HemaSphere最新文献

{"title":"NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities","authors":"Milad Rasouli,&nbsp;Selina Troester,&nbsp;Florian Grebien,&nbsp;Bianca F. Goemans,&nbsp;C. Michel Zwaan,&nbsp;Olaf Heidenreich","doi":"10.1002/hem3.70013","DOIUrl":"https://doi.org/10.1002/hem3.70013","url":null,"abstract":"<p>Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a heterogeneous molecular landscape. In the pediatric context, the <i>NUP98</i> gene is a frequent target of chromosomal rearrangements that are linked to poor prognosis and unfavorable treatment outcomes in different AML subtypes. The translocations fuse <i>NUP98</i> to a diverse array of partner genes, resulting in fusion proteins with novel functions. NUP98 fusion oncoproteins induce aberrant biomolecular condensation, abnormal gene expression programs, and re-wired protein interactions which ultimately cause alterations in the cell cycle and changes in cellular structures, all of which contribute to leukemia development. The extent of these effects is steered by the functional domains of the fusion partners and the influence of concomitant somatic mutations. In this review, we discuss the complex characteristics of NUP98 fusion proteins and potential novel therapeutic approaches for NUP98 fusion-driven AML.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive sequential genetic analysis delineating frequency, patterns, and prognostic impact of genomic dynamics in a real-world cohort of patients with lower-risk MDS","authors":"Paolo Mazzeo,&nbsp;Christina Ganster,&nbsp;John Wiedenhöft,&nbsp;Katayoon Shirneshan,&nbsp;Katharina Rittscher,&nbsp;Elzbieta B. Brzuszkiewicz,&nbsp;Doris Steinemann,&nbsp;Maximilian Schieck,&nbsp;Catharina Müller-Thomas,&nbsp;Hannes Treiber,&nbsp;Friederike Braulke,&nbsp;Ulrich Germing,&nbsp;Katja Sockel,&nbsp;Ekaterina Balaian,&nbsp;Julie Schanz,&nbsp;Uwe Platzbecker,&nbsp;Katharina S. Götze,&nbsp;Detlef Haase","doi":"10.1002/hem3.70014","DOIUrl":"10.1002/hem3.70014","url":null,"abstract":"<p>The acquisition of subsequent genetic lesions (clonal evolution, CE) and/or the expansion of existing clones (CEXP) contributes to clonal dynamics (CD) in myelodysplastic syndromes (MDS). Although CD plays an important role in high-risk patients in disease progression and transformation into acute myeloid leukemia (AML), knowledge about CD in lower-risk MDS (LR-MDS) patients is limited due to lack of robust longitudinal data considering the long clinically stable courses of the disease. In this retrospective analysis, we delineate the frequency and the prognostic impact of CD in an unselected real-world cohort of LR-MDS patients. We screened 68 patients with a median follow-up of 40.5 months and a median of 7.5 (range: 2–22) timepoints for CE and CEXP detected by chromosomal banding analysis, fluorescence in situ hybridization, sequencing, and molecular karyotyping. In 30/68 patients, 47 CE events and a CD rate of 1 event per 4 years were documented. Of note, patients with at least 1 CE event had an increased probability for subsequent treatment. Unexpectedly, CE did not correlate with inferior outcomes, which could be reasonably explained by CD detection triggering the subsequent start of a disease-modifying therapy.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of myeloid-derived suppressor cells in the peripheral blood and bone marrow of patients with chronic idiopathic neutropenia","authors":"Nikoleta Bizymi,&nbsp;Athina Damianaki,&nbsp;Nikoletta Aresti,&nbsp;Anastasios Karasachinidis,&nbsp;Zacharenia Vlata,&nbsp;Matthieu Lavigne,&nbsp;Emmanuel Dialynas,&nbsp;Niki Gounalaki,&nbsp;Irene Stratidaki,&nbsp;Grigorios Tsaknakis,&nbsp;Aristea Batsali,&nbsp;Irene Mavroudi,&nbsp;Maria Velegraki,&nbsp;Ioannis Sperelakis,&nbsp;Charalampos Pontikoglou,&nbsp;Panayotis Verginis,&nbsp;Helen A. Papadaki","doi":"10.1002/hem3.70005","DOIUrl":"10.1002/hem3.70005","url":null,"abstract":"&lt;p&gt;Chronic idiopathic neutropenia (CIN) is characterized by the persistent and unexplained reduction of peripheral blood (PB) absolute neutrophil counts (ANCs).