Localization of galectin-3 in normal and diseased pancreatic tissue.
Schaffert C. Pour PM. Chaney WG.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha 68198-4525, USA.
CONCLUSION: Galectin-3 is expressed in both human and hamster pancreatic tumors and tumor cell lines and this expression is increased over normal. BACKGROUND: Galectin-3 is overexpressed in many gastrointestinal tumors. This study examined the expression of galectin-3 in human and hamster pancreatic tumors to determine if galectin-3 could be used as a marker for pancreatic cancer. METHODS: Membranes were prepared from human and hamster pancreatic tumor cell lines. Galectin-3 was visualized by immunoblot analysis of separated membrane proteins using the monoclonal antibody (MAb) M3/38. Paraffin-embedded sections from normal, pancreatitis, and cancerous human pancreatic tissue and normal, N-nitrosobis(2-oxopropyl)amine (BOP)-treated hyperplastic, and cancerous hamster pancreatic tissues were processed immunohistochemically for galectin-3 using the MAb M3/38. RESULTS: Galectin-3 was heavily expressed in cytoplasmic and nuclear regions of 50% of normal human pancreatic tissue. Expression of galectin-3 in ductal cells in chronic pancreatitis and cancerous pancreatic tissue was increased over normal and was more uniform (>95% cells/duct stained). Normal hamster pancreatic ducts showed weak or no expression of galectin-3. Hyperplastic pancreatic ductal cells from BOP-treated hamsters heavily expressed galectin-3 (60-95% cells/duct stained). Galectin-3 expression in ductal cells in cancerous pancreatic lesions was increased to >95%. Galectin-3 was also detected in the pancreatic nerves in all human tissue specimens tested.
Expression of pancreatitis-associated protein (PAP) mRNA in gastrointestinal cancers.
Motoo Y. Itoh T. Su SB. Nakatani MT. Watanabe H. Okai T. Sawabu N.
Department of Internal Medicine, Cancer Research Institute, Kanazawa University, Japan.
CONCLUSION: Pancreatitis-associated protein (PAP) mRNA is expressed in some cases of gastric and colorectal cancers resulting from an ectopic expression in dedifferentiated cancer cells. BACKGROUND: The PAP gene is identical to the hepatoma-intestine-pancreas (HIP) gene, which is expressed in hepatoma. Expression in cancer might be another characteristic of PAP. METHODS: Fresh surgical specimens of 100 gastrointestinal cancers, 14 benign digestive diseases, and six normal organs were studied with nonisotopic in situ hybridization (ISH) using biotin-labeled cDNA probe. RESULTS: PAP mRNA was detected in 10% (6/60) of gastric cancers, 21.4% (6/28) of colorectal cancers, 20.0% (1/5) of pancreatic cancers and 0% of biliary tract (three), esophageal (one), and hepatocellular cancers (three). Reverse transcription-polymerase chain reaction (RT-PCR) detected PAP mRNA in these ISH-positive cases. PAP mRNA was not detected in noncancerous portions, benign disease tissues, or normal organs except for the small intestine. There was no relationship between PAP mRNA expression and any clinicopathological factors.
Determination of fecal fat concentration by near infrared spectrometry for the screening of pancreatic steatorrhea.
Ventrucci M. Cipolla A. Di Stefano M. Ubalducci GM. Middonno M. Ligabue A. Roda E.
Department of Internal Medicine and Gastroenterology, University of Bologna, Italy.
CONCLUSIONS: Near infrared reflectance analysis (NIRA) is a useful test for diagnosing fat malabsorption. Three-day stool collection and determination of fecal fat output are recommended. The measurement of fat concentration on spot samples may be of some use only in screening malabsorption of pancreatic origin; moreover, it does not discriminate between steatorrhea resulting from pancreatic insufficiency and that caused by gastrointestinal disorders. BACKGROUND: NIRA has been proposed as an accurate method for the determination of fecal fat excretion. The aim of this study was to ascertain whether utilization of this technique to measure fat concentration in spot samples of feces is useful in screening for malabsorption. METHODS: Twenty-five patients with chronic pancreatic disease and 95 with other digestive disorders were studied. In all patients, fecal fat assay with NIRA was performed on three different samples from each daily stool collection for 3 d. In 14 patients with pancreatic disease and 21 with gastrointestinal disorders, a colorimetric assay for fecal fat was performed for comparison. RESULTS: When mean 3-d or daily fat fecal output were considered, a strict linear relationship was found between NIRA and the colorimetric method (r = 0.97 and 0.94, respectively). Using fat concentration, the two tests correlated less well (r= 0.74). Fat concentration was significantly higher in pancreatic than in nonpancreatic steatorrhea, even though values overlapped widely, and thus discrimination was not possible. The diagnostic efficiency of fat concentration for pancreatic and nonpancreatic steatorrhea was 72 and 61%, respectively.
