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Predictive factors for malignancy or invasive carcinoma in intraductal papillary-mucinous neoplasms (IPMN) of the pancreas
Vol. 9, No. 4 2005
this protein co-localizes to the ER in COS-7 cells. Western blot analysis of Myc-conjugated protein identified the protein in the insoluble fraction. Loss of heterozygosity (LOH) was studied in a cohort of patients with history of pancreatic cancer. We detected over 40% rate of LOH using an intragenic microsatellite marker. We have demonstrated a novel gene that is disrupted by chromosomal rearrangement in a pancreatic cancer patient. The protein product has a motif important in cancer-related pathways. We have observed the loss of this gene in cancer cell lines and in over 40% of pancreatic cancer patients. Further characterization of the gene and its isoforms to confirm the potential tumor suppresser activity and mutation screening is currently ongoing.
22 Bcl-XL DEPLETION SENSITIZES PANCREATIC CANCER CELLS TO LIGAND-MEDIATED APOPTOSIS Jirong Bai, DVM, PhD, Aram N. Demirjian, MD, Charles M. Vollmer, Jr., MD, Mark P. Callery, MD, Beth Israel Deaconess Medical Center, Boston, MA To identify potential molecular mechanisms underlying the profound chemoresistance of pancreatic cancer, we examined the expression and potency of three major death receptors, TNF-R, TRAIL-R, and Fas, in mediating cytotoxicity in four invasive pancreatic cancer cell lines. In addition, we analyzed the expression of major anti-apoptotic factors, cell cycle regulators, and death receptor decoys (DcRs) in comparison with normal pancreas tissues and five other human malignant tumor cell lines. Different pancreatic cancer cell lines coexpressed high-levels of TRAIL-R, Fas, and TNF-R1, but were strongly resistant to apoptosis triggered by those death receptors. DcR2 and DcR3 were overexpressed and this coincided with the resistance of pancreatic cancer cells to TRAIL-R and Fas-mediated cytotoxicity. Bcl-XL was predominantly overexpressed in certain pancreatic cancer cell lines, and was also overexpressed in prostate, colorectal and intestinal cancer cells. To determine whether targeted downregulation of Bcl-XL could disable anti-apoptotic mechanisms responsible for chemoresistance, we used RNA interference (RNAi) to knockdown its expression. BclXL knockdown significantly reduced the viability of pancreatic cancer cells to TNF-α and TRAIL-mediated apoptosis. Furthermore, this cytotoxicity was significantly potentiated when Bcl-XL knockdown cells were exposed to novel sublethal-dose antitumor regimens that included geldanamycin (GA), PS-341, Trichostatin A, and Doxorubicin. Geldanamyin and PS-341, in particular, synergistically blocked NF-κB activation, suppressed the Akt/PKB pathway, and downregulated Bcl-2, cIAP-1 and cyclin D1 expression. These alterations of anti-apoptotic and cell cycle checkpoints are likely critical in ligandmediated cytotoxicity, since GA and PS-341 combined dramatically enhanced the cytotoxic effects of TRAIL and fully broke through chemoresistance. Bcl-XL plays a vital role in pancreatic cancer chemoresistance, and its selective depletion may contribute to novel drug design strategies for the treatment of pancreatic cancer.
23 MICROVESSEL DENSITY CORRELATES WITH LYMPH NODE METASTASIS, BUT NOT WITH PROGNOSIS, IN HUMAN PANCREATIC CANCER Christoph Benckert, MD, Armin Thelen, MD, Guido Schumacher, MD, Jan Langrehr, MD, Peter Neuhaus, MD, Sven Jonas, MD, Humboldt University, Charite´, Campus-Virchow Clinic, Berlin, Germany; Humboldt University, Charite´, Campus-Virchow Clinic, Berlin, Germany Microvessel density (MVD) has been described as a poor prognostic marker in many malignant diseases. We compared the quantitative
Abstracts
529
expression of the MVD and vascular endothelial growth factor (VEGF) in normal, inflamed and malignantly transformed pancreatic tissue and determined the prognostic relevance. In 47 tissue samples from patients with adenocarcinoma of the pancreas, 18 of these with nontransformed pancreatic tissue at the resection margins, 11 samples from patients with chronic pancreatitis, who all underwent the Whipple procedure, VEGF and MVD were determined after immunostaining with a CD31 specific monoclonal antibody according to the method of Weidner et al. MVD was correlated with WHO classification, histopathologic grading, lymph node status, tumor size and survival. MVD ranged from 28 to 189 vessels/field. MVD was significantly higher in transformed compared to nontransformed pancreatic tissue (P ⭐ 0.01). Lymph node positive pancreatic tumor specimen showed a higher MVD than lymph node negative tumors (P ⭐ 0.001). No correlation between MVD and survival, tumor size or histopathological grading was found. In a multivariate analysis no prognostic factors for survival were identified. VEGF was expressed in transformed as well as in nontransformed pancreatic tissue and no significant differences were observed. MVD does not provide a useful prognostic marker for patients suffering from pancreatic cancer. The correlation between MVD and lymph node status suggests a role for angiogenesis in early lymphatic metastasis. MVD is significantly higher in transformed compared to nontransformed pancreatic tissue and may serve as an additional diagnostic marker to differentiate chronic pancreatitis from pancreatic cancer.
