Role of color Doppler ultrasonography in the preoperative staging of pancreatic cancer.
Casadei R. Ghigi G. Gullo L. Moretti CC. Greco VM. Salizzoni E. Canini R. Marrano D.
Dipartimento di Scienze Chirurgiche e Anestesiologiche--Clinica Chirurgica I, Bologna, Italy.
We describe our experience with color Doppler ultrasonography (CDU) in the preoperative staging of pancreatic cancer and, particularly, in detecting the involvement of the portal-mesenteric trunk (PMT). Of the 54 patients studied, 43 (79.6%) underwent surgery and 11 (20.4%) did not because of evident infiltration of the PMT. Of the 43 patients operated on, the CDU study was normal in 8 cases (18.6%), abnormal in 33 (76.7%), and not possible in the remaining 2 cases (4.7%). Results of the CDU were confirmed intraoperatively in 39 cases (diagnostic accuracy, 95.1%). In only two cases (4.9%) did the CDU not show involvement of the PMT, which was, instead, demonstrated by intraoperative ultrasonography (false negatives). Of the 11 nonoperated patients, all showed morphological alterations at CDU, while only 7 showed hematic flow changes. The sensitivity of CDU was 94.2% and the specificity 100%. The positive predictive value was 100%; the negative predictive value, 75%. The results indicate that CDU may be the first imaging technique for preoperative assessment of PMT involvement in pancreatic cancer.
Integrated radiosurgical treatment of resectable pancreatic head carcinoma.
Crucitti F. Doglietto GB. Frontera D. Viola G. Morganti AG. Valentini V. Alfonsi G. Trodella L. Cellini N.
Department of Surgery, Catholic University School of Medicine, Rome, Italy.
Thirty-six patients with pancreatic head carcinoma entered a protocol, but only 20 were suitable for resection and evaluation of long-term survival. They were nine males and 11 females, with a mean age of 64.3 years. Following surgical resection, 10 Gy was delivered to the tumor bed intraoperatively. Postoperative radiotherapy was performed 4-6 weeks after surgery: patients were treated with 50.4 Gy (1.8 Gy/day, 5 days/week) to the tumor and nodal bed. Since 1991, 10 patients have also received preoperative short-course radiotherapy (5 Gy) of the liver and pancreas. Postoperative morbidity was 25%; two postoperative deaths were observed in patients with locally advanced neoplasms, in whom a vascular resection was also performed. Only 14 patients started postoperative radiotherapy, which was interrupted in two cases. At present, 14 patients are dead and four are alive and disease free. The local recurrence rate was 11.1% and distant metastases were observed in 66.7% of cases. The median actuarial survival was 11.9 months, but it was 18.5 months in patients with disease-free resection margins. A significantly better survival was also observed in patients submitted to short-course preoperative radiotherapy. These preliminary results show that intraoperative and perioperative radiotherapy is feasible and may improve local control of disease. Unfortunately, these results are not matched by a significant improvement in survival due to the high incidence of intraabdominal metastases. Thus, new therapeutic modalities, including preoperative radiotherapy (with or without chemotherapy), should be tested.
Immunohistochemical and molecular biological studies of serous cystadenoma of the pancreas.
Ishikawa T. Nakao A. Nomoto S. Hosono J. Harada A. Nonami T. Takagi H.
Department of Surgery II, Nagoya University School of Medicine, Japan.
Seven cases of pancreatic serous cystadenoma were examined immunohistochemically and molecular biologically. Six were benign tumors and one was clinically malignant. Immunohistochemical studies were performed with the avidin-biotin peroxidase complex technique on paraffin-embedded tumor tissue and were stained with antibody to carcinoembryonic antigen (CEA), CA19-9, and p53 protein. Two-stage polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect K-ras oncogene mutation at codon 12. No tumor cells were stained with anti-CEA and anti-p53 protein, but two cases were stained focally with anti-CA19-9. One case was benign and one was clinically malignant. In the anti-CA19-9 staining, tumor cells of the benign case were positive only on the apical membrane and supranuclear cytoplasm of the cells, whereas those of the clinically malignant case were positive over the entire surface and cytoplasm of the cells. All seven cases were without K-ras gene mutation. So the features of serous cystadenoma of the pancreas suggest a tumor genesis different from that of ductal adenocarcinoma. They also suggest a relationship between immunohistochemical localizations of CA19-9 in the tumor cells and the biological behavior of the tumor itself.
A comparison of lipase and amylase in the diagnosis of acute pancreatitis in patients with abdominal pain.
Keim V. Teich N. Fiedler F. Hartig W. Thiele G. Mossner J.
Medizinische Klinik und Poliklinik II, Universitat Leipzig, Germany.
The clinical value of amylase and lipase measurement for the diagnosis of acute pancreatitis was evaluated in 253 patients presenting with acute abdominal pain. Acute pancreatitis was detected in 32 patients by computed tomography or ultrasound. In the serum samples collected on days 0-1 after the onset of symptoms, lipase was elevated in 100% and amylase in 95%. A 95% sensitivity/specificity was reached at a lipase cutoff near twofold above normal. The receiver-operating characteristics (ROC) showed similar curves for both enzymes, lipase being slightly superior to amylase. The ROC curves from days 2-3 demonstrated a much lower sensitivity/specificity of both enzymes. Lipase, however, was notably superior to amylase: at a sensitivity of 85% the specificity of lipase (amylase) was 82% (68%). In samples from days 4-5 the accuracy of the enzyme assays was even worse; at a sensitivity of 60% the specificity did not increase above 70%. The diagnostic value of simultaneous measurement of amylase and lipase was tested at different cutoffs in two groups: the OR group, in which one of the two parameters had to be elevated, and the AND group, in which both parameters had to be above normal. Combination of both parameters mainly improved the specificity of the assay (from 91 to 98% on days 2-3 and from 93 to 97% on day 4-5) but only when, in the OR group, twofold elevated amylase was combined with lipase. We conclude that the simultaneous determination of serum lipase and amylase marginally improved the diagnosis of acute pancreatitis in patients with acute abdominal pain, however, the sensitivity of the assay with samples collected 4-5 days after onset of the disease remained low.
1996 Comfort Symposium on Pancreatic Carcinogenesis.
Urrutia R. Miller LJ. DiMagno EP.
Gastroenterology Research Unit, Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
This article summarizes the proceedings of the 1996 Comfort Symposium on Pancreatic Carcinogenesis that took place at the Mayo Clinic in Rochester, Minnesota, September 11-13, 1996. The annual series of Comfort lectures are aimed at discussing leading theories and advanced technological developments in the area of pancreatic research. The goals of this year's symposium were to summarize epidemiologic and experimental findings in the field of pancreatic cancer research, to foster communications among scientists studying this disease, and to identify areas of research that are likely to bridge the gaps between basic science and patient care. The topics discussed included (i) current algorithms for the diagnosis of early pancreatic cancer, (ii) animal and cellular models of pancreatic carcinogenesis, (iii) mechanisms of pain in pancreatic cancer, (iv) the role of signaling cascades and transcription factors in the regulation of pancreatic cell growth and differentiation, (v) methods to study genetic alterations associated with neoplastic diseases, and (vi) recent developments in gene-targeting techniques. The lectures and discussions during the symposium successfully achieved the goals outlined above and resulted in the identification of novel areas of research that may increase our understanding of the etiology and pathogenesis, and lead to early diagnosis and treatment of pancreatic cancer.
Evaluation of p53 mutation in pancreatic acinar cell carcinomas of humans and transgenic mice.
