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Biomedical subjects

P R Galle

Publications and source records attributed to P R Galle.

At least 19 recordsLinked to original sources

[Acute liver failure--medical viewpoints].

Acute liver failure is a rare disease that can cause death in the majority of untreated cases. Sudden loss of liver function in the absence of a preexisting liver disease is considered the true form and has to be distinguished from impaired function following exacerbation of an underlying liver disease (acute or chronic failure). Common causes include acute viral hepatitis, drug induced liver injury (DILI) and toxins. The loss of the excretory and synthetic function of the liver marks the clinical presentation and results in icterus, coagulopathy and encephalopathy. Additionally impairment of renal function and sepsis occur and contribute to the high mortality of this disease. The activation of cell death mechanisms (apoptosis) leading to a reductio of viable, functional liver tissue is considered to be an important pathophysiologic mechanism. Curative therapy of this disease includes liver transplantation that has been performed in Germany for the first time in 1969. In the year 2004 a total of 91 liver transplantation were performed for acute liver failure (10.3% of all transplants) in German transplant centers.

Acute Disease↗

Multiplex neuritis in a patient with autoimmune hepatitis: a case report.

A 37-year old woman presented with a 9-year history of hepatitis of unknown origin and aminotransferases within a 3-fold upper limit of normal. Autoimmune hepatitis (AIH) was diagnosed on the basis of elevated aminotransferases, soluble liver antigen/liver pancreas (SLA/LP) autoantibodies and characteristic histology. Immunosuppressive therapy led to rapid normalization of aminotransferases. Two years later, the patient developed left sided hemisensory deficits under maintenance therapy of prednisolone and azathioprine (AZT). Later she developed right foot drop and paraesthesia in the ulnar innervation territory on both sides. Magnetic resonance imaging (MRI) and cerebral panangiography suggested cerebral vasculitis. Neurological investigation and electromyography disclosed multiplex neuritis (MN) probably due to vasculitis. Consistent with this diagnosis, autoantibodies to extractable nuclear antigens were detectable in serum. Immunosuppression was changed to oral 150 mg cyclophosphamide (CPM0) per day. Prednisolone was increased to 40 mg/d and then gradually tapered to 5 mg. Oral CPM was administered up to a total dose of 40 g and then substituted by 6 times of an intervall infusion therapy of CPM (600 mg/m(2)). Almost complete motoric remission was achieved after 3 mo of CPM. Sensibility remained reduced in the right peroneal innervation territory. Follow-up of cranial MRI provided stable findings without any new or progressive lesions. This is the first report of multiplex neuritis in a patient with autoimmune hepatitis.

Adult↗

Genetic and environmental contributions to plasma C-reactive protein and interleukin-6 levels--a study in twins.

Elevated baseline levels of acute-phase proteins such as C-reactive protein (CRP) or cytokines like interleukin-6 (IL-6) are known risk factors for atherosclerosis and cardiovascular disease (CVD) events. However, until today, there is only controversial information about the contribution of genetic and environmental factors. Therefore, we performed an open prospective study in 108 monozygotic (MZ) and 60 same-sex dizygotic (DZ) twin pairs to analyse the genetic and environmental contributions to plasma CRP and IL-6 levels. Heritability of IL-6 was 0.61, indicating that plasma IL-6 levels are to a major part influenced by genetic determinants; however, for CRP, heritability was only 0.22, pointing to a moderate genetic influence. Plasma CRP levels were strongly influenced by female gender, older age and especially the body mass index. Our data underline the central role of IL-6 in low-grade inflammation contributing to atherosclerosis and CVD.

Adult↗

Dissemination of hepatocellular carcinoma is mediated via chemokine receptor CXCR4.

