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Biomedical subjects

A L Warshaw

Publications and source records attributed to A L Warshaw.

At least 37 records · Page 2Linked to original sources
PubMed2000

Cystic lesions in the pancreas: when to watch, when to resect.

The diagnosis of cystic lesions in the pancreas is becoming more common, largely due to the increases in diagnostic imaging done for other reasons. This review considers pseudocysts, mucinous cystic neoplasms, intraductal papillary mucinous tumors, and serous cystadenomas in some detail. The emphasis is on the fact that, through a careful history, physical examination, radiologic studies, and, often, cyst fluid analysis, a diagnosis can be reached expeditiously. This pursuit is important because two thirds of pancreatic cystic neoplasms are malignant or premalignant and should be resected, whereas pseudocysts and serous cystadenomas are benign, and, depending on the case, may be treated through observation, resection, or, for pseudocysts, by internal drainage.

Diagnosis, Differential↗
PubMed2000

Outcome of pancreaticoduodenectomy with pylorus preservation or with antrectomy in the treatment of chronic pancreatitis.

OBJECTIVE: To compare the short- and long-term results of pancreaticoduodenectomy with pylorus preservation (PPPD) or with antrectomy (Whipple procedure) in the treatment of selected patients with chronic pancreatitis. BACKGROUND: PPPD may be preferred over Whipple because of its purported nutritional advantages and the reduced likelihood of postgastrectomy syndromes. METHODS: A retrospective review was performed of 72 consecutive patients undergoing pancreaticoduodenectomy for chronic pancreatitis between 1991 and 1997. RESULTS: PPPD was performed in 39 patients and Whipple in 33. The two patient populations had similar characteristics. Short-term complications included (PPPD vs. Whipple): pancreatic or biliary fistulas (5.1% vs. 15%), delayed gastric emptying (33% vs. 12%), cholangitis (2.6% vs. 6.1%), and death (0 vs. 3%). Delayed gastric emptying was not associated with other complications and resulted in longer hospital stays for PPPD than for Whipple patients (15 vs. 12 days). The duration of follow-up averaged 41 +/- 24 months. Long-term weight status was similar, with body-mass indices of 22.1 and 22.9 after PPPD and Whipple, respectively. Postoperative enzyme supplementation (63% vs. 77%) and new-onset diabetes (10% vs. 12%) did not differ significantly between the PPPD and Whipple groups. Dumping, bile gastritis, or peptic ulcer disease occurred in three patients after PPPD and in three after Whipple. Complete or partial pain relief was attained in 60% and 70% of patients after PPPD and Whipple, respectively. Multivariate analysis of preoperative variables revealed that site-specific pathology in the head of the pancreas was the only independent factor associated with successful pain relief after pancreatic resection. CONCLUSION: PPPD results in higher frequencies of postoperative delayed gastric emptying compared with the Whipple procedure. Both operations achieve comparable long-term nutritional results, cause new insulin dependence in surprisingly few patients, and provide equivalent pain relief to 65% of selected patients. Patients with disproportionate pathology in the head of the pancreas have a higher likelihood of successful pain relief.

Adult↗
PubMed2000

Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: an additive strategy for cancer control.

