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M2030 Geographic and Patient-Level Variations in Utilization of Endoscopic Ultrasonography in Patients with Pancreatic Cancer
AGA Abstracts
received chemotherapy with low dose gemcitabine (800-1000mg/body) on days 1, 8, and 15 every 4 weeks, or observation. Results: Twenty-one patients had locally advanced cancer, and 38 had metastatic pancreatic cancer. Thirty-nine patients had Eastern Cooperative Oncology Group performance status of 0 to 2, and 19 had the performance status of 3. Thirty-five patients received the chemotherapy. Five could not complete the chemotherapy of one cycle. Of 30 patients receiving the chemotherapy of more than 1 cycle, 1 achieved partial response and 11 disease stabilisation; however, progressive disease was noted in 18 patients. Median survival time was 8.0 months and 3.0 months, respectively, in patients receiving the chemotherapy and observation. In 58 patients, chemotharpay with low dose gemcitabine (odds ratio 6.84, 95% confidence interval 1.04-44.8, P = 0.04) and no metastasis (odds ratio 13.0, 95% confidence interval 2.50-67.4, P = 0.002) were associated with 6month survival by using multivariate logistic regression analysis, and performance status was not selected. Patients with disease stabilization had better survival than those with progressive disease (median survival time 13.2 months versus 6.7 months, P = 0.02, BreslowGehan-Wilcoxon). Furthermore, patients with progressive disease had better survival than those with those receiving observation (P = 0.02, Breslow-Gehan-Wilcoxon). Conclusion: This study indicates that the chemotherapy with low dose gemcitabine may improve the prognosis of elderly patients with unresectable advanced pancreatic cancer. We consider that, even in elderly patients, the effect of gemcitabine is worth investigating in future studies.
and requires expensive instruments and trained personnel, these differences are also likely to be true with respect to other gastrointestinal cancers. M2031 Tumor-Associated Macrophages (TAMS) Are Poor Prognostic Indicators in Pancreatic Cancer James J. Farrell, Miguel Garcia, Adam P. Dicker, Chandan Guha, Hany Elsaleh Background:The importance of inflammation in the development of pancreatic cancer is well established. However, the role that inflammation plays in pancreatic cancer prognosis and response to treatment remains unclear. Tumor-associated macrophages (TAMs) are a major component of the protumor function of inflammation through a variety of proposed mechanisms, including suppression of immune function, matrix remodeling capacity, synthesis of growth and angiogenesis factors, intravasation, and seeding at distant sites. While TAMs have been associated with tumor growth, metastasis and poor prognosis in other cancers, their role in human pancreatic cancer, often characterized by extensive stroma, is undefined. We studied the prognostic value of TAMs in a cohort of pancreatic adenocarcinoma patients from RTOG 9704, a large prospective randomized adjuvant treatment trial. Methods: RTOG 9704 randomized 538 patients after surgical resection of pancreatic adenocarcinoma to treatment containing either 5-FU or gemcitabine. A tissue microarray was constructed using three separate cores from 225 resected pancreatic tumors from RTOG 9704. Immunohistochemistry for CD68 positive staining TAMs in the peritumoral stroma was performed and scored as having low or high staining. Associations between CD68 staining level and tumor stage and treatment outcomes, were analyzed by the Cox proportional hazards model. The two treatment arms of the study were analyzed separately and together. A Hazard Ratio (HR) > 1 indicates an increased risk of death for the high staining CD 68 group. Results: Of the 538 patients entered into RTOG 9704, 198 from both arms of the study were eligible and had analyzable CD68. High expression of CD68 was seen in 34 (17%) of analyzable cases. There was no association between CD68 expression and tumor stage. By both univariate (H.R. 1.63 ( 95% CI(1.08, 2.44), p=0.02) and multivariate analysis (after adjusting for nodal status:H.R. 1.63 ( 95% CI(1.08, 2.44), p=0.02), high CD 68 expression was associated with worse overall survival, irrespective of treatment arm. Overall, the median survival was 1.18 yrs for the high CD68 expressing group and 1.47 yrs for the low CD68 group. Conclusion: In this prospective randomized trial, immunohistochemical evaluation of resectable pancreatic cancer shows that TAMs are associated with a poor outcome independent of other established prognostic indicators including tumor stage. While this is the first evidence of its kind in human pancreatic cancer, further study of the specific mechanism of the protumor action of TAMs and of possible treatment strategies aimed at modulation of TAMs in pancreatic cancer is warranted.
