Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients.

BACKGROUND: A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome'). OBJECTIVES: To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome. METHODS: One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow-up, were recorded. RESULTS: The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow-up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild-to-moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C-reactive protein levels and less frequent chondritis). The 5-year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis. CONCLUSIONS: VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.

Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.

Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53 VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53 VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53 VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2 VAF predicted for monocytosis (P=0.003), RUNX1 VAF with thrombocytopenia (P=0.01) and SF3B1 with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS.

Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI.

Graft failure remains a severe complication of hematopoietic stem cell transplantation (HSCT). Several risk factors have already been published. In this study, we re-evaluated them in a large cohort who had the benefit of the recent experience in HSCT (2006-2012). Data from 4684 unrelated donor HSCT from 2006 to 2012 were retrospectively collected from centers belonging to the French Society for Stem Cell Transplantation. Among the 2716 patients for whom HLA typing was available, 103 did not engraft leading to a low rate of no engraftment at 3.8%. In univariate analysis, only type of disease and status of disease at transplant for malignant diseases remained significant risk factors (P=0.04 and P<0.0001, respectively). In multivariate analysis, only status of disease was a significant risk factor (P<0.0001). Among the 61 patients who did not engraft and who were mismatched for 1 HLA class I and/or HLA-DP, 5 donor-specific antibodies (DSAs) were detected but only 1 was clearly involved in graft failure, for the others their role was more questionable. Second HSCT exhibited a protective although not statistically significant effect on OS (hazard ratio=0.57 [0.32-1.02]). In conclusion, only one parameter (disease status before graft) remains risk factor for graft failure in this recent cohort.

[Left auricle myxoma, a rare cause of myocardial infarction]. / Le myxome de l'oreillette gauche, une cause rare d'infarctus du myocarde.

INTRODUCTION: The association of left auricle myxoma and myocardial infarction is exceptional. Nevertheless, a causal relationship exists between the 2 affections. OBSERVATION: A 54 year-old woman was hospitalised in a rush for myocardial infarction. Sonography revealed a voluminous tumoral formation in the left auricle. The diagnosis of myxoma was confirmed by the anatomopathological examination. DISCUSSION: Although systemic embolism represents the most frequent causal link between left auricle myxoma and myocardial infarction, hypercoagulability is another possible cause. This can be explained by the secretion of interleukins 6 and 8 by the myxoma.

[New tools and treatments in myelodysplastic syndromes]. / Nouveaux outils et traitements pour les syndromes myélodysplasiques.

Over the last decade, physicians and researchers have increasingly focused their interest in myelodysplastic syndromes. With the general ageing population, these diseases have become more common. Several clinical and fundamental studies have also permitted a better understanding of those disorders and to propose new therapeutic strategies. Large scale genomic analyses have allowed identifying new genes involved in the pathophysiology of this diseases. In the next future, classification of myelodysplastic syndromes will include a cartography of different molecular markers at diagnosis that could help in treatment decision making, as it is increasingly the case in acute myeloid leukemia.

Total genomic alteration as measured by SNP-array-based molecular karyotyping is predictive of overall survival in a cohort of MDS or AML patients treated with azacitidine.

Metaphase cytogenetics (MC) has a major role in the risk stratification of patients with myelodysplastic syndromes (MDSs) and can affect the choice of therapies. Azacitidine (AZA) has changed the outcome of patients with MDS or acute myeloid leukemia (AML) unfit for intensive chemotherapy. Identification of patients without the benefit of AZA would allow AZA combination or other drugs in first-line treatments. New whole-genome scanning technologies such as single nucleotide polymorphism microarray (SNP-A)-based molecular karyotyping (MK) improve the risk stratification in MDS and AML. Maintenance of genomic integrity is less than three megabases (Mbs) total disruption of the genome correlated with better overall survival (OS) in patients with lower-risk MDS. In this SNP-A study, we aimed at defining a cutoff value for total genomic copy number (CN) alterations (TGA) influencing the median OS in a cohort of 51 higher-risk MDS/AML patients treated with AZA. We observed that the relative risk of worse OS increased >100 Mb of TGA, as detected by SNP-A-based MK (8 and 15 months respectively, P=0.02). Our data suggest that precise measurement of TGA could provide predictive information in poor and very poor revised International Prognostic Scoring system (IPSS-R) patients treated with AZA.

The caspase 6 derived N-terminal fragment of DJ-1 promotes apoptosis via increased ROS production.

