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Mara Gavazzoni, Enrico Vizzardi, Elio Gorga, Ivano Bonadei, Laura Rossi, Angelo Belotti, Giuseppe Rossi, Rossella Ribolla, Marco Metra, Riccardo Raddino
Proteasome Inhibitors (PI) have now become the cornerstone of treatment of multiple myeloma (MM). Carfilzomib has been demonstrated to cause more frequent cardiovascular side effects such as dyspnea, hypertension, and heart failure. Recent pre-clinical studies have investigated the effects of proteasome on myocardial and vascular cells, but the pathogenic mechanism underlying the effects of proteasome inhibition on these cells is poorly understood. We reviewed the evidence from clinical trials, post-hoc analysis and small observational studies currently available and summarized the data from experimental, focusing on the pathogenic mechanisms potentially implicated in the cardiovascular toxicity of proteasome inhibitor, particularly of carfilzomib that is most responsible for cardiovascular side effects...
March 15, 2018: European Journal of Pharmacology
Michael McGee, Nicholas Whitehead, Jennifer Martin, Nicholas Collins
INTRODUCTION: While pulmonary arterial hypertension remains an uncommon diagnosis, various therapeutic agents are recognized as important associations. These agents are typically categorized into "definite", "likely", "possible", or "unlikely" to cause pulmonary arterial hypertension, based on the strength of evidence. OBJECTIVE: This review will focus on those therapeutic agents where there is sufficient literature to adequately comment on the role of the agent in the pathogenesis of pulmonary arterial hypertension...
March 6, 2018: Clinical Toxicology
Dae Hyun Lee, Michael G Fradley
PURPOSE OF REVIEW: Multiple myeloma treatment regimens consist of proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), and steroids. In this paper, we will review the pathophysiology and associated cardiotoxicities of the different multiple myeloma therapeutic modalities and present methods to mitigate the development of cardiovascular complications. RECENT FINDINGS: Although proteasome inhibitors and immunomodulatory drugs have led to significant improvements in oncologic outcomes, there is increasing evidence of serious cardiovascular side effects which may be exacerbated in the setting of underlying cardiovascular risk factors or disease...
March 6, 2018: Current Treatment Options in Cardiovascular Medicine
Mohammad Ali, Edward S Mocarski
Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor of apoptosis (cIAP)1 and cIAP2 in TNF-mediated cell death. Here, we sought to evaluate the contribution of necroptosis to the cell death pattern induced by the specific proteasome inhibitor Carfilzomib (Cf). Proteasome inhibitor-sensitive multiple myeloma cell lines die in response to Cf by apoptosis in combination with serine protease-dependent death, without any contribution of RIPK3-dependent necroptosis...
March 1, 2018: Cell Death & Disease
Nicholas Forsythe, Alaa Refaat, Arman Javadi, Hajrah Khawaja, Jessica-Anne Weir, Heba Emam, Wendy L Allen, Frank Burkamp, Vlad Popovici, Puthen V Jithesh, Claudio Isella, Melissa J LaBonte, Ian G Mills, Patrick G Johnston, Sandra Van Schaeybroeck
BRAFV600E mutations occur in 10% of colorectal cancer (CRC) cases, are associated with poor survival and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT CRC. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n=31; validation set: n=26) CRC and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome...
February 26, 2018: Molecular Cancer Therapeutics
Ayşe Uysal, Nur Akad Soyer, Melda Özkan, Fahri Şahin, Filiz Vural, Mahmut Töbü, Murat Tombuloğlu, Güray Saydam
Background/aim: Carfilzomib (CFZ) is a new-generation proteasome inhibitor with significant activity in relapsed or refractory multiple myeloma (R/R-MM). We have retrospectively evaluated R/R-MM patients who were treated with CFZ plus dexamethasone. Materials and methods: Twenty-one R/R-MM patients who were treated with CFZ plus dexamethasone between October 2013 and January 2016 were screened. The patients were followed until March 2016 after CFZ treatment. Results: Ten (47.6%) of the patients were female and 11 (52...
February 23, 2018: Turkish Journal of Medical Sciences
Sara Bringhen, Roberto Mina, Anna Maria Cafro, Anna Marina Liberati, Stefano Spada, Angelo Belotti, Gianluca Gaidano, Francesca Patriarca, Rossella Troia, Renato Fanin, Lorenzo De Paoli, Giuseppe Rossi, Alessandra Lombardo, Paola Bertazzoni, Antonio Palumbo, Pieter Sonneveld, Mario Boccadoro
No abstract text is available yet for this article.