M2029 Expression of MRP2 (Multidrug Resistance-Associated Protein2) Regulates the Drug Resistance of Human Pancreatic Cancer Bunjiro Noma, Tamito Sasaki, Yoshifumi Fujimoto, Kenichi Kuwahara, Masahiro Serikawa, Kenso Kobayashi, Hiroshi Ituki, Kazuaki Chayama Backgrounds. Now, GEM has come to be the standard treatment for advanced pancreatic cancer, but the prognosis is insufficient. Therefore, the effectiveness of combination chemotherapy such as GEM + CDDP is examined. On the other hand, there is a report that multidrug resistance-associated proteins 2 (MRP2) takes part in the decrease in sensitivity of CDDP to several kind of cancers. However, the relation between MRP2 and CDDP has not been reported in the pancreatic cancer. The aims of this study was to examine the expression of the MRP2 and to evaluate the correlation between MRP2 and CDDP resistance in human pancreatic cancer. Methods. In our present study, we used five human pancreatic cancer cell lines (PANC-1, MIAPaCa-2, Capan-2, BXPC-3 and SUIT-2)and surgically resected human pancreatic tissues, and experimented on RT-PCR, real-time PCR and immunohistochemistry to confirm the expression of MRP2 mRNA and protein. Next, we made a CDDPresistant variants (SUIT-2-CD3 and SUIT-2-CD4) by administering 10 nM CDDP to pancreatic cancer cell lines (SUIT-2) continuously for three and four months, respectively. We continuously examined the change of the MRP2 mRNA expression by Real-time PCR. Afterwards, we cultivated the cells with CDDP in the presence of anti-MRP2 antibody or MK-571 (MRP2-inhibitor), an experiment of the growth inhibition assay was performed by using a Cell proliferation ELISA system. Result. RT-PCR demonstrated that the expression of MRP2 mRNA was detected in all pancreatic cancer cell lines. In human pancreatic cancer tissues, we experimented on RT-PCR and real-time PCR, and confirmed that the expression of MRP2 mRNA in cancer lesions was higher than that in matched normal pancreas, ranging from 1.2 to 30 fold. On immunohistochemistry, MRP2 protein expression was found in 77.5% (31/40) cancer tissues, mainly in the cytoplasm of cancer cells, but was not observed in normal pancreatic tissue. The growth inhibition assay demonstrated that the CDDPresistant variants were more resistant to CDDP than the parent cell line, and this resistance was diminished by anti-MRP2 antibody and MK-571. Moreover, the induction of MRP2 mRNA in the CDDP-resistant variants was increased compared to parent cells by 1.5 and 2.5 fold, respectively. Conclusion. These observations suggest that MRP2 may correlate to CDDP resistance in human pancreatic cancer. Moreover MRP2 expression may be considered as a novel chemoresistance marker in patients with pancreatic cancer treated with CDDPbased chemotherapy. And in the pancreatic cancer with treatement of CDDP, MRP2 may become the target of the improvement of sensitivity.
M2032 Efficacy of Endoscopic Ultrasound (EUS) Guided Celiac Plexus Neurolysis (CPN) for Managing Abdominal Pain Associated with Pancreas Cancer: A Meta-Analysis Gurpreet Singh, Marina S. Kaufman, Jonathan A. Erber, Sourish Das, Carlos Micames, Bogdan Cristescu, Frank G. Gress Background: Chronic abdominal pain due to Pancreas cancer is often difficult to control and a challenging problem for the Gastroenterologist. Treatment options include non-opioid analgesics, pancreatic enzymes, opioid analgesics, and CPN. In EUS-guided CPN, alcohol or phenol is injected into the celiac plexus to induce neurolysis. Only a few studies have been performed, but the sparse data reports a significant benefit and supports its efficacy for alleviating abdominal pain in Pancreas cancer and its use, therefore, remains controversial. Aim: To evaluate the efficacy of EUS-guided CPN in alleviating chronic abdominal pain due to Pancreas cancer. Methods: Using Medline and Embase databases through October 2007, a thorough search of the English literature for prospective trials evaluating the efficacy of EUS-CPN for the management of chronic abdominal pain in Pancreas cancer was conducted, along with a hand search of reference lists. Patients had known or suspected Pancreas cancer by EUS and/or CT scan findings, and required narcotic analgesics for pain control. Studies that involved less than 10-patients were excluded. Data on pain relief was extracted, pooled, and analyzed. A Bayesian Hierarchical model for Meta Analysis was developed. Results: 4relevant studies were identified, comprising a total of 129 patients. EUS-guided CPN was effective in alleviating abdominal pain in 74.52% of patients (95% CI 0.4829, 0.9407), Figure1. Conclusion: Meta-analysis demonstrates that EUS-guided CPN results in the reduction of abdominal pain due to Pancreas cancer in at least 75% of patients. Appropriate patient selection, timing, and refinement in technique will likely lead to improved efficacy.
