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  • 1
    Abstract: BACKGROUND: To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. PATIENTS AND METHODS: CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated. RESULTS: Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%; IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%; IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months; hazard ratio (HR) 1.53; 95% Cl, 1.15-2.04; P = 0.004] and longer overall survival (36.6 versus 21.3 months; HR 1.73; 95% Cl, 1.24-2.43; P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results. CONCLUSION: In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab. CLINICAL TRIALS NUMBER: NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3.
    Type of Publication: Journal article published
    PubMed ID: 27234640
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  • 2
    Abstract: BACKGROUND: FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes (KRAS and NRAS exons 2-4). We report here efficacy results for the FIRE-3 final RAS (KRAS/NRAS, exons 2-4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival. METHODS: FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher's exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials.gov, number NCT00433927. FINDINGS: In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33.1 months [95% CI 24.5-39.4] vs 25.0 months [23.0-28.1]; hazard ratio 0.70 [0.54-0.90]; p=0.0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72.0% [95% CI 64.3-78.8] vs 97 of 173, 56.1% [48.3-63.6]; p=0.0029), frequency of early tumour shrinkage (107 of 157, 68.2% [60.3-75.4] vs 85 of 173, 49.1% [41.5-56.8]; p=0.0005), and median depth of response (-48.9% [-54.3 to -42.0] vs -32.3% [-38.2 to -29.2]; p〈0.0001) were significantly better in extended RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab. No differences in duration of response and time to response were observed between treatment groups. INTERPRETATION: This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup. FUNDING: Merck KGaA and Pfizer.
    Type of Publication: Journal article published
    PubMed ID: 27575024
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  • 3
    Keywords: ASSOCIATION ; polymorphism ; colorectal cancer
    Abstract: It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT
    Type of Publication: Journal article published
    PubMed ID: 19920828
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  • 4
    Abstract: OBJECTIVES: Autoimmune pancreatitis (AIP) is thought to be an immune-mediated inflammatory process, directed against the epithelial components of the pancreas. The objective was to identify novel markers of disease and to unravel the pathogenesis of AIP. METHODS: To explore key targets of the inflammatory process, we analyzed the expression of proteins at the RNA and protein level using genomics and proteomics, immunohistochemistry, western blot, and immunoassay. An animal model of AIP with LP-BM5 murine leukemia virus-infected mice was studied in parallel. RNA microarrays of pancreatic tissue from 12 patients with AIP were compared with those of 8 patients with non-AIP chronic pancreatitis. RESULTS: Expression profiling showed 272 upregulated genes, including those encoding for immunoglobulins, chemokines and their receptors, and 86 downregulated genes, including those for pancreatic proteases such as three trypsinogen isoforms. Protein profiling showed that the expression of trypsinogens and other pancreatic enzymes was greatly reduced. Immunohistochemistry showed a near-loss of trypsin-positive acinar cells, which was also confirmed by western blotting. The serum of AIP patients contained high titers of autoantibodies against the trypsinogens PRSS1 and PRSS2 but not against PRSS3. In addition, there were autoantibodies against the trypsin inhibitor PSTI (the product of the SPINK1 gene). In the pancreas of AIP animals, we found similar protein patterns and a reduction in trypsinogen. CONCLUSIONS: These data indicate that the immune-mediated process characterizing AIP involves pancreatic acinar cells and their secretory enzymes such as trypsin isoforms. Demonstration of trypsinogen autoantibodies may be helpful for the diagnosis of AIP.
    Type of Publication: Journal article published
    PubMed ID: 20407433
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  • 5
    Abstract: INTRODUCTION: In metastatic pancreatic ductal adenocarcinoma (mPDAC) treatment, erlotinib is known to be more effective in patients developing skin rash. Treatment with the FOLFIRINOX regimen is only performed in fit patients following defined inclusion criteria. The present study investigates the efficacy of gemcitabine plus erlotinib (gem/erlotinib) in rash-positive patients fit for FOLFIRINOX. PATIENTS AND METHODS: For this prospective phase II study, 150 patients were recruited in 20 centres. All patients received gem/erlotinib for 4 weeks (run-in phase); the subsequent treatment was determined by the development of skin rash: patients with rash grades 1-4 continued with gem/erlotinib, rash-negative patients were switched to FOLFIRINOX. Primary study end-point was to achieve a 1-year survival rate in rash-positive patients 〉/=40%. RESULTS: Ninety patients were deemed positive for skin rash by the end of the run-in phase, showing a 1-year survival rate of 40.0% (95% confidence interval [CI] 29.8-50.9). Median overall survival (OS) was 10.1 months, progression-free survival (PFS) was 3.8 months and overall response rate (ORR) was 23.3%. Patients switched to FOLFIRINOX (n = 27) had a 1-year survival rate of 48.1% (95% CI 28.7-68.1), a median OS of 10.9 months, a median PFS of 6.6 months and an ORR of 33.3%. Rash-negative patients had a lower quality of life at baseline but seemed to experience an improved control of pain during FOLFIRINOX. CONCLUSIONS: First-line treatment with gem/erlotinib was effective in fit, rash-positive mPDAC patients achieving a 1-year survival rate comparable to previous reports for FOLFIRINOX. The study was registered at clinicaltrials.gov (NCT0172948) and Eudra-CT (2011-005471-17).