Establishment and characterization of a new hamster pancreatic cancer cell line: the biological activity and the binding characteristics of EGF or TGF-alpha.
Morita Y. Moriai T. Takiyama Y. Makino I.
Second Department of Internal Medicine, Asahikawa Medical College, Japan.
CONCLUSIONS: This new animal cell line may be a useful model to study the effect of growth factors on malignant cell proliferation and differentiation in both in vivo and in vitro systems. METHODS: We established a new pancreatic cancer cell line from pancreatic cancer in the hamster (HPC) induced by N-nitrosobis(2-oxopropyl)amine (BOP) and characterized its morphological, pathological, and biological patterns. RESULTS: Cells grew rapidly, with a doubling time of 22.5 h. Chromosome number ranged from 33 to 144, and flow cytometric analysis showed two peaks of DNA distribution as a proliferative pattern. Ultrastructural analyses using transmission and scanning electron microscopy of HPC cells revealed desmosomes and loose interdigitation, with pseudopods and microvilli on the cell surface. The overexpression of epidermal growth factor (EGF) receptors on HPC cells was shown by immunohistochemistry. Binding characteristics and biological activity of EGF and type alpha transforming growth factor (TGF-alpha) were studied. TGF-alpha stimulated DNA synthesis in a dose-dependent manner, whereas EGF was without effect. Scatchard analysis of 125I-EGF binding data at pH 7.4 indicated the presence of two orders of binding sites, where that of 125I-TGF-alpha showed only a single order. Regarding the effect of pH on 125I-EGF or 125I-TGF-alpha dissociation, one-half maximal dissociation of 125I-EGF or 125I-TGF-alpha occurred at pH 6.0 or 6.5, respectively. Characteristics of the EGF receptor are similar to those of cultured human pancreatic cancer cells.
Establishment and characterization of a new transplantable pancreatic cancer xenograft (PZX-5) in immunosuppressed mice.
Zalatnai A. Bocsi J. Timar F. Babo I.
1st Institute of Pathology and Experimental Cancer Research, Semmelweis University of Medicine, Budapest, Hungary.
CONCLUSION: A new, stable, transplantable human pancreatic cancer xenograft (PZX-5) model has been established in CBA immunosuppressed mice. BACKGROUND: Numerous human pancreatic carcinomas have been successfully transplanted into athymic nude mice. However, artificially immunosuppressed animals have rarely been used as recipients. Because this model system proved to be reliable for hosting many human malignancies at our institute, successive xenotransplantations of a ductal adenocarcinoma have been carried out. METHOD: Immunosuppression of CBA/CA mice was achieved by thymectomy, whole-body irradiation and bone-marrow reconstruction. Tumor fragments were subcutaneously implanted from a well/moderately differentiated ductal pancreatic adenocarcinoma and serially transplanted for more than 20 mo. The xenografted tumors were characterized using morphological, immunohistochemical, biochemical, and flow cytometric methods. RESULTS: During the serial transplantations, the neoplasm maintained its original morphological-pathobiological characteristics. It produced a large amount of mucin and expressed carcinoembryonic antigen (CEA). Neither the mitotic activity nor the degree of differentiation was altered, and CEA was permanently detected. Flow cytometric DNA analysis revealed an aneuploid pattern (DNA index 1.45+/-0.03), which has remained within the same range during xenograftings. The doubling time in an in vitro system proved to be 18 h. The human character has been well preserved even 9 mo posttransplantation, as was evidenced by LDH-isoenzyme electrophoresis. The results indicate that the thymectomized--whole-body irradiated--bone-marrow reconstructed immunosuppressed mice are also appropriate hosts for pancreatic cancer xenografts.