OBJECTIVE: To investigate the effect of a matrix metalloproteinase (MMP) inhibitor, BB-94, on the viability, invasion, and metastases of pancreatic cancer. SUMMARY BACKGROUND DATA: Inhibitors of MMPs, enzymes that degrade extracellular matrix, have been tested as single chemotherapeutic agents for pancreatic cancer. METHODS: Capan1 and AsPC1 cell lines were studied. BB-94 cytotoxicity was evaluated by cell proliferation assays. Production of MMP2 and MMP9 in conditioned media was demonstrated by gelatin zymography. The in vitro effect of BB-94 on cell invasion was assayed using invasion chambers. Hepatic metastases from pancreatic cancer were induced by intrasplenic injections of Capan1 or AsPC1 cells in nude mice. The in vivo effect of BB-94 on liver metastases was evaluated by comparing animals receiving BB-94 treatment with controls receiving vehicle alone. Variables measured included death rate and tumor burden (liver-to-body weight ratio). RESULTS: BB-94 was not cytotoxic between 3 and 3,000 ng/mL. Zymography demonstrated production of MMP2 and MMP9 by both cell lines, with complete inhibition of these enzymes by BB-94 at 48 ng/mL. Invasion chamber assays showed that BB-94 (48-400 ng/mL) impeded cell invasion in vitro compared with untreated controls. In vivo, BB-94 prevented death or reduced the death rate from hepatic metastases in animals injected with Capan1 or AsPC1 cells. BB-94 treatment resulted in significant reductions in hepatic tumor burden compared with untreated controls. CONCLUSIONS: Inhibition of MMP reduces both growth of pancreatic cancer metastases and the death rate. These actions do not reflect cytotoxicity but rather result from impaired cancer cell attachment, migration, and organ invasion. MMP inhibitors may provide an additive effect to cytotoxic agents in multidimensional treatment regimens for pancreatic cancer.

Animals↗
PubMed2000

Overexpression of cyclin D1 occurs frequently in human pancreatic endocrine tumors.

The molecular pathogenesis of human pancreatic endocrine tumors (PETs) is poorly understood. Three independent animal models have pointed to the pivotal role of the G1/S cell cycle transition in pancreatic endocrine cell proliferation. We thus hypothesized that the cell cycle regulator cyclin D1 may contribute to the pathogenesis of human PETs. Overexpression of cyclin D1 was identified in 43% of cases, and no correlation was observed with clinical phenotype. The novel observation of frequent overexpression of cyclin D1 suggests that this established oncogene may be implicated in the pathogenesis of human PETs. The absence of detectable alterations in cyclin D1 genomic structure suggests that the mechanism for its oncogenic activation in PETs may be transcriptional or posttranscriptional.

Adolescent↗
PubMed2000

[Parenchymal necrosis: infection and other indications for debridement and drainage].

In the present review we describe our experience with debridement in necrotizing pancreatitis, with particular emphasis on the indications for surgery and the outcome in patients with infected and sterile necrosis. Within 7 years 64 patients with necrotizing pancreatitis underwent surgery with a median preoperative APACHE II score of 9. The indications for surgery were either proven infection or persistence of symptoms. Thirty-six patients were found to have infected necrosis, while 28 patients had sterile necrosis. There was no significant difference between the two groups regarding pre- and postoperative parameters. The surgical technique involved a blunt necrosectomy followed by closed packing with Penrose drains. This technique produced the lowest reported mortality of 6.2% with a reoperation rate of only 17%, demonstrating that even with sterile necrosis surgical management can be carried out safely.

Adult↗
PubMed1999

Immunohistochemical characterization of pancreatic tumors induced by dimethylbenzanthracene in rats.

Dimethylbenzanthracene (DMBA) induces pancreatic adenocarcinomas in rats 9 months after carcinogen exposure, with precursor lesions (tubular complexes) developing 1 month after initiation of treatment. Because previous studies have suggested an acinar cell of origin for these tumors, we investigated the expression pattern of ductal, acinar, and islet cell markers in these cancers to gain insight into their phenotype and cell of origin. Pancreatic neoplasms were induced in rats by implantation of DMBA into the head of the pancreas. Lesions studied included 10 early tubular complexes (DMBA for 2 weeks), 8 tubular complexes (DMBA for 1 month), and 10 adenocarcinomas (DMBA for 9 months). Normal rat pancreas served as a control. For comparison, 5 human ductal adenocarcinomas were also evaluated. Immunohistochemistry with ductal (keratin, cytokeratin 19, cytokeratin 20), acinar (chymotrypsin), and islet (chromogranin A) cell markers was performed to analyze the tissues. Rat tubular complexes and adenocarcinomas revealed strong expression of keratin, cytokeratin 19, and cytokeratin 20 in the cytoplasm of all neoplastic cells, absence of chymotrypsin, and rare immunoreactivity to chromogranin A. Human adenocarcinomas showed strong expression of keratin and cytokeratin 19 in all neoplastic cells, expression of cytokeratin 20 in 5-20% of cells, and absence of chymotrypsin and chromogranin A. Pancreatic adenocarcinomas induced by DMBA in rats express markers consistent with a ductal phenotype, as observed in human tumors. Ductal marker expression in early tumor stages suggests a ductal cell of origin.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1999

