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MTS2 in pancreatic tumors
April 1 9 9 5
e"FULMINANT" ACUTE PANCREATITIS, ASSOCIATED WITH CHRONIC LIVER DISEASE. N. Sata, W. Kimura, T. Muto. First Department of Surgery, University of Tokyo, Tokyo, JAPAN Acute pancreatitis and chronic liver disease (CLD) have the common background, alcohol abuse. We retrospectively reviewed 44 cases of severe acute pancreatitis in Tokyo University Hospital and some other hospitals from 1975 to 1994. The diagnosis of severe acute pancreatitis are based on the criteria of Japanese Pancreatic Society (JPS), that consist of five clinical manifestations, ten laboratory data and CT findings. We analyzed from the viewpoint with or without CLD (liver cirrhosis or chronic hepatitis). The diagnosis of CLD is made by clear past history, macroscopically or histologically at the operation or autopsy. 6 cases have a clear past history of chronic liver disease (4:liver cirrhosis, 2:chronic hepatitis). All of them were dead within 8 days from onset, and their clinical profile and course were quite characteristic. They were all middle-aged male, and both CLD and acute pancreatitis were induced by huge alcohol intake. They showed significantly higher incidence of shock, respiratory distress, and consciousness disturbance than the other 38 cases without CLD (22 dead, 16 survived). In laboratory data, low incidence of leukocytosis (8700-+2700/mm ~, p<0.05 vs. 15300-+ 1300/ram ~the dead without CLD, 16700+1300/mm 2 the survived without CLD), severe hypocalcemia (5.3_+0.46mg/dl, p<0.05 vs. 7.2---0.52mg/dl the dead without CLD, 7.7 ---0.48mg/dl the survived without CLD), and severe acidosis (-16.1 +4.0mEq/I vs. -10.5+ 1.SmEq/I the dead without CLD, -4.6-+2.SmEq/I the survived without CLD) are observed. Ranson score and severity score calculated by the criteria of JPS were significantly higher than the other cases. We conclude that acute pancreatitis with CLD are the most severe form of acute pancreatitis and could be called "fulminant" acute pancreatitis.
D E X T R A N S R E V E R S E P A N C R E A T I C CAPILLARY F L O W DEPRESSION IN N E C R O T I Z I N G PANCREATITIS. J. SCHMIDT I, H.G. HOTZ 1'3, C. LANGER 1, M.M. GEBHARDT 2, Ch. HERFARTH ~, and E. KLAR t. Dept. of Surgeryt, and ExperimentalSurgery2, Universityof Heidelberg, Germany and BenjaminFranklinClinic~, Universityof Berlin, Germany.
Necrotizing pancreatitis is characterized by a substantial decrease in nutritive pancreatic capillary blood flow. Previous studies have demonstrated a protective effect of isovolemic hemodilution with dextran. This study investigates the effect of molecular weight and concentration of the dextrans as well as the addition of hypertonic saline. Methods: Necrotizing pancreatitis was induced in 42 dextran-tolerant Wistar-rats by intraductal glycodeoxycholic acid (10mM/L) and intravenous caerulein (5#glkg/h) for 6 hrs. Control animals received intreduetal and intravenous saline (n =7). The pancreas was exteriorized in a temperature controlled water bath. Using intravital microscopy and FITC-labelled erythrocytes as flow markers areas of low pancreatic capillary flow were identified, mapped and baseline measurements taken. Thereafter, either saline (32ml/kg) or various dextrans (8ml/kg) with (HHS) or without (DEX) hypertonic (7.5%) saline were infused over lh and flow measurements repeated after 2 hrs. Results: There was no difference between saline and dextran treated animals with respect to MAP, hematocrit, and arterial blood gases prior to therapy. Capillary Flow Increase Capillary Stasis (%) (nl/min/Cap.) * = p < 0 . 0 5 vs SALINE Controls 0.02 +0.10 0.10 +0.00 SALINE 0.45 +0.07 7.25 +0.41 DEX-70 6% 0.81 _+0.05* 1.55 _+0.97* DEX-70 10% 1.13 _+0.06* 1.11 _+0.57* DEX-500 10% 1.05 _+0.06* 1.37 +1.30" HHS-70 0.73 +0.07* 0.57 -+0.37* HI-IS-500 0.46 +0.05 2.30 -+0.99* Conclusions: Intravenous infusion of dextran reverses the impairment of pancreatic microeirculation in experimental necrotizing pancreatitis. These effects are largely independent of the molecular size, concentration and the addition of hypertonic saline.
