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We describe a case of suspected “T-cell-mediated” hypereosinophilic syndrome presenting with cerebral watershed infarcts. An extensive search for potential embolic sources was negative, supporting the hypothesis that cerebrovascular endothelial dysfunction could have caused the infarcts.

Context: While the evidence supporting the benefits of integration of palliative care into cancer care for patients and informal caregivers is growing, it poses challenges for hematological cancer patients due to rapidly changing disease trajectories, uncertain prognosis, and diverse care needs., Objectives: This systematic review aims to provide an overview of the intervention components, the targeted outcomes, the effectiveness in improving patient and informal caregiver outcomes, and the implementation into clinical practice., Methods: We systematically searched PubMed (MEDLINE), EMBASE, CENTRAL, PsycINFO, and CINAHL in March 2023. The studies included described interventions in palliative care, with multiple components, targeting patients with hematological cancer and/or their informal caregivers, and producing primary data on effectiveness or implementation. Quality was assessed using the QualSyst tool., Results: We identified 19 reports on 16 different palliative care interventions, including four quasi-randomized controlled trials. These interventions were provided by secondary and tertiary palliative care providers in a hospital setting. Tertiary interventions significantly improved the most common patient outcomes, including pain, quality of life, symptom burden, depression, and anxiety. Meanwhile, secondary interventions were feasible and well-accepted by healthcare professionals and patients. Despite limited inclusion of informal caregivers, the results indicated significant improvements in quality of life and depression., Conclusion: While palliative care interventions are found to improve patient outcomes, future research is needed on the effectiveness of secondary palliative care interventions, integrating primary palliative care, and more reliable and frequent implementation measurements. More focus on informal caregivers and resource allocation based on patient needs is warranted., Competing Interests: Disclosure and Acknowledgments The authors confirm that there are no potential conflicts of interest concerning authorship or publication of this manuscript. All authors have thoroughly read and approved the manuscript and consent to its submission to JPSM. This manuscript has not been submitted or published elsewhere. During the preparation of this work the author(s) used OpenAI in order to make sentences or small parts of paragraphs more concise or easier to read. After using this tool/service, the primary author reviewed and edited the content as needed and takes full responsibility for the content of the publication. We would like to thank Katrien Alewaeters, head of the medical library and library information specialist, for supporting us in developing and evaluating the search string, and Lise Rosquin for taking the time to proofread this systematic review. Kom op Tegen Kanker (grant number: KOTK/2022/12451)., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Umbilical cord blood (UCB) is an alternative source of stem cells for patients lacking a 9/10 or 10/10 HLA identical donor. However, after UCB transplantation, time to engraftment and immune recovery are prolonged, increasing the risk of fatal complications. Mesenchymal stromal cells (MSC) can support hematopoietic engraftment and have immunosuppressive effects. The primary objective of this phase I/II multicenter study was to determine the feasibility and safety of UCB transplantation with co-infusion of third party MSC, as assessed by treatment related mortality (TRM) at day 100. Secondary objectives were engraftment, immune recovery, occurrence of graft versus host disease (GVHD), infections, disease free survival, relapse incidence and overall survival. Eleven patients were grafted according to this protocol. Allogeneic transplantation after co-infusion appears feasible with 18 % TRM at day 100. Engraftment data show a median time of 16 days to neutrophil and 27 days to platelet recovery, which is shorter than what is usually reported after UCB transplantation. Only 1 episode of acute GVHD was reported. In conclusion, MSC and UCB co-transplantation is feasible and might help overcome some of the drawbacks of UCB transplantation., Competing Interests: Conflicts of interest Helene Schoemans: reports having received personal fees from Incyte, Janssen, Novartis, Sanofi and from the Belgian Hematological Society (BHS), as well as research grants from Novartis and the BHS, all paid to her institution and not directly related to this work. She has also received non-financial support (travel grants) from Gilead, Pfizer, the EBMT (European Society for Blood and Marrow transplantation) and the CIBMTR (Center for International Bone Marrow Transplantation Research). The other authors (SP, ADB, TK, FB, CG, IVR, CL, EB, RS, YB) didn't report any conflicts of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Over the last decades, the survival of multiple myeloma (MM) patients has considerably improved. However, despite the availability of new treatments, most patients still relapse and become therapy-resistant at some point in the disease evolution. The mutation profile has an impact on MM patients' outcome, while typically evolving over time. Because of the patchy bone marrow (BM) infiltration pattern, the analysis of a single bone marrow sample can lead to an underestimation of the known genetic heterogeneity in MM. As a result, interest is shifting towards blood-derived liquid biopsies, which allow for a more comprehensive and non-invasive genetic interrogation without the discomfort of repeated BM aspirations. In this review, we compare the application potential for mutation profiling in MM of circulating-tumor-cell-derived DNA, cell-free DNA and extracellular-vesicle-derived DNA, while also addressing the challenges associated with their use.

