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Selwyn M Vickers

Publications and source records attributed to Selwyn M Vickers.

At least 19 recordsLinked to original sources
PubMed2006

Prognostic factors for survival in pancreatic cancer: a population-based study.

BACKGROUND: We performed a population-based study of patients from the deep South of the United States (with >25% black residents) to evaluate the survival rate of patients with pancreatic cancer. Our aims were to analyze prognostic factors influencing pancreatic cancer survival using the population-based Alabama Statewide Cancer Registry and to determine whether race/ethnicity is an independent determinant of outcomes in patients with pancreatic cancer. METHODS: Eligible participants included all persons diagnosed with pancreatic cancer from 1996 to 2000 and reported to the Alabama Statewide Cancer Registry. Survival time was calculated from time of diagnosis to death for pancreatic cancer deaths or to date of last contact or death from other causes for censored participants. Risk factors associated with survival were assessed with the Kaplan-Meier survival method and the log-rank test. Demographic, tumor, and treatment variables were assessed using the Cox proportional hazards model. RESULTS: Of 2230 patients, the median age at diagnosis was 71 years and the male to female ratio was approximately 1:1. Seventy-three percent of patients were white, and 27% of patients were black. The distribution by stage was 12.5% localized disease, 29.6% regional, 35.3% distant, and 22.6% unstaged. The median survival time for all patients was .39+/-.01 years. Patients who underwent surgical treatment were less likely to die of pancreatic cancer (hazard ratio, .48; 95% confidence interval, .41-.56). Similarly, patients who underwent either chemotherapy or radiation therapy had improved survival rates (hazard ratio, .62; 95% confidence interval, .53-.73). Across all stages, black patients were significantly less likely to receive chemotherapy compared with white patients (26.7% vs 32.3%, P=.02), and were less likely to receive surgical intervention (14.02% vs 17.0%, P=.09). When examining patients who were offered their therapy of choice but refused, we found across all stages that a greater proportion of black patients refused therapies versus whites: 5.6% versus 2.9% (P=.02) for chemotherapy, 3.8% versus 1.6% (P=.04) for radiation, and 9.0% versus 3.3% (P=.001 for surgery). The Cox proportional hazard model showed no effect of race on overall survival time while controlling for stage at presentation, type of therapy received, age at diagnosis, and site of primary tumor. CONCLUSIONS: Survival in patients with pancreatic cancer remains dismal. Tumor characteristics and treatment factors are related directly to survival time in patients with pancreatic cancer. Black patients were less likely to receive therapy but also were more likely to refuse the indicated therapy. Factors leading to racial disparity in the treatment of pancreatic cancer warrant further investigation.

Adult↗
PubMed2006

Outcomes of cholecystectomy after endoscopic sphincterotomy for choledocholithiasis.

Laparoscopic cholecystectomy (LC) for treatment of symptomatic common bile duct stones (CBDS) after endoscopic sphincterotomy (ES) is associated with increased conversion and complications compared with other indications. We examined factors associated with conversion and complications of LC after ES. A retrospective study of 32 patients undergoing ES for CBDS followed by cholecystectomy was undertaken. Surgical outcomes for this group were compared with a control population of 499 LCs for all other indications. Factors associated with open cholecystectomy and complications in the ES group were analyzed. Patients undergoing LC preceded by ES had a significantly higher complication (odds ratio [OR] = 7.97; 95% CI, 2.84-22.5) and conversion rate (OR = 3.45; 95% CI, 1.56-7.66) compared with LC for all other indications. Pre-ES serum bilirubin greater than 5 mg/dL was predictive of conversion (positive predictive value = 63%, P < 0.005). Patients with symptomatic CBDS that undergo LC after ES have higher complication and conversion rates than patients undergoing LC without ES. Pre-ES serum bilirubin is useful in identifying patients who may not have a successful laparoscopic approach at cholecystectomy.

