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Mode of action of granulocyte colony-stimulating factor in sodium taurocholate pancreatitis of the rat
Al154 AGA ABSTRACTS
GASTROENTEROLOGY Vol. US, No.4
5312
5314
DETECTION OF K.RAS CODON 12 POINT MUTATIONS AND P53 OVEREXPRESSION IN NORMAL PANCREATIC TISSUE, HYPERPLASTIC AND ADENOCARCINOMATOUS LESIONS OF THE PANCREAS.
MODE OF ACTION OF GRANULOCYTE COLONY-STIMULATING FACTOR IN SODIUM TAUROCHOLATE PANCREATITIS OF THE RAT.
Guillaume Sauve, Pierre-Edouard Queneau, Gabriel Viennet, Stephane Koch, Bruno Heyd, Georges Mantion, Pierre Carayon, Gerard-Louis Adessi, CHU J Minjoz, Besancon, France. Aims: Pancreatic carcinogenesis is considered to follow the hyperplasiadysplasia-carcinoma sequence. Point mutations of the oncogene K.ras and overexpression of the p53 protein are frequently encountered in pancreatic adenocarcinoma. In order to clarify their respective influence on the different steps of pancreatic carcinogenesis, we determined the proportion of these two mutations in normal. hyperplastic and adenocarcinomatous lesions of the pancreas. Methodology: Pancreatic sample (n =42) were obtained from 28 patients operated for various bilio-pancreatic disorders. Pathological diagnosis was distributed as follows: normal pancreatic duct (n = 15), hyperplasia (n = 18), pancreatic adenocarcinoma (n=9). Kras point mutations were detected by PCR-RFLP and controlled by direct DNA sequencingu. p53 overexpression was determined by immunohistochemistry and scored on the basis of percent nuclear staining (> 15% is considered positive p53 staining). Results:ln all 15 normal pancreatic duct and all 18 pancreatic hyperplasia, none showed positive p53 staining and K.ras codon 12 mutation. In 9 pancreatic adenocarcinoma, 5 had positive p53 staining and 8 had K.ras codon 12 point mutation. Conclusion: These findings suggest that Kras codon 12 and p53 mutations are relatively late events in the pancreatic carcinogenesis. Screening of cancer by determination of p53 and Kras codon 12 point mutations needs to be evaluated.
5313 PALLIATIVE TREATMENT OPTIONS IN PATIENTS WITH UNRESECTABLE PANCREATIC CANCER - A RETROSPECTIVE ANALYSIS. Christian Scheurlen, Christina Rammert, Carsten Ziske, Michael Neubrand, Pan Decker, Tilman Sauerbruch, Dept Internal Medicine I, Univ of Bonn, Bonn, Germany; Dept of Surg, Univ of Bonn, Bonn, Germany. Introduction: Palliative treatment of the symptoms in unresectable pancreatic cancer aims at the relief of obstructive jaundice and the improvement of quality of life. However, the best therapeutic regimen has not yet been identified. Methods: Therefore, the effects of endoscopic biliary stenting (7, 10, 11.5 plastics drainage, 30 F Walls tents) with (therapy group TG I; n=23; 10 f', mean 63 yr, range 48-75 ys; gemcitabine 1.5 g/week) and without chemotherapy (TG 2; n=52; 22 f, mean 69 ys, range 39-92 ys) were assessed as well as the effects of chemotherapy alone (TG 3; n= 21; 7 f, mean 65 ys, range 37-81 ys) and of surgical bypass procedures (TG 4; n= 13; 5 f, mean 65 ys, range 51-81 ys) with respect to survival (days), performance status (Kamofsky index, KI; %), jaundice (bilirubin; mg/dl) and pain scores were assessed retrospecti vely on day 0, 30 and 90 of the therapy, respectively. Results: All patients had the same average tumor stage according to the VICC (3.25 :': 0.2). There was no effect of the different treatment options on survival (tab) or pain scores in neither patient group. However, chemotherapy alone or in combination with endoscopic biliary drainage or surgical bypass procedures had a significant (p < 0.05) impact on performance status (tab) as compared to biliary drainage only. In the surviving patients receiving endoscopic biliary drainage the stent patencies correlated well with their luminal diameters (P < 0.05) (7 F: 120 :': 15 d; 10 F: 218 :': 26 d; 11.5 F: 198 :': 43 d; 30 F Wallstents: 310 :': 36 d; mean:': SDM). Conclusions: Our data suggest that survival is similar in patients with advanced pancreatic cancer no matter which palliative treatment is used. Chemotherapy with gemcitabine may have some beneficial effect on the performance status.