Introduction: Two phase 3 studies demonstrated superior efficacy of intravenous daratumumab (DARA IV) plus bortezomib/melphalan/prednisone (ALCYONE) or lenalidomide/dexamethasone (Rd; MAIA) versus standard-of-care regimens for transplant-ineligible newly diagnosed multiple myeloma. In these studies, patients could switch from DARA IV to subcutaneous daratumumab (DARA SC) while receiving daratumumab monotherapy in ALCYONE (as of Cycle 11) or daratumumab plus Rd in MAIA. The phase 3 COLUMBA study demonstrated noninferiority of DARA SC to DARA IV. DARA SC reduced administration time, allowing patients to spend less time in healthcare settings, a relevant practical consideration for patient care in the COVID-19 pandemic/settings of limited healthcare resources., Methods: DARA SC 1800 mg was administered every 4 weeks, per approved dosing schedules. We evaluated safety and patient-reported experience (ALCYONE only) among patients who switched from DARA IV to DARA SC., Results: Fifty-seven patients in ALCYONE and 135 in MAIA switched to DARA SC. Three (2.2%; MAIA) patients reported injection-site reactions, all of which were mild. No infusion-related reactions occurred with DARA SC. In ALCYONE, >80% of patients preferred DARA SC over DARA IV. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 5.3% of patients in ALCYONE and 25.9% in MAIA; one (0.7%; MAIA) patient experienced a TEAE with an outcome of death., Conclusion: For transplant-ineligible newly diagnosed multiple myeloma, DARA SC (monotherapy/with Rd) was safe and preferred over DARA IV. ClinicalTrials.gov, NCT02195479/NCT02252172.

Allogeneic hematopoietic cell transplant (allo-HCT) provides the only potential route to long-term remission in patients diagnosed with blast phase transformation of myeloproliferative neoplasm (BP-MPN). We report on a large, retrospective European Society for Blood and Marrow Transplantation registry-based study of BP-MPN patients undergoing allo-HCT. BP-MPN patients undergoing first allo-HCT between 2005 and 2019 were included. A total of 663 patients were included. With a median follow-up of 62 months, the estimated 3-year overall survival (OS) was 36% (95% confidence interval [CI], 32-36). Factors associated with lower OS were Karnofsky Performance Score (KPS) <90 (hazard ratio [HR] 1.65, p < .001) and active disease at allo-HCT (HR 1.45, p < .001), whereas patients undergoing allo-HCT more recently associated with a higher OS (HR 0.96, p = .008). In a selected patient's population, the 3-year OS of patients undergoing allo-HCT in complete response (CR) and with a KPS ≥90 was 60%. KPS < 90 (HR 1.4, p = .001) and active disease (HR 1.44, p = .0004) were associated with a lower progression-free survival (PFS). Conversely, most recent allo-HCT associated with a higher PFS (HR 0.96, p = .008). Active disease at allo-HCT (HR 1.34, p = .03) was associated with a higher cumulative incidence of relapse (RI) and allo-HCT in earlier calendar years (HR 0.96, p = .02) associated with a lower RI. Last, KPS < 90 (HR 1.91, p < .001), active disease (HR 1.74, p = .003) and allo-HCT from mismatched related donors were associated with a higher non-relapse mortality (HR 2.66, p = .003). In this large series of BP-MPN patients, about one third were alive at 3 years after transplantation. Patients undergoing allo-HCT in the more recent era, with a KPS ≥90 and in CR at transplant had a better prognosis., (© 2023 Wiley Periodicals LLC.)