Alkaline Phosphatase↗
PubMed2006

Treatment with gemcitabine and TRA-8 anti-death receptor-5 mAb reduces pancreatic adenocarcinoma cell viability in vitro and growth in vivo.

Gemcitabine is a first line agent for pancreatic cancer, but yields minimal survival benefit. This study evaluated in vitro and in vivo effects of a monoclonal antibody (TRA-8) to human death receptor 5, combined with gemcitabine, using two human pancreatic cancer cell lines, S2VP10 and MIA PaCa-2. A subcutaneous model of pancreatic cancer was employed to test in vivo efficacy. S2VP10 and MIA PaCa-2 cells were treated with varying doses of gemcitabine and TRA-8. Cell viability and apoptosis were determined with an adenosine triphosphate assay and annexin V staining, respectively. Mitochondrial membrane destabilization was evaluated with fluorescence-activated cell sorting analysis of JC-1 stained cells. Caspase activation was evaluated by Western blot analysis. MIA PaCa-2 subcutaneous xenografts in athymic nude mice were evaluated for response to treatment with 200 mug of TRA-8 (intraperitoneal on days 9, 13, 16, 20, 23, and 27 postimplant) and 120 mg/kg gemcitabine (I.P. on days 10, 17, and 24). Tumor growth was measured with calipers. MIA PaCa-2 and S2VP10 cells receiving combination treatment with TRA-8 and gemcitabine demonstrated enhanced cytotoxicity, annexin V staining, and mitochondrial destabilization compared to either agent alone. Combination treatment produced enhanced caspase-3 and -8 activation in both cell lines compared with either agent alone. In vivo studies demonstrated mean subcutaneous tumor surface area (produce of two largest diameters) doubling times of 38 days untreated, 32 days gemcitabine, 49 days TRA-8, and 64 days combination treatment. TRA-8 is an apoptosis-inducing agonistic monoclonal antibody that produced synergistic cytotoxicity in combination with gemcitabine in vitro through enhanced caspase activation. These findings, with substantial inhibition of tumor growth in a mouse pancreatic cancer xenograft model receiving combination therapy, are encouraging for anti-death receptor therapy in the treatment of pancreatic cancer.

Animals↗
PubMed2006

Incidence of vitamin deficiency after laparoscopic Roux-en-Y gastric bypass in a university hospital setting.

Vitamin deficiency after gastric bypass surgery is a known complication. The purpose of this study was to measure the incidence of vitamin deficiency after laparoscopic Roux-en-Y gastric bypass in a university hospital setting. All patients who underwent laparoscopic Roux-en-Y gastric bypass from January 2002 to December 2004 and completed a 1- and 2-year follow-up after surgery were selected. Of the total 493 patients, 318 (65%) had vitamin results at 1-year follow-up. Of the 366 eligible for the 2-year follow-up, 141 (39%) had vitamin results. Patients were further grouped based on gender, race, and Roux limb length, and incidence of vitamin deficiencies were studied. The incidence of vitamin A (retinol) deficiency was 11 per cent, vitamin C was 34.6 per cent, vitamin D25OH was 7 per cent, vitamin B1 was 18.3 per cent, vitamin B2 was 13.6 per cent, vitamin B6 was 17.6 per cent, and vitamin B12 was 3.6 per cent 12 months after surgery. There was no statistical difference in the incidence of vitamin deficiencies between 1 and 2 years. In univariate and multivariate logistic regression of 1- and 2-year follow up, black patients (vitamins A, D, and B1 for 1 year and B1 and B6 for 2 years) and women (vitamin C at 1 year) were more likely to have vitamin deficiencies. Vitamin deficiencies after laparoscopic Roux-en-Y gastric bypass are more common and involve more vitamins, even those that are water soluble, than previously appreciated. Black patients tend to have more deficiencies than other groups. The bariatric surgeon should be committed to the long-term follow-up and care of these patients. Further prospective and randomized studies are necessary to provide appropriate guidelines for supplementation.