In pathological conditions, the amount of DJ-1 determines whether a cell can survive or engage a cell death program. This is exemplified in epithelial cancers, in which DJ-1 expression is increased, while autosomal recessive early onset Parkinson's disease mutations of DJ-1 generally lead to decreased stability and expression of the protein. We have shown previously that DJ-1 is cleaved by caspase-6 during induction of apoptosis. We demonstrate here that the N-terminal cleaved fragment of DJ-1 (DJ-1 Nt) is specifically expressed in the nucleus and promotes apoptosis in SH-SY5Y neuroblastoma cell lines. In addition, overexpression of DJ-1 Nt in different cell lines leads to a loss of clonogenic potential and sensitizes to staurosporin and 1-methyl-4-phenylpyridinium (MPP+)-mediated caspase activation and apoptosis. Importantly, inhibition of endogenous DJ-1 expression with sh-RNA or DJ-1 deficiency mimics the effect of DJ-1 Nt on cell growth and apoptosis. Moreover, overexpression of DJ-1 Nt increases reactive oxygen species (ROS) production, and sensitizes to MPP+-mediated apoptosis and DJ-1 oxidation. Finally, specific exclusion of DJ-1 Nt from the nucleus abrogates its pro-apoptotic effect. Taken together, our findings identify an original pathway by which generation of a nuclear fragment of DJ-1 through caspase 6-mediated cleavage induces ROS-dependent amplification of apoptosis.

Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias.

The impact of ten-eleven-translocation 2 (TET2) mutations on response to azacitidine (AZA) in MDS has not been reported. We sequenced the TET2 gene in 86 MDS and acute myeloid leukemia (AML) with 20-30% blasts treated by AZA, that is disease categories wherein this drug is approved by Food and Drug Administration (FDA). Thirteen patients (15%) carried TET2 mutations. Patients with mutated and wild-type (WT) TET2 had mostly comparable pretreatment characteristics, except for lower hemoglobin, better cytogenetic risk and longer MDS duration before AZA in TET2 mutated patients (P=0.03, P=0.047 and P=0.048, respectively). The response rate (including hematological improvement) was 82% in MUT versus 45% in WT patients (P=0.007). Mutated TET2 (P=0.04) and favorable cytogenetic risk (intermediate risk: P=0.04, poor risk: P=0.048 compared with good risk) independently predicted a higher response rate. Response duration and overall survival were, however, comparable in the MUT and WT groups. In higher risk MDS and AML with low blast count, TET2 status may be a genetic predictor of response to AZA, independently of karyotype.

[Patients and the Web]. / Les patients et Internet.

In recent years, Internet has become an indispensable tool for all types of information. Its importance has increased in medicine and particularly in human malignancies. The data issued by the Internet are many and varied sources ranging from official websites to patient's blogs. HIV infection is an infection highly publicized in recent years, we take the case of Hodgkin's disease associated with HIV to compare data from the Internet and scientific articles. The information from the Internet is mostly good but not updated and erroneous data are regularly found. This confirms that the consultation by a specialist doctor referral should remain the main source of information for the patient.

[Implications of ALK (anaplastic lymphoma kinase) in oncohematology]. / Implications d'ALK (anaplastic lymphoma kinase) en oncohématologie.

The anaplastic lymphoma kinase gene (ALK) code for a receptor tyrosine-kinase. The fusion proteins from the ALK gene have been identified in oncohaematology malignancies including ALK positive anaplastic lymphoma large cell and non small cells lung cancer with EML4-ALK fusion gene. Constitutive activation generated by modification of this protein leads activation of anti apoptotic and survey pathways that makes it a prime target for these 2 subtypes of disease. Strategies and therapeutic molecules targeting the fusion protein are under development and preliminary results are encouraging. Therefore the mapping of the tumors is essential to help provide treatment specific to each entity. The best example is the chronic myeloid leukemia and the discovery of the fusion gene bcr-abl and of imatinib.

[Histone deacetylase inhibitors: highlight on epigenetic regulation]. / Inhibiteurs des histone-désacétylases: la régulation épigénétique sort de l'ombre.

HDAC, by modifiing relations between DNA and histones, are major proteins of the epigenetic regulation. They play part in the signal transduction and in many cellular processes: cell cycle control, apoptosis, protein degradation, angiogenesis, invasion and cell motility. In several models of cancer HDAC inhibitors (HDACIs) are able to up regulate tumor suppressing gene (p53, p21, pRB...) and to down regulate oncogenes (SRC, HIF-Ialpha,HER2...). Many inhibitors are currently in clinical development and promising results have been reported in cutaneous T cell lymphoma, Hodgkin's disease and non-hodgkin lymphoma. Combination with chemotherapy and molecular targeted agents seem to be effective in myeloma, lung cancer and myeloïd neoplasms. In this review, we focus on recent biologic and clinical data that highlitght the anti-neoplastic role of HDACIs.