Purpose: The aim of the present study was to evaluate the role of ejection fraction (EF), left ventricular (LV) global longitudinal strain (LVGLS) and global constructive work (GCW) as prognostic variables in patients with cardiac amyloidosis (CA)., Methods: CA patients were retrospectively identified between 2015 and 2021 at a tertiary care hospital. Comprehensive clinical, biochemical, and imaging evaluation including two-dimensional (2D) echocardiography with myocardial work (MW) analysis was performed. A clinical combined endpoint was defined as all-cause mortality and heart failure readmission., Results: 70 patients were followed for 16 (7-37) months and 37 (52.9%) reached the combined endpoint. Patient with versus without clinical events had a significantly lower LVEF (40.71% vs. 48.01%, p = 0.039), LVGLS (-9.26 vs. -11.32, p = 0.034) and GCW (1034.47mmHg% vs. 1424.86mmHg%, p = 0.011). Multivariable analysis showed that LVEF ( odds ratio (OR): 0.904; 95% confidence interval (CI): 0.839-0.973, p = 0.007), LVGLS ( OR: 0.620; 95% CI: 0.415-0.926, p = 0.020) and GCW ( OR: 0.995; 95% CI: 0.990-0.999, p = 0.016) were significant predictors of outcome, but the model including GCW had the best discriminative ability to predict the combined endpoint (C-index = 0.888). A GCW less than 1443mmHg% was able to predict the clinical endpoint with a sensitivity of 94% and a specificity of 64% (Area under the curve (AUC): 0.771 (95% CI: 0.581-0.961; p = 0.005))., Conclusion: In CA patients, GCW may be of additional prognostic value to LVEF and GLS in predicting heart failure hospitalization and all-cause mortality., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Erythrocytosis is associated with increased red blood cell mass and can be either congenital or acquired. Congenital secondary causes are rare and include germline variants increasing haemoglobin (Hb)-oxygen affinity (e.g., Hb or bisphosphoglycerate mutase (BPGM) variants) or affecting oxygen-sensing pathway proteins. Here, we describe five adults from three kindreds with erythrocytosis associated with heterozygosity for BPGM variants, including one novel. Functional analyses showed partial BPGM deficiency, reduced 2,3-bisphosphoglycerate levels and/or increased Hb-oxygen affinity. We also review currently known BPGM variants. This study contributes to raising awareness of BPGM variants, and in particular that heterozygosity for BPGM deficiency may already manifest clinically., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The analysis of bone marrow (BM) samples in multiple myeloma (MM) patients can lead to the underestimation of the genetic heterogeneity within the tumor. Blood-derived liquid biopsies may provide a more comprehensive approach to genetic characterization. However, no thorough comparison between the currently available circulating biomarkers as tools for mutation profiling in MM has been published yet and the use of extracellular vesicle-derived DNA for this purpose in MM has not yet been investigated. Therefore, we collected BM aspirates and blood samples in 30 patients with active MM to isolate five different DNA types, i.e., cfDNA, EV-DNA, BM-DNA and DNA isolated from peripheral blood mononucleated cells (PBMNCs-DNA) and circulating tumor cells (CTC-DNA). DNA was analyzed for genetic variants with targeted gene sequencing using a 165-gene panel. After data filtering, 87 somatic and 39 germline variants were detected among the 149 DNA samples used for sequencing. cfDNA showed the highest concordance with the mutation profile observed in BM-DNA and outperformed EV-DNA, CTC-DNA and PBMNCs-DNA. Of note, 16% of all the somatic variants were only detectable in circulating biomarkers. Based on our analysis, cfDNA is the preferable circulating biomarker for genetic characterization in MM and its combined use with BM-DNA allows for comprehensive mutation profiling in MM.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT., (© 2022 by The American Society of Hematology.)

Background and Objectives: Belgian health authorities launched a national platform in 2011 to improve the quality of transfusion practices and blood use in Belgian hospitals. No data were available about the quality of hospital transfusion practice at the national level., Materials and Methods: Three consecutive national surveys (2012, 2014 and 2016) were performed in all 111 Belgian hospitals to assess the degree of implementation of standards in four process domains related to red blood cell (RBC) transfusion: general quality aspects, ordering of RBC, electronic traceability and reporting of adverse events. The surveys were part of a methodology based on informing, feedback and benchmarking. Responses to questions were analysed semi-quantitatively, and hospitals could score 10 points on each of the domains., Results: The proportion of hospitals scoring below 5 per domain decreased from 16%, 70%, 14% and 11% (2012) to 2%, 17%, 1% and 1% (2016), respectively. Similarly, scores above 7.5 increased from 25%, 1%, 23% and 36% (2012) to 64%, 30%, 68% and 81% (2016), respectively. In 2016, overall quality of transfusion practices, including the four pre-specified domains, improved continuously with an average total score (max = 40) increasing from 24.2 to 30.5 (p = 0.0005). In addition, there was a decrease in the number of distributed and transfused RBC per 1000 population between 2011 and 2019 from 47.0 to 36.5 and 43.5 to 36.1, respectively., Conclusion: These data show that the applied methodology was a powerful tool to improve quality of transfusion practices and to optimize utilization of RBC at the national level., (© 2021 International Society of Blood Transfusion.)