Adult↗
PubMed2006

Biomarkers in Diagnosis of pancreatic carcinoma in fine-needle aspirates.

This study was undertaken to determine whether recently identified proteins could be translated to clinical practice as markers to distinguish pancreatic adenocarcinoma from chronic pancreatitis on fine-needle aspirate (FNA) samples. Resected pancreatic tissue sections (n = 40) and FNA samples (n = 65) were stained for clusterin-beta, MUC4, survivin, and mesothelin. For each biomarker, the staining patterns in adenocarcinoma and in reactive ductal epithelium were evaluated and compared. Clusterin-beta stained reactive ductal epithelium significantly more frequently than pancreatic adenocarcinoma (P < .001). In comparison, MUC4 and mesothelin were expressed more frequently in pancreatic adenocarcinoma on tissue sections. Positive staining for MUC4 (91% vs 0%; P < .001) and mesothelin (62% vs 0%; P = .01) and absence of staining for clusterin-beta (90% vs 7%; P < .001) were noted significantly more frequently in adenocarcinoma cells than in reactive cells in FNA samples. Clusterin-beta and MUC4 can help distinguish reactive ductal epithelial cells from the cells of pancreatic adenocarcinoma in FNA samples.

Adenocarcinoma↗
PubMed2006

Multiple gene expression analyses in paraffin-embedded tissues by TaqMan low-density array: Application to hedgehog and Wnt pathway analysis in ovarian endometrioid adenocarcinoma.

Recent studies have shown the hedgehog and Wnt families of signaling proteins to be associated with tumor initiation, growth, and survival. However, these pathways remain unexplored in ovarian endometrioid adenocarcinoma (OEA). Here, we describe a novel TaqMan low-density array to examine the expression of 26 and 20 genes in the hedgehog and Wnt pathways, respectively, in six matched snap-frozen and formalin-fixed, paraffin-embedded (FPE) OEA specimens. Expression values were normalized to uninvolved ovarian epithelium. Gene expression in matched frozen and FPE tissues demonstrated significant concordance (r = 0.92, P < 0.0001). However, comparison of amplified and unamplified RNA from frozen OEA tissues revealed an altered molecular profile in amplified RNA. Amplification of RNA from FPE tissues was not successful. The expression of Desert hedgehog (DHH), Indian hedgehog (IHH), Hedge-hog interacting protein (HHIP), Wnt10B, Wnt9B, and Wnt inhibitory factor (WIF1) were tumor-specific with no detectable expression in normal ovarian epithelium. In addition, several genes were significantly (P < 0.025) down-regulated in OEA, including cyclin E2, Porcupine, c-Myc, and Axin 2 (4.8-, 3.6-, 2.9-, and 1.9-fold, respectively). TaqMan low-density array provides an effective multivariate technique for examining gene expression in RNA isolated from either snap-frozen or archival FPE tissues and can identify tumor-specific genes, possibly leading to novel treatments.

Animals↗
PubMed2005

Antitumor efficacy of capecitabine and celecoxib in irradiated and lead-shielded, contralateral human BxPC-3 pancreatic cancer xenografts: clinical implications of abscopal effects.