24 PREDICTIVE FACTORS FOR MALIGNANCY OR INVASIVE CARCINOMA IN INTRADUCTAL PAPILLARY-MUCINOUS NEOPLASMS (IPMN) OF THE PANCREAS Ken-ichiro Uemura, MD, Yoshiaki Murakami, MD, Mahiko Morifuji, MD, Yasuo Hayashidani, MD, Takeshi Sudo, MD, Taijiro Sueda, MD, Hiroshima University Hospital, Hiroshima, Japan Recently, organ-preserving pancreatic resections for intraductal papillary-mucinous neoplasms (IPMNs) have been reported. Preoperative differential diagnosis between benign and malignant IPMNs, or between non-invasive and invasive IPMNs is crucial for these procedures. The purpose of present study was to identify useful predictive factors for malignant or invasive IPMNs of pancreas by univariate and multivariate analysis. Sixty-two patients with IPMNs of pancreas treated surgically at Hiroshima University Hospital from 1990 to 2003 were reviewed. These patients consisted of 29 patients with adenoma, 10 patients with borderline lesion, 11 patients with noninvasive carcinoma, and 12 patients with invasive carcinoma (according to WHO classification of tumors). Preoperative predictive factors of malignant or invasive IPMNs were analyzed among 10 factors by univariate and multivariate analysis. Size of cystic mass (⭓28 mm), diameter of main pancreatic duct (⭓6 mm), presence of patulous papilla, and cytological examinations of pancreatic juice (the presence of malignant cells) were associated with malignancy by univariate analysis (P ⬍ 0.05). Diameter of main pancreatic duct (⭓6 mm) and cytological examination of pancreatic juice were identified as independent predictive factors of malignant IPMNs by multivariate analysis (P ⬍ 0.05). Size of cystic mass (⭓28 mm), diameter of main pancreatic duct (⭓6 mm), presence of patulous papilla, mural nodule, and malignant cells in pancreatic juice were associated with invasive IPMNs by univariate analysis (P ⬍ 0.05). Only presence of malignant cells in pancreatic juice by cytological examination was identified as an independent predictor of invasive IPMNs by multivariate analysis (P ⬍ 0.05). Carried out single-institution analysis showed predictive factors for malignant or invasive IPMNs of pancreas. These factors should be considered in the preoperative diagnosis of IPMNs to facilitate appropriate surgical management.
this protein co-localizes to the ER in COS-7 cells. Western blot analysis of Myc-conjugated protein identified the protein in the insoluble fraction. Loss of heterozygosity (LOH) was studied in a cohort of patients with history of pancreatic cancer. We detected over 40% rate of LOH using an intragenic microsatellite marker. We have demonstrated a novel gene that is disrupted by chromosomal rearrangement in a pancreatic cancer patient. The protein product has a motif important in cancer-related pathways. We have observed the loss of this gene in cancer cell lines and in over 40% of pancreatic cancer patients. Further characterization of the gene and its isoforms to confirm the potential tumor suppresser activity and mutation screening is currently ongoing.
22 Bcl-XL DEPLETION SENSITIZES PANCREATIC CANCER CELLS TO LIGAND-MEDIATED APOPTOSIS Jirong Bai, DVM, PhD, Aram N. Demirjian, MD, Charles M. Vollmer, Jr., MD, Mark P. Callery, MD, Beth Israel Deaconess Medical Center, Boston, MA To identify potential molecular mechanisms underlying the profound chemoresistance of pancreatic cancer, we examined the expression and potency of three major death receptors, TNF-R, TRAIL-R, and Fas, in mediating cytotoxicity in four invasive pancreatic cancer cell lines. In addition, we analyzed the expression of major anti-apoptotic factors, cell cycle regulators, and death receptor decoys (DcRs) in comparison with normal pancreas tissues and five other human malignant tumor cell lines. Different pancreatic cancer cell lines coexpressed high-levels of TRAIL-R, Fas, and TNF-R1, but were strongly resistant to apoptosis triggered by those death receptors. DcR2 and DcR3 were overexpressed and this coincided with the resistance of pancreatic cancer cells to TRAIL-R and Fas-mediated cytotoxicity. Bcl-XL was predominantly overexpressed in certain pancreatic cancer cell lines, and was also overexpressed in prostate, colorectal and intestinal cancer cells. To determine whether targeted downregulation of Bcl-XL could disable anti-apoptotic mechanisms responsible for chemoresistance, we used RNA interference (RNAi) to knockdown its expression. BclXL knockdown significantly reduced the viability of pancreatic cancer cells to TNF-α and TRAIL-mediated apoptosis. Furthermore, this cytotoxicity was significantly potentiated when Bcl-XL knockdown cells were exposed to novel sublethal-dose antitumor regimens that included geldanamycin (GA), PS-341, Trichostatin A, and Doxorubicin. Geldanamyin and PS-341, in particular, synergistically blocked NF-κB activation, suppressed the Akt/PKB pathway, and downregulated Bcl-2, cIAP-1 and cyclin D1 expression. These alterations of anti-apoptotic and cell cycle checkpoints are likely critical in ligandmediated cytotoxicity, since GA and PS-341 combined dramatically enhanced the cytotoxic effects of TRAIL and fully broke through chemoresistance. Bcl-XL plays a vital role in pancreatic cancer chemoresistance, and its selective depletion may contribute to novel drug design strategies for the treatment of pancreatic cancer.