&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; The pathogenesis of CIN has been associated with increased apoptosis of the granulocytic progenitor cells due to an inflammatory bone marrow (BM) microenvironment consisting of activated T lymphocytes, proinflammatory monocytes, and proapoptotic cytokines.&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt; The myeloid-derived suppressor cells (MDSCs) are immature myeloid cells, deviating from the standard differentiation pathway during emergency myelopoiesis, that display immunomodulatory properties mainly by suppressing T-cell responses. They are recognized by the immunophenotype CD11b&lt;sup&gt;+&lt;/sup&gt;CD33&lt;sup&gt;+&lt;/sup&gt;HLA-DR&lt;sup&gt;–/low&lt;/sup&gt; and further characterized as CD14&lt;sup&gt;+&lt;/sup&gt; (monocytic, M-MDSCs) and CD15&lt;sup&gt;+&lt;/sup&gt; (polymorphonuclear, PMN-MDSCs) subpopulations.&lt;span&gt;&lt;sup&gt;6-13&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In the present study, we explore, for the first time, the possible involvement of MDSCs in the pathophysiology of CIN by investigating their number, functional characteristics, and transcriptome profile in a group of patients (&lt;i&gt;n&lt;/i&gt; = 102) and age- and sex-matched healthy controls (&lt;i&gt;n&lt;/i&gt; = 77). The patients fulfilled the previously described diagnostic criteria for CIN (File S1).&lt;span&gt;&lt;sup&gt;2, 14, 15&lt;/sup&gt;&lt;/span&gt; Sixteen patients had clonal hematopoiesis identified by next-generation sequencing analysis of 40 recurrently mutated myeloid genes.&lt;span&gt;&lt;sup&gt;15&lt;/sup&gt;&lt;/span&gt; The clinical and laboratory data of the patients are presented in Supporting Information S1: Tables 1 and 2. The study was approved by the Institutional Review Board of the University Hospital of Heraklion and informed consent was obtained from all subjects.&lt;/p&gt;&lt;p&gt;MDSC subsets were quantitated and sorted by flow cytometry in the PB mononuclear cell (PBMC) and BM mononuclear cell (BMMC) fractions according to the recommended protocol.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The gating strategies for MDSC quantification and sorting are presented in Figure 1A,B respectively. The methodology of the T-cell suppression assay to evaluate the function of MDSCs was performed according to the recommended standards (File S1).&lt;span&gt;&lt;sup&gt;6, 18, 19&lt;/sup&gt;&lt;/span&gt; In brief, the suppression of normal T cells was demonstrated in a heterologous system including co-culture of immunomagnetically sorted carboxy-fluorescein succinimidyl ester (CFSE)-stained T cells with PMN-MDSCs or M-MDSCs (Figure 1C) and an autologous system including cultures of CFSE-stained PBMCs versus CD33-immunomagnetically depleted PBMCs (Figure 1D). To identify the biochemical and molecular parameters associated with MDSC characterization,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; we performed transcriptional profiling of MDSCs from patients (&lt;i&gt;n&lt;/i&gt; = 6) and healthy controls (&lt;i&gt;n&lt;/i&gt; = 5) using RNA sequencing (File S1 and Supporting Information S1: Table 3). The data were analyzed using the Gra","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic strategies and treatment sequencing in patients with chronic lymphocytic leukemia: An international study of ERIC, the European Research Initiative on CLL","authors":"Thomas Chatzikonstantinou,&nbsp;Lydia Scarfò,&nbsp;Eva Minga,&nbsp;Georgios Karakatsoulis,&nbsp;Dimitra Chamou,&nbsp;Jana Kotaskova,&nbsp;Gloria Iacoboni,&nbsp;Christos Demosthenous,&nbsp;Elisa Albi,&nbsp;Miguel Alcoceba,&nbsp;Salem Al-Shemari,&nbsp;Thérèse Aurran-Schleinitz,&nbsp;Francesca Bacchiarri,&nbsp;Sofia Chatzileontiadou,&nbsp;Rosa Collado,&nbsp;Zadie Davis,&nbsp;Marcos Daniel de Deus Santos,&nbsp;Maria Dimou,&nbsp;Elena Dmitrieva,&nbsp;David Donaldson,&nbsp;Gimena Dos Santos,&nbsp;Barbara Dreta,&nbsp;Maria Efstathopoulou,&nbsp;Shaimaa El-Ashwah,&nbsp;Alicia Enrico,&nbsp;Andrzej