PURPOSE: X-ray therapy (XRT) remains one of the major modalities used to treat patients diagnosed with locally advanced pancreatic adenocarcinoma. However, the effect of XRT on metastatic tumors outside the field of irradiation (abscopal effect) remains largely unknown. In the current study, we examined the effect of XRT alone and in combination with capecitabine and/or celecoxib in both irradiated and lead-shielded contralateral BxPC-3 pancreatic cancer xenografts. This chemoradiation regimen was chosen based on our molecular analysis of pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Athymic mice were injected bilaterally with BxPC-3 cells and treatment was initiated 28 days postimplant. During XRT (2 Gy for 5 consecutive days, administered on days 0 and 24), one flank was irradiated whereas the rest of the body (including the contralateral tumor) was lead shielded. Capecitabine (350 mg/kg) was administered on days 0 to 13 and 24 to 37. Celecoxib was initiated in the diet at 100 ppm (equivalent to 20 mg/kg/d p.o.) and administered throughout the study. RESULTS: In irradiated xenografts, capecitabine and XRT showed synergistic anitiumor efficacy (P=0.008), which was further improved with the addition of celecoxib (P<0.001). In contralateral shielded xenografts, abscopal effects were observed. Whereas monotherapy with XRT showed significant reduction in tumor area in irradiated xenografts, growth was promoted by 23% (P<0.001) in contralateral lead-shielded tumors in the same animals relative to untreated tumors. Interestingly, synergistic antiproliferative efficacy occurred in these contralateral tumors when capecitabine was administered (P<0.001), despite being outside the irradiated field. The addition of celecoxib further inhibited tumor growth (P<0.001). This trimodal combination most effectively stabilized disease in both shielded and irradiated tumors; however, tumor eradication was not observed. There were no significant changes in thymidine phosphorylase, dihydropyrimidine dehydrogenase, or cyclooxygenase-2 mRNA levels in irradiated or lead-shielded tumors, suggesting that efficacy cannot be predicted solely from these previously identified indicators of response. Immunohistochemistry examining the proliferation marker Ki-67 showed concordance with tumor response in both irradiated and contralateral shielded xenografts. CONCLUSIONS: These results have implications in the rational design of treatment paradigms for pancreatic cancer where metastatic disease remains the primary cause of patient morbidity and abscopal effects in tumors outside the field of irradiation may affect tumor response.

5'-Nucleotidase↗
PubMed2005

Oncolytic adenoviral therapy in gallbladder carcinoma.

BACKGROUND: Oncolytic adenoviral therapy is a promising new approach for cancer treatment. The aim of this study was to improve the conditionally replicative adenoviruses (CRAds) for gallbladder cancer therapy by modifying the fiber-knob region for infectivity enhancement and by incorporating tumor-specific promoters (TSPs) for enhanced specificity. METHODS: For promoter-controlled replication, in vitro efficacy of eight TSPs was investigated in two gallbladder cancer cell lines (NOZ and OCUG-1). Infectivity enhancement was analyzed by two different fiber modifications: Arg-Gly-Asp (RGD) incorporation into the HI loop (RGD modification) and a chimeric construct with a serotype 5 shaft and a serotype 3 knob (5/3 fiber modification). Comparisons were made by infectivity analysis and cytotoxicity assays in vitro, followed by tumor suppressive effects tested in vivo. RESULTS: Among TSPs, highest potency was exhibited by the cyclooxygenase-2 (COX-2), Midkine, and vascular endothelial growth factor promoters in both cell lines tested. Fiber chimera (Ad5/3Luc1) conferred significant enhancement of Ad infectivity in comparison with unmodified and RGD-modified vectors. COX-2 CRAds demonstrated selective cytocidal effect in gallbladder cancer cells in vitro. COX-2 promoter-based Ad5/3 CRAds showed significantly enhanced tumor-suppressive effect compared with nonreplicative and RGD-modified CRAd vectors in vivo. CONCLUSIONS: The 5/3 fiber-modified, COX-2 promoter-driven CRAds may prove to be a new agent for the treatment of gallbladder carcinoma.

Adenoviridae↗
PubMed2005

SCF(beta-TrCP1) controls Smad4 protein stability in pancreatic cancer cells.

