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Abstract: Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. Although genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations, and copy-neutral loss of heterozygosity were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91%, 43%, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and loss of heterozygosity at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow (BM) blast percentage across groups ranged from 1.5% to 10%, and the median overall survival ranged from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of BM blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and might inform future classification schemas and translational therapeutic research., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Mutations in UBA1, which are disease-defining for VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet polymerase chain reaction profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established World Health Organization (WHO) disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n = 2027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n = 12) and of unknown significance (n = 15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO 2016 criteria as MDS with multilineage dysplasia or MDS with single-lineage dysplasia. Patients had a median of 1 additional myeloid gene mutation, often in TET2 (n = 12), DNMT3A (n = 10), ASXL1 (n = 3), or SF3B1 (n = 3). Retrospective clinical review, where possible, showed that 82% (28/34) UBA1-mutant cases had VEXAS syndrome-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1 mutations in patients with MDS argues for systematic screening for UBA1 in the management of MDS., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: Chronic myelomonocytic leukemia (CMML) is a heterogeneous disease presenting with either myeloproliferative or myelodysplastic features. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative option, but the inherent toxicity of this procedure makes the decision to proceed to allo-HCT challenging, particularly because patients with CMML are mostly older and comorbid. Therefore, the decision between a nonintensive treatment approach and allo-HCT represents a delicate balance, especially because prospective randomized studies are lacking and retrospective data in the literature are conflicting. International consensus on the selection of patients and the ideal timing of allo-HCT, specifically in CMML, could not be reached in international recommendations published 6 years ago. Since then, new, CMML-specific data have been published. The European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee assembled a panel of experts in the field to provide the first best practice recommendations on the role of allo-HCT specifically in CMML. Recommendations were based on the results of an international survey, a comprehensive review of the literature, and expert opinions on the subject, after structured discussion and circulation of recommendations. Algorithms for patient selection, timing of allo-HCT during the course of the disease, pretransplant strategies, allo-HCT modality, as well as posttransplant management for patients with CMML were outlined. The keynote message is, that once a patient has been identified as a transplant candidate, upfront transplantation without prior disease-modifying treatment is preferred to maximize chances of reaching allo-HCT whenever possible, irrespective of bone marrow blast counts., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

In the pursuit of novel antioxidant therapies for the prevention and treatment of neurodegenerative diseases, three new arylpiperazine derivatives (LQFM181, LQFM276, and LQFM277) were synthesized through a molecular hybridization approach involving piribedil and butylated hydroxytoluene lead compounds. To evaluate the antioxidant and neuroprotective activities of the arylpiperazine derivatives, we employed an integrated approach using both in vitro (SH-SY5Y cells) and in vivo (neurotoxicity induced by 3-nitropropionic acid in Swiss mice) models. In the in vitro tests, LQFM181 showed the most promising antioxidant activity at the neuronal membrane and cytoplasmic levels, and significant neuroprotective activity against the neurotoxicity induced by 3-nitropropionic acid. Hence, this compound was further subjected to in vivo evaluation, which demonstrated remarkable antioxidant capacity such as reduction of MDA and carbonyl protein levels, increased activities of succinate dehydrogenase, catalase, and superoxide dismutase. Interestingly, using the same in vivo model, LQFM181 also reduced locomotor behavior and memory dysfunction through its ability to decrease cholinesterase activity. Consequently, LQFM181 emerges as a promising candidate for further investigation into its neuroprotective potential, positioning it as a new therapeutic agent for neuroprotection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The guidelines for classification, prognostication, and response assessment of myelodysplastic syndromes/neoplasms (MDS) have all recently been updated. In this report on behalf of the International Consortium for MDS (icMDS) we summarize these developments. We first critically examine the updated World Health Organization (WHO) classification and the International Consensus Classification (ICC) of MDS. We then compare traditional and molecularly based risk MDS risk assessment tools. Lastly, we discuss limitations of criteria in measuring therapeutic benefit and highlight how the International Working Group (IWG) 2018 and 2023 response criteria addressed these deficiencies and are endorsed by the icMDS. We also address the importance of patient centered care by discussing the value of quality-of-life assessment. We hope that the reader of this review will have a better understanding of how to classify MDS, predict clinical outcomes and evaluate therapeutic outcomes., Competing Interests: Declaration of Competing Interest Maximilian Stahl consulted for Curis Oncology and Boston Consulting; served on the advisory board for Novartis and Kymera, GSK, Rigel, Sierra Oncology; and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options (CCO). Elizabeth A. Griffiths has received honoraria for advisory board membership from AbbVie, Alexion Pharmaceuticals, Apellis, Celgene/BMS, CTI Biopharma, Genentech, Novartis, Picnic Health, Takeda Oncology, Taiho Oncology. EAG has received research funding from Astex Pharmaceuticals, AstraZeneca Rare Disease, Alexion Pharmaceuticals, Apellis Pharmaceuticals, Blueprint Medicines, Genentech Inc., and honoraria for CME activities from Physicians Educational Resource, MediComWorldwide, American Society of Hematology, AAMDS International Foundation. Ravindra Majeti is on the Advisory Boards of Kodikaz Therapeutic Solutions, Syros Pharmaceuticals, TenSixteen Bio, Roche, and Cullgen Inc. and is an inventor on several patents related to CD47 cancer immunotherapy licensed to Gilead Sciences. R.M. receives research support from Gilead Sciences. Ravindra Majeti. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics. Stephanie Halene consulted for Forma Therapeutics. Daniel T. Starczynowski is a consultant and received research funding from Kymera Therapeutics, Kurome Therapeutics, Captor Therapeutics, and Tolero Therapeutics. Daniel T. Starczynowski has equity in Kurome Therapeutics. Gail Roboz: Consultancy: Abbvie, Amgen, Argenx, Astra Zeneca, Bluebird Bio, Blueprint Medicines, Bristol-Myers Squibb, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses Pharma, GlaxoSmithKline, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Novartis, Pfizer, Rigel, Roche, Syndax, Takeda (IRC Chair), Telix Pharma Research support: Janssen. David A. Sallman served on the advisory board of Aprea, AvenCell, BlueBird Bio, BMS, Intellia, Kite, Novartis, Shattuck Labs, Servier, Syndax. David A. Sallman served as a consultant for AbbVie, Magenta, Molecular Partners AG, Takeda and on the speakers' bureau for BMS, Incyte, Servier; David A. Sallman received research funding from Aprea, Jazz. Mrinal Patnaik received research funding from Kura Oncology and StemLine Pharmaceuticals. Andrew Brunner received consulting or advisory board honoraria from Novartis, Acceleron, Agios, Abbvie, Takeda, Celgene/BMS, Keros Therapeutics, Taiho, Gilead. Andrew Brunner has research support from the NIH SPORE in Myeloid Malignancies, and from the Edward P. Evans Foundation. Tae Kon Kim received research funding from Nextcure and is a consultant for Agenus. Alan List is employed by and has equity in Precision BioSciences, and has served as a consultant for Halia Therapeutics, CTI Biopharma, Aileron. Naval Daver has received research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. Guillermo Sanz received honoraria, advisory board membership or consultation fees from AbbVie, BMS, ExCellThera, Novartis, Roche, and Takeda and participated in sponsored speaker's bureau for BMS, Novartis, and Takeda. Mikkael A. Sekeres has served on advisory boards for BMS, Novartis, Kurome, and Gilead. Pierre Fenaux received research funding from BMS, Abbvie, Jazz Pharmaceuticals, Novartis, and Janssen. Pierre Fenaux had a consultancy with and received honoraria from BMS, Abbvie, Jazz Pharmaceuticals, and Novartis. Fabio Efficace had a consultancy or advisory role for AbbVie, Incyte, Janssen, and Syros, outside the submitted work. Omar Abdel-Wahab has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder; Omar Abdel-Wahab has received prior research funding from H3B Biomedicine and LOXO Oncology unrelated to the current manuscript. Andrew H.Wei has served on advisory boards for Novartis, Astra Zeneca, Astellas, Janssen, Jazz, Amgen, Roche, Pfizer, Abbvie, Servier, Gilead, BMS, Shoreline, Macrogenics, Novartis and Agios; receives research funding to the Institution from Novartis, Abbvie, Servier, Janssen, BMS, Syndax, Astex, Astra Zeneca, Amgen; serves on speaker's bureaus for Abbvie, Novartis, BMS, Servier, Astellas; Andrew H.Wei is an employee of the Walter and Eliza Hall Institute (WEHI). WEHI receives milestone and royalty payments related to the development of Venetoclax. Current and past employees of Walter and Eliza Hall Institute may be eligible for financial benefits related to these payments. Andrew H. Wei receives such a financial benefit. Amer M. Zeidan received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron and Celgene/BMS. The National Heart, Lung, and Blood Institute receives research funding for the laboratory of Dr. Hourigan from Sellas and from the Foundation of the NIH AML MRD Biomarkers Consortium. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Biological events that contribute to the pathogenesis of myelodysplastic syndromes/neoplasms (MDS) are becoming increasingly characterized and are being translated into rationally designed therapeutic strategies. Herein, we provide updates from the first International Workshop on MDS (iwMDS) of the International Consortium for MDS (icMDS) detailing recent advances in understanding the genetic landscape of MDS, including germline predisposition, epigenetic and immune dysregulation, the complexities of clonal hematopoiesis progression to MDS, as well as novel animal models of the disease. Connected to this progress is the development of novel therapies targeting specific molecular alterations, the innate immune system, and immune checkpoint inhibitors. While some of these agents have entered clinical trials (e.g., splicing modulators, IRAK1/4 inhibitors, anti-CD47 and anti-TIM3 antibodies, and cellular therapies), none have been approved for MDS. Additional preclinical and clinical work is needed to develop a truly individualized approach to the care of MDS patients., Competing Interests: Declaration of Competing Interest Maximilian Stahl consulted for Curis Oncology and Boston Consulting; served on the advisory board for Novartis and Kymera; and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options (CCO). Elizabeth A. Griffiths has received honoraria for advisory board membership from AbbVie, Alexion Pharmaceuticals, Apellis, Celgene/BMS, CTI Biopharma, Genentech, Novartis, Picnic Health, Takeda Oncology, Taiho Oncology. EAG has received research funding from Astex Pharmaceuticals, AstraZeneca Rare Disease, Alexion Pharmaceuticals, Apellis Pharmaceuticals, Blueprint Medicines, Genentech Inc., and honoraria for CME activities from Physicians Educational Resource, MediComWorldwide, American Society of Hematology, AAMDS International Foundation. Ravindra Majeti is on the Advisory Boards of Kodikaz Therapeutic Solutions, Syros Pharmaceuticals, TenSixteen Bio, Roche, and Cullgen Inc. and is an inventor on a number of patents related to CD47 cancer immunotherapy licensed to Gilead Sciences. R.M. receives research support from Gilead Sciences. Ravindra Majeti. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics. Stephanie Halene consulted for Forma Therapeutics. Daniel T. Starczynowski is a consultant and received research funding from Kymera Therapeutics, Kurome Therapeutics, Captor Therapeutics, and Tolero Therapeutics. Daniel T. Starczynowski has equity in Kurome Therapeutics. David A. Sallman served on the advisory board of Aprea, AvenCell, BlueBird Bio, BMS, Intellia, Kite, Novartis, Shattuck Labs, Servier, Syndax. David A. Sallman served as a consultant for AbbVie, Magenta, Molecular Partners AG, Takeda and on the speakers' bureau for BMS, Incyte, Servier; David A. Sallman received research funding from Aprea, Jazz. Mrinal Patnaik received research funding from Kura Oncology and StemLine Pharmaceuticals. Andrew Brunner received consulting or advisory board honoraria from Novartis, Acceleron, Agios, Abbvie, Takeda, Celgene/BMS, Keros Therapeutics, Taiho, Gilead. Andrew Brunner has research support from the NIH SPORE in Myeloid Malignancies, and from the Edward P. Evans Foundation. Tae Kon Kim received research funding from Nextcure and is a consultant for Agenus. Alan List is employed by and has equity in Precision BioSciences, and has served as a consultant for Halia Therapeutics, CTI Biopharma, Aileron. Naval Daver has received research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. Guillermo Sanz received honoraria, advisory board membership or consultation fees from AbbVie, BMS, ExCellThera, Novartis, Roche, and Takeda and participated in sponsored speaker's bureau for BMS, Novartis, and Takeda. Mikkael A. Sekeres has served on advisory boards for BMS, Novartis, Kurome, and Gilead. Pierre Fenaux received research funding from BMS, Abbvie, Jazz Pharmaceuticals, Novartis, and Janssen. Pierre Fenaux had a consultancy with and received honoraria from BMS, Abbvie, Jazz Pharmaceuticals, and Novartis. Omar Abdel-Wahab has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder; Omar Abdel-Wahab has received prior research funding from H3B Biomedicine and LOXO Oncology unrelated to the current manuscript. Andrew H.Wei has served on advisory boards for Novartis, Astra Zeneca, Astellas, Janssen, Jazz, Amgen, Roche, Pfizer, Abbvie, Servier, Gilead, BMS, Shoreline, Macrogenics, Novartis and Agios; receives research funding to the Institution from Novartis, Abbvie, Servier, Janssen, BMS, Syndax, Astex, Astra Zeneca, Amgen; serves on speaker's bureaus for Abbvie, Novartis, BMS, Servier, Astellas; Andrew H.Wei is an employee of the Walter and Eliza Hall Institute (WEHI). WEHI receives milestone and royalty payments related to the development of Venetoclax. Current and past employees of Walter and Eliza Hall Institute may be eligible for financial benefits related to these payments. Andrew H.Wei receives such a financial benefit. Valeria Santini served in advisory boards from Abbvie, BMS, Geron, Gilead,Menarini, Novartis, Servier, Syros, ad received research support from BMS. Amer M. Zeidan received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron and Celgene/BMS. The National Heart, Lung, and Blood Institute receives research funding for the laboratory of Dr. Hourigan from Sellas and from the Foundation of the NIH AML MRD Biomarkers Consortium. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria lead to variability in interpretation and interobserver inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in HR-MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery and CR with partial hematologic recovery as provisional response criteria, the elimination of marrow CR, and specific recommendations for the standardization of time-to-event end points and the derivation and reporting of responses. The updated criteria should lead to a better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action., (© 2023 by The American Society of Hematology.)