Detection of minimal residual disease (MRD) to guide therapy has been a standard practice in treatment of childhood acute lymphoblastic leukemia (ALL) for decades. In multiple myeloma (MM), a clear correlation is found between absence of MRD and longer survival. Quantitative allele-specific oligonucleotide (qASO)-PCR is the standard molecular method for MRD detection in these hematologic malignant tumors. However, this technique has some drawbacks that can be overcome by next-generation sequencing (NGS). In this study, NGS is validated as an alternative method for qASO-PCR for MRD detection in both ALL and MM. MRD results obtained by NGS and qASO-PCR were compared in 59 and 39 bone marrow samples of 33 and 14 patients with ALL and MM, respectively. Our results indicate that the use of gBlocks as calibrators makes the NGS approach a powerful tool to quantify MRD. With an input of 400 ng of DNA (corresponding to approximately 7 × 10 4 cells), a limit of detection of 0.01% can be achieved. The specificity of the NGS-MRD technique was 100%, and a correlation with qASO-PCR for quantifiable MRD results of 0.93 and 0.91 was found in ALL and MM, respectively. Especially for MM, the higher applicability (100%) of the NGS-MRD protocol, compared with qASO-PCR (57%), was clearly demonstrated. These results demonstrate that NGS is an even better alternative to qASO-PCR., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Study Question: Can oocytes extracted from excised ovarian tissue and matured in vitro be a useful adjunct for urgent fertility preservation (FP)?, Summary Answer: Ovarian tissue oocyte in-vitro maturation (OTO-IVM) in combination with ovarian tissue cryopreservation (OTC) is a valuable adjunct technique for FP., What Is Known Already: Despite the impressive progress in the field, options for FP for cancer patients are still limited and, depending on the technique, clinical outcome data are still scarce., Study Design, Size, Duration: This was a retrospective cohort study conducted at a university hospital-affiliated fertility clinic between January 2012 and May 2019., Participants/materials, Setting, Methods: The study included 77 patients who underwent unilateral oophorectomy for OTC. Cumulus-oocyte complexes (COCs) obtained during ovarian tissue processing were matured in vitro for 28-42 h. Oocytes reaching metaphase II stage were vitrified or inseminated for embryo vitrification., Main Results and the Role of Chance: Overall, 1220 COCs were collected. The mean oocyte maturation rate was 39% ± 23% (SD). There were 64 patients who had vitrification of oocytes (6.7 ± 6.3 oocytes per patient). There were 13 patients who had ICSI of mature oocytes after IVM, with 2.0 ± 2.0 embryos vitrified per patient. Twelve patients have returned to the clinic with a desire for pregnancy. For seven of these, OTO-IVM material was thawed. Two patients had OTO-IVM oocytes warmed, with survival rates of 86% and 60%. After ICSI, six oocytes were fertilised in total, generating three good quality embryos for transfer, leading to a healthy live birth for one patient. In five patients, for whom a mean of 2.0 ± 0.8 (SD) embryos had been vitrified, seven embryos were warmed in total: one embryo did not survive the warming process; two tested genetically unsuitable for transfer; and four were transferred in separate cycles to three different patients, resulting in two healthy babies. In this small series, the live birth rate per patient after OTO-IVM, ICSI and embryo transfer was 43%., Limitations, Reasons for Caution: The retrospective study design and the limited sample size should be considered when interpreting results., Wider Implications of the Findings: The results of the study illustrate the added value of OTO-IVM in combination with OTC. We report the first live birth following the use of this appended technique combined with oocyte vitrification., Study Funding/competing Interest(s): No external funding was used for this study. M.D.V. reports honoraria for lectures in the last 2 years from MSD and Ferring, outside the submitted work, as well as grant support from MSD. The other authors have nothing to declare., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The incidence, the clinical characteristics, and the outcome of Kaposi sarcoma (KS) in patients after hematopoietic stem cell transplantation (HSCT) were assessed. During the period 1987-2018, 13 cases of KS were diagnosed, 3 females and 10 males, median age of 50 years, median time from HSCT of 7 months. KS had an incidence of 0.17% in allogeneic and 0.05% in autologous HSCT. HHV-8 was documented in eight of nine tumor tissue samples assessed. The organ involvement was: skin in nine, lymph nodes in six, oral cavity in four, and visceral in three patients, respectively; seven patients had >1 organ involved. Five patients had immunosuppression withdrawn, whereas four and three patients received radiotherapy and chemotherapy, respectively. Eight patients are alive (median follow-up 48 months, range 5-128), whereas five patients died after a median time of 8 months from the diagnosis of KS. However, no death was caused by KS. We conclude that the incidence of KS after HSCT is very low. Although KS can be managed with the reduction of immunosuppression, visceral forms may require chemotherapy and/or radiotherapy. The low prevalence of KS indicates that screening for HHV-8 serology and surveillance for HHV-8 viremia are not indicated in HSCT patients.