Frygier,&nbsp;Sara Galimberti,&nbsp;Andrea Galitzia,&nbsp;Eva Gimeno,&nbsp;Valerio Guarente,&nbsp;Romain Guieze,&nbsp;Sean Harrop,&nbsp;Eleftheria Hatzimichael,&nbsp;Yair Herishanu,&nbsp;José-Ángel Hernández-Rivas,&nbsp;Ozren Jaksic,&nbsp;Elżbieta Kalicińska,&nbsp;Kamel Laribi,&nbsp;Volkan Karakus,&nbsp;Arnon P. Kater,&nbsp;Bonnie Kho,&nbsp;Maria Kislova,&nbsp;Εliana Konstantinou,&nbsp;Maya Koren-Michowitz,&nbsp;Ioannis Kotsianidis,&nbsp;Zuzana Kubova,&nbsp;Jorge Labrador,&nbsp;Deepesh Lad,&nbsp;Luca Laurenti,&nbsp;Thomas Longval,&nbsp;Alberto Lopez-Garcia,&nbsp;Juan Marquet,&nbsp;Stanislava Maslejova,&nbsp;Carlota Mayor-Bastida,&nbsp;Biljana Mihaljevic,&nbsp;Ivana Milosevic,&nbsp;Fatima Miras,&nbsp;Riccardo Moia,&nbsp;Marta Morawska,&nbsp;Uttam K. Nath,&nbsp;Almudena Navarro-Bailón,&nbsp;Jacopo Olivieri,&nbsp;Irina Panovska-Stavridis,&nbsp;Maria Papaioannou,&nbsp;Cheyenne Pierie,&nbsp;Anna Puiggros,&nbsp;Gianluigi Reda,&nbsp;Gian M. Rigolin,&nbsp;Rosa Ruchlemer,&nbsp;Mattia Schipani,&nbsp;Annett Schiwitza,&nbsp;Yandong Shen,&nbsp;Tereza Shokralla,&nbsp;Martin Simkovic,&nbsp;Svetlana Smirnova,&nbsp;Dina S. A. Soliman,&nbsp;Stephan Stilgenbauer,&nbsp;Tamar Tadmor,&nbsp;Kristina Tomic,&nbsp;Eric Tse,&nbsp;Theodoros Vassilakopoulos,&nbsp;Andrea Visentin,&nbsp;Candida Vitale,&nbsp;George Vrachiolias,&nbsp;Vojin Vukovic,&nbsp;Renata Walewska,&nbsp;Zhenshu Xu,&nbsp;Munci Yagci,&nbsp;Lucrecia Yañez,&nbsp;Mohamed Yassin,&nbsp;Jana Zuchnicka,&nbsp;David Oscier,&nbsp;Alessandro Gozzetti,&nbsp;Panagiotis Panagiotidis,&nbsp;Francesc Bosch,&nbsp;Paolo Sportoletti,&nbsp;Blanca Espinet,&nbsp;Gerassimos A. Pangalis,&nbsp;Viola M. Popov,&nbsp;Stephen Mulligan,&nbsp;Maria Angelopoulou,&nbsp;Fatih Demirkan,&nbsp;Tomas Papajík,&nbsp;Bella Biderman,&nbsp;Roberta Murru,&nbsp;Marta Coscia,&nbsp;Constantine Tam,&nbsp;Antonio Cuneo,&nbsp;Gianluca Gaidano,&nbsp;Rainer Claus,&nbsp;Niki Stavroyianni,&nbsp;Livio Trentin,&nbsp;Darko Antic,&nbsp;Lukas Smolej,&nbsp;Olga B. Kalashnikova,&nbsp;Mark Catherwood,&nbsp;Martin Spacek,&nbsp;Sarka Pospisilova,&nbsp;Michael Doubek,&nbsp;Eugene Nikitin,&nbsp;Anastasia Chatzidimitriou,&nbsp;Paolo Ghia,&nbsp;Kostas Stamatopoulos","doi":"10.1002/hem3.70004","DOIUrl":"https://doi.org/10.1002/hem3.70004","url":null,"abstract":"&lt;p&gt;Novel small molecule inhibitors have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Indeed, BTK (BTKi) and BCL2 inhibitors (BCL2i) alone or in combination with each other or other compounds have proven superior to chemoimmunotherapy (CIT) in both the frontline and the relapsed/refractory (R/R) setting.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;ERIC, the European Research Initiative on CLL, conducted this international multicenter retrospective study focused on the era of CIT, aiming to (i) reveal the treatment patterns in the “real world” and (ii) assess the outcomes of patients who received frontline treatment between 2000 and 2016. Overall, 7382 patients with CLL (7134, 96.6%) or SLL (248, 3.4%) from 76 centers in 25 countries in five continents were included. The median age at diagnosis was 64 (interquartile range [IQR]: 56–71) years and the median age at first treatment was 66 (IQR: 58–74) years. The median follow-up was 7.33 (IQR: 4.56–10.81) years from diagnosis and 5.27 (IQR: 3.04–7.99) from first treatment. The vast majority of patients (6873/7134, 93.2%) received at least one line of chemotherapy or CIT; only 197/7134 (2.7%) received exclusively novel agents. Baseline characteristics and disease-specific biomarkers are listed in Supporting Information Material.&lt;/p&gt;&lt;p&gt;The most common first-line regimen was FCR (2609, 35.3%), mostly in young patients (median age at first treatment: 60 years, IQR: 54–66), followed by chlorambucil monotherapy (1293, 17.5%), mostly in older patients (median age at first treatment: 74 years, IQR: 65–80). BTKis as first-line treatment were used in 149/7134 (2%) patients who either participated in clinical trials and/or had &lt;i&gt;TP53&lt;/i&gt; aberrations; 20/7134 (0.3%) received frontline venetoclax-based regimens, all in the context of clinical trials (Figure 1). Detailed outcomes for the most common frontline regimens are provided in Supporting Information Material.