TY - JOUR A1 - Proetel, Ulrike A1 - Pletsch, Nadine A1 - Lauseker, Michael A1 - Müller, Martin C. A1 - Hanfstein, Benjamin A1 - Krause, Stefan W. A1 - Kalmanti, Lida A1 - Schreiber, Annette A1 - Heim, Dominik A1 - Baerlocher, Gabriela M. A1 - Hofmann, Wolf-Karsten A1 - Lange, Elisabeth A1 - Einsele, Hermann A1 - Wernli, Martin A1 - Kremers, Stephan A1 - Schlag, Rudolf A1 - Müller, Lothar A1 - Hänel, Mathias A1 - Link, Hartmut A1 - Hertenstein, Bernd A1 - Pfirrmann, Markus A1 - Hochhaus, Andreas A1 - Hasford, Joerg A1 - Hehlmann, Rüdiger A1 - Saußele, Susanne T1 - Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV JF - Annals of Hematology N2 - The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874 KW - chronic myeloid leukemia KW - older patients KW - different imatinib dose regimens KW - early applied higher imatinib dosages Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121574 SN - 0939-5555 VL - 93 IS - 7 ER - TY - JOUR A1 - Bedke, Tanja A1 - Iannitti, Rossana G. A1 - De Luca, Antonella A1 - Giovannini, Gloria A1 - Fallarino, Francesca A1 - Berges, Carsten A1 - Latgé, Jean-Paul A1 - Einsele, Hermann A1 - Romani, Luigina A1 - Topp, Max S. T1 - Distinct and complementary roles for Aspergillus fumigatus-specific Tr1 and \(Foxp3^+\) regulatory T cells in humans and mice JF - Immunology and Cell Biology N2 - Unlike induced \(Foxp3^+\) regulatory T cells (\(Foxp3^+\) \(iT_{reg}\)) that have been shown to play an essential role in the development of protective immunity to the ubiquitous mold Aspergillus fumigatus, type-(1)-regulatory T cells (Tr1) cells have, thus far, not been implicated in this process. Here, we evaluated the role of Tr1 cells specific for an epitope derived from the cell wall glucanase Crf-1 of A. fumigatus (Crf-1/p41) in antifungal immunity. We identified Crf-1/p41-specific latent-associated \(peptide^+\) Tr1 cells in healthy humans and mice after vaccination with Crf-1/p41+zymosan. These cells produced high amounts of interleukin (IL)-10 and suppressed the expansion of antigen-specific T cells in vitro and in vivo. In mice, in vivo differentiation of Tr1 cells was dependent on the presence of the aryl hydrocarbon receptor, c-Maf and IL-27. Moreover, in comparison to Tr1 cells, \(Foxp3^+\) \(iT_{reg}\) that recognize the same epitope were induced in an interferon gamma-type inflammatory environment and more potently suppressed innate immune cell activities. Overall, our data show that Tr1 cells are involved in the maintenance of antifungal immune homeostasis, and most likely play a distinct, yet complementary, role compared with \(Foxp3^+\) \(iT_{reg}\). Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121449 VL - 92 IS - 8 ER - TY - JOUR A1 - Mousset, Sabine A1 - Buchheidt, Dieter A1 - Heinz, Werner A1 - Ruhnke, Markus A1 - Cornely, Oliver A. A1 - Egerer, Gerlinde A1 - Krüger, William A1 - Link, Hartmut A1 - Neumann, Silke A1 - Ostermann, Helmut A1 - Panse, Jens A1 - Penack, Olaf A1 - Rieger, Christina A1 - Schmidt-Hieber, Martin A1 - Silling, Gerda A1 - Südhoff, Thomas A1 - Ullmann, Andrew J. A1 - Wolf, Hans-Heinrich A1 - Maschmeyer, Georg A1 - Böhme, Angelika T1 - Treatment of invasive fungal infections in cancer patients—updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) JF - Annals of Hematology N2 - Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. Early antifungal treatment is mandatory to improve survival. Today, a number of effective and better-tolerated but more expensive antifungal agents compared to the former gold standard amphotericin B deoxycholate are available. Clinical decision-making must consider results from numerous studies and published guidelines, as well as licensing status and cost pressure. New developments in antifungal prophylaxis improving survival rates result in a continuous need for actualization. The treatment options for invasive Candida infections include fluconazole, voriconazole, and amphotericin B and its lipid formulations, as well as echinocandins. Voriconazole, amphotericin B, amphotericin B lipid formulations, caspofungin, itraconazole, and posaconazole are available for the treatment of invasive aspergillosis. Additional procedures, such as surgical interventions, immunoregulatory therapy, and granulocyte transfusions, have to be considered. The Infectious Diseases Working Party of the German Society of Hematology and Oncology here presents its 2008 recommendations discussing the dos and do-nots, as well as the problems and possible solutions, of evidence criteria selection. KW - cancer KW - invasive fungal infections KW - antifungals KW - mycoses KW - hematologic