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Biomedical subjects

S D Leach

Publications and source records attributed to S D Leach.

At least 19 recordsLinked to original sources
PubMed2001

Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma.

Serial analysis of gene expression (SAGE) can be used to quantify gene expression in human tissues. Comparison of gene expression levels in neoplastic tissues with those seen in nonneoplastic tissues can, in turn, identify novel tumor markers. Such markers are urgently needed for highly lethal cancers like pancreatic adenocarcinoma, which typically presents at an incurable, advanced stage. The results of SAGE analyses of a large number of neoplastic and nonneoplastic tissues are now available online, facilitating the rapid identification of novel tumor markers. We searched an online SAGE database to identify genes preferentially expressed in pancreatic cancers as compared with normal tissues. SAGE libraries derived from pancreatic adenocarcinomas were compared with SAGE libraries derived from nonneoplastic tissues. Three promising tags were identified. Two of these tags corresponded to genes (lipocalin and trefoil factor 2) previously shown to be overexpressed in pancreatic carcinoma, whereas the third tag corresponded to prostate stem cell antigen (PSCA), a recently discovered gene thought to be largely restricted to prostatic basal cells and prostatic adenocarcinomas. PSCA was expressed in four of the six pancreatic cancer SAGE libraries, but not in the libraries derived from normal pancreatic ductal cells. We confirmed the overexpression of the PSCA mRNA transcript in 14 of 19 pancreatic cancer cell lines by reverse transcription-PCR, and using immunohistochemistry, we demonstrated PSCA protein overexpression in 36 of 60 (60%) primary pancreatic adenocarcinomas. In 59 of 60 cases, the adjacent nonneoplastic pancreas did not label for PSCA. PSCA is a novel tumor marker for pancreatic carcinoma that has potential diagnostic and therapeutic implications. These results establish the validity of analyses of SAGE databases to identify novel tumor markers.

Adenocarcinoma↗
PubMed2001

A phase I study of vitamin E, 5-fluorouracil and leucovorin for advanced malignancies.

Six patients with incurable malignancies were originally treated with vitamin E, 3200 IU/day for fourteen days, followed by the same dose of vitamin E daily plus LCV (20 mg/m2 i.v. bolus daily x 5) with 5FU (425 mg/m2 i.v. bolus immediately following LCV). The same schedule of LCV and 5FU was repeated 4 weeks later, then every 5 weeks indefinitely. When 3 of the first 6 had grade 3/4 toxicity, six more patients were treated on the identical drugs and schedule. Seven of twelve total patients had one or more grade 3/4 toxicities. Neutropenia, abdominal pain, and diarrhea were most common. No patient had a documented response, though seven patients did have stable disease. Though the combination of vitamin E and chemotherapy was toxic, this trial demonstrated maximal therapeutic doses of vitamin E can be combined with standard 5FU and LCV, without significantly increasing the side effects of the chemotherapy itself.

Abdominal Pain↗
PubMed2001

Lineage commitment and cellular differentiation in exocrine pancreas.

Exocrine pancreatic cell types comprise greater than 90% of parenchymal cell mass in the adult pancreas. However, the factors regulating differentiation of acinar and ductal epithelial cells remain incompletely characterized. Like pancreatic islet cells, acinar and ductal cells arise from pluripotent precursors within embryonic pancreatic epithelium. Recent studies have suggested that a common pool of pluripotent stem cells is responsible for generating both endocrine and exocrine cell types, and that specific signaling pathways regulate a critical balance between endocrine and exocrine lineage commitment.

Animals↗
PubMed2001

Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE).