In different tumour entities, expression of the chemokine receptor 4 (CXCR4) has been linked to tumour dissemination and poor prognosis. Therefore, we evaluated, if the expression of CXCR4 exerts similar effects in human hepatocellular carcinoma (HCC). Expression analysis and functional assays were performed in vitro to elucidate the impact of CXCL12 on human hepatoma cells lines. In addition, expression of CXCR4 was evaluated in 39 patients with HCC semiquantitatively and correlated with both, tumour and patients characteristics. Human HCC and hepatoma cell lines displayed variable intensities of CXCR4 expression. Loss of p53 function did not impact on CXCR4 expression. Exposure to CXCL12 mediated a perinuclear translocation of CXCR4 in Huh7/Hep3B cells and increased the invasive potential of Huh7 cells. In HCC patients, CXCR4 expression significantly correlated with progressed local tumours (T-status; P=0.006), lymphatic metastasis (N-status; P=0.005) and distant dissemination (M-status; P=0.009), as well as with a decreased 3-year-survival rate (P=0.01). In summary, strong expression of CXCR4 is significantly associated with progressed hepatocellular cancer.

Active Transport, Cell Nucleus↗

A phase I/II multicentric trial of gemcitabine and epirubicin in patients with advanced pancreatic carcinoma.

Potential synergistic interaction between gemcitabine (GEM) and epirubicin (EPI) in pancreatic cancer have been described previously. The maximum-tolerated dose in this trial was GEM 1000 mg m(-2) and EPI 45 mg m(-2). Median time to progression was 5.1 months and median survival time 7.4 months. This combination appears well tolerated and shows promising clinical activity.

Adult↗

[Endomicroscopy--technology with future].

Endomicroscopy becomes possible due to the integration of a miniaturized confocal microscope in the distal tip of a conventional endoscope. Endomicroscopy enables subsurface analysis of the gut mucosa and in vivo histology during ongoing endoscopy in full resolution by point scanning laser fluorescence analysis. Cellular, vascular and connective structures can be seen in detail. Graduation of cellular changes with endomicroscopy allows an immediate in-vivo diagnosis of different gastrointestinal diseases. The diagnostic spectrum of confocal endomicroscopy is currently expanding from screening and surveillance for colorectal cancer towards Barrett's esophagus, Helicobacter pylori associated gastritis and early gastric cancer. The new detailed images seen with confocal laser endomicroscopy are unequivocally the beginning of a new era where this optical development will allow a unique look on cellular structures and functions at and below the surface of the gut.

Biotechnology↗

[Giant bile duct stones in a patient with a 4-year remaining biliary stent].

We report on a 67-year-old female patient who presented in July 2005 with sudden onset of pain in the right upper abdomen. The patient had undergone cholecystectomy in 1987. Because of recurrent complaints in the right upper abdomen, a pigtail stent was placed into the common hepatic duct in 2001. When the patients presented now, the laboratory tests including liver enzymes were within normal ranges. Endoscopic retrograde cholangiography, however, revealed a remaining 10-French, impacted double pigtail endoprosthesis that was obstructed by sludge as well as multiple giant bile duct stones of 20 to 30 mm in size. The giant stones could be finally removed by the combined use of ESWL and endoscopic techniques. This case demonstrates that impacted stents may favour the development of giant bile duct stones that may result in clinical symptoms only after prolonged periods of time.

Aged↗

[Immunotherapy of colorectal cancer--overview and perspectives].

The specific immunotherapy of colorectal cancer initially revealed promising results. However, a significant clinical benefit for patients has still to be proven in phase III trails. In order to compare the different clinical approaches and early phase I - II studies, there is an urgent need for the establishment and acceptance of new standardized diagnostic tools for detecting and quantifying induced and clinical relevant immune responses in patients. Whether or not subgroups with a certain genetic background, such as specific HLA alleles, reveal a better benefit from tumour vaccinations needs to be further analysed. Currently, only two specific antibodies, targeting membraneous receptors or their ligands, such as EGF or VEGF, have been approved by diverse national drug authorities. The question as to whether these antibodies also induce an antibody-dependent cellular toxicity (ADCC) is currently being analysed.

Antibodies, Monoclonal↗

[Attitudes towards cadaveric organ donation--results from a representative survey of the German population].