malignancies KW - aspergillosis KW - antifungal agents KW - invasive candidiasis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121340 VL - 96 ER - TY - JOUR A1 - Wendler, Jörg A1 - Burmester, Gerd R. A1 - Sörensen, Helmut A1 - Krause, Andreas A1 - Richter, Constanze A1 - Tony, Hans-Peter A1 - Rubbert-Roth, Andrea A1 - Bartz-Bazzanella, Peter A1 - Wassenberg, Siegfried A1 - Haug-Rost, Iris A1 - Dörner, Thomas T1 - Rituximab in patients with rheumatoid arthritis in routine practice (GERINIS): six-year results from a prospective, multicentre, non-interventional study in 2,484 patients JF - Arthritis Research & Therapy N2 - INTRODUCTION: The aim of this study was to evaluate the safety and efficacy of rituximab (RTX) in a large cohort of patients with rheumatoid arthritis in routine care, and to monitor changes in daily practice since the introduction of RTX therapy. METHODS: This was a multicentre, prospective, non-interventional study conducted under routine practice conditions in Germany. Efficacy was evaluated using Disease Activity Score in 28 joints (DAS28) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Safety was assessed by recording adverse drug reactions (ADRs). Physician and patient global efficacy and tolerability assessments were also evaluated. RESULTS: Overall, 2,484 patients (76.7% female, mean age 56.4 years, mean disease duration 11.7 years) received RTX treatment (22.7% monotherapy). The total observation period was approximately six-years (median follow-up 14.7 months). RTX treatment led to improvements in DAS28 and HAQ-DI that were sustained over multiple courses. DAS28 improvements positively correlated with higher rheumatoid factor levels up to 50 IU/ml. Response and tolerability were rated good/very good by the majority of physicians and patients. Mean treatment intervals were 10.5 and 6.8 months for the first and last 400 enrolled patients, respectively. Infections were the most frequently reported ADRs (9.1%; 11.39/100 patient-years); approximately 1% of patients per course discontinued therapy due to ADRs. CONCLUSIONS: Prolonged RTX treatment in routine care is associated with good efficacy and tolerability, as measured by conventional parameters and by physicians' and patients' global assessments. Rheumatoid factor status served as a distinct and quantitative biomarker of RTX responsiveness. With growing experience, physicians repeated treatments earlier in patients with less severe disease activity. KW - Rituximab Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121184 VL - 16 IS - 2 ER - TY - JOUR A1 - Fuj, Shigeo A1 - Kapp, Markus A1 - Einsele, Hermann T1 - Possible Implication of Bacterial Infection in Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation JF - Frontiers in Oncology N2 - Graft-versus-host disease (GVHD) is still one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). In the pathogenesis of acute GVHD, it has been established that donor-derived T-cells activated in the recipient play a major role in GVHD in initiation and maintenance within an inflammatory cascade. To reduce the risk of GVHD, intensification of GVHD prophylaxis like T-cell depletion is effective, but it inevitably increases the risk of infectious diseases and abrogates beneficial graft-versus-leukemia effects. Although various cytokines are considered to play an important role in the pathogenesis of GVHD, GVHD initiation is such a complex process that cannot be prevented by means of single inflammatory cytokine inhibition. Thus, efficient methods to control the whole inflammatory milieu both on cellular and humoral view are needed. In this context, infectious diseases can theoretically contribute to an elevation of inflammatory cytokines after allogeneic HSCT and activation of various subtypes of immune effector cells, which might in summary lead to an aggravation of acute GVHD. The appropriate treatments or prophylaxis of bacterial infection during the early phase after allogeneic HSCT might be beneficial to reduce not only infectious-related but also GVHD-related mortality. Here, we aim to review the literature addressing the interactions of bacterial infections and GVHD after allogeneic HSCT. KW - pathogen-associated molecular patterns KW - LPS KW - GVHD KW - bacterial infection KW - allogeneic hematopoietic stem cell transplantation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120674 SN - 2234-943X VL - 4 IS - 89 ER - TY - JOUR A1 - Kunzmann, Volker A1 - Herrmann, Ken A1 - Bluemel, Christina A1 - Kapp, Markus A1 - Hartlapp, Ingo A1 - Steger, Ulrich T1 - Intensified neoadjuvant chemotherapy with nab-paclitaxel plus