PURPOSE: Effective new markers of pancreatic carcinoma are urgently needed. In a previous analysis of gene expression in pancreatic adenocarcinoma using serial analysis of gene expression (SAGE), we found that the tag for the mesothelin mRNA transcript was present in seven of eight SAGE libraries derived from pancreatic carcinomas but not in the two SAGE libraries derived from normal pancreatic duct epithelial cells. In this study, we evaluate the potential utility of mesothelin as a tumor marker for pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Mesothelin mRNA expression was evaluated in pancreatic adenocarcinomas using reverse-transcription PCR (RT-PCR) and in situ hybridization, whereas mesothelin protein expression was evaluated by immunohistochemistry. RESULTS: Using an online SAGE database (http://www.ncbi.nlm.gov/SAGE), we found the tag for mesothelin to be consistently present in the mesothelioma, ovarian cancer, and pancreatic cancer libraries but not in normal pancreas libraries. Mesothelin mRNA expression was confirmed by in situ hybridization in 4 of 4 resected primary pancreatic adenocarcinomas and by RT-PCR in 18 of 20 pancreatic cancer cell lines, whereas mesothelin protein expression was confirmed by immunohistochemistry in all 60 resected primary pancreatic adenocarcinomas studied. The adjacent normal pancreas in these 60 cases did not label, or at most only rare benign pancreatic ducts showed weak labeling for mesothelin. CONCLUSIONS: Mesothelin is a new marker for pancreatic adenocarcinoma identified by gene expression analysis. Mesothelin overexpression in pancreatic adenocarcinoma has potential diagnostic, imaging, and therapeutic implications.

Adenocarcinoma↗
PubMed2000

EUS, PET, and CT scanning for evaluation of pancreatic adenocarcinoma.

BACKGROUND: Preoperative diagnosis of pancreatic adenocarcinoma can be difficult. Computed tomography (CT) is the standard, noninvasive imaging method for evaluation of suspected pancreatic adenocarcinoma, but it has limited sensitivity for diagnosis, local staging, and metastases. Endoscopic ultrasound (EUS) and fluoro-deoxyglucose/positron emission tomography (FDG-PET) are imaging methods that may improve diagnostic accuracy. METHODS: Thirty-five patients with presumed resectable pancreatic adenocarcinoma were prospectively evaluated with helical CT, EUS, and FDG-PET. RESULTS: Sensitivity for the detection of pancreatic cancer was higher for EUS (93%) and FDG-PET (87%) than for CT (53%). EUS was more sensitive than CT for local vascular invasion of the portal and superior mesenteric veins. EUS diagnosis of vascular invasion was associated with poor outcome after surgery. EUS-guided, fine-needle aspiration allowed tissue diagnosis in 14 of 21 attempts (67%). FDG-PET diagnosed 7 of 9 cases of proven metastatic disease, 4 of which were missed by CT. Two of three metastatic liver lesions suspected by CT were indeterminate for metastases. FDG-PET confirmed metastases. CONCLUSIONS: EUS and PET improve diagnostic capability in pancreatic adenocarcinoma. EUS is useful in determining local vascular invasion and obtaining tissue diagnosis. FDG-PET is useful in identifying metastatic disease. Both techniques are more sensitive than helical CT for identification of the primary tumor. (Gastrointest Endosc 2000;52:367-71).

Adenocarcinoma↗
PubMed2000

p53-dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas.

The mechanisms linking acinar cell apoptosis and ductal epithelial proliferation remain unknown. To determine the relationship between these events, pancreatic duct ligation (PDL) was performed on p53(+/+) and p53(-/-) mice. In mice bearing a wild-type p53 allele, PDL resulted in upregulation of p53 protein in both acinar cells and proliferating duct-like epithelium. In contrast, upregulation of Bcl-2 occurred only in duct-like epithelium. Both p21(WAF1/CIP1) and Bax were also upregulated in duct-ligated lobes. After PDL in p53(+/+) mice, acinar cells underwent widespread apoptosis, while duct-like epithelium underwent proliferative expansion. In the absence of p53, upregulation of p53 target genes and acinar cell apoptosis did not occur. The absence of acinar cell apoptosis in p53(-/-) mice also eliminated the proliferative response to duct ligation. These data demonstrate that PDL-induced acinar cell apoptosis is a p53-dependent event and suggest a direct link between acinar cell apoptosis and proliferation of duct-like epithelium in duct-ligated pancreas.

