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Biomedical subjects

R M Schmid

Publications and source records attributed to R M Schmid.

At least 19 recordsLinked to original sources

[Pancreatic cancer].

Pancreatic cancer is the fourth leading cause of death due to cancer. The most common cancer in the pancreas is ductal adenocarcinoma. Pancreatic cancer is characterized by alterations in K-Ras, INK4a, Tp53 and SMAD4. Similar to colon cancer a cancer progression model for pancreatic cancer has been proposed. The precursor lesions are called pancreatic intraepithelial neoplasia. Patients with tumors in the head of the pancreas may present deep jaundice without pain. Multidetector CT incorporating dual-phase imaging in the arterial and venous phases of enhancement is the preferred imaging modality for the diagnosis and staging of pancreatic cancer. Gemcitabine is still the standard for unresectable locally advanced disease or distant metastasis.

Carcinoma in Situ↗

Lack of RUNX3 regulation in human gastric cancer.

It has been proposed that the transcription factor RUNX3 is the product of a gastric tumour suppressor gene. We examined RUNX3 expression in gastric biopsies from 105 patients with different histological presentations. Surprisingly, immunohistochemical staining detected RUNX3 protein expression only in infiltrating leukocytes but not in the gastric epithelium. Using laser capture microdissection and quantitative reverse transcription-polymerase chain reaction, we confirmed that the level of RUNX3 mRNA expression in the gastric epithelium was very low and was influenced neither by H. pylori infection nor by neoplastic transformation. Instead, RUNX3 was highly expressed in the gastric stroma and the level of expression correlated with the magnitude of H. pylori-induced gastric inflammation. The low level of RUNX3 expression in gastric epithelium and the absence of downregulation in gastric cancer do not support the hypothesis that RUNX3 functions as a gastric tumour suppressor gene.

Adenocarcinoma↗

Hepatocellular carcinoma associated with hereditary hemochromatosis occurring in non-cirrhotic liver.

The occurrence of primary hepatocellular carcinoma (HCC) in patients with hereditary hemochromatosis (HH) is well known. Thereby, the development of liver cirrhosis seems to be a prerequisite. Whether or not a hepatic iron overload in the context of hereditary hemochromatosis is an independent risk factor for HCC remains unclear. To date there are only a few reports about HCC arising in non-cirrhotic livers in the presence of HH. We report the case of a 64-year-old man who presented to our outpatient clinic with HCC. Liver cirrhosis could be excluded. Detailed exploration of the patient's history revealed that he had been treated by venesection for about 10 years up to 15 years ago. Subsequent investigations showed an elevated serum ferritin and transferrin saturation. The diagnosis of HH was confirmed by genetic testing, with homozygosity for the Cys282Tyr mutation. The patient received palliative chemotherapy and finally died 15 months after initial diagnosis of HCC.

Carcinoma, Hepatocellular↗

[Partial Budd-Chiari syndrome associated with a hypereosinophilic syndrome].

We report a rare case of hypereosinophilic syndrome associated with a partial obstruction of the hepatic veins (Budd-Chiari syndrome). The case was assessed by ultrasonic examination, computed tomography and magnetic resonance tomography. We postulate an association because endothelium damage and thrombosis is reported in hypereosinophilic syndromes. Elevated liver enzymes in a patient with hypereosinophilic syndrome could be associated with a Budd-Chiari syndrome.

Aged↗

Argon plasma ablation of gastric inlet patches in the cervical esophagus may alleviate globus sensation: a pilot trial.

BACKGROUND AND STUDY AIMS: Globus sensation and/or sore throat have been associated with both gastroesophageal reflux disease and the presence of a gastric inlet patch. There have been no reports, however, on whether ablation of heterotopic mucosa in the cervical esophagus leads to improvement of chronic globus sensation. PATIENTS AND METHODS: Ten patients with a histologically proved gastric inlet patch who complained of chronic globus sensation and/or sore throat were included in this prospective pilot study. After a thorough assessment, including videofluoroscopy, laryngoscopy, manometry, and 24-hour two-channel pH monitoring, patients underwent argon plasma coagulation (APC) to ablate the heterotopic mucosa. A questionnaire with a visual analog scale ranging from 0 to 10 was used for assessment of globus sensation, sore throat, and other typical or atypical reflux symptoms. Follow-up examinations (including symptom assessment) were performed 4 weeks and 8 weeks after APC therapy. RESULTS: Ablation of the gastric inlet patch resulted in a significant reduction of median symptom scores for globus sensation (from 2.7 to 0) and sore throat (from 2.8 to 0) 8 weeks after therapy ( P < 0.05), but there was no improvement in other reflux-related symptoms. Acid reflux in the distal and proximal esophagus, determined by two-channel pH monitoring, did not change after therapy. CONCLUSIONS: Our preliminary data suggest that ablation of gastric inlet patches by APC can alleviate chronic globus sensation or sore throat. Acid reflux or its treatment is unlikely to influence these results. A randomized and blinded study is warranted.