Interstitial trypsinogen release and its relevance to the transformation of mild into necrotizing pancreatitis in rats.

BACKGROUND & AIMS: Intracellular activation of trypsinogen is currently believed to initiate pancreatitis. Factors responsible for the progression of mild to necrotizing pancreatitis are poorly understood. This study evaluated the significance of interstitial protease release and activation in this process. METHODS: In rats with cerulein-induced pancreatitis, concentrations of trypsinogen and its activation peptide TAP were measured in lymph and blood, and pancreatic injury was determined. Activation of extracellular trypsinogen was induced by intravenous infusion of enterokinase, which does not enter the acinar cell. Gabexate mesilate (acinar cell permeable) or soybean trypsin inhibitor (acinar cell nonpermeable) was administered to distinguish the effects of intracellular or extracellular protease activation. RESULTS: In cerulein pancreatitis, trypsinogen levels increased prominently and were highest in lymph and portal vein blood, whereas TAP increments were modest. Combined cerulein/enterokinase infusions resulted in marked TAP increases in lymph and blood and in severe necrohemorrhagic pancreatitis. Gabexate mesilate as well as soybean trypsin inhibitor significantly decreased TAP levels in both lymph and blood and reduced pancreatic injury, with no significant differences between groups. CONCLUSIONS: In secretagogue-induced pancreatitis, large amounts of trypsinogen are present in the interstitium and drain via the portal and lymphatic circulation. Activation of this extracellular trypsinogen induces hemorrhagic necrosis in a setting of mild edematous pancreatitis. This phenomenon may be the central event in the progression to fulminant necrotizing pancreatitis.

Animals↗
PubMed1999

Specific therapy for local and systemic complications of acute pancreatitis with monoclonal antibodies against ICAM-1.

OBJECTIVE: To analyze the time points and levels of the expression of adhesion molecules in the pancreas and lung in pancreatitis of different severities, and to assess whether treatment with a monoclonal antibody against intercellular adhesion molecule-1 (ICAM-1) can reduce local and systemic complications. BACKGROUND: The outcome of severe acute pancreatitis relates to its pulmonary and septic complications. Leukocyte adhesion and infiltration, both mediated by ICAM-1, are central events in the pathogenesis of necrotizing pancreatitis. METHODS: Expression of ICAM-1 at different time points was assessed by immunohistochemistry and Western blot analysis in pancreas and lungs from rats with mild edematous or severe necrotizing pancreatitis. ICAM-1 expression was correlated with leukocyte infiltration and histologic changes. The possible therapeutic effect of monoclonal antibodies against ICAM-1 was assessed by measuring pancreatic and lung injury. RESULTS: In edematous pancreatitis, increased ICAM-1 expression in pancreas was evident by 6 hours but did not occur in lung. In contrast, ICAM-1 was upregulated at 3 hours in the pancreas and at 12 hours in lung in necrotizing pancreatitis. Increased expression of ICAM-1 preceded leukocyte infiltration. Treatment of severe necrotizing pancreatitis with monoclonal antibodies against ICAM-1 decreased both local pancreatic injury and systemic lung injury compared with untreated controls. CONCLUSIONS: Upregulation of ICAM-1 and subsequent leukocyte infiltration appear to be significant mediators of pancreatic and pulmonary injury in pancreatitis, and both the onset and extent correlate with severity. The time course should permit effective prevention of tissue damage by treatment with ICAM-1 antibodies.