gemcitabine followed by FOLFIRINOX in a patient with locally advanced unresectable pancreatic cancer JF - Case Reports in Oncology N2 - The prognosis of patients with locally advanced pancreatic cancer can be improved if secondary complete (R0) resection is possible. In patients initially staged as unresectable this may be achieved with neoadjuvant treatment which is usually chemoradiotherapy based. We report the case of a 46-year-old patient with an unresectable, locally advanced pancreatic cancer (pT4 Nx cM0 G2) who was treated with a sequential neoadjuvant chemotherapy regimen consisting of 2 cycles of nab-paclitaxel plus gemcitabine followed by 4 cycles of FOLFIRINOX. Neoadjuvant chemotherapy resulted in secondary resectability (R0 resection). After 2 cycles of nab-paclitaxel plus gemcitabine, the patient already had a complete metabolic remission as measured by integrated fludeoxyglucose ((18)F) positron emission tomography and computerized tomography. After a follow-up of 18 months the patient is alive without progression of disease. We propose to assess the clinical benefit of sequencing the combinations nab-paclitaxel plus gemcitabine and FOLFIRINOX as neoadjuvant therapy for patients with locally advanced and initially unresectable pancreatic cancer in a controlled clinical trial. KW - nab-paclitaxel KW - neoadjuvant chemotherapy KW - oxaliplatin KW - pancreatic cancer KW - locally advanced disease KW - irinotecan KW - gemcitabine KW - folinic acid KW - 5-Fluorouracil Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120189 SN - 1662-6575 VL - 7 IS - 3 ER - TY - JOUR A1 - Schwarzer, R. A1 - Nickel, N. A1 - Godau, J. A1 - Willie, B. M. A1 - Duda, G. N. A1 - Schwarzer, R. A1 - Cirovic, B. A1 - Leutz, A. A1 - Manz, R. A1 - Bogen, B. A1 - Dörken, B. A1 - Jundt, F. T1 - Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model JF - Blood Cancer Journal N2 - Despite evidence that deregulated Notch signalling is a master regulator of multiple myeloma (MM) pathogenesis, its contribution to myeloma bone disease remains to be resolved. Notch promotes survival of human MM cells and triggers human osteoclast activity in vitro. Here, we show that inhibition of Notch through the γ-secretase inhibitor XII (GSI XII) induces apoptosis of murine MOPC315.BM myeloma cells with high Notch activity. GSI XII impairs murine osteoclast differentiation of receptor activator of NF-κB ligand (RANKL)-stimulated RAW264.7 cells in vitro. In the murine MOPC315.BM myeloma model GSI XII has potent anti-MM activity and reduces osteolytic lesions as evidenced by diminished myeloma-specific monoclonal immunoglobulin (Ig)-A serum levels and quantitative assessment of bone structure changes via high-resolution microcomputed tomography scans. Thus, we suggest that Notch inhibition through GSI XII controls myeloma bone disease mainly by targeting Notch in MM cells and possibly in osteoclasts in their microenvironment. We conclude that Notch inhibition is a valid therapeutic strategy in MM. KW - MOPC315.BM Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119683 SN - 2044-5385 VL - 4 IS - e217 ER - TY - JOUR A1 - Weiss, Johannes A1 - Rau, Monika A1 - Geier, Andreas T1 - Non-Alcoholic Fatty Liver Disease Epidemiology, Clinical Course, Investigation, and Treatment JF - Deautsches Ärzteblatt International N2 - Background: The global obesity epidemic has increased the prevalence of fatty liver disease. At present, 14% to 27% of the general population in the industrialized world has non-alcoholic fatty liver disease (NAFLD). Methods: We review pertinent publications retrieved by a selective search of the PubMed database for the years 1995 to 2013. Results: The term “non-alcoholic fatty liver disease” covers cases of a wide spectrum of severity, ranging from bland fatty liver without any inflammation and with little or no tendency to progress all the way to non-alcoholic steatohepatitis (NASH) with inflammatory reactions and hepatocyte damage, with or without fibrosis. Some 5% to 20% of patients with NAFLD develop NASH, which undergoes a further transition to higher-grade fibrosis in 10% to 20% of cases. In fewer than 5% of cases, fibrosis progresses to cirrhosis. These approximate figures lead to an estimate of 0.05% to 0.3% for the prevalence of cirrhosis in the general population. About 2% of all cirrhosis patients per year develop hepatocellular carcinoma. The diagnosis of fatty liver disease can be suspected initially on the basis of abnormally high aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) levels and abnormal ultrasonographic findings. The positive predictive value