Multiple myeloma (MM) is well-known for the development of drug resistance, leading to relapse. Therefore, finding novel treatment strategies remains necessary. By performing a lipidomics assay on MM patient plasma, we aimed to identify new targets. We observed a dysregulation in the sphingolipid metabolism, with the upregulation of several ceramides and downregulation of sphingomyelin. This imbalance suggests an increase in sphingomyelinase, the enzyme responsible for hydrolyzing sphingomyelin into ceramide. We confirmed the upregulation of acid sphingomyelinase (ASM) in primary MM cells. Furthermore, we observed an increase in ASM expression in MM cell lines treated with melphalan or bortezomib, as well as in their exosomes. Exosomes high in ASM content were able to transfer the drug-resistant phenotype to chemosensitive cells, hereby suggesting a tumor-protective role for ASM. Finally, inhibition of ASM by amitriptyline improved drug sensitivity in MM cell lines and primary MM cells. In summary, this study is the first to analyze differences in plasma lipid composition of MM patients and match the observed differences to an upregulation of ASM. Moreover, we demonstrate that amitriptyline is able to inhibit ASM and increase sensitivity to anti-myeloma drugs. This study, therefore, provides a rational to include ASM-targeting-drugs in combination strategies in myeloma patients., Competing Interests: The authors declare no conflict of interest.

Recent advances in the treatment of multiple myeloma have increased the need for accurate diagnosis of the disease. The detection of bone and bone marrow lesions is crucial in the investigation of multiple myeloma and often dictates the decision to start treatment. Furthermore, detection of minimal residual disease is important for prognosis determination and treatment planning, and it has underscored an unmet need for sensitive imaging methods that accurately assess patient response to multiple myeloma treatment. Low-dose whole-body CT has increased sensitivity compared with conventional skeletal survey in the detection of bone disease, which can reveal information leading to changes in therapy and disease management that could prevent or delay the onset of clinically significant morbidity and mortality as a result of skeletal-related events. Given the multiple options available for the detection of bone and bone marrow lesions, ranging from conventional skeletal survey to whole-body CT, PET/CT, and MRI, the International Myeloma Working Group decided to establish guidelines on optimal use of imaging methods at different disease stages. These recommendations on imaging within and outside of clinical trials will help standardise imaging for monoclonal plasma cell disorders worldwide to allow the comparison of results and the unification of treatment approaches for multiple myeloma., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Progression of multiple myeloma (MM) is largely dependent on the bone marrow (BM) microenvironment wherein communication through different factors including extracellular vesicles takes place. This cross-talk not only leads to drug resistance but also to the development of osteolysis. Targeting vesicle secretion could therefore simultaneously ameliorate drug response and bone disease. In this paper, we examined the effects of MM exosomes on different aspects of osteolysis using the 5TGM1 murine model. We found that 5TGM1 sEVs, or 'exosomes', not only enhanced osteoclast activity, they also blocked osteoblast differentiation and functionality in vitro. Mechanistically, we could demonstrate that transfer of DKK-1 led to a reduction in Runx2, Osterix, and Collagen 1A1 in osteoblasts. In vivo, we uncovered that 5TGM1 exosomes could induce osteolysis in a similar pattern as the MM cells themselves. Blocking exosome secretion using the sphingomyelinase inhibitor GW4869 not only increased cortical bone volume, but also it sensitized the myeloma cells to bortezomib, leading to a strong anti-tumor response when GW4869 and bortezomib were combined. Altogether, our results indicate an important role for exosomes in the BM microenvironment and suggest a novel therapeutic target for anti-myeloma therapy.

High-count monoclonal B cell lymphocytosis (MBL) with a chronic lymphocytic leukemia (CLL) phenotype is a well-known entity, featuring 1-4% annual risk of progression towards CLL requiring treatment. Lymphoma-like MBL (L-MBL), on the other hand, remains poorly defined and data regarding outcome are lacking. We retrospectively evaluated 33 L-MBL cases within our hospital population and compared them to 95 subjects with CLL-like MBL (C-MBL). Diagnoses of L-MBL were based on asymptomatic B cell clones with Matutes score < 3, B cells < 5.0 × 10 3 /μl, and negative computerized tomography scans. We found that median B cell counts were considerably lower compared to C-MBL (0.6 vs 2.3 × 10 3 /μl) and remained stable over time. Based on immunophenotyping and immunogenetic profiling, most L-MBL clones did not correspond to known lymphoma entities. A strikingly high occurrence of paraproteinemia (48%), hypogammaglobulinemia (45%), and biclonality (21%) was seen; these incidences being significantly higher than in C-MBL (17, 21, and 5%, respectively). Unrelated monoclonal gammopathy of undetermined significance was a frequent feature, as the light chain type of 5/12 paraproteins detected was different from the clonal surface immunoglobulin. After 46-month median follow-up, 2/24 patients (8%) had progressed towards indolent lymphoma requiring no treatment. In contrast, 41% of C-MBL cases evolved to CLL and 17% required treatment. We conclude that clinical L-MBL is characterized by pronounced immune dysregulation and very slow or absent progression, clearly separating it from its CLL-like counterpart.

