Biomedical subjects
Richard H Bell
Publications and source records attributed to Richard H Bell.
Chromosomal instability in pancreatic ductal cells from patients with chronic pancreatitis and pancreatic adenocarcinoma.
Pancreatic adenocarcinoma is a disease with high mortality for which chronic pancreatitis confers a markedly increased risk. We hypothesize that chromosome instability and genomic damage occur in pre-neoplastic pancreatic ductal epithelium, and that this damage may be related to oxidative stress. We used dual-color fluorescence in situ hybridization with centromere probes and locus-specific arm probes for chromosome arms 11q, 17p, and 18q to identify genomic instability in cultures of normal-appearing human pancreatic ductal epithelium from normal organ donor controls compared to patients with chronic pancreatitis or pancreatic adenocarcinoma. To examine early pancreatic tumorigenesis, we studied only normal-appearing pancreatic ductal cells adjacent to pancreatitis or carcinoma. We found that, compared to the finding in normal controls, chromosomal abnormalities are present in normal-appearing human pancreatic ductal epithelia obtained from patients with chronic pancreatitis or pancreatic adenocarcinoma. Furthermore, these chromosomal abnormalities could be induced in cultured pancreatic ductal epithelium from normal organ donors by chronic exposure to dilute hydrogen peroxide, suggesting that oxidative stress may contribute to the development of chromosomal instability in the pancreas. These results elucidate a potential mechanism linking chronic pancreatitis to pancreatic cancer and suggest that chromosomal instability may be an early event in the pathogenesis of pancreatic cancer.
Residency program models, implications, and evaluation: results of a think tank consortium on resident work hours.
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Neural invasion in the staging of pancreatic cancer.
The natural history of pancreatic ductal adenocarcinoma makes it one of the most malignant human diseases. Unknown etiology, lack of early symptoms, explosive outcome, short survival, and resistance to therapy are hallmarks of this cancer. Although surgery has been shown to be an effective therapeutic approach, the inevitable tendency for recurrence, even after apparently curative operation, has remained a mystery. Ironically, the reasons for this recurrence, which usually leads to the death of the patient within 1 or 2 years after surgery, have not been a focus of research. Several studies highlighting this problem and the possible explanations have been performed by Japanese investigators.
CT scan in the management of acute appendicitis.
BACKGROUND: Recent studies demonstrate a 98% accuracy of a CT scan in the diagnosis of acute appendicitis. We aimed to determine the accuracy and clinical value of CT scans in patients suspected of having acute appendicitis. PATIENTS AND MATERIALS: We reviewed outcomes of 125 patients over a 5-month period who had CT scans for the initial diagnosis of acute appendicitis. CT scan interpretations were correlated with surgical and pathologic findings. Follow-up was attempted in all patients who did not undergo appendectomy. RESULTS: CT scans and clinical courses were complete in 110 patients (88%); 14 patients were lost to follow-up and 1 was excluded. One patient had two CT scans. Thus, there were 111 CT scans available for review. Radiologic interpretation of these CT scans yielded 36 positive (33%), 67 negative (60%), and 8 indeterminate (7%), resulting in a sensitivity of 90%, a specificity of 89%, a PPV of 78%, and a NPV of 96%. CONCLUSIONS: CT scan may be useful in the diagnosis of acute appendicitis, but the reported high accuracy rate was not reproduced at our institution. CT scan was not clinically useful in 21% of patients. We conclude that a CT scan may be beneficial in the diagnosis of appendicitis with selected patients who have equivocal findings. Thus, at our institution, the accuracy of a CT scan does not justify its routine use in patients with clinical findings of appendicitis.
Pancreatic stellate cell activation and MMP production in experimental pancreatic fibrosis.
