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Dimopoulos M.A.,National and Kapodistrian University of Athens | Terpos E.,National and Kapodistrian University of Athens | Goldschmidt H.,Universitatsklinikum | Goldschmidt H.,National Center for Tumor Diseases | And 3 more authors.
Cancer Treatment Reviews | Year: 2012

Renal impairment (RI) is a common complication affecting patients with multiple myeloma (MM). Timely identification of MM-related RI and early treatment with novel antimyeloma agents can reverse renal damage in a high proportion of patients and improve outcomes. The IMiDs® immunomodulatory compound lenalidomide (Len) in combination with dexamethasone (Dex) is an effective and well-tolerated regimen for patients with relapsed or refractory (RR) MM. A retrospective analysis of Phase III data has shown that Len/Dex remains effective and well-tolerated in patients with moderate or severe RI, albeit with an increase in myelosuppression. This analysis demonstrated that in a high proportion of patients Len/Dex treatment can reverse MM-related RI and restore normal function. Lenalidomide has a predominantly renal route of excretion and in patients with RI the plasma concentration and half-life of the drug are significantly increased. As a consequence, lower starting doses are required in patients with RI to avoid over-exposure and an increased risk of adverse events, while maintaining good therapeutic index. A prospective cohort study in 50 patients with RRMM has reported that when Len/Dex dosing was adjusted according to renal function, response rates and survival outcomes were similar in patients with and without RI, and there was no increase in adverse events in patients with RI. Further clinical studies are required to confirm the efficacy and tolerability of Len/Dex regimens in MM patients with RI, and to evaluate the impact of reversing renal damage in terms of patient survival. © 2012 Elsevier Ltd.

Schmidt M.E.,German Cancer Research Center | Chang-Claude J.,German Cancer Research Center | Vrieling A.,German Cancer Research Center | Heinz J.,University of Hamburg | And 3 more authors.
Journal of Cancer Survivorship | Year: 2012

Introduction: Fatigue is a frequent problem during and after cancer treatment. We investigated different courses of fatigue from pre-diagnosis, through therapy, to long-term survivorship and evaluated potential implications on long-term quality of life (QoL). Methods: Breast cancer patients diagnosed in 2001-2005 were recruited in a case-control study in Germany (MARIE). At follow-up in 2009 (median 5. 8 years, MARIEplus), patients self-reported current fatigue and QoL status using validated questionnaires (FAQ, EORTC QLQ-C30). In addition, survivors retrospectively rated fatigue levels pre-diagnosis, during different treatment phases, and 1 year post-surgery. Our analyses included 1,928 disease-free cancer survivors and comparisons with fatigue and QoL scores from the general population. Results: Fatigue levels were substantially increased during chemotherapy and radiotherapy. Among patients who received both therapies, 61. 4% reported higher, 30. 0% same, and 8. 6% lower fatigue levels during chemotherapy compared to radiotherapy. Courses of fatigue varied widely between individuals. Survivors with persisting long-term fatigue had significantly and markedly worse scores for all QoL functions and symptoms about 6 years post-diagnosis than other survivors and compared to the general population. Survivors without substantial fatigue post-treatment had QoL scores largely comparable to the general population. Discussions/conclusion: Chemotherapy appears to have a stronger impact on fatigue than radiotherapy. Breast cancer survivors may experience long-term QoL comparable to the general population, even when suffering from substantial fatigue during treatment. Yet, persistent fatigue post-treatment may lead to extensive long-term loss in QoL concerning physical, social, cognitive, and financial aspects. Implications for cancer survivors: Fatigue management should be obligatory during and post cancer treatment. © 2011 Springer Science+Business Media, LLC.

Strasser B.,University Institute of Health Sciences | Steindorf K.,German Cancer Research Center | Steindorf K.,National Center for Tumor Diseases | Wiskemann J.,National Center for Tumor Diseases | And 6 more authors.
Medicine and Science in Sports and Exercise | Year: 2013

