Biomedical subjects

S D Leach

Publications and source records attributed to S D Leach.

41 records · Page 3Linked to original sources

PubMedDate not supplied

Major vascular resection as part of pancreaticoduodenectomy for cancer: radiologic, intraoperative, and pathologic analysis.

Intraoperative assessment is inaccurate in defining the relationship of a pancreatic head neoplasm to adjacent vascular structures. We evaluated the ability of preoperative contrast-enhanced CT to predict the need for vascular resection during pancreaticoduodenectomy and examined the resected vessels for histologic evidence of tumor invasion. During a 7-year period, 63 patients underwent pancreaticoduodenectomy with en bloc resection of adjacent vascular structures for a presumed pancreatic head malignancy. Clinical, radiologic, operative, and pathologic data were reviewed and analyzed. Fifty-six patients underwent resection of the superior mesenteric-portal vein confluence, three patients required inferior vena cava resection, and the hepatic artery was resected and reconstructed in eight patients. The operative mortality rate was 1.6%, and the overall complication rate was 22%. CT predicted the need for resection of the superior mesenteric or portal veins in 84% of patients. Pathologic analysis revealed tumor invasion of the vein wall in 71% of resected specimens. Tumor invasion of vascular structures adjacent to the pancreas can be predicted with preoperative CT and should alert the surgeon that vascular resection may be required. Histologic evidence of tumor cell infiltration of vessel walls was present in the majority of the resected specimens.

Adenocarcinoma↗

PubMedDate not supplied

K-Ras-independent effects of the farnesyl transferase inhibitor L-744,832 on cyclin B1/Cdc2 kinase activity, G2/M cell cycle progression and apoptosis in human pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma is a highly lethal malignancy that is resistant to traditional cytotoxic therapy. High rates of activating codon 12 K-Ras mutations in this disease have generated considerable interest in the therapeutic application of novel farnesyl transferase inhibitors (FTIs). However, a comprehensive analysis of the effects of FTI treatment on pancreatic cancer cells has not been performed. Treatment of five different human pancreatic cancer cell lines with FTI L-744,832 resulted in inhibition of anchorage-dependent growth, with wide variation in sensitivity among different lines. Effective growth inhibition by L-744,832 correlated with accumulation of cells with a tetraploid (4N) DNA content and high levels of cyclin B1/cdc2 kinase activity, implying cell cycle arrest downstream from the DNA damage-inducible G2/M cell cycle checkpoint. In addition, sensitive cell lines underwent apoptosis as evidenced by changes in nuclear morphology and internucleosomal DNA fragmentation. L-744,832 at a concentration of 1 microM additively enhanced the cytotoxic effect of ionizing radiation, apparently by overriding G2/M checkpoint activation. The effects of FTI treatment on cell growth and cell cycle regulation were associated with changes in posttranslational processing of H-Ras and N-Ras, but not K-Ras. The results confirm the potential therapeutic efficacy of FTI treatment in pancreatic cancer, and suggest that farnesylated proteins other than K-Ras may act as important regulators of G2/M cell cycle kinetics.

Antineoplastic Agents↗

PubMedDate not supplied

Developmental aspects of early pancreatic cancer.

The specific cell of origin responsible for generating pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma remains unknown. During development, epithelial stem cells within embryonic pancreatic epithelium give riseto mature acinar, ductal, and islet elements. Emerging evidence suggests that cells with precursor potential also exist within adult pancreas, resulting in significant developmental plasticity among both endocrine and exocrine cell types. In this review, the contribution of developmental plasticity in initiating pancreatic metaplasia and neoplasia is considered, and evidence supporting a role for epithelial stem cells in pancreatic cancer is discussed.

Carcinoma, Pancreatic Ductal↗

PubMedDate not supplied

Intracellular proteolysis of pancreatic zymogens.

Activation of pancreatic digestive zymogens within the pancreatic acinar cell may be an early event in the development of pancreatitis. To detect such activation, an immunoblot assay has been developed that measures the relative amounts of inactive zymogens and their respective active enzyme forms. Using this assay, high doses of cholecystokinin or carbachol were found to stimulate the intracellular conversion of at least three zymogens (procarboxypeptidase A1, procarboxypeptidase B, and chymotrypsinogen 2) to their active forms. Thus, this conversion may be a generalized phenomenon of pancreatic zymogens. The conversion is detected within ten minutes of treatment and is not associated with changes in acinar cell morphology; it has been predicted that the lysosomal thiol protease, cathepsin B, may initiate this conversion. Small amounts of cathepsin B are found in the secretory pathway, and cathepsin B can activate trypsinogen in vitro; however, exposure of acini to a thiol protease inhibitor (E64) did not block this conversion. Conversion was inhibited by the serine protease inhibitor, benzamidine, and by raising the intracellular pH, using chloroquine or monensin. This limited proteolytic conversion appears to require a low pH compartment and a serine protease activity. After long periods of treatment (60 minutes), the amounts of the active enzyme forms began to decrease; this observation suggested that the active enzyme forms were being degraded. Treatment of acini with E64 reduced this late decrease in active enzyme forms, suggesting that thiol proteases, including lysosomal hydrolases, may be involved in the degradation of the active enzyme forms. These findings indicate that pathways for zymogen activation as well as degradation of active enzyme forms are present within the pancreatic acinar cell.

Animals↗

PubMedDate not supplied

Detection of mutated c-Ki-ras in the bile of patients with pancreatic cancer.

BACKGROUND: Because treatment of advanced pancreatic cancer is often unsuccessful, early detection is important. Codon 12 c-Ki-ras mutations have been found in 80-90% of pancreatic cancer cases and are a potential early marker for pancreatic cancer, but obtaining tissue or fluid for analysis can be difficult. We therefore evaluated whether mutant c-Ki-ras could be detected in bile samples obtained from pancreatic cancer patients. METHODS: DNA was isolated from bile specimens obtained from 20 patients with pancreatic cancer. The mutant-enriched PCR technique (ME-PCR) was used to amplify and detect point mutations at codon 12 of the c-Ki-ras oncogene. RESULTS: In 17 cases sufficient DNA for amplification was obtained; 14 had mutant c-Ki-ras alleles. Cytological evaluation of the bile was performed in 11 of these cases, but was positive in only two cases; both were positive for codon 12 c-Ki-ras mutations. Of the 9 cytologically negative biliary specimens, ME-PCR was positive in six. CONCLUSIONS: Codon 12 c-Ki-ras mutations can be successfully identified in PCR-amplified DNA from bile samples obtained from patients with advanced pancreatic cancer. This technique may supplement cytologic techniques for diagnosing pancreatic cancer and may be capable of identifying individuals at risk for this disease.

Bile↗