[Autoimmune pancreatitis: new concepts of an often overlooked disease]. / Autoimmune Pankreatitis: Aktuelle Konzepte einer häufig übersehenen Krankheit.

Autoimmune pancreatitis is characterized by a lympho-plasmacytic infiltrate centred around the pancreatic ducts along with venulitis; it can produce a mass-like fibroinflammatory lesion and often simulates pancreatic malignancy or chronic pancreatitis of other types. This may lead to unnecessary surgical interventions. Patients, who are usually over 40 years of age, show 1) mild unspecific abdominal pain, 2) increased serum immunoglobulins (specifically IgG4) and autoantibodies, and 3) diffuse or focal enlargement of the pancreas with pancreatic strictures and sometimes jaundice due to biliary obstruction (detectable by US, CT, MRI, ERCP and/or endoscopic ultrasound (EUS)). The diagnosis can be strongly supported by EUS- or US-guided biopsies showing typical histological changes and specific indirect immunohistochemistry with the patient's serum or a steroid trial showing often a dramatic decrease of pathological findings within weeks.

[Barrett's esophagus: diagnosis and therapy]. / Barrett-Osophagus: Diagnostik und Therapie.

Barrett's esophagus is usually diagnosed by the endoscopic and histological finding of columnar epithelium with intestinal metaplasia in the distal esophagus. The prevalence of Barrett's esophagus (long segment) is <2% in the general population and 3-5% in patients with chronic reflux symptoms. Barrett mucosa predisposes patients to adenocarcinoma that develops in approximately 0.5% of these patients per year (Barrett mucosa --> dysplasia --> cancer sequence). The incidence of esophageal adenocarcinoma over the past few decades; the present incidence, however, is still rather low and is reported to be approximately 4 and approximately 0.5 per 100,000 in males and females, respectively. The malignant potential of the Barrett mucosa increases with dysplastic changes. Guidelines for surveillance and therapy are based on the presence and the degree of dysplastic lesions. Long-term studies on cost-effectiveness of these guidelines are, however, still missing.

PD-136,450: a CCK2 (gastrin) receptor antagonist with antisecretory, anxiolytic and antiulcer activity.

This study investigated the effects of PD-136,450 (PD), a highly selective ligand for the CCK2 receptor, on gastric acid and pancreatic secretions, gastric cytoprotection and anxious behaviour in the rat and rabbit. PD inhibited gastrin (but not dimaprit) stimulated acid secretion in anaesthetized and conscious rats (IC50 of 1 mg kg(-1) sc) and inhibited 14C-aminopyrine uptake in isolated gastric glands from rabbits. In addition, PD decreased dose-dependently gastric haemorrhagic lesions in rats treated orally with acidified ethanol. Both, the antisecretory effects on gastric acid secretion and the gastric cytoprotective effects were less potent compared with the proton pump inhibitor omeprazole. PD strongly increased pancreatic secretion, which was substantially inhibited by the CCK1 antagonist L-364,718 (but not by the CCK2 antagonist L-365,260). PD also showed significant anxiolytic activity as assessed by a black and white box two-compartment activity assay. Both, time spent in the dark compartment and latency for movement from the light to the dark compartment was increased by PD (similarly with 5 mg kg(-1) diazepam). In conclusion, PD inhibited gastrin-stimulated gastric acid secretion, decreased ethanol-induced damage to the gastric mucosa, stimulated pancreatic secretion (via CCK1 receptors) and displayed anxiolytic activity. Thus, PD may have utility as an adjunct therapy in peptic ulcer disease by countering the actions of gastrin and increasing acid neutralization and mucosal protection.

[Aphthous esophagitis as an atypical manifestation of a primary HIV-infection]. / Aphtöse Osophagitis als atypische Erstmanifestation einer primären HIV-Infektion.