BACKGROUND: The early events in pancreatic fibrosis are poorly understood. We examined the production of collagen and matrix metalloproteinases as well as the activation of pancreatic stellate cells in a rodent model of pancreatic fibrosis. MATERIALS AND METHODS: Pancreatitis was induced in rats by hyperstimulation with cerulein (50 microg/kg/day ip) and concurrent pancreatic duct obstruction (SHOP model) for 96 h (n = 48). Sham animals were injected with saline and underwent laparotomy and manipulation of the pancreas with no duct obstruction (n = 28). Rats were sacrificed daily for 18 days. Serial pancreatic sections were stained with H&E [histology], trichrome [collagen], and alpha smooth muscle actin (alpha-SMA) antibodies [activated stellate cells]. Total pancreatic matrix metalloproteinase (MMP)-2 and 9 were determined by gelatin zymography. MMP-1 production was examined using Western blotting. RESULTS: There were occasional alpha-SMA-positive cells in the pancreatic parenchyma of normal and sham animals. Within 48 h of pancreatitis induction in SHOP animals, histologic evidence of pancreatic inflammation was present, and stellate cells (alpha-SMA-positive cells) appeared surrounding pancreatic acini. The appearance of these cells was followed by collagen deposition in the same area. MMP-1 and 2 proteins increased significantly during pancreatitis while MMP-9 did not. The pancreatic architecture returned to normal by 18 days after the induction of pancreatitis. CONCLUSION: Acute pancreatic inflammation results in stellate cell activation and collagen deposition in the same area. Collagen is then resorbed at a time when MMP-1 and 2 peak. The fibrosis of acute pancreatic inflammation in this model completely resolves with restoration of normal architecture.
Effect of hypergastrinemia on pancreatic carcinogenesis.
BACKGROUND: Previous studies in our laboratory demonstrated that pancreatic carcinomas in rodents express receptors for the peptide hormone gastrin that are not present in normal adult pancreas. In view of an abundant literature suggesting that gastrin may promote growth of various gastrointestinal tissues and tumors, the effect of hypergastrinemia on the process of pancreatic carcinogenesis was evaluated. METHODS: Rats received subcutaneous injections of the pancreatic carcinogen azaserine at 19 and 26 days of age. Starting at 12 months of age, animals were randomized to treatment with the proton pump inhibitor lansoprazole or vehicle by gavage for 6 months. At autopsy, pancreatic wet weight normalized to body weight was recorded, as well as the number of benign and malignant pancreatic lesions. RESULTS: Serum gastrin levels were determined by radioimmunoassay and showed a greater than two-fold increase in lansoprazole-treated animals. Pancreatic wet weight in hypergastrinemic rats was increased compared to controls (p <0.05). Premalignant lesions such as acidophilic atypical acinar cell foci, adenomas, heterogeneous phenotypic populations of nodules within nodules, and carcinoma-in-situ were not increased in the hypergastrinemic group. Likewise, there was no difference in the incidence of invasive carcinoma in hypergastrinemic animals (10%) compared to controls (5.7%). CONCLUSION: Hypergastrinemia stimulated an increase in pancreatic weight, but did not stimulate development of premalignant lesions or progression to cancer in the azaserine model of rat pancreatic acinar cell carcinoma.
Myofibroblasts are responsible for the desmoplastic reaction surrounding human pancreatic carcinomas.
BACKGROUND: The cell type responsible for the desmoplastic reaction surrounding human pancreatic carcinoma is unknown. Hepatic stellate cells, which activate to a myofibroblast-like form, are responsible for collagen deposition in cirrhosis and around hepatocellular carcinomas. Recently, pancreatic stellate cells have been described and implicated in the fibrosis of chronic pancreatitis. We sought to determine whether these cells are responsible for the scirrhous reaction surrounding pancreatic adenocarcinomas. METHODS: Archival formalin-fixed, paraffin-embedded pancreatic tissues from 10 patients undergoing pancreaticoduodenectomy for ductal adenocarcinoma and from 2 patients with pancreatic islet cell tumors were examined immunohistochemically for alpha-smooth muscle actin (alpha-SMA), smooth muscle myosin heavy chain (SMMHC), procollagen I, collagen IV, and endothelial cell markers, von Willebrand factor and cluster of differentiation 31. RESULTS: In non-neoplastic areas, staining for alpha-SMA and SMMHC was confined to interlobular septal regions. In contrast, the desmoplastic reaction surrounding all 10 pancreatic adenocarcinoma specimens displayed intense interstitial staining for alpha-SMA, SMMHC, and collagen IV but no staining for von Willebrand factor and cluster of differentiation 31. Procollagen I staining localized intracellularly to fibroblast-shaped cells within this alpha-SMA/SMMHC-positive scirrhous region. Islet cell tumors demonstrated an increase in alpha-SMA staining, although this was not as marked as in ductal adenocarcinomas. CONCLUSIONS: A massive increase in myofibroblast activity, compatible with the activation of stellate cells, is associated with the deposition of collagen types I and IV in the desmoplastic reaction around pancreatic adenocarcinomas.
