Biomedical subjects

Matthias Löhr

Publications and source records attributed to Matthias Löhr.

26 records · Page 2Linked to original sources

PubMed2003

Autoimmune pancreatitis: pathological, clinical, and immunological features.

INTRODUCTION: In recent years a type of chronic pancreatitis has been described that is clearly distinct from alcoholic chronic pancreatitis. It is characterized by its special pathology, immunologic features, clinical presentation, and steroid responsiveness. Because of its histologic hallmarks, i.e., ductal and periductal infiltration by lymphocytes, plasma cells, and granulocytes, it has been called duct-destructive chronic pancreatitis. The frequent association of this type of pancreatitis with other autoimmune diseases such as Sjögren's disease and a number of other immune phenomena has led to the concept that it is an autoimmune disease. Hence, the term autoimmune pancreatitis has been introduced and will be used in this review. AIMS: This review focuses on the pathology and related clinical and immunologic features of this new type of pancreatitis. CONCLUSIONS: As the ability to diagnose autoimmune pancreatitis on the basis of clinical, imaging, and laboratory findings improves, it seems likely that fewer patients with this diagnosis will undergo resection. Thus, there is a need to accumulate and study additional retrospective series of patients undergoing resection because of mass-forming chronic pancreatitis.

Autoimmune Diseases↗

PubMed2003

Lack of apoptosis in PanIN-1 and PanIN-2 lesions associated with pancreatic ductal adenocarcinoma is not dependent on K-ras status.

INTRODUCTION: K-ras mutations are present in most ductal adenocarcinomas (DACs) of the pancreas and may also be found in ductal precursor lesions and even in normal ductal epithelium. The question is addressed whether mutated K-ras interferes with the regulation of apoptosis or proliferation. METHODOLOGY: In 50 Whipple resection specimens, tissue adjacent to DACs was histologically screened for ductal lesions that were classified as pancreatic intraepithelial neoplasia (PanIN) according to WHO criteria. PanIN lesions were microdissected and analyzed for K-ras mutations by means of a nested PCR. Apoptosis was identified by the TUNEL method. Proliferation and the expression of p53 and Bcl-2 were immunohistochemically determined. RESULTS: On average, 30% of PanIN-1A and B lesions showed mutated K-ras. In PanIN-2 and PanIN-3 lesions, the rate of mutated K-ras increased to 45% and 56%, respectively. Apoptosis was present only in 2 of 26 PanIN-3 lesions. There was a gradual increase in proliferative activity from PanIN-1 to PanIN-3. p53 expression was found in 11% of PanIN-2 and 44% of PanIN-3 lesions. Bcl-2 expression was lacking in PanIN lesions of all grades. In invasive DACs, the apoptotic rate correlated with the degree of tumor differentiation and proliferation, with grade 3 carcinomas showing the highest apoptotic rate. CONCLUSION: In view of the discrepancy between the considerable rate of K-ras mutations in PanIN-1 and PanIN-2 lesions and the lack of apoptosis and Bcl-2 expression, coupled with very low p53 immunoreactivity, it is unlikely that mutated K-ras affects the apoptotic activity in low grade PanINs. Instead, K-ras mutations may have an effect on proliferation in PanIN-1 and PanIN-2.

Adenocarcinoma↗

PubMed2003

Intra-arterial instillation of microencapsulated, Ifosfamide-activating cells in the pig pancreas for chemotherapeutic targeting.

BACKGROUND: The therapeutic efficacy of intratumoral instillation of genetically engineered, CYP2B1-expressing, microencapsulated cells in combination with ifosfamide had been previously demonstrated in xenografted human pancreatic ductal carcinomas [Gene Ther 1998;5:1070-1078]. Prior to a clinical study, the feasibility of an intra-arterial application of microencapsulated cells to the pancreas and its consequences to the organ had to be evaluated. MATERIAL AND METHODS: Microencapsulated, CYP2B1-producing cells were instilled both in vivo (transfemoral angiographical access) and in vitro (perfusion model) in the splenic lobe of the pig pancreas. In vivo, animals were monitored clinically for 7 days, then treated with ifosfamide and sacrificed. In vitro, ifosfamide was administered intra-arterially. RESULTS: In all animals, 100 microcapsules could be instilled safely via the femoral route without clinical, biochemical or histological signs of pancreatitis. Histological examination revealed partial obstruction of small arteries by the capsules, without causing any parenchymal damage. In vitro, instillation reduced blood flow by half. Ifosfamide, also in combination with the capsules, did not add any damage to the pancreas. CONCLUSION: Intra-arterial instillation of microencapsulated cells to the pig pancreas is feasible and safe. Neither pancreatitis, foreign body reactions nor circulatory disturbances were observed. Clinical application of this genetically enhanced chemotherapeutic method seems possible.