23 MICROVESSEL DENSITY CORRELATES WITH LYMPH NODE METASTASIS, BUT NOT WITH PROGNOSIS, IN HUMAN PANCREATIC CANCER Christoph Benckert, MD, Armin Thelen, MD, Guido Schumacher, MD, Jan Langrehr, MD, Peter Neuhaus, MD, Sven Jonas, MD, Humboldt University, Charite´, Campus-Virchow Clinic, Berlin, Germany; Humboldt University, Charite´, Campus-Virchow Clinic, Berlin, Germany Microvessel density (MVD) has been described as a poor prognostic marker in many malignant diseases. We compared the quantitative
Abstracts
529
expression of the MVD and vascular endothelial growth factor (VEGF) in normal, inflamed and malignantly transformed pancreatic tissue and determined the prognostic relevance. In 47 tissue samples from patients with adenocarcinoma of the pancreas, 18 of these with nontransformed pancreatic tissue at the resection margins, 11 samples from patients with chronic pancreatitis, who all underwent the Whipple procedure, VEGF and MVD were determined after immunostaining with a CD31 specific monoclonal antibody according to the method of Weidner et al. MVD was correlated with WHO classification, histopathologic grading, lymph node status, tumor size and survival. MVD ranged from 28 to 189 vessels/field. MVD was significantly higher in transformed compared to nontransformed pancreatic tissue (P ⭐ 0.01). Lymph node positive pancreatic tumor specimen showed a higher MVD than lymph node negative tumors (P ⭐ 0.001). No correlation between MVD and survival, tumor size or histopathological grading was found. In a multivariate analysis no prognostic factors for survival were identified. VEGF was expressed in transformed as well as in nontransformed pancreatic tissue and no significant differences were observed. MVD does not provide a useful prognostic marker for patients suffering from pancreatic cancer. The correlation between MVD and lymph node status suggests a role for angiogenesis in early lymphatic metastasis. MVD is significantly higher in transformed compared to nontransformed pancreatic tissue and may serve as an additional diagnostic marker to differentiate chronic pancreatitis from pancreatic cancer.
24 PREDICTIVE FACTORS FOR MALIGNANCY OR INVASIVE CARCINOMA IN INTRADUCTAL PAPILLARY-MUCINOUS NEOPLASMS (IPMN) OF THE PANCREAS Ken-ichiro Uemura, MD, Yoshiaki Murakami, MD, Mahiko Morifuji, MD, Yasuo Hayashidani, MD, Takeshi Sudo, MD, Taijiro Sueda, MD, Hiroshima University Hospital, Hiroshima, Japan Recently, organ-preserving pancreatic resections for intraductal papillary-mucinous neoplasms (IPMNs) have been reported. Preoperative differential diagnosis between benign and malignant IPMNs, or between non-invasive and invasive IPMNs is crucial for these procedures. The purpose of present study was to identify useful predictive factors for malignant or invasive IPMNs of pancreas by univariate and multivariate analysis. Sixty-two patients with IPMNs of pancreas treated surgically at Hiroshima University Hospital from 1990 to 2003 were reviewed. These patients consisted of 29 patients with adenoma, 10 patients with borderline lesion, 11 patients with noninvasive carcinoma, and 12 patients with invasive carcinoma (according to WHO classification of tumors). Preoperative predictive factors of malignant or invasive IPMNs were analyzed among 10 factors by univariate and multivariate analysis. Size of cystic mass (⭓28 mm), diameter of main pancreatic duct (⭓6 mm), presence of patulous papilla, and cytological examinations of pancreatic juice (the presence of malignant cells) were associated with malignancy by univariate analysis (P ⬍ 0.05). Diameter of main pancreatic duct (⭓6 mm) and cytological examination of pancreatic juice were identified as independent predictive factors of malignant IPMNs by multivariate analysis (P ⬍ 0.05). Size of cystic mass (⭓28 mm), diameter of main pancreatic duct (⭓6 mm), presence of patulous papilla, mural nodule, and malignant cells in pancreatic juice were associated with invasive IPMNs by univariate analysis (P ⬍ 0.05). Only presence of malignant cells in pancreatic juice by cytological examination was identified as an independent predictor of invasive IPMNs by multivariate analysis (P ⬍ 0.05). Carried out single-institution analysis showed predictive factors for malignant or invasive IPMNs of pancreas. These factors should be considered in the preoperative diagnosis of IPMNs to facilitate appropriate surgical management.