Nils Homann

Publications of Nils Homann

• Pathological complete remission in patients with oesophagogastric cancer receiving preoperative 5-fluorouracil, oxaliplatin and docetaxel.

  Authors: Nils Homann, Claudia Pauligk, Kim Luley, Thomas Werner Kraus, Hans-Peter Bruch, Akin Atmaca, Frank Noack, Hans-Michael Altmannsberger, Elke Jäger, Salah-Eddin Al-Batran

  International journal of cancer. Journal international du cancer. 05/2011; 130(7):1706-13.

  The aim of this study was to determine the pathological complete remission (pCR) rate, and its relationship to clinical outcome, in patients with adenocarcinoma of the stomach or oesophagogastricThe aim of this study was to determine the pathological complete remission (pCR) rate, and its relationship to clinical outcome, in patients with adenocarcinoma of the stomach or oesophagogastric junction receiving preoperative 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) every 2 weeks. Data from these patients who received at least one cycle of preoperative FLOT followed by surgery were prospectively collected in three German centres. Outcome analyses were conducted and tumour samples were evaluated for pathological remission by a central pathologist. A total of 46 patients were included in this analysis. All patients had clinical T3- and/or N+-stages and 11 (23.9%) had distant metastases (M1). After a median of 4 (range 2-8) preoperative cycles, 8 of 46 patients (17.4%) achieved a pCR. The pCR rate was highest in tumours of intestinal type histology (30.8%) and in those located in the oesophagogastric junction (30.4%) and lowest in patients with diffuse/mixed type tumours (0%) or tumours located in the stomach (4.3%; p < 0.05 for both comparisons). Patients with pCR had 100% probability of overall and disease-free survival (DFS) during the observation period, which was significantly higher (p = 0.037 and p = 0.009, respectively) than the survival probability in patients without pCR. In conclusion, treatment intensification using FLOT was associated with significant pCR rates in patients with oesophagogastric cancer. The distribution of pCR appeared to be significantly different according to histological type and location of the tumours.

• Local calprotectin production in colorectal cancer and polyps--active neutrophil recruitment in carcinogenesis.

  Authors: Kim Luley, Frank Noack, Hendrik Lehnert, Nils Homann

  International journal of colorectal disease. 03/2011; 26(5):603-7.

  The aim of this study is to examine the expression level and localization of calprotectin in cancer tissue, tumor-adjacent mucosa, and polyps in colonic biopsies. Calprotection expression wasThe aim of this study is to examine the expression level and localization of calprotectin in cancer tissue, tumor-adjacent mucosa, and polyps in colonic biopsies. Calprotection expression was correlated with neutrophil infiltration, markers of bacteremia, and systemic inflammation. Patients with colorectal cancer (n = 28) and adenoma (n = 38) were compared with healthy controls (n = 33). Calprotectin expression levels were measured by ELISA, and its localization was visualized by immunohistochemistry and correlated with the degree of neutrophil infiltration (visualized by Esterase staining). The expression of tumor necrosis factor (TNF)-alpha, procalcitonin, endotoxemia, carcinoembryonic antigen (CEA), and C-reactive protein was also investigated. Mucosal calprotectin was expressed in significantly higher concentrations in carcinoma (94.2 ± 31.2 ng/mg total protein) and adenoma (122.8 ± 60.3 ng/mg total protein) in comparison with mucosal biopsies from healthy controls (20.4 ± 5.4 ng/mg total protein), tumor-adjacent mucosa from patients with colorectal carcinoma (21.6 ± 5.1 ng/mg total protein), and adenoma (45 ± 14.6 ng/mg total protein, all p < 0.05). Immunohistochemistry showed calprotectin reactivity mainly in granulocytes and macrophages with only singular reactive epithelial cells. Positive staining (quantified by the number of positive cells per square millimeter) was markedly increased in carcinoma tissue (85 ± 21.5) and in adenoma (67.5 ± 20) as compared with tumor-adjacent epithelia (18.8 ± 4.3, p = 0.0007, p = 0.003, respectively), and there was a highly significant correlation, r = 0.89, p = 0.001) between calprotectin staining and neutrophil infiltration. No significant differences were found in the systemic levels of TNF-alpha, procalcitonin, and endotoxemia, whereas CEA and C-reactive protein levels were significantly higher in the cancer group (p < 0.05). Our results support the evidence that increased calprotectin expression is an early step in the neoplastic transformation during colorectal carcinogenesis. Moreover, its expression is closely related to an inflammatory response and points out a possible biological link between inflammation and neoplastic transformation in colorectal cancer.

• Ethanol-mediated carcinogenesis in the human esophagus implicates CYP2E1 induction and the generation of carcinogenic DNA-lesions.

  Authors: Gunda Millonig, Ying Wang, Nils Homann, Friederike Bernhardt, Hua Qin, Sebastian Mueller, Helmut Bartsch, Helmut K Seitz

  International journal of cancer. Journal international du cancer. 02/2011; 128(3):533-40.