Effects of high-lipase pancreatin on fecal fat, neutral sterol, bile acid, and short-chain fatty acid excretion in patients with pancreatic insufficiency resulting from chronic pancreatitis.
Nakamura T. Tandoh Y. Terada A. Yamada N. Watanabe T. Kaji A. Imamura K. Kikuchi H. Suda T.
3rd Department of Internal Medicine, Hirosaki University School of Medicine, Aomori, Japan.
CONCLUSIONS: Steatorrhea was almost completely stopped and malabsorption of neutral sterols and short-chain fatty acids was reduced by treatment of high-lipase pancreatin in Japanese patients with pancreatic insufficiency whose dietary fat consumption is low. METHODS: Fifteen patients with chronic pancreatitis complicated by steatorrhea who consumed an average of 48 g of dietary fats a day were selected as subjects and given 3 g of high-lipase pancreatin (lipase, 379,800 USP U/g), at each meal (total daily dose is 9 g) for a mean duration of 28.5 d. Fecal output and fecal fat neutral sterol, bile acid, and short-chain fatty acid excretion were determined before and after the course of pancreatin therapy. RESULTS: Pancreatin administration resulted in significant reductions (P < 0.01) in fecal output (from 243.2 to 149.1 g), excretion of fecal fat, (from 12.3 to 3.9 g), animal sterols (from 816.3 to 604.6 mg), and short-chain fatty acids (from 52.6 to 18.5 mM). In contrast, no marked changes were recorded in fecal excretion of beta-sitosterol (a plant sterol), bile acids, or the hydroxy fatty acid fraction. Fecal fat and short-chain fatty-acid excretion showed strong correlations with fecal output.
Sclerosing cholangitis: a rare etiology for acute pancreatitis.
Imrie CW. Brombacher GD.
Royal Infirmary, Glasgow, UK.
Primary sclerosing cholangitis as the cause of acute pancreatitis is a rare phenomenon with only one previous case having been found by ourselves in the English literature. Over a period of 2 yr, two patients with acute pancreatitis secondary to primary sclerosing cholangitis were seen in this unit. The first patient is currently being treated with ursodeoxycholic acid and repeat endoscopic sphincterotomies, whereas the second required liver transplantation.
The use of molecular technology in the differentiation of pancreatic cancer and chronic pancreatitis.
University Department of Surgery, Queen Elizabeth Hospital, Birmingham, UK.
CONCLUSION. It is concluded that currently there are limitations in the use of some of the proposed tests, whereas in the future, further progress in our understanding of the molecular biology of pancreatic disease and the development and application of existing techniques should have a greater impact on clinical practice. BACKGROUND. Fifteen to 20% of patients with pancreatic cancer present with a resectable mass in the head of the pancreas, but there is a subgroup of patients for whom it is difficult to reach the correct diagnosis. METHOD. This article addresses how molecular technology can be used to aid in the diagnosis of this group of patients. The clinical and scientific literature is reviewed by accessing papers through the Medline database. RESULTS. This article reviews the limitations of conventional imaging techniques and the limitations of fine needle aspiration cytology and cytological examination of pancreatic duct secretions. The molecular biology of both pancreatic cancer and chronic pancreatitis is then reviewed with emphasis on the common molecular defects seen in these diseases. The current use of molecular techniques in the examination of cytological and histological specimens, stool, blood, and pancreatic duct secretions and how this helps discriminate between benign and malignant lesions of the pancreas is addressed. Finally, the use of novel serum screening tests in groups at high risk of pancreatic cancer is discussed.
Near-infrared spectrometry analysis of fat, neutral sterols, bile acids, and short-chain fatty acids in the feces of patients with pancreatic maldigestion and malabsorption.
Nakamura T. Takeuchi T. Terada A. Tando Y. Suda T.
Third Department of Internal Medicine, Hirosaki University School of Medicine, Aomori, Japan.
