Todd D. Francone

L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition

Activating mutations in either BRAF or NRAS are seen in a significant number of malignant melanomas, but their incidence appears to be dependent to ultraviolet light exposure. Thus, BRAF mutations have the highest incidence in non‐chronic sun damaged (CSD), and are uncommon in acral, mucosal and CSD melanomas. More recently, activating KIT mutations have been described in rare cases of metastatic melanoma, without further reference to their clinical phenotypes. This finding is intriguing since KIT expression is downregulated in most melanomas progressing to more aggressive lesions. In this study, we investigated a group of anal melanomas for the presence of BRAF, NRAS, KIT and PDGFRA mutations. A heterozygous KIT exon 11 L576P substitution was identified in 3 of 20 cases tested. The 3 KIT mutation‐carrying tumors were strongly immunopositive for KIT protein. No KIT mutations were identified in tumors with less than 4+ KIT immunostaining. NRAS mutation was identified in one tumor. No BRAF or PDGFRA mutations were identified in either KIT positive or negative anal melanomas. In vitro drug testing of stable transformant Ba/F3 KITL576P mutant cells showed sensitivity for dasatinib (previously known as BMS‐354825), a dual SRC/ABL kinase inhibitor, and imatinib. However, compared to an imatinib‐sensitive KIT mutant, dasatinib was potent at lower doses than imatinib in the KITL576P mutant. These results suggest that a subset of anal melanomas show activating KIT mutations, which are susceptible for therapy with specific kinase inhibitors.

MET Expression and Amplification in Patients with Localized Gastric Cancer

Background: MET, the receptor for hepatocyte growth factor, has been proposed as a therapeutic target in gastric cancer. This study assessed the incidence of MET expression and gene amplification in tumors of Western patients with gastric cancer. Methods: Tumor specimens from patients enrolled on a preoperative chemotherapy study (NCI 5700) were examined for the presence of MET gene amplification by FISH, MET mRNA expression by quantitative PCR, MET overexpression by immunohistochemistry (IHC), and for evidence of MET pathway activation by phospho-MET (p-MET) IHC. Results: Although high levels of MET protein and mRNA were commonly encountered (in 63% and 50% of resected tumor specimens, respectively), none of these tumors had MET gene amplification by FISH, and only 6.6% had evidence of MET tyrosine kinase activity by p-MET IHC. Conclusions: In this cohort of patients with localized gastric cancer, the presence of high MET protein and RNA expression does not correlate with MET gene amplification or pathway activation, as evidenced by the absence of amplification by FISH and negative p-MET IHC analysis. Impact: This article shows a lack of MET amplification and pathway activation in a cohort of 38 patients with localized gastric cancer, suggesting that MET-driven gastric cancers are relatively rare in Western patients. Cancer Epidemiol Biomarkers Prev; 20(5); 1021–7. ©2011 AACR.

A laparoscopic approach does reduce short-term complications in patients undergoing ileal pouch-anal anastomosis.

BACKGROUND: Studies to date examining the impact of laparoscopy in the IPAA have failed to demonstrate a significant, consistent benefit in terms of a reduction in short-term morbidity or length of stay. OBJECTIVE: The aim of this study was to establish the impact of the operative approach (laparoscopic or open) on outcomes after IPAA formation. DESIGN, SETTING, AND PATIENTS: With use of the American College of Surgeons National Surgical Quality Improvement Program participant use file (2005–2008), the records of patients who underwent open or laparoscopic IPAA with diverting ileostomy were examined. MAIN OUTCOME MEASURES: Risk-adjusted 30-day outcomes and length of stay were assessed by use of regression modeling, adjusting for patient characteristics, comorbidities, and operative approach. RESULTS: Six hundred seventy-six cases were included, of which 339 (50.1%) were laparoscopic procedures. After adjustment, a laparoscopic approach was associated with a lower rate of major (OR = 0.67, 95% CI: 0.45–0.99, P = .04) and minor (OR = 0.44, 95% CI: 0.27–0.70, P = .01) complications. Laparoscopy was not associated with a significant reduction in length of postoperative stay compared with open pouch formation (laparoscopic vs open approach, −0.05 ± 0.30 d (P = .87)). LIMITATIONS: The sampling strategy used by the National Surgical Quality Improvement Program means that only a proportion of all relevant cases would have been analyzed and no data are available about the potential impact of surgeon experience on outcome. CONCLUSIONS: A laparoscopic approach to ileal pouch formation was associated with a significant reduction in both major and minor complications compared with the traditional open approach. Given the high financial costs associated with complications arising from this procedure, this study provides support for the adoption of the laparoscopic approach in the formation of an IPAA.