  Chronic alcohol consumption is a major risk factor for esophageal cancer. Various mechanisms may mediate carcinogenesis including the genotoxic effect of acetaldehyde and oxidative stress. EthanolChronic alcohol consumption is a major risk factor for esophageal cancer. Various mechanisms may mediate carcinogenesis including the genotoxic effect of acetaldehyde and oxidative stress. Ethanol exerts its carcinogenic effect in the liver among others via the induction of cytochrome P450 2E1 (CYP2E1) and the generation of carcinogenic etheno-DNA adducts. Here we investigated if such effects can also be observed in the human esophagus. We studied nontumorous esophageal biopsies of 37 patients with upper aerodigestive tract cancer and alcohol consumption of 102.3 ± 131.4 g/day (range: 15-600 g) as well as 16 controls without tumors (12 teetotalers and 4 subjects with a maximum of 25 g ethanol/day). CYP2E1, etheno-DNA adducts and Ki67 as a marker for cell proliferation were determined immunohistologically. Chronic alcohol ingestion resulted in a significant induction of CYP2E1 (p = 0.015) which correlated with the amount of alcohol consumed (r = 0.6, p < 0.001). Furthermore, a significant correlation between CYP2E1 and the generation of the carcinogenic exocyclic etheno-DNA adducts 1,N(6)-ethenodeoxyadenosine (r = 0.93, p < 0.001) and 3,N(4)-ethenodeoxycytidine (r = 0.92, p < 0.001) was observed. Etheno-DNA adducts also correlated significantly with cell proliferation (p < 0.01), which was especially enhanced in patients who both drank and smoked (p < 0.001). Nonsmokers and nondrinkers had the lowest rate of cell proliferation, CYP2E1 expression and DNA lesions. Our data demonstrate for the first time an induction of CYP2E1 in the esophageal mucosa by ethanol in a dose dependent manner in man and may explain, at least in part, the generation of carcinogenic DNA lesions in this target organ.

• Preclinical and clinical aspects of carboplatin and gemcitabine combined with whole-body hyperthermia for pancreatic adenocarcinoma.

  Authors: Afsaneh Bakshandeh-Bath, Anne S Stoltz, Nils Homann, Thomas Wagner, Stephanie Stölting, Stefan O Peters

  Anticancer research. 09/2009; 29(8):3069-77.

  Advanced pancreatic adenocarcinoma is usually treated with single-agent gemcitabine chemotherapy or combinations that include gemcitabine application that have palliative benefit but do not lead toAdvanced pancreatic adenocarcinoma is usually treated with single-agent gemcitabine chemotherapy or combinations that include gemcitabine application that have palliative benefit but do not lead to survival benefits. We present the results of preclinical and clinical studies using combination chemotherapies that include 41.8 degrees C whole-body hyperthermia for pancreatic adenocarcinoma. MATERIALS AND METHODS: DAN-G pancreatic carcinoma cells were treated with carboplatin and gemcitabine in vitro under hyperthermic conditions of 37 degrees C, 39 degrees C, 41.8 degrees C and 43 degrees C and cytotoxic drug effects were measured under various conditions using crystal violet assays. Data on outcome and toxicity of a clinical study using gemcitabine and carboplatin with 41.8 degrees C whole-body hyperthermia in a compassionate manner in patients with advanced and heavily pretreated pancreatic adenocarcinoma are also shown. RESULTS: In vitro data showed the DAN-G cells did not show increased responses to gemcitabine with or without carboplatinum under hyperthermic culture conditions at 39 and 41.8 degrees C. Only temperatures of 43 degrees C led to increased hyperthermic damage. Clinical data showed that a therapy of whole-body hyperthermia at 41.8 degrees C with gemcitabine and carboplatin was well tolerated leading mainly to the expected hematological side-effects due to chemotherapy. The median overall survival after whole-body-hyperthemia was of 357 days, with a median progression-free survival of 140 days. CONCLUSION: Preclinical data indicate that hyperthermia does not increase the chemosensitivity of DAN-G pancreatic carcinoma cells to gemcitabine and carboplatin. Clinical data show that a treatment of pancreatic adenocarcinoma with C whole-body hyperthermia at 41.8 degrees with gemcitabine and carboplatin is feasible for patients with advanced disease.

• Alcohol and Colorectal Cancer: The Role of Alcohol Dehydrogenase 1C Polymorphism.

  Authors: Nils Homann, Inke R König, Michael Marks, Monika Benesova, Felix Stickel, Gunda Millonig, Sebastian Mueller, Helmut K Seitz

  Alcoholism, clinical and experimental research. 01/2009;

  Background: Chronic alcohol consumption is a risk factor for colorectal cancer. Animal experiments as well as genetic linkage studies in Japanese individuals with inactive acetaldehyde dehydrogenaseBackground: Chronic alcohol consumption is a risk factor for colorectal cancer. Animal experiments as well as genetic linkage studies in Japanese individuals with inactive acetaldehyde dehydrogenase leading to elevated acetaldehyde concentrations following ethanol ingestion support the hypothesis that acetaldehyde may be responsible for this carcinogenic effect of alcohol. In Caucasians, a polymorphism of alcohol dehydrogenase 1C (ADH1C) exists resulting in different acetaldehyde concentrations following ethanol oxidation. Methods: To evaluate whether the association between alcohol consumption and colorectal tumor development is modified by ADH1C polymorphism, we recruited 173 individuals with colorectal tumors diagnosed by colonoscopy and 788 control individuals without colorectal tumors. Genotyping was performed using genomic DNA extracted from whole blood followed by polymerase chain reaction. Results: Genotype ADH1C*1/1 was more frequent in patients with alcohol-associated colorectal neoplasia compared to patients without cancers in the multivariate model controlling for age, gender, and alcohol intake (odds ratio = 1.674, 95% confidence interval = 1.110-2.524, 2-sided p from Wald test = 0.0139). In addition, the joint test of the genetic effect and interaction between ADH1C genotype and alcohol intake (2-sided p = 0.0007) indicated that the difference in ADH1C*1 polymorphisms between controls and colorectal neoplasia is strongly influenced by the alcohol consumption and that only individuals drinking more than 30 g ethanol per day with the genotype ADH1C*1/1 had an increased risk for colorectal tumors. Conclusions: These data identify ADH1C homozygosity as a genetic risk marker for colorectal tumors in individuals consuming more than 30 g alcohol per day and emphasize the role of acetaldehyde as a carcinogenic agent in alcohol-related colorectal carcinogenesis.