Animals↗
PubMed1999

Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor alpha.

BACKGROUND & AIMS: The progenitor cells responsible for transforming growth factor (TGF)-alpha-induced pancreatic ductal metaplasia and neoplasia remain uncharacterized. During pancreatic development, differentiated cell types arise from ductal progenitor cells expressing the Pdx1 homeodomain transcription factor. The aims of this study were, first, to evaluate the role of Pdx1-expressing stem cells in MT-TGFalpha transgenic mice, and second, to further characterize cell proliferation and differentiation in this model. METHODS: To assess Pdx1 gene expression in normal and metaplastic epithelium, we performed in vivo reporter gene analysis using heterozygous Pdx1(lacZ/+) and bigenic Pdx1(lacZ/+)/MT-TGFalpha mice. RESULTS: Pdx1(lacZ/+)/MT-TGFalpha bigenics showed up-regulated Pdx1 expression in premalignant metaplastic ductal epithelium. In addition to Pdx1 gene activation, TGF-alpha-induced metaplastic epithelium demonstrated a pluripotent differentiation capacity, as evidenced by focal expression of Pax6 and initiation of islet cell neogenesis. The majority of Pdx1-positive epithelial cells showed no expression of insulin, similar to the pattern observed during embryonic development. CONCLUSIONS: Overexpression of TGF-alpha induces expansion of a Pdx1-expressing epithelium characterized by focal expression of Pax6 and initiation of islet neogenesis. These findings suggest that premalignant events induced by TGF-alpha in mouse pancreas may recapitulate a developmental program active during embryogenesis.

Animals↗
PubMed1999

Response to neoadjuvant chemotherapy best predicts survival after curative resection of gastric cancer.

OBJECTIVE: In Western populations, long-term survival rates after curative resection of gastric cancer remain extremely poor. The lack of effective adjuvant therapy has prompted the evaluation of neoadjuvant approaches. Since 1988, we have conducted three separate phase II trials using neoadjuvant chemotherapy to treat patients with potentially resectable gastric cancer. The present study was conducted to evaluate whether response to neoadjuvant chemotherapy is predictive of survival in patients with resectable gastric cancer. METHODS: Eighty-three patients with pathologically confirmed gastric adenocarcinoma were treated with neoadjuvant chemotherapy before planned surgical resection. Response was assessed by upper gastrointestinal series, endoscopy, computed tomography scan, and pathologic examination. RESULTS: For the three phase II trials, clinical response rates ranged from 24% to 38%. Three patients (4%) had a complete pathologic response. Sixty-one patients (73%) underwent a curative resection. Median follow-up was 26 months. Univariate analysis revealed T stage, number of positive nodes, and response to chemotherapy to be significant predictors of overall survival. However, on multivariate analysis, response to chemotherapy was found to be the only independent prognostic factor. CONCLUSIONS: Response to neoadjuvant chemotherapy is the single most important predictor of overall survival after neoadjuvant chemotherapy for gastric cancer. These findings support further evaluation of neoadjuvant approaches in the treatment of this disease.

Adenocarcinoma↗
PubMed1999

18Fluorodeoxyglucose-positron emission tomography in the management of patients with suspected pancreatic cancer.

