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Sa1469 Differential Expression of Hedgehog Signaling Pathway in Pancreatic Ductal Adenocarcinoma (PDAC) and Chronic Pancreatitis (CP)
Sa1470
AGA Abstracts
Comparison of Prognostic Markers for Patients' Prognosis in Advanced Pancreatic Ductal Adenocarcinoma Rei Suzuki, Tadayuki Takagi, Takuto Hikichi, Ko Watanabe, Mitsuru Sugimoto, Yuichi Waragai, Hitomi Kikuchi, Hiroyuki Asama, Mika Takasumi, Hiromasa Ohira Background: One of the primary treatments for advanced pancreatic ductal adenocarcinoma (PDAC) is chemotherapy (e.g., gemcitabine), because more than 80% of patients present with unresectable or metastatic disease. There are various prognostic markers to predict patients' survival. Aim and Methods: In this study, we aimed to analyze prognostic value of several markers. We included PDAC patients who underwent gemcitabine treatment in our institution. Firstly, optimal cut-off value predicting poor prognosis (overall survival less than 240 days) was calculated using ROC curve analysis. Predictive significance of each marker (NLR: neutrophil-to-lymphocyte ratio, PLR: platelet-to-lymphocyte ratio, GPS: Glasgow prognostic score, PNI: prognostic nutrition index, CONUT score and serum tumor markers) for overall survival (OS) was determined. Survival analysis was performed using Kaplan-Meier method with log-rank test in univariate analysis. Cox regression analysis was used for multivariate survival analysis and for calculation of hazard ratios. All statistical analyses were performed using SPSS version 21 for Windows. Results: We enrolled consecutive 33 patients. Univariate analysis revealed that there were no significant differences in OS as a function of sex, age (<60 vs. ‡60 years old), tumor size (<22 vs. ‡22 mm), location of tumor (head vs. body and tail of the pancreas), serum CEA (<3.0 vs. ‡3.0 ng/ml) and CA 19-9 level (<3840 vs. ‡3840 U/ml) and CONUT score (<5 vs. ‡5 points). Even though NLR ‡4 (p = 0.001), PLR ‡180 (p<0.001), PNI ‡40 (p = 0.02) and GPS = 2 ( p = 0.04) were associated with poor OS in univariate analysis, NLR was determined as an independent prognostic markers in multivariate analysis (HR = 7.15, 95% CI 1.53 - 33.3). Conclusion: NLR was independent prognostic marker for OS among several prognostic markers in patient with advanced PDAC who underwent chemotherapy.
Sa1468 The Peripheral Blood Lymphocyte to Monocyte Ratio Can Predict Mortality in Patients With Pancreatic Adenocarcinoma Gurshawn Singh, David D. Kim, Hong Zhu, Ammar B. Nassri, Stuart J. Spechler, Sergio Huerta, Zeeshan Ramzan Introduction: Inflammation is known to play an important role in cancer progression and metastasis. Lymphocytes can be cytotoxic to tumor cells and can induce apoptosis in them, whereas monocytes have properties that might promote tumorigenesis. These features might explain why a high lymphocyte to monocyte ratio (LMR) in peripheral blood has been found to be a favorable prognostic marker for a number of malignancies. The utility of the LMR as a prognostic indicator in pancreatic adenocarcinoma is not clear. The aim of this study was to determine if LMR could be used to predict survival in patients with pancreatic adenocarcinoma. Methods: We reviewed the medical records of all patients diagnosed with pancreatic cancer in the VA North Texas Healthcare System from January 2005 to December 2010. Patients with pancreatic tumors other than adenocarcinomas were excluded from the final analysis. The LMR was calculated from peripheral blood cell counts obtained at the time of diagnosis of pancreatic cancer as the absolute count of lymphocytes divided by the absolute count of monocytes. Univariate Cox regression statistical analysis was performed using these data, and hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Furthermore, log rank test was used to compare survival between groups of patients with high-LMR and low-LMR. Results: We identified 97 patients with pancreatic adenocarcinoma (all men, 66% white, 30% African-American). Stage at presentation was I (1%), II (24%), III (14%), and IV (61%). Treatments included surgery (23%), neoadjuvant (3%), post-op adjuvant (10%) and palliative chemotherapy (37%). Kaplan-Meier analysis revealed an overall median survival of 128 days (95% CI 80-162 days). Ninety-three of the 97 patients (96%) had sufficient data available to calculate the LMR. Their mean age and weight at diagnosis were 66±9.2 [SD] years and 81±17.4 kg. Mean absolute lymphocyte and monocyte values were 1.53±0.65 K/uL and 0.74±0.29 K/uL respectively. Mean, median and range of LMR was 2.38, 2.05 and 0.4-12 respectively. In univariate Cox regression analysis, we found that an increased LMR was a significant indicator of better overall survival in patients with pancreatic adenocarcinoma (HR 0.83; 95% CI 0.70-0.98; p=0.027). We used the median LMR (2.05) to dichotomize the patients into low-LMR (<2.05) and high-LMR groups (>2.05). The median survival of patients in the high-LMR group was significantly greater than the low-LMR group (194 days vs. 93 days; p=0.03), validating a significant survival advantage in patients with high LMR. Conclusions: A high LMR predicts better overall survival for patients with pancreatic adenocarcinoma. These results suggest that LMR can provide useful prognostic information for patients with pancreatic adenocarcinoma, and potentially guide them in making treatment choices.