• No role of matrixmetalloproteinase-3 genetic promoter polymorphism 1171 as a risk factor for cirrhosis in alcoholic liver disease.

  Authors: Felix Stickel, Christoph H Osterreicher, Juliane Halangk, Thomas Berg, Nils Homann, Claus Hellerbrand, Eleonora Patsenker, Vreni Schneider, Armin Kolb, Helmut Friess, Detlef Schuppan, Gero Puhl, Helmut K Seitz, Julian L B Leathart, Christopher P Day

  Alcoholism, clinical and experimental research. 07/2008; 32(6):959-65.

  BACKGROUND: As only a minority of alcoholics develop cirrhosis, polymorphic genes, whose products are involved in fibrosis development were suggested to confer individual susceptibility. We testedBACKGROUND: As only a minority of alcoholics develop cirrhosis, polymorphic genes, whose products are involved in fibrosis development were suggested to confer individual susceptibility. We tested whether a functional promoter polymorphism in the gene encoding matrix metalloproteinase-3 (MMP-3; 1171 5A/6A) was associated liver cirrhosis in alcoholics. METHODS: Independent cohorts from the UK and Germany were studied. (i) UK cohort: 320 alcoholic cirrhotics and 183 heavy drinkers without liver damage and (ii) German cohort: 149 alcoholic cirrhotics, 220 alcoholic cirrhotics who underwent liver transplantation and 151 alcoholics without liver disease. Patients were genotyped for MMP-3 variants by restriction fragment length polymorphism, single strand confirmation polymorphism, and direct sequencing. In addition, MMP-3 transcript levels were correlated with MMP-3 genotype in normal liver tissues. RESULTS: Matrix metalloproteinase-3 genotype and allele distribution in all 1023 alcoholic patients were in Hardy-Weinberg equilibrium. No significant differences in MMP-3 genotype and allele frequencies were observed either between alcoholics with or without cirrhosis. There were no differences in hepatic mRNA transcription levels according to MMP-3 genotype. CONCLUSIONS: Matrix metalloproteinase-3 1171 promoter polymorphism plays no role in the genetic predisposition for liver cirrhosis in alcoholics. Stringently designed candidate gene association studies are required to exclude chance observations.

• Evaluation of the transforming growth factor beta1 codon 25 (Arg-->Pro) polymorphism in alcoholic liver disease.

  Authors: Christoph H Osterreicher, Juliane Halangk, Thomas Berg, Eleonora Patsenker, Nils Homann, Claus Hellerbrand, Helmut K Seitz, Dennis Eurich, Felix Stickel

  Cytokine. 05/2008; 42(1):18-23.

  INTRODUCTION: Liver cirrhosis develops only in a minority of heavy drinkers. Genetic factors may account for some variation in the progression of fibrosis in alcoholic liver disease (ALD).INTRODUCTION: Liver cirrhosis develops only in a minority of heavy drinkers. Genetic factors may account for some variation in the progression of fibrosis in alcoholic liver disease (ALD). Transforming growth factor beta 1 (TGFbeta1) is a key profibrogenic cytokine in fibrosis and its gene contains several polymorphic sites. A single nucleotide polymorphism at codon 25 has been suggested to affect fibrosis progression in patients with chronic hepatitis C virus infection, fatty liver disease, and hereditary hemochromatosis. Its contribution to the progression of ALD has not been investigated sufficiently so far. PATIENTS AND METHODS: One-hundred-and-fifty-one heavy drinkers without apparent ALD, 149 individuals with alcoholic cirrhosis, and 220 alcoholic cirrhotics who underwent liver transplantation (LTX) were genotyped for TGFbeta1 codon 25 variants. RESULTS: Univariate analysis suggested that genotypes Arg/Pro or Pro/Pro are associated with decompensated liver cirrhosis requiring LTX. However, after adjusting for patients' age these genotypes did not confer a significant risk for cirrhosis requiring LTX. CONCLUSION: TGFbeta1 codon 25 genotypes Arg/Pro or Pro/Pro are not associated with alcoholic liver cirrhosis. Our study emphasizes the need for adequate statistical methods and accurate study design when evaluating the contribution of genetic variants to the course of chronic liver diseases.

• Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie.

  Authors: Salah-Eddin Al-Batran, Joerg Thomas Hartmann, Stephan Probst, Harald Schmalenberg, Stephan Hollerbach, Ralf Hofheinz, Volker Rethwisch, Gernot Seipelt, Nils Homann, Gerhard Wilhelm, Gunter Schuch, Jan Stoehlmacher, Hans Günter Derigs, Susanna Hegewisch-Becker, Johannes Grossmann, Claudia Pauligk, Akin Atmaca, Carsten Bokemeyer, Alexander Knuth, Elke Jäger

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 03/2008; 26(9):1435-42.