Objectives: The Innovative Medicines Initiative-funded, multistakeholders project Healthcare Alliance for Resourceful Medicine Offensive Against Neoplasms in Hematology (HARMONY) created a task force involving patient organizations, medical associations, pharmaceutical companies, and health technology assessment/regulator agencies' representatives to evaluate the suitability of previously established value frameworks (VFs) for assessing the clinical and societal impact of new interventions for hematologic malignancies (HMs)., Methods: Since the HARMONY stakeholders identified the inclusion of patients' points of view on evaluating VFs as a priority, surveys were conducted with the patient organizations active in HMs and part of the HARMONY network, together with key opinion leaders, pharmaceutical companies, and regulators, to establish which outcomes were important for each HM. Next, to evaluate VFs against the sources of information taken into account (randomized clinical trials, registries, real-world data), structured questionnaires were created and filled by HARMONY health professionals to specify preferred data sources per malignancy. Finally, a framework evaluation module was built to analyze existing clinical VFs (American Society of Clinical Oncology, European Society of Medical Oncology, Magnitude of Clinical Benefit Scale, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, Institute for Clinical and Economic Review, National Comprehensive Cancer Network Evidence Blocks, and patient-perspective VF)., Results: The comparative analysis describes challenges and opportunities for the use of each framework in the context of HMs and drafts possible lines of action for creating or integrating a more specific, patient-focused clinical VF for HMs., Conclusions: None of the frameworks meets the HARMONY goals for a tool that applies to HMs and assesses in a transparent, reproducible, and systematic way the therapeutic value of innovative health technologies versus available alternatives, taking a patient-centered approach and using real-world evidence., (Copyright © 2022. Published by Elsevier Inc.)