M2030 Geographic and Patient-Level Variations in Utilization of Endoscopic Ultrasonography in Patients with Pancreatic Cancer Feng Li, Ying Zhou, Amitabh Chak, Gregory S. Cooper, Ananya Das Endoscopic ultrasonography (EUS) is frequently used in the evaluation and staging of patients with pancreatic cancers. No information currently exists regarding geographic and patientlevel variations in the utilization of EUS procedures in these patients. Objective: To study the association of sociodemographic and geographic factors with receipt of EUS. Methods: We identified all persons aged 66 years or older, who were recently diagnosed with pancreatic cancer, resided in a SEER area, and were captured in both the SEER cancer registry and the Medicare claims database between January 1994, and December 2002. The association of categorical variables with performance of EUS was assessed by Chi-square test. A logistic regression model was developed with performance of EUS as the dependent variable to study the independent association of these demographic and clinical variables. Results: We identified 10,716 patients with pancreatic cancer (10% with local stage, 30.8% with regional stage, 59.2% with metastatic cancer) during the study period. Only 767 (7.2%) patients had a EUS examination for tumor evaluation and staging. Evaluation with EUS was significantly more common in patients younger than 75 years (9.2% vs. 5.4% , P < 0.0001), white patients (7.6% vs. 5.1%, p <0.001), in men (7.9% vs. 6.6%, p <0.02), married (8.7% vs. 5.6%, p < 0.001) and with loco-regional tumor stage (12.6% vs. 3.5%, p < 0.0001). Patients who received EUS were more likely to live in locales with lower poverty level, lower percentage of population with less than high school level education and also, with lower percentage of blacks at census tract level. There was marked variation in the rates of utilization of EUS in different SEER locations with rates ranging from 1.2% to 14.8% in different SEER registry areas. In multivariate analysis, age, gender, race, marital status, and stage and also, SEER location were significant predictors of utilization of EUS. Conclusion: There is significant geographic and some patient-level variations in the utilization of EUS procedure for evaluation of pancreatic cancer. Given that EUS is a technically sophisticated investigation,
AGA Abstracts
Figure 1
A-454
received chemotherapy with low dose gemcitabine (800-1000mg/body) on days 1, 8, and 15 every 4 weeks, or observation. Results: Twenty-one patients had locally advanced cancer, and 38 had metastatic pancreatic cancer. Thirty-nine patients had Eastern Cooperative Oncology Group performance status of 0 to 2, and 19 had the performance status of 3. Thirty-five patients received the chemotherapy. Five could not complete the chemotherapy of one cycle. Of 30 patients receiving the chemotherapy of more than 1 cycle, 1 achieved partial response and 11 disease stabilisation; however, progressive disease was noted in 18 patients. Median survival time was 8.0 months and 3.0 months, respectively, in patients receiving the chemotherapy and observation. In 58 patients, chemotharpay with low dose gemcitabine (odds ratio 6.84, 95% confidence interval 1.04-44.8, P = 0.04) and no metastasis (odds ratio 13.0, 95% confidence interval 2.50-67.4, P = 0.002) were associated with 6month survival by using multivariate logistic regression analysis, and performance status was not selected. Patients with disease stabilization had better survival than those with progressive disease (median survival time 13.2 months versus 6.7 months, P = 0.02, BreslowGehan-Wilcoxon). Furthermore, patients with progressive disease had better survival than those with those receiving observation (P = 0.02, Breslow-Gehan-Wilcoxon). Conclusion: This study indicates that the chemotherapy with low dose gemcitabine may improve the prognosis of elderly patients with unresectable advanced pancreatic cancer. We consider that, even in elderly patients, the effect of gemcitabine is worth investigating in future studies.