OBJECTIVE: To assess the accuracy and clinical impact of 18fluorodeoxyglucose-positron emission tomography (18FDG-PET) on the management of patients with suspected primary or recurrent pancreatic adenocarcinoma, and to assess the utility of 18FDG-PET in grading tumor response to neoadjuvant chemoradiation. SUMMARY BACKGROUND DATA: The diagnosis, staging, and treatment of pancreatic cancer remain difficult. Small primary tumors and hepatic metastases are often not well visualized by computed tomographic scanning (CT), resulting in a high incidence of nontherapeutic celiotomy and the frequent need for "blind resection." In addition, the distinction between local recurrence and nonspecific postoperative changes after resection can be difficult to ascertain on standard anatomic imaging. 18FDG-PET is a new imaging technique that takes advantage of increased glucose metabolism by tumor cells and may improve the diagnostic accuracy of preoperative studies for pancreatic adenocarcinoma. METHODS: Eighty-one 18FDG-PET scans were obtained in 70 patients undergoing evaluation for suspected primary or recurrent pancreatic adenocarcinoma. Of this group, 65 underwent evaluation for suspected primary pancreatic cancer. Nine patients underwent 18FDG-PET imaging before and after neoadjuvant chemoradiation, and in eight patients 18FDG-PET scans were performed for possible recurrent adenocarcinoma after resection. The 18FDG-PET images were analyzed visually and semiquantitatively using the standard uptake ratio (SUR). The sensitivity and specificity of 18FDG-PET and CT were determined for evaluation of the preoperative diagnosis of primary pancreatic carcinoma, and the impact of 18FDG-PET on patient management was retrospectively assessed. RESULTS: Among the 65 patients evaluated for primary tumor, 52 had proven pancreatic adenocarcinoma and 13 had benign lesions. 18FDG-PET had a higher sensitivity and specificity than CT in correctly diagnosing pancreatic carcinoma (92% and 85% vs. 65% and 62%). Eighteen patients (28%) had indeterminate or unrecognized pancreatic masses on CT clarified with 18FDG-PET. Seven patients (11%) had indeterminate or unrecognized metastatic disease clarified with 18FDG-PET. Overall, 18FDG-PET suggested potential alterations in clinical management in 28/65 patients (43%) with suspected primary pancreatic adenocarcinoma. Of the nine patients undergoing 18FDG-PET imaging before and after neoadjuvant chemoradiation, four had evidence of tumor regression by PET, three showed stable disease, and two showed tumor progression. CT was unable to detect any response to neoadjuvant therapy in this group. Eight patients had 18FDG-PET scans to evaluate suspected recurrent disease after resection. Four were noted to have new regions of 18FDG-uptake in the resection bed; four had evidence of new hepatic metastases. All proved to have metastatic pancreatic adenocarcinoma. CONCLUSIONS: These data confirm that 18FDG-PET is useful in the evaluation of patients with suspected primary or recurrent pancreatic carcinoma. 18FDG-PET is more sensitive and specific than CT in the detection of small primary tumors and in the clarification of hepatic and distant metastases. 18FDG-PET was also of benefit in assessing response to neoadjuvant chemoradiation. Although 18FDG-PET cannot replace CT in defining local tumor resectability, the application of 18FDG-PET in addition to CT may alter clinical management in a significant fraction of patients with suspected pancreatic cancer.

Adenocarcinoma↗
PubMed1999

p21(Waf1/Cip1) inhibition of cyclin E/Cdk2 activity prevents endoreduplication after mitotic spindle disruption.