HISTORY: A 56-year-old patient from Burkina Faso (Western Africa), living in Switzerland for 12 years, was referred to hospital because of acute onset of severe painful swallowing. He returned from a 3-week visit to his home country 4 weeks prior to admission. CLINICAL FINDINGS AND INVESTIGATIONS: Whereas clinical and radiological findings were normal, routine laboratory testing showed increased parameters of infection. Endoscopy revealed an aphthous esophagitis, suggesting a viral infection. Biopsy confirmed an active erosive esophagitis. Herpes simplex, cytomegalovirus and candida could not be detected in the biopsy specimens (immunohistochemistry, microbiology) and in serum. Both, the anti-HIV screening-test and the Western blot antibody test for HIV-1 and HIV-2 were negative on admission. Because of the persistent suspicion for an underlying HIV Infection, a combined HIV p24-antigen/ antibody-test was performed, showing an indeterminate result. Following PCR-based tests for HIV-RNA on days 5 and 12 showed 86 100 and 103 700 HIV-1 RNA copies/ml plasma, respectively, revealing the diagnosis of primary HIV-1 infection. Subsequent serological testing (WB) finally documented HIV-1 antibody seroconversion, showing indeterminate and positive results on days 5 and 19, respectively. TREATMENT AND COURSE: Within 5 days all signs of infection returned to normal and as documented by endoscopy on day 12, the esophagitis healed up spontaneously. As the patient intended to go back to his home country and the CD4 cell count was 615 x10(6)/l, no antiviral therapy was initiated. CONCLUSION: This case report is the first demonstrating an atypical symptomatic primary HIV-infection prior to seroconversion, which presented itself exclusively as an aphthous esophagitis with no symptoms of the classic acute retroviral syndrome. Therefore, each clinical suspicion of an underlying HIV-infection should be followed up carefully, even if the patient presents with unusual symptoms.

Cyclooxygenase 2-implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives.

Cyclooxygenase (COX), the key enzyme for synthesis of prostaglandins, exists in two isoforms (COX-1 and COX-2). COX-1 is constitutively expressed in the gastrointestinal tract in large quantities and has been suggested to maintain mucosal integrity through continuous generation of prostaglandins. COX-2 is induced predominantly during inflammation. On this premise selective COX-2 inhibitors not affecting COX-1 in the gastrointestinal tract mucosa have been developed as gastrointestinal sparing anti-inflammatory drugs. They appear to be well tolerated by experimental animals and humans following acute and chronic (three or more months) administration. However, there is increasing evidence that COX-2 has a greater physiological role than merely mediating pain and inflammation. Thus gastric and intestinal lesions do not develop when COX-1 is inhibited but only when the activity of both COX-1 and COX-2 is suppressed. Selective COX-2 inhibitors delay the healing of experimental gastric ulcers to the same extent as non-COX-2 specific non-steroidal anti-inflammatory drugs (NSAIDs). Moreover, when given chronically to experimental animals, they can activate experimental colitis and cause intestinal perforation. The direct involvement of COX-2 in ulcer healing has been supported by observations that expression of COX-2 mRNA and protein is upregulated at the ulcer margin in a temporal and spatial relation to enhanced epithelial cell proliferation and increased expression of growth factors. Moreover, there is increasing evidence that upregulation of COX-2 mRNA and protein occurs during exposure of the gastric mucosa to noxious agents or to ischaemia-reperfusion. These observations support the concept that COX-2 represents (in addition to COX-1) a further line of defence for the gastrointestinal mucosa necessary for maintenance of mucosal integrity and ulcer healing.

Role of cyclooxygenase-2 in gastric mucosal defense.