&lt;/p&gt;&lt;p&gt;BTKis were the most common type of R/R treatment (1581/8145, 19.4%). Reflecting the approval of novel agents for patients with R/R CLL, the use of all types of chemotherapy and CIT decreased after 2014, except bendamustine plus rituximab (Figure 2).&lt;/p&gt;&lt;p&gt;There were 387 patients with an early (&lt;24 months) need for second-line treatment after 2016: 203/387 (52.4%) received chemotherapy and CIT, 147/387 (38%) novel agents (108/387 [27.9%] BTKi, 24/387 [6.2%] PI3Ki, and 15/387 [3.9%] venetoclax-based treatments), and 37/387 (9.6%) other treatments (Figure 2 &amp; File S1). ORR and discontinuation rates due to progression of patients treated with novel agents are given in the File S1.&lt;/p&gt;&lt;p&gt;Among patients treated with BTKi with or without anti-CD20 monoclonal antibodies (Mab), 55/567 (9.7%) discontinued treatment due to toxicity in second and 120/1014 (11.8%) in later lines. The median time to discontinuation was 5 months (95% confidence interval [CI]: 3.7–12.5) for patients treated in second line and 14 months (95% CI: 8–20.9) for patie","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Are we ready for disease modification in myeloproliferative neoplasms?","authors":"Claire N. Harrison","doi":"10.1002/hem3.70003","DOIUrl":"https://doi.org/10.1002/hem3.70003","url":null,"abstract":"&lt;p&gt;Myeloproliferative neoplasms (MPN) are chronic myeloid diseases characterized by clinical heterogeneity and disordered JAK/STAT signaling. For the purposes of this perspective, the three common MPN, essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), will be considered.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; These are closely related conditions as recognized by William Dameshek in 1951; in recent decades, multiple scientific and clinical advances have improved our understanding of their pathophysiology and outcomes for patients (&lt;i&gt;vida infra&lt;/i&gt;). Risks for these patients include reduced life expectancy due to thrombosis, hemorrhage, and disease transformation (Figure 1). However, while for other myeloid malignancies, notably chronic and acute myeloid leukemia, disease modification is largely measured by morphological and molecular responses correlating with survival benefits. Currently, the situation for MPN management is perceived to be less advanced. This may in part be due to the relatively late designation of MPN as a malignancy.&lt;/p&gt;&lt;p&gt;Here, we shall define disease modification as treatments or interventions that affect the underlying pathophysiology of the disease and have beneficial outcomes on the clinical course and address the question: “Are we ready for disease modification in MPN?”&lt;/p&gt;&lt;p&gt;Major clinical events for patients with MPN as stated above are thrombosis, hemorrhage, and disease transformation; particularly to myelofibrosis, these require long-term studies to assess. But in recent years, at least for treating myelofibrosis, attention has also been focused on splenomegaly and the impact of disease-related symptoms on quality of life as relevant endpoints.&lt;/p&gt;&lt;p&gt;Specifically, for ET and PV treatment, algorithms focus on risk stratification based on perceived thrombotic and, to a lesser extent, hemorrhagic risk but not on reducing disease transformation. Therapeutic approaches focus on addressing modifiable factors from the perspective of vascular disease; for example, smoking, obesity, and hypertension; venesection or phlebotomy in PV; followed by antiplatelet drugs and then, in selected patients, cytoreductive therapy.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The aim of cytoreductive therapy is thus to reduce thrombosis or hemorrhage. In PV, these approaches have been shown to reduce the risk of thrombosis. For example, in the CYTOPV study, hematocrit (HCT) target &lt;45% or 45%–50% at a median follow-up of 31 months; thrombotic events or deaths from vascular causes: &lt;45% HCT (2.7%); 45%–50% HCT (9.8%).