Adult↗

Hemodynamics after endoscopic submucosal injection of epinephrine in patients with nonvariceal upper gastrointestinal bleeding: a matter of concern.

We report about detailed hemodynamic changes and one major cardiac complication occurring after submucosal injection of epinephrine (1 : 10 000) for management of upper gastrointestinal bleeding in a series of four consecutive patients. Cardiac contractility and afterload, determined by the cardiac index and the systemic vascular resistence index (SVRI), were assessed by transpulmonary thermodilution using the Pulse Contour Cardiac Output monitoring system (PiCCO; Pulsion Medical Systems, Munich, Germany), and the mean arterial pressure and heart rate were recorded. We observed a distinct rise in both mean arterial pressure and heart rate, and this effect was pronounced in the three patients with esophageal lesions. The increase in the mean arterial pressure was caused by an elevation of the cardiac index in two patients, a rise in both cardiac index and SVRI in one patient, and a rise in the SVRI only in the fourth patient. One patient, who had received 30 ml epinephrine for treatment of a bleeding Mallory-Weiss tear, developed an acute myocardial infarction during the postprocedural follow-up period. In conclusion, submucosal injection of epinephrine may cause significant hemodynamic changes that can potentially lead to adverse cardiac events. Close cardiac monitoring during and after submucosal application of epinephrine therefore seems a prudent precaution. In the treatment of esophageal lesions, the total amount of epinephrine injected should be carefully titrated, so that the lowest possible volume that achieves adequate hemostasis is used.

Adult↗

Pharmacokinetic and clinical phase II trial of imatinib in patients with impaired liver function and advanced hepatocellular carcinoma.

OBJECTIVES: No effective chemotherapy for advanced hepatocellular carcinoma (HCC) exists. Expression of the platelet-derived growth factor receptor (PDGFR) has been demonstrated in HCC, which may derive from hepatic stem cells that express c-kit. The aim of this trial was to evaluate imatinib, a tyrosine kinase inhibitor of PDGFR and c-kit, in patients with advanced HCC and impaired liver function. PATIENTS AND METHODS: Patients were treated with 400-600 mg imatinib daily. Immunohistochemical staining was performed for PDGFR and c-kit. Response was assessed by CT scans every 8 weeks. For pharmacokinetics studies, 74 plasma samples were assessed. RESULTS: Of the 17 patients enrolled in the study, 15 were evaluable for response. Only 1 tumor was positive for PDGFR and none was positive for c-kit. Grade 3/4 neutropenia occurred in 2 patients (1 had neutropenic fever). There was no objective response, and 5 (33%) patients had stable disease. Median time to treatment failure was 1.8 months in the whole study cohort and 3.7 months in the patients with stable disease. Patients treated with 400 mg imatinib did not significantly differ in pharmacokinetics from patients with chronic myelogenous leukemia (CML). CONCLUSION: In this small group of patients with advanced, mostly PDGFR- and c-kit-negative HCC, imatinib showed no therapeutic effect. In contrast to CML patients, the pharmacokinetics of imatinib were not significantly affected by impaired liver function.

Adult↗

[Diagnosis and therapy of weakly-acid/non-acidic gastroesophageal reflux disease].

The therapy of gastroesophageal reflux disease (GERD) is uncomplicated in most cases. However, 20 % of GERD patients suffer from reflux-associated symptoms under therapy with proton pump inhibitors (PPI). The cause of this resistance to PPI-therapy remains unclear. Today, the most discussed theory is the presence of the non- or weakly acidic reflux. Objective measurements of the weakly/non-acidic reflux are available since the development of intraluminal impedance monitoring in combination with pH-monitoring. The therapy of weakly/non-acidic GERD is not well established, so far. In the course of clinical studies the therapeutic spectrum (i. e. modification of the medical therapy, endoscopic anti-reflux procedures or surgical therapy) has to be tested.

Baclofen↗

[Pathogenesis of the ductal pancreatic adenocarcinoma: implications for future therapies?].

Despite the advances in the knowledge of the molecular pathogenesis, pancreatic cancer remains a devastating disease with an 5-year survival rate below 5%. Current therapeutic approaches are not successful in respect to overall survival. There is a need to transfer the knowledge of basic science to new therapeutic strategies. This review describes the disturbed cell cycle control, anti-apoptotic mechanisms, the process of invasion and metastasis and angioneogenesis of pancreatic cancer cells. This knowledge will allow the development of novel therapeutic strategies for the future.