Pancreatic Disorders
A389
DYSREGULATION OF CELL-CYCLE-INHIBITORS p161MTSI and pI5/MTS2 IN PANCREATIC TUMORS. N. Savitskaia, A. Sehramm, H. Kalthoff 1, M. Naumann, and W. Schmieg~l. RuhrUniversity Bochum, Medical Clinic -IMBL-, Knappschafts-Khs.. 44892 Bochum, Germany. 1) University Hospital Kiel, Dept. of General Surgery, 24105 Kiel, Germany. In our study we provide further evidence that the cellcycle inhibitors pl6 and p15, which can deprive cells of critical antiproliferative devices, might be relevant for pancreatic tumorigenesis. M e t h o d s : Homozygous deletions were analyzed from genomic DNA of pancreatic carcinoma cell-lines and primary tumors by PCR. The expression level were investigated by using Western blot technique. R e s u l t s : pl6 and p15 inhibit the catalytic activity of the G1 cyclin-dependent complexes and exert this function through direct association with cdk6 or cdk4, preventing damaged ceils from progression during the mitotic cell cycle to either let DNA repair or apoptosis taking place. The analysis of pancreatic tumors for genomic alterations revealed frequent homozygous deletions of the p161MTS1 and p15/MTS2 genes (46%). In contrast, pancreatic tumors investigated for genomic alterations in the cell-cycle-inhibitor p27, exhibit no homozygous deletions. No pl6 expression was obtained from 58% of the investigated tumor cell-lines, but strong expression from the other cell-lines. Nearly half of the tumors, which lost pl6, carry a wildtype phenotype of p53, the major cell-cycle control molecule. Concerning the target molecules of cell-cycle inhibitors pl6 and p15, we found overexpression of the cyciin-dependentkinase cdk4 in all pancreatic tumor cell-lines, whereas the G1 cyelins of the D-group were weakly expressed or not detectable. D i s c u s s i o n : We conclude from our data, that the toss of the pl6 and/or p15 protein in pancreatic tumors could possibly contribute to neoplastic transformation of cells. The observed overexpression of cdk4 in all investigated pancreatic tumors, might represent an oncogenic conversion of this kinase. Frequent alterations either in the p53-gene or pl6 protein or other cell-cycle control molecules lead to the current view, that genetic alterations in pancreatic tumors include frequent mutations in a common oneogene (K-ras) and the deregulation of one or more cell-cycle control pathways.
INTERVENTIONAL THERAPY OF CHRONIC PANCREATITIS: DO STONES AND STRICTURES INFLUENCE THE TECHNICAL SUCCESS AND CLINICAL B E N E F I T ? H.T. Schneider. M. Farnbacher, A. May, E.G. Hahn, C. Ell. Dept. of Medicine I, University of Erlangen-Nuremberg, Germany
Recent reports indicate that chronic obstructive pancreatits (CP) characterized by concrements and duet strictures can successfully be managed by new interventional techniques. Less data, however, are available how stone distribution and localization of stenoses influence the technical success and the clinical benefit (pain relief) of the patient. Methods: Between 1/91 and 8/94 symptomatic patients (n=81; 15f, 66m; 47+12 yrs) suffering from CP were treated with endoscopic sphincterotomy including needleknffe incision, extraeorporeal shockwave lithotripsy (ESWL), stone extraction and insertion of endoprostheses. According to ERCP-imaging the patients were divided in different groups: I- eonerements in the main pancreatic duct, II- pancreatolithiasis and duct strictures located in the head of the pancreas, III- advanced alterations of the pancreas including stones and marked duct changes predominantly located in the distal part of the pancreas. Results: In all patients (100%) at least one interventional treatment procedure had been performed. Treatment group (n)
I (33)
I I (15)
I I I (33)
Interventional techniaues - Sphineterotomy 31 15 27 - ESWL 31 13 23 - Stone extraction 13 4 11 - Endonrosthesis 9 ~ 19 In 53% of the patients the main pancreatic duct was totally free of stones (41%) or showed only minimal fragments (12%) after the treatment (I52/15%, II- 53/13%, III- 24/9%). 74% of the patients reported on pain relief after the last therapeutic intervention (I- 85%, II- 73%, III- 64%). Conclusions: Interventional techniques are most effective in patients with localized stones and/or strictures in the pancreatic heed. In contrast to the low technical success rate in the majority of the patients with advanced CP even a remarkable pain reduction was achieved. Therefore, interventional measures seem to be justified in all patients with CP independent of extent and localization of stones and strictures.