Background: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group., Methods: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance., Results and Conclusion: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic., Competing Interests: DIsclosure CB reports honoraria from Roche/Genentech, Janssen, BeiGene, Novartis, Pfizer, Incyte, AbbVie, Gilead Sciences, Celltrion, MorphoSys, Regeneron; he reports consulting or advisory role: Gilead Sciences, Janssen, Roche, Pfizer, BeiGene, Celltrion, AbbVie, Incyte, Regeneron, MorphoSys, Novartis; he reports speaker’s engagement: Roche, Janssen, BeiGene, Celltrion, AbbVie, Pfizer, Gilead Sciences; he reports research funding: Roche/Genentech, Janssen, Celltrion, Merck Sharp & Dohme (MSD), Pfizer, Amgen. MD reports honoraria as Advisory Board Member of AstraZeneca, Bayer, BeiGene, Celgene, Genmab, Gilead, Incyte, Janssen, Lilly, MorphoSys, Novartis, Roche; he reports honoraria for speaker’s engagement from Amgen, AstraZeneca, Bayer, Celgene, Gilead, Janssen, Novartis, Roche; he reports institutional research grants from AbbVie, Bayer, Gilead, Celgene, Janssen, Roche. AA-L has declared no conflicts of interest. JA reports personal financial interests as advisory board and invited speaker from Incyte, advisory board from Mallinckrodt, advisory board and invited speaker from Novartis, advisory board and invited speaker from Pfizer; she reports non-financial interests as principal investigator from Incyte, principal investigator from Novartis. LA received advisory honoraria from Roche, Celgene, Janssen-Cilag, Verastem, Eusa Pharma, Incyte, ADC Therapeutics and Gilead; research support from Gilead, and travel expenses from Roche, Celgene, Janssen-Cilag, and Eusa Pharma; speakers bureau from Novartis. CB has declared no conflicts of interest. LB reports Advisory Committee activities for AbbVie, Amgen, Astellas, Bristol Myers Squibb (BMS), Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Sanofi, Seattle Genetics and has research support from Bayer and Jazz Pharmaceuticals. PC has declared no conflicts of interest. MGDP has declared no conflicts of interest. MD reports personal fees from Amgen, personal fees from Takeda, personal fees from Janssen, personal fees from BeiGene, personal fees from BMS, outside the submitted work. SD reports personal financial interests as advisory board, invited speaker, fellow funding, and coordinating PI from BeiGene, writing engagement from Karger, advisory board and coordinating PI from Sanofi, funding, and other from Janssen; she reports non-financial interests as advisory role at British Society for Haematology Lymphoma Special Interest Group, advisory role at Lymphoma Action, member of board of directors at WMUK Charity. HTE has declared no conflicts of interest. RF reports honoraria for advisory boards and/or speaker bureau from Janssen, Gilead, AbbVie, Amgen, Novartis, Roche, Incyte, Pfizer, all outside the submitted work. PG reports grants and personal fees from AbbVie, grants and personal fees from Acerta/AstraZeneca, personal fees from BeiGene, personal fees from Celgene/Juno/BMS, grants and personal fees from Janssen, personal fees from Lilly/Loxo, personal fees from MEI, personal fees from Roche, personal fees from Sanofi, personal fees from ArQule/MSD, outside the submitted work; MGdS reports grants, personal fees, non-financial support and other from Gilead Sciences, grants from AstraZeneca, personal fees, non-financial support, and other from Janssen Cilag, personal fees and non-financial support from Roche, non-financial support from AbbVie, personal fees and non-financial support from BMS, personal fees and non-financial support from MSD, personal fees and non-financial support from Takeda, personal fees from Novartis, personal fees from ADC Therapeutics, outside the submitted work. JG reports personal fees from AbbVie, grants and personal fees from AstraZeneca, grants and personal fees from BMS/Celgene, grants and personal fees from Janssen, personal fees from Kite/Gilead, personal fees from MorphoSys, personal fees from Novartis, personal fees from TG Therapeutics, outside the submitted work. RH has had a consultant or advisory relationship with Janssen, Amgen, Celgene, AbbVie, BMS, Novartis, PharmaMar, and Takeda; has received honoraria from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda; has received research funding from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda. CH reports grants and personal fees from Novartis, grants and personal fees from BMS, personal fees from Sierra Oncology, personal fees from CTI pharmaceuticals, personal fees from Jannsen, personal fees from Geron, grants and personal fees from AOP Orphan Pharma, personal fees from Galecto, grants, personal fees and other from Constellation, outside the submitted work. MH reports personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from AbbVie, personal fees from Daiichi Sankyo, personal fees from Bayer Pharma AG, personal fees from Jazz Pharmaceuticals, personal fees from BMS, personal fees from Tolremo, outside the submitted work. BK has received honoraria for lectures from Ipsen, Novartis and MSD (all outside of the submitted work). J-JK reports consulting fees and honoraria from Novartis, consulting fees from AbbVie, honoraria from AOP Orphan Pharma, participation on a monitoring board or advisory board from BMS/Celgene, participation on a monitoring board or advisory board from Incyte. NK reports grants and honoraria from Neovii, honoraria from Sanofi, grants and honoraria from Jazz, grants and honoraria from Celgene, grants and honoraria from Riemser, honoraria from Gilead/Kite, honorarium from AOP Oprhan Pharma, grants and honorarium from Novartis, honorarium from Amgen. PM reports personal fees from Celgene, Amgen, Janssen, AbbVie, Sanofi, outside the submitted work. JP has declared no conflicts of interest. FP has declared no conflicts of interest. DR received honoraria from Incyte, Novartis Pharma, Pfizer; clinical trial steering committee membership: Novartis; membership on advisory boards: Incyte, Novartis Pharma, Pfizer. J-MR reports grants and honoraria from Novartis, Amgen, Pfizer, Takeda, Incyte, and Servier. TR has declared no conflicts of interest. JF-M reports consulting and advisory boards honoraria (received by CUN ) from AbbVie, Amgen, BMS, Celgene, Janssen, GlaxoSmithKline, Karyopharm, MSD, Novartis, Takeda, Sanofi, SecuraBio, Regeneron, Roche, outside the submitted work. VS has declared no conflicts of interest. GFS reports personal fees and other from AbbVie, other from Amgen, other from Astellas, other from Boehringer-Ingelheim, grants, personal fees and other from Celgene, other from Helsinn Healthcare, grants, personal fees, and other from Janssen-Cilag, grants and other from Novartis, other from Onconova, grants, personal fees and other from Roche, and other from Takeda, outside the submitted work. PS reports honoraria from Amgen, Celgene, Janssen, Karyopharm, SkylineDx, Takeda, and research support from Celgene, Janssen, Amgen, Takeda, BMS, SkylineDx, Karyopharm, all outside the submitted work. MvL-T has received travel grants and honoraria from Celgene, Gilead, Chugai, Janssen, Novartis, Amgen, Takeda, BMS, Medac, Oncopeptides, Merck, CDDF, Pfizer, Medac, Thermo Fisher, AstraZeneca; is a consultant for Celgene, Gilead, Oncopeptides, MSD, 4D Pharma, Janssen, Shionogi and received research funding from BMBF, Deutsche Jose Carreras Leukämie-Stiftung, IZKF Jena, Novartis, Gilead, Deutsche Krebshilfe, Celgene, Oncopeptides, Deutsche Forschungsgemeinschaft (DFG). CW has declared no conflicts of interest. GP reports grants from Amgen, grants, personal fees and non-financial support from Merck, grants and non-financial support from AstraZeneca, grants and personal fees from Roche, grants and personal fees from BMS, grants from Lilly, grants and personal fees from MSD, grants and personal fees from Novartis, outside the submitted work. FP reports grants from Novartis, Celgene, BMS, Abbvie, Karyopharma, Janssen., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Omidubicel is an ex vivo expanded hematopoietic progenitor cell and nonexpanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit. We report results of a phase 3 trial to evaluate the efficacy of omidubicel compared with standard umbilical cord blood transplantation (UCBT). Between January 2017 and January 2020, 125 patients age 13 to 65 years with hematologic malignancies were randomly assigned to omidubicel vs standard UCBT. Patients received myeloablative conditioning and prophylaxis with a calcineurin inhibitor and mycophenolate mofetil for graft-versus-host disease (GVHD). The primary end point was time to neutrophil engraftment. The treatment arms were well balanced and racially diverse. Median time to neutrophil engraftment was 12 days (95% confidence interval [CI], 10-14 days) for the omidubicel arm and 22 days (95% CI, 19-25 days) for the control arm (P < .001). The cumulative incidence of neutrophil engraftment was 96% for patients receiving omidubicel and 89% for patients receiving control transplants. The omidubicel arm had faster platelet recovery (55% vs 35% recovery by 42 days; P = .028), had a lower incidence of first grade 2 to 3 bacterial or invasive fungal infection (37% vs 57%; P = .027), and spent more time out of hospital during the first 100 days after transplant (median, 61 vs 48 days; P = .005) than controls. Differences in GVHD and survival between the 2 arms were not statistically significant. Transplantation with omidubicel results in faster hematopoietic recovery and reduces early transplant-related complications compared with standard UCBT. The results suggest that omidubicel may be considered as a new standard of care for adult patients eligible for UCBT. The trial was registered at www.clinicaltrials.gov as #NCT02730299., (© 2021 by The American Society of Hematology.)