Terhune PG. Memoli VA. Longnecker DS.
Department of Pathology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
Mutation of the p53 tumor suppressor gene is found in a large number of exocrine pancreatic tumors. The majority of these tumors is of the ductal cell phenotype. We examined 12 human acinar cell carcinomas and 42 transgenic mouse carcinomas (including 36 acinar cell tumors, four islet cell tumors, and two liver metastases of primary acinar cell tumors) for evidence of p53 mutation. Immunohistochemistry was used to identify p53 protein in tumor sections. To evaluate p53 exons 5-8, heteroduplex analysis was used on formalin-fixed, paraffin-embedded human tumor DNA, and single-strand conformation polymorphism analysis was used on frozen mouse tumor DNA. No molecular evidence of p53 mutation was found in any of the tumor DNAs and immunohistochemical data were regarded as negative. This study provides evidence that acinar cell carcinogenesis in both humans and transgenic mice is independent of p53 mutation.
Establishment of a human pancreatic tumor xenograft model: potential application for preclinical evaluation of novel therapeutic agents.
Mohammad RM. Dugan MC. Mohamed AN. Almatchy VP. Flake TM. Dergham ST. Shields AF. Al-Katib AA. Vaitkevicius VK. Sarkar FH.
Department of Internal Medicine, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan 48201, USA.
Adenocarcinoma of the pancreas is currently the fifth leading cause of death in the United States. It remains generally incurable by available treatment modalities. We report here on the characterization of a permanent pancreatic cell line (KCI-MOH1), established as a xenograft in severe combined immune deficient (SCID) mice, from a 74 year-old African American male patient diagnosed with pancreatic cancer. Sections from paraffin-embedded tumors excised from SCID mice revealed typical adenocarcinoma of the pancreas. Karyotypic analysis of cultured cells derived from tumors grown in SCID mice revealed a male karyotype with multiple clonal aberrations: 42, XY, add (3)(p11.2), der(7) t(7;12) (p22;q12), -10, -12, add (14)(p11), -18, add (20)(q13)-22/84, idemx2. Immunostaining of KCI-MOH1 tissues shows strong expression of p53 and p21 proteins. The xenograft model was established by transplanting the KCI-MOH1 cells subcutaneously (s.c.) in SCID mice. When the s.c. tumor was transplanted in vivo to other SCID mice, the success rate was 100%, with a doubling time of 8.5 days. The SCID mouse xenograft model was used to test the efficacy of selected standard chemotherapeutic drugs (taxol, gemcitabine, 5-fluorouracil, and Ara-C) and novel biological agents (Bryostatin 1 and Auristatin-PE). Results show that gemcitabine, Ara-C, and Bryostatin 1 were active against KCI-MOH1. The xenograft described herein can be used as an animal model to facilitate the development of novel therapeutic agents against human pancreatic cancers.
Inhibition of pancreatic tumor cell growth in culture by p21WAF1 recombinant adenovirus.
Joshi US. Dergham ST. Chen YQ. Dugan MC. Crissman JD. Vaitkevicius VK. Sarkar FH.
Department of Pathology, Wayne State University School of Medicine, Karmanos Cancer Institute and Harper Hospital, Detroit, Michigan 48201, USA.
New innovations are needed for the treatment of pancreatic cancer, as current treatments do not offer significant improvements in overall survival. p21WAF1--a tumor suppressor gene--acts as a downstream effector of p53 function and mediates G1 cell cycle arrest by inhibiting cyclin-dependent kinases, which promote cell growth. p21 expression has also been shown to increase more than 20-fold in senescent cells in culture. The replication-defective recombinant adenoviral system (rAd), a major innovation in gene transfer technology, has recently been used in gene therapy applications for various malignancies but not for pancreas cancer. In this study we used rAd-p21 in cell growth inhibition studies of pancreatic tumor cell lines in vitro to explore its potential as a prospective gene therapy for pancreatic adenocarcinoma. We studied two pancreatic cell lines in culture, HPAC and Hs766T. HPAC revealed higher endogenous levels of p21 gene expression at the protein and RNA levels compared to Hs766T. p21 induction was tested using different doses of rAd-p21 to establish an optimum dose for significant induction of p21 gene expression. Tumor cell growth in culture following rAd-p21 infection was also analyzed in both cell lines. HPAC and Hs766T cell lines showed a significant dose-dependent increase in p21 protein expression when infected with rAd-p21. Both cell lines showed significant growth arrest, but Hs766T showed less cell growth inhibition than HPAC cells. Flow cytometric cell cycle analysis of rAd-p21-infected cells showed a statistically significant increase in the number of cells in G0/G1 in HPAC cells. Similar results were also obtained in Hs766T cells, however, the data were not statistically significant. In conclusion, pancreatic tumor cell growth can be inhibited by rAd-p21 in vitro, with significant numbers of tumor cells reverting from S to G0/G1. Thus rAd-p21 may be effective as a candidate gene therapy for pancreatic cancer and should be further evaluated with in vivo studies.
Application of pure pancreatic juice collection to the pancreatic exocrine function test.
Wada K. Yamadera K. Yokoyama K. Goto M. Makino I.
Second Department of Internal Medicine, Asahikawa Medical College, Japan.
We determined the usefulness of pure pancreatic juice collected by endoscopic procedures for assaying impaired pancreatic function in patients with chronic pancreatitis. The functional findings were compared with the degree of morphological change in endoscopic retrograde pancreatograms. Samples of pancreatic juice were collected from 23 patients with suspected chronic pancreatitis by endoscopic cannulation after a bolus intravenous injection of secretin, 100 IU, for 20 min in four 5-min samples. Volume and amylase and bicarbonate concentrations were measured. The maximum bicarbonate concentration (MBC) was found in fractions collected after 10 min. The MBC in patients with chronic pancreatitis (n = 7) was lower than in normal subjects (n = 10) (p < 0.05). When we regarded 125 mEq/L (mean - 1.5 SD) as the normal limit of MBC, the sensitivity, specificity, and overall efficiency of the pancreatic functional test using pancreatic juice to detect chronic pancreatitis were 86, 100, and 94%, respectively. In comparison with the group with normal pancreatogram findings (n = 10), the MBC, volume, amylase output, and bicarbonate output were lower in the combined group (n = 9) of Cambridge II and III (p < 0.05). MBC was the most reliable parameter in the evaluation of the exocrine pancreatic functional test using pancreatic juice samples.
Effects of early ductal decompression in human biliary acute pancreatitis.
Pezzilli R. Billi P. Barakat B. Baroncini D. D'Imperio N. Miglio F.
Emergency Department, Sant'Orsola Hospital, Bologna, Italy.