Two isoenzymes of cyclooxygenase (COX), the key enzyme in prostaglandin (PG) biosynthesis, COX-1 and COX-2, have been identified. COX-1 was proposed to regulate physiological functions, COX-2 to mediate pathophysiological reactions such as inflammation. In particular, it was suggested that maintenance of gastric mucosal integrity relies exclusively on COX-1. Recently, it was shown that a selective COX-1 inhibitor does not damage the mucosa in the healthy rat stomach, although mucosal prostaglandin formation is near-maximally suppressed. However, concurrent treatment with a COX-1 and a COX-2 inhibitor induces severe gastric damage. This indicates that in normal mucosa both COX-1 and COX-2 have to be inhibited to evoke ulcerogenic effects. In the acid-challenged rat stomach inhibition of COX-1 alone is associated with dose-dependent injury which is aggravated by additional inhibition of COX-2 activity or prevention of acid-induced up-regulation of COX-2 expression by dexamethasone. After acid exposure, COX-2 inhibitors cause substantial gastric injury when nitric oxide formation is suppressed or afferent nerves are defunctionalized. Ischemia-reperfusion of the gastric artery increases levels of COX-2 but not COX-1 mRNA. COX-2 inhibitors or dexamethasone aggravate ischemia-reperfusion-induced mucosal damage up to 4-fold, an effect abolished by concurrent administration of 16,16-dimethyl-PGE2. Furthermore, the protective effects elicited by a mild irritant or intragastric peptone perfusion are antagonized by COX-2 inhibitors. Finally, COX-2 expression is increased in experimental ulcers. COX-2 inhibitors delay the healing of chronic gastric ulcers in experimental animals and decrease epithelial cell proliferation, angiogenesis and maturation of the granulation tissue to the same extent as non-steroidal anti-inflammatory drugs. These observations indicate that, in contrast to the initial concept, COX-2 plays an important role in gastric mucosal defense.

Cholecystokinin-B/gastrin receptors enhance wound healing in the rat gastric mucosa.

Although physiological functions of the CCK-B/gastrin receptor are well explored, little is known about its role during healing. Here, we evaluated the role of this receptor in the rat oxyntic mucosa following the introduction of a cryoulcer. In this model, we located and quantified CCK-B/gastrin receptors by reverse transcriptase PCR and receptor autoradiography. Rats with cryoulcers were treated with placebo, omeprazole, the CCK-B/gastrin receptor antagonist YF-476, omeprazole plus YF-476, gastrin-17, and gastrin 17 plus YF-476. During wound healing, CCK-B/gastrin receptors were specifically expressed and localized to the regenerative mucosal ulcer margin. This high expression was limited in time, and the pattern of expression of CCK-B/gastrin receptors correlated closely with the proliferative activity of the regenerative mucosa. Functionally, omeprazole and gastrin-17 caused profound hypergastrinemia, increased cell proliferation in the mucosal ulcer margin and accelerated the late ulcer healing phase. These effects were completely reversed by cotherapy with YF-476. These in vivo and vitro data suggest that CCK-B/gastrin receptors in regenerative rat gastric oxyntic mucosa enhance trophic effects during wound healing.

Accuracy of endoscopic ultrasonography in preoperative staging of esophageal carcinoma.

BACKGROUND: With the advent of stage-adapted multimodal regimens for many gastrointestinal malignancies, accurate staging has become of utmost importance. In esophageal cancer, endoscopic ultrasonography (EUS) emerged as standard to determine T and N stage. OBJECTIVE: Since growth patterns of squamous carcinoma (SC) differs from adenocarcinoma (AC) and lymph nodes are located at various distances from the esophagus in a horizontal plane, we studied the accuracy of esophageal EUS as a function of tumor type and localization of the tumor within the esophagus. RESULTS: Overall staging accuracy was 79% for T and for N staging. Staging was more accurate for T3/4, when compared to T1/2 tumors, and for SC when compared to AC. Histological T1/2 stages were overstaged by EUS in 8/17 patients, mostly in patients with AC (6/10). The sensitivity of retrosternal pain and of dysphagia for extramural disease was 57 and 92% respectively, the specificity of pain for extramural disease was 73%, and of dysphagia 36%. Preoperative weight loss in this series correlated linearly with tumor stages. CONCLUSIONS: The accurate preoperative staging of T2 esophageal endodermal malignancies is crucial for treatment stratification but difficult to achieve by visual analysis of endosonography alone. Postacquisition processing of echoendosonographic images might further increase the accuracy of echoendosonography and aid in the critical differentiation of T2 versus T3 esophageal malignancies. Preoperative weight loss and retrosternal pain are good clinical indicators of extramural disease.

Distinction of gastric Helicobacter spp. in humans and domestic pets by scanning electron microscopy.