TG1 TG2 TG3 TG4 • p < 005
Survival (days)
Kamofsky index(%) day0 day90
321 ± 60 236± 33 299± 43 295+ 78
85±2 80± 2 83 ± 2 86+ 2
81 ±3 69 ±2' 77 ± 2 82 + 5
Bilirubin (mgfdl) day0 day30
57± 1.1 10 ± l' 48 ± 15 8.4 + 1.9
34± 06 49± 2.2 39 ± 1.1 35 + 1.2
Claus G. Schneider, Gunnar Lankenau, Marco Hafemann, Oliver Mann, Emre F. Yekebas, Christian Bloechle, Jakob R. Izbicki, Univ of Hamburg, Hamburg, Germany. Background and Aim of the study: Prophylactically administered antiinflammatory cytokine granulocyte colony-stimulating factor (G-CSF) reduced tissue damage in acute sodium taurocholate (ST) pancreatitis in rats. The proposed mechanism, i.e. a suppression of tumor necrosis factor a (TNF), was not observed. Aim of this study was to evaluate the therapeutic effects of G-CSF on survival, microcirculation and tissue damage. Material and Methods: a) 24 Sprague-Dawley were given G-CSF (50 JLg/kg, s.c.) or Ringers solution (s.c.) as control 15 min. after induction of pancreatitis (ST 4%,400 JLI within 5min.). Observation lasted 12 hrs. b) In-vivo pancreatic microcirculation was observed with an epiluminescent microscope and recorded on video tape. Acridine orange was given to label leukocytes. Pancreatitis was induced as mentioned above. Results: a) Therapeutical administration of G-CSF does not influence survival (2/12 G-CSF vs. 3/12 controls). It reduces necrosis (score by Schmidt 1992: 2.25 G-CSF vs. 3.5 controls, medians. p=0.046) but not overall tissue damage (7.5 G-CSF vs. 9.0 controls, medians p=0.125). Neither TNF (serum and ascites), nor TAP (serum, ascites and urine) or amylase (serum) levels were different in treatment and control group, respectively. b) Total capillary stasis was observed in G-CSF treated animals and controls within 105 sec. and 95 sec., respectively (p>0.05). Leukocyte adherence was 82% (G-CSF) and 77% (controls); p>0.05. Conclusion: Therapeutic administration ofG-CSF attenuates the beneficial effect observed in G-CSF prophylaxis in ST pancreatitis. Although necrosis was reduced, the overall histological damage was not significantly influenced. Since microcirculatory examinations did not explain the mode of G-CSF action, we hypothesize that the increased clearing effect of neutrophils and/or an activated endothelium may playa key role.
5315 STAGING OF PANCREATIC CARCINOMA - ANALYSIS OF 64 CONSECUTIVE PATIENTS WITH SPECIAL RESPECT REGARDING LAPAROSCOPY. Arne R. Schneider, Joachim C. Arnold, Henning E. Adamek, Claus Benz, Ralf Jakobs, Dieter Schilling, Juergen F. Riemann, Clin Ludwigshafen, Ludwigshafen, Germany.
Objectives: Staging of pancreatic carcinoma implies the use of different imaging techniques among which the value of laparoscopy is increasingly discussed. Staging laparoscopy basically focuses on the detection of intraabdominal metastases. We hereby compare preoperative laparoscopy with different methods of staging and their relevance in the diagnostic cascade. Methods: 64 patients with either pre- or postoperatively histologically confirmed adenocarcinoma of the pancreas underwent diagnostic laparoscopy. Abdominal ultrasound (US) was performed in all patients. Additionally, MRI of the upper abdomen with concomitant MR-cholangiopancreatography (MRCP) (n=26) and CT (n=25) were performed in a subgroup of patients. Those in whom metastases could not be documented histologically underwent laparotomy under curative intention. Results: In 13/17 patients, metastases were correctly detected by laparoscopy, thus yielding a sensitivity of 72% and a specifity of 95%. MRI predicted resectability with 90% sensitivity and 56% specifity. Liver metastases were correctly identified in 3 of 4 cases, lymph node metastases in 6 of 8 patients (75%), whereas MRI failed to detect peritoneal metastases (n=2). Liver and peritoneal metastases which MRI failed to detect were correctly diagnosed by laparoscopy. CT showed 88% sensitivity and 21% specifity for the prediction of resectability. 8/9 patients considered stage Tl or T2 by US, CT or MRI successfully underwent tumor resection without liver or peritoneal metastases in any of the 9 patients. Conclusions: During the last years, the quality of MRI and the know-how on its use have considerably improved. MRI predicts resectability with a high degree of accuracy. However, it is still restricted to a minority of institutions. As a consequence, laparoscopy is further recommended for the reliable detection of intraabdominal metastases, complemented by CT for the estimation of local tumor spread. Laparoscopy may be abandoned in tumors staged T I or T2 by abdominal ultrasound, because in these cases liver and peritoneal metastases are unlikely to be found.