  PURPOSE: This study was designed to compare fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin in patients with advanced gastric cancer. PATIENTS AND METHODS:PURPOSE: This study was designed to compare fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin in patients with advanced gastric cancer. PATIENTS AND METHODS: Patients with previously untreated advanced adenocarcinoma of the stomach or esophagogastric junction were randomly assigned to receive either fluorouracil 2,600 mg/m(2) via 24-hour infusion, leucovorin 200 mg/m(2), and oxaliplatin 85 mg/m(2) (FLO) every 2 weeks or fluorouracil 2,000 mg/m(2) via 24-hour infusion, leucovorin 200 mg/m(2) weekly, and cisplatin 50 mg/m(2) every 2 weeks (FLP). The primary end point was progression-free survival (PFS). RESULTS: Two hundred twenty patients (median age, 64 years; metastatic, 94%) were randomly assigned. FLO was associated with significantly less (any grade) anemia (54% v 72%), nausea (53% v 70%), vomiting (31% v 52%), alopecia (22% v 39%), fatigue (19% v 34%), renal toxicity (11% v 34%), thromboembolic events (0.9% v 7.8%), and serious adverse events related to the treatment (9% v 19%). FLP was associated with significantly less peripheral neuropathy (22% v 63%). There was a trend toward improved median PFS with FLO versus FLP (5.8 v 3.9 months, respectively; P = .077) and no significant difference in median overall survival (10.7 v 8.8 months, respectively). However, in patients older than 65 years (n = 94), treatment with FLO resulted in significantly superior response rates (41.3% v 16.7%; P = .012), time to treatment failure (5.4 v 2.3 months; P < .001), and PFS (6.0 v 3.1 month; P = .029) and an improved OS (13.9 v 7.2 months) as compared with FLP, respectively. CONCLUSION: FLO reduced toxicity as compared with FLP. In older adult patients, FLO also seemed to be associated with improved efficacy.

• Prognostic factors affecting locally recurrent rectal cancer and clinical significance of hemoglobin.

  Authors: Dirk Rades, Hildegard Kuhn, Juergen Schultze, Nils Homann, Bernd Brandenburg, Rainer Schulte, Andreas Krull, Steven E Schild, Juergen Dunst

  International journal of radiation oncology, biology, physics. 03/2008; 70(4):1087-93.

  PURPOSE: To investigate potential prognostic factors, including hemoglobin levels before and during radiotherapy, for associations with survival and local control in patients with unirradiatedPURPOSE: To investigate potential prognostic factors, including hemoglobin levels before and during radiotherapy, for associations with survival and local control in patients with unirradiated locally recurrent rectal cancer. PATIENTS AND METHODS: Ten potential prognostic factors were investigated in 94 patients receiving radiotherapy for recurrent rectal cancer: age (<or=68 vs. >or=69 years), gender, Eastern Cooperative Oncology Group performance status (0-1 vs. 2-3), American Joint Committee on Cancer (AJCC) stage (<or=II vs. III vs. IV), grading (G1-2 vs. G3), surgery, administration of chemotherapy, radiation dose (equivalent dose in 2-Gy fractions: <or=50 vs. >50 Gy), and hemoglobin levels before (<12 vs. >or=12 g/dL) and during (majority of levels: <12 vs. >or=12 g/dL) radiotherapy. Multivariate analyses were performed, including hemoglobin levels, either before or during radiotherapy (not both) because these are confounding variables. RESULTS: Improved survival was associated with better performance status (p<0.001), lower AJCC stage (p=0.023), surgery (p=0.011), chemotherapy (p=0.003), and hemoglobin levels>or=12 g/dL both before (p=0.031) and during (p<0.001) radiotherapy. On multivariate analyses, performance status, AJCC stage, and hemoglobin levels during radiotherapy maintained significance. Improved local control was associated with better performance status (p=0.040), lower AJCC stage (p=0.010), lower grading (p=0.012), surgery (p<0.001), chemotherapy (p<0.001), and hemoglobin levels>or=12 g/dL before (p<0.001) and during (p<0.001) radiotherapy. On multivariate analyses, chemotherapy, grading, and hemoglobin levels before and during radiotherapy remained significant. Subgroup analyses of the patients having surgery demonstrated the extent of resection to be significantly associated with local control (p=0.011) but not with survival (p=0.45). CONCLUSION: Predictors for outcome in patients who received radiotherapy for locally recurrent rectal cancer were performance status, AJCC stage, chemotherapy, surgery, extent of resection, histologic grading, and hemoglobin levels both before and during radiotherapy.

• Delayed complications after placement of self-expanding stents in malignant esophageal obstruction: treatment strategies and survival rate.

  Authors: Nils Homann, Maria R Noftz, Rolf D Klingenberg-Noftz, Diether Ludwig

  Digestive diseases and sciences. 02/2008; 53(2):334-40.

