[Clinical research in Germany at the example of oncology]. / Klinische Forschung in Deutschland am Beispielder Onkologie.

Oncology is a major topic at many German universities. Research in oncology is funded by various programs of the Federal Ministry of Education and Research, the German Research Council, and by charities. Programs such as the foundation of coordinating centers for clinical research or the Program of Excellence of the German Cancer Aid to establish Comprehensive Cancer Centers in Germany shall improve the quality of clinical research in oncology. This is important because the 14th amendment of the German Medicines Law has markedly raised the standards for the design and conduct of clinical trials, accompanied by a substantial increase in costs. Consequently,the pharmaceutical industry plays an ever-increasing role in funding of clinical trials in oncology in Germany, but is mostly focused on the further development of their own products. In addition, research in clinical oncology often suffers from the fact that it takes a long time from the design of a trial to its publication, making it more difficult to achieve academic goals such as a habilitation. In the future, an improved training of medical doctors in clinical research and a further improved public funding structure for clinical research in oncology, e.g. by a National German Cancer Center,could be advantageous.

Vitamin C supplement use may protect against gallstones: an observational study on a randomly selected population.

BACKGROUND: Animal experiments have shown a protective effect of vitamin C on the formation of gallstones. Few data in humans suggest an association between reduced vitamin C intake and increased prevalence of gallstone disease. The aim of this study was to assess the possible association of regular vitamin C supplementation with gallstone prevalence. METHODS: An observational, population-based study of 2129 subjects aged 18-65 years randomly selected from the general population in southern Germany was conducted. Abdominal ultrasound examination, completion of a standardized questionnaire, compilation of anthropometric data and blood tests were used. Data were collected in November and December 2002. Data analysis was conducted between December 2005 and January 2006. RESULTS: Prevalence of gallstones in the study population was 7.8% (167/2129). Subjects reporting vitamin C supplementation showed a prevalence of 4.7% (11/232), whereas in subjects not reporting regular vitamin C supplementation, the prevalence was 8.2% (156/1897). Female gender, hereditary predisposition, increasing age and body-mass index (BMI) were associated with increased prevalence of gallstones. Logistic regression with backward elimination adjusted for these factors showed reduced gallstone prevalence for vitamin C supplementation (odds ratio, OR 0.34; 95% confidence interval, CI 0.14 to 0.81; P = 0.01), increased physical activity (OR 0.62; 95% CI, 0.42 to 0.94; P = 0.02), and higher total cholesterol (OR 0.65; 95% CI, 0.52 to 0.79; P < 0.001). CONCLUSION: Regular vitamin C supplementation and, to a lesser extent, increased physical activity and total cholesterol levels are associated with a reduced prevalence of gallstones. Regular vitamin C supplementation might exert a protective effect on the development of gallstones.

Identification, sequencing, and cellular localization of hepcidin in guinea pig (Cavia porcellus).

Hepcidin, a cysteine-rich peptide hormone with antimicrobial and iron-regulatory activity, plays a central role in regulating iron metabolism during inflammation, hypoxia, iron deficiency, and iron overload. The aim of this study was to isolate and sequence the guinea pig hepcidin gene and show peptide's tissue distribution to identify the guinea pig as good animal model to study the regulation and function of hepcidin. The guinea pig hepcidin cDNA contains a 252 bp open reading frame encoding for an 83 amino acid protein with eight highly conserved cysteine residues. Phylogenetic analyses showed that guinea pig hepcidin was more related to human and chimpanzee than to rodents like mouse or rat. RT-PCR studies revealed that hepcidin mRNA was most abundant in liver, less ample in pancreas, heart, and kidney and not detectable in lung and biliary system. Western blot analyses showed a distinct immunoreactive band of approximately 8 kDa, consistent with the predicted size of prohepcidin, and revealed that guinea pig hepcidin protein is synthesized predominantly in the liver, and with lower expression in kidney, heart, and pancreas. Immunohistochemical studies showed hepcidin predominantly at the basolateral membrane domain of hepatocytes in periportal regions. In pancreas, hepcidin immunoreactivity was confined to endocrine islets of Langerhans, while hepcidin was seen in tubules, but not in the glomeruli in the kidney. Our data identify guinea pig as a convenient model organism to study the role of hepcidin, given the remarkable sequence similarity and tissue distribution pattern largely identical to human.

A randomized multicentre phase II trial comparing adjuvant therapy in patients with interferon alpha-2b and 5-FU alone or in combination with either external radiation treatment and cisplatin (CapRI) or radiation alone regarding event-free survival - CapRI-2.

BACKGROUND: The 5-year survival of patients with resected pancreatic adenocarcinoma is still unsatisfying. The ESPAC-1 and the CONKO 001 trial proofed that adjuvant chemotherapy improves 5-year survival significantly from approximately 14% to 21%. In parallel, investigators from the Virginia Mason Clinic reported a 5-year survival rate of 55% in a phase II trial evaluating a combination of adjuvant chemotherapy, immunotherapy and external beam radiation (CapRI-scheme). Two other groups confirmed in phase II trials these results to a certain extent. However, these groups reported severe gastrointestinal toxicity (up to 93% grade 3 or 4 toxicity). In a randomized controlled phase III trial, called CapRI, 110 patients were enrolled from 2004 to 2007 in Germany and Italy to check for reproducibility. Interestingly, much less gastrointestinal toxicity was observed. However, dose-reduction due to haematological side effects had to be performed in nearly all patients. First clinical results are expected for the end of 2009. METHODS/DESIGN: CapRI-2 is an open, controlled, prospective, randomized, multicentre phase II trial with three parallel arms. A de-escalation of the CapRI-scheme will be tested in two different modifications. Patients in study arm A will be treated as outpatients with the complete CapRI-scheme consisting of cisplatin, Interferon alpha-2b and external beam radiation and three cycles of 5-fluorouracil continuous infusion. In study arm B the first de-escalation will be realised by omitting cisplatin. Next, patients in study arm C will additionally not receive external beam radiation. A total of 135 patients with pathologically confirmed R0 or R1 resected pancreatic adenocarcinoma are planned to be enrolled. Primary endpoint is the comparison of the treatment groups with respect to six-month event-free-survival. An event is defined as grade 3 or grade 4 toxicity, objective tumour recurrence, or death. DISCUSSION: The aim of this clinical trial is to evaluate de-escalation of the CapRI-scheme. It is hypothesised that removal of cisplatin and radiotherapy will have no significant effect or only a minor impact on the clinical response but result in substantially lower toxicity. TRIAL REGISTRATION: Current Controlled Trials ISRCTN79802092.