Competing Interests: Disclosure PF has received honoraria and/or research support from Celgene, Janssen, AbbVie, Jazz, Novartis, Roche and Aprea; GFS has received honoraria from and/or played an advisory role for AbbVie, Amgen, Böehringer Ingelheim, Celgene, Helsinn Healthcare, Roche, Janssen-Cilag, Novartis, Takeda and Onconova; VS has received honoraria from Astex, Celgene, Novartis, Pfizer, Janssen-Cilag and Takeda; UP has received honoraria and/or research support from Celgene, Janssen, AbbVie, Jazz, Novartis and Amgen; DH has received honoraria from Celgene, Novartis and Takeda, and research support from Novartis and Celgene; UM has reported honoraria from Celgene, Roche and Amgen.

Inhibition of mouse double minute 2 homolog (MDM2)-p53 interaction and reactivation of p53 signaling have been explored as effective anticancer therapeutic strategy. The potent and specific antitumor activity shown by Nutlins, first class of MDM2-p53 inhibitors discovered, has made these compounds potential antitumor candidates. To this end, we synthesized Nutlin-1 and Nutlin-2 analogs through molecular simplification and selected the compound with the most efficient antitumoral activity. Cytotoxicity of Nutlin-2 analog LQFM126 on B16F10 melanoma cells induced intense cytoplasmic vacuolization, reduction of cell size, chromatin condensation, cytoplasmic degeneration and nuclear fragmentation. LQFM126 antiproliferative effects mediated cell cycle retention in G 0 /G 1 phase and increased the levels of cell cycle regulatory proteins p21 and p27. This Nutlin analog increased mitochondrial membrane potential, activated caspase-8, -9 and -3/7 and reduced VEGF levels in B16F10 cells. Therefore, LQFM126 promoted alterations suggestive of apoptosis, G0/G1 cell cycle arrest and suppression of angiogenesis through modulation of VEGF expression in B16F10 cells. Additionally, LQFM126 was classified as UN GHS category 4 (LD50 > 300-2000 mg/kg), suggesting it has low acute systemic toxicity. LQFM126 can be a promising prototype for anticancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Background: The placenta controls exchanges between the mother and the fetus and therefore fetal development and growth. The maternal environment can lead to disturbance of placental functions, with consequences on the health of the offspring. Since the rabbit placenta is very close to that of humans, rabbit models can provide biomedical data to study human placental function. Yet, to limit the use of animal experiments and to investigate the mechanistic aspects of placental function, we developed a new cell culture model in which rabbit trophoblast cells are differentiated from rabbit trophoblast stem cells., Methods: Rabbit trophoblast stems cells were derived from blastocysts and differentiated onto a collagen gel and in the presence of a flow of culture medium to mimic maternal blood flow. Transcriptome analysis was performed on the stem and differentiated cells., Results: Our culture model allows the differentiation of trophoblast stem cells. In particular, the fluid shear stress enhances microvilli formation on the differentiated cell surface, lipid droplets formation and fusion of cytotrophoblasts into syncytiotrophoblasts. In addition, the transcriptome analysis confirms the early trophoblast identity of the derived stem cells and reveals upregulation of signaling pathways involved in trophoblast differentiation., Conclusion: Thereby, the culture model allows mimicking the in vivo conditions in which maternal blood flow exerts a shear stress on trophoblast cells that influences their phenotype., General Significance: Our culture model can be used to study the differentiation of trophoblast stem cells into cytotrophoblasts and syncytiotrophoblasts, as well as the trophoblast function in physiological and pathological conditions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Next-generation sequencing (NGS) has redefined the genetic landscape of acute myeloid leukemia (AML), providing new molecular markers for diagnostic and prognostic classifications. However, its application in the clinical setting is still challenging. We hypothesized that a 19-gene AML-targeted NGS panel could be a valid approach to obtain clinically relevant information. Thus, we assessed the ability of this panel to classify AML patients according to diagnostic and prognostic indexes in a cohort of 162 patients. The assay yielded a median read depth >2000×, with 88% of on-target reads and a mean uniformity >93% without significant global strand bias. The method was sensitive and specific, with a valid performance at the clinical variant allele frequency cutoff of 3% for point mutations and 5% for insertions or deletions (INDELs). Three-hundred thirty-nine variants were found (36% INDELs and 64% single nucleotide variants). Concordance between NGS and other conventional techniques was 100%, but the NGS approach was able to identify more clinically relevant mutations. Finally, all patients could be classified into one of the 2016 World Health Organization diagnostic categories and virtually all into the recently proposed prognostic indexes (2017 European LeukemiaNet and Genomic classification). To sum up, we validate a reliable and reproducible method for AML diagnosis and demonstrate that small, well-designed NGS panels are sufficient to guide clinical decisions according to the current standards., (Copyright © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Inhibition of p53-MDM2 complex has been emerging as a strategy for antitumoral drug development considering the pro-apoptotic role of functional p53 in tumor cells. In our study, the prototype LQFM166 (2), designed through molecular simplification strategy inspired in the Nutlins compounds, was synthetized, characterized and the mechanisms of cell death were investigated. In addition, we estimated the starting doses for acute oral systemic toxicity tests according to the OECD Guidance Document No.129 - 3T3 NRU. The cytotoxic profile of LQFM166 (2) was determined in K-562 cells, a p53-null cell line, since previous studies also showed activity of LQFM166 (2) on this cells. After 24, 48 or 72 h of compound treatment, using MTT reduction assay, the IC50 values found were 100.1 μM, 56.76 μM and 45.11 μM, respectively. LQFM166 (2) was cytotoxic for leukemia cells in a concentration-time-dependent manner. Cell death mechanisms studies of LQFM166 on K-562 cells, revealed that the compound induced cell cycle arrest, increased the expression of caspase 3/7, 8 and 9, cytochrome c, Bax, p21 and p27. Additionally, a decrease in the expression of the Bcl-2 and cyclin-B1 was observed. The apoptotic inducer profile of the compound was confirmed by phosphatidylserine externalization. Investigation of complexation of p53/MDM2 was carried out by ELISA assay using 3T3 cell, showing a decrease in the p53-MDM2 complex induced by the compound. Furthermore, the cytotoxicity in basal fibroblasts 3T3 was determined to estimate LD50. LQFM166 (2) reduced 3T3 cells viability with the IC50 of 185.3 μM and estimated LD50 of 706.7 mg/kg (category 4 of GHS). The rationally designed of the prototype LQFM166 (2) induced cell death by apoptotic mechanisms in leukemic cells and showed MDM2 complexation antagonism in 3T3 cells., (Copyright © 2018. Published by Elsevier B.V.)

An international expert panel, active within the European Society for Blood and Marrow Transplantation, European LeukemiaNet, Blood and Marrow Transplant Clinical Trial Group, and the International Myelodysplastic Syndromes Foundation developed recommendations for allogeneic hematopoietic stem cell transplantation (HSCT) in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Disease risks scored according to the revised International Prognostic Scoring System (IPSS-R) and presence of comorbidity graded according to the HCT Comorbidity Index (HCT-CI) were recognized as relevant clinical variables for HSCT eligibility. Fit patients with higher-risk IPSS-R and those with lower-risk IPSS-R with poor-risk genetic features, profound cytopenias, and high transfusion burden are candidates for HSCT. Patients with a very high MDS transplantation risk score, based on combination of advanced age, high HCT-CI, very poor-risk cytogenetic and molecular features, and high IPSS-R score have a low chance of cure with standard HSCT and consideration should be given to treating these patients in investigational studies. Cytoreductive therapy prior to HSCT is advised for patients with ≥10% bone marrow myeloblasts. Evidence from prospective randomized clinical trials does not provide support for specific recommendations on the optimal high intensity conditioning regimen. For patients with contraindications to high-intensity preparative regimens, reduced intensity conditioning should be considered. Optimal timing of HSCT requires careful evaluation of the available effective nontransplant strategies. Prophylactic donor lymphocyte infusion (DLI) strategies are recommended in patients at high risk of relapse after HSCT. Immune modulation by DLI strategies or second HSCT is advised if relapse occurs beyond 6 months after HSCT., (© 2017 by The American Society of Hematology.)