Angiography↗

PubMed2003

Treatment of inoperable pancreatic carcinoma using a cell-based local chemotherapy: results of a phase I/II clinical trial.

BACKGROUND: The use of ifosfamide for conventional chemotherapy of pancreatic tumors is limited by systemic toxicity caused, in part, by its activation by liver-specific cytochrome enzymes and the subsequent systemic distribution of metabolites. Activation at the tumor site, on the other hand, should reduce systemic toxicity and provide more effective local therapeutic concentrations. The results of a phase I/II open, single-arm clinical trial of local intratumor activation of ifosfamide are presented. METHODS: Treatment involved angiographic implantation of encapsulated allogeneic cells, genetically modified to overexpress the enzyme cytochrome P-450 2B1, into the vasculature leading to the tumor. The cells are protected from immune rejection and locally activate systemically administered ifosfamide to antitumor metabolites. RESULTS: Of the 14 patients treated, 4 showed tumor regression and the other 10 patients showed stable disease, i.e., no further tumor growth. The median survival of the patient cohort was twice that of the control group. The 1-year survival was 36%, i.e., threefold that of the control group (twice that reported for gemcitabine). As far as clinical benefit was concerned, 4 of the 13 evaluable patients reported improvements in pain assessment at the last observation, with 6 remaining unchanged (4 of these experienced no pain) and 3 patients experiencing slightly greater pain. Using a worst case scenario, 50% experienced a clinical benefit, which rose to 71% of patients if a best case scenario was applied. The best predictor of clinical benefit was lack of pain, whereas significant weight loss possibly predicts a poor clinical benefit. CONCLUSIONS: The data obtained from this phase I/II clinical trial are promising and suggest that further clinical trials are warranted.

Adenocarcinoma↗

PubMed2002

Helicobacter pylori and the risk of benign and malignant biliary tract disease.

BACKGROUND: The etiology of tumors arising in the biliary tract remains unclear. Several previous studies have detected Helicobacter pylori organisms in bile from patients with gallstones or cholecystitis. The objective of this study was to determine whether there is an association between H. pylori in bile and biliary tract carcinoma. METHODS: The authors used polymerase chain reaction (PCR) assays to detect the presence of H. pylori in the stomach and bile from 89 patients: Sixty-three disease free patients had biliary calculi, 15 patients had carcinoma of the biliary tract, and 11 patients had neither gallstones nor carcinoma. Bile was considered to contain H. pylori only if the results of PCR determinations were positive in two or more samples assayed independently in two separate laboratories. RESULTS: There was a strong association between the presence of H. pylori in the stomach and in the bile (P < or = 0.01). Biliary H. pylori was associated with age but not with gender, and it was associated strongly with the clinical diagnosis. Patients with gallstones were 3.5 times as likely to have H. pylori in the bile compared with patients in a control group (95% confidence interval [95%CI], 0.8-15.8; P = 0.100), and H. pylori was 9.9 times more frequent in patients with biliary tract carcinoma compared with patients in the control group (95%CI, 1.4-70.5; P = 0.022). CONCLUSIONS: There is a strong association between biliary tract carcinoma and H. pylori in bile. If these results are confirmed by prospective studies, H. pylori may be responsible for a significant proportion of malignant biliary tract disease.

Adult↗

PubMed2002

Microencapsulated, CYP2B1-transfected cells activating ifosfamide at the site of the tumor: the magic bullets of the 21st century.