Considerations and complications in patients undergoing ileal pouch anal anastomosis.

Total proctocolectomy with ileal pouch anal anastomosis (IPAA) preserves fecal continence as an alternative to permanent end ileostomy in select patients with ulcerative colitis and familial adenomatous polyposis. The procedure is technically demanding, and surgical complications may arise. This article outlines both the early and late complications that can occur after IPAA, as well as the workup and management of these potentially morbid conditions.

Ultimate Fate of the Leaking Intestinal Anastomosis: Does Leak Mean Permanent Stoma?

BackgroundThe ultimate fate of the leaking intestinal anastomosis is unknown. We sought to analyze long-term outcomes of anastomotic leak with an emphasis on identifying the likelihood of re-establishing intestinal continuity and the potential for releak with corrective surgery.MethodsAll consecutive subjects treated for clinical anastomotic leak from January 2001 through December 2007 were retrospectively reviewed. Patients were stratified by management of leak: (1) drainage alone, (2) proximal loop diversion, (3) repair/revision without diversion, (4) end stoma, or (5) tube enterostomy. We then determined management of anastomotic leak, mortality, corrective procedures, releak, and re-establishment of intestinal continuity.ResultsIn a database of 2,627 intestinal procedures, 79 patients had 88 anastomotic leaks with a final overall mortality of 10.1%. The aggregate rate of re-establishment of intestinal continuity was lowest for the patients treated by end stoma (44.4%) as compared to other initial management options (p < 0.01). Of the patients who survived their initial anastomotic leak, 20.5% had another leak (releak).ConclusionsPatients who underwent resection of the leaking anastomosis and end stoma or proximal loop diversion have a high rate of long-term fecal diversion. The proportion of patients who experience an anastomotic releak is substantial following further corrective surgery to re-establish intestinal continuity.

Novel xenograft model expressing human hepatocyte growth factor shows ligand-dependent growth of c-Met–expressing tumors

c-Met, a receptor tyrosine kinase responsible for cellular migration, invasion, and proliferation, is overexpressed in human cancers. Although ligand-independent c-Met activation has been described, the majority of tumors are ligand dependent and rely on binding of hepatocyte growth factor (HGF) for receptor activation. Both receptor and ligand are attractive therapeutic targets; however, preclinical models are limited because murine HGF does not activate human c-Met. The goal of this study was to develop a xenograft model in which human HGF (hHGF) is produced in a controllable fashion in the mouse. Severe combined immunodeficient mice were treated with adenovirus encoding the hHGF transgene (Ad-hHGF) via tail vein injection, and transgene expression was determined by the presence of hHGF mRNA in mouse tissue and hHGF in serum. Ad-hHGF administration to severe combined immunodeficient mice resulted in hHGF production that was (a) dependent on quantity of virus delivered; (b) biologically active, resulting in liver hypertrophy; and (c) sustainable over 40 days. In this model, the ligand-dependent human tumor cell line SW1417 showed enhanced tumor growth, whereas the ligand-independent cell lines SW480 and GTL-16 showed no augmented tumor growth. This novel xenograft model is ideal for investigating c-Met/HGF–dependent human tumor progression and for evaluating c-Met targeted therapy. [Mol Cancer Ther 2007;6(4):1460–6]