It was recently demonstrated in experimental models that, after pancreatic outflow obstruction, serum amylase levels first increase and then progressively decline regardless of whether the obstruction was maintained or relieved. Furthermore, early decompression of the ductal biliary system may prevent the progression of the disease. This finding prompted us to look for a similar pattern in patients with obstructive acute pancreatitis due to biliary stones. Forty-two patients with biliary acute pancreatitis were prospectively studied. Twenty-one patients underwent urgent endoscopic sphincterotomy (ES), and 21 received conservative medical treatment (CMT). The two groups were comparable for sex, age, onset of pain, and severity. Serum amylase and lipase were determined in all patients on admission and 24 h later. The percentage variation of serum amylase and lipase was calculated considering, for each patient, the concentrations of the two enzymes assayed on admission and 24 h later. On admission, all patients had elevated serum concentrations of amylase (mean +/- SEM: ES, 2,560+/-473 U/L; CMT, 1,783+/-481 U/L) and lipase (ES, 3,037+/-574 U/L; CMT, 3,179+/-724 U/L). The serum amylase variation (mean +/- SEM) was -65.6+/-5.5% in the ES and -47.2.1+/-8.1% in the CMT patients. The serum lipase variation was -59.1+/-7.7 and -33.1+/-18% in the same groups, respectively. These differences were not statistically significant. Acute pancreatitis worsened in one patient in the ES group and in seven in the CMT group; this difference was statistically significant (p < 0.02). The mean length of hospitalization was 8.9 days in the ES group and 19.7 days in the CMT group (p < 0.001). Serum pancreatic enzymes determination is not useful to evaluate the results of the early decompression of biliary duct in human acute pancreatitis. Indeed, early endoscopic sphincterotomy may result in a substantial improvement in the outcome of biliary acute pancreatitis.
Characterization of functional thrombin receptors in human pancreatic tumor cells (MIA PACA-2).
Rudroff C. Schafberg H. Nowak G. Weinel R. Scheele J. Kaufmann R.
Department of Surgery, Friedrich Schiller University Jena, Germany.
In this article, the "tethered ligand" thrombin receptor was identified on human pancreatic tumor cells, MIA PaCa-2, using immunofluorescence studies with a monoclonal anti-thrombin receptor antibody. Pharmacological characterization, using 3H-labeled thrombin receptor activating peptide-6 (TRAP-6) as radioligand, demonstrated a single class of high-affinity binding sites (KD = 9.1+/-1.8 x 10(-7) M) and a binding capacity of 13.9+/-0.7 fmol/mg protein. These binding sites represent functional thrombin receptors, as shown by alpha-thrombin- and TRAP-6-induced mobilization of free intracellular calcium, protein kinase C translocation from cytosol to the cell membrane, and stimulation of DNA synthesis in MIA PaCa-2 cells. These results provide the first identification of tethered ligand thrombin receptor in human pancreatic cancer cells and suggest thrombin receptor involvement in mechanisms of human pancreatic tumor progression.
Macrolipasemia in Crohns disease.
Okumura Y. Tamba J. Shintani Y. Yoshioka U. Inoue H. Fujiyama Y. Bamba T.
Second Department of Internal Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, Japan.
A 38-year-old male patient who had been treated for Crohn's disease was found to have serum lipase activity that was persistently increased approximately 10-fold above the normal upper limit. He was diagnosed with chronic pancreatitis based on slightly elevated elastase-1 level and retrograde pancreatography showing slight dilatation of the main pancreatic duct. Therefore, the hyperlipasemia was thought to be due to pancreatitis. However, the serum amylase and trypsin was not increased at any time, and no serious findings suggestive of pancreatitis were detected on morphologic examination. Thus, there were discrepancies between the serum lipase activity and other laboratory and clinical findings. Exclusion chromatography of the patient's serum suggested macromolecular lipase, and further immunologic testing including affinity chromatography, enzyme-linked immunosorbent assay, and immunoprecipitation assay showed that serum lipase was bound to immunoglobulin Gkappa. Therefore, the hyperlipasemia was caused by immunoglobulin-linked lipase, termed "macrolipasemia." Macrolipasemia has rarely been reported, and this is the first reported case of macrolipasemia accompanied by Crohn's disease.
Pancreatic surgery in Japan: historical review.
Satake K. Saitoh Y. Takayama Y.
First Department of Surgery, Osaka City University Medical School, Osaka, Japan.
The advent of surgical techniques for the management of pancreatic cancer has had a long and varied history in the Western culture. The development of current surgical techniques and treatment modalities is based on (rooted in) techniques developed over time. Although the first written anecdotes of pancreatic resection--primarily from the 1600s through the late 1800s--did not alter the mortality of pancreatic cancer, they did pave the way for advances in surgical techniques that subsequently attained lower morbidity and mortality rates. Although there were some meager attempts at pancreatic resection in Japanese institutions before and during World War II, it was not until after the war, and particularly after the mid-1950s, that pancreatic surgery developed tremendously. The development of more radical approaches to pancreatic surgery developed tremendously. The development of more radical approaches to pancreatic resection as well as other surgical developments resulted in lower morbidity and mortality rates.
Pancreatic surgery: cutting-edge developments and technology.
First Department of Surgery, Nagoya University School of Medicine, Japan.
In the 1980s, Japanese pancreatic surgeons used aggressive strategies to treat pancreatic cancer under the influence of Fortner's regional pancreatectomy and developed several surgical approaches including extended lymph node and connective tissue clearance with autonomic nerve dissection around the celiac and superior mesenteric arteries. Nagakawa's "translateral retroperitoneal approach" in extended radical pancreatectomy was accepted and used by many Japanese surgeons; however, whereas this operation prolonged postoperative survival, it also induced high rates of postoperative complications and ultimately failed to improve the quality of the patient's life. A pylorus-preserving pancreatoduodenectomy with modified extended dissection of the lymph node and connective tissues did not decrease the survival rate for resected patients but improved their quality of life. In the next decade, Takada developed duodenum-preserving total pancreatic head resection, which preserves the integrity of the digestive and biliary tracts. This operation, to anastomose the main pancreatic duct with the duodenum, is unique and is applicable to benign or low-grade malignant lesions of the pancreas. Adjuvant treatments have not offered satisfactory results as expected. Finally, it is recommended that the aggressive Japanese surgical strategies be reevaluated in a formal trial with a prospective randomized study to improve the quality and longevity of the patients' lives.
The epidemiology of pancreatic diseases in Japan.
Oomi K. Amano M.
Office of International Cooperation, Minister's Secretariat, Ministry of Health and Welfare, Chiyoda, Tokyo, Japan.
We reviewed the trends and death rates of pancreatic cancer and pancreatitis in Japan over the past four decades. It is a disturbing fact that the death rate due to pancreatic cancer is rising, parallel to that of lung cancer and colon cancer and that it is affecting primarily the elderly 65 years and older in both sexes. The cause of this increase is partially attributable to improvements in the diagnosis, changes in life-style, and smoking. The death rate due to chronic and acute pancreatitis has remained constant during the past four decades.
Japan Pancreatic Cancer Registry: current status.
Yamamoto M. Ohashi O. Saitoh Y.
The First Department of Surgery Kobe University School of Medicine, Japan.
The Pancreatic Cancer Registration Committee of the Japan Pancreas Society registered a total 17,130 patients with pancreatic cancer from 350 major hospitals in Japan from 1981 through 1995. Diagnosis with ultrasonography and computed tomography has become increasingly important as the methods used for first detecting a pancreatic lesion. Tumor resection was performed in 36% of the patients, and the 5-year survival rate of the patients who received resection was 18.2%. The rate of resection and results of surgical treatment have improved, which may be attributed to the increase in detection of resectable tumor and benefits of aggressive and extended surgery.
Criteria for diagnosis of acute pancreatitis in Japan and clinical implications.
Sunamura M. Lozonschi L. Takeda K. Kobari M. Matsuno S.
First Department of Surgery, Tohoku University School of Medicine Sendai, Aobaku, Japan.
The Japanese grading system for severity of acute pancreatitis has evolved from results of a national survey on 2,553 patients managed in 523 major medical centers in Japan between 1982 and 1986. It was devised to embrace the predictive factors that would offer high sensitivity and specificity in rendering an accurate diagnosis. In this system, computed tomographic (CT) examination is used for estimating the severity of acute pancreatitis. Combining criteria from laboratory data, clinical signs, and CT findings, the system appears cumbersome. However, it is actually more flexible in that only few criteria, from the wide range of findings actually covered, are needed to predict severity. Its rationale stems from a national effort to improve the outcome of this life-threatening disease. Further prospective studies are needed to determine its accuracy and superiority.