Smad4, also known as deleted in pancreatic carcinoma locus 4 (DPC4), is a critical co-factor in signal transduction pathways activated by transforming growth factor (TGF)-beta-related ligands that regulate cell growth and differentiation. Mutations in Smad4/DPC4 have been identified in approximately 50% of pancreatic adenocarcinomas. Here we report that SCF(beta-TrCP1), a ubiquitin (E3) ligase, is a critical determinant for Smad4 protein degradation in pancreatic cancer cells. We found that F-box protein beta-TrCP1 in this E3 ligase interacted with Smad4 and that SCF(beta-TrCP1) inhibited TGF-beta biological activity in pancreatic cancer cells by decreasing Smad4 stability. Very low Smad4 protein levels in human pancreatic ductal adenocarcinoma cells were observed by immunohistochemistry. By analyzing pancreatic tumor-derived Smad4 mutants, we found that most point-mutated Smad4 proteins, except those within or very close to a mutation cluster region, exhibited higher interaction affinity with beta-TrCP1 and significantly elevated protein ubiquitination by SCF(beta-TrCP1). Furthermore, AsPC-1 and Caco-2, two cancer cell lines harboring Smad4 point mutations, exhibited rapid Smad4 protein degradation due to the effect of SCF(beta-TrCP1). Both Smad4 levels and TGF-beta signaling were elevated by retrovirus-delivered beta-TrCP1 siRNA in pancreatic cancer cells. Therefore, inhibition of Smad4-specific E3 ligase might be a target for therapeutic intervention in pancreatic cancer.

Adenocarcinoma↗
PubMed2005

Impact of obesity on resource utilization for general surgical procedures.

OBJECTIVE: To determine the impact of the obesity epidemic on workload for general surgeons. SUMMARY BACKGROUND DATA: In 2001, the prevalence of obesity in the United States reached 26%, more than double the rate in 1990. This study focuses on the impact of obesity on surgical practice and resource utilization. METHODS: A retrospective analysis was done on patients undergoing cholecystectomy, unilateral mastectomy, and colectomy from January 2000 to December 2003 at a tertiary care center. The main outcome variables were operative time (OT), length of stay (LOS), and complications. The key independent variable was body mass index. We analyzed the association of obesity status with OT, LOS, and complications for each surgery, using multivariate regression models controlling for surgeon time-invariant characteristics. RESULTS: There were 623 cholecystectomies, 322 unilateral mastectomies, and 430 colectomies suitable for analysis from 2000 to 2003. Multivariable regression analyses indicated that obese patients had statistically significantly longer OT (P < 0.01) but not longer LOS (P > 0.05) or more complications (P > 0.05). Compared with a normal-weight patient, an obese patient had an additional 5.19 (95% confidence interval [CI], 0.15-10.24), 23.67 (95% CI, 14.38-32.96), and 21.42 (95% CI, 9.54-33.30) minutes of OT with respect to cholecystectomy, unilateral mastectomy, and colectomy. These estimates were robust in sensitivity analyses. CONCLUSIONS: Obesity significantly increased OT for each procedure studied. These data have implications for health policy and surgical resource utilization. We suggest that a CPT modifier to appropriately reimburse surgeons caring for obese patients be considered.

Aged↗
PubMed2005

Regulators of apoptosis in cholangiocarcinoma.

