Mark Bloomston

Matrix metalloproteinases and their role in pancreatic cancer: a review of preclinical studies and clinical trials.

Matrix metalloproteinases (MMPs) have received much attention in recent years for their role in a variety of malignancies. Pancreatic cancer is no exception; MMP-2 and MMP-9 show high levels of expression in clinical and experimental models. Inhibition of MMPs has shown great promise with synthetic inhibitors, such as BB-94, as tumorostatic agents in preclinical models, particularly when these are combined with gemcitabine. These findings have led to several clinical trials using the MMP inhibitors Marimastat and BAY 12-9566. Herein, we discuss the roles of MMPs and their inhibition in pancreatic cancer.

Fibrinogen γ overexpression in pancreatic cancer identified by large-scale proteomic analysis of serum samples

Detection of serum markers for pancreatic cancer has been elusive. Although CA 19-9 is most commonly used, its sensitivity and specificity are modest. We used large-scale proteomics to identify potential serum markers for pancreatic cancer. Samples were analyzed using high-resolution two-dimensional gel electrophoresis to identify differentially expressed proteins in 32 normal and 30 pancreatic cancer patients. Up to 1,744 protein spots were resolved for each serum sample. Candidate proteins were identified using mass spectrometry. ANOVA was used to identify proteins that could discriminate cancer from normal sera. Serum fibrinogen level was also measured using enzymatic assay. Immunohistochemistry was used to detect fibrinogen in resected pancreatic cancers. One hundred fifty-four proteins were commonly overexpressed in all pancreatic cancers. Nine protein spots (four with identifications by mass spectrometry) could effectively separate cancer from normal controls using cross-validation. These proteins successfully discriminated all pancreatic cancer samples (30 of 30) and 94% of normal (30 of 32) samples. Prominent among these candidates was fibrinogen gamma, which was subsequently confirmed to be overexpressed in pancreatic cancer sera by enzymatic analysis (54.1 +/- 64.1 versus 0.0 +/- 0.0 mg/dL, P < 0.05) and tissue by immunohistochemistry (67% versus 29%, P < 0.05) relative to normal pancreas. Proteomic analysis combining two-dimensional gel electrophoresis and mass spectrometry successfully identified 154 potential serum markers for pancreatic cancer. Of these, fibrinogen gamma, a protein associated with the hypercoagulable state of pancreatic cancer, discriminated cancer from normal sera. Fibrinogen is a potential tumor marker in pancreatic cancer.

Outcome Following Bariatric Surgery in Super versus Morbidly Obese Patients: Does Weight Matter?

Background: Numerous investigators have attempted to identify prognostic indicators for successful outcome following bariatric surgery. The purpose of this study was to determine whether degree of obesity affects outcome in super obese [>225% ideal body weight (IBW)] versus morbidly obese patients (160-225% IBW) undergoing gastric restrictive/bypass procedures. Methods: Since 1984, 157 patients underwent either gastric bypass or vertical banded gastroplasty. Super obese (78) and morbidly obese (79) patients were followed prospectively, documenting outcome and complications. Results: Super obese patients reached maximum weight loss 3 years following bariatric surgery, exhibiting a decrease in body mass index (BMI) from 61 to 39 kg/m2 and an average loss of 42% excess body weight (EBW). Morbidly obese patients had a decrease in BMI from 44 to 31 kg/m2 and carried 39% EBW at 1 year. After their respective nadirs, each group began to regain the lost weight with the super obese exhibiting a current BMI of 45 kg/m2 (61% EBW) versus 34 kg/m2 (52% EBW) in the morbidly obese at 72 months cumulative follow-up. Currently, loss of 50% or more of EBW occurred in 53% of super obese patients versus 72% of morbidly obese (P < 0.01). Twenty-six percent of super obese patients returned to within 50% of ideal body weight (IBW) while 71% of morbidly obese were able to reach this goal (P < 0.01). Co-morbidities and complications related to surgery were similar in each group. Conclusions: Super obese patients have a greater absolute weight loss after bariatric surgery than do morbidly obese patients. Using commonly utilized measures of success based on weight, morbidly obese patients tend to have better outcomes following bariatric surgery.

H-graft portacaval shunts versus TIPS: ten-year follow-up of a randomized trial with comparison to predicted survivals.

