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Dreger P.,University of Heidelberg | Schetelig J.,TU Dresden | Andersen N.,Rigshospitalet | Corradini P.,Istituto Nazionale dei Tumori | And 7 more authors.
Blood | Year: 2014

Allogeneic hematopoietic stem cell transplantation (HSCT) has been considered as the treatment of choice for patients with high-risk chronic lymphocytic leukemia (HR-CLL; ie, refractory to purine analogs, short response [<24 months] to chemoimmunotherapy, and/or presence of del[17p]/TP53 mutations). Currently, treatment algorithms for HR-CLL are being challenged by the introduction of novel classes of drugs. Among them, BCR signal inhibitors (BCRi) and B-cell lymphoma 2 antagonists (BCL2a) appear particularly promising. As a result of the growing body of favorable outcome data reported for BCRi/BCL2a, uncertainty is emerging on how to advise patients with HR-CLL about indication for and timing of HSCT. This article provides an overview of currently available evidence and theoretical considerations to guide this difficult decision process. Until the risks and benefits of different treatment strategies are settled, all patients with HR-CLL should be considered for treatment with BCRi/BCL2a. For patients who respond to these agents, there are 2 treatment possibilities: (1) performingan HSCT or (2) continuing treatment with the novel drug. Individual disease-specific and transplant-related risk factors, along with patient's preferences, should be taken into account when recommending one of these treatments over the other. © 2014 by The American Society of Hematology. Source

Fasolo A.,Istituto Nazionale dei Tumori | Sessa C.,Oncology Institute of Southern Switzerland
Expert Opinion on Investigational Drugs | Year: 2011

Introduction: The mammalian target of the rapamycin (mTOR) signalling pathway has a central role in the regulation of cell growth, survival and angiogenesis and the frequent dysregulation of this pathway in tumor cells makes it a crucial target in the treatment of cancer. Temsirolimus and everolimus are approved for use in metastatic renal cell carcinoma and temsirolimus is also approved for mantle cell lymphoma. All three rapalogs, temsirolimus, everolimus and deforolimus, are currently being evaluated in Phase III studies in several tumors. Areas covered: This paper provides a review of the published literature on the mTOR pathway and related pathway signaling, analogs and novel mTOR inhibitors. The most recent and important data on the mTOR pathway, the role of mTOR inhibitors in cancer treatment and the current status of development of second-generation highly potent and selective mTOR inhibitors are overviewed. Expert opinion: The published data on new mTOR inhibitors are still limited, but the available preclinical results indicate that they have a potent antiproliferative activity against a broad panel of tumor cell lines, have a favorable safety profile, can obtain disease stabilization or even tumor regression and, in some cases, enhance the efficacy of other targeted or standard-of-care anticancer drugs when used in vivo in preclinical studies. © 2011 Informa UK, Ltd. Source

Moskowitz C.H.,Sloan Kettering Cancer Center | Nademanee A.,City of Hope National Medical Center | Masszi T.,Szent Istvan and Szent Laszlo Corporate Hospital Hematology | Agura E.,Baylor University | And 16 more authors.
The Lancet | Year: 2015

Background High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkin's lymphoma. Roughly 50% of patients might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem-cell transplantation. Methods We did this randomised, double-blind, placebo-controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkin's lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1·8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30-45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkin's lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01100502. Findings Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio [HR] 0·57, 95% CI 0·40-0·81; p=0·0013). Median progression-free survival by independent review was 42·9 months (95% CI 30·4-42·9) for patients in the brentuximab vedotin group compared with 24·1 months (11·5-not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 [56%] of 167 patients vs 25 [16%] of 160 patients in the placebo group) and neutropenia (58 [35%] vs 19 [12%] patients). At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group. Interpretation Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin's lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation. Funding Seattle Genetics and Takeda Pharmaceuticals International. © 2015 Elsevier Ltd. Source

Esposito F.,University of Naples Federico II | de Martino M.,University of Naples Federico II | Petti M.G.,University of Naples Federico II | Forzati F.,University of Naples Federico II | And 5 more authors.
Oncotarget | Year: 2014

The High Mobility Group A (HMGA) are nuclear proteins that participate in the organization of nucleoprotein complexes involved in chromatin structure, replication and gene transcription. HMGA overexpression is a feature of human cancer and plays a causal role in cell transformation. Since non-coding RNAs and pseudogenes are now recognized to be important in physiology and disease, we investigated HMGA1 pseudogenes in cancer settings using bioinformatics analysis. Here we report the identification and characterization of two HMGA1 non-coding pseudogenes, HMGA1P6 and HMGA1P7. We show that their overexpression increases the levels of HMGA1 and other cancer-related proteins by inhibiting the suppression of their synthesis mediated by microRNAs. Consistently, embryonic fibroblasts from HMGA1P7-overexpressing transgenic mice displayed a higher growth rate and reduced susceptibility to senescence. Moreover, HMGA1P6 and HMGA1P7 were overexpressed in human anaplastic thyroid carcinomas, which are highly aggressive, but not in differentiated papillary carcinomas, which are less aggressive. Lastly, the expression of the HMGA1 pseudogenes was significantly correlated with HMGA1 protein levels thereby implicating HMGA1P overexpression in cancer progression. In conclusion, HMGA1P6 and HMGA1P7 are potential proto-oncogenic competitive endogenous RNAs. Source

Wong R.K.S.,University of Toronto | Bensadoun R.-J.,University of Poitiers | Boers-Doets C.B.,Leiden University | Bryce J.,Istituto Nazionale dei Tumori | And 3 more authors.
Supportive Care in Cancer | Year: 2013

Radiation dermatitis (RD) results from radiotherapy and often occurs within the first 4 weeks of treatment, although late effects also occur. While RD may resolve over time, it can have a profound effect on patients' quality of life and lead to dose modifications. A study group of international, interdisciplinary experts convened to develop RD prevention and treatment guidelines based on evidence from randomized, controlled trials. Evidence-based recommendations were developed after an extensive literature review. Randomized, controlled trials with standardized measurement of outcomes were considered the best evidence, and a majority of the recommendations were formulated from this literature. The adoption of washing with water, with or without a mild soap, and allowing the use of antiperspirants is supported by randomized trials. Use of topical prophylactic corticosteroids (mometasone) is recommended to reduce discomfort and itching. There is some evidence that silver sulfadiazine cream can reduce dermatitis score. There is insufficient evidence to support, and therefore the panel recommends against the use of trolamine, topical sulcrate, hyaluronic acid, ascorbic acid, silver leaf dressing, light-emitting diode lasers, Theta cream, dexpanthenol, calendula, proteolytic enzymes, sulcralfate, oral zinc, and pentoxifylline. Moreover, there is no evidence to support the superiority for any specific intervention in a reactive fashion. For patients with established radiation-induced telangiectasia and fibrosis, the panel suggests the use of pulse dye laser for visual appearance, and the use of pentoxifylline and vitamin E for the reduction of fibrosis. © 2013 Springer-Verlag Berlin Heidelberg. Source

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