We evaluated the impact of recipient and cord blood unit (CBU) genetic polymorphisms related to immune response on outcomes after unrelated cord blood transplantations (CBTs). Pretransplant DNA samples from 696 CBUs with malignant diseases were genotyped for NLRP1, NLRP2, NLRP3, TIRAP/Mal, IL10, REL, TNFRSF1B, and CTLA4. HLA compatibility was 6 of 6 in 10%, 5 of 6 in 39%, and ≥4 of 6 in 51% of transplants. Myeloablative conditioning was used in 80%, and in vivo T-cell depletion in 81%, of cases. The median number of total nucleated cells infused was 3.4 × 10 7 /kg. In multivariable analysis, patients receiving CBUs with GG-CTLA4 genotype had poorer neutrophil recovery (hazard ratio [HR], 1.33; P = .02), increased nonrelapse mortality (NRM) (HR, 1.50; P < .01), and inferior disease-free survival (HR, 1.41; P = .02). We performed the same analysis in a more homogeneous subset of cohort 1 (cohort 2, n = 305) of patients who received transplants for acute leukemia, all given a myeloablative conditioning regimen, and with available allele HLA typing (HLA-A, -B, -C, and -DRB1). In this more homogeneous but smaller cohort, we were able to demonstrate that GG-CTLA4-CBU was associated with increased NRM (HR, 1.85; P = .01). Use of GG-CTLA4-CBU was associated with higher mortality after CBT, which may be a useful criterion for CBU selection, when multiple CBUs are available., (© 2017 by The American Society of Hematology.)

Background: The most common side effect in population screening programmes is a false-positive result which leads to unnecessary risks and costs., Aims: To identify factors associated with false-positive results in a colorectal cancer screening programme with the faecal immunochemical test (FIT)., Methods: Cross-sectional study of 472 participants with a positive FIT who underwent colonoscopy for confirmation of diagnosis between 2013 and 2014. A false-positive result was defined as having a positive FIT (≥20μg haemoglobin per gram of faeces) and follow-up colonoscopy without intermediate/high-risk lesions or cancer., Results: Women showed a two-fold increased likelihood of a false-positive result compared with men (adjusted OR, 2.3; 95%CI, 1.5-3.4), but no female-specific factor was identified. The other variables associated with a false-positive result were successive screening (adjusted OR, 1.5; 95%CI, 1.0-2.2), anal disorders (adjusted OR, 3.1; 95%CI, 2.1-4.5) and the use of proton pump inhibitors (adjusted OR, 1.8; 95%CI, 1.1-2.9). Successive screening and proton pump inhibitor use were associated with FP in men. None of the other drugs were related to a false-positive FIT., Conclusion: Concurrent use of proton pump inhibitors at the time of FIT might increase the likelihood of a false-positive result. Further investigation is needed to determine whether discontinuing them could decrease the false-positive rate., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

In myelodysplastic syndromes (MDSs), the evolution of risk for disease progression or death has not been systematically investigated despite being crucial for correct interpretation of prognostic risk scores. In a multicenter retrospective study, we described changes in risk over time, the consequences for basal prognostic scores, and their potential clinical implications. Major MDS prognostic risk scoring systems and their constituent individual predictors were analyzed in 7212 primary untreated MDS patients from the International Working Group for Prognosis in MDS database. Changes in risk of mortality and of leukemic transformation over time from diagnosis were described. Hazards regarding mortality and acute myeloid leukemia transformation diminished over time from diagnosis in higher-risk MDS patients, whereas they remained stable in lower-risk patients. After approximately 3.5 years, hazards in the separate risk groups became similar and were essentially equivalent after 5 years. This fact led to loss of prognostic power of different scoring systems considered, which was more pronounced for survival. Inclusion of age resulted in increased initial prognostic power for survival and less attenuation in hazards. If needed for practicability in clinical management, the differing development of risks suggested a reasonable division into lower- and higher-risk MDS based on the IPSS-R at a cutoff of 3.5 points. Our data regarding time-dependent performance of prognostic scores reflect the disparate change of risks in MDS subpopulations. Lower-risk patients at diagnosis remain lower risk whereas initially high-risk patients demonstrate decreasing risk over time. This change of risk should be considered in clinical decision making., (© 2016 by The American Society of Hematology.)

Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation., (© 2015 by The American Society of Hematology.)

The blood-brain barrier (BBB) is the main entry route for chemicals into the mammalian central nervous system (CNS). Two transmembrane transporters of the ATP-binding cassette (ABC) family - breast cancer resistance protein (ABCG2 in humans, Abcg2 in rodents) and P-glycoprotein (ABCB1 in humans, Abcb1 in rodents) - play a key role in mediating this process. Pharmacological and genetic evidence suggests that Abcg2 prevents CNS access to a group of highly potent and selective O-arylcarbamate fatty-acid amidohydrolase (FAAH) inhibitors, which include the compound URB937 (cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester). To define structure-activity relationships of the interaction of these molecules with Abcg2, in the present study we tested various peripherally restricted and non-restricted O-arylcarbamate FAAH inhibitors for their ability to serve as transport substrates in monolayer cultures of Madin-Darby Canine Kidney-II (MDCKII) cells over-expressing Abcg2. Surprisingly, we found that the majority of compounds tested - even those able to enter the CNS in vivo - were substrates for Abcg2 in vitro. Additional experiments in MDCKII cells overexpressing ABCB1 revealed that only those compounds that were dual substrates for ABCB1 and Abcg2 in vitro were also peripherally restricted in vivo. The extent of such restriction seems to depend upon other physicochemical features of the compounds, in particular the polar surface area. Consistent with these in vitro results, we found that URB937 readily enters the brain in dual knockout mice lacking both Abcg2 and Abcb1, whereas it is either partially or completely excluded from the brain of mice lacking either transporter alone. The results suggest that Abcg2 and Abcb1 act together to restrict the access of URB937 to the CNS., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Ischemic heart disease and stroke are the leading causes of death worldwide. What was once thought to be an endemic disease of high income countries has become a global epidemic, as low and middle income countries have adopted Western lifestyles, to the point that noncommunicable diseases are now the main cause of death in these regions, above and beyond communicable diseases, malnutrition, and injury. As a result, a large proportion of individuals at high 10-year risk of a cardiovascular event live in low- and middle-income countries, and the most of all cardiovascular events occur in developing countries. A large amount of evidence supports the use of pharmacological treatment for the prevention of cardiovascular death in this population, including antiplatelet drugs, β-blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors, however, the efficacy of cardiovascular event prevention is hampered by several problems, including inadequate prescription of medication, poor adherence to treatment, limited availability of medications, and unaffordable cost of treatment. Here we examine the use of fixed-dose combination therapy, and how this therapy could improve adherence to treatment, reduce the cost, and improve treatment affordability in low-income countries., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Chagas' disease is becoming a public health problem in Europe because of migratory movements. Cardiac magnetic resonance (CMR) has emerged as a non-invasive tool to assess cardiac tissue characteristics. There is scarce data available on CMR in patients with Chagas' disease., Objective: To describe CMR findings in patients with Chagas' disease living in a non-endemic area focusing on differentiation from other cardiomyopathies and relation with clinical status., Methods and Results: Sixty-seven Chagas' disease patients divided into 3 groups-group 1 (indeterminate form: positive serology without ECG or 2D-echocardiographic abnormalities; N = 27), group 2 (ECG abnormalities of Chagas' disease but normal 2D-echocardiography; N = 19), and group 3 (regional wall motion abnormalities, LV end-diastolic diameter >55 mm or LV ejection fraction <50% on echocardiography; N = 21)--were studied. The presence of wall motion abnormalities and delayed enhancement (DE) by CMR was more frequent in the inferolateral and apical segments. DE distribution in the myocardial wall was heterogeneous (subendocardial 26.8%, midwall 14.0%, subepicardial 22.6%, and transmural 36.0% of total segments with DE) and related to larger cardiac chambers and worse systolic function., Conclusion: Pattern of DE in Chagas' disease may mimic that of both ischemic and nonischemic cardiomyopathies, with especial predilection for the apical and inferolateral segments of the left ventricle. These findings support that myocardial involvement in chronic Chagas' cardiomyopathy (CCC) may be due to both microvascular disturbances and chronic myocarditis and may favor CCC in the differential diagnosis of patients with compatible epidemiological history and heart failure of uncertain etiology., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The natural course of chronic myelomonocytic leukemia (CMML) is highly variable but a widely accepted prognostic scoring system for patients with CMML is not available. The main aim of this study was to develop a new CMML-specific prognostic scoring system (CPSS) in a large series of 558 patients with CMML (training cohort, Spanish Group of Myelodysplastic Syndromes) and to validate it in an independent series of 274 patients (validation cohort, Heinrich Heine University Hospital, Düsseldorf, Germany, and San Matteo Hospital, Pavia, Italy). The most relevant variables for overall survival (OS) and evolution to acute myeloblastic leukemia (AML) were FAB and WHO CMML subtypes, CMML-specific cytogenetic risk classification, and red blood cell (RBC) transfusion dependency. CPSS was able to segregate patients into 4 clearly different risk groups for OS (P < .001) and risk of AML evolution (P < .001) and its predictive capability was confirmed in the validation cohort. An alternative CPSS with hemoglobin instead of RBC transfusion dependency offered almost identical prognostic capability. This study confirms the prognostic impact of FAB and WHO subtypes, recognizes the importance of RBC transfusion dependency and cytogenetics, and offers a simple and powerful CPSS for accurately assessing prognosis and planning therapy in patients with CMML.