BACKGROUND: A number of different Helicobacter spp. can colonize the stomach of humans and domestic pets. Difficulties encountered with primary isolation of these spiral microorganisms and their unusual inertia with respect to biochemical reactions still represent considerable obstacles to their characterization with classic tools. In addition, the high degree of similarity in the 16S rRNA sequence hampers differentiation of Helicobacter spp. using routine molecular biological assays. MATERIALS AND METHODS: Samples from experimentally monoinfected mice, of naturally infected hosts, and of cultured strains were examined by scanning electron microscopy (SEM). In parallel, all samples were analyzed by molecular techniques to ascertain the Helicobacter spp. involved. RESULTS: Using the mouse samples as a reference, microorganisms found in naturally infected hosts were identified by SEM as belonging to H. pylori, H. felis, or a group consisting of H. bizzozeronii and H. heilmannii. A further spiral microorganism with unique morphology was found in a dog that was positive for H. salomonis, but the organism could not be recovered from experimentally infected mice. In culture, most Helicobacter strains lost their ultrastructural characteristics. CONCLUSIONS: When gastric Helicobacter spp. were collected from their natural habitat and examined by SEM, relevant differences could be detected between H. felis, H. bizzozeronii and H. heilmannii, and H. salomonis, respectively. SEM, therefore, seems to be a useful auxillary tool for the distinction of various gastric Helicobacter spp. as based on their ultrastructure.

Significance of proliferative activity and DNA ploidy in pancreatic cancer and chronic pancreatitis.

BACKGROUND: Precise preoperative assessment of diagnosis and prognosis in patients with pancreatic tumors would facilitate improvement of treatment strategies. In this context, we evaluated the significance of the proliferative index and of static DNA cytophotometry in the diagnosis and prognosis of pancreatic tumors. METHODS: Consecutive surgical specimens from 26 patients with ductal pancreatic cancers and eight patients with chronic pancreatitis were investigated by: 1. Staging; 2. Conventional histological and cytological grading; 3. MIB-1 (Ki-67 labeling) proliferating index; and 4. Static DNA cytophotometry. RESULTS: All patients with chronic pancreatitis had a normal MIB-1 labeling index and a euploid DNA content. In contrast, patients with pancreatic cancers rarely had a normal labeling index (1 of 26 patients) or a euploid DNA content (6 of 26 patients). Staging significantly correlated with survival time. However, it did not correlate with cytological criteria. Cytological criteria, such as conventional grading, MIB-1 proliferating index, and DNA ploidy, were not significantly correlated with survival time. Conventional grading was significantly correlated (p < 0.02) with proliferating index, but not with DNA ploidy. CONCLUSION: Proliferating index and DNA ploidy are relevant cytological markers that can help to discriminate between chronic pancreatitis and pancreatic cancer. The prognostic significance of these markers in pancreatic cancer patients, however, seems to be less relevant than tumor stage and of limited relevance for the individual cancer patient.

[Esophageal carcinoma: accurate staging thanks to modern diagnostic methods open up new therapeutic strategies]. / Osophaguskarzinom: Exaktes Staging dank moderner Diagnostik eröffnet neue Therapiewege.

INTRODUCTION: Since the tumour stage has significant prognostic and therapeutic implications, accurate preoperative staging is decisive. ALGORITHM FOR DIAGNOSTIC STUDIES: Flexible endoscopy of the oesophagus with biopsies is the first diagnostic step in patients with signs of oesophageal cancer and allows assessment of (1) tumour localisation, (2) tumour size, (3) grade of stricture, (4) type of histology, and (5) cellular grading. Thereafter, CT scan of the chest and upper abdomen is performed to assess the provisional TNM stage. The local TN stage is verified in operable patients by endosonography and additionally by bronchoscopy if the tumour is located in the upper half of the oesophagus. The M stage can be preoperatively verified by laparoscopy. CONCLUSION: Modern diagnostic methods yield accurate staging, which makes it possible to optimise selection of the most appropriate therapeutic strategy.

Nonsurgical therapies for hepatocellular and cholangiocellular carcinoma.

