology remains to be clarified. Recent work in childhood sarcoma identified RON as a mediator of resistance to insulin-like growth factor receptor (IGF1-R)-directed therapy. To better understand RON function in pancreatic cancer cells, we sought to identify novel RON interactants. Using multidimensional protein identification analysis, IGF-1R was identified and confirmed to interact with RON in pancreatic cancer cell lines. IGF-1 induces rapid phosphorylation of RON, but RON signaling did not activate IGF-1R indicating unidirectional signaling between these RTKs. We next demonstrate that IGF-1 induces pancreatic cancer cell migration that is RON dependent, as inhibition of RON signaling by either shRNA-mediated RON knockdown or by a RON kinase inhibitor abrogated IGF-1 induced wound closure in a scratch assay. In pancreatic cancer cells, unlike childhood sarcoma, STAT-3, rather than RPS6, is activated in response to IGF-1, in a RON-dependent manner. The current study defines a novel interaction between RON and IGF-1R and taken together, these two studies demonstrate that RON is an important mediator of IGF1-R signaling and that this finding is consistent in both human epithelial and mesenchymal cancers. These findings demand additional investigation to determine if IGF-1R independent RON activation is associated with resistance to IGF-1R-directed therapies in vivo and to identify suitable biomarkers of activated RON signaling.

NSQIP reveals significant incidence of death following discharge.

BACKGROUND The rates of post-discharge deaths after surgical procedures are unknown and may represent areas of quality improvement. The NSQIP database captures 30-d outcomes not included within normal administrative databases, and can thus differentiate between in-hospital and post-discharge deaths. METHODS Retrospective analysis of NSQIP from 2005 through 2007. Inclusion criteria were procedures whose median length of stay was greater than 1 d (to exclude outpatient procedures), and whose overall death rate was greater than 2% (to include only procedures where mortality was a significant issue). Procedures where less than 25 deaths occurred were excluded (for sample size concerns). RESULTS There were 363,897 patients with 2236 different CPT codes captured in NSQIP. There were 6395 deaths; among them, 1486 (23.2%) occurred after discharge. Thirty-eight CPT codes met the analysis threshold. In two of the CPT codes, there were no post-discharge deaths (repair of ruptured abdominal aortic aneurysm [AAA], repair of ruptured AAA involving iliacs). In the other 36 CPT codes, the proportion of deaths occurring after discharge ranged from 6.3% (repair of thoracoabdominal aneurysm) to 50.0% (femoral-distal bypass with vein). The highest percentage of post-discharge mortality occurs on d 1 after discharge. Fifty percent of post-discharge mortality occurs by d 7; 95% occurs by d 21. CONCLUSION Approximately one-fourth of postoperative deaths occur after hospital discharge. There is significant variation across surgical procedures in the likelihood of postoperative deaths occurring after discharge. These data indicate a need for closer and more frequent monitoring of post-surgical patients. These data also call into question conclusions drawn from hospital-based outcomes analyses for at least some key diseases/procedures. This analysis demonstrates the power of the risk-adjusted 30-d follow-up NSQIP data, but perhaps more importantly, the responsibility of surgeons to monitor and optimize the discharge process.

Delayed presentation of traumatic infrapopliteal arteriovenous fistula and pseudoaneursym in a 10-year-old boy managed by coil embolization.

Blunt traumatic arteriovenous fistulae of the extremities are rare in children. We report the case of a 10-year-old boy with a traumatic infrapopliteal arteriovenous fistula and concomitant pseudoaneurysm diagnosed 2 months after he was struck by a car. It was definitively managed with coil embolization. Postprocedure, the vascular anatomy of the patients right calf was well preserved. He had complete resolution of his symptoms immediately after the intervention and continues to do well 6 months later.

Can universal coverage eliminate health disparities? Reversal of disparate injury outcomes in elderly insured minorities

BACKGROUND Health outcome disparities in racial minorities are well documented. However, it is unknown whether such disparities exist among elderly injured patients. We hypothesized that such disparities might be reduced in the elderly owing to insurance coverage under Medicare. We investigated this issue by comparing the trauma outcomes in young and elderly patients in California. METHODS A retrospective analysis of the California Office of Statewide Health Planning and Development hospital discharge database was performed for all publicly available years from 1995 to 2008. Trauma admissions were identified by International Classification of Disease, Ninth Revision, primary diagnosis codes from 800 to 959, with certain exclusions. Multivariate analysis examined the adjusted risk of in-hospital mortality in young (<65 y) and elderly (≥65 y) patients, controlling for age, gender, injury severity as measured by the survival risk ratio, Charlson comorbidity index, insurance status, calendar year, and teaching hospital status. RESULTS A total of 1,577,323 trauma patients were identified. Among the young patients, the adjusted odds ratio of death relative to non-Hispanic whites for blacks, Hispanics, Asians, and Native Americans/others was 1.2, 1.2, 0.90, and 0.78, respectively. The corresponding adjusted odds ratios of death for elderly patients were 0.78, 0.87, 0.92, and 0.61. CONCLUSIONS Young black and Hispanic trauma patients had greater mortality risks relative to non-Hispanic white patients. Interestingly, elderly black and Hispanic patients had lower mortality risks compared with non-Hispanic whites.

The battle of the sexes: women win out in gastrointestinal surgery.