e"FULMINANT" ACUTE PANCREATITIS, ASSOCIATED WITH CHRONIC LIVER DISEASE. N. Sata, W. Kimura, T. Muto. First Department of Surgery, University of Tokyo, Tokyo, JAPAN Acute pancreatitis and chronic liver disease (CLD) have the common background, alcohol abuse. We retrospectively reviewed 44 cases of severe acute pancreatitis in Tokyo University Hospital and some other hospitals from 1975 to 1994. The diagnosis of severe acute pancreatitis are based on the criteria of Japanese Pancreatic Society (JPS), that consist of five clinical manifestations, ten laboratory data and CT findings. We analyzed from the viewpoint with or without CLD (liver cirrhosis or chronic hepatitis). The diagnosis of CLD is made by clear past history, macroscopically or histologically at the operation or autopsy. 6 cases have a clear past history of chronic liver disease (4:liver cirrhosis, 2:chronic hepatitis). All of them were dead within 8 days from onset, and their clinical profile and course were quite characteristic. They were all middle-aged male, and both CLD and acute pancreatitis were induced by huge alcohol intake. They showed significantly higher incidence of shock, respiratory distress, and consciousness disturbance than the other 38 cases without CLD (22 dead, 16 survived). In laboratory data, low incidence of leukocytosis (8700-+2700/mm ~, p<0.05 vs. 15300-+ 1300/ram ~the dead without CLD, 16700+1300/mm 2 the survived without CLD), severe hypocalcemia (5.3_+0.46mg/dl, p<0.05 vs. 7.2---0.52mg/dl the dead without CLD, 7.7 ---0.48mg/dl the survived without CLD), and severe acidosis (-16.1 +4.0mEq/I vs. -10.5+ 1.SmEq/I the dead without CLD, -4.6-+2.SmEq/I the survived without CLD) are observed. Ranson score and severity score calculated by the criteria of JPS were significantly higher than the other cases. We conclude that acute pancreatitis with CLD are the most severe form of acute pancreatitis and could be called "fulminant" acute pancreatitis.
D E X T R A N S R E V E R S E P A N C R E A T I C CAPILLARY F L O W DEPRESSION IN N E C R O T I Z I N G PANCREATITIS. J. SCHMIDT I, H.G. HOTZ 1'3, C. LANGER 1, M.M. GEBHARDT 2, Ch. HERFARTH ~, and E. KLAR t. Dept. of Surgeryt, and ExperimentalSurgery2, Universityof Heidelberg, Germany and BenjaminFranklinClinic~, Universityof Berlin, Germany.
Necrotizing pancreatitis is characterized by a substantial decrease in nutritive pancreatic capillary blood flow. Previous studies have demonstrated a protective effect of isovolemic hemodilution with dextran. This study investigates the effect of molecular weight and concentration of the dextrans as well as the addition of hypertonic saline. Methods: Necrotizing pancreatitis was induced in 42 dextran-tolerant Wistar-rats by intraductal glycodeoxycholic acid (10mM/L) and intravenous caerulein (5#glkg/h) for 6 hrs. Control animals received intreduetal and intravenous saline (n =7). The pancreas was exteriorized in a temperature controlled water bath. Using intravital microscopy and FITC-labelled erythrocytes as flow markers areas of low pancreatic capillary flow were identified, mapped and baseline measurements taken. Thereafter, either saline (32ml/kg) or various dextrans (8ml/kg) with (HHS) or without (DEX) hypertonic (7.5%) saline were infused over lh and flow measurements repeated after 2 hrs. Results: There was no difference between saline and dextran treated animals with respect to MAP, hematocrit, and arterial blood gases prior to therapy. Capillary Flow Increase Capillary Stasis (%) (nl/min/Cap.) * = p < 0 . 0 5 vs SALINE Controls 0.02 +0.10 0.10 +0.00 SALINE 0.45 +0.07 7.25 +0.41 DEX-70 6% 0.81 _+0.05* 1.55 _+0.97* DEX-70 10% 1.13 _+0.06* 1.11 _+0.57* DEX-500 10% 1.05 _+0.06* 1.37 +1.30" HHS-70 0.73 +0.07* 0.57 -+0.37* HI-IS-500 0.46 +0.05 2.30 -+0.99* Conclusions: Intravenous infusion of dextran reverses the impairment of pancreatic microeirculation in experimental necrotizing pancreatitis. These effects are largely independent of the molecular size, concentration and the addition of hypertonic saline.