GASTROENTEROLOGY Vol. US, No.4
5312
5314
DETECTION OF K.RAS CODON 12 POINT MUTATIONS AND P53 OVEREXPRESSION IN NORMAL PANCREATIC TISSUE, HYPERPLASTIC AND ADENOCARCINOMATOUS LESIONS OF THE PANCREAS.
MODE OF ACTION OF GRANULOCYTE COLONY-STIMULATING FACTOR IN SODIUM TAUROCHOLATE PANCREATITIS OF THE RAT.
Guillaume Sauve, Pierre-Edouard Queneau, Gabriel Viennet, Stephane Koch, Bruno Heyd, Georges Mantion, Pierre Carayon, Gerard-Louis Adessi, CHU J Minjoz, Besancon, France. Aims: Pancreatic carcinogenesis is considered to follow the hyperplasiadysplasia-carcinoma sequence. Point mutations of the oncogene K.ras and overexpression of the p53 protein are frequently encountered in pancreatic adenocarcinoma. In order to clarify their respective influence on the different steps of pancreatic carcinogenesis, we determined the proportion of these two mutations in normal. hyperplastic and adenocarcinomatous lesions of the pancreas. Methodology: Pancreatic sample (n =42) were obtained from 28 patients operated for various bilio-pancreatic disorders. Pathological diagnosis was distributed as follows: normal pancreatic duct (n = 15), hyperplasia (n = 18), pancreatic adenocarcinoma (n=9). Kras point mutations were detected by PCR-RFLP and controlled by direct DNA sequencingu. p53 overexpression was determined by immunohistochemistry and scored on the basis of percent nuclear staining (> 15% is considered positive p53 staining). Results:ln all 15 normal pancreatic duct and all 18 pancreatic hyperplasia, none showed positive p53 staining and K.ras codon 12 mutation. In 9 pancreatic adenocarcinoma, 5 had positive p53 staining and 8 had K.ras codon 12 point mutation. Conclusion: These findings suggest that Kras codon 12 and p53 mutations are relatively late events in the pancreatic carcinogenesis. Screening of cancer by determination of p53 and Kras codon 12 point mutations needs to be evaluated.
5313 PALLIATIVE TREATMENT OPTIONS IN PATIENTS WITH UNRESECTABLE PANCREATIC CANCER - A RETROSPECTIVE ANALYSIS. Christian Scheurlen, Christina Rammert, Carsten Ziske, Michael Neubrand, Pan Decker, Tilman Sauerbruch, Dept Internal Medicine I, Univ of Bonn, Bonn, Germany; Dept of Surg, Univ of Bonn, Bonn, Germany. Introduction: Palliative treatment of the symptoms in unresectable pancreatic cancer aims at the relief of obstructive jaundice and the improvement of quality of life. However, the best therapeutic regimen has not yet been identified. Methods: Therefore, the effects of endoscopic biliary stenting (7, 10, 11.5 plastics drainage, 30 F Walls tents) with (therapy group TG I; n=23; 10 f', mean 63 yr, range 48-75 ys; gemcitabine 1.5 g/week) and without chemotherapy (TG 2; n=52; 22 f, mean 69 ys, range 39-92 ys) were assessed as well as the effects of chemotherapy alone (TG 3; n= 21; 7 f, mean 65 ys, range 37-81 ys) and of surgical bypass procedures (TG 4; n= 13; 5 f, mean 65 ys, range 51-81 ys) with respect to survival (days), performance status (Kamofsky index, KI; %), jaundice (bilirubin; mg/dl) and pain scores were assessed retrospecti vely on day 0, 30 and 90 of the therapy, respectively. Results: All patients had the same average tumor stage according to the VICC (3.25 :': 0.2). There was no effect of the different treatment options on survival (tab) or pain scores in neither patient group. However, chemotherapy alone or in combination with endoscopic biliary drainage or surgical bypass procedures had a significant (p < 0.05) impact on performance status (tab) as compared to biliary drainage only. In the surviving patients receiving endoscopic biliary drainage the stent patencies correlated well with their luminal diameters (P < 0.05) (7 F: 120 :': 15 d; 10 F: 218 :': 26 d; 11.5 F: 198 :': 43 d; 30 F Wallstents: 310 :': 36 d; mean:': SDM). Conclusions: Our data suggest that survival is similar in patients with advanced pancreatic cancer no matter which palliative treatment is used. Chemotherapy with gemcitabine may have some beneficial effect on the performance status.