The increasing deficit of organs causes a drastic decline in the quality of life and survival of numerous patients in need of a transplantation. The purpose of this representative community study was to survey attitudes toward transplantation in the German population and to identify underlying determinants. Unlike previous surveys, fears and concerns were elicited based on a concrete case vignette. Among the 1,002 participants, 90 % were in favour of organ donation in general; 21 % reported having signed an organ donor card. Consent to organ donation was associated with younger age and higher social class; the same was true for the possession of an organ donor card. In the virtual decision situation, the majority (77 %) voted in favour of an organ donation based on saving lives, consolation for bereaved and the absence of disadvantages for the donor. Common (up to 50 %), however, were also fears and concerns regarding determination of the time of death, displacement of medical concern from the donor to the recipient of the organ, utilisation of organs for other purposes, or explantation before death. The knowledge of the determinants identified, of existing fears and concerns are helpful not only for informing the public, but also for the dialogue with the next of kin of potential donors. Here, it may be helpful not only to address arguments pro organ donation, but also to address potential fears and concerns.

Attitude to Health↗

Confocal laser endomicroscopy: technical status and current indications.

Confocal laser endomicroscopy is a newly introduced endoscopic tool that makes it possible to carry out confocal microscopic examination of the mucosal layer during ongoing endoscopy. Different types of tissue and diseases can be diagnosed immediately, facilitating early diagnosis of gastrointestinal cancer. Analysis of the in vivo microarchitecture is helpful in targeting biopsies to relevant areas. In addition, subsurface imaging can unmask microscopic diseases - (microscopic colitis) or bacterial infection ( HELICOBACTER PYLORI), for example. Molecular imaging is becoming feasible, and this will shortly open the door to new indications in gastrointestinal endoscopy (e.g., in vivo receptor analysis).

Barrett Esophagus↗

Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95- and TRAIL receptor-mediated apoptosis and chemotherapy.

Hepatocellular carcinoma (HCC) is highly resistant to chemotherapy, leading to a poor prognosis of advanced disease. Inhibitors of histone deacetylase (HDACi) induce re-differentiation in tumor cells and thereby re-establish sensitivity towards apoptotic stimuli. HDACi are entering the clinical stage of tumor treatment, and several substances are currently being tested in clinical trials to prove their efficacy in the treatment of leukemias and solid tumors. In this study, we investigated the impact of the HDACi valproic acid (VA) on TRAIL- and CD95-mediated apoptosis in hepatoma cells, as well as its sensitizing effect on a chemotherapeutic agent. Treatment of HepG2 cells with VA increased sensitivity to CD95-mediated apoptosis (4% apoptosis vs. 42%), and treatment with epirubicin (74% vs. 90% viability). Caspase-3 activity was significantly enhanced in cells treated with VA plus anti-CD95 antibodies compared to cells treated with antibodies alone. In parallel, VA strongly augmented the effect of TNF-related apoptosis-inducing ligand (TRAIL or Apo2 ligand) on HepG2 cells (10% vs. 58% apoptosis). VA induced down-regulation of cellular FLICE-inhibitory protein (c-FLIP/CASH, also known as Casper/iFLICE/FLAME-1/CLARP/MRIT/usurpin), providing a possible molecular mechanism underlying the increased sensitivity towards cell death-mediated apoptosis. HDAC inhibitors are a promising class for the treatment of leukemias. In addition, among other class members, VA deserves further evaluation as a treatment option for patients with advanced HCC.

Antineoplastic Combined Chemotherapy Protocols↗

Randomised phase II evaluation of irinotecan plus high-dose 5-fluorouracil and leucovorin (ILF) vs 5-fluorouracil, leucovorin, and etoposide (ELF) in untreated metastatic gastric cancer.