Surgical resection is the first choice of treatment for patients with hepatocellular (HCC) and cholangiocellular carcinomas. Prolongation of survival is, however, the only realistic goal for most patients, which can be often achieved by nonsurgical therapies. Inoperable patients with large or multiple HCCs are usually treated with transarterial chemoembolization (TACE) with lipiodol in combination with a chemotherapeutic drug and gelfoam. Three-year survival depends on the stage of the disease and is about 20%. Patients with earlier tumor stages (one or two tumor nodules less than 3 cm in size) are suitable for treatment with percutaneous ethanol injection (PEI) alone or in combination with TACE. Several studies have shown that in these early stages, the 3-year survival rate is approximately 55%-70% in the actively treated patients which is significantly higher than in untreated patients. In advanced stages of the disease, TACE and PEI have no effect on survival and should not be performed. Some of these patients have been successfully treated with octreotide. Patients with inoperable cholangiocellular carcinoma are treated by endoscopic or percutaneous stent placement. If stenting does not achieve adequate biliary drainage, multidisciplinary therapy including internal/external radiotherapy or photodynamic therapy should be considered in patients with potential long-term survival. In conclusion, nonresectional therapies play an essential role in the therapy of inoperable hepato- and cholangiocellular carcinomas as they lead to satisfactory survival. Multidisciplinary therapy appears to be the current trend of management.

Use of a urea breath test to evaluate short-term treatments for cats naturally infected with Helicobacter heilmannii.

OBJECTIVE: To evaluate efficacy of 3 short-term treatments in cats naturally infected with Helicobacter heilmannii. ANIMALS: 29 cats infected with H heilmannii that had positive results for a urea breath test, rapid urease test, and Helicobacter species-specific polymerase chain reaction test. PROCEDURES: Cats anesthetized for routine surgical procedures were randomly allocated to 4 groups: group 1, control cats; group 2, cats treated with azithromycin, tinidazole, ranitidine, and bismuth once daily for 4 days; group 3, cats treated with clarithromycin, metronidazole, ranitidine, and bismuth twice daily for 4 days; and group 4, cats treated with clarithromycin, metronidazole, ranitidine, and bismuth twice daily for 7 days. Efficacy was determined on the basis of results of a urea breath test performed 10 and 42 days after end of treatment. RESULTS: Ten days after treatment, 0 of 4, 4 of 6, 11 of 11, and 8 of 8 cats in groups 1 to 4, respectively, had a negative result for a urea breath test. Forty-two days after treatment, 0 of 4, 3 of 6, 7 of 11, and 4 of 8 cats in groups 1 to 4, respectively, still had a negative result. CONCLUSIONS AND CLINICAL RELEVANCE: Treatments used in this study regularly suppressed breath 13CO2 production. However, although 23 of 25 (92%) cats had negative results for a urea breath test 10 days after treatment, only 14 of 25 (56%) cats still had negative results 42 days after treatment. It is difficult to achieve a definitive long-term cure in cats naturally infected with H heilmannii.

Frequency of advanced neoplasia in the proximal colon without an index polyp in the rectosigmoid.

PURPOSE: Screening endoscopy has the potential to reduce colorectal cancer mortality. However, the efficacy of screening flexible sigmoidoscopy compared with colonoscopy strongly depends on the frequency of advanced proximal neoplasms without an index polyp in the rectosigmoid. We have therefore determined this frequency in our endoscopy population. METHODS: Endoscopic and histologic data were analyzed from all patients on whom integral colonoscopy was performed between 1980 and 1995. Advanced neoplasia was defined as cancer or adenomas >10 mm in diameter, adenomas with a villous component, or severe dysplasia. Patients with polyposis syndrome or inflammatory bowel disease were excluded. RESULTS: Colonoscopy was performed on 11,760 patients. 2,272 (19.3 percent) had at least one colorectal neoplasm, of which 39 percent had the neoplasm above the rectosigmoid. Twenty-two percent of all patients with neoplasia had no index polyp in the rectosigmoid and 16 percent of these had no index polyp, but at least one advanced proximal neoplasm. CONCLUSIONS: Although 39 percent of patients had neoplasms above the rectosigmoid, only 16 percent had an advanced proximal neoplasm without an index polyp in the rectosigmoid. This gives a figure on which to base the evaluation of screening sigmoidoscopy programs against those of screening colonoscopy.

Utility of abdominal sonography in patients with idiopathic deep vein thrombosis.