TG1 TG2 TG3 TG4 • p < 005
Survival (days)
Kamofsky index(%) day0 day90
321 ± 60 236± 33 299± 43 295+ 78
85±2 80± 2 83 ± 2 86+ 2
81 ±3 69 ±2' 77 ± 2 82 + 5
Bilirubin (mgfdl) day0 day30
57± 1.1 10 ± l' 48 ± 15 8.4 + 1.9
34± 06 49± 2.2 39 ± 1.1 35 + 1.2
Claus G. Schneider, Gunnar Lankenau, Marco Hafemann, Oliver Mann, Emre F. Yekebas, Christian Bloechle, Jakob R. Izbicki, Univ of Hamburg, Hamburg, Germany. Background and Aim of the study: Prophylactically administered antiinflammatory cytokine granulocyte colony-stimulating factor (G-CSF) reduced tissue damage in acute sodium taurocholate (ST) pancreatitis in rats. The proposed mechanism, i.e. a suppression of tumor necrosis factor a (TNF), was not observed. Aim of this study was to evaluate the therapeutic effects of G-CSF on survival, microcirculation and tissue damage. Material and Methods: a) 24 Sprague-Dawley were given G-CSF (50 JLg/kg, s.c.) or Ringers solution (s.c.) as control 15 min. after induction of pancreatitis (ST 4%,400 JLI within 5min.). Observation lasted 12 hrs. b) In-vivo pancreatic microcirculation was observed with an epiluminescent microscope and recorded on video tape. Acridine orange was given to label leukocytes. Pancreatitis was induced as mentioned above. Results: a) Therapeutical administration of G-CSF does not influence survival (2/12 G-CSF vs. 3/12 controls). It reduces necrosis (score by Schmidt 1992: 2.25 G-CSF vs. 3.5 controls, medians. p=0.046) but not overall tissue damage (7.5 G-CSF vs. 9.0 controls, medians p=0.125). Neither TNF (serum and ascites), nor TAP (serum, ascites and urine) or amylase (serum) levels were different in treatment and control group, respectively. b) Total capillary stasis was observed in G-CSF treated animals and controls within 105 sec. and 95 sec., respectively (p>0.05). Leukocyte adherence was 82% (G-CSF) and 77% (controls); p>0.05. Conclusion: Therapeutic administration ofG-CSF attenuates the beneficial effect observed in G-CSF prophylaxis in ST pancreatitis. Although necrosis was reduced, the overall histological damage was not significantly influenced. Since microcirculatory examinations did not explain the mode of G-CSF action, we hypothesize that the increased clearing effect of neutrophils and/or an activated endothelium may playa key role.
5315 STAGING OF PANCREATIC CARCINOMA - ANALYSIS OF 64 CONSECUTIVE PATIENTS WITH SPECIAL RESPECT REGARDING LAPAROSCOPY. Arne R. Schneider, Joachim C. Arnold, Henning E. Adamek, Claus Benz, Ralf Jakobs, Dieter Schilling, Juergen F. Riemann, Clin Ludwigshafen, Ludwigshafen, Germany.
Objectives: Staging of pancreatic carcinoma implies the use of different imaging techniques among which the value of laparoscopy is increasingly discussed. Staging laparoscopy basically focuses on the detection of intraabdominal metastases. We hereby compare preoperative laparoscopy with different methods of staging and their relevance in the diagnostic cascade. Methods: 64 patients with either pre- or postoperatively histologically confirmed adenocarcinoma of the pancreas underwent diagnostic laparoscopy. Abdominal ultrasound (US) was performed in all patients. Additionally, MRI of the upper abdomen with concomitant MR-cholangiopancreatography (MRCP) (n=26) and CT (n=25) were performed in a subgroup of patients. Those in whom metastases could not be documented histologically underwent laparotomy under curative intention. Results: In 13/17 patients, metastases were correctly detected by laparoscopy, thus yielding a sensitivity of 72% and a specifity of 95%. MRI predicted resectability with 90% sensitivity and 56% specifity. Liver metastases were correctly identified in 3 of 4 cases, lymph node metastases in 6 of 8 patients (75%), whereas MRI failed to detect peritoneal metastases (n=2). Liver and peritoneal metastases which MRI failed to detect were correctly diagnosed by laparoscopy. CT showed 88% sensitivity and 21% specifity for the prediction of resectability. 8/9 patients considered stage Tl or T2 by US, CT or MRI successfully underwent tumor resection without liver or peritoneal metastases in any of the 9 patients. Conclusions: During the last years, the quality of MRI and the know-how on its use have considerably improved. MRI predicts resectability with a high degree of accuracy. However, it is still restricted to a minority of institutions. As a consequence, laparoscopy is further recommended for the reliable detection of intraabdominal metastases, complemented by CT for the estimation of local tumor spread. Laparoscopy may be abandoned in tumors staged T I or T2 by abdominal ultrasound, because in these cases liver and peritoneal metastases are unlikely to be found.