January 30, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Emilia Scalzulli, Sara Grammatico, Federico Vozella, Maria Teresa Petrucci
Multiple Myeloma (MM) management is rapidly evolving, with a spectrum of novel treatments that have changed our approach to the therapy. Proteasome inhibitors (PIs) have revolutionized the scenario of both relapsed/refractory and newly diagnosed patients. The efficacy of bortezomib, the first PI approved, followed by carfilzomib and, the oral ixazomib, have been tested in several trials as single agents or in combination. Areas covered: In this review, the authors summarize mechanism of action, efficacy and safety of proteasome inhibitors in MM and focus on data derived from clinical trials, analyzing adverse events and their relative management...
February 26, 2018: Expert Opinion on Pharmacotherapy
Rosana H C N Freitas, Carlos A M Fraga
BACKGROUND: Nuclear factor κB (NF-κB) comprises a family of proteins that act as transcription factors promoting the expression of many genes. Activation of NF-κB biochemical cascades is associated with the regulation of innate and adaptive immune responses and inflammation, among other physiological responses. However, genetic abnormalities and continuous stimulation of the NF-κB-IKKβ pathway are directly related to many types of inflammatory and autoimmune diseases, as well as to the genesis and survival of tumor cells...
February 19, 2018: Current Drug Targets
Chintan Shah, Rohit Bishnoi, Ankur Jain, Harini Bejjanki, Sican Xiong, Yu Wang, Fei Zou, Jan S Moreb
Carfilzomib is a second-generation proteasome inhibitor (PI) that is approved for patients with relapsed or refractory multiple myeloma (RRMM) who failed ≥1 prior lines of therapy. We performed a systematic review of carfilzomib literature with meta-analysis to determine cumulative incidence of cardiotoxicity. After the literature search, we included a total of 29 eligible phase I/II, phase II and phase III clinical trials which used carfilzomib. The cumulative incidence and overall odds ratios (OR) were calculated with random effect model, using 'R' software with metaphor package...
February 21, 2018: Leukemia & Lymphoma
Meletios Athanasios Dimopoulos, Jonathan L Kaufman, Darrell White, Gordon Cook, Maria Rizzo, Yingxin Xu, Kyle Fahrbach, Maren Gaudig, Mary Slavcev, Lindsay Dearden, Annette Lam
BACKGROUND: Previous network meta-analyses combined studies of immunomodulatory drug (IMiD)-containing and IMiD-free regimens, despite a lack of head-to-head randomized controlled trials to robustly link them. However, patients with relapsed or refractory multiple myeloma (RRMM) treated with IMiD-containing regimens differ from those treated with IMiD-free regimens, especially relating to treatment history, which is an important treatment-effect modifier requiring clinical consideration when evaluating the most appropriate subsequent treatment options...
January 5, 2018: Clinical Lymphoma, Myeloma & Leukemia
Phui-Ly Liew, Rui-Lan Huang, Yu-Chun Weng, Chia-Lang Fang, Tim Hui-Ming Huang, Hung-Cheng Lai
Mucinous type of epithelial ovarian cancer (MuOC) is a unique subtype with a poor survival outcome in recurrent and advanced stages. The role of type-specific epigenomics and its clinical significance remain uncertain. We analyzed the methylomic profiles of six benign mucinous adenomas, 24 MuOCs, 103 serous type of epithelial ovarian cancers (SeOCs), and 337 nonepithelial ovarian cancers. MuOC and SeOC exhibited distinct DNA methylation profiles comprising 101 genes, 81 of which exhibited low methylation in MuOC and were associated with the response to glucocorticoid, ATP hydrolysis-coupled proton transport, proteolysis involved in the cellular protein catabolic process, and ion transmembrane transport...
February 16, 2018: International Journal of Cancer. Journal International du Cancer
Maria-Victoria Mateos, Hartmut Goldschmidt, Jesus San-Miguel, Joseph Mikhael, Lucy DeCosta, Lifen Zhou, Mihaela Obreja, Julie Blaedel, Zsolt Szabo, Xavier Leleu
We performed analyses of the randomized phase 3 ASPIRE and ENDEAVOR trials to investigate the efficacy of carfilzomib among subgroups of relapsed or refractory multiple myeloma patients who had early or late disease relapse following initiation of the immediately prior therapy. In ASPIRE and ENDEAVOR, patients had received 1 to 3 prior lines of therapy. Patients in ASPIRE received carfilzomib, lenalidomide, and dexamethasone (KRd) or lenalidomide and dexamethasone (Rd), and patients in ENDEAVOR received carfilzomib and dexamethasone (Kd) or bortezomib and dexamethasone (Vd)...