  PURPOSE: Placement of self-expanding metal stents is regarded as a safe and effective treatment in patients with incurable malignant esophagogastric obstruction. However, proceeding and possiblePURPOSE: Placement of self-expanding metal stents is regarded as a safe and effective treatment in patients with incurable malignant esophagogastric obstruction. However, proceeding and possible benefit of re-interventions in patients with recurrent dysphagia due to delayed complications (>4 weeks after stent insertion) is unclear. PATIENTS AND METHODS: In 133 patients with malignant stricture of the esophagus or the esophagogastric junction 164 expandable metal stents were placed. About 89 patients were followed up until death. All tumor- or stent-related complications and consequent re-interventions were recorded. RESULTS: The overall incidence of delayed complications was 53.4% (71 of 133 pts.), with 34 patients (25.6%) experiencing more than one complication. Recurrent dysphagia due to tumor ingrowth (22%) or overgrowth (15%), bolus obstruction (21%), stent migration (9%), and development of esophagorespiratory fistula (9%) was successfully treated by dilatation (24%), placement of a second/third stent (27%), laser therapy (16%), and/or placement of a feeding tube (PEG, 19%). The median survival of patients with endoscopic therapy was significantly longer (222 +/- 26 days) compared to patients without re-intervention (86 +/- 14 days, P < 0.0001). CONCLUSIONS: Delayed complications after metal stent placement for malignant esophageal stricture are common, but can be treated successfully by endoscopic re-intervention in most cases. Regular interventional therapy may also improve survival.

• Genetic polymorphisms of manganese-superoxide dismutase and glutathione-S-transferase in chronic alcoholic pancreatitis.

  Authors: Christoph H Osterreicher, Jürgen Schultheiss, Markus Wehler, Nils Homann, Claus Hellerbrand, Beat Künzli, Helmut Friess, Helmut K Seitz, Felix Stickel

  Mutagenesis. 10/2007; 22(5):305-10.

  Chronic alcohol consumption is a major risk factor for the development of chronic pancreatitis. However, chronic pancreatitis occurs only in a minority of heavy drinkers. This variability may be dueChronic alcohol consumption is a major risk factor for the development of chronic pancreatitis. However, chronic pancreatitis occurs only in a minority of heavy drinkers. This variability may be due to yet unidentified genetic factors. Several enzymes involved in the degradation of reactive oxidants and xenobiotics, such as glutathione-S-transferase P1 (GSTP1) and manganese-superoxide dismutase (MnSOD) reveal functional polymorphisms that affect the antioxidative capacity and may therefore modulate the development of chronic pancreatitis and long-term complications like endocrine and exocrine pancreatic insufficiency. Two functional polymorphisms of the MnSOD and the GSTP1 gene were assessed by polymerase chain reaction and restriction fragment length polymorphism in 165 patients with chronic alcoholic pancreatitis, 140 alcoholics without evidence of pancreatic disease and 160 healthy control subjects. The distribution of GSTP1 and MnSOD genotypes were in Hardy-Weinberg equilibrium in the total cohort. Genotype and allele frequencies for both genes were not statistically different between the three groups. Although genotype MnSOD Ala/Val was seemingly associated with the presence of exocrine pancreatic insufficiency, this subgroup was too small and the association statistically underpowered. None of the tested genotypes affected the development of endocrine pancreatic insufficiency. Polymorphisms of MnSOD and GSTP1 are not associated with chronic alcoholic pancreatitis. The present data emphasize the need for stringently designed candidate gene association studies with well-characterized cases and controls and sufficient statistical power to exclude chance observations.

• Premedication with orally administered lorazepam in adults undergoing ERCP: a randomized double-blind study.

  Authors: Gunther Weitz, Nils Homann, Dorothea Clara von Jagow, Peter Wellhöner, Arik Sauer, Diether Ludwig

  Gastrointestinal endoscopy. 09/2007; 66(3):450-6.

  BACKGROUND: Restlessness often complicates ERCP and may be a reason for premature termination of the procedure. OBJECTIVE: Our purpose was to evaluate whether a premedication with orally administeredBACKGROUND: Restlessness often complicates ERCP and may be a reason for premature termination of the procedure. OBJECTIVE: Our purpose was to evaluate whether a premedication with orally administered lorazepam could reduce the need for sedatives and improve sedation quality. DESIGN: Randomized double-blind trial. SETTING: Therapeutic ERCP with an intravenous sedation containing midazolam, propofol, and S(+)-ketamine. PATIENTS: 95 inpatients (aged 20-91 years). INTERVENTIONS: 1 mg of lorazepam (n=47) or placebo (n=48) given orally before ERCP. MAIN OUTCOME MEASUREMENT: Total amount of administered propofol. RESULTS: Heart rate, blood pressure, number of oxygen desaturations, and states of restlessness did not differ between the groups. The same amount of midazolam was administered in both groups. There was no significant difference in the total amount of propofol to achieve adequate sedation (lorazepam vs placebo: 71+/-5 vs 63+/-4 microg/kg/min, mean+/-SE). Paradoxically, patients pretreated with lorazepam even needed more propofol in the early phase of sedation (275+/-39 vs 159+/-37 microg/kg in minutes 5-10, P<.05) and the total amount of ketamine administered was higher in this group as well (15.8+/-1.4 vs 11.3+/-1.2 microg/kg/min, P<.05). In both groups there were high rates of satisfaction with the course of the procedure evaluated both by the endoscopists and the patients. CONCLUSION: The trial failed to show an advantage of an oral premedication with lorazepam. The amount of sedatives administered in the lorazepam group even tended to be higher. A premedication with lorazepam may be counterproductive when followed by sedation containing another benzodiazepine.