and requires expensive instruments and trained personnel, these differences are also likely to be true with respect to other gastrointestinal cancers. M2031 Tumor-Associated Macrophages (TAMS) Are Poor Prognostic Indicators in Pancreatic Cancer James J. Farrell, Miguel Garcia, Adam P. Dicker, Chandan Guha, Hany Elsaleh Background:The importance of inflammation in the development of pancreatic cancer is well established. However, the role that inflammation plays in pancreatic cancer prognosis and response to treatment remains unclear. Tumor-associated macrophages (TAMs) are a major component of the protumor function of inflammation through a variety of proposed mechanisms, including suppression of immune function, matrix remodeling capacity, synthesis of growth and angiogenesis factors, intravasation, and seeding at distant sites. While TAMs have been associated with tumor growth, metastasis and poor prognosis in other cancers, their role in human pancreatic cancer, often characterized by extensive stroma, is undefined. We studied the prognostic value of TAMs in a cohort of pancreatic adenocarcinoma patients from RTOG 9704, a large prospective randomized adjuvant treatment trial. Methods: RTOG 9704 randomized 538 patients after surgical resection of pancreatic adenocarcinoma to treatment containing either 5-FU or gemcitabine. A tissue microarray was constructed using three separate cores from 225 resected pancreatic tumors from RTOG 9704. Immunohistochemistry for CD68 positive staining TAMs in the peritumoral stroma was performed and scored as having low or high staining. Associations between CD68 staining level and tumor stage and treatment outcomes, were analyzed by the Cox proportional hazards model. The two treatment arms of the study were analyzed separately and together. A Hazard Ratio (HR) > 1 indicates an increased risk of death for the high staining CD 68 group. Results: Of the 538 patients entered into RTOG 9704, 198 from both arms of the study were eligible and had analyzable CD68. High expression of CD68 was seen in 34 (17%) of analyzable cases. There was no association between CD68 expression and tumor stage. By both univariate (H.R. 1.63 ( 95% CI(1.08, 2.44), p=0.02) and multivariate analysis (after adjusting for nodal status:H.R. 1.63 ( 95% CI(1.08, 2.44), p=0.02), high CD 68 expression was associated with worse overall survival, irrespective of treatment arm. Overall, the median survival was 1.18 yrs for the high CD68 expressing group and 1.47 yrs for the low CD68 group. Conclusion: In this prospective randomized trial, immunohistochemical evaluation of resectable pancreatic cancer shows that TAMs are associated with a poor outcome independent of other established prognostic indicators including tumor stage. While this is the first evidence of its kind in human pancreatic cancer, further study of the specific mechanism of the protumor action of TAMs and of possible treatment strategies aimed at modulation of TAMs in pancreatic cancer is warranted.
M2029 Expression of MRP2 (Multidrug Resistance-Associated Protein2) Regulates the Drug Resistance of Human Pancreatic Cancer Bunjiro Noma, Tamito Sasaki, Yoshifumi Fujimoto, Kenichi Kuwahara, Masahiro Serikawa, Kenso Kobayashi, Hiroshi Ituki, Kazuaki Chayama Backgrounds. Now, GEM has come to be the standard treatment for advanced pancreatic cancer, but the prognosis is insufficient. Therefore, the effectiveness of combination chemotherapy such as GEM + CDDP is examined. On the other hand, there is a report that multidrug resistance-associated proteins 2 (MRP2) takes part in the decrease in sensitivity of CDDP to several kind of cancers. However, the relation between MRP2 and CDDP has not been reported in the pancreatic cancer. The aims of this study was to examine the expression of the MRP2 and to evaluate the correlation between MRP2 and CDDP resistance in human pancreatic cancer. Methods. In our present study, we used five human pancreatic cancer cell lines (PANC-1, MIAPaCa-2, Capan-2, BXPC-3 and SUIT-2)and surgically resected human pancreatic tissues, and experimented on RT-PCR, real-time PCR and immunohistochemistry to confirm the expression of MRP2 mRNA and protein. Next, we made a CDDPresistant variants (SUIT-2-CD3 and SUIT-2-CD4) by administering 10 nM CDDP to pancreatic cancer cell lines (SUIT-2) continuously for three and four months, respectively. We continuously examined the change of the MRP2 mRNA expression by Real-time PCR. Afterwards, we cultivated the cells with CDDP in the presence of anti-MRP2 antibody or MK-571 (MRP2-inhibitor), an experiment of the growth inhibition assay was performed by using a Cell proliferation ELISA system. Result. RT-PCR demonstrated that the expression of MRP2 mRNA was detected in all pancreatic cancer cell lines. In human pancreatic cancer tissues, we experimented on RT-PCR and real-time PCR, and confirmed that the expression of MRP2 mRNA in cancer lesions was higher than that in matched normal pancreas, ranging from 1.2 to 30 fold. On immunohistochemistry, MRP2 protein expression was found in 77.5% (31/40) cancer tissues, mainly in the cytoplasm of cancer cells, but was not observed in normal pancreatic tissue. The growth inhibition assay demonstrated that the CDDPresistant variants were more resistant to CDDP than the parent cell line, and this resistance was diminished by anti-MRP2 antibody and MK-571. Moreover, the induction of MRP2 mRNA in the CDDP-resistant variants was increased compared to parent cells by 1.5 and 2.5 fold, respectively. Conclusion. These observations suggest that MRP2 may correlate to CDDP resistance in human pancreatic cancer. Moreover MRP2 expression may be considered as a novel chemoresistance marker in patients with pancreatic cancer treated with CDDPbased chemotherapy. And in the pancreatic cancer with treatement of CDDP, MRP2 may become the target of the improvement of sensitivity.