Criteria for pancreatic disease diagnosis in Japan: diagnostic criteria for chronic pancreatitis.
Shinshu University School of Medicine, Matsumoto, Japan.
Chronic pancreatitis was not a clinical entity until around 1960 in Japanese gastroenterology. The diagnosis of chronic pancreatitis had been vague and difficult to ascertain. The diagnostic criteria for chronic pancreatitis were first proposed in 1971, and they were subsequently revised in 1983. Patient numbers of chronic pancreatitis were summed by national surveys under each of the common diagnostic criteria. Total patient number and incidence rate of chronic pancreatitis are recognized as increasing throughout Japan, based on results of two national surveys of chronic pancreatitis. The diagnostic criteria for chronic pancreatitis in Japan were again revised in 1995, because the 1983 criteria were too complicated, and there had been more recent progress in clinical investigations of the pancreas. The essential revised points of the Diagnostic Criteria, 1995, are introduced in this review along with some discussion.
Stage classifications of pancreatic cancer: comparison of the Japanese and UICC classifications and proposal for a new staging system. Union Internationale Contre le Cancer.
Kawarada Y. Isaji S.
First Department of Surgery, Mie University School of Medicine, Tsu, Japan.
In the 4th edition of General Rules for the Study of Pancreatic Cancer by the Japan Pancreas Society (JPS), published in 1993 (English version published in 1996), a system resembling the TNM classification by the Union Internationale Contre le Cancer (UICC) was adopted, based on the results of precise analysis of data from 11,317 cases of carcinoma of the pancreas registered by the JPS during the 10-year period from 1981 to 1990. We compare the two TNM classifications and staging groups, focusing on the simplicity and reproducibility of the diagnostic criteria and the reliability of predicting outcome. To compare the prognostic value of the two classification systems, we analyzed the published data on resected cases registered by Pancreatic Cancer Registration Committee of the JPS. The results showed that a major drawback of the JPS classification is that is difficult to apply and has poor reproducibility. Survival rates differed significantly among the four stages in the JPS classification, whereas the UICC staging system did not reflect differences in outcome among the four stages, especially between stages II and III. The prognostic value of the UICC T category is better than that of the JPS T category, whereas the N category of JPS has better prognostic value than that of the UICC system. Believing that a combination of the two systems would solve this problem, we propose a new TNM classification and stage-grouping system that draws on the merits of both. This new system may provide improvements in staging classification that will lead to the establishment of a more practical and universal staging system for ductal carcinoma of the pancreas.
A new model for pancreatitis.
Satake K. Hiura A.
First Department of Surgery, Osaka City University Medical School, Osaka, Japan.
Pancreatitis induced by ligation of the pancreatic duct produces morphologic similarities to human pancreatitis. This model is easily performed in big animals, but it is very difficult to perform pancreatic duct ligation in small animals. Many experimental studies of pharmaceutical treatments for pancreatitis used pancreatic duct-ligation models, but it is also difficult to evaluate the efficacy of the drugs used, because the animals used are of different species with individual differences. To overcome these problems, we ligated the main pancreatic duct of the splenic lobe by a 5.0 absorbable suture by using a surgical microscope and left the gastroduodenal lobe intact in the same rats. This model produced damaged pancreatic tissue in one part and normal pancreatic tissue in another part of the pancreas in the same animals, biochemically and histologically. We evaluated the effect of a new protease inhibitor (ONO-3404) on this preliminary model and found this new protease inhibitor demonstrated a hypertrophic effect on the damaged pancreatic tissue and the normal pancreatic tissue in the same animals. This model is also useful to study pharmaceutic treatment for pancreatic insufficiency and to study chemically induced pancreatic carcinogenesis in the damaged pancreatic tissue and the normal pancreatic tissue in the same animals.
Acute pancreatitis: overview of medical aspects.
Department of Gastroenterology and Internal Medicine, Tokyo Women's Medical College, Japan.
In this article we describe the current status of treatment of acute pancreatitis in Japan and the guidelines established for the treatment of severe acute pancreatitis. In 1987 the Research Committee for Intractable Diseases of the Pancreas of the Ministry of Health and Welfare conducted a nationwide survey on acute pancreatitis to determine the prevalence of the disease between 1982 and 1986 and the treatment modalities used. Based on a detailed assessment of the results of the survey, the Committee developed criteria for rating the severity of acute pancreatitis and guidelines for the treatment of acute pancreatitis, which was revised in 1995. The five points cited as the principal aspects of treatment of severe acute pancreatitis in Japan include (a) rating the severity of the disease according to the severity rating criteria; (b) differentiating between edematous and necrotic pancreatic lesions and performing dynamic CT of the pancreas to define the extent of pancreatic necrosis; (c) performing ultrasonography to determine whether there are gallstones; (d) in principle, not performing surgery except in patients who clearly have early infection or complications after the onset; and (e) providing conservative intensive care immediately after the onset. In the absence of complications, the treatment of acute pancreatitis in Japan is primarily medical. In contrast to other countries, however, administration of antiprotease agents has become an important method of treating acute pancreatitis in Japan. Special treatment modalities, such as peritoneal lavage, blood purification, and continuous arterial infusion of protease inhibitor, are being performed in severe acute pancreatitis, in addition to intensive care.
Acute pancreatitis and cytokines: second attack by septic complication leads to organ failure.
Second Department of Surgery, Kumamoto University Medical School, Japan.
Acute pancreatitis is accompanied by destruction and digestion of tissues, causing hypercytokinemia and hyperreactivity of leukocytes (macrophages and neutrophils) and vascular endothelial cells. As one of the biological defense mechanisms in this condition, neutrophils infiltrate vital organs such as the lung, liver, and digestive organs. When acute pancreatitis is complicated by infection, hyperreactive macrophages release a large amount of proinflammatory cytokines that activate primed neutrophils, as a "second attack." Utilizing proteolytic enzymes and oxidant, neutrophils injure the infiltrated vital organs, causing cellular damage and dysfunction of vital organs distant from the pancreas. Multiple organ failure in acute pancreatitis with septic complications can develop, at least in part, by proinflammatory cytokine release and neutrophil activation.
Surgical aspects and management of acute necrotizing pancreatitis: recent results of a cooperative national survey in Japan.
Takeda K. Matsuno S. Sunamura M. Kobari M.
The First Department of Surgery, Tohoku University, School of Medicine, Sendai, Japan.
A cooperative national survey between 1991 and 1994 recently clarified the status of acute necrotizing pancreatitis in Japan. The overall mortality rate was 20.8%; however, the mortality rate in patients with infection was 33.3%, and the mortality rate in patients who underwent surgery was 27.4%. With regard to surgical procedures, drainage procedures (mobilization of the pancreatic bed and retroperitoneal drainage) were performed most frequently, and one third of the patients who underwent drainage procedures needed reoperation. Although debridement of the necrotic tissue (necrosectomy or resection of the pancreas) was performed in 33.3%, the mortality rate was 35.3%. There was no difference in the mortality rate between early and delayed operation. Recently two new modalities have been advocated for the management of severe acute pancreatitis in Japan. One is continuous regional arterial infusion of protease inhibitor and antibiotics, and the other is continuous hemodiafiltration. Further work is needed to establish the most effective procedures for the management of acute necrotizing pancreatitis and debridement of pancreatic infection.