The impact of pregnancy on surgical Crohn disease: an analysis of the Nationwide Inpatient Sample

BACKGROUND The impact of pregnancy on the course of Crohn disease is largely unknown. Retrospective surveys have suggested a variable effect, but there are limited population-based clinical data. We hypothesized pregnant women with Crohn disease will have similar rates of surgical disease as a nonpregnant Crohn disease cohort. MATERIAL AND METHODS International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify female Crohn patients from all patients admitted using the Nationwide Inpatient Sample (1998-2009). Women were stratified as either pregnant or nonpregnant. We defined Crohn-related surgical disease as peritonitis, gastrointestinal hemorrhage, intra-abdominal abscess, toxic colitis, anorectal suppuration, intestinal-intestinal fistulas, intestinal-genitourinary fistulas, obstruction and/or stricture, or perforation (excluding appendicitis). RESULTS Of the 92,335 women admitted with a primary Crohn-related diagnosis, 265 (0.3%) were pregnant. Pregnant patients were younger (29 versus 44 y; P<0.001) and had lower rates of tobacco use (6% versus 13%; P<0.001). Pregnant women with Crohn disease had higher rates of intestinal-genitourinary fistulas (23.4% versus 3.0%; P<0.001), anorectal suppuration (21.1% versus 4.1%; P<0.001), and overall surgical disease (59.6% versus 39.2%; P<0.001). On multivariate logistic regression analysis controlling for malnutrition, smoking, age, and prednisone use, pregnancy was independently associated with higher rates of anorectal suppuration (odds ratio [OR], 5.2; 95% confidence interval [CI], 3.8-7.0; P<0.001), intestinal-genitourinary fistulas (OR, 10.4; 95% CI, 7.8-13.8; P<0.001), and overall surgical disease (OR, 2.9; 95% CI, 2.3-3.7; P<0.001). CONCLUSIONS Pregnancy in women with Crohn disease is a significant risk factor for Crohn-related surgical disease, in particular, anorectal suppuration and intestinal-genitourinary fistulas.

Crohn's disease and pregnancy: the impact of perianal disease on delivery methods and complications.

BACKGROUND: The optimal delivery method in patients with Crohn’s disease is unknown, and there is no large-scale evidence on which to base decisions. OBJECTIVE: The aim of this study was to compare delivery methods and outcomes in patients with and without Crohn’s disease. DESIGN AND PATIENTS: The Nationwide Inpatient Sample and International Classification of Diseases, Ninth Revision codes were used to identify childbirth deliveries. Patients were stratified by the presence or absence of Crohn’s disease and perianal disease (anorectal fistula or abscess, rectovaginal fistula, anal fissure, and anal stenosis). SETTINGS: A large population-cohort database was used for the analysis. MAIN OUTCOME MEASURES: The primary outcomes measured were cesarean delivery and perineal lacerations. RESULTS: Of 6,794,787 pregnant women who delivered, 2882 had a diagnosis of Crohn’s disease. Rates of cesarean delivery were higher in patients who had Crohn’s disease with (83.1%) and without (42.8%) perianal disease in comparison with patients who did not have Crohn’s disease with (38.9%) and without (25.6%) perianal disease (p < 0.001). Rates of 4th degree perineal lacerations were similar between patients who had or did not have Crohn’s disease without perianal disease (1.4% vs 1.3%), but these rates increased significantly in patients with perianal disease (12.3%, p < 0.001). On multivariate analysis, perianal disease (OR, 10.9; 95% CI, 8.3–4.1; p < 0.001) and smoking (OR, 1.6; 95% CI, 1.5–1.7; p < 0.001) were independently associated with higher rates of 4th degree laceration. Crohn’s disease was not independently associated with 4th degree laceration. LIMITATIONS: This was a retrospective study with the inherent limitations of large databases. CONCLUSIONS: Patients with Crohn’s disease have higher rates of cesarean delivery. Perianal disease predicts severe perineal laceration independent of the presence of Crohn’s disease. In the absence of perianal disease, the method of delivery in women with Crohn’s disease should be predicated on obstetric indication.