Apoptosis↗

A prospective multicenter clinical and endoscopic follow-up study of patients with gastroesophageal reflux disease.

BACKGROUND: Despite its high prevalence, data on the course of gastroesophageal reflux disease (GERD) are still sparse. There is also an ongoing debate on the natural history of its various manifestations, i.e., non-erosive reflux disease (NERD) vs. erosive reflux disease (ERD) vs. Barrett's esophagus (BE). PATIENTS AND METHODS: This study was conducted within the framework of a prospective multicenter study on the course and prevalence of intestinal metaplasia at the gastroesophageal junction. 1014 dyspeptic patients were screened by the means of upper GI endoscopy. Clinical data were recorded by the use of a questionnaire. At least 15 months after the initial examination, all patients were invited for follow-up (FU) examination. Patients were analyzed separately with respect to their clinical and endoscopic findings. For the latter, only patients without any treatment with proton-pump-inhibitors (PPI) prior to initial and follow-up examinations were included. Patients were categorized as GERD positive if typical symptoms were present and/or proton pump inhibitors were used. RESULTS: Sufficient clinical and/or endoscopic data were available in 590 GERD patients with heartburn at least once a week. Follow-up data could be obtained in 320 patients (clinical FU: n = 304; endoscopic FU: n = 52) after a mean follow-up period of 35 months (18-48 months). 96 of 144 previously asymptomatic patients (67%) remained asymptomatic at follow-up, the rest (n = 48) were symptomatic. 143 of 304 previously symptomatic patients (47%) were symptom-free at follow-up, and only 161 patients (53%) remained symptomatic or had concomitant therapy with proton-pump-inhibitors (PPI). For follow-up endoscopy in patients off PPI (n = 52), ERD was no longer confirmed in 7/12 ERD patients (58%), whereas progress to ERD was found in 3/34 patients (9%) in the NERD group. BE was newly diagnosed in two NERD patients but could no longer be detected in 2 of 6 patients with an initial diagnosis of BE. CONCLUSIONS: With respect to its clinical as well as its endoscopic manifestations, gastroesophageal reflux disease does not appear to be very stable over time. However, in most cases this is due to regression rather than progression of the disease.

Endoscopes, Gastrointestinal↗

Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-kappaB independent mechanisms.

Radioresistance markedly impairs the efficacy of tumor radiotherapy and may involve antiapoptotic signal transduction pathways that prevent radiation-induced cell death. A common cellular response to genotoxic stress induced by radiation is the activation of the nuclear factor kappa B (NF-kappaB). NF-kappaB activation in turn can lead to an inhibition of radiation-induced apoptotic cell death. Thus, inhibition of NF-kappaB activation is commonly regarded as an important strategy to abolish radioresistance. Among other compounds, the fungal metabolite gliotoxin (GT) has been reported to be a highly selective inhibitor of NF-kappaB activation. Indeed, low doses of GT were sufficient to significantly enhance radiation-induced apoptosis in HL-60 cells. However, this effect turned out to be largely independent of NF-kappaB activation since radiation of HL-60 cells with clinically relevant doses of radiation induced only a marginal increase in NF-kappaB activity, and selective inhibition of NF-kappaB by SN50 did not result in a marked enhancement of GT-induced apoptosis. GT induced activation of JNKs, cytochrome c release from the mitochondria and potently stimulated the caspase cascade inducing cleavage of caspases -9, -8, -7 and -3. Furthermore, cleavage of the antiapoptotic protein X-linked IAP and downregulation of the G2/M-specific IAP-family member survivin were observed during GT-induced apoptosis. Finally, the radiation-induced G2/M arrest was markedly reduced in GT-treated cells most likely due to the rapid induction of apoptosis. Our data demonstrate that various other pathways apart from the NF-kappaB signaling complex can sensitize tumor cells to radiation and propose a novel mechanism for radiosensitization by GT, the interference with the G2/M checkpoint that is important for repair of radiation-induced DNA damage in p53-deficient tumor cells.

Apoptosis↗

[Pancreatic carcinogenesis. Clinical implications].

Our understanding of the molecular pathology of pancreatic carcinoma has improved tremendously over the past few years due to the development of sophisticated molecular techniques. This knowledge has led to the postulation of a pancreatic tumor progression model. This article describes the molecular oncogenesis of pancreatic carcinoma and points out potential targets for therapeutic interventions. Pancreatic cancer is characterized by the sequential acquisition of somatic mutations in the proto-oncogene K-RAS and the tumor suppressors INK4a,TP53 and DPC4/SMAD4 and by epigenetic alterations, including the overexpression of the "epidermal growth factor" receptor/ligand system. These genetic changes cause a profound disturbance to cell cycle regulation and continuous growth. Further analysis of the underlying molecular mechanisms will offer new diagnostic and therapeutic options and hopefully improve the outcome of this grim disease in the future.