    Type of Publication: Journal article published
    PubMed ID: 29549862
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  • 6
    Abstract: Many colorectal cancers (CRCs) develop in genetically susceptible individuals most of whom are not carriers of germ line mismatch repair or APC gene mutations and much of the heritable risk of CRC appears to be attributable to the co-inheritance of multiple low-risk variants. The accumulated experience to date in identifying this class of susceptibility allele has highlighted the need to conduct statistically and methodologically rigorous studies and the need for the multi-centre collaboration. This has been the motivation for establishing the COGENT (COlorectal cancer GENeTics) consortium which now includes over 20 research groups in Europe, Australia, the Americas, China and Japan actively working on CRC genetics. Here, we review the rationale for identifying low-penetrance variants for CRC and the current and future challenges for COGENT.
    Type of Publication: Journal article published
    PubMed ID: 22294761
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  • 7
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    German Medical Science; Düsseldorf, Köln
    In:  51. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie; 20060910-20060914; Leipzig; DOC06gmds363 /20060901/
    Publication Date: 2006-09-25
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 8
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  127. Kongress der Deutschen Gesellschaft für Chirurgie; 20100420-20100423; Berlin; DOC10dgch236 /20100517/
    Publication Date: 2010-05-17
    Keywords: ddc: 610
    Type: conferenceObject
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  • 9
    Publication Date: 2010-01-12
    Description: On the basis of our current knowledge about the physical properties and biological effects of low temperature plasmas the possibilities and prospects of plasma medicine are discussed in an interdisciplinary dialogue in order to generate hypotheses for further basic and applied research. The following possibilities are seemed feasible for the medical application of low-temperature plasmas: Prevention and treatment of diseases (chronic wounds, skin and mucosal infectious diseases, localized tumors, keloid formation, promotion of angiogenesis, tissue ablation, hemostasis) Inhibition of biofilm formation by surface treatment and by direct action on biofilms Promotion of incorporation of implants into viable tissue by changing the surface (hydrophobicity, plasma steered application of antimicrobial active layers with drug delivery function) Promotion of improved penetration of topically applied drugs with therapeutic outcome Employment for veterinary indications Improved cleaning performance in the treatment process of medical devices by surface modification.
    Description: Auf der Grundlage des aktuellen Wissenstands zu den physikalischen Eigenschaften und den biologischen Wirkungen von Tissue Tolerable Plasma (TTP) werden die Möglichkeiten und Perspektiven der Plasmamedizin diskutiert, um im interdisziplinären Dialog Hypothesen für die weitere Grundlagen- und Anwendungsforschung zu generieren. Folgende Möglichkeiten bieten sich zur medizinischen Anwendung von TTP an: Prävention und Therapie von Erkrankungen (chronische Wunden, infektiöse Haut- und Schleimhauterkrankungen, lokalisierte Tumoren, Keloidbildung, Förderung der Angiogenese, Gewebeabtragung, Blutstillung) Hemmung der Biofilmbildung durch Oberflächenbehandlung und durch direkte Einwirkung auf Biofilme Förderung der Einheilung von Implantaten durch veränderte Oberflächen (Hydrophobie, plasmagesteuerte Auftragung antimikrobiell wirksamer Schichten mit der Funktion eines Drug delivery Systems) Förderung der Penetration topisch applizierter Arzneimittel mit verbessertem Therapieergebnis Einsatz für veterinärmedizinische Indikationen Verbesserte Reinigungsleistung im Aufbereitungsprozess von Medizinprodukten durch Oberflächenveränderung.