The International Prognostic Scoring System (IPSS) is an important standard for assessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). To refine the IPSS, MDS patient databases from international institutions were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], n = 7012, IPSS, n = 816) for analysis. Multiple statistically weighted clinical features were used to generate a prognostic categorization model. Bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation. This system comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS. As such, this IPSS-R should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.

Fatty-acid amide hydrolase (FAAH) catalyzes the intracellular hydrolysis of the endocannabinoid anandamide and other bioactive lipid amides. In the present study, we conducted a comparative characterization of the effects of the newly identified brain-impermeant FAAH inhibitor, URB937 ([3-(3-carbamoylphenyl)-4-hydroxy-phenyl] N-cyclohexylcarbamate), in various rodent models of acute and persistent pain. When administered by the oral route in mice, URB937 was highly active (median effective dose, ED(50), to inhibit liver FAAH activity: 0.3mgkg(-1)) and had a bioavailability of 5.3%. The antinociceptive effects of oral URB937 were investigated in mouse models of acute inflammation (carrageenan), peripheral nerve injury (chronic sciatic nerve ligation) and arthritis (complete Freund's adjuvant). In all models, URB937 was as effective or more effective than standard analgesic and anti-inflammatory drugs (indomethacin, gabapentin, dexamethasone) and reversed pain-related responses (mechanical hyperalgesia, thermal hyperalgesia, and mechanical allodynia) in a dose-dependent manner. ED(50) values ranged from 0.2 to 10mgkg(-1), depending on model and readout. Importantly, URB937 was significantly more effective than two global FAAH inhibitors, URB597 and PF-04457845, in the complete Freund's adjuvant model. The effects of a combination of URB937 with the non-steroidal anti-inflammatory agent, indomethacin, were examined in the carrageenan and chronic sciatic nerve ligation models. Isobolographic analyses showed that the two compounds interacted synergistically to attenuate pain-related behaviors. Furthermore, URB937 reduced the number and severity of gastric lesions produced by indomethacin, while exerting no ulcerogenic effect when administered alone. The results indicate that the peripheral FAAH inhibitor URB937 is more effective than globally active FAAH inhibitors at inhibiting inflammatory pain. Our findings further suggest that FAAH and cyclooxygenase inhibitors interact functionally in peripheral tissues, to either enhance or hinder each other's actions., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

This phase 3, randomized, double-blind study assessed the efficacy and safety of lenalidomide in 205 red blood cell (RBC) transfusion-dependent patients with International Prognostic Scoring System Low-/Intermediate-1-risk del5q31 myelodysplastic syndromes. Patients received lenalidomide 10 mg/day on days 1-21 (n = 69) or 5 mg/day on days 1-28 (n = 69) of 28-day cycles; or placebo (n = 67). Crossover to lenalidomide or higher dose was allowed after 16 weeks. More patients in the lenalidomide 10- and 5-mg groups achieved RBC-transfusion independence (TI) for ≥ 26 weeks (primary endpoint) versus placebo (56.1% and 42.6% vs 5.9%; both P < .001). Median duration of RBC-TI was not reached (median follow-up, 1.55 years), with 60% to 67% of responses ongoing in patients without progression to acute myeloid leukemia (AML). Cytogenetic response rates were 50.0% (10 mg) versus 25.0% (5 mg; P = .066). For the lenalidomide groups combined, 3-year overall survival and AML risk were 56.5% and 25.1%, respectively. RBC-TI for ≥ 8 weeks was associated with 47% and 42% reductions in the relative risks of death and AML progression or death, respectively (P = .021 and .048). The safety profile was consistent with previous reports. Lenalidomide is beneficial and has an acceptable safety profile in transfusion-dependent patients with Low-/Intermediate-1-risk del5q myelodysplastic syndrome. This trial was registered at www.clinicaltrials.gov as #NCT00179621.

The O-arylcarbamate URB937 is a potent inhibitor of fatty-acid amide hydrolase (FAAH), an intracellular serine hydrolase responsible for the deactivation of the endocannabinoid anandamide. URB937 is unique among FAAH inhibitors in that is actively extruded from the central nervous system (CNS), and therefore increases anandamide levels exclusively in peripheral tissues. Despite its limited distribution, URB937 exhibits marked analgesic properties in rodent models of pain. Pharmacological evidence suggests that the extrusion of URB937 from the CNS may be mediated by the ABC membrane transporter ABCG2 (also called Breast cancer resistance protein, BCRP). In the present study, we show that URB937 is a substrate for both mouse and human orthologues of ABCG2. The relative transport ratios for URB937 in Madin-Darby canine kidney (MDCKII) cells monolayers over-expressing either mouse Abcg2 or human ABCG2 were significantly higher compared to parental monolayers (13.6 and 13.1 vs. 1.5, respectively). Accumulation of the compound in the luminal/apical side was prevented by co-administration of the selective ABCG2 inhibitor, Ko-143. In vivo studies in mice showed that URB937 (25 mg kg(-1)) readily entered the brain and spinal cord of Abcg2-deficient mice following intraperitoneal administration, whereas the same dose of drug remained restricted to peripheral tissues in wild-type mice. By identifying ABCG2 as a transport mechanism responsible for the extrusion of URB937 from the CNS, the present results should facilitate the rational design of novel peripherally restricted FAAH inhibitors., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: Determine treatment adherence in patients with multiple chronic conditions (MCC)., Methods: A random patient sample ≥ 15 years, discharged from hospital with ≥1 chronic conditions (CC) was interviewed after 6-12 months. Analysis included variables in 5 dimensions (WHO): socio-demographics, disease, treatment, patient and health system characteristics. Morisky-Green adherence questionnaire was used. High chronic treatment complexity was defined as: >3 pills/day, >6 inhalations/day, >1 injection/day, pharmacological treatment plus diet or self-monitoring techniques., Results: 301 patients were interviewed (62 ± 15 years, 59% males). Despite good treatment information perception (79%), only 3% followed the patient education programme. Poor adherents (82%) were older (64 ± 14 years vs. 55 ± 16 years), had more CC (3.25 ± 2.02 vs. 2.62 ± 2.72), a higher frequency of hypertension (44% vs. 15%), ischaemic heart diseases: (21% vs. 4%), hyperlipidaemia (19% vs. 6%), more pills/day (5.78 ± 4.14 vs. 3.20 ± 4.70) and more complex treatments (95% vs. 70%) (p<0.05). On multivariate analysis number of CC [3.68 (0.75-18.15)], pills/day [2.23 (1.02-4.84)], treatment complexity [4.00 (1.45-11.04)], and hypertension [2.57 (1.06-6.25)] were predictive of poor adherence (OR 95% CI p<0.05)., Conclusion: The WHO conceptual framework allows the construction of poor adherence risk profiles in patients with MCC after hospital discharge., Practice Implications: Predictive variables of poor adherence could help clinicians detect patients with MCC most likely to present poor adherence., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Chagas disease is no longer limited to Latin America and is becoming frequent in industrialised countries in Europe and United States., Methods: A descriptive study of Latin American immigrants in Barcelona attending two centres for imported diseases during a period of 3 years. The main outcome was the identification of Trypanosoma cruzi-infected individuals in a non-endemic country and the characterization of their clinical and epidemiological features., Results: A total of 489 Latin American patients participated in the study. Forty-one percent were infected by T. cruzi, and the most frequent country of origin was Bolivia. All T. cruzi infected patients were in chronic stages of infection. 19% of cases had cardiac disorders and 9% had digestive disorders., Conclusions: A high percentage of participants in this study were infected by T. cruzi and various factors were found to be associated to the infection. It is important to improve clinical and epidemiological knowledge of T. cruzi infection in non-endemic countries and to develop appropriate screening and treatment protocols in these settings.