During a normal cell cycle, entry into S phase is dependent on completion of mitosis and subsequent activation of cyclin-dependent kinases (Cdks) in G1. These events are monitored by checkpoint pathways. Recent studies and data presented herein show that after treatment with microtubule inhibitors (MTIs), cells deficient in the Cdk inhibitor p21(Waf1/Cip1) enter S phase with a >/=4N DNA content, a process known as endoreduplication, which results in polyploidy. To determine how p21 prevents MTI-induced endoreduplication, the G1/S and G2/M checkpoint pathways were examined in two isogenic cell systems: HCT116 p21(+/+) and p21(-/-) cells and H1299 cells containing an inducible p21 expression vector (HIp21). Both HCT116 p21(-/-) cells and noninduced HIp21 cells endoreduplicated after MTI treatment. Analysis of G1-phase Cdk activities demonstrated that the induction of p21 inhibited endoreduplication through direct cyclin E/Cdk2 regulation. The kinetics of p21 inhibition of cyclin E/Cdk2 activity and binding to proliferating-cell nuclear antigen in HCT116 p21(+/+) cells paralleled the onset of endoreduplication in HCT116 p21(-/-) cells. In contrast, loss of p21 did not lead to deregulated cyclin D1-dependent kinase activities, nor did p21 directly regulate cyclin B1/Cdc2 activity. Furthermore, we show that MTI-induced endoreduplication in p53-deficient HIp21 cells was due to levels of p21 protein below a threshold required for negative regulation of cyclin E/Cdk2, since ectopic expression of p21 restored cyclin E/Cdk2 regulation and prevented endoreduplication. Based on these findings, we propose that p21 plays an integral role in the checkpoint pathways that restrain normal cells from entering S phase after aberrant mitotic exit due to defects in microtubule dynamics.

CDC2-CDC28 Kinases↗
PubMed1999

Adjuvant/neoadjuvant chemoradiation for gastric and pancreatic cancer.

Both gastric and pancreatic cancer remain leading causes of cancer death in the United States and worldwide. While surgical resection continues to be required for long-term cure of both these neoplasms, 5-year survival rates remain poor following surgery alone. For both gastric and pancreatic cancers, studies examining patterns of recurrence following apparently curative resection repeatedly demonstrate high rates of locoregional relapse. In this setting, the addition of chemoradiation delivered either before or following surgery represents a logical strategy to improve local tumor control and possibly improve survival. Data suggest that 5-fluorouracil-based chemoradiation, when given at sufficient doses, can effectively palliate patients with unresectable gastric cancer. Whether this approach improves response and survival in patients with resectable gastric cancer remains investigational. Results of ongoing and recently completed trials will provide further information on the utility of 5-fluorouracil-based regimens, as well as the use of other radiation sensitizers, in the adjuvant setting. In patients with resectable pancreatic cancer, the primary goal should be to perform a margin-negative pancreaticoduodenectomy. The use of neoadjuvant chemoradiation may increase the likelihood of achieving this goal, and this approach is being investigated.

Adenocarcinoma↗
PubMed1999

Optimal interpretation of FDG PET in the diagnosis, staging and management of pancreatic carcinoma.

UNLABELLED: This study had two purposes: to optimize the semiquantitative interpretation of 18F-fluorodeoxyglucose (FDG) PET scans in the diagnosis of pancreatic carcinoma by analyzing different cutoff levels for the standardized uptake value (SUV), with and without correction for serum glucose level (SUV(gluc)); and to evaluate the usefulness of FDG PET when used in addition to CT for the staging and management of patients with pancreatic cancer. METHODS: Sixty-five patients who presented with suspected pancreatic carcinoma underwent whole-body FDG PET in addition to CT imaging. The PET images were analyzed visually and semiquantitatively using the SUV and SUV(gluc). The final diagnosis was obtained by pathologic (n = 56) or clinical and radiologic follow-up (n = 9). The performance of CT and PET at different cutoff levels of SUV was determined, and the impact of FDG PET in addition to CT on patient management was reviewed retrospectively. RESULTS: Fifty-two patients had proven pancreatic carcinoma, whereas 13 had benign lesions, including chronic pancreatitis (n = 10), benign biliary stricture (n = 1), pancreatic complex cyst (n = 1) and no pancreatic pathology (n = 1). Areas under receiver operating characteristic curves were not significantly different for SUV and SUV(gluc). Using a cutoff level of 3.0 for the SUV, FDG PET had higher sensitivity and specificity than CT in correctly diagnosing pancreatic carcinoma (92% and 85% versus 65% and 61%). There were 2 false-positive PET (chronic pancreatitis, also false-positive with CT) and 4 false-negative PET (all with true-positive CT, abnormal but nondiagnostic) examinations. There were 5 false-positive CT (4 chronic pancreatitis and 1 pancreatic cyst) and 18 false-negative CT (all with true-positive FDG PET scans) examinations. FDG PET clarified indeterminate hepatic lesions or identified additional distant metastases (or both) in 7 patients compared with CT. Overall, FDG PET altered the management of 28 of 65 patients (43%). CONCLUSION: FDG PET is more accurate than CT in the detection of primary tumors and in the clarification and identification of hepatic and distant metastases. The optimal cutoff value of FDG uptake to differentiate benign from malignant pancreatic lesions was 2.0. Correction for serum glucose did not significantly improve the accuracy of FDG PET. Although FDG PET cannot replace CT in defining local tumor extension, the application of FDG PET in addition to CT alters the management in up to 43% of patients with suspected pancreatic cancer.