CONCLUSION. Near-infrared spectrometry is a new, rapid, and accurate method for measuring fecal fat that does not require a great deal of chemical knowledge and that can be used by anyone. This method is considered indispensable for the diagnosis of pancreatic steatorrhea and treatment follow-up. METHODS. Fecal fats (GLC method, van de Kamer method), neutral sterols (GLC method), bile acids (GLC method) and short-chain fatty acids (HPLC method) were assayed by the respective conventional methods in 120 subjects, including patients with pancreatic dysfunction, and the results were compared with the those obtained by near-infrared spectrometry. The correlations between fecal fat excretion measured by the GLC method (x) and van de Kamer method (x) and by near-infrared spectrometry (y) were expressed by y = 1.10x - 0.16 (r = 0.949, P < 0.01) and y = 0.750x + 1.654 (r = 0.930, p < 0.01), respectively. RESULTS. The sensitivity and specificity of near-infrared spectrometry for fecal fats were 94.9 and 98.2%, respectively, when compared with the GLC method, and 87.5 and 90.0%, respectively, when compared with the van de Kamer method. In contrast, near-infrared spectrometry was not nearly as accurate as the conventional methods for determining neutral sterols, bile acids, and short-chain fatty acids.
Endoscopic ductal drainage may avoid resective surgery in painful chronic pancreatitis without large ductal dilatation.
Laugier R. Renou C.
Department of Gastroenterology, University Hospital La Conception, Marseille, France.
CONCLUSION. Endoscopic stenting treatment, in cases of chronic pancreatitis unsuitable for decompressive surgery, appears to be safe and efficient. Perfect anatomical results are only obtained if large stents are used after balloon dilatation. BACKGROUND. Decompressive surgery in cases of painful chronic pancreatitis is only feasible if the main pancreatic duct exceeds approx 8 mm over a sufficient length. When those anatomical changes are not present, surgery must be resective. This study evaluates the results of endoscopic stent drainage and decompression of painful chronic pancreatitis without large dilatation of the main pancreatic duct. METHODS. Sixteen of our chronic pancreatitis patients were included in this study. They presented a mean of 5.3 episodes of pain in the 6 mo before treatment. Decompressive surgery was not possible because of a mean pancreatic duct diameter of 5.8 mm. Stents were 7F in eight patients and 12F in the other eight. They were left in the duct after endoscopic dilation for 9.5 +/- 1.0 mo. RESULTS. During stenting we observed two early obstructions and seven episodes of pain. All cysts disappeared and stenosis of the duct disappeared anatomically in six cases, was improved in four, but persisted in six. During follow-up, two episodes of mild pain were recorded. No cysts reappeared. Complete disappearance of stenosis was only observed in patients whose pancreatic duct was equipped with a 12F stent (p < 0.02).
Carcinoid tumors of the pancreas. Status report based on two cases and review of the worlds literature.
Mao C. el Attar A. Domenico DR. Kim K. Howard JM.
Department of Surgery, Toledo Hospital, OH, USA.
CONCLUSION. The diagnosis of a pancreatic carcinoid should be based on the measurement of serotonin in serum or its demonstration in the tumor and/or by the measurement of its derivative (5-HIAA) in urine. Carcinoid of the pancreas is a rare but definite entity; usually having metastasized by the time of diagnosis. The term "serotonin-producing tumor of the pancreas" has been suggested as an alternative designation for "pancreatic carcinoid." BACKGROUND. The literature on carcinoid tumors of the pancreas is confusing because much of it preceded the development of the more specific immunological, chemical and staining techniques currently available. METHODS. 43 case reports were collected from the world's literature, based on a demonstrable pancreatic neuroendocrine tumor plus a positive finding of at least one of the following without another dominant hormone being demonstrated: elevation of 5-Hydroxytryptamine (5-HT) (serotonin) in the serum or detected in tumor tissue, and/or elevation of 5-Hydroxyindole acetic acid (5-HIAA) in the urine. In addition to these two hormone-specific assays, information was collected on the silver-staining properties of the tumor; properties which have traditionally been associated with carcinoid tumors. Positive silver staining in tumor cells (argyrophilic and/or argentaffin reaction) is strongly indicative of the carcinoid tumor but the findings are less specific than the hormone assays and immunohistologic stains. RESULTS. In this review of 43 cases, including two current ones, the pancreatic carcinoid tumor has the following important features: 1. It is a rare tumor that is usually diagnosed late when the tumor is large and has metastasized. Thirty-eight (88.4%) have been malignant. They are, therefore, associated with a high incidence of the "carcinoid syndrome." 2. To date, prognosis in therapy is poor, based on delayed diagnosis, a resultant low incidence of resectability, and an uncertain duration of survival after resection. 3. Pancreatic carcinoid tumors remain difficult to differentiate from other endocrine tumors. The measurement of urinary 5-HIAA excretion or the demonstration of elevated serotonin level in the tumor or in serum is essential to its distinction. Silver staining of the tumor, although of historic importance, has been superceded by the hormone-specific studies. 4. To distinguish it from other endocrine tumors of the pancreas, the terms "pancreatic serotoninoma" or "serotonin-producing tumor of the pancreas" have been suggested as possible alternatives. Its growth characteristics may be related more to its cell of origin than to its extent of hormone secretion. Not all of the tumors result in recognizable hyperserotoninemia.