&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Second, in the ECLAP study where low-dose aspirin compared to placebo was shown to reduce the risk of the end point of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes: (relative risk, 0.40; 95% confidence interval, 0.18–0.91; &lt;i&gt;p&lt;/i&gt; = 0.03).&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In MF, the advent of JAK inhibitor-based thera","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Informed consent is almost impossible","authors":"Louise Caldwell,&nbsp;Stephen P. Hibbs","doi":"10.1002/hem3.70002","DOIUrl":"https://doi.org/10.1002/hem3.70002","url":null,"abstract":"&lt;p&gt;Informed consent underpins the practice of medicine. Beyond signing a form, the consent process provides both space and time for patients to gain a better understanding of the practicalities of the treatment and to ask questions of their clinician. If done well, informed consent can enable patient autonomy, facilitate a better understanding of the short- and long-term implications of treatments, and share power with patients in the decision-making process.&lt;/p&gt;&lt;p&gt;But many of us will have encountered situations where ‘informed consent’ has been recorded, yet a myeloma patient is later surprised and distressed to learn that their chemotherapy was never expected to cure them. A study of over one thousand patients on palliative chemotherapy for lung or colorectal cancer found that the majority did not understand the intent of their treatment.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; While our consent practices may be acceptable within legal and bureaucratic norms, how often do patients truly understand the treatments we recommend and prescribe?&lt;/p&gt;&lt;p&gt;Some of the difficulty lies in the approach or capacity of the clinician. The consent process can become rushed, perfunctory and at times transactional. Even the terminology of ‘taking’ consent is telling, evoking a rushed conversation to extract a signature on a consent form so that treatment can commence.&lt;/p&gt;&lt;p&gt;Clinicians often draw arbitrarily sharp lines around decisions that require written consent and those that do not. The &lt;i&gt;written&lt;/i&gt; component may be less important than the ‘hard stop’ it provides to clinicians, requiring a detailed conversation with the patient before proceeding with treatment. Any chemotherapy—of whatever level of intensity—requires a formal written consent process. In contrast, steroids for immune thrombocytopenia, transfusions in sickle cell disease, or anticoagulation incurs significant risk, but consent practices for these interventions are minimal or inconsistent.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Aside from hurried clinicians, patients face other challenges during consent conversations. In fraught and high-stakes situations where patients are reeling from a new diagnosis of life-limiting cancer or are overwhelmed by symptoms of their disease, the intricacies of the treatment they are being consented for may seem marginal or irrelevant. The intensity and immediacy of illness can distort a patient's ability to ‘hear’ the risks of the treatment. Some may approach treatment with complete optimism, suppressing any imagining of risk or failure. Others may be unable to perceive any sort of future whilst confronting an overwhelming present. Can a person ever truly fathom the potential risks that accompany a treatment, when hope demands they believe they will escape them?