• Radio(chemo)therapy plus resection versus radio(chemo)therapy alone for the treatment of stage III esophageal cancer.

  Authors: Dirk Rades, Rainer Schulte, Emre F Yekebas, Nils Homann, Steven E Schild, Juergen Dunst

  Strahlentherapie und Onkologie : Organ der Deutschen Röntgengesellschaft ... [et al]. 02/2007; 183(1):10-6.

  PURPOSE: To compare radio(chemo)therapy with 41.4-50.4 Gy (moderate dose, MD-RCT) plus resection versus radio(chemo)therapy with 59.4-66.6 Gy (higher dose, HD-RCT) alone for outcome in stage IIIPURPOSE: To compare radio(chemo)therapy with 41.4-50.4 Gy (moderate dose, MD-RCT) plus resection versus radio(chemo)therapy with 59.4-66.6 Gy (higher dose, HD-RCT) alone for outcome in stage III esophageal cancer, and to investigate potential prognostic factors including preradiotherapy (pre-RT) hemoglobin. PATIENTS AND METHODS: 148 patients with stage III esophageal cancer, treated with MD-RCT plus resection (n = 41) or HD-RCT alone (n = 107), were retrospectively evaluated for age, gender, performance status, tumor location, tumor length, stage, histology, grading, number of chemotherapy courses, pre-RT hemoglobin, resection, overall survival (OS), metastases-free survival (MFS), and locoregional control (LC). RESULTS: On univariate analysis, MD-RCT plus resection resulted in better 2-year OS (57% vs. 25%; p = 0.049), 2-year MFS (71% vs. 39%; p = 0.041), and 2-year LC (76% vs. 39%; p = 0.003). On multivariate analysis, results maintained significance for LC (p = 0.021). According to multivariate analysis, pre-RT hemoglobin was associated with OS (p = 0.003), MFS (p = 0.043), and LC (p = 0.041), tumor length with OS (p = 0.002) and MFS (p = 0.017), and the number of chemotherapy courses with OS (p = 0.008). Complications were more frequent in the MD-RCT-plus-surgery group (p < 0.001). Acute (p = 0.47) and late toxicity (p = 0.86) were similar in both groups. In patients receiving surgery, R0 resection was superior to R1/2 resection for OS (p < 0.001), MFS (p = 0.030), and LC (p < 0.001). MD-RCT plus R0 resection was also superior to HD-RCT alone. CONCLUSION: MD-RCT plus resection resulted in better LC than HD-RCT alone. If R0 resection is possible, MD-RCT plus resection appears preferable, as it results in better outcome. If only R1/2 resection can be performed, HD-RCT alone appears preferable regarding outcome and the greater morbidity associated with resection.

• The role of acetaldehyde in alcohol-associated cancer of the gastrointestinal tract.

  Authors: Helmut K Seitz, Nils Homann

  Novartis Foundation symposium. 02/2007; 285:110-9; discussion 119-4, 198-9.

  Acetaldehyde has been classified as a carcinogen in experimental animal research. Acetaldehyde is highly toxic, mutagenic and carcinogenic. Acetaldehyde causes point mutations, sister chromatidAcetaldehyde has been classified as a carcinogen in experimental animal research. Acetaldehyde is highly toxic, mutagenic and carcinogenic. Acetaldehyde causes point mutations, sister chromatid exchanges and gross chromosomal aberrations. In the liver, acetaldehyde binds to DNA and the formation of stable adducts represents one mechanism by which acetaldehyde could trigger the occurrence of replication errors and/or mutations in oncogenes or tumour suppressor genes. In experimental colorectal carcinogenesis the inhibition of acetaldehyde dehydrogenase with elevated acetaldehyde levels results in an acceleration of cancer development. The production of acetaldehyde is reduced when germ-free animals are studied, emphasizing the role of bacteria in the generation of colorectal acetaldehyde. Acetaldehyde levels in the colorectum correlate with crypt cell production rate and result in hyper-regeneration, a precancerous condition. Genetic linkage studies give further evidence for acetaldehyde as a carcinogen. Individuals who accumulate acetaldehyde due to polymorphism and/or mutations in the genes coding for enzymes responsible for acetaldehyde generation and detoxification have an increased cancer risk. This is true for Asians with low acetaldehyde dehydrogenase 2 and for Caucasians with alcohol dehydrogenase 1C*1/1. In conclusion, there is an enormous body of evidence from in vitro studies, animal experiments and genetic linkage studies, that acetaldehyde is the major factor responsible for tumour development in alcohol-associated carcinogenesis of the gastrointestinal tract.

• Increased serum levels of complement C3a anaphylatoxin indicate the presence of colorectal tumors.

  Authors: Jens K Habermann, Uwe J Roblick, Brian T Luke, Darue A Prieto, William J J Finlay, Vladimir N Podust, John M Roman, Elisabeth Oevermann, Thomas Schiedeck, Nils Homann, Michael Duchrow, Thomas P Conrads, Timothy D Veenstra, Stanley K Burt, Hans-Peter Bruch, Gert Auer, Thomas Ried

  Gastroenterology. 10/2006; 131(4):1020-9; quiz 1284.