Chronic pancreatitis: overview of medical aspects.
Naruse S. Kitagawa M. Ishiguro H. Nakae Y. Kondo T. Hayakawa T.
Department of Internal Medicine II, Nagoya University School of Medicine, Japan.
Based primarily on our experience, we review current problems on etiology, pathogenesis, classification, diagnosis, and treatment of chronic pancreatitis. Much of the confusion and difficulty associated with chronic pancreatitis originates from the relative inaccessibility of this organ. A lack of specific and sensitive markers that are suitable for the follow-up of a long natural course of chronic pancreatitis also hinders our understanding of this disease. The resolution of the present imaging tests, even by the latest technology, is not good enough to detect early changes of the pancreas. In the past 10 years, several subgroups of patients with alcoholic and idiopathic pancreatitis have been identified based on the long-term follow-up study. Pain disappeared spontaneously in many patients during the course of the disease, but its mechanism is still poorly understood. Removal of pancreatic stones and protein plugs by chemical, endoscopic, or extracorporeal shock-wave therapy has been tried with some success, but their clinical values remain to be established. Attempts have been made to understand the etiology and pathogenesis of chronic pancreatitis at molecular levels. This approach, together with a prospective follow-up of patients, will improve our understanding on chronic pancreatitis.
Pancreatic dysfunction and treatment options.
Nakamura T. Takeuchi T. Tando Y.
Third Department of Internal Medicine, Hirosaki University School of Medicine, Aomori, Japan.
Pancreatic steatorrhea and pancreatic diabetes are the dominant symptoms of patients in the decompensated stage of chronic pancreatitis (CP). In this stage, the nutritional state is greatly disturbed and hypoglycemia and labile infection are involved. Pancreatic enzyme replacement therapy is the principal treatment method for pancreatic steatorrhea. Before initiating this therapy, dietary fat intake must be determined and pancreatic lipase and bicarbonate secretion function must be evaluated. Upper small intestinal pH is regulated by gastric acid secretion, and abnormal gastric emptying changes lipolysis. In addition, precipitation of bile acids in the upper small intestine and ileal brakes due to undigested fats and carbohydrates must be considered. Porcine pancreatin, bacterial lipase, and acid-resistant fungal lipase are used as enzymes for replacement therapy. Conventional, entero-coating, and enteric-coated microsphere preparations of porcine pancreatin are available for treatment and are formulated to protect against gastric acids, to dissolve enzymes at optimum pH, and to be emptied simultaneously with food from the stomach. Gastric acid secretion suppressants, such as H2 blockers or a proton pump inhibitor, can also be used concomitantly with pancreatin preparations. In consideration of both strengths and weaknesses of these preparations, types and dosages of enzyme replacement therapy should be carefully prescribed, and fecal fats should be examined repeatedly by a simple and rapid method during treatment. Attention should also be paid to changes in body weight and nutritional indices (e.g., nutritional parameters, fat-soluble vitamins). The relationship between carbohydrate maldigestion/malabsorption in CP patients and treatment of pancreatic diabetes are topics for future research.
Current surgical trends in Japan for managing chronic pancreatitis.
Takada T. Yasuda H. Amano H. Yoshida M. Uchida T.
First Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.
The main aims of surgery for treating chronic pancreatitis are to relieve the patient's persistent pain and to preserve pancreatic functioning. The indications for surgery include treating complications, such as the presence of pancreatic pseudocysts or biliary stenosis associated with chronic pancreatitis or both. A resection, ductal drainage, or both, may commonly be required. Furthermore, some surgeons recommend pancreatic denervation. We analyze the details of 2,936 patients with chronic pancreatitis who were treated surgically and were listed in the 1985 National Statistics in Japan. We have also evaluated the present surgical methods for treating chronic pancreatitis in Japan. In addition, we discuss a new surgical method being used to treat chronic pancreatitis. This is a recently improved technique involving a complete duodenum-preserving resection of the head of the pancreas, which also preserves the biliary and alimentary tracts.
Chronic pancreatitis: functional testing.
Ochi K. Mizushima T. Harada H. Matsumoto S. Matsumura N. Seno T.
Department of Laboratory Medicine, Okayama University Medical School, Okayama-shi, Japan.
This article reviews the evolution of functional testing of the pancreas in Japan for the diagnosis and treatment of chronic pancreatitis (CP), contrasting the pre- with the postsecretin test (S test) era. In the pre-S test era, the diagnosis was based on symptoms, clinical findings, fasting serum diastase levels, and the vagostigmin- and ether-stimulation test unless morphologic evidence was available. The S test and CCK-pancreozymin (PZ) test (PS test) were introduced into Japan around 1963 and have been used as the gold standard of the exocrine pancreatic-function test. Through a series of attempts at standardization in 1971, 1985, and 1987, the method was standardized to collect duodenal juice for 60 min through a double- or triple-lumen tube after a bolus or during a continuous i.v. injection of secretin (100 U). The S test, however, is an invasive and cumbersome procedure. As a result, N-benzoyl-L-tyrosal-p-aminobenzoic acid (BT-PABA) testing and fecal chymotrypsin testing were introduced into Japan in the middle and late 1970s, respectively. Although simple and noninvasive, these two methods were found have lower sensitivity and specificity than the conventional S test. These two methods, therefore, are presently used more often for monitoring the course of disease and therapeutic effects. Additionally, the glucose tolerance test can be performed to detect endocrine pancreatic insufficiency.
Pancreatic cancer: medical aspects.
Okada S. Yoshimori M. Kakizoe T.
Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.
Although pancreatic cancer (PC) continues to be a formidable disease, numerous treatment strategies are evolving that we hope will result in improved patient survival. To prolong the survival of patients with PC, it is essential to detect PC at the earliest stage possible and to develop effective nonsurgical treatments for this disease. The current strategies for the early diagnosis of PC include the development of diagnostic modalities and screening programs for the early detection of PC and the determination of high-risk groups for PC. K-ras mutations in pancreatic juice obtained endoscopically have been studied recently in association with the early diagnosis of PC, although the interpretation of the presence of a mutated K-ras gene requires caution. The role of the current nonsurgical treatments for PC has been limited. Identification of an effective new chemotherapeutic agent is a high priority, and the enrollment of patients with PC with metastatic disease into well-designed clinical trials is essential. New targets for therapy based on the understanding of the molecular biology of PC may provide avenues for future trials. We must continue to search actively for more accurate methods of diagnosis and more effective methods of treatment for PC.
Staging and extended resection for pancreatic cancer.
Naganuma T. Isaji S. Kawarada Y.
First Department of Surgery, Mie University School of Medicine, Tsu, Japan.
Extended surgery is being widely performed to treat pancreatic cancer in Japan, but it has not been evaluated in the same way as in other countries. We, therefore, compared the Japanese Stage Classification (JPN-SC) with the Union Internationale Contre le Cancer Stage Classification (UICC-SC) in the surgical cases of pancreatic cancer treated in our department and then assessed the results of extended resection and associated problems. Problems existed in the resection rates and actuarial survival rates in stages II and III in the UICC-SC, and the JPN-SC was found to reflect more accurately the outcome. On the other hand, although improvements in curative resection and actuarial survival rate have been achieved as a result of extended resection in Japan, the outcome in JPN-SC surgical stage IVb and highly advanced cases in which these resections proved to be noncurative even though they were classified as surgical stage IVa was extremely poor. In the future, it will be necessary to decide on a single-stage classification that is accepted throughout the world and to conduct prospective studies matched to the degree of tumor progression.