Sa1471 Pathological Features and Image Findings of 16 Cases With Pancreatic Carcinoma in Situ Keiji Hanada, Tomoyuki Minami, Akihito Okazaki, Juri Ikemoto, Naomichi Hirano, Shuji Yonehara, Hironobu Amano, Tomoyuki Abe Backgrounds: Early detection of pancreatic carcinoma (PC) is essential for a better prognosis. According to the recent report from Japan Pancreatic Cancer Registry, the 5-year survival of patients with Union for International Cancer Control (UICC) stage 0 is 85.8%. However, it is very difficult to diagnose PC in situ as cancers by image diagnosis. In this study, we evaluated pathological features and image findings of PC in situ. Materials and methods: From January 2007 to September 2014, 399 cases were histologically diagnosed as PC in our institution using a regional program between specialists and general practitioners for early diagnosis of PC (Onomichi Project). Out of these cases, 16 cases were pathologically diagnosed as PC in situ after surgical therapies. 14 out of 16 cases were diagnosed as adenocarcinoma by repeated cytodiagnosis using the endoscopic nasopancreatic drainage. There were 9 men and 7 women ranging from 52 to 84 years. Numbers of tumor location in the head, body, and tail were 4, 11, and 1. In these 16 cases, we evaluated pathological features and image findings including computed tomography (CT), endoscopic ultrasonography (EUS), endoscopic retrograde pancreatography (ERP) and magnetic resonance cholangiopancreatography (MRCP). Results: Numbers of tumor localization in the main pancreatic duct (MPD), branch, and both were 4, 2, and 10. In 15 cases, irregular stenosis of MPD and small cystic lesions around the stenosis were detected by EUS and MRCP. In one case, this stenosis was detected by ERP alone. In 9 cases, focal dilatation of MPD was detected by EUS and MRCP. Focal pancreatitis and fibrotic change was detected in the pancreas parenchyma close to PC in situ in all cases. This region was demonstrated by EUS as the faint low echoic area in 6 cases, and as the strong low echoic area in 3 cases. The distribution of PC in situ did not completely correspond to the low echoic area or irregular stenosis of MPD demonstrated by EUS. Additionally, seven out of 16 cases had various degrees of fatty pancreatic infiltration (FPI) of the pancreatic parenchyma adjacent to PC in situ. Especially, 3 out of 7 cases had a high degree of FPI, which was clearly recognized by CT. In 13 out of 16 cases, various degrees of chronic pancreatitis were detected in the non-cancerous lesion. Conclusions: These results suggested that irregular stenosis of MPD, small cystic lesions around the stenosis detected by EUS and MRCP should be important signs in the image diagnosis of PC in situ, and that a high degree of FPI recognized by CT could indicate PC in situ.