&lt;/p&gt;&lt;p&gt;Some consent conversations are particularly demanding to both the clinician and the patient. In UK haemato-oncology practice, patients with a new diagnosis of acute leukaemia are invited to consent to whole-genome sequen","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The oral ferroportin inhibitor vamifeport prevents liver iron overload in a mouse model of hemochromatosis","authors":"Naja Nyffenegger,&nbsp;Anna Flace,&nbsp;Ahmet Varol,&nbsp;Patrick Altermatt,&nbsp;Cédric Doucerain,&nbsp;Hanna Sundstrom,&nbsp;Franz Dürrenberger,&nbsp;Vania Manolova","doi":"10.1002/hem3.147","DOIUrl":"https://doi.org/10.1002/hem3.147","url":null,"abstract":"<p>Hemochromatosis is an inherited iron overload condition caused by mutations that reduce the levels of the iron-regulatory hormone hepcidin or its binding to ferroportin. The hepcidin–ferroportin axis is pivotal to iron homeostasis, providing opportunities for therapeutic intervention in iron overload disorders like hemochromatosis. The aim of this study was to evaluate the efficacy of the oral ferroportin inhibitor vamifeport in the <i>Hfe</i> C282Y mouse model, which carries the most common mutation found in patients with hemochromatosis. A single oral dose of vamifeport lowered serum iron levels in <i>Hfe</i> C282Y mice, with delayed onset and shorter duration than observed in wild-type mice. Vamifeport induced transient hypoferremia by inhibiting ferroportin and resulted in a feedback regulation of liver <i>Hamp</i> in wild-type mice, which was absent in <i>Hfe</i> C282Y mice, reflecting the dysregulated systemic iron sensing in this hemochromatosis model. Chronic dosing with vamifeport led to sustained serum and liver iron reductions in <i>Hfe</i> C282Y mice, as well as markedly reducing liver <i>Hamp</i> expression in <i>Hfe</i> C282Y mice, suggesting distinct regulation of liver <i>Hamp</i> expression following acute or continuous iron restriction via vamifeport. At the tested dose, vamifeport retained its activity when combined with phlebotomy and did not significantly interfere with liver iron removal by phlebotomy in <i>Hfe</i> C282Y mice. These data demonstrate that chronic vamifeport treatment significantly reduces serum iron levels and prevents liver iron loading in the <i>Hfe</i> C282Y mouse model of hemochromatosis, thus providing preclinical proof of concept for the efficacy of vamifeport in hemochromatosis with or without phlebotomy.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.147","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Battle of the sexes: Understanding donor:recipient sex differences in transplantation biology","authors":"David G. Kent","doi":"10.1002/hem3.70000","DOIUrl":"https://doi.org/10.1002/hem3.70000","url":null,"abstract":"&lt;p&gt;Studying hematopoietic stem cell (HSC) function is most powerfully done with serial transplantation assays that can formally demonstrate the hallmark functional properties of durability, self-renewal, and multilineage differentiation capacity. Transplantation assays have taken many forms over the decades to provide evidence of HSC function, with mouse:mouse studies representing the bulk of studies to date. Competing for the limelight as a “gold standard” assay for nearly as long, however, is the human HSC:mouse recipient xenotransplantation assay, which has been powerfully used to help define the relative function of both normal HSCs and HSCs isolated from leukemia patients. The latter presents the most urgent need for establishing robust assays in the hematological community. It represents the opportunity to study the function of HSCs isolated from patients with the diseases that we are trying to cure. While there are a number of studies that have used human:human transplantations in clinical settings to study the dynamics of HSCs,&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; the ability to characterize leukemic HSCs at a detailed molecular level and to treat them with experimental compounds to potentially modify those clonal dynamics for therapeutic purposes remains extremely limited. This is where the xenotransplantation assay comes to the fore, but defining an agreed set of standards in the field is a complex business, and a recent study in &lt;i&gt;HemaSphere&lt;/i&gt; by Mian et al. sheds some light on one of the key factors in transplantation biology—sex differences.