Adenocarcinoma↗
PubMed1998

Mitotic phosphorylation of Bcl-2 during normal cell cycle progression and Taxol-induced growth arrest.

There is increasing evidence that prolonged mitotic arrest initiates apoptosis; however, little is known about the signaling pathways involved. Several studies have associated deregulated Cdc2 activity with apoptosis. Herein, we report that the anti-apoptotic protein, Bcl-2, undergoes cell cycle-dependent phosphorylation during mitosis when there is elevated Cdc2 activity. We found that paclitaxel (Taxol(R)) treatment of epithelial tumor cells induced a prolonged mitotic arrest, elevated levels of mitotic kinase activity, hyperphosphorylation of Bcl-2, and subsequent cell death. The Taxol-induced Bcl-2 phosphorylation was dose-dependent. Furthermore, phosphorylated Bcl-2 remained complexed with Bax in Taxol-treated cells undergoing apoptosis. Immunoprecipitation experiments revealed a Bcl-2-associated kinase capable of phosphorylating histone H1 in vitro. However, the kinase was likely not cyclin B1/Cdc2, since cyclin B1/Cdc2 was not detectable in Bcl-2 immunoprecipitates, nor was recombinant Bcl-2 phosphorylated in vitro by cyclin B1/Cdc2. The results of this study further define a link between mitotic kinase activation and the apoptotic machinery in the cell. However, the role, if any, of prolonged Bcl-2 phosphorylation in Taxol-mediated apoptosis awaits further definition of Bcl-2 mechanism of action. Taxol may increase cellular susceptibility to apoptosis by amplifying the normal downstream events associated with mitotic kinase activation.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Negative regulation of Wee1 expression and Cdc2 phosphorylation during p53-mediated growth arrest and apoptosis.

The G2 cell cycle checkpoint protects cells from potentially lethal mitotic entry after DNA damage. This checkpoint involves inhibitory phosphorylation of Cdc2 at the tyrosine-15 (Y15) position, mediated in part by the Wee1 protein kinase. Recent evidence suggests that p53 may accelerate mitotic entry after DNA damage and that the override of the G2 checkpoint may play a role in the induction of apoptosis by p53. To determine the biochemical mechanism by which p53 inactivates the G2 checkpoint, the effects of p53 activation on Wee1 expression, Cdc2-Y15 phosphorylation, and cyclin B1-associated Cdc2 kinase activity were examined. Under conditions of either growth arrest or apoptosis, p53 activation resulted in the down-regulation of Wee1 expression and dephosphorylation of Cdc2. A parallel increase in cyclin B1/Cdc2 kinase activity was observed during p53-mediated apoptosis. Negative regulation of the Wee1 expression and Cdc2 phosphorylation by p53 was also evident in thymus tissue from p53+/+ mice but not from p53-/- mice. Inactivation of the G2 checkpoint may contribute to the tumor suppressor activity of p53.

Animals↗
PubMed1998

Survival following pancreaticoduodenectomy with resection of the superior mesenteric-portal vein confluence for adenocarcinoma of the pancreatic head.