ErbB Receptors↗

Lipopolysaccharide represses cholesterol 7-alpha hydroxylase and induces binding activity to the bile acid response element II.

BACKGROUND: Inflammatory states such as hepatitis and sepsis are frequently associated with alterations of bile acid synthesis. These conditions are mediated by bacterial wall products like lipopolysaccharide (LPS). Cholesterol 7-alpha hydroxylase is the rate-limiting enzyme of bile acid synthesis. Hydrophobic bile acids repress cholesterol 7-alpha hydroxylase transcription via binding to the farnesoid X receptor and interaction with the bile acid response element II in the cholesterol 7-alpha hydroxylase promoter. METHODS: We tested the effect of LPS on hepatic expression of cholesterol 7-alpha hydroxylase in C57BL/6 mice and Wistar rats. Further, we analyzed the binding activity of hepatic nuclear extracts to the bile acid response element II and the binding site for farnesoid X receptor heterodimers (ecdysone response element). RESULT: Lipopolysaccharide caused a 100-fold reduction of cholesterol 7-alpha hydroxylase mRNA levels in mice and a 10-fold reduction in rats. Protein levels of cholesterol 7-alpha hydroxylase also decreased in both species. These changes inversely correlated with the increased binding activity of nuclear proteins to the bile acid response element II and the ecdysone response element. CONCLUSION: Lipopolysaccharide-induced repression of cholesterol 7-alpha hydroxylase occurs at the transcriptional level. The underlying mechanism involves an increased binding activity of nuclear proteins to the bile acid response element II and the ecdysone response element. In conclusion, the farnesoid and retinoid X receptors participate in LPS-induced cholesterol 7-alpha hydroxylase repression.

Animals↗

Mechanisms of nordihydroguaiaretic acid-induced growth inhibition and apoptosis in human cancer cells.

Lipoxygenase metabolites of arachidonic acid can act as growth promoting factors for various cancer cell lines. Here we demonstrate that the 5-lipoxygenase inhibitor nordihydroguaiaretic acid potently inhibits anchorage-independent growth of human pancreatic and cervical cancer cells in soft agar and delays growth of pancreatic and cervical tumours established in athymic mice. Furthermore, nordihydroguaiaretic acid induces apoptosis of these cancer cells in vitro and in vivo. Potential mechanisms mediating these effects of nordihydroguaiaretic acid were examined. Nordihydroguaiaretic acid had no inhibitory effect on growth and survival signals such as tyrosine phosphorylation of the epidermal growth factor receptor or basal and growth factor-stimulated activities of extracellular signal-regulated kinase 1/2, p70(s6k) and AKT but selectively inhibited expression of cyclin D1 in the cancer cells. In addition, treatment with nordihydroguaiaretic acid lead to a disruption of the filamentous actin cytoskeleton in human pancreatic and cervical cancer cells which was accompanied by the activation of Jun-NH(2)-terminal kinase and p38(mapk). Similar effects were obtained by treatment of the cancer cells with cytochalasin D. These results suggest that nordihydroguaiaretic acid induces anoikis-like apoptosis as a result of disruption of the actin cytoskeleton in association with the activation of stress activated protein kinases. In conclusion, nordihydroguaiaretic acid could constitute a lead compound in the development of novel therapeutic agents for various types of cancer.

Actins↗

Analysis of the cytochrome c-dependent apoptosis apparatus in cells from human pancreatic carcinoma.

Defects in the apoptotic system are likely to play a role in tumorigenesis. Pancreatic carcinoma cells are extremely resistant to apoptosis induction by chemotherapy suggesting that the apoptosis machinery is faulty. We investigated the integrity of the cytochrome c-dependent apoptotic apparatus in 10 human pancreatic carcinoma cell lines. Expression of Apaf-1, caspase-3, -6, -7, -8 and -9, Hsp-70 and XIAP was detected in all cell lines. The expression levels of Apaf-1 and caspase-8 were homogenous in all cell lines whereas differences in expression of other caspases were seen. In cytosolic fractions, all investigated caspases were processed in response to cytochrome c but the extent of processing varied between the cell lines. No stringent correlation between the amount of processing of caspase-9 and effector caspases was seen. Cytochrome c-induced effector caspase activity was quantitated by enzyme assay. Especially at low concentrations of added cytochrome c, this response varied greatly between the cell lines. These data demonstrate that the apoptotic system downstream of the mitochondria is qualitatively intact in pancreatic carcinoma. They further show that the response to cytochrome c can be quantitated in a cell-free system and that determinants other than mere expression of apoptotic molecules can regulate cytochrome c-induced apoptosis.

Apoptosis↗