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Sex differences in transplantation have been known about for some time, although the studies do not always agree on the how's and why's of these differences. Single HSC transplantation studies in mouse:mouse donor:recipient pairs showed that male HSCs did not perform well in female recipients, potentially due to a weak antigen coded for by the Y chromosome.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Another study,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; in human:mouse xenotransplants, showed that female immunodeficient NOD/SCID/IL-2Rgc-null (NSG) mice were far superior as recipients of human cells with increases in both engraftment and proliferation of human HSCs (and this was also evidenced at the single-cell level). In this latter study, two potential reasons were speculated: first, that “female NSG mice might be more immunodeficient than males,” and second that “sex-associated factors, such as steroid hormones, can positively or negatively regulate human HSCs.” It is clear that sex matters, but with the emergence of new immunodeficient models and a general lack of comparative studies between male and female recipients, it is difficult to articulate a set of field recommendations for how to undertake xenotransplantation experiments with precious patient samples.&lt;/p&gt;&lt;p&gt;The recently published study by Mian et al.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; goes some way to addressing this. Using various immunodeficient mou","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human immunodeficiency virus-associated Lymphomas: EHA–ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","authors":"Kai Hübel,&nbsp;Mark Bower,&nbsp;Igor Aurer,&nbsp;Mariana Bastos-Oreiro,&nbsp;Caroline Besson,&nbsp;Uta Brunnberg,&nbsp;Chiara Cattaneo,&nbsp;Simon Collins,&nbsp;Kate Cwynarski,&nbsp;Alessia D. Pria,&nbsp;Marcus Hentrich,&nbsp;Christian Hoffmann,&nbsp;Marie J. Kersten,&nbsp;Silvia Montoto,&nbsp;Jose-Tomas Navarro,&nbsp;Eric Oksenhendler,&nbsp;Alessandro Re,&nbsp;Josep-Maria Ribera,&nbsp;Philipp Schommers,&nbsp;Bastian von Tresckow,&nbsp;Christian Buske,&nbsp;Martin Dreyling,&nbsp;Andy Davies,&nbsp;the EHA and ESMO Guidelines Committees","doi":"10.1002/hem3.150","DOIUrl":"https://doi.org/10.1002/hem3.150","url":null,"abstract":"&lt;p&gt;Non-Hodgkin lymphoma (NHL) remains the most common type of cancer and a leading cause of mortality in people who are living with human immunodeficiency virus (HIV).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; This is despite a marked decrease in the incidence of HIV-associated NHL (HIV–NHL) following the introduction of combination antiretroviral therapy (ART) in the mid-1990s.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; In contrast, the incidence of Hodgkin lymphoma (HL) increased slightly but has remained stable since 2000.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Compared with the age- and gender-matched general population, the incidences of HIV–NHL and HIV-associated HL (HIV–HL) are increased ~10- to 20-fold.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The most common histological types of HIV-associated lymphomas are diffuse large B-cell lymphoma (DLBCL; 37%), HL (26%) and Burkitt lymphoma (BL; 20%).&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Independent risk factors for DLBCL in people living with HIV (PLWH) include a low cluster of differentiation (CD)4 T-cell count and an uncontrolled HIV-1 viral load (VL).&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; The availability of ART and better management of opportunistic infections allow PLWH to receive the same treatments as people without HIV, including intensive therapies, such as autologous stem-cell transplantation (ASCT), allogeneic stem-cell transplantation (allo-SCT) and chimeric antigen receptor T-cell (CAR-T) therapy. Patients with HIV-associated lymphomas should be enrolled in clinical trials whenever possible.