CONTEXT: Dysregulation of mediators of apoptosis is associated with carcinogenesis. For biliary duct cancers, p53 gene mutation is an important contributor to carcinogenesis. Mutations in the p53 gene affect transcription of the Fas gene, resulting in lack of Fas expression on cell membrane. It has been previously shown that cloned Fas-negative but not Fas-positive human cholangiocarcinoma cells are resistant to anti-Fas-mediated apoptosis and develop tumors in nude mice. In addition, interferon gamma induces Fas expression in Fas-negative cholangiocarcinoma cells and makes them susceptible to apoptosis. Therefore, it becomes important to characterize immunophenotypic expression of p53 and Fas in normal and neoplastic human tissues of the biliary tract to further understand the pathogenesis of the disease. To date, human studies to characterize differences in immunophenotypic expression of the Fas protein between intrahepatic and extrahepatic biliary duct cancers and in their precursor lesions have not been performed. OBJECTIVE: To report the immunophenotypic expression of p53 and Fas expression in various stages in the development of bile duct cancers (intrahepatic and extrahepatic tumor location) and their association with tumor differentiation. DESIGN: Thirty bile duct cancer samples (13 intrahepatic and 17 extrahepatic) from 18 men and 12 women who ranged in age from 44 to 77 years (mean age, 65.6 years) were retrieved from the surgical pathology files. Hematoxylin-eosin-stained slides were evaluated for the type and grade of tumor and dysplastic changes in the biliary tract epithelium. Additional slides were immunohistochemically stained with p53 and anti-Fas mouse monoclonal antibody. The pattern of Fas distribution and percentage of cells positive for p53 and Fas expression were determined. RESULTS: The percentage of Fas-expressing cells is significantly (P = .01) more frequently noted in extrahepatic tumors compared with intrahepatic tumors. Furthermore, Fas expression decreased from dysplastic epithelium to cholangiocarcinoma (P = .01), and this decreasing trend continued from well to poorly differentiated tumors. Nuclear p53 expression was not identified in normal and dysplastic epithelium but was noted in 30% of carcinomas (P = .02). CONCLUSION: Fas expression is an early event in pathogenesis of bile duct cancers. Immunophenotypic expression of Fas is associated with well to moderately differentiated tumors but not with poor tumor differentiation.

Adult↗
PubMed2005

Obesity status and use of general surgery resources.

Obesity is a rapidly growing epidemic. This study assesses the impact of obesity on surgeon workload for general surgical services. A retrospective study of patients undergoing cholecystectomy, unilateral mastectomy, and colectomy between January 2000 and December 2003 was undertaken. Obesity was defined as body mass index > or = 30. The proportion of obese patients was compared to the 2002 BRFSS obesity prevalence data for Alabama. Data were adjusted to control for potential confounders. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. A total of 1,385 patients were included in analysis. The prevalence of obesity in the study population was 35.5 per cent compared to the statewide prevalence of 25.2 per cent (OR = 1.73, 95% CI = 1.51, 1.98). These data were stratified by procedure, age, and gender. The cholecystectomy group had a significantly higher proportion of obese for all age groups and female gender. The mastectomy group had a higher proportion of obese in the 45-64 age group. The stratified colectomy group did not reach statistical significance. There was no evidence of referral bias to explain these findings. This study demonstrates there is a greater use of general surgery services, particularly cholecystectomy and mastectomy, in obese patients than predicted by the prevalence of obesity in the population.

Cholecystectomy↗
PubMed2004

Endoscopic ultrasound-guided fine-needle aspiration biopsy: a powerful tool to obtain samples from small lesions.

BACKGROUND: Endoscopic ultrasound (EUS) is a powerful imaging modality to identify and determine the extent of a lesion. In addition, EUS is superior to a computed tomography scan in detecting lesions < 3 cm. The objective of the current study was to determine whether small lesions (< or = 25 mm) affected the specimen adequacy and the diagnostic accuracy for lesions aspirated under EUS guidance. METHODS: In the current study, 209 consecutive EUS-guided fine-needle aspiration biopsy (EUS-FNAB) samples < or = 25 mm (100 samples) or > 25 mm (109 samples) as determined by EUS were obtained from 151 patients with a mean age of 62 years (range, 39-94 years). A cytopathologist present in the endoscopy suite determined specimen adequacy. Yield of adequate samples for diagnosis, number of passes, and operating characteristics of EUS-FNAB for small (< or = 25 mm) and large lesions (>25 mm) were compared. RESULTS: The overall yield of obtaining adequate samples for diagnosis was 96% (201 of 209). There was no difference noted with regard to the yield of obtaining samples (96% vs. 96%) from small or large lesions. A mean of 2.5 passes (range, 1-9 passes) was needed to obtain adequate samples from lesions < or = 25 mm, whereas a mean of 4.5 passes (range, 1-11 passes) was needed to obtain adequate samples from lesions > 25 mm. The sensitivity (96% vs. 96%), specificity (100% vs. 100%), and diagnostic accuracy (98% vs. 97%) for EUS-FNAB were comparable whether the lesion was < or = 25 mm or > 25 mm. CONCLUSIONS: EUS-FNAB was a highly effective technique to obtain samples from small (< or = 25 mm) and large (> 25 mm) lesions without affecting the sensitivity, specificity, or diagnostic accuracy.