Acute Disease↗
PubMed1999

Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy.

OBJECTIVE: Pancreatic mucinous cystic neoplasms (MCNs) provide a spectrum of neoplastic changes ranging from benign to malignant. The authors have correlated K-ras mutations and p53 overexpression with the evolution of these tumors. METHODS: Areas of mild, moderate, or severe dysplasia were microdissected from paraffin-embedded tissue sections of 28 different MCNs (10 benign, 9 borderline, 9 malignant). Nonneoplastic pancreatic ducts were also microdissected from tissues adjacent to the tumors. Ten serous cystadenomas served as negative controls. K-ras codon 12 mutations were identified by a mutant-enriched nested polymerase chain reaction-restriction fragment length polymorphism assay and confirmed by sequencing. p53 overexpression was demonstrated by immunohistochemistry. RESULTS: K-ras mutations were detected in 20% of benign, 33% of borderline, and 89% of malignant MCNs. Histologically, mutations were found in 26% (7/27) of MCN epithelia with mild dysplasia, 38% (5/13) of MCN epithelia with moderate dysplasia, and 89% (8/9) of MCN epithelia with severe dysplasia or carcinoma. Ten percent (4/39) of nonneoplastic pancreatic ducts at the margins of MCN harbored mutations, all associated with borderline or malignant tumors. Overexpression of p53 occurred in none of the benign or borderline MCNs but in 44% (4/9) of the malignant tumors (p = 0.006 benign/borderline vs. malignant). p53 immunoreactivity was concentrated in areas of severe dysplasia/carcinoma or invasion, where K-ras mutation had been detected. CONCLUSION: These findings demonstrate a sequential accumulation of genetic changes in the carcinogenesis of MCN. K-ras mutations appear early and increase in proportion with increasing dysplasia. Overexpression of p53 is a late finding observed only in carcinomas, and in combination with mutated K-ras genes. The presence of K-ras mutations in nonneoplastic ducts supports formal pancreatic resection over enucleation for treatment. Mucinous cystic neoplasms may be a useful model to study the evolution of pancreatic ductal adenocarcinomas, in which precursor lesions remain unknown.

DNA Mutational Analysis↗
PubMed1999

Trypsin and activation of circulating trypsinogen contribute to pancreatitis-associated lung injury.

Pancreatic proteases are secreted in acute pancreatitis, but their contribution to associated lung injury is unclear. Applying models of mild edematous (intravenous caerulein) and severe necrotizing (intraductal glycodeoxycholic acid) pancreatitis in rats, we showed that both trypsinogen and trypsin concentrations in peripheral blood, as well as lung injury, correlate with the severity of the disease. To isolate the potential contribution of proteases to lung injury, trypsin or trypsinogen was injected into healthy rats or trypsinogen secreted in caerulein pancreatitis was activated by intravenous enterokinase. Pulmonary injury induced by protease infusions was dose dependent and was ameliorated by neutrophil depletion. Trypsinogen activation worsened lung injury in mild pancreatitis. In vitro incubation of leukocytes with trypsinogen showed that stimulated leukocytes can convert trypsinogen to trypsin. In conclusion, this study demonstrates that the occurrence and severity of pancreatitis-associated lung injury (PALI) corresponds to the levels of circulating trypsinogen and its activation to trypsin. Neutrophils are involved in both protease activation and development of pulmonary injury.

Acute Disease↗
PubMed1999

Chemotactic peptide uptake in acute pancreatitis: correlation with tissue accumulation of leukocytes.