Background: Despite the use of newer immunosuppressors such as sirolimus (SRL) and tacrolimus (TRL) in heart transplantation, the rate of humoral rejection has remained unchanged. The aim of this study was to analyze the immunologic and histologic effects of cyclosporine (CsA), SRL, and TRL in a porcine model of arterial transplantation., Methods: Each transplant recipient animal (n = 49) received an autograft and an allograft and was then allocated to one of four treatment groups and a 7- or 30-day follow-up period, as follows: a WOT group (without immunosuppressor treatment), 7 days (n = 6) and 30 days (n = 5); a CsA group, 7 days (n = 5) and 30 days (n = 6); an SRL group, 7 days (n = 7) and 30 days (n = 8); and a TRL group, 7 days (n = 6) and 30 days (n = 6). The presence of donor-specific antibodies (DSA) was tested at the end of the follow-up period. Morphometric parameters and inflammatory infiltration were analyzed in the explanted grafts., Results: At 30-day follow-up, SRL was the only treatment capable of suppressing DSA formation (0 of 7 vs 4 of 5 in the WOT group; p < 0.05). SRL completely prevented aneurismal dilation and reduced the number of macrophages in the allografts. TRL treatment achieved a greater reduction of T lymphocytes. CsA did not prevent the reduction in total vascular area at 7 days that was achieved with the SRL and TRL groups. Animals treated with CsA had the largest number of T lymphocytes and macrophages in both follow-up periods., Conclusions: SRL prevented DSA formation and reduced the number of macrophages as compared with TRL and CsA.

Objective: To analyze the short-term effects of estradiol (E2) on the expression of nitric oxide synthase (NOS III) and estrogen receptors (ER) alpha and beta., Methods: We studied 20 post-menopausal women with coronary artery disease (CAD) undergoing CABG surgery with left internal mammary artery (LIMA) grafting. Ten women received treatment with transdermal E2 prior to surgery (48-72 h) and 10 did not. The distal segment of the LIMA was excised and processed to determine mRNA expression of NOS III and ER alpha and beta (RT-PCR). Expression of NOS III and ER alpha and beta was measured in arbitrary densitometric units (ADUs) relative to GPdH expression, constitutively expressed in human vessels., Results: NOS III and ER alpha and beta mRNA expression was enhanced in women treated with E2 as compared to the control group (NOS III: 1.69+/-0.61 versus 1.14+/-0.48 ADUs, p=0.04; ER alpha: 6.52+/-6.80 versus 1.83+/-1.22 ADUs, p=0.04; ER beta: 4.20+/-3.42 versus 1.56+/-0.59 ADUs, p=0.03). ER alpha, but not ER beta expression, correlated with NOS III expression (r=0.70, p<0.001)., Conclusions: After treatment with E2, NOS III, ER alpha, and ER beta mRNA expression was enhanced in arterial vessels of postmenopausal women with CAD. NOS III mRNA expression was only correlated to ER alpha expression, suggesting that NOS III activation could be more mediated by ER alpha.

Background: The number of revascularization procedures including coronary and lower extremity bypass, have increased greatly in the last decade. It suggests a growing need for vascular grafts. Cryopreserved allografts could represent a viable alternative but their immunologic reactivity remains controversial., Methods: 71 pigs (40 recipients and 31 donors) were used. Two femoral grafts per recipient animal were implanted for 3, 7, and 30 days. Types of grafts: fresh autograft as a control graft (n=19), fresh allograft (n=31) and cryopreserved allograft (n=30). Histological and immunohistochemical studies were performed., Results: Fresh allografts compared to autografts showed intimal inflammatory infiltration at 3 days (328 vs. 0 macrophages/mm2; P<0.05) and 7 days (962 vs. 139 T lymphocytes/mm2; P<0.05) post-transplantation. At 30 days, there was a loss of endothelial cells, presence of luminal thrombus and aneurismal lesions (total area=15.8 vs. 8.4 mm2; P<0.05). Cryopreservation did not reduce these lesions nor modify endothelial nitric oxide synthase (eNOS) expression nor modify the number of animals that developed anti-SLA antibodies. Moreover, at 7 days, cryopreserved allografts compared to fresh allografts showed a higher expression of P-selectin (5 out of 5 vs. 1 out of 5; P<0.05) and, at 30 days, a greater inflammatory reactivity (2692 vs. 1107 T lymphocytes/mm2 in media; P<0.05) with a trend towards a higher presence of multinucleated giant cells than in the fresh ones., Conclusions: The cryopreservation method used maintained immunogenicity of allografts and increased the inflammatory reactivity found in fresh allografts up to 30 days of vascular transplantation.

Increased plasma levels of adrenomedullin (ADM) have been reported in patients with congestive heart failure Immunohistochemical ADM has been identified in failing human ventricle, but the gene expression pattern of ADM messenger RNA (mRNA) in myocardial tissue of patients with heart failure has not been elucidated. In this study, gene expression of ADM mRNA (analyzed by northern blot) and tissue concentration of ADM (measured by radioimmunoassay) were assessed in the explanted hearts of 17 patients with idiopathic dilated cardiomyopathy (IDC) and in 7 organ donors with no cardiopathy (controls). Myocardial tissue samples of patients with IDC showed increased ADM mRNA gene expression (p < 0.05) and decreased immunoreactive ADM protein content (p < 0.02) compared with controls.

The base excision repair (BER) pathway plays a key role in protecting the genome from endogenous DNA damage. Current methods to measure BER activities are indirect and cumbersome. Here, we introduce a direct method to assay DNA excision repair that is suitable for automation and industrial use, based on the fluorescence quenching mechanism of molecular beacons. We designed a single-stranded DNA oligonucleotide labelled with a 5'-fluorescein (F) and a 3'-Dabcyl (D) in which the fluorophore, F, is held in close proximity to the quencher, D, by the stem-loop structure design of the oligonucleotide. Following removal of the modified base or incision of the oligonucleotide, the fluorophore is separated from the quencher and fluorescence can be detected as a function of time. Several modified beacons have been used to validate the assay on both cell-free extracts and purified proteins. We have further developed the method to analyze BER in cultured cells. As described, the molecular beacon-based assay can be applied to all DNA modifications processed by DNA excision/incision repair pathways. Possible applications of the assay are discussed, including high-throughput real-time DNA repair measurements both in vitro and in living cells.

Objective: To analyze the incidence and characteristics of documented infections in patients with hematologic malignancies undergoing unrelated donor bone marrow transplantation (UD-BMT)., Methods: We studied the occurrence of infections in 22 patients with hematologic malignancies or severe aplastic anemia who underwent UD-BMT from April 1990 to December 2000. The median age was 26 years (range 13-46). Acyclovir-ganciclovir, co-trimoxazole, fluconazole-nystatin and ciprofloxacin were administered for anti-infectious prophylaxis., Results: We registered 61 infectious episodes. During the early post-transplant period, there were eight clinically documented infections (CDIs), four cases of fever of unknown origin (FUO), seven cases of bacteremia, two cases of cytomegalovirus (CMV) antigenemia, and one case of CMV disease. In the intermediate period (days 30-100 after BMT), there were nine cases of CMV antigenemia, three bacterial infections, two fungal infections, one case of disseminated toxoplasmosis, and one case of FUO. In the late period (day 100 and later), we documented 13 viral infections, eight bacterial infections, one CDI, and one case of invasive aspergillosis. Infections contributed to death in 10 of 17 patients. Citrobacter bacteremia and sepsis of unknown origin were the main causes of infectious mortality in the early period. Infection was the main cause of death in six of seven patients in the late period., Conclusion: A high incidence of life-threatening infections and infection-related mortality was observed. A high rate of CMV infection in the early period, and death caused by multiresistant Gram-negative microorganisms in the late period, were the main findings in this series.

The potential role of unrelated donor cord blood transplantation (UD-CBT) in adults remains unclear. This study reports the results of UD-CBT in 22 adults with hematologic malignancies following conditioning with thiotepa, busulfan, cyclophosphamide, and antithymocyte globulin in 21, with thiotepa, fludarabine, and antithymocyte globulin in 1, and graft-versus-host disease (GVHD) prophylaxis with cyclosporine and prednisone. Median age was 29 years (range, 18-46 years), and median weight was 69.5 kg (range, 41-85 kg). HLA match was 6 of 6 in 1 case, 5 of 6 in 13 cases, and 4 of 6 in 8 cases. Median number of nucleated cells infused was 1.71 x 10(7)/kg (range, 1.01 x 10(7)/kg to 4.96 x 10(7)/kg). All 20 patients surviving more than 30 days had myeloid engraftment, and only 1, who received the lowest cell dose, developed secondary graft failure. Median time to reach an absolute neutrophil count of at least 0.5 x 10(9)/L was 22 days (range, 13-52 days). Median time to platelets numbered at least 20 x 10(9)/L was 69 days (range, 49-153 days). Seven patients (32%) developed acute GVHD above grade II, and 9 of 10 patients at risk developed chronic GVHD, which became extensive in 4 patients. Twelve patients remained alive and disease-free 3 to 45 months after transplantation. Disease-free survival (DFS) at 1 year was 53%. Age strongly influenced DFS (P =.01). For patients aged 30 years or younger, the DFS at 1 year was 73%. These preliminary results suggest that UD-CBT should be considered a reasonable alternative in young adults with hematologic malignancy and no appropriate bone marrow donor.