Problems in the diagnosis and treatment of a so-called mucin-producing tumor of the pancreas.
Kimura W. Kuroda A. Makuuchi M.
Department of Surgery, Faculty of Medicine, University of Tokyo, Japan.
Reports of a so-called "mucin-producing tumor of the pancreas" are increasing worldwide. Although the clinicopathologic features and therapeutic strategies of this tumor have been enthusiastically investigated, there are still many unanswered questions regarding this ailment. In this study, problems in the diagnosis and treatment of mucin-producing tumor were analyzed, based on the 259 reported cases of this tumor. The overall 5-year survival rate for resected cases is 83%, which is much higher than that for ordinary duct cell carcinoma (17.3%). However, the 5-year survival rate for carcinoma cases with infiltration into other organs is 28%, which is much lower than those for carcinoma cases without infiltration (86%) and carcinoma cases with infiltration that remained within the pancreatic parenchyma (74%). These results demonstrate that patients with this tumor have a poor prognosis if the tumor infiltrates other organs. In addition, when the spread of the tumor is >6 cm, the prognosis is significantly worse than when the tumor has a spread of
Surgical aspect of enteroinsular axis after gastrointestinal surgery with reference to incretin secretion.
Naito H. Sasaki I. Matsuno S.
First Department of Surgery, Tohoku University School of Medicine, Sendai, Japan.
An alteration of the enteroinsular axis (EIA) may be an important etiologic factor in postsurgical changes in gastrointestinal (GI) function. In this review, we present recent works, both from our laboratory and others, on how changes in the EIA function may be involved in postsurgical GI complications, especially late dumping syndrome (LDS). We found no or minimal direct role for vagal signals in the control of gastric inhibitory polypeptide (GIP) and enteroglucagon secretion, which regulate EIA function. In gastrectomized patients, it is suggested that the hypersecretion of glicentin and glucagon-like peptide-1 (GLP-1) induced by a rapid arrival of nutrients to the distal gut suppresses glucagon secretion and may be a cause of LDS. In patients who underwent proctocolectomy, we observed no significant postoperative changes in EIA function, although there are some conflicting reports. It seems unlikely that ordinary pancreaticobiliary diversion would cause a significant change in EIA function after an oral glucose load. Our experimental model of ileojejunal transposition produced marked hypersecretion of incretin secreted from the distal gut, which may alter EIA function. Further elucidation of the regulatory mechanism of EIA may provide a new strategy for the medical and surgical treatment of LDS.
Pancreatic diabetes in Japan.
Koizumi M. Yoshida Y. Abe N. Shimosegawa T. Toyota T.
The Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Pancreatic diabetes is usually a complication of other pancreatic disorders. Diabetes was a complication in 55.5% of 2,774 patients with chronic pancreatitis (CP) in Japan. More than half of alcoholic patients with CP in our clinic showed diabetes, and approximately 50% of those patients with diabetes were treated with insulin injections. On the other hand, cases of nonalcoholic CP showed mild endocrine dysfunction in terms of diabetic frequency and severity. Epidemiologic studies suggest that diabetes resulting from chronic pancreatitis accounts for
Imaging of small pancreatic ductal adenocarcinoma.
Ariyama J. Suyama M. Satoh K. Sai J.
Department of Gastroenterology, Juntendo University, Tokyo, Japan.
Symptoms and laboratory studies provide only limited assistance in the diagnosis of small pancreatic carcinomas. Ultrasound and computed tomography are best suited for screening small pancreatic carcinomas because of their ease and accuracy. When findings of ultrasound and computed tomography suggest small pancreatic carcinomas, MR cholangiopancreatography and endoscopic ultrasound should be indicated. Both techniques can show very small tumors. Follow-up of 77 patients with pancreatic carcinoma in whom the tumor was resected showed a 100% 5-year survival rate of patients with tumor limited to the duct epithelium. The majority of these tumors were
Department of Laboratory, Tokyo Women's Medical College, Daini Hospital, Japan.
Localization and spread of pancreatic diseases has been a reality since the availability of endoscopic pancreatography in the late 1960s, particularly after development of a fiberscope for this purpose. Endoscopic pancreatography allowed the clinician to discern the position and site of cancers, cysts, and localized inflammations. Ductal anomalies, such as annular pancreas, nonfusion, and anomalous junction of pancreatobiliary connection, were clearly recognized also. The pancreatography opacified the real lumen instead of the virtual images of ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI), so that precise studies comparing histopathologic details could be performed. The pancreatic ductal information visualized by using the fiberscope changed our understanding of chronic inflammation of the pancreas. Chronic diffuse pancreatitis, upstream pancreatitis, ductitis, and duct-narrowing pancreatitis were specified from their pathogenetic differences. Although the noninvasive methods such as US and CT will be the first choice for the diagnosis of pancreatic diseases, pancreatography will still be important for the morphologic studies of the pancreas in various disease conditions.
Peroral pancreatoscopy for the diagnosis of pancreatic diseases.
Tajiri H. Kobayashi M. Ohtsu A. Ryu M. Yoshida S.
Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
The efficacy associated with peroral pancreatoscopy to diagnose and differentiate pancreatic diseases is herein reviewed and clarified, and problems with this modality are discussed. Three types of pancreatoscopes are presently available: (a) a thin fiberscope with a diameter of 3.3 or 4.5 mm, which has an angulation system and a forceps channel; (b) an ultrathin pancreatoscope with a diameter of 0.75 or 0.8 mm, which can be inserted via an ordinary endoscopic retrograde cholangiopancreatography (ERCP) cannula without endoscopic sphincterotomy; and (c) an ultrathin pancreatoscope combined with a catheter that has an outer diameter of 1.67 mm. Peroral pancreatoscopy facilitates the detection of small lesions of the duct in malignancy or chronic pancreatitis. In particular, it is quite useful in differentiating pancreatic cancer from chronic pancreatitis in cases with local stenosis or elevated lesions of the main pancreatic duct. Among patients with a mucus-producing tumor of the pancreas, pancreatoscopy is also very useful, especially in determining lesion extent. Despite some unresolved problems, we predict that pancreatoscopy will retain a limited or specific and definite role in diagnostic and therapeutic endoscopy for pancreatic diseases.
Inui K. Nakazawa S. Yoshino J. Ukai H.
Department of Internal Medicine, Fujita Health University, School of Medicine, Second Teaching Hospital, Nagoya, Japan.
We used a new magnetic resonance endoscope with a small radiofrequent (RF) coil attached to the tip. After insertion of the instrument into the second portion of the duodenum, patients were placed in a magnetic resonance imaging (MRI) scanner. Fast spoiled gradient-recalled acquisition (SPGR) pulse sequences were used for this method. After plain scans, six axial scans were performed after intravenous injection of 20 ml of gadolinium-diethylenetriaminepentaacetic acid (DTPA) contrast medium. We performed endo-MRI on 22 patients, 13 with pancreatic carcinoma, four with pancreatic cystoadenoma, and five with other diseases. In the patients with pancreatic carcinoma, tumors were delineated as low-intensity masses after injection of contrast medium. Dilated main pancreatic ducts were clearly defined. In eight patients with carcinoma of the head of the pancreas, tumors were clearly defined in seven (87.5%) cases. In the eighth case, motion artifact prevented acquisition of a clear image of the pancreas. For diagnosis of invasion of the portal vein, the sensitivity of endo-MRI was 80%, the specificity was 100%, and overall accuracy was 87.5%. The new technique of endo-MRI allows the precise diagnosis of pancreatic tumors.