Chemotactic peptides bind specifically to receptors on leukocyte membranes. This property makes them prospective vehicles to evaluate inflammation and infection. We used two well-established models of acute pancreatitis to quantitate the binding of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine-lysine (fMLFK) to leukocytes and its correlation to degree of organ inflammation. Uptake of the (99m)Tc-labeled nicotinyl hydrazine-derivatized chemotactic peptide analog fMLFK-HYNIC was measured in blood, pancreas, lung, and muscle specimens in rats with edematous or necrotizing pancreatitis and was compared with neutrophil sequestration assessed by myeloperoxidase activity and histology. Chemotactic peptide uptake in the pancreas was increased in mild and severe pancreatitis compared with controls, with higher levels in severe than in mild disease, and correlated with tissue myeloperoxidase activity (r = 0.7395, P < 0.001). Increased pulmonary uptake only in severe pancreatitis reflected pancreatitis-induced neutrophil sequestration in the lungs. Muscle uptake was unchanged compared with controls. Edema formation did not affect chemotactic peptide uptake. The data suggest that uptake of chemotactic peptides can contribute to quantitative assessment of neutrophils in localized inflammatory processes and is independent of associated edema formation or microcirculatory compromise.

Animals↗
PubMed1999

Pancreatic-phase versus portal vein-phase helical CT of the pancreas: optimal temporal window for evaluation of pancreatic adenocarcinoma.

OBJECTIVE: Our objective was to use helical CT to compare the enhancement attenuation values of pancreatic adenocarcinoma, adjacent normal pancreas, and critical vascular structures during the pancreatic phase and portal vein phase. SUBJECTS AND METHODS: Forty-one patients with pathologically proven pancreatic adenocarcinoma underwent dual-phase thin-section dynamic helical CT using a pancreatic-phase and portal vein-phase protocol. The scan delay after initiation of the contrast bolus was 40 sec for the pancreatic phase and 70 sec for the portal vein phase. Attenuation values after i.v. contrast administration were calculated during both phases of scanning for normal pancreas, pancreatic tumor, celiac axis, superior mesenteric artery, superior mesenteric vein, splenic vein, and portal vein. Quantitative values were assessed using regions of interest. RESULTS: Mean differences of enhancement between tumor and normal pancreas were significantly greater in the pancreatic phase (57 H) than the portal vein phase (35 H) (p = .0001). Enhancement values of all the critical vascular structures were also significantly greater in the pancreatic phase than the portal vein phase (p < .001). CONCLUSION: With dynamic thin-section helical CT, pancreatic-phase scanning provides greater differences in contrast enhancement between normal pancreas and pancreatic tumor and between pancreatic tumors and surrounding critical vascular structures than does portal vein-phase scanning.

Adenocarcinoma↗
PubMed1999

Adenocarcinoma of the head of the pancreas: determination of surgical unresectability with thin-section pancreatic-phase helical CT.

OBJECTIVE: This study was conducted to evaluate newly introduced criteria for unresectability of pancreatic cancer with thin-section pancreatic-phase helical CT. MATERIALS AND METHODS: Twenty-five patients with adenocarcinoma in the head of the pancreas underwent thin-section pancreatic-phase helical CT. The major peripancreatic vessels were categorized on a scale of 1-4, according to the degree of circumferential involvement by tumor. The maximum diameters of the small peripancreatic veins--gastrocolic trunk, anterosuperior pancreaticoduodenal vein, and posterosuperior pancreaticoduodenal vein--were recorded. Findings on CT were compared with the results of surgery in each patient. RESULTS: Sixteen patients had surgically resectable tumors, and nine patients had surgically unresectable tumors. CT and surgical correlation was available for 98 major peripancreatic vessels; 85 were resectable and 13 were unresectable. Of category 1 vessels, 72 (97%) of 74 were resectable at surgery. Of category 2 vessels, 12 (71%) of 17 were resectable. One (50%) of two category 3 vessels and none (0%) of five category 4 vessels were resectable at surgery. CT showed a dilated gastrocolic trunk in two patients; one of these patients had a surgically resectable tumor, but the other patient had a surgically unresectable tumor. CONCLUSION: In patients with adenocarcinoma in the head of the pancreas, the degree of circumferential vessel involvement by tumor as shown by CT is useful in predicting which patients will have surgically unresectable tumors. A dilated gastrocolic trunk should not be used as an independent sign of surgical unresectability.

Adenocarcinoma↗