BACKGROUND: Conventional chemotherapy of pancreatic carcinoma is only marginally effective. This is in part due to the severity of side effects following systemic administration of the cytostatic drug. The aim was to create a therapeutic tool allowing the targeting of the conversion site of a cytotoxic prodrug to the site of the tumor. This was realized by transfection of the CYP2B1 gene, the major ifosfamide-converting P450 enzyme, in cells with subsequent microencapsulation and administration of these microcapsules to or into the tumor. The enzyme activity (resorufin assay) remained stable for weeks in vitro and in vivo within the microencapsulated CYP2B1-expressing cells. We demonstrated a significant antitumor effect of the intratumorally injected capsules against xenotransplanted human pancreatic carcinomas in the nude mouse. Angiographic experiments in the pig confirmed the feasibility of an intraarterial placement of the capsules into the pancreas. A clinical protocol was established and approved. PATIENTS, MATERIAL AND METHODS: L293 cells were transfected with the CYP2B1 gene, microencapsulated (diameter 0.7 mm) under GCP conditions and packed sterile. Patients with confirmed inoperable adenocarcinoma of the pancreas underwent angiography, and capsules were injected into a vessel leading into the tumor. The patients were monitored for 48 h to exclude allergic reactions or pancreatitis. A day later, ifosfamide was administered for three consecutive days to be repeated on days 21-23. The patients were followed up for 5 months. RESULTS: A total of 17 patients were enrolled. The patients tolerated the procedure without any complications. No allergic reactions or pancreatitis were encountered. Chemotherapy was uneventful. All patients had stable disease, and two patients a partial remission. The median survival was 44 weeks which compared favorably with that of a historical control group (22 weeks). CONCLUSIONS: The intraarterial administration of microcapsules for targeted chemotherapy was well tolerated. Control of local tumor growth was achieved.

Animals↗

PubMed2002

The gut origin of bacterial pancreatic infection during acute experimental pancreatitis in rats.

BACKGROUND: Infections are frequent complications and determine clinical course and outcome in severe pancreatitis. A novel animal model was used to assess minimal transit time of bacterial translocation (BT) across the gut mucosa in vivo using green fluorescent protein-transfected Escherichia coli and intravital video microscopy. METHODS: Three hours after induction of acute pancreatitis by i.p. injection of 40 microg/kg cerulein, 0.5 ml of a suspension of green fluorescent protein-transfected E. coli were injected into the lumen of a small bowel reservoir formed by ligature in anesthetized Wistar rats. Translocation of E. coli was assessed by intravital microscopy. Animals were sacrificed 5 h after induction of pancreatitis. RESULTS: BT across the mucosa and into the muscularis propria took a mean +/- SD of 36.4 +/- 8 min and 80.9 +/- 9.5 min, respectively, in sham animals. Pancreatitis resulted in a significantly shorter minimal transit time across the mucosa (16.4 +/- 4.9 min, p = 0.007) and into the muscularis propria (47.7 +/- 2.5 min, p = 0.001). E. coli were detected on frozen cross-sections and on bacteriological examination of pancreatic tissue in animals with acute pancreatitis but not in controls. DISCUSSION: Intravital microscopy of fluorescent bacteria is a new approach towards studying BT in vivo. Minimal transit time of BT serves as a novel functional aspect of mucosal barrier function during acute pancreatitis. The observation of fluorescent bacteria translocating from the small bowel lumen into the pancreas provides substantial experimental proof for the gut-origin-hypothesis of infectious complications in pancreatitis.

Acute Disease↗

PubMed2002

Novel treatments and therapies in development for pancreatic cancer.

Until recently, 5-fluorouracil was the most widely used treatment for non-resectable pancreatic cancer. This treatment, however, only resulted in a median survival time of approximately 4 months. In the last few years, gemcitabine has rapidly become the new treatment benchmark, due more to its superior clinical benefit rather than to it conferring an increased median survival (approximately 5-6 months). Thus, the outlook for patients with pancreatic cancer is still relatively bleak. A number of new treatment options are presently being investigated. Some of these are combination therapies involving gemcitabine and other chemotherapeutic agents or radiation. Other novel treatment strategies are also already being evaluated in clinical studies. Some of the more promising treatments in development are discussed and evaluated in this article.

Animals↗