Standardized criteria for assessing response are essential to ensure comparability among clinical trials for patients with myelodysplastic syndromes (MDS). An international working group of experienced clinicians involved in the management of patients with MDS reviewed currently used response definitions and developed a uniform set of guidelines for future clinical trials in MDS. The MDS differ from many other hematologic malignancies in their chronicity and the morbidity and mortality caused by chronic cytopenias, often without disease progression to acute myeloid leukemia. Whereas response rates may be an important endpoint for phase 2 studies of new agents and may assist regulatory agencies in their evaluation and approval processes, an important goal of clinical trials in MDS should be to prolong patient survival. Therefore, these response criteria reflected 2 sets of goals in MDS: altering the natural history of the disease and alleviating disease-related complications with improved quality of life. It is anticipated that the recommendations presented will require modification as more is learned about the molecular biology and genetics of these disorders. Until then, it is hoped these guidelines will serve to improve communication among investigators and to ensure comparability among clinical trials. (Blood. 2000;96:3671-3674)

Purpose: The purpose of this study was to design an adequate technique with which to cryopreserve pig femoral arteries and to assess the influence of storage times in vascular function., Methods: Fifty-two femoral arteries were distributed in seven groups. In group A (control), 10 arteries were studied after harvest; in groups B1 and B2, 19 arteries were suspended in RPMI 1640 plus fetal calf serum plus dimethylsulfoxide and were cryopreserved at 1 degrees C per minute or 0.3 degrees C per minute, respectively. In groups C1 to C4, 23 arteries were suspended in modified Krebs-Henseleit plus dimethylsulfoxide plus sucrose, cryopreserved at 0.7 degrees C per minute, and kept frozen for 1, 15, 60, or 180 days, respectively. After being thawed, arteries were examined for contraction and endothelial-dependent vasodilation (organ bath studies), antithrombotic properties of the endothelial layer(perfusion studies), and vessel structure (electron microscopy)., Results: Endothelial cells were present in both cryopreserved and control arteries. The control vessels showed a mean contraction to norepinephrine (10(-7) mol/L) of 13010 +/- 3181 mg. Arteries in groups B1 and B2 did not respond to norepinephrine. Contraction in groups C1 to C4 was as follows: C1, 5354 +/- 1222 mg; C2, 5187 +/- 2672 mg; C3, 6867 +/- 2292 mg; C4, 7000 +/- 2858 mg, which represent 50% of the control values (P <.001). Vasodilation was similar in control (99% +/- 3%) and cryopreserved arteries (C1, 90% +/- 13%; C2, 93% +/- 12%; C3, 89% +/- 15%; C4, 88% +/- 22%). Storage time did not influence vascular function. Platelet interaction was almost absent and similar in all groups., Conclusion: A modified cryopreservation technique preserves endothelial function independently of the storage time up to 6 months.

Background: Increased levels of circulating cytokines have been previously reported in patients with congestive heart failure; however, whether they have prognostic implications is still unknown. The aim of this study was to assess the prognostic implications of elevated serum cytokines in patients with heart failure and to identify the predictors of cytokine activation., Methods and Results: We assessed neurohormonal determinations, circulating cytokines, ejection fraction (EF) and end-diastolic and end-systolic left ventricular lengths in 87 patients (aged 57 +/- 9 years) with left ventricular dysfunction (EF 24% +/- 6%). In 48 patients, we also assessed cytokine receptors. During follow-up (mean, 14 +/- 9 months), 8 patients died and 12 had new heart failure episodes that required hospital admission, 5 of whom underwent heart transplantation. The univariate predictors of these events were serum interleukin-6 (IL-6) (p = 0.00001), New York Heart Association (NYHA) functional class (p = 0.0004), tumor necrosis factor-soluble receptor I (p = 0. 001), atrial natriuretic peptide (p = 0.002), tumor necrosis factor-soluble receptor II (p = 0.004), angiotensin II (p = 0.006), serum interleukin-1 beta (p = 0.01), and plasma renin activity (p = 0.02). Increased serum interleukin-6 (>10 pg/ml) was a significant predictor of death or new heart failure episodes according to the Kaplan-Meier survival method by log-rank test (p = 0.004). By Cox regression analysis, serum IL-6 (p = 0.0005) and the NYHA functional class (p = 0.005) were identified as independent predictors of prognosis., Conclusions: In patients with congestive heart failure, increased serum IL-6 was identified as a powerful independent predictor of the combined end point: death, new heart failure episodes, and need for heart transplantation.

Objectives: To examine whether inducible nitric oxide synthase is expressed in myocardial tissue of patients with heart failure., Background: There is increasing evidence that alterations in nitric oxide synthesis are of pathophysiologic importance in heart failure. Nitric oxide (NO) can exert negative inotropic and cytotoxic effects on cardiomyocytes. A number of studies have shown altered nitric oxide production by the endothelial constitutive isoform of nitric oxide synthase (NOS III), but there is little information on the role of NOS II. Expression of NOS II could lead to excessive production of NO in the myocardium and affect cardiac contractility., Methods: NOS II mRNA expression in myocardial tissue of 18 patients with idiopathic dilated cardiomyopathy (DCM), 7 patients with ischemic cardiopathy and severe ventricular dysfunction (ISCH), 4 patients with acute myocardial infarction (AMI) and 11 controls. Serum concentration of NO2-/NO3- (NOx) was also measured., Results: NOS II gene expression occurred in all the patients with DCM, in 1 out of the 7 ISCH patients, in 2 out of the 4 patients with AMI and in none of the controls. Moreover, DCM patients showed a significant 6-fold increase in NOx concentration (253+/-47 nm/ml) as compared to controls (40+/-2 nm/ml) P < 0.001, a phenomenon not observed in ISCH patients (56+/-3 nm/ml)., Conclusions: NOS II expression occurs in failing human cardiac myocytes and can play an specific role in the pathogenesis of DCM.

Factors for predicting the prognosis of myelodysplastic syndromes (MDS) have been widely used over the last few years. The proportion of bone marrow blasts, number and severity of cytopenias, and cytogenetic abnormalities are the main prognostic factors and can be used in combination to determine prognostic scores capable of predicting the outcome with fairly high accuracy. Molecular biology parameters, such as RAS and p53 mutations, can also be of assistance in establishing a prognosis. Factors that predict responsiveness to therapy are usually the same as those that predict survival. Current prognostic scores are unable to identify the minority of patients who will have very long survivals and therefore require no treatment.

Despite multiple disparate prognostic risk analysis systems for evaluating clinical outcome for patients with myelodysplastic syndrome (MDS), imprecision persists with such analyses. To attempt to improve on these systems, an International MDS Risk Analysis Workshop combined cytogenetic, morphological, and clinical data from seven large previously reported risk-based studies that had generated prognostic systems. A global analysis was performed on these patients, and critical prognostic variables were re-evaluated to generate a consensus prognostic system, particularly using a more refined bone marrow (BM) cytogenetic classification. Univariate analysis indicated that the major variables having an impact on disease outcome for evolution to acute myeloid leukemia were cytogenetic abnormalities, percentage of BM myeloblasts, and number of cytopenias; for survival, in addition to the above, variables also included age and gender. Cytogenetic subgroups of outcome were as follows: "good" outcomes were normal, -Y alone, del(5q) alone, del(20q) alone; "poor" outcomes were complex (ie, > or = 3 abnormalities) or chromosome 7 anomalies; and "intermediate" outcomes were other abnormalities. Multivariate analysis combined these cytogenetic subgroups with percentage of BM blasts and number of cytopenias to generate a prognostic model. Weighting these variables by their statistical power separated patients into distinctive subgroups of risk for 25% of patients to undergo evolution to acute myeloid leukemia, with: low (31% of patients), 9.4 years; intermediate-1 (INT-1; 39%), 3.3 years; INT-2 (22%), 1.1 years; and high (8%), 0.2 year. These features also separated patients into similar distinctive risk groups for median survival: low, 5.7 years; INT-1, 3.5 years; INT-2, 1.2 years; and high, 0.4 year. Stratification for age further improved analysis of survival. Compared with prior risk-based classifications, this International Prognostic Scoring System provides an improved method for evaluating prognosis in MDS. This classification system should prove useful for more precise design and analysis of therapeutic trials in this disease.