M2032 Efficacy of Endoscopic Ultrasound (EUS) Guided Celiac Plexus Neurolysis (CPN) for Managing Abdominal Pain Associated with Pancreas Cancer: A Meta-Analysis Gurpreet Singh, Marina S. Kaufman, Jonathan A. Erber, Sourish Das, Carlos Micames, Bogdan Cristescu, Frank G. Gress Background: Chronic abdominal pain due to Pancreas cancer is often difficult to control and a challenging problem for the Gastroenterologist. Treatment options include non-opioid analgesics, pancreatic enzymes, opioid analgesics, and CPN. In EUS-guided CPN, alcohol or phenol is injected into the celiac plexus to induce neurolysis. Only a few studies have been performed, but the sparse data reports a significant benefit and supports its efficacy for alleviating abdominal pain in Pancreas cancer and its use, therefore, remains controversial. Aim: To evaluate the efficacy of EUS-guided CPN in alleviating chronic abdominal pain due to Pancreas cancer. Methods: Using Medline and Embase databases through October 2007, a thorough search of the English literature for prospective trials evaluating the efficacy of EUS-CPN for the management of chronic abdominal pain in Pancreas cancer was conducted, along with a hand search of reference lists. Patients had known or suspected Pancreas cancer by EUS and/or CT scan findings, and required narcotic analgesics for pain control. Studies that involved less than 10-patients were excluded. Data on pain relief was extracted, pooled, and analyzed. A Bayesian Hierarchical model for Meta Analysis was developed. Results: 4relevant studies were identified, comprising a total of 129 patients. EUS-guided CPN was effective in alleviating abdominal pain in 74.52% of patients (95% CI 0.4829, 0.9407), Figure1. Conclusion: Meta-analysis demonstrates that EUS-guided CPN results in the reduction of abdominal pain due to Pancreas cancer in at least 75% of patients. Appropriate patient selection, timing, and refinement in technique will likely lead to improved efficacy.
M2030 Geographic and Patient-Level Variations in Utilization of Endoscopic Ultrasonography in Patients with Pancreatic Cancer Feng Li, Ying Zhou, Amitabh Chak, Gregory S. Cooper, Ananya Das Endoscopic ultrasonography (EUS) is frequently used in the evaluation and staging of patients with pancreatic cancers. No information currently exists regarding geographic and patientlevel variations in the utilization of EUS procedures in these patients. Objective: To study the association of sociodemographic and geographic factors with receipt of EUS. Methods: We identified all persons aged 66 years or older, who were recently diagnosed with pancreatic cancer, resided in a SEER area, and were captured in both the SEER cancer registry and the Medicare claims database between January 1994, and December 2002. The association of categorical variables with performance of EUS was assessed by Chi-square test. A logistic regression model was developed with performance of EUS as the dependent variable to study the independent association of these demographic and clinical variables. Results: We identified 10,716 patients with pancreatic cancer (10% with local stage, 30.8% with regional stage, 59.2% with metastatic cancer) during the study period. Only 767 (7.2%) patients had a EUS examination for tumor evaluation and staging. Evaluation with EUS was significantly more common in patients younger than 75 years (9.2% vs. 5.4% , P < 0.0001), white patients (7.6% vs. 5.1%, p <0.001), in men (7.9% vs. 6.6%, p <0.02), married (8.7% vs. 5.6%, p < 0.001) and with loco-regional tumor stage (12.6% vs. 3.5%, p < 0.0001). Patients who received EUS were more likely to live in locales with lower poverty level, lower percentage of population with less than high school level education and also, with lower percentage of blacks at census tract level. There was marked variation in the rates of utilization of EUS in different SEER locations with rates ranging from 1.2% to 14.8% in different SEER registry areas. In multivariate analysis, age, gender, race, marital status, and stage and also, SEER location were significant predictors of utilization of EUS. Conclusion: There is significant geographic and some patient-level variations in the utilization of EUS procedure for evaluation of pancreatic cancer. Given that EUS is a technically sophisticated investigation,
AGA Abstracts
Figure 1
A-454