PURPOSE: Studies have confirmed an association between idiopathic deep vein thrombosis (DVT) and malignant tumors. We assessed the usefulness of routine abdominal sonography in patients with idiopathic DVT to detect malignant tumors and other relevant findings. METHODS: We retrospectively analyzed abdominal sonograms and records from 135 consecutive patients with confirmed idiopathic DVT and interviewed patients and their physicians during the follow-up period (mean, 30 months). Malignancy and other clinically relevant findings determined by sonography were tabulated, and the cost of each malignancy detected by abdominal sonography in this study was calculated. RESULTS: Malignant tumors were found in 14 patients (10%), 7 by routine abdominal sonography, 3 by other means during hospitalization, and 4 during the follow-up period. Other clinically relevant findings detected by routine abdominal sonography were found in 33 patients (24%). The estimated cost of discovering malignancy by using screening abdominal sonography was approximately US$3,000/malignancy. CONCLUSIONS: Abdominal sonography was useful in detecting a variety of clinically relevant findings in addition to half of the malignant tumors found in our study.

Receptor autoradiographic evaluation of cholecystokinin, neurotensin, somatostatin and vasoactive intestinal peptide receptors in gastro-intestinal adenocarcinoma samples: where are they really located?

Receptors for cholecystokinin (CCK), gastrin, neurotensin, somatostatin and vasoactive intestinal peptide (VIP) are over-expressed in several human tumors, where they have diagnostic and therapeutic implications. Since reports on the expression of these peptide receptors in primary gastric and colonic adenocarcinomas are either non-existent or conflicting, a detailed evaluation with particular emphasis on the tissue localization was undertaken. CCK-A, CCK-B, neurotensin, somatostatin and VIP receptors were localized by in vitro receptor autoradiography with iodinated radioligands on histological sections of surgical samples of 27 gastric and 25 colonic adenocarcinomas. CCK-A, CCK-B and neurotensin-1 receptors were found in a minority of both tumor types. Somatostatin receptors were found in 18/27 gastric and 2/25 colonic cancers. VIP receptors were found in 14/26 gastric and 23/25 colonic cancers; subtype characterization suggests VIP1 receptors. In addition, resected tumor samples contained non-malignant tissues (mucosa, smooth muscle, nerves or vessels) with high amounts of the various peptide receptors. Therefore, regulatory peptide receptors are expressed differentially in gastric and colonic cancers but also very frequently in "contaminating" non-malignant tissues. Since results using morphological techniques are superior to those using homogenates, we recommend that localization of these receptors to the tissues should always be attempted, to minimize receptor over-estimation in tumors and to prevent spurious results.

Risk factor assessment of endoscopically removed malignant colorectal polyps.

BACKGROUND: Malignant colorectal polyps are defined as endoscopically removed polyps with cancerous tissue which has invaded the submucosa. Various histological criteria exist for managing these patients. AIMS: To determine the significance of histological findings of patients with malignant polyps. METHODS: Five pathologists reviewed the specimens of 85 patients initially diagnosed with malignant polyps. High risk malignant polyps were defined as having one of the following: incomplete polypectomy, a margin not clearly cancer-free, lymphatic or venous invasion, or grade III carcinoma. Adverse outcome was defined as residual cancer in a resection specimen and local or metastatic recurrence in the follow up period (mean 67 months). RESULTS: Malignant polyps were confirmed in 70 cases. In the 32 low risk malignant polyps, no adverse outcomes occurred; 16 (42%) of the 38 patients with high risk polyps had adverse outcomes (p<0.001). Independent adverse risk factors were incomplete polypectomy and a resected margin not clearly cancer-free; all other risk factors were only associated with adverse outcome when in combination. CONCLUSION: As no patients with low risk malignant polyps had adverse outcomes, polypectomy alone seems sufficient for these cases. In the high risk group, surgery is recommended when either of the two independent risk factors, incomplete polypectomy or a resection margin not clearly cancer-free, is present or if there is a combination of other risk factors. As lymphatic or venous invasion or grade III cancer did not have an adverse outcome when the sole risk factor, operations in such cases should be individually assessed on the basis of surgical risk.