&lt;/p&gt;&lt;p&gt;The aim of this guideline is to provide practical clinical guidance and recommendations to clinicians who manage HIV-associated lymphomas.&lt;/p&gt;&lt;p&gt;Diagnostic procedures in patients with HIV-associated lymphoma generally mirror those recommended for lymphoma in the general population and those necessary to assess the severity and complications of HIV and its treatment (see Supporting Information S1: Table S1).&lt;/p&gt;&lt;p&gt;Lymphoma should be diagnosed via tumour biopsy, preferably excisional, that is evaluated by an expert haematopathologist using immunohistochemistry (IHC) and molecular techniques. In exceptional cases when no tumour mass can be biopsied, diagnosis can be made by cytology and flow cytometry.&lt;/p&gt;&lt;p&gt;Lymphoma staging should involve a contrast-enhanced computed tomography (CT) scan of the neck, chest, abdomen and pelvis and a bone marrow biopsy. A staging [&lt;sup&gt;18&lt;/sup&gt;F]2-fluoro-2-deoxy-&lt;span&gt;d&lt;/span&gt;-glucose (FDG)–positron emission tomography (PET)–CT scan is more sensitive, especially for extranodal disease. FDG–PET–CT may, however, have a higher false-positive rate in PLWH due to immune deficiency-related lymphoid hyperplasia and non-suppressed HIV infection.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Interim FDG–PET–CT (iFDG–PET–CT) results should, therefore, be interpreted cautiously if used to escalate treatment and when analysing end-of-treatment response; if there is doubt, FDG-avid lesions should be re-biopsied. Otherwise, response criteria do not differ from those used in imm","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.150","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142130443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA sequencing of pediatric Hodgkin lymphoma to study the inhibition of T cell subtypes","authors":"Jurrian K. de Kanter,&nbsp;Alexander S. Steemers,&nbsp;Daniel Montiel Gonzalez,&nbsp;Ravian L. van Ineveld,&nbsp;Catharina Blijleven,&nbsp;Niels Groenen,&nbsp;Laurianne Trabut,&nbsp;Marijn A. Scheijde-Vermeulen,&nbsp;Liset Westera,&nbsp;Auke Beishuizen,&nbsp;Anne C. Rios,&nbsp;Frank C. P. Holstege,&nbsp;Arianne M. Brandsma,&nbsp;Thanasis Margaritis,&nbsp;Ruben van Boxtel,&nbsp;Friederike Meyer-Wentrup","doi":"10.1002/hem3.149","DOIUrl":"10.1002/hem3.149","url":null,"abstract":"<p>Pediatric classic Hodgkin lymphoma (cHL) patients have a high survival rate but suffer from severe long-term side effects induced by chemo- and radiotherapy. cHL tumors are characterized by the low fraction (0.1%–10%) of malignant Hodgkin and Reed–Sternberg (HRS) cells in the tumor. The HRS cells depend on the surrounding immune cells for survival and growth. This dependence is leveraged by current treatments that target the PD-1/PD-L1 axis in cHL tumors. The development of more targeted therapies that are specific for the tumor and are therefore less toxic for healthy tissue compared with conventional chemotherapy could improve the quality of life of pediatric cHL survivors. Here, we applied single-cell RNA sequencing (scRNA-seq) on isolated HRS cells and the immune cells from the same cHL tumors. Besides <i>TNFRSF8</i> (CD30), we identified other genes of cell surface proteins that are consistently overexpressed in HRS cells, such as <i>NRXN3</i> and <i>LRP8</i>, which can potentially be used as alternative targets for antibody–drug conjugates or CAR T cells. Finally, we identified potential interactions by which HRS cells inhibit T cells, among which are the galectin-1/CD69 and HLA-II/LAG3 interactions. RNAscope was used to validate the enrichment of CD69 and LAG3 expression on T cells near HRS cells and indicated large variability of the interaction strength with the corresponding ligands between patients and between tumor tissue regions. In conclusion, this study identifies new potential therapeutic targets for cHL and highlights the importance of studying heterogeneity when identifying therapy targets, specifically those that target tumor-immune cell interactions.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}