Background: The treatment of advanced cancer often involves potentially life-shortening end-of-life decisions (ELDs). This study aimed to examine the prevalence and characteristics of ELDs in different cancer types., Methods: A nationwide death certificate study was conducted based on a large random sample of all deaths in Flanders, Belgium, between 1 January and 30 June 2013. All cancer deaths were selected (n = 2392). Attending physicians were sent a questionnaire about ELDs and the preceding decision-making process., Results: The response rate was 58.3%. Across cancer types, a non-treatment decision occurred in 7.6-14.0%, intensified pain and symptom alleviation in 37.5-41.7%, euthanasia or physician-assisted suicide in 8.7-12.6%, and life shortening without explicit patient request in 1.0-2.4%. ELD prevalence did not differ significantly by cancer type. Reasons for ELDs were most frequently patient's physical suffering and lack of prospect of improvement. 'Anticipated further suffering' and 'unbearable situation for relatives' were reasons more often reported in haematological cancer than in other cancer types. Patient, family, and caregiver involvement in decision-making did not differ across cancer types., Conclusions: Euthanasia or physician-assisted suicide rates were relatively high in all cancer types. Neither the prevalence of ELDs nor characteristics of the decision-making process differed substantially between cancer types. This indicates a uniform approach to end-of-life care, including palliative care, across oncological settings.

Lenalidomide is a potent anti-myeloma drug with immunomodulatory properties. It is increasingly used in a low-dose maintenance setting to prolong remission duration after standard treatment. Data on the in vivo effects of lenalidomide are scarce and sometimes different from the well-described in vitro effects. We therefore evaluated the numerical, phenotypical and functional impact of lenalidomide maintenance on several immune cell types in a cohort of seventeen homogeneously treated myeloma patients achieving a low residual myeloma burden after a bortezomib based-induction followed by autologous stem cell transplantation. Lenalidomide maintenance: 1) increased the fraction of naïve CD8 + T cells and several memory T-cell subsets, 2) reduced the numbers of terminal effector CD8 + T cells, 3) resulted in a higher expression of co-stimulatory molecules on resting T cells and of the inhibitory checkpoint molecules LAG-3 on CD4 + T cells and TIM-3 on CD4 + and CD8 + T cells, 4) reduced the number of TIGIT + CD8 + T cells, 5) increased the number of regulatory T cells with a phenotype associated with strong suppressive capacity. Purified CD8 + T cells showed increased and more polyfunctional recall viral responses. However, PBMC responses were not enhanced during lenalidomide maintenance and CD4 + T-cell responses specific for the myeloma-associated antigen MAGE-C1 even tended to become lower. We conclude that lenalidomide maintenance after autologous stem cell transplantation has complex pleotropic effects on the immune environment. Immune interventions such as anti-myeloma vaccination should include measures to tackle an expanded inhibitory Treg compartment., Competing Interests: CONFLICTS OF INTEREST None.