Adult↗
PubMed2004

Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1.

Smad4 is a key intracellular mediator for the transforming growth factor-beta (TGF-beta) superfamily of growth factors and is also an important tumor suppressor. The receptor-regulated Smad (R-Smad) proteins are regulated by ubiquitin-mediated degradation, yet the precise control of Smad4 protein stability is unclear. We have identified SCF(beta-TrCP1), a ubiquitin (E3) ligase, as a critical determinant for the protein degradation of Smad4 protein. F-box protein beta-TrCP1 in this E3 ligase interacts with Smad4 both in yeast and in mammalian cells, but has no interaction with Smad2 and has weak interaction with Smad3. The beta-TrCP1/Smad3 interaction was abolished by Smad4 gene silencing, indicating the interaction is indirect and is through Smad4. Ectopic expression of SCF complex containing beta-TrCP1 is sufficient to induce the ubiquitination and degradation of Smad4. Furthermore, small interfering RNA-triggered endogenous beta-TrCP1 suppression increases the expression of Smad4 protein. Consistent with these results, cells that overexpress the SCF complex display an inhibited TGF-beta-dependent transcriptional activity and an impaired cell cycle arrest function. Thus, SCF(beta-TrCP1) abrogates TGF-beta function in vivo by decreasing Smad4 stability.

Blotting, Western↗
PubMed2004

Mechanisms of resistance to Erbitux (anti-epidermal growth factor receptor) combination therapy in pancreatic adenocarcinoma cells.

We previously demonstrated that pancreatic adenocarcinoma BxPC-3 xenografts display resistance to treatment with Erbitux, gemcitabine, and radiation, whereas MIA PaCa-2 xenografts are highly sensitive to the same therapy. Here, we elucidate in vitro mechanisms that may explain the observed differential response of epidermal growth factor receptor (EGFR) expressing pancreatic adenocarcinoma xenografts to Erbitux-based combination therapy in vivo. MIA PaCa-2 and BxPC-3 protein lysates were probed with antibodies to EGFR, ErbB2, ErbB3, and ErbB4. Constitutive ErbB3 activity was visualized by immunoblot analysis using anti-phosphotyrosine antibodies and receptor-specific immunoprecipitates. erbB2 and erbB3 gene expression in both cell lines was quantified with real-time polymerase chain reaction. Erbitux-induced internalization of EGFR was determined by flow cytometry following Erbitux treatment for different incubation times at 0 degrees C and 37 degrees C. MIA PaCa-2 and BxPC-3 protein extracts were also probed with anti-phospho-mitogen-activated protein kinase antibody after stimulation with EGF and in the presence of Erbitux. Although both cell lines expressed EGFR and ErbB2 protein, ErbB3 protein was selectively expressed by BxPC-3 cells, where it also showed evidence of constitutive phosphorylation. There was a 10-fold increase of erbB3 transcript levels in BxPC-3 cells compared with MIA PaCa-2. ErbB4 protein was not detectable in either cell line. Erbitux mediated EGFR internalization in MIA PaCa-2 cells after 2 hours of incubation, whereas it did not promote EGFR internalization in BxPC-3 cells. Likewise, EGF-dependent phosphorylation of MAPK p44/42 was blocked by Erbitux treatment in MIA PaCa-2 but not BxPC-3 cells. Erbitux selectively interfered with EGF-induced MAPK activation in MIA PaCa-2 but not BxPC-3 cells. Persistent MAPK activation and impaired in vitro internalization of EGFR by BxPC-3 pancreatic cancer cells may be due to constitutive ErbB3 signaling, facilitated by heterodimerization with EGFR, which may explain resistance to Erbitux-based combination therapy in vivo.