Serous cystadenoma of the pancreas with atypical cells. Case report.
Fujii H. Kubo S. Hirohashi K. Kinoshita H. Yamamoto T. Wakasa K.
Second Department of Surgery, Osaka City University Medical School, Japan.
CONCLUSION. Serous cystadenomas of the pancreas may have the biologic ability to undergo malignant transformation. BACKGROUND. It is generally recognized that: serous cystadenomas of the pancreas are benign and that their malignant potential is low. METHODS. A serous cystadenoma of the pancreas was resected from a 53-yr-old woman. In the central portion of the tumor, papillary structures were found on the cyst wall. Immunohistologic studies using antibodies to carbohydrate antigen 19-9, carcinoembryonic antigen, and proliferating cell nuclear antigen were performed to determine the malignant potential of this tumor. RESULTS. On histology, most tumor cells were positive for periodic acid-Schiff but were negative for periodic acid-Schiff after diastase digestion and Alcian blue, a staining pattern typical of serous cystadenomas. The cells found in the papillary structure of the cyst wall were mildly atypical. These cells were stained with antibodies to carbohydrate antigen 19-9, carcinoembryonic antigen, and proliferating cell nuclear antigen, indicating that the cells comprising the papillary structure were proliferating more rapidly than cells in other parts of the tumor and strongly suggesting that the cells are premalignant.
Acute terminal pancreatitis occurring in jejunal heterotopic pancreas.
Shimizu M. Matsumoto T. Sakurai T. Ohmoto K. Moriya T. Hirokawa M. Manabe T.
Department of Pathology, Kawasaki Medical School, Kurashiki, Japan.
CONCLUSION. We report a unique case of acute terminal pancreatitis occurring in the jejunal heterotopic pancreas. Unlike previously reported cases, acute pancreatitis was not found histologically in the ordinary pancreas. BACKGROUND. Heterotopic pancreas may show the same inflammatory or neoplastic changes, such as acute pancreatitis and adenocarcinoma, as those that occur in the ordinary pancreas. However, histologically proven acute pancreatitis occurring in heterotopic pancreas is very rare and only three reports have been described. METHODS. A 53-yr-old Japanese man died of hepatic failure, and autopsy was performed. RESULTS. Autopsy incidentally revealed heterotopic pancreas of the jejunum. Microscopically, focal acute pancreatitis was observed in the jejunal heterotopic pancreas, whereas the pancreas of the normal location showed no abnormality. In addition, no clinical evidence of pancreatic disease was noted before death. Therefore, we diagnosed this case as acute terminal pancreatitis occurring in the jejunal heterotopic pancreas.
Angiopathies in pancreatic diabetes resulting from chronic pancreatitis.
Wakasugi H. Hara Y. Abe M. Katsuda Y.
National Kyushu Cancer Center, Fukuoka, Japan.
CONCLUSION. Marked diabetic micro- and macroangiopathies were recognized in three autopsy cases with pancreatic diabetes resulting from chronic pancreatitis. BACKGROUND. Recent reports have suggested that diabetic retinopathy occurs as one of the microangiopathies in patients with secondary diabetes following chronic pancreatitis. METHODS. We report three autopsy cases with pancreatic diabetes. Cases 1 and 2 showed alcoholic chronic pancreatitis. Case 3 was a patient with chronic pancreatitis resulting from hyperparathyroidism. All three cases had pancreatic calcification and markedly decreased exocrine pancreatic function. There was no family history of diabetes in these patients. The HbA1 values were elevated, with diminished secretion of both insulin and glucagon. RESULTS. The common features of the clinical courses were poor glycemic control, including insulin-induced hypoglycemic attacks in the early stage and microangiopathy, followed by difficulties in treatment for hypertension in the late stage of pancreatic diabetes. Autopsies, performed after 12-18 yr of diabetes, revealed fibrosis of the pancreas, disappearance of acinar cells in the exocrine pancreas, atrophy, a diminished number of islets of Langerhans, and diabetic glomerulosclerosis, with arteriosclerosis in the brain, heart, and kidneys. Cerebral hemorrhage, heart failure, and myocardial infarction were suggested to be the main causes of death. Although the serum lipid levels were rather low in cases 1 and 2, arteriosclerosis was marked by the age of 60, and serum protein levels were also low in all three cases.