February 15, 2018: Hematological Oncology
Luciano J Costa, Heather J Landau, Saurabh Chhabra, Parameswaran Hari, Racquel Innis-Shelton, Kelly N Godby, Mehdi Hamadani, Roni Tamari, Kate Anderton, Pamela Dixon, Sergio A Giralt
We performed a phase 1/2 trial to investigate the safety and activity of the second generation proteasome inhibitor Carfilzomib (K) on days -3/-2 in combination with melphalan 200 mg/m2 (MEL200) on day -2 (K-MEL) in patients with relapsed multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (phases 1 and 2). Patients without progression received 12 cycles of K maintenance at 36 mg/m2 days 1,8,15 (schedule A) or days 1,2,15,16 (schedule B), with patients being treated for 2 cycles in each schedule and on the patient-preferred schedule for the remaining cycles (phase 2)...
February 1, 2018: Biology of Blood and Marrow Transplantation
Hongjin Wu, Sean Chen, Charles Wang, Juehua Yu, Ying Li, Xiao-Yan Zhang, Ling Yang, Hongfang Zhang, Qiang Hou, Mingfeng Jiang, F Charles Brunicardi, Shixiu Wu
Paclitaxel is widely used in the combination chemotherapy for many cancers including esophageal squamous cell carcinoma (ESCC). However, the paclitaxel resistance occurs frequently in treating ESCC and the mechanism is not fully understood yet. The heterogeneity of gene expression within the drug-resistant cancer cells may be one of the major factors contributing to its resistance. In the present study, we successfully induced paclitaxel resistance in ESCC cell line KYSE-30 through low dose and long-term treatment of paclitaxel...
January 30, 2018: Cancer Letters
Akihiko Mitsutake, Hideyuki Matsumoto, Keiko Hatano, Koreaki Irie, Nobuhiro Tsukada, Hideji Hashida
We describe the case of a 34-year-old woman with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. She developed transient ischemic attack after the introduction of lenalidomide plus dexamethasone (Rd) therapy despite no vascular risk factors. Magnetic resonance and computed tomography angiographies showed bilateral internal carotid artery stenosis. Rd therapy was suspended because of its thromboembolic risk. She had been neurologically stable during the suspension of Rd therapy...
January 29, 2018: Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association
Dan T Vogl, David Dingli, Robert Frank Cornell, Carol Ann Huff, Sundar Jagannath, Divaya Bhutani, Jeffrey Zonder, Rachid Baz, Ajay Nooka, Joshua Richter, Craig Cole, Ravi Vij, Andrzej Jakubowiak, Rafat Abonour, Gary Schiller, Terri L Parker, Luciano J Costa, David Kaminetzky, James E Hoffman, Andrew J Yee, Ajai Chari, David Siegel, Rafael Fonseca, Scott Van Wier, Gregory Ahmann, Ilsel Lopez, Michael Kauffman, Sharon Shacham, Jean-Richard Saint-Martin, Carla D Picklesimer, Cassandra Choe-Juliak, A Keith Stewart
Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease)...
January 30, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Hak-Min Lee, Eunmyong Lee, So-Young Yeo, Sang Shin, Hyun-Kyu Park, Do-Hyun Nam, Seok-Hyung Kim
Cancer associated fibroblasts (CAFs) are the most abundant components of cancer-microenvironment. They play important roles in cancer initiation, progression, and metastasis. In addition, CAFs can confer drug-resistance to cancer cells. Considering their pro-tumorigenic roles, it is recommended to remove CAFs to prevent cancer recurrence after chemotherapy. Despite their clinical significance, few anti-CAF drugs have been developed. The objective of this study was to find a drug that could suppress the viability of patient-derived CAFs through repurposed screening of 51 drugs that were in clinical trials or received FDA approval...
January 18, 2018: Investigational New Drugs
David S Siegel, Meletios A Dimopoulos, Heinz Ludwig, Thierry Facon, Hartmut Goldschmidt, Andrzej Jakubowiak, Jesus San-Miguel, Mihaela Obreja, Julie Blaedel, A Keith Stewart
Purpose In the ASPIRE study of carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide plus dexamethasone (Rd) in patients with relapsed or refractory multiple myeloma, progression-free survival was significantly improved in the carfilzomib group (hazard ratio, 0.69; two-sided P < .001). This prespecified analysis reports final overall survival (OS) data and updated safety results. Patients and Methods Adults with relapsed multiple myeloma (one to three prior lines of therapy) were eligible and randomly assigned at a one-to-one ratio to receive KRd or Rd in 28-day cycles until withdrawal of consent, disease progression, or occurrence of unacceptable toxicity...
January 17, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Shiro Fujii, Shingen Nakamura, Asuka Oda, Hirokazu Miki, Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Ariunzaya Bat-Erdene, Yusaku Maeda, Masahiro Oura, Mamiko Takahashi, Masami Iwasa, Itsuro Endo, Sumiko Yoshida, Ken-Ichi Aihara, Kiyoe Kurahashi, Takeshi Harada, Kumiko Kagawa, Michiyasu Nakao, Shigeki Sano, Masahiro Abe
Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447...
January 2018: British Journal of Haematology
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