BACKGROUND Women have been shown to have worse outcomes compared with men after cardiac surgery, but fare better after traumatic injury. No study considers the impact of gender on outcomes after major gastrointestinal surgery. We hypothesize that the physiologic insults of a major abdominal operation are similar to an injury model; therefore, women will have improved outcomes. MATERIAL AND METHODS We performed a retrospective review of the NIS database from 1998 to 2007. Patients undergoing major gastrointestinal surgery were identified by ICD-9 procedure codes: esophageal (42.4), gastric (43.5-43.9), small intestine (45.6), large intestine (45.7-45.8 and 17.3), rectal (48.4-48.6), hepatic (50.2-50.3), biliary (51.3 and 51.6), and pancreatic (52.5-52.7). Exclusion criteria included age over 60 y and under 18 y, multiple operations, and a sexual developmental disorder (25.52, 75.27, and 25.9). The primary outcome measure was in-hospital death. RESULTS A total of 307,124 patients were identified, of whom 50.3% were women. Overall, there were 6574 (2.14%) deaths; 2.45% of men and 1.84% of women died (P < 0.001). In multivariate analysis, women were 21.1% less likely to die than men (OR = 0.789, 95% CI = 0.74-0.84). When subset analysis was performed, women had improved mortality in the following types of surgery: gastric (OR = 0.751, 95% CI = 0.60-0.94), small intestine (OR = 0.704, 95% CI = 0.63-0.79), large intestine (OR = 0.845, 95% CI = 0.77--0.93), hepatic (OR = 0.562, 95% CI = 0.41-0.77), and pancreatic (OR = 0.658, 95% CI = 0.49-0.89, see Fig. 1). CONCLUSIONS Our study demonstrates that women may have improved outcomes after some types of major gastrointestinal surgery; however, the mechanism by which this occurs is unclear. Future studies are needed to further evaluate this interesting phenomenon.

New Disposable Transanal Endoscopic Surgery Platform: Longer Channel, Longer Reach

Background: Transanal endoscopic surgical (TES) resection using rigid transanal platforms (TEM, TEO) is associated with improved outcomes compared to traditional transanal excision (TAE) of rectal lesions. An alternative technique using a disposable single incision surgery platform was developed in 2009, transanal minimally invasive surgery (TAMIS), resulting in a surge in interest and access to transanal access platforms to perform TES. However, compared to rigid transanal access platforms, the disposable platforms do not facilitate internal rectal retraction and have limited proximal reach. A new long channel disposable transanal access platform has been developed (15 cm in length, 4cm in width) thereby facilitating endoluminal surgical access to the upper rectum and rectosigmoid colon.Methods: This is a retrospective case series report. Patient demographics and peri-operative outcome variables were recorded. The Gelpoint Path Long Channel was utilized in three patients with proximal rectal lesions that were not accessible using a standard disposable transanal access platform.Results: Three patients underwent TES excision of rectal adenomas using a long channel, disposable, transanal access platform. All patients were female, aged 51-53, BMI 23-32kg/m^2. The tumor size ranged from 2.4-8.5cm, 15-100% circumference, and proximal location from the dentate line ranged from 9-11cm. Final pathology revealed adenoma with negative margins in all three cases. The hospital length of stay ranged from 1-3 days and there were no perioperative complications. None of the patients have developed a local recurrence during the follow up period ranging from 5-11 months.Conclusions: The new long channel, disposable, transanal access platform facilitates transanal endoluminal surgical removal of lesions in the mid to upper rectum that may be difficult to reach using the standard disposable transanal access devices. We have successfully achieved 100% margin negative rate using this new device in this small series of patients with proximal rectal adenomas.

Can Hospitals "Game the System" by Avoiding High-Risk Patients?

BACKGROUND It has been suggested that implementation of quality-improvement benchmarking programs can lead to risk-avoidance behaviors in some physicians and hospitals in an attempt to improve their rankings, potentially denying patients needed treatment. We hypothesize that avoidance of high-risk patients will not change risk-adjusted rankings. STUDY DESIGN We conducted a simulation analysis of 6 complex operations in the Nationwide Inpatient Sample, including abdominal aortic aneurysm repair, aortic valve replacement, coronary artery bypass grafting, percutaneous coronary intervention, esophagectomy, and pancreatic resection. Primary outcomes included in-hospital mortality. Hospitals were ranked into quintiles based on observed-to-expected (O/E) mortality ratios, with their expected mortalities calculated based on models generated from the previous 3 years. Half of the hospitals were then randomly selected to undergo risk avoidance by avoiding 25% of patients with higher than median risks (ie, Charlson, Elixhauser, age, minority, or uninsured status). Their new O/E ratios and hospital-rank categories were compared with their original values. RESULTS A total of 2,235,298 patients were analyzed, with an overall observed mortality rate of 1.9%. Median change in O/E ratios across all simulations was zero, and O/E ratios did not change in 97.5% to 99.3% of the hospitals, depending on the risk definitions. Additionally, 70.5% to 98.0% of hospital rankings remained unchanged, 1.3% to 13.1% of hospital rankings improved, and 0.7% to 14.3% of hospital rankings worsened after risk avoidance. CONCLUSIONS Risk-adjusted rankings of hospitals likely cannot be changed by simply avoiding high-risk patients. In the minority of scenarios in which risk-adjusted rankings changed, they were as likely to improve as worsen after risk avoidance.

607 Etamis: Transanal Minimally Invasive Surgical Submucosal Excision of a Large, Circumferential, Rectal Adenoma With Endoscopic Visualization

Surgical resection for benign subepithelial tumors near the gastroesophageal junction is difficult, often leading to esophagectomy. Here we demonstrate the feasibility of a novel technique of dual endoscopic resection using retroflexed standard adult upper endoscope and second smaller caliber (baby) endoscope to resect benign GE junction leiomyomas (26 cm size) in four patients. Maneuvering the small caliber endoscope allowed offaxis retraction of the mass while the adult endoscope was used to carry out the dissection from the submucosal tissue. Our experience highlights the feasibility of this minimally invasive approach by enabling triangulation using endoscopic tools.