Pancreatic diseases: evaluation with MR cholangiopancreatography.
Ueno E. Takada Y. Yoshida I. Toda J. Sugiura T. Toki F.
Department of Radiology, Institute of Gastroenterology, Tokyo Women's Medical College, Japan.
Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive diagnostic modality capable of producing high-quality images of the biliary tree and pancreatic duct. We evaluated the MRCP capability of depicting the normal pancreatic duct and, based on data achieved, studied the usefulness in the pathologic pancreatic duct. MRCP was performed in 42 patients without any pancreatic lesion and in 162 patients with pancreatic diseases, including congenital anomalies of biliary tree and pancreatic duct. Results were compared with endoscopic retrograde cholangiopancreatography (ERCP) in 93 patients. The visualization of the pancreatic duct and its branches and the presence or absence of dilatation, stenosis, and filling defects were recorded. All images were interpreted retrospectively and blindly by three radiologists. Among control patients, the main pancreatic duct (MPD) was depicted in the head, body, and tail of the pancreas in 41 (98%), 39 (93%), and 31 (74%), and accessory pancreatic duct and secondary branches in the head, body, and tail of the pancreas were depicted in 11 (26%), eight (19%), four (10%), and two (5%) of these patients. Compared with ERCP, MRCP overestimated the stenosis of MPD and underestimated the dilatation of the branches and filling defects in the pancreatic duct in pancreatic diseases, especially pancreatitis. However, MRCP was distinctly advantageous over ERCP in diagnosing mucin-producing tumor of the pancreas, cystic lesions, and depicting the whole, including the part distal to the obstructed site. Four of the eight cases of pancreas divisum, and 10 of the 12 cases of anomalous pancreaticobiliary duct union also were demonstrated. MRCP can accurately demonstrate the normal pancreatic duct as well as various pancreatic duct abnormalities, including congenital anomalies of the biliary tree and pancreatic duct.
Pharmaceutical development for treating pancreatic diseases.
Kitagawa M. Naruse S. Ishiguro H. Hayakawa T.
Department of Internal Medicine II, Nagoya University School of Medicine, Japan.
The efficacy of medications to treat pancreatic diseases, even when proven effective by experimental studies, are difficult to prove by controlled clinical trials. In the treatment of acute pancreatitis, prophylactic antibiotics, somatostatin, protease inhibitors, and cholecystokinin (CCK)-receptor antagonists are advocated for use in the early stages of acute pancreatitis, but the data are insufficient to mandate prophylaxis use or recommend their use as a standard of care. In the treatment of chronic pancreatitis, digestive enzymes, oral active protease inhibitors, CCK-receptor antagonists, or somatostatin are administered for pain relief. Extracorporeal shock-wave lithotripsy and oral dissolution therapy with trimethadione are used to treat pancreatic stones. The goals of treatment of acute pancreatitis should be to ameliorate the severity of pancreatic inflammation or to prevent its complications. Although several treatments seem to be promising from the studies reviewed, these medications require prospective comparison with the standard procedures and long-term evaluation.
The calendar and acute pancreatitis.
Lankisch PG. Assmus C. Pflichthofer D.
Department of Internal Medicine, Municipal Hospital, Luneburg, Germany.
To find out whether a seasonal pattern exists for acute pancreatitis, the weekday and month of admission were retrospectively checked for 263 patients admitted to our hospital from 1987 to 1995 with their first attack of this disease. Etiology was biliary in 105 (40%), alcoholic in 84 (32%), unknown in 54 (21%), and presumed to be other in 20 (7%) patients. Forty-two (16%) patients had necrotizing acute pancreatitis. There was no significant correlation between admission and a specific month or weekday. Furthermore, there was no significant correlation between the etiology or onset of symptoms and a specific weekday. In contrast to other gastroenterological diseases such as peptic ulcer and inflammatory bowel disease, there is no seasonal or weekly pattern for acute pancreatitis.
Expression of transforming growth factor beta1 (TGFbeta1) and its receptors in pancreatic duct cell carcinoma and in chronic pancreatitis.
Satoh K. Shimosegawa T. Hirota M. Koizumi M. Toyota T.
Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Transforming growth factor beta1 (TGF beta1) is a multifunctional factor that regulates many aspects of cellular functions such as epithelial cell growth and synthesis of extracellular matrices. TGFbeta transduces signaling through a heterodimeric complex of type I and type II TGFbeta receptors (TbetaRI and TbetaRII). Recently, it has been shown that enhanced expression of TGFbeta1 is associated with the progress of pancreatic duct cell carcinoma (PDC) and chronic pancreatitis (CP). In this study, the expression of TGFbeta1 and its receptors, TbetaRI and TbetaRII, is examined in 21 cases of PDC by immunohistochemistry using specific antibodies, and the results are compared with those for 13 cases of CP. In the epithelial cells of PDC and CP, there are no significant differences in the expression of TGFbeta1, TbetaRI, and TbetaRII. In contrast, stromal expression of this cytokine and its receptors tends to be stronger in PDC than in CP; especially, the expression of TbetaRII is significantly stronger in PDC (p < 0.05). These findings suggest that there are some pathological differences in the properties of stromal reactions between PDC and CP, although the morphologies of their stroma resemble each other.
Quantification of human lithostathine S2-5 forms using the antibody to the N-terminal peptide region.
Yamadera K. Wada K. Goto M. Yokoyama K. Morita Y. Kitano Y. Makino I.
Second Department of Internal Medicine, Asahikawa Medical College, Japan.
Lithostathine S2-5 inhibits in vitro crystal growth of CaCO3. We developed an antibody against the peptide region responsible for inhibitory effect to determine whether lithostathine S2-5 levels are different in the pancreatic juice of patients with and without chronic pancreatitis. The antibody against the synthetic peptide of the N-terminal end of lithostathine S2-5 detected lithostathine S2-5 but not lithostathine S1 or lithostathine extracted from pancreatic calculi. Lithostathine S2-5 was detected in samples of pancreatic juice protein by immunoblotting using the specific antibody. The concentration of lithostathine S2-5 was compared between control and chronic pancreatitis groups. The mean concentrations of lithostathine S2-5 were significantly (p=0.002) lower in chronic pancreatitis, 16.3 microg/mg of total protein, than in the control, 47.1 microg/mg of total protein. A decreased concentration of lithostathine S2-5 seems to increase the risk of stone formation in the ducts during the course of chronic pancreatitis because of insufficient inhibition of CaCO3 crystal growth.
Hydrogen breath test with glucose in exocrine pancreatic insufficiency.
Casellas F. Guarner L. Vaquero E. Antolin M. de Gracia X. Malagelada JR.
Digestive System Research Unit, Hospital General Vall d'Hebron, Barcelona, Spain.
The present study was designed to investigate the prevalence of bacterial overgrowth in patients with exocrine pancreatic insufficiency by using the hydrogen breath test with glucose. Thus, in 30 patients with exocrine pancreatic insufficiency (in 15 due to chronic pancreatitis and in 15 associated to primary immunodeficiency), established by quantifying trypsin output before and after stimulation with cerulein using a duodenal perfusion technique, a glucose test was performed by administering 50 g of glucose and quantifying H2 in the breath by gas chromatography. The glucose test was positive in six of 15 patients with chronic pancreatitis but in only one of 15 immunodeficient patients (p < 0.05). Age, sex, etiology, time of evolution, associated diabetes, pancreatic calcifications, duodenal pH, or duodenal trypsin output did not differ between patients with and those without bacterial overgrowth. Previous gastroduodenal surgery was more common in chronic pancreatitis patients with overgrowth (six of six vs. four of nine; p < 0.05). Five patients with a positive glucose test were treated with antibiotics for 2 weeks and became negative in two of them. These results suggest that a positive glucose test indicating overgrowth is relatively common in exocrine pancreatic insufficiency due to chronic pancreatic, especially in patients with previous gastroduodenal surgery.