  BACKGROUND & AIMS: Late diagnosis of colorectal carcinoma results in a significant reduction of average survival times. Yet despite screening programs, about 70% of tumors are detected at advancedBACKGROUND & AIMS: Late diagnosis of colorectal carcinoma results in a significant reduction of average survival times. Yet despite screening programs, about 70% of tumors are detected at advanced stages (International Union Against Cancer stages III/IV). We explored whether detection of malignant disease would be possible through identification of tumor-specific protein biomarkers in serum samples. METHODS: A discovery set of sera from patients with colorectal malignancy (n = 58) and healthy control individuals (n = 32) were screened for potential differences using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Candidate proteins were identified and their expression levels were validated in independent sample sets using a specific immunoassay (enzyme-linked immunosorbent assay). RESULTS: By using class comparison and custom-developed algorithms we identified several m/z values that were expressed differentially between the malignant samples and the healthy controls of the discovery set. Characterization of the most prominent m/z values revealed a member of the complement system, the stable form of C3a anaphylatoxin (ie, C3a-desArg). Based on a specific enzyme-linked immunosorbent assay, serum levels of complement C3a-desArg predicted the presence of colorectal malignancy in a blinded validation set (n = 59) with a sensitivity of 96.8% and a specificity of 96.2%. Increased serum levels were also detected in 86.1% of independently collected sera from patients with colorectal adenomas (n = 36), whereas only 5.6% were classified as normal. CONCLUSIONS: Complement C3a-desArg is present at significantly higher levels in serum from patients with colorectal adenomas (P < .0001) and carcinomas (P < .0001) than in healthy individuals. This suggests that quantification of C3a-desArg levels could ameliorate existing screening tests for colorectal cancer.

• Alcohol dehydrogenase 1C*1 allele is a genetic marker for alcohol-associated cancer in heavy drinkers.

  Authors: Nils Homann, Felix Stickel, Inke R König, Arne Jacobs, Klaus Junghanns, Monika Benesova, Detlef Schuppan, Susanne Himsel, Ina Zuber-Jerger, Claus Hellerbrand, Dieter Ludwig, Wolfgang H Caselmann, Helmut K Seitz

  International journal of cancer. Journal international du cancer. 04/2006; 118(8):1998-2002.

  Chronic alcohol consumption is associated with an increased risk for upper aerodigestive tract cancer and hepatocellular carcinoma. Increased acetaldehyde production via alcohol dehydrogenase (ADH)Chronic alcohol consumption is associated with an increased risk for upper aerodigestive tract cancer and hepatocellular carcinoma. Increased acetaldehyde production via alcohol dehydrogenase (ADH) has been implicated in the pathogenesis. The allele ADH1C*1 of ADH1C encodes for an enzyme with a high capacity to generate acetaldehyde. So far, the association between the ADH1C*1 allele and alcohol-related cancers among heavy drinkers is controversial. ADH1C genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism in a total of 818 patients with alcohol-associated esophageal (n=123), head and neck (n=84) and hepatocellular cancer (n=86) as well as in patients with alcoholic pancreatitis (n=117), alcoholic liver cirrhosis (n=217), combined liver cirrhosis and pancreatitis (n=17) and in alcoholics without gastrointestinal organ damage (n=174). The ADH1C*1 allele and genotype ADH1C*1/1 were significantly more frequent in patients with alcohol-related cancers than that in individuals with nonmalignant alcohol-related organ damage. Using multivariate analysis, ADH1C*1 allele frequency and rate of homozygosity were significantly associated with an increased risk for alcohol-related cancers (p<0.001 in all instances). The odds ratio for genotype ADH1C*1/1 regarding the development of esophageal, hepatocellular and head and neck cancer were 2.93 (CI, 1.84-4.67), 3.56 (CI, 1.33-9.53) and 2.2 (CI, 1.11-4.36), respectively. The data identify genotype ADH1C*1/1 as an independent risk factor for the development of alcohol-associated tumors among heavy drinkers, indicating a genetic predisposition of individuals carrying this genotype.

• Mean corpuscular volume and ADH1C genotype in white patients with alcohol-associated diseases.

  Authors: Leimin Sun, Inke R König, Arne Jacobs, Helmut K Seitz, Klaus Junghanns, Thomas Wagner, Diether Ludwig, Arne Jacrobs, Nils Homann

  Alcoholism, clinical and experimental research. 06/2005; 29(5):788-93.

  BACKGROUND: Alcohol abuse is associated with several gastrointestinal diseases, such as esophageal carcinoma, chronic alcoholic pancreatitis, and liver cirrhosis. Increased mean corpuscular volumeBACKGROUND: Alcohol abuse is associated with several gastrointestinal diseases, such as esophageal carcinoma, chronic alcoholic pancreatitis, and liver cirrhosis. Increased mean corpuscular volume (MCV) has been recognized as a biomarker for alcohol abuse and heavy drinkers. Recent studies from Japan revealed that macrocytosis is related to ALDH-2/2 genotype, leading to increased acetaldehyde accumulation. It has also demonstrated that increased MCV values could also be an independent biomarker for esophageal cancer in Asians. Therefore, the aim of the current study was to investigate possible associations of MCV value with polymorphisms of ADH1C in white patients with alcohol-associated esophageal carcinoma, chronic alcoholic pancreatitis, and alcoholic cirrhosis as well as in heavy drinkers without organ damage. METHODS: In this study, a total of 510 alcoholic patients were enrolled with esophageal cancer (n = 98), chronic pancreatitis (n = 98), alcoholic liver cirrhosis (n = 151), and alcohol abuse without gastrointestinal disease (n = 163). ADH1C genotyping was performed by PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis from whole blood. The relation between MCV and ADH1C gene polymorphisms (ADH1C*1 and 1C*2) controlled for the amount of drinking, smoking, and age were investigated using both univariate and multivariate analysis. RESULTS: In univariate analysis, higher alcohol consumption was associated with increased MCV. Other variables were not associated with macrocytosis. In multiple linear regression analysis, after adjustment for age and smoking, higher alcohol consumption and female sex were independently associated with higher MCV values. No other variables, including which alcohol-associated disease the patient had, had an independent effect. Adding ADH genotype rendered no independent significant effect on MCV value. CONCLUSIONS: In a white population, MCV values were not associated with genotype polymorphisms of ADH1C. In contrast to findings in Asians, macrocytosis does not seem to be an independent biomarker for esophageal cancer. The role of ADH1C polymorphism in increasing MCV and the potential use of MCV as a marker for esophageal carcinoma are still pending.