    Keywords: plasma medicine ; tissue tolerable plasma ; perspectives of application ; treatment of wounds ; elimination of biofilms ; improve take of implants ; increase of penetration into tissues ; cleaning reinforcement ; Plasmamedizin ; tissue tolerable plasma ; Einsatzperspektiven ; Wundbehandlung ; Biofilmbekämpfung ; Implantateinheilung ; Penetrationsförderung in Gewebe ; Reinigungsverstärkung ; ddc: 610
    Language: German
    Type: article
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  • 10
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Krankenhaushygiene Interdisziplinär; VOL: 6; DOC13 /20111215/
    Publication Date: 2011-12-16
    Description: Background: Prevention of post-endoscopy infections is an important objective to assure patient safety. Endowashers, or high throughput irrigation water pumps, are a frequently used device on endoscopes. Recommendations published by professional bodies and regulatory health agencies cover not only adequate reprocessing of fiber-endoscopes but also state accepted methods of regular microbial sampling. Although major instruments like endoscopes are covered by these recommendations, other devices used as optional add-ons for endoscopes are not included. Objective: The aim of this prospective study was to investigate the potential for endowashers to act as a possible source of infection.Method: 24 endowashers were sampled. Sterile rinse-water was pumped through the endowasher and tested microbiologically according to standardised tests. Sampling was performed in 18 hospitals, including 2 university teaching hospitals, in northern Germany. If endowashers were contaminated, devices were reprocessed and re-tested.Results: Of 44 samples, 6 (14%) were contaminated with pathogens of up to 〉20,000 cfu/ml. Pseudomonas aeruginosa and other Gram-negative non-fermenters such as Stenotrophomonas spp. (18x) and Acinetobacter spp. (2x), followed by Staphylococcus aureus (1x), Enterobacter cloacae (1x), Candida albicans (1x), Serratia spp. (1x), Streptococcus spp . (1x) and others (2x).Conclusion: Endowashers can be a potential source of infection. Despite their common use, they are not routinely sampled microbiologically. Endowashers should be clearly mentioned in respective guidelines and routine quality control sampling of endowashers should be part of such recommendations. If endowashers are not monitored regularly, devices with single-use hoses should be used.
    Description: Hintergrund: Die Prävention von Infektionen nach endoskopischen Eingriffen ist Bestandteil der Gewährleistung der Patientensicherheit. Endowasher oder Hochdruckirrigationswasser-pumpen sind ein häufig benutztes Device in der Endoskopie. Empfehlungen von Fachgremien und Institutionen betreffen nicht nur die adäquate Aufbereitung von flexiblen Endoskopen, sondern auch die richtige mikrobiologische Probenahme. Obwohl die hauptsächlichen Instrumente wie Endoskope in den Empfehlungen berücksichtigt sind, trifft das nicht für Devices als optionaler Zusatz zu Endoskopen zu.Zielsetzung: Mittels einer prospektiven Studie sollte das Risiko für Endowasher als mögliche Infektionsquelle untersucht werden.Methode: Zur Untersuchung der Endowasher (n=24) wurde steriles Wasser durch den Endowasher gepumpt und mikrobiologisch gemäß Standardmethode untersucht. Die Proben wurden in 18 Krankenhäusern einschließlich zwei Universitätsklinika in Nordostdeutschland entnommen. Bei positivem bakteriologischem Befund wurden die Endowasher aufbereitet, erneut mikrobiologisch überprüft und erst bei negativem Befund erneut eingesetzt.Ergebnisse: Von 44 Proben waren 6 (14%) mit Krankheitserregern in einer Menge von bis zu 〉20.000 KbE/ml kontaminiert. Es dominierten Pseudomonas aeruginosa und andere Gram-negative Non-Fermenter wie Stenotrophomonas spp . (18x), gefolgt von Acinetobacter spp. (2x), je 1x von Staphylococcus aureus , Enterobacter cloacae , Candida albicans , Serratia spp ., Streptococcus spp . und anderen (2x).Schlussfolgerung: Endowasher können eine potentielle Infektionsquelle sein. Trotz ihres häufigen Einsatzes werden sie nicht routinemäßig mikrobiologisch überprüft. In Anbetracht der Befunde sollte die mikrobiologische Überprüfung von Endowashern in die einschlägigen Empfehlungen und Richtlinien aufgenommen werden. Falls Endowasher nicht in die reguläre Überwachung aufgenommen werden, sollten Einwegsysteme eingesetzt werden.
    Keywords: endowasher ; post-endoscopic infection ; endoscope ; disinfection ; reprocessing ; Endowasher ; Kontamination ; Infektionsprävention ; ddc: 610
    Language: English
    Type: article
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