Role of Helicobacter pylori infection in iron deficiency during pregnancy.

OBJECTIVE: We investigated the possible role of Helicobacter pylori infection in iron deficiency during pregnancy in a large group of mothers in Germany after the birth of their baby under special consideration of iron supplementation. STUDY DESIGN: All women who were delivered of their baby between November 2000 and November 2001 at the Department of Gynecology and Obstetrics at the University of Ulm, Germany, were recruited for the study. Hemoglobin levels at various points of time during pregnancy were obtained from the mothers' health charts. Current H pylori infection was determined by 13 C-urea breath test. We used multiple linear regression analyses to assess the impact of infection status on hemoglobin level at the beginning of pregnancy and on hemoglobin change during pregnancy. RESULTS: Twenty-three percent of the 898 mothers had a H pylori infection, and 20% of the mothers had a hemoglobin level below 12 g/dL at the beginning of pregnancy. Compared with uninfected mothers, mothers with H pylori infection had a lower mean hemoglobin level at the beginning of pregnancy (-0.25 g/dL; 95% CI, -0.49, -0.003) and a more unfavorable change in hemoglobin level during pregnancy (-0.14 g/dL; 95% CI, -0.38, 0.10). CONCLUSION: This study supports a possible moderate, but still relevant, independent role of H pylori infection in iron deficiency during pregnancy.

Treatment of chronic hepatitis B with high-dose intravenous N-acetyl-L-cysteine.

BACKGROUND/AIMS: Therapy of hepatitis B with alpha-interferon is only successful in 30-40%; therefore new therapeutic options are needed. N-acetyl-L-cysteine is well known as an antidote against paracetamol intoxication and as mucolytic agent in pulmonary diseases. Furthermore, it restrains human immunodeficiency virus replication and inhibits hepatitis B virus replication at a posttranscriptional level in vitro. This study aims to evaluate the efficacy of N-acetyl-L-cysteine in 5 patients chronically infected with hepatitis B virus. METHODOLOGY: N-acetyl-L-cysteine was given intravenously at a daily dose of 150 mg/kg body weight. Treatment was performed for 28 days. RESULTS: The N-acetyl-L-cysteine infusions were tolerated without any side effects. Except a mild increase in thrombocyte-counts within the last week of N-acetyl-L-cysteine infusion blood tests did not change. We could not detect any changes in quantitative hepatitis B virus-DNA levels as well as in the HBeAg-status. CONCLUSIONS: We conclude from our data that N-acetyl-L-cysteine given in a high dose intravenously for 28 days is well tolerated. In contrast to in vitro studies no significant effects on the hepatitis B-virus load were detectable in vivo.

Effect of systemic glucocorticoid therapy on bone metabolism and the osteoprotegerin system in patients with active Crohn's disease.

BACKGROUND AND AIMS: Osteoporosis may occur in 25-30% of patients with Crohn's disease. Its pathogenesis is not completely understood. Both systemic inflammation in acute disease and treatment with systemic glucocorticoids have been implicated. The aim of the present study was to investigate changes in bone density and biochemical markers of bone metabolism before and during a 3-month period of high-dose glucocorticoid treatment for acute flare-up of Crohn's disease. METHODS: Twenty-five patients with active Crohn's disease requiring systemic glucocorticoid treatment (prednisolone, 60 mg/day) were investigated. Lumbar spine and femoral neck bone mineral densitometry was performed at baseline and again after 3 months. Clinical examinations including evaluation of the Crohn's disease activity index and measurement of the biochemical markers osteocalcin, deoxypyridinoline, osteoprotegerin and the soluble receptor activator of NF-kappaB ligand were performed prior to, and at 1, 2 and 12 weeks following steroid administration. RESULTS Median lumbar bone mineral density decreased significantly during the observation period by 1.04% from -0.84 (t score; range, -2.8 to +0.57) to -0.95 (range, -3.1 to +0.40; P = 0.022), while bone density of the total femur decreased by 2.9% from -0.83 (range, -2.61 to +1.86) to -0.90 (range, -2.65 to +0.19; P = 0.01). Serum levels of osteocalcin, a bone formation marker, and osteoprotegerin, an anti-resorptive cytokine produced by osteoblasts, decreased after the first 2 weeks of treatment and reached baseline levels after 3 months. No significant change was found for the bone resorption marker deoxypyridinoline, while soluble receptor activator of NF-kappaB ligand, a cytokine promoting bone resorption, tended to increase during steroid treatment. CONCLUSION: A decrease in bone mineral density in patients with Crohn's disease appears to result, at least in part, from a short-term effect of systemic glucocorticoid. Modulation of osteoclastogenesis by the receptor activator of NF-kappaB ligand/osteoprotegerin cytokine system and decreased osteoblastic function may be the underlying molecular basis.