Pancreatic Disorders
A389
DYSREGULATION OF CELL-CYCLE-INHIBITORS p161MTSI and pI5/MTS2 IN PANCREATIC TUMORS. N. Savitskaia, A. Sehramm, H. Kalthoff 1, M. Naumann, and W. Schmieg~l. RuhrUniversity Bochum, Medical Clinic -IMBL-, Knappschafts-Khs.. 44892 Bochum, Germany. 1) University Hospital Kiel, Dept. of General Surgery, 24105 Kiel, Germany. In our study we provide further evidence that the cellcycle inhibitors pl6 and p15, which can deprive cells of critical antiproliferative devices, might be relevant for pancreatic tumorigenesis. M e t h o d s : Homozygous deletions were analyzed from genomic DNA of pancreatic carcinoma cell-lines and primary tumors by PCR. The expression level were investigated by using Western blot technique. R e s u l t s : pl6 and p15 inhibit the catalytic activity of the G1 cyclin-dependent complexes and exert this function through direct association with cdk6 or cdk4, preventing damaged ceils from progression during the mitotic cell cycle to either let DNA repair or apoptosis taking place. The analysis of pancreatic tumors for genomic alterations revealed frequent homozygous deletions of the p161MTS1 and p15/MTS2 genes (46%). In contrast, pancreatic tumors investigated for genomic alterations in the cell-cycle-inhibitor p27, exhibit no homozygous deletions. No pl6 expression was obtained from 58% of the investigated tumor cell-lines, but strong expression from the other cell-lines. Nearly half of the tumors, which lost pl6, carry a wildtype phenotype of p53, the major cell-cycle control molecule. Concerning the target molecules of cell-cycle inhibitors pl6 and p15, we found overexpression of the cyciin-dependentkinase cdk4 in all pancreatic tumor cell-lines, whereas the G1 cyelins of the D-group were weakly expressed or not detectable. D i s c u s s i o n : We conclude from our data, that the toss of the pl6 and/or p15 protein in pancreatic tumors could possibly contribute to neoplastic transformation of cells. The observed overexpression of cdk4 in all investigated pancreatic tumors, might represent an oncogenic conversion of this kinase. Frequent alterations either in the p53-gene or pl6 protein or other cell-cycle control molecules lead to the current view, that genetic alterations in pancreatic tumors include frequent mutations in a common oneogene (K-ras) and the deregulation of one or more cell-cycle control pathways.
INTERVENTIONAL THERAPY OF CHRONIC PANCREATITIS: DO STONES AND STRICTURES INFLUENCE THE TECHNICAL SUCCESS AND CLINICAL B E N E F I T ? H.T. Schneider. M. Farnbacher, A. May, E.G. Hahn, C. Ell. Dept. of Medicine I, University of Erlangen-Nuremberg, Germany
Recent reports indicate that chronic obstructive pancreatits (CP) characterized by concrements and duet strictures can successfully be managed by new interventional techniques. Less data, however, are available how stone distribution and localization of stenoses influence the technical success and the clinical benefit (pain relief) of the patient. Methods: Between 1/91 and 8/94 symptomatic patients (n=81; 15f, 66m; 47+12 yrs) suffering from CP were treated with endoscopic sphincterotomy including needleknffe incision, extraeorporeal shockwave lithotripsy (ESWL), stone extraction and insertion of endoprostheses. According to ERCP-imaging the patients were divided in different groups: I- eonerements in the main pancreatic duct, II- pancreatolithiasis and duct strictures located in the head of the pancreas, III- advanced alterations of the pancreas including stones and marked duct changes predominantly located in the distal part of the pancreas. Results: In all patients (100%) at least one interventional treatment procedure had been performed. Treatment group (n)
I (33)
I I (15)
I I I (33)
Interventional techniaues - Sphineterotomy 31 15 27 - ESWL 31 13 23 - Stone extraction 13 4 11 - Endonrosthesis 9 ~ 19 In 53% of the patients the main pancreatic duct was totally free of stones (41%) or showed only minimal fragments (12%) after the treatment (I52/15%, II- 53/13%, III- 24/9%). 74% of the patients reported on pain relief after the last therapeutic intervention (I- 85%, II- 73%, III- 64%). Conclusions: Interventional techniques are most effective in patients with localized stones and/or strictures in the pancreatic heed. In contrast to the low technical success rate in the majority of the patients with advanced CP even a remarkable pain reduction was achieved. Therefore, interventional measures seem to be justified in all patients with CP independent of extent and localization of stones and strictures.