Prolyl hydroxylase and tissue inhibitor of metalloproteinase in pure pancreatic juice in patients with chronic pancreatitis.
Ochi K. Matsumura N. Yamamoto R. Chowdhury R. Mizushima T. Tanaka J. Harada H.
Department of Laboratory Medicine, Okayama University Medical School, Japan.
Prolyl hydroxylase is a key enzyme in collagen synthesis, and tissue inhibitor of metalloproteinase (TIMP) is known to suppress collagenolytic enzymes. To see whether the levels of these two enzymes in serum and human pure pancreatic juice (PPJ) are good indicators of pancreatic fibrosis in chronic pancreatitis (CP), we examined 15 controls, 14 alcoholics without evident pancreatic diseases (7 current drinkers and 7 former drinkers), and 19 patients with CP. Levels of the two enzymes were determined by a sandwich enzyme immunoassay method. TIMP-1 levels in PPJ were significantly higher in patients with CP than in controls and alcoholics, with overlap in only a few exceptional patients. A significant inverse correlation between TIMP-1 and bicarbonate output in PPJ was observed. Prolyl hydroxylase levels in PPJ, in contrast, were significantly higher in current drinkers than in patients with CP, controls, and former drinkers, with overlap in only a few exceptional patients with relapsing CP. Identical results were obtained even when the enzyme levels were expressed as nanograms per milligram of protein. Serum levels of prolyl hydroxylase and TIMP-1 showed no significant differences among controls, current alcoholics, former alcoholics, and patients with CP. These results indicate that the raised level of TIMP-1 in PPJ, unlike that of prolyl hydroxylase, is a good indicator of pancreatic fibrosis in CP.
Jun and MAP kinases are activated by cholecystokinin in the pancreatic carcinoma cell line KP-1N.
Tateishi K. Funakoshi A. Misumi Y. Matsuoka Y.
Department of Biochemistry, School of Medicine, Fukuoka University, Japan.
Growth of the human pancreatic carcinoma cell line KP-1N was stimulated with cholecystokinin (CCK)-8. A 40% increase in cell numbers was observed in the presence of 10(-10) MCCK-8 and this increase was inhibited by the addition of 25 microM CCK-A receptor antagonist (CR1505). The binding affinity of CCK-8 to KP-1N cells was 21-fold higher than that of gastrin 17-I. No significant increase in intracellular Ca2+ concentration was found upon stimulation with CCK-8. Components of signal transduction pathways that were activated in KP-1N cells after stimulation with CCK-8 were studied. CCK-8 stimulated tyrosine phosphorylation of a mitogen-activated protein kinase (MAPK) of approximately 42 kDa (p42map). c-Jun amino-terminal kinases (JNKs) of 46 kDa (p46jnk) and 55 kDa (p55jnk) were also activated by CCK-8 and increased the phosphorylation of c-Jun. CCK-8 at 10(-7) M induced 1.5-fold increases in the phosphorylation of MAPK and of c-Jun by JNKs, respectively. These results suggest that cell proliferation stimulated with CCK-8 in KP-1N cells may be mediated by signal transduction cascades leading to activation of JNKs and MAPKs.
Up-regulation of cytochrome P450 1A2, 2C9, and 2E1 in chronic pancreatitis.
Wacke R. Kirchner A. Prall F. Nizze H. Schmidt W. Fischer U. Nitschke FP. Adam U. Fritz P. Belloc C. Drewelow B.
Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, University of Rostock, Germany.
The oxidative metabolism of xenobiotics is effected mainly by cytochrome P450 enzymes (CYP), which are expressed as a family of genetically related enzymes primarily in hepatocytes. The pancreas is among the extrahepatic tissues expressing CYP, and it has been suggested that intermediates generated by them might be of pathogenetic significance for diseases of the pancreas such as chronic pancreatitis. We studied 10 surgical resection specimens by immunohistochemistry with polyclonal antibodies against recombinant human CYP 1A1, 1A2, 2C9, 2E1, and 3A and used tissues from 11 normal pancreata as controls. In addition, we assayed microsomal preparations for their capacity to metabolize verapamil. In normal pancreata weak to moderate expression of all enzymes was demonstrated immunohistochemically in up to 50% of duct epithelia, acinar cells, and islet cells. In contrast, in chronic pancreatitis an up-regulation was observed, with immunohistochemical positivity in some cases in up to 100% of duct epithelia and acinar cells. The oxidative capacity of microsomal preparations from chronic pancreatitis was higher than that of preparations obtained from control tissues; compared to liver microsomes, however, it was low. The up-regulation of CYP may have pathogenetic significance for chronic pancreatitis. Yet considering the pancreas' capacity for conjugation reactions, conceivably low levels of reactive intermediates could effectively undergo inactivation.
Calcitonin-secreting tumors of the pancreas: about six cases.
Fleury A. Flejou JF. Sauvanet A. Molas G. Vissuzaine C. Hammel P. Levy P. Belghiti J. Bernades P. Ruszniewski P.
Department of Gastroenterology, Hopital Beaujon, Clichy, France.
Calcitonin release has rarely been reported in patients (pts) with neuroendocrine pancreatic tumors (NPT). The aim of this study was to describe the characteristics of calcitonin-secreting tumors (CST) of the pancreas. Serum calcitonin determination was part of the prospective evaluation of 66 pts with NPT referred to our institution over a 3-year period. Six pts (9%) had elevated calcitonin levels [at least twice the limit of the normal value (N)]. Abdominal ultrasonography, computed tomography scan, and endoscopic ultrasound were performed to identify the primary tumor(s) and metastases. Immunostaining using anticalcitonin and other antibodies was performed on the surgical resection specimen (four pts) or biopsy of liver metastases (two pts). Three of the six pts (four males, two females; median age, 51.5 years) had diarrhea. Serum calcitonin levels (median, range) were 17.5 N (6N-40N). Slight elevations in serum somatostatin (1.2N-2.3N) were associated in three pts. Pancreatic tumors were single in five of six pts and evenly distributed in the head and in the tail. Five pts had metastases, mainly in the liver. Multiple endocrine neoplasia type I was present in one pt. Immunostaining using calcitonin and somatostatin antibodies was positive in four pts each, respectively, and areas that were positive for one peptide were negative for the other. Diarrhea disappeared in the two pts who responded to treatment of the tumor(s). Three of the four pts with liver metastases died from tumor progression after 2, 10, and 24 months, respectively. CST of the pancreas are often malignant and can be considered as functional in half of the cases, irrespective of the serum calcitonin levels. Somatostatin secretion is often associated. Although rare, calcitonin secretion should be investigated in NPT pts presenting with diarrhea that cannot be explained by an increase in other hormone levels or in patients with nonfunctioning NPT.
Subcutaneous manifestations of severe acute pancreatitis.
Bem J. Bradley EL 3rd.
Department of Surgery, State University of New York at Buffalo, USA.
Subcutaneous manifestations of severe acute pancreatitis (Grey Turner's sign, Cullen's sign, and disseminated fat necrosis) are often discussed but seldom observed. Grey Turner's sign and Cullen's sign develop in