of an ultrasonographic study for mild steatosis is 67% at most. The NAFLD fibrosis score, which is computed on the basis of multiple parameters (age, body-mass index, diabetes status, ASAT, ALAT, platelet count, and albumin level), has a positive predictive value of 82% to 90% and a negative predictive value of 88% to 93%. Liver biopsy is the gold standard for diagnosis but should be performed sparingly in view of its rare but sometimes life-threatening complications, such as hemorrhage. The treatment of NAFLD and NASH consists mainly of changes in lifestyle and nutrition. Conclusion: NAFLD can, in principle, be reversed. This is only possible with weight reduction by at least 3% to 5%. KW - fatty liver disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119557 VL - 111 IS - 26 ER - TY - JOUR A1 - Liu, Dan A1 - Hu, Kai A1 - Störk, Stefan A1 - Herrmann, Sebastian A1 - Kramer, Bastian A1 - Cikes, Maja A1 - Gaudron, Philipp Daniel A1 - Knop, Stefan A1 - Ertl, Georg A1 - Bijnens, Bart A1 - Weidemann, Frank T1 - Predictive Value of Assessing Diastolic Strain Rate on Survival in Cardiac Amyloidosis Patients with Preserved Ejection Fraction JF - PLOS ONE N2 - Objectives: Since diastolic abnormalities are typical findings of cardiac amyloidosis (CA), we hypothesized that speckle-tracking-imaging (STI) derived longitudinal early diastolic strain rate (LSRdias) could predict outcome in CA patients with preserved left ventricular ejection fraction (LVEF >50%). Background: Diastolic abnormalities including altered early filling are typical findings and are related to outcome in CA patients. Reduced longitudinal systolic strain (LSsys) assessed by STI predicts increased mortality in CA patients. It remains unknown if LSRdias also related to outcome in these patients. Methods: Conventional echocardiography and STI were performed in 41 CA patients with preserved LVEF (25 male; mean age 65±9 years). Global and segmental LSsys and LSRdias were obtained in six LV segments from apical 4-chamber views. Results: Nineteen (46%) out of 41 CA patients died during a median of 16 months (quartiles 5–35 months) follow-up. Baseline mitral annular plane systolic excursion (MAPSE, 6±2 vs. 8±3 mm), global LSRdias and basal-septal LSRdias were significantly lower in non-survivors than in survivors (all p<0.05). NYHA class, number of non-cardiac organs involved, MAPSE, mid-septal LSsys, global LSRdias, basal-septal LSRdias and E/LSRdias were the univariable predictors of all-cause death. Multivariable analysis showed that number of non-cardiac organs involved (hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.17–3.26, P = 0.010), global LSRdias (HR = 7.30, 95% CI 2.08–25.65, P = 0.002), and E/LSRdias (HR = 2.98, 95% CI 1.54–5.79, P = 0.001) remained independently predictive of increased mortality risk. The prognostic performance of global LSRdias was optimal at a cutoff value of 0.85 S−1 (sensitivity 68%, specificity 67%). Global LSRdias <0.85 S−1 predicted a 4-fold increased mortality in CA patients with preserved LVEF. Conclusions: STI-derived early diastolic strain rate is a powerful independent predictor of survival in CA patients with preserved LVEF. KW - diagnostic medicine KW - echocardiography KW - prognosis KW - calcium imaging KW - ejection fraction KW - death rates KW - amyloidosis KW - deformation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118024 SN - 1932-6203 VL - 9 IS - 12 ER - TY - JOUR A1 - Engelhardt, Monika A1 - Terpos, Evangelos A1 - Kleber, Martina A1 - Gay, Francesca A1 - Wäsch, Ralph A1 - Morgan, Gareth A1 - Cavo, Michele A1 - van de Donk, Niels A1 - Beilhack, Andreas A1 - Bruno, Benedetto A1 - Johnsen, Hans Erik A1 - Hajek, Roman A1 - Driessen, Christoph A1 - Ludwig, Heinz A1 - Beksac, Meral A1 - Boccadoro, Mario A1 - Straka, Christian A1 - Brighen, Sara A1 - Gramatzki, Martin A1 - Larocca, Alessandra A1 - Lokhorst, Henk A1 - Magarotto, Valeria A1 - Morabito, Fortunato A1 - Dimopoulos, Meletios A. A1 - Einsele, Hermann A1 - Sonneveld, Pieter A1 - Palumbo, Antonio T1 - European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma JF - Haematologica N2 - Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high-versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B). KW - undetermined significance MGUS KW - stem-cell transplantation KW - multiparameter flow-cytpmetry KW - bortezomib plus dxamethasone KW - monoclonal gammopathy KW - randomized phase-3 trial KW - elderly patients KW - thalidomide maintenance KW - cereblon expression KW - autologous transplantation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117477 VL - 99 IS - 2 ER -