Do patient safety indicators explain increased weekend mortality

BACKGROUND We sought to determine the differential role of patient safety indicator (PSI) events on mortality after weekend as compared with weekday admission. MATERIALS AND METHODS We evaluated Agency for Healthcare Research and Quality PSI events within a cohort of patients with nonelective admissions. First, we identified all patients with a PSI based on day of admission (weekend versus weekday). Then, we evaluated the outcome of mortality after each PSI event. Finally, we entered age, sex, race, median household income, payer information, and Charlson comorbidity scores in regression models to develop risk ratios of weekend to weekday PSI events and mortality. RESULTS There were 28,236,749 patients evaluated with 428,685 (1.5%) experiencing one or more PSI events. The rate of PSI was the same for patients admitted on weekends as compared to weekdays (1.5%). However, the risk of mortality was 7% higher if a PSI event occurred to a patient admitted on a weekend as compared with a weekday. In addition, compared to patients admitted on weekdays, patients admitted on weekends had a 36% higher risk of postoperative wound dehiscence, 19% greater risk of death in a low-mortality diagnostic-related group, 19% increased risk of postoperative hip fracture, and 8% elevated risk of surgical inpatient death. CONCLUSIONS Risk adjusted data reveal that PSI events are substantially higher among patients admitted on weekends. The considerable differences in death after PSI events in patients admitted on weekends as compared with weekdays indicate that responses to adverse events may be less effective on weekends.

Quality Improvement Initiatives in Colorectal Surgery: Value of Physician Feedback

BACKGROUND: The impact of process improvement through surgeon feedback on outcomes is unclear. OBJECTIVE: We sought to evaluate the effect of biannual surgeon-specific feedback on outcomes and adherence to departmental and Surgical Care Improvement Project process measures on colorectal surgery outcomes. DESIGN: This was a retrospective analysis of prospectively collected 100% capture surgical quality improvement data. SETTING: This study was conducted at the department of colorectal surgery at a tertiary care teaching hospital from January 2008 through December 2013. MAIN OUTCOME MEASURES: Each surgeon was provided with biannual feedback on process adherence and surgeon-specific outcomes of urinary tract infection, deep vein thrombosis, surgical site infection, anastomotic leak, 30-day readmission, reoperation, and mortality. We recorded adherence to Surgical Care Improvement Project process measures and departmentally implemented measures (ie, anastomotic leak testing) as well as surgeon-specific outcomes. RESULTS: We abstracted 7975 operations. There was no difference in demographics, laparoscopy, or blood loss. Adherence to catheter removal increased from 73% to 100% (p < 0.0001), whereas urinary tract infection decreased 52% (p < 0.01). Adherence to thromboprophylaxis administration remained unchanged as did the deep vein thrombosis rate (p = not significant). Adherence to preoperative antibiotic administration increased from 72% to 100% (p < 0.0001), whereas surgical site infection did not change (7.6%–6.6%; p = 0.3). There were 2589 operative encounters with anastomoses. For right-sided anastomoses, the proportion of handsewn anastomoses declined from 19% to 1.5% (p < 0.001). For left-sided anastomoses, without diversion, anastomotic leak testing adherence increased from 88% to 95% (p < 0.01). Overall leak rate decreased from 5.2% to 2.9% (p < 0.05). LIMITATIONS: Concurrent process changes make isolation of the impact from individual process improvement changes challenging. CONCLUSIONS: Nearly complete adherence to process measures for deep vein thrombosis and surgical site infection did not lead to measureable outcomes improvement. Process measure adherence was associated with decreased rate of anastomotic leak and urinary tract infection. Biannual surgeon-specific feedback of outcomes was associated with improved process measure adherence and improvement in surgical quality.