An open-label randomised comparison of efficacy and tolerability of irinotecan plus high-dose 5-fluorouracil (5-FU) and leucovorin (LV) (ILF) with etoposide plus 5-FU/LV (ELF) in patients with untreated metastatic or locally advanced gastric cancer. One cycle of ILF comprised six once-weekly infusions of irinotecan 80 mg m(-2), LV 500 mg m(-2), 24-h 5-FU 2000 mg m(-2), and ELF comprised three once-daily doses of etoposide 120 mg m(-2), LV 300 mg m(-2), 5-FU 500 mg m(-2). In all, 56 patients received ILF and 58 ELF. Median age was 62 years, Karnofsky performance 90%, and disease status was comparable for both arms. The objective clinical response rates after 14 weeks treatment (primary end point) were 30% for ILF and 17% for ELF (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.29-1.13, P = 0.0766). Overall response rates over the entire treatment period for ILF and ELF were 43 and 24%, respectively (RR 0.56, 95% CI 0.33-0.97; P = 0.0467). For ILF and ELF, respectively, median progression-free survival was 4.5 vs 2.3 months, time to treatment failure was 3.6 vs 2.2 months (P = 0.4542), and overall survival was 10.8 vs 8.3 months (P = 0.2818). Both regimens were well tolerated, the main grade 3/4 toxicities being diarrhoea (18%, ILF) and neutropenia (57%, ELF). The data from this randomised phase II study indicate that ILF provides a better response rate than ELF, and that ILF should be investigated further for the treatment of metastatic gastric cancer.

Adenocarcinoma↗

IL-6 signaling promotes tumor growth in colorectal cancer.

Recent investigations support an important role for TGF-beta in the development of colorectal cancer. However, the molecular consequences of TGF-beta signaling in the colon remains incompletely understood. In a recent study in Immunity, we analyzed the role of TGF-beta in a murine model of colon cancer. Using transgenic mice overexpressing TGF-beta or a dominant negative TGF-beta receptor II under control of the CD2 minigene, we show that TGF-beta signaling in tumor infiltrating T lymphocytes regulates the growth of dysplastic colon epithelial cells, as determined by histology and a novel system for high resolution chromoendoscopy in vivo. At the molecular level, TGF-beta signaling in T cells regulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell derived soluble IL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6 trans-signaling prevented tumor progression in vivo. Similar to these observations in mice, here we show that human colon cancer tissue expressed only low amounts of membrane bound IL-6R. In contrast, expression and activity of the matrix metalloproteinase TACE were increased. In summary, our data provide novel insights into the role of TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on an inhibition of TGF-beta-dependent IL-6 trans-signaling.

ADAM Proteins↗

[Primary sclerosing cholangitis is a premalignant condition].

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown aetiology. The course of the disease is usually progressive with the development of liver cirrhosis leading to death or liver transplantation within an average of 12 years. To date it is well known that the development of hepatobiliary malignancies and the rate of colonic mucosal dysplasia and carcinoma in patients with concomitant ulcerative colitis are greatly enhanced in patients with PSC. PSC can therefore be regarded as a premalignant condition. The following review will focus on the development of cholangiocellular carcinoma in patients with PSC and the associated diagnostic and therapeutic challenges.

Biliary Tract Neoplasms↗

[Combined simulation training: a new concept and workshop is useful for crisis management in gastrointestinal endoscopy].

INTRODUCTION: Crisis management as well as realistic emergency situations can be trained in the new developed simulation workshop "Gastrointestinal Endoscopy and Crisis Resource Management" by combining a full-scale simulator and the Erlanger Endoscopy Trainer. The aim of the current study was to evaluate the efficiency of the newly developed simulation workshop. METHODS: Endoscopists with more than 12 months experience can train their endoscopic skills and crisis resource management with the help of different simulators. In addition, two different scenarios (GI bleeding with significant blood loss and sedation overdoses) embedded in a realistic surrounding (emergency room) have to be managed by the participants. Vital parameters, endoscopic skills, as well as personal interactions were recorded and graded. RESULTS: 100 participants took part in the newly developed workshop (between June and December 2003). The participants showed a significantly better endoscopic performance and a significantly better crisis management after the standardized training program. CONCLUSIONS: Simulation training plays an essential role in aviation and minimizes the risk for human errors. In the current study it is clearly shown that simulation training is also useful in gastrointestinal endoscopy. The newly developed workshop may thus be of crucial importance to improve personal crisis management. Simulation also leads to an improvement of endoscopic and emergency skills. Accordingly, simulation training should be recommended or offered as an education option in gastrointestinal endoscopy.

Computer-Assisted Instruction↗