Celiac axis infusion chemotherapy in advanced nonresectable pancreatic cancer.
Maurer CA. Borner MM. Lauffer J. Friess H. Z'graggen K. Triller J. Buchler MW.
Institute of Visceral and Transplantation Surgery, University of Bern, Switzerland.
CONCLUSION: Based on these data we suggest that regional intra-arterial chemotherapy for advanced pancreatic cancer seems not to be superior to common treatment modalities, such as combined radiochemotherapy. BACKGROUND: The prognosis for advanced pancreatic cancer is very poor. No standard treatment is available. Recently, better survival and quality of life was reported from regional cancer treatment via celiac axis infusion. In an attempt to confirm these results we conducted a phase II study of intra-arterial chemotherapy for nonresectable pancreatic cancer. METHODS: From May 1994 to February 1995, 12 consecutive patients with biopsy-proven advanced ductal carcinoma of the exocrine pancreas were given intra-arterial infusions consisting of Mitoxantrone, 5-FU + folinic acid, and Cisplatin via a transfemorally placed catheter in the celiac axis. Six patients were classified as UICC stage III and six as stage IV with the liver as the sole site of distant metastasis. Nine patients had primary and three had recurrent pancreatic carcinoma after a Whipple procedure. Nonresectability of primary tumors was assessed in all patients by laparotomy or laparoscopy. RESULTS: A total of 31 cycles of chemotherapy (mean 2.6 cycles/patient) was administered. Catheter placement was technically feasible in all cycles. A groin hematoma was the only catheter complication. The follow-up by CT scans at 2-mo intervals revealed partial remission in 1 patient (8%), temporary stable disease in 4 patients (33%), and disease progression in 7 patients (58%). The same response was obtained after analyzing the CA 19-9 course. Median survival in stage III patients was 8.5 mo (3-12 mo) and in stage IV patients 5 mo (2-11 mo). Toxicity according to WHO criteria consisted of grade III (4 events), grade II (10 events), and grade I (17 events), mainly resulting from leucopenia and diarrhea/vomiting. Nine of 11 patients experienced temporary relief of pain immediately after regional treatment.
Prevention of hyperlipidemic acute pancreatitis during pregnancy with medium-chain triglyceride nutritional support.
Mizushima T. Ochi K. Matsumura N. Ichimura M. Ishibashi T. Tsuboi K. Harada H.
Department of Clinical Laboratory Medicine, Okayama University Medical School, Japan.
CONCLUSION: A combination of diet therapy, nutritional support with medium-chain triglycerides (MCT), and well-planned preterm Cesarean delivery on demand is an effective measure to prevent gestational hyperlipidemic pancreatitis and leads to successful childbirth. BACKGROUND: Prevention and therapy of gestational hyperlipidemic pancreatitis are important, although difficult, because the condition carries a high maternal and fetal morbidity and mortality. RESULTS: We describe a 32-yr-old female with lipoprotein lipase-deficient familial hypertriglyceridemia who had recurrent episodes of acute pancreatitis. The third episode occurred with worsened hyperlipidemia 7 yr earlier at 32 wk of her first pregnancy and resulted in fetal death. The fourth and fifth episodes were also accompanied by marked hyperlipidemia probably caused by drug discontinuance and dietary noncompliance. She became pregnant. Serum triglyceride levels were controlled below 2000 mg/dL by strict monitoring with low-fat, low-calorie diet and MCT nutritional support. A premature but healthy infant was born by Cesarean delivery at 36 wk of gestation when the mother presented with mild abdominal pain and was found to have uterine contractions. The ensuing clinical course has been uneventful.