Adenocarcinoma↗
PubMed2004

Endoscopic ultrasound-guided fine needle aspiration biopsy of suspected cholangiocarcinoma.

BACKGROUND AND AIMS: Despite advances in endoscopic techniques for sampling bile duct strictures, the diagnosis of cholangiocarcinoma remains a challenge. The purpose of this study was to evaluate the yield of EUS-FNA and its impact on patient management for patients with suspected cholangiocarcinoma. METHODS: All patients undergoing EUS for the evaluation of suspected malignant biliary strictures were prospectively evaluated over a 23-month period. A single gastroenterologist performed all EUS-FNAs in the presence of a cytopathologist. Reference standard for final diagnosis included surgery, death from disease, and clinical and/or imaging follow-up. RESULTS: Twenty-eight patients (mean age 67 years [SD +/- 11], 72% male) were evaluated. Most patients (91%) presented with obstructive jaundice, and all except 1 had nondiagnostic sampling of the biliary lesions either at ERCP (88%), percutaneous transhepatic cholangiogram (n = 2), and/or computed tomography-guided biopsy (n = 1). Sixty-seven percent (14/21) had no definitive mass seen on prior abdominal imaging studies. The mean tumor size by EUS was 19 mm x 16 mm with a median number of passes to diagnosis of 3 (range 1-7). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 86%, 100%, 100%, 57%, and 88%, respectively. EUS-FNA had a positive impact on patient management in 84% of patients: preventing surgery for tissue diagnosis in patients with inoperable disease (n = 10), facilitating surgery in patients with unidentifiable cancer by other modalities (n = 8), and avoiding surgery in benign disease (n = 4). CONCLUSIONS: Given the apparent accuracy and safety of EUS with FNA for imaging bile duct mass lesions and for obtaining a tissue diagnosis in patients with suspected cholangiocarcinoma, this technology may represent a new approach to diagnosis especially when other methods fail. The ability to obtain a definite diagnosis has a significant impact on patient management.

Adult↗
PubMed2004

Serum lactic acid determines the outcomes of CT diagnosis of pneumatosis of the gastrointestinal tract.

Computed tomography (CT) diagnosis of pneumatosis involving the gastrointestinal tract can represent a broad range of clinical entities from a benign process to ischemic bowel. The purpose of this study is to define the significance and outcome of pneumatosis intestinalis (PI). All CT scans from 5/93 to 12/01 with the finding of PI were reviewed. Eighty-six CT scans had the finding of PI, with the colon being the most frequent location (51%), followed by small bowel (36%) and gastric (9%). Forty per cent of patients underwent surgery, with an overall mortality rate of 42 per cent and a surgical mortality rate of 47 per cent. Univariate analysis demonstrated significant correlation between serum lactic acid (LA) > 2.0 mmol/L [odds ratio (OR) = 23.4; 95% confidence interval (C.I.), 7.21-75.92] and serum creatinine > 1.5 mg/dL (OR = 3.05; 95% C.I., 1.25-7.42) with mortality. Age was suggestive but not a significant risk factor for mortality (P = 0.09). Multivariate analysis found serum LA > 2.0 (OR = 30.37; 95% C.I., 7.31-126.2) to be the only significant predictor of mortality. CT diagnosis of PI is associated with significant in-hospital mortality, especially in the elderly. Serum LA level > 2.0 mmol/L at time of diagnosis is associated with a greater than 80 per cent mortality. Surgical consultation is necessary to determine which patients need urgent surgical intervention.

Adolescent↗