Sa1469 Differential Expression of Hedgehog Signaling Pathway in Pancreatic Ductal Adenocarcinoma (PDAC) and Chronic Pancreatitis (CP) Katarzyna Winter, Janusz Strzelczyk, Monika Dzieniecka, Malgorzata WagrowskaDanilewicz, Marian Danilewicz, Ewa Malecka-Panas Introduction: Analyses of global genomic sequencing have recently identified the Hh pathway as one of the "core" pathways of central importance for the biology of human pancreatic cancer. The pathway was found to be activated in about 70% of human pancreatic cancer cases. Sh is aberrantly expressed in PDAC and in precursor PanIN lesions. The implication of Hh signaling and pancreatic fibrosis has also been firmly documented as a result of in vitro studies, specimen of diseased pancreas, and xenograft model of pancreatic cancer. The role of Hh pathway in CP is less documented. The aim of the study was to evaluate the possible diagnostic and prognostic role of the Hedgehog signaling pathway molecules: Sonic hedgehog (Shh), Smoothened (Smo) and Glioblastoma transcription factor 1 (Gli1) and a smooth muscle actin (aSMA) in patients with PDAC and CP. Patients & Methods: We enrolled 114 patients undergoing pancreatic resection: 83 with PDAC and 31 with CP. Normal control pancreatic tissue was obtained from autopsy material from 21 patients. The immunoexpression of Shh, Smo, Gli1, aSMA and Ki67 were detected in tissue specimen by immunohistochemistry (Abcam antibodies, GB). The intensity and extent of staining of Shh, Smo, aSMA were recorded semi-quantitatively and for nuclear expression of Gli 1 and Ki67 labeling index (LI) was calculated. Results: Mean Shh staining score in PDAC was: 2,24 (+0,57), which was significantly higher than in CP patients: 1,17(+0,25) and in control group: 0,79(+0,34)(p<0,01). Smo protein expression was 2,62(+0,34) in PDAC, 1,21(+0,23) in CP and 0,94(+0,15) in control group (p<0,01). Likewise Gli1 protein expression was higher in PDAC: 1,74(+0,74) than in CP: 1,15(+0,72) and in control group: 1(+0)(p<0,01). In addition, Shh and Smo immunoreactivity in CP was significantly higher than in the control group (p=0,024; p=0,007 respectively). Significant correlation was found between immunoexpression of Shh, Gli and Ki67 in PDAC group (r=0,379; r=0,28, respectively; p<0,05). The immunoexpression of Shh, Smo, Gli1, aSMA did not correlate with lymph nodes metastases, histopathological PDAC grading and time of survival. Conclusions: Presented findings further support the hypothesis on the role of Hedgehog signaling pathway in pancreatic carcinogenesis as well as cell hyperproliferation in CP. Shh and Gli1 correlation with Ki67 may suggest their prognostic role in early carcinogenesis.
AGA Abstracts
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AGA Abstracts
Comparison of Prognostic Markers for Patients' Prognosis in Advanced Pancreatic Ductal Adenocarcinoma Rei Suzuki, Tadayuki Takagi, Takuto Hikichi, Ko Watanabe, Mitsuru Sugimoto, Yuichi Waragai, Hitomi Kikuchi, Hiroyuki Asama, Mika Takasumi, Hiromasa Ohira Background: One of the primary treatments for advanced pancreatic ductal adenocarcinoma (PDAC) is chemotherapy (e.g., gemcitabine), because more than 80% of patients present with unresectable or metastatic disease. There are various prognostic markers to predict patients' survival. Aim and Methods: In this study, we aimed to analyze prognostic value of several markers. We included PDAC patients who underwent gemcitabine treatment in our institution. Firstly, optimal cut-off value predicting poor prognosis (overall survival less than 240 days) was calculated using ROC curve analysis. Predictive significance of each marker (NLR: neutrophil-to-lymphocyte ratio, PLR: platelet-to-lymphocyte ratio, GPS: Glasgow prognostic score, PNI: prognostic nutrition index, CONUT score and serum tumor markers) for overall survival (OS) was determined. Survival analysis was performed using Kaplan-Meier method with log-rank test in univariate analysis. Cox regression analysis was used for multivariate survival analysis and for calculation of hazard ratios. All statistical analyses were performed using SPSS version 21 for Windows. Results: We enrolled consecutive 33 patients. Univariate analysis revealed that there were no significant differences in OS as a function of sex, age (<60 vs. ‡60 years old), tumor size (<22 vs. ‡22 mm), location of tumor (head vs. body and tail of the pancreas), serum CEA (<3.0 vs. ‡3.0 ng/ml) and CA 19-9 level (<3840 vs. ‡3840 U/ml) and CONUT score (<5 vs. ‡5 points). Even though NLR ‡4 (p = 0.001), PLR ‡180 (p<0.001), PNI ‡40 (p = 0.02) and GPS = 2 ( p = 0.04) were associated with poor OS in univariate analysis, NLR was determined as an independent prognostic markers in multivariate analysis (HR = 7.15, 95% CI 1.53 - 33.3). Conclusion: NLR was independent prognostic marker for OS among several prognostic markers in patient with advanced PDAC who underwent chemotherapy.