Objective:To report long-term outcome of patients undergoing prosthetic 8-mm H-graft portacaval shunts (HGPCS) or TIPS and to compare actual with predicted survival data. Methods:A randomized trial comparing TIPS to HGPCS for bleeding varices began in 1993. Predicted survival was determined using MELD (Model for End-stage Liver Disease). Results:Patients undergoing TIPS (N = 66) or HGPCS (N = 66) were very similar by Childs class and MELD scores and predicted survival. After TIPS (P = 0.01) and HGPCS (P = 0.001), actual survival was superior to predicted survival. Through 24 months, actual survival after HGPCS was superior to actual survival after TIPS (P = 0.04). Compared with TIPS, survival was superior after HGPCS for patients of Childs class A and B (P = 0.07) and with MELD scores less than 13 (P = 0.04) with follow-up at 5 to 10 years. Shunt failure was less following HGPCS (P < 0.01). Conclusions:Predicted survival data for patients undergoing TIPS or HGPCS confirms an unbiased randomization. Actual survival following TIPS or HGPCS was superior to predicted survival. Shunt failure favored HGPCS, as did survival after shunting, particularly for the first few years after shunting and for patients of Childs class A or B or with MELD scores less than 13. This trial irrefutably establishes a role for surgical shunting, particularly HGPCS.

Identification of molecular markers specific for pancreatic neuroendocrine tumors by genetic profiling of core biopsies

AbstractBackground: There is a paucity of known molecular markers that distinguish pancreatic neuroendocrine tumors from other pancreatic tumor types. We hypothesized that novel markers for pancreatic neuroendocrine tumors could be identified with molecular fingerprinting of pooled RNA samples from core biopsies. Methods: Total RNA was harvested from nine core biopsies of normal pancreas, pancreatitis, pancreatic adenocarcinoma, pancreatic adenocarcinoma metastases, and pancreatic neuroendocrine tumors. RNA from each group of samples was pooled and hybridized to an oligonucleotide-based microarray. Four genes (ANG2, NPDC1, ELOVL4, and CALCR) were selected for further investigation by reverse transcriptase polymerase chain reaction from the top 20 highest expressed genes, on the basis of potential as novel markers. Results: Neuroendocrine tumors were most unique from normal pancreas. Pancreatitis, pancreatic adenocarcinoma, and metastases are more closely related to each other and to normal pancreas. ANG2 was overexpressed in 89% of neuroendocrine tumors, compared with 22% of normal pancreas, making it the best potential molecular marker or therapeutic target of the four genes selected for analysis. Conclusion: We have identified a specific set of molecular markers for pancreatic neuroendocrine tumors distinct from pancreatitis and pancreatic adenocarcinoma. These novel markers may prove useful as molecular markers or therapeutic targets unique to pancreatic neuroendocrine tumors.

Transjugular intrahepatic portosystemic shunt versus H-graft portacaval shunt in the management of bleeding varices: a cost-benefit analysis.

BACKGROUND Transjugular intrahepatic portosystemic shunt (TIPS) is popular in treating portal hypertension because of its perceived efficacy and cost benefits, although it has never been compared with surgical shunting in a cost-benefit analysis. This study was undertaken to determine the cost benefit of TIPS versus small-diameter prosthetic H-graft portacaval shunt (HGPCS). METHODS Cost of care was determined in 80 patients prospectively randomized to receive TIPS or HGPCS as definitive treatment for bleeding varices, beginning with shunt placement and including subsequent admissions for complications or follow-up related to shunting. RESULTS Patients were similar in age, gender, severity of illness/liver dysfunction, and urgency of shunting. After TIPS or HGPCS, variceal rehemorrhage (8 versus O, respectively; p = 0.03), shunt occlusion (13 versus 4; p = 0.03), shunt revision (16 versus 4; p < 0.005), and shunt failure (18 versus 10; p = 0.10) were compared; all were more common after TIPS. Through the index admission, TIPS cost

Financial Status Does Not Predict Weight Loss After Bariatric Surgery

48,188 +/-

One hundred consecutive advanced breast biopsy instrumentation procedures: complications, costs, and outcome.

43,355 whereas HGPCS cost

Risk-adjusted Outcomes of Clinically Relevant Pancreatic Fistula Following Pancreatoduodenectomy: A Model for Performance Evaluation.

61,552 +/-

Post-Shunt Resource Consumption Favors Small-Diameter Prosthetic H-Graft Portacaval Shunt over TIPS for Patients with Poor Hepatic Reserve

47,615. With follow-up, TIPS cost