BACKGROUND: The survival of patients who underwent pancreaticoduodenectomy with or without en bloc resection of the superior mesenteric-portal vein (SMPV) confluence for adenocarcinoma of the pancreatic head was compared. METHODS: To be considered for surgery, patients were required to fulfil the following computed tomography criteria for resectability: (1) absence of extrapancreatic disease, (2) no evidence of tumour extension to the superior mesenteric artery (SMA) or coeliac axis, and (3) a patent SMPV confluence. Tumour adherence to the superior mesenteric vein (SMV) or SMPV confluence was assessed at operation and en bloc venous resection was performed when necessary to achieve complete tumour extirpation. RESULTS: Seventy-five consecutive patients underwent pancreaticoduodenectomy, 44 without venous resection and 31 with en bloc resection of the SMPV confluence. There were no perioperative deaths in either group; late (more than 6 months) occlusion of the reconstructed SMPV confluence contributed to the death of two patients. Median survival in the 31 patients who required venous resection at the time of pancreaticoduodenectomy was 22 months, and that for the 44 control patients was 20 months (P = 0.25). CONCLUSION: Patients with adenocarcinoma of the pancreatic head who require venous resection during pancreaticoduodenectomy for isolated tumour extension to the SMV or SMPV confluence (in the absence of tumour extension to the SMA or coeliac axis) have a duration of survival no different from that of patients who undergo standard pancreaticoduodenectomy. These data suggest that venous involvement is a function of tumour location rather than an indicator of aggressive tumour biology.

Adult↗
PubMed1998

Enhanced Krev-1 expression inhibits the growth of pancreatic adenocarcinoma cells.

Pancreatic ductal adenocarcinoma is characterized by a high rate of activating mutations involving codon 12 of the K-ras protooncogene. As a means of ras-targeted intervention, the effects of enhanced Krev-1 gene expression on the growth and tumorigenicity of the hamster pancreatic adenocarcinoma cell line PC-1 were evaluated. Overexpression of the Krev-1 gene product resulted in morphologic reversion to a less transformed phenotype, as well as retarded growth kinetics and diminished potential for anchorage-independent growth. Among six transfected cell lines, the magnitude of these changes correlated with the degree of Krev-1 overexpression as assessed by Western blot. When PC-1 cells overexpressing high levels of the Krev-1 gene product were assessed for tumorigenicity in syngeneic animals, an increased latency to tumor growth and a decreased tumor size were noted. The results confirm that overexpression of the Krev-1 gene may provide a useful strategy for ras-targeted intervention in this disease.

Adenocarcinoma↗
PubMed1997

Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma.

BACKGROUND: The prognosis for patients with extrahepatic bile duct cancer remains poor. The purpose of this study was to evaluate our initial results with preoperative chemoradiation for extrahepatic cholangiocarcinoma, in the context of our experience with conventional treatment of this disease over the past 13 years. METHODS: From 1983 through 1996, analysis of all patients treated for extrahepatic cholangiocarcinoma was performed. RESULTS: Of 91 total patients, 51 had unresectable disease and 40 underwent resection. Median survival was significantly different for patients who underwent resection (22.2 months) versus those treated palliatively (10.7 months; P <0.0001). Nine patients underwent preoperative chemoradiation (5 perihilar, 4 distal) prior to resection. Three patients in the preoperative chemoradiation group had a pathologic complete response, while the remainder showed varying degrees of histologic response to treatment. The rate of margin-negative resection was 100% for the preoperative chemoradiation group versus 54% for the group who did not receive preoperative chemoradiation (P <0.01). There were no major intra-abdominal complications in the patients treated with preoperative chemoradiation. CONCLUSIONS: These results suggest that preoperative chemoradiation for extrahepatic bile duct cancer can be performed safely, produces significant antitumor response, and may improve the ability to achieve tumor-free resection margins. Additional trials of preoperative chemoradiation are warranted.

Adult↗