Sa1468 The Peripheral Blood Lymphocyte to Monocyte Ratio Can Predict Mortality in Patients With Pancreatic Adenocarcinoma Gurshawn Singh, David D. Kim, Hong Zhu, Ammar B. Nassri, Stuart J. Spechler, Sergio Huerta, Zeeshan Ramzan Introduction: Inflammation is known to play an important role in cancer progression and metastasis. Lymphocytes can be cytotoxic to tumor cells and can induce apoptosis in them, whereas monocytes have properties that might promote tumorigenesis. These features might explain why a high lymphocyte to monocyte ratio (LMR) in peripheral blood has been found to be a favorable prognostic marker for a number of malignancies. The utility of the LMR as a prognostic indicator in pancreatic adenocarcinoma is not clear. The aim of this study was to determine if LMR could be used to predict survival in patients with pancreatic adenocarcinoma. Methods: We reviewed the medical records of all patients diagnosed with pancreatic cancer in the VA North Texas Healthcare System from January 2005 to December 2010. Patients with pancreatic tumors other than adenocarcinomas were excluded from the final analysis. The LMR was calculated from peripheral blood cell counts obtained at the time of diagnosis of pancreatic cancer as the absolute count of lymphocytes divided by the absolute count of monocytes. Univariate Cox regression statistical analysis was performed using these data, and hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Furthermore, log rank test was used to compare survival between groups of patients with high-LMR and low-LMR. Results: We identified 97 patients with pancreatic adenocarcinoma (all men, 66% white, 30% African-American). Stage at presentation was I (1%), II (24%), III (14%), and IV (61%). Treatments included surgery (23%), neoadjuvant (3%), post-op adjuvant (10%) and palliative chemotherapy (37%). Kaplan-Meier analysis revealed an overall median survival of 128 days (95% CI 80-162 days). Ninety-three of the 97 patients (96%) had sufficient data available to calculate the LMR. Their mean age and weight at diagnosis were 66±9.2 [SD] years and 81±17.4 kg. Mean absolute lymphocyte and monocyte values were 1.53±0.65 K/uL and 0.74±0.29 K/uL respectively. Mean, median and range of LMR was 2.38, 2.05 and 0.4-12 respectively. In univariate Cox regression analysis, we found that an increased LMR was a significant indicator of better overall survival in patients with pancreatic adenocarcinoma (HR 0.83; 95% CI 0.70-0.98; p=0.027). We used the median LMR (2.05) to dichotomize the patients into low-LMR (<2.05) and high-LMR groups (>2.05). The median survival of patients in the high-LMR group was significantly greater than the low-LMR group (194 days vs. 93 days; p=0.03), validating a significant survival advantage in patients with high LMR. Conclusions: A high LMR predicts better overall survival for patients with pancreatic adenocarcinoma. These results suggest that LMR can provide useful prognostic information for patients with pancreatic adenocarcinoma, and potentially guide them in making treatment choices.