The deletion (5q) karyotype (del [5q]) in patients with myelodysplastic syndrome (MDS) is the most common karyotypic abnormality in de novo MDS. An increased number of blasts and additional karyotypic abnormalities (del [5q]+) are associated with a poor outcome. We analyzed the outcome of allogeneic hematopoietic cell transplants (HCT) in patients suffering from MDS with only del (5q) or del (5q)+ . A total of 162 patients, of median age 54 years (range, 9 to 73), having MDS and del (5q) abnormalities received HCT from identical siblings (n = 87) or unrelated donors (n = 75). The cumulative incidence of nonrelapse mortality and relapse incidence at 4 years was 29% (95% CI, 22 to 36) and 46% (95% CI, 38 to 54), whereas the estimated 4 year survival, relapse-free and overall, was 25% (95% CI, 18 to 33) and 30% (95% CI, 23 to 38), respectively. In a multivariate analysis patients with del (5q) and a blast excess displayed poorer survival (hazard ratio, 2.38; 95% CI, 1.44 to 3.93; P < .001), whereas female recipient sex resulted in improved survival (hazard ratio, .61; 95% CI, .41 to .90; P = .01). We conclude that allogeneic HCT can cure a subset of patients with MDS and a del (5q) abnormality., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Atypical chronic myeloid leukaemia (aCML) is an aggressive malignancy for which allogeneic haematopoietic stem cell transplantation (allo-HSCT) represents the only curative option. We describe transplant outcomes in 42 patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who underwent allo-HSCT for aCML between 1997 and 2006. Median age was 46 years. Median time from diagnosis to transplant was 7 months. Disease status was first chronic phase in 69%. Donors were human leucocyte antigen (HLA)-identical siblings in 64% and matched unrelated (MUD) in 36%. A reduced intensity conditioning was employed in 24% of patients. T-cell depletion was applied in 87% and 26% of transplants from MUD and HLA-identical siblings, respectively. According to the EBMT risk-score, 45% of patients were 'low-risk', 31% 'intermediate-risk' and 24% 'high-risk'. Following allo-HSCT, 87% of patients achieved complete remission. At 5 years, relapse-free survival was 36% and non-relapse mortality (NRM) was 24%, while relapse occurred in 40%. Patient age and the EBMT score had an impact on overall survival. Relapse-free survival was higher in MUD than in HLA-identical sibling HSCT, with no difference in NRM. In conclusion, this study confirmed that allo-HSCT represents a valid strategy to achieve cure in a reasonable proportion of patients with aCML, with young patients with low EBMT risk score being the best candidates., (© 2017 John Wiley & Sons Ltd.)

Overcoming drug resistance is one of the greatest challenges in the treatment of multiple myeloma (MM). The interaction of myeloma cells with the bone marrow (BM) microenvironment is a major factor contributing to drug resistance. Tumour-associated macrophages (TAMs) with different polarization states constitute an important component of this microenvironment. Previous studies have revealed a role of TAMs in MM cell survival and drug resistance; however, the impact of macrophage polarization (anti-tumoural 'M1' versus pro-tumoural 'M2'-like phenotype) in this process has not yet been described. Here, the presence of TAMs was confirmed in BM sections from MM patients, both at diagnosis and relapse, with two M2 markers, CD163 and CD206. By following different TAM subpopulations during disease progression in the syngeneic murine 5T33MM model, we demonstrated a decrease in the number of inflammatory monocytes and an increase in the number of M2-oriented TAMs in BM. Co-culture experiments demonstrated that macrophages provide a survival benefit to myeloma cells that is maintained after treatment with several classes of anti-myeloma agent (melphalan and bortezomib); the greatest effect was observed with M2-polarized macrophages. The pro-survival effect was associated with activation of the STAT3 pathway in 5T33MM cells, less cleavage of caspase-3, and thus less apoptosis. AZD1480, an ATP-competitive JAK2 inhibitor, abrogated the observed TAM-mediated MM cell survival, and partially inhibited resistance to bortezomib. Despite having only a small quantitative impact on myeloid cells in vivo, AZD1480 treatment alone and in combination with bortezomib significantly reduced tumour load. In conclusion, M2 TAMs are present in the MM microenvironment, and contribute to MM cell survival and protection from drug-induced apoptosis. As a result of TAM-induced activation of the STAT3 pathway, 5T33MM cells are sensitized to AZD1480 treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The bone marrow (BM) represents a complex microenvironment containing stromal cells, immune cells, osteoclasts, osteoblasts, and hematopoietic cells, which are crucial for the immune response, bone formation, and hematopoiesis. Apart from soluble factors and direct cell-cell contact, extracellular vesicles (EVs), including exosomes, were recently identified as a third mediator for cell communication. Solid evidence has already demonstrated the involvement of various BM-derived cells and soluble factors in the regulation of multiple biological processes whereas the EV-mediated message delivery system from the BM has just been explored in recent decades. These EVs not only perform physiological functions but can also play a role in cancer development, including in Multiple Myeloma (MM) which is a plasma cell malignancy predominantly localized in the BM. This review will therefore focus on the multiple functions of EVs derived from BM cells, the manipulation of the BM by cancer-derived EVs, and the role of BM EVs in MM progression., Competing Interests: The authors declare no conflict of interest.