The gastrin receptor promotes pancreatic growth in transgenic mice.
INTRODUCTION: We demonstrated previously, in two different rodent models of pancreatic cancer, that the gastrin receptor is present on malignant pancreatic tumors in spite of the fact that the normal adult rat and mouse pancreas does not express gastrin receptors. AIMS AND METHODOLOGY: To determine whether gastrin receptors mediate pancreatic growth or promote carcinogenesis or both, we created a transgenic mouse that constitutively expresses gastrin receptors in the exocrine pancreas. The transgene construct contained the full-length rat gastrin receptor cDNA sequence under the control of the rat elastase promoter. RESULTS: Receptor presence and function on exocrine pancreatic tissue of transgenic but not control mice were confirmed by (125)I-gastrin-I binding studies and by gastrin stimulation of intracellular calcium release. Eighteen-month-old transgenic animals had larger pancreas-to-body weight ratios than their nontransgenic littermate controls (p < 0.001 for females; p < 0.01 for males); however, histopathologic examination revealed no neoplasms or other abnormalities. CONCLUSION: In both female and male transgenic mice, the expression of the gastrin receptor in the exocrine pancreas is associated with a significant increase in pancreas weight, but it does not appear to promote the development of spontaneous pancreatic tumors.
Analysis of factors affecting surface expression and immunogenicity of recombinant proteins expressed by gram-positive commensal vectors.
Several key protein structural attributes were altered in an effort to optimize expression and immunogenicity of a foreign protein (M protein from Streptococcus pyogenes) exposed on the surface of Streptococcus gordonii commensal bacterial vectors: (i) a shorter N-terminal region, (ii) the addition of a 94-amino-acid spacer, and (iii) the addition of extra C-repeat regions (CRR) from the M6 protein. A decrease in the amount of cell surface M6 was observed upon deletion of 10 or more amino acid residues at the N terminus. On the other hand, reactivity of monoclonal antibody to surface M6 increased with the addition of the spacer adjacent to the proline- and glycine-rich region, and an increase in epitope dosage was obtained by adding another CRR immediately downstream of the original CRR. The results obtained should facilitate the design of improved vaccine candidates using this antigen delivery technology.
Outcome after pancreaticoduodenectomy for periampullary cancer: an analysis from the Veterans Affairs National Surgical Quality Improvement Program.
The aim of this study is to define the risk factors that predict adverse outcomes for patients undergoing pancreaticoduodenectomy for periampullary cancer in the Department of Veterans Affairs Healthcare System (VA). The VA National Surgical Quality Improvement Program prospectively collected data on 462 patients undergoing pancreaticoduodenectomy in 123 VA medical centers from 1990 to 2000. Independent variables included 68 preoperative and 12 intraoperative variables. The main outcome measures were 30-day postoperative mortality and morbidity, as measured by a set of 20 pre-defined complications. Predictive models for 30-day morbidity and mortality were constructed using logistic regression analysis. The 30-day morbidity rate was 45.9% (212/462). The 30-day postoperative mortality rate was 9.3% (43/462). Significant predictors of mortality included: preoperative serum albumin, American Society of Anesthesiologists classification, preoperative bilirubin >20mg/dl, and operative time. The use of preoperative biliary tract instrumentation did not predict postoperative death or septic complications. This study provides a set of preoperative risk factors that are predictive of adverse outcome following pancreaticoduodenectomy. These factors may assist in patient selection for this procedure and are likely to facilitate risk-adjusted comparison of pancreaticoduodenectomy outcomes between different health care systems.