Sa1471 Pathological Features and Image Findings of 16 Cases With Pancreatic Carcinoma in Situ Keiji Hanada, Tomoyuki Minami, Akihito Okazaki, Juri Ikemoto, Naomichi Hirano, Shuji Yonehara, Hironobu Amano, Tomoyuki Abe Backgrounds: Early detection of pancreatic carcinoma (PC) is essential for a better prognosis. According to the recent report from Japan Pancreatic Cancer Registry, the 5-year survival of patients with Union for International Cancer Control (UICC) stage 0 is 85.8%. However, it is very difficult to diagnose PC in situ as cancers by image diagnosis. In this study, we evaluated pathological features and image findings of PC in situ. Materials and methods: From January 2007 to September 2014, 399 cases were histologically diagnosed as PC in our institution using a regional program between specialists and general practitioners for early diagnosis of PC (Onomichi Project). Out of these cases, 16 cases were pathologically diagnosed as PC in situ after surgical therapies. 14 out of 16 cases were diagnosed as adenocarcinoma by repeated cytodiagnosis using the endoscopic nasopancreatic drainage. There were 9 men and 7 women ranging from 52 to 84 years. Numbers of tumor location in the head, body, and tail were 4, 11, and 1. In these 16 cases, we evaluated pathological features and image findings including computed tomography (CT), endoscopic ultrasonography (EUS), endoscopic retrograde pancreatography (ERP) and magnetic resonance cholangiopancreatography (MRCP). Results: Numbers of tumor localization in the main pancreatic duct (MPD), branch, and both were 4, 2, and 10. In 15 cases, irregular stenosis of MPD and small cystic lesions around the stenosis were detected by EUS and MRCP. In one case, this stenosis was detected by ERP alone. In 9 cases, focal dilatation of MPD was detected by EUS and MRCP. Focal pancreatitis and fibrotic change was detected in the pancreas parenchyma close to PC in situ in all cases. This region was demonstrated by EUS as the faint low echoic area in 6 cases, and as the strong low echoic area in 3 cases. The distribution of PC in situ did not completely correspond to the low echoic area or irregular stenosis of MPD demonstrated by EUS. Additionally, seven out of 16 cases had various degrees of fatty pancreatic infiltration (FPI) of the pancreatic parenchyma adjacent to PC in situ. Especially, 3 out of 7 cases had a high degree of FPI, which was clearly recognized by CT. In 13 out of 16 cases, various degrees of chronic pancreatitis were detected in the non-cancerous lesion. Conclusions: These results suggested that irregular stenosis of MPD, small cystic lesions around the stenosis detected by EUS and MRCP should be important signs in the image diagnosis of PC in situ, and that a high degree of FPI recognized by CT could indicate PC in situ.
Sa1469 Differential Expression of Hedgehog Signaling Pathway in Pancreatic Ductal Adenocarcinoma (PDAC) and Chronic Pancreatitis (CP) Katarzyna Winter, Janusz Strzelczyk, Monika Dzieniecka, Malgorzata WagrowskaDanilewicz, Marian Danilewicz, Ewa Malecka-Panas Introduction: Analyses of global genomic sequencing have recently identified the Hh pathway as one of the "core" pathways of central importance for the biology of human pancreatic cancer. The pathway was found to be activated in about 70% of human pancreatic cancer cases. Sh is aberrantly expressed in PDAC and in precursor PanIN lesions. The implication of Hh signaling and pancreatic fibrosis has also been firmly documented as a result of in vitro studies, specimen of diseased pancreas, and xenograft model of pancreatic cancer. The role of Hh pathway in CP is less documented. The aim of the study was to evaluate the possible diagnostic and prognostic role of the Hedgehog signaling pathway molecules: Sonic hedgehog (Shh), Smoothened (Smo) and Glioblastoma transcription factor 1 (Gli1) and a smooth muscle actin (aSMA) in patients with PDAC and CP. Patients & Methods: We enrolled 114 patients undergoing pancreatic resection: 83 with PDAC and 31 with CP. Normal control pancreatic tissue was obtained from autopsy material from 21 patients. The immunoexpression of Shh, Smo, Gli1, aSMA and Ki67 were detected in tissue specimen by immunohistochemistry (Abcam antibodies, GB). The intensity and extent of staining of Shh, Smo, aSMA were recorded semi-quantitatively and for nuclear expression of Gli 1 and Ki67 labeling index (LI) was calculated. Results: Mean Shh staining score in PDAC was: 2,24 (+0,57), which was significantly higher than in CP patients: 1,17(+0,25) and in control group: 0,79(+0,34)(p<0,01). Smo protein expression was 2,62(+0,34) in PDAC, 1,21(+0,23) in CP and 0,94(+0,15) in control group (p<0,01). Likewise Gli1 protein expression was higher in PDAC: 1,74(+0,74) than in CP: 1,15(+0,72) and in control group: 1(+0)(p<0,01). In addition, Shh and Smo immunoreactivity in CP was significantly higher than in the control group (p=0,024; p=0,007 respectively). Significant correlation was found between immunoexpression of Shh, Gli and Ki67 in PDAC group (r=0,379; r=0,28, respectively; p<0,05). The immunoexpression of Shh, Smo, Gli1, aSMA did not correlate with lymph nodes metastases, histopathological PDAC grading and time of survival. Conclusions: Presented findings further support the hypothesis on the role of Hedgehog signaling pathway in pancreatic carcinogenesis as well as cell hyperproliferation in CP. Shh and Gli1 correlation with Ki67 may suggest their prognostic role in early carcinogenesis.
AGA Abstracts
X : 10052$CH01 03-28-16 00:57:27 PDFd : 10052B : e
S-324
Page 324