PURPOSE: Current evidence suggests many health benefits from physical activity during and after cancer treatment. However, the optimal exercise program for cancer survivors has not yet been established. The purpose of this meta-analysis was to summarize evidence for the efficacy of resistance training (RT) interventions to improve muscle strength and body composition among adult cancer survivors. We also investigate potential dose-response relationships between intensity, duration, and frequency of RT and assessed outcomes. METHODS: A systematic literature review of the Clinical Trial Register, Cochrane Trial Register, MEDLINE, and EMBASE literature databases was undertaken. Studies were included if they were randomized controlled trials (RCT) comparing RT with an exercise or nonexercise control group in cancer survivors during and after treatment. Thirteen articles from 11 RCT met our inclusion criteria. We performed a random-effects meta-analysis to determine weighted mean differences (WMD) with 95% confidence intervals using the Cochrane Review Manager 5.0.25. A random-effects metaregression model was performed to examine dose-response relationships between RT variables and assessed outcomes. RESULTS: Quantitative evidence shows a large effect of RT on lower-limb and upper-limb muscle strength (WMD: +14.57 kg, P = 0.0005 and +6.90 kg, P < 0.00001, respectively) and moderate effects on lean body mass and percentage of body fat (WMD: +1.07 kg, P < 0.0001 and -2.08%, P = 0.003, respectively). A small positive effect of RT was noted on Functional Assessment of Cancer Therapy-Fatigue (P = 0.05). Upper-limb muscle strength and percentage of body fat improved to a greater extent when RT interventions were of low to moderate intensity (≤75% one-repetition maximum, P = 0.042). CONCLUSIONS: RT was shown to be associated with clinically important positive effects on muscular function and body composition in patients during treatment or in long-term follow-up. Copyright © 2013 by the American College of Sports Medicine.

Endris V.,University of Heidelberg | Penzel R.,University of Heidelberg | Warth A.,University of Heidelberg | Muckenhuber A.,University of Heidelberg | And 4 more authors.
Journal of Molecular Diagnostics | Year: 2013

In the context of personalized oncology, screening for somatic tumor mutations is crucial for prediction of an individual patient's response to therapy. Massive parallel sequencing (MPS) has been suggested for routine diagnostics, but this technology has not been sufficiently evaluated with respect to feasibility, reliability, and cost effectiveness with routine diagnostic formalin-fixed, paraffin-embedded material. We performed ultradeep targeted semiconductor-based MPS (190 amplicons covering hotspot mutations in 46 genes) in a variety of formalin-fixed, paraffin-embedded diagnostic samples of lung adenocarcinoma tissue with known EGFR mutations (n = 28). The samples reflected the typical spectrum of tissue material for diagnostics, including small biopsies and samples with low tumor-cell content. Using MPS, we successfully sequenced all samples, with a mean read depth of 2947 reads per amplicon. High-quality sequence reads were obtained from samples containing ≥10% tumor material. In all but one sample, variant calling identified the same EGFR mutations as were detected by conventional Sanger sequencing. Moreover, we identified 43 additional mutations in 17 genes and detected amplifications in the EGFR and ERBB2 genes. MPS performance was reliable and independent of the type of material, as well as of the fixation and extraction methods, but was influenced by tumor-cell content and the degree of DNA degradation. Using sample multiplexing, focused MPS approached diagnostically acceptable cost rates. Copyright © 2013 American Society for Investigative Pathology.

Gupta I.,Genome Biology Unit | Clauder-Munster S.,Genome Biology Unit | Klaus B.,Center for Statistical Data Analysis | Jarvelin A.I.,Genome Biology Unit | And 8 more authors.
Molecular Systems Biology | Year: 2014

Recent research has uncovered extensive variability in the boundaries of transcript isoforms, yet the functional consequences of this variation remain largely unexplored. Here, we systematically discriminate between the molecular phenotypes of overlapping coding and non-coding transcriptional events from each genic locus using a novel genome-wide, nucleotide-resolution technique to quantify the half-lives of 3′ transcript isoforms in yeast. Our results reveal widespread differences in stability among isoforms for hundreds of genes in a single condition, and that variation of even a single nucleotide in the 3′ untranslated region (UTR) can affect transcript stability. While previous instances of negative associations between 3′ UTR length and transcript stability have been reported, here, we find that shorter isoforms are not necessarily more stable. We demonstrate the role of RNA-protein interactions in conditioning isoform-specific stability, showing that PUF3 binds and destabilizes specific polyadenylation isoforms. Our findings indicate that although the functional elements of a gene are encoded in DNA sequence, the selective incorporation of these elements into RNA through transcript boundary variation allows a single gene to have diverse functional consequences. © 2014 The Authors.

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