• Mesenteric pulsatility index analysis predicts response to azathioprine in patients with Crohn's disease.

  Authors: Nils Homann, Ute Klarmann, Klaus Fellermann, Andreas Brüning, Rolf Klingenberg-Noftz, Thomas Witthöft, Eduard F Stange, Diether Ludwig

  Inflammatory bowel diseases. 03/2005; 11(2):126-32.

  OBJECTIVE: Mesenteric blood flow measurement has been found to predict relapse after steroid-induced remission in patients with Crohn's disease (CD) and ulcerative colitis (UC). Therefore, weOBJECTIVE: Mesenteric blood flow measurement has been found to predict relapse after steroid-induced remission in patients with Crohn's disease (CD) and ulcerative colitis (UC). Therefore, we assessed prospectively the possible relationship between changes in mesenteric blood flow and prognosis in chronically active patients with need of immunosuppressive therapy with azathioprine (AZA) or 6-mercaptopurine (6-MP). METHODS: Doppler ultrasound (DUS) measurements of the pulsatility index (PI) of the superior mesenteric artery (SMA) and inferior mesenteric artery (IMA) were performed in 52 patients with chronically active inflammatory bowel disease (CD 31 patients; UC 21 patients) before beginning therapy with AZA/6-MP (US1) and during clinical remission (CD activity index <150, Truelove index score I) (US2). Patients were weaned from concomitant therapy with corticosteroids as soon as possible and were followed up for 12 months. RESULTS: After 1 year, 16 patients with CD (51.6%) and 13 patients with UC (61.9%) were in remission, whereas 23 patients had recurrent disease or had undergone surgery. A decreased SMA PI at US2 predicted clinical relapse in all patients with CD [100%; P < 0.001; mean (+/-SD) 77 +/- 67 d after US1], but only 4 of 8 patients (50%; difference not significant; mean 84 +/- 75 d after US1) with UC. Conversely, an increase of SMA PI was associated with sustained remission in the majority of CD patients (12/16 patients; 75%; P < 0.002), but in only 7 of 13 patients (54%) with UC. Flow measurements in the IMA and postprandial values for both arteries were less reliable. CONCLUSION: Repeated DUS measurements of the SMA PI predict response to AZA/6-MP in patients with chronic active CD.

• Pathogenetic mechanisms of upper aerodigestive tract cancer in alcoholics.

  Authors: Helmut K Seitz, Felix Stickel, Nils Homann

  International journal of cancer. Journal international du cancer. 03/2004; 108(4):483-7.

• Response of refractory colitis to intravenous or oral tacrolimus (FK506).

  Authors: Klaus Fellermann, Zita Tanko, Klaus R Herrlinger, Thomas Witthoeft, Nils Homann, Andreas Bruening, Diether Ludwig, Eduard F Stange

  Inflammatory bowel diseases. 10/2002; 8(5):317-24.

  Intravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis, whereas the experience with FK506 is limited. In this report we compareIntravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis, whereas the experience with FK506 is limited. In this report we compare intravenous to oral FK506 treatment in 38 patients with refractory ulcerative (n = 33) or indeterminate (n = 5) colitis. FK506 was started intravenously in the first group (n = 18) at a dose of 0.01 to 0.02 mg/kg up to 14 days, followed by 0.1 to 0.2 mg/kg orally, or was started orally at this dose in a second group (n = 20). Additional azathioprine/6-mercaptopurine was given and steroids were tapered in responding patients, followed by a dose reduction of FK506. Clinical disease activity and laboratory parameters were assessed to evaluate efficacy and safety. Primary objectives were the induction of remission (Truelove index of mild) and colectomy-free survival. Treatment lasted for a mean of 7.6 months, and the mean observation period was 16.2 months. Eighteen of 38 patients improved within 14 days, and a complete remission was achieved in 13 patients after 1 month. A colectomy within 1 month was performed in 3 of 38 patients. The overall colectomy rate was 34%. One-half of the patients with a minimum follow-up of 2 years required a colectomy. Intravenous and per oral administration were equally safe and effective. The most frequent adverse events included tremor, hyperglycemia, hypertension, and infection, but none were severe. Renal impairment was rare and subsided upon drug withdrawal. In conclusion. FK506 is effective in the treatment of refractory colitis with per oral dosing being equivalent to intravenous administration.