Background: Kaposi's sarcoma (KS) is a tumor formed by angioproliferations driven by Human herpes virus 8 also known as Kaposi's sarcoma-associated herpes virus (KSHV). It is best known as an acquired immune deficiency syndrome (AIDS) defining illness that may be fatal. There are only a few reports of KS after hematopoietic cell transplantation (HCT). This is the first case describing the disappearance of KS with immune recovery after autologous HCT., Case Presentation: We present the case of a 61-year-old male heterosexual patient of Moroccan origin treated for primary mediastinal non-Hodgkin lymphoma. Because of refractory disease he received multiple lines of chemotherapy prior to autologous HCT. After the second course of low-dose bis-chloroethylnitrosourea, etoposide, cytarabine, melphalan (BEAM) the patient developed several round blue skin lesions. A biopsy was performed, showing many small vessels and positive immune histochemical staining for Human herpes virus 8 (HHV-8), confirming diagnosis of KS. Human immunodeficiency virus testing was negative and work-up showed that there were no visceral lesions. When KS are limited to the skin, prognosis is usually better. The extensive chemotherapy resulted in an important immunosuppression; on day 105 after autologous HCT CD4(+) count was 82/mm(3). Since KS were limited to the skin and attributed to severe immune suppression a watchful waiting strategy was adopted even though in the first months after autologous HCT new skin lesions appeared. With immune recovery (CD4(+) count > 200/mm(3)) 277 days after transplant, skin lesions faded., Conclusion: Kaposi's sarcoma remains a rare tumor that should be thought of in any patient whose immunity is down. If immune recovery is expected and disease is limited to the skin, a watchful waiting strategy can be more rewarding than intensive chemotherapy.

Renal impairment is associated with poor prognosis in myeloma. This analysis of the pivotal phase 3 FIRST trial examined the impact of renally adapted dosing of lenalidomide and dexamethasone on outcomes of patients with different degrees of renal impairment. Transplant-ineligible patients not requiring dialysis were randomized 1:1:1 to receive continuous lenalidomide and dexamethasone until disease progression (n=535) or for 18 cycles (72 weeks; n=541), or melphalan, prednisone, and thalidomide for 12 cycles (72 weeks; n=547). Follow-up is ongoing. Patients were grouped by baseline creatinine clearance into no (≥ 80 mL/min [n=389]), mild (≥ 50 to < 80 mL/min [n=715]), moderate (≥ 30 to < 50 mL/min [n=372]), and severe impairment (< 30 mL/min [n=147]) subgroups. Continuous lenalidomide and dexamethasone therapy reduced the risk of progression or death in no, mild, and moderate renal impairment subgroups vs. melphalan, prednisone, and thalidomide therapy (HR = 0.67, 0.70, and 0.65, respectively). Overall survival benefits were observed with continuous lenalidomide and dexamethasone treatment vs. melphalan, prednisone, and thalidomide treatment in no or mild renal impairment subgroups. Renal function improved from baseline in 52.6% of lenalidomide and dexamethasone-treated patients. The safety profile of continuous lenalidomide and dexamethasone was consistent across renal subgroups, except for grade 3/4 anemia and rash, which increased with increasing severity of renal impairment. Continuous lenalidomide and dexamethasone treatment, with renally adapted lenalidomide dosing, was effective for most transplant-ineligible patients with myeloma and renal impairment. Trial registration: ClinicalTrials.gov (NCT00689936); EudraCT (2007-004823-39). Funding: Intergroupe Francophone du Myélome and the Celgene Corporation., (Copyright© Ferrata Storti Foundation.)

Little is known about the prognostic impact of prior paclitaxel therapy and response to induction chemotherapy defined as the regimen preceding high-dose chemotherapy (HDCT) for the salvage therapy of advanced germ cell tumors. Twenty European Society for Blood and Marrow Transplantation centers contributed data on patients treated between 2002 and 2012. Paclitaxel used in either prior lines of therapy or in induction-mobilization regimens was considered. Multivariable Cox analyses of prespecified factors were undertaken on PFS and overall survival (OS). As of October 2013, data for 324 patients had been contributed to this study. One hundred and ninety-two patients (59.3%) had received paclitaxel. Sixty-one patients (19%) had a progression to induction chemotherapy, 234 (72%) a response (29 (9%) missing or granulocyte colony-stimulating factor without chemotherapy). Both progression to induction chemotherapy and prior paclitaxel were significantly associated with shorter OS univariably (P<0.001 and P=0.032). On multivariable analysis from the model with fully available data (N=216) progression to induction was significantly prognostic for PFS and OS (P=0.003), but prior paclitaxel was not (P=0.674 and P=0.739). These results were confirmed after multiple imputation of missing data. Progression to induction chemotherapy could be demonstrated as an independent prognostic factor, in contrast to prior paclitaxel.