Background
The impact of coronavirus disease 2019 (COVID‐19) in haematological patients (HP) has not been comprehensively reported.
Methods
We analysed 39 patients with SARS‐CoV‐2 infection and ...haematological malignancies. Clinical characteristics and outcomes were compared to a matched control group of 53 non‐cancer patients with COVID‐19. Univariate and multivariate analyses were carried out to assess the risk factors associated with poor outcome.
Results
The most frequent haematological diseases were lymphoma (30%) and multiple myeloma (30%). Eighty‐seven % HP developed moderate or severe disease. Patients with haematological malignancies had a significantly higher mortality rate compared to non‐cancer patients (35.9% vs 13.2%; P = .003 (odds ratio 6.652). The worst outcome was observed in chronic lymphocytic leukaemia patients. Only age >70 years and C reactive protein >10 mg/dl at admission were associated with higher risk of death (odds ratio 34.86, P = .003 and 13.56,P = .03). Persistent viral sheddind was detected in 5 HP. Active chemotherapy, viral load at diagnosis and COVID‐19 therapy were not predictors of outcome.
Conclusion
Mortality of COVID‐19 is significantly higher in patients with haematological malignancies compared to non‐cancer patients. The impact of persistent viral shedding must be considered in order to re‐start therapies and maintain infectious control measures.
CAR-T-cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be ...designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this approach by analyzing the antitumor activity of activated and expanded NK cells (NKAE) and CD45RA
T cells from MM patients that were engineered to express an NKG2D-based CAR. NKAE cells were cultured with irradiated Clone9.mbIL21 cells. Then, cells were transduced with an NKG2D-4-1BB-CD3z-CAR. CAR-NKAE cells exhibited no evidence of genetic abnormalities. Although memory T cells were more stably transduced, CAR-NKAE cells exhibited greater in vitro cytotoxicity against MM cells, while showing minimal activity against healthy cells. In vivo, CAR-NKAE cells mediated highly efficient abrogation of MM growth, and 25% of the treated mice remained disease free. Overall, these results demonstrate that it is feasible to modify autologous NKAE cells from MM patients to safely express a NKG2D-CAR. Additionally, autologous CAR-NKAE cells display enhanced antimyeloma activity demonstrating that they could be an effective strategy against MM supporting the development of NKG2D-CAR-NK-cell therapy for MM.
Myeloproliferative neoplasms (MPNs) are a group of diseases that cause myeloid hematopoietic cells to overproliferate. Epidemiological and familial studies suggest that genetic factors contribute to ...the risk of developing MPN, but the genetic susceptibility of MPN is still not well known. Indeed, only few loci are known to have a clear role in the predisposition to this disease. Some studies reported a diagnosis of MPNs and multiple myeloma (MM) in the same patients, but the biological causes are still unclear. We tested the hypothesis that the two diseases share at least partly the same genetic risk loci. In the context of a European multicenter study with 460 cases and 880 controls, we analyzed the effect of the known MM risk loci, individually and in a polygenic risk score (PRS). The most significant result was obtained among patients with chronic myeloid leukemia (CML) for PS0RS1C1‐rs2285803, which showed to be associated with an increased risk (OR = 3.28, 95% CI 1.79‐6.02, P = .00012, P = .00276 when taking into account multiple testing). Additionally, the PRS showed an association with MPN risk when comparing the last with the first quartile of the PRS (OR = 2.39, 95% CI 1.64‐3.48, P = 5.98 × 10−6). In conclusion, our results suggest a potential common genetic background between MPN and MM, which needs to be further investigated.
What's new?
Myeloproliferative neoplasms (MPN) are a rare and heterogeneous group of diseases, and the genetic susceptibility is still not well understood. Several cases have been reported of patients with both MPN and multiple myeloma (MM). These authors tested whether MPN and MM have overlapping genetic susceptibility loci. They analyzed 23 known MM risk loci in participants from a case‐control study of MPN, including 460 cases and 880 controls. While no individual SNP reached statistical significance, a polygenic risk score showed an association with MPN risk, suggesting that several MM risk loci in combination could influence the risk of MPN.
Progenitors of the first hematopoietic cells in the mouse arise in the early embryo from Brachyury‐positive multipotent cells in the posterior‐proximal region of the epiblast, but the mechanisms that ...specify primitive blood cells are still largely unknown. Pluripotency factors maintain uncommitted cells of the blastocyst and embryonic stem cells in the pluripotent state. However, little is known about the role played by these factors during later development, despite being expressed in the postimplantation epiblast. Using a dual transgene system for controlled expression at postimplantation stages, we found that Nanog blocks primitive hematopoiesis in the gastrulating embryo, resulting in a loss of red blood cells and downregulation of erythropoietic genes. Accordingly, Nanog‐deficient embryonic stem cells are prone to erythropoietic differentiation. Moreover, Nanog expression in adults prevents the maturation of erythroid cells. By analysis of previous data for NANOG binding during stem cell differentiation and CRISPR/Cas9 genome editing, we found that Tal1 is a direct NANOG target. Our results show that Nanog regulates primitive hematopoiesis by directly repressing critical erythroid lineage specifiers.
Synopsis
Mechanisms that specify primitive blood cells during embryonic development are largely unknown. Here, the stem cell factor NANOG is shown to exert important roles during specification from mesoderm to the first hematopoietic cells, instructing haematopoiesis by direct repression of critical lineage specifiers.
NANOG blocks erythroid differentiation in the gastrulating embryo in a cell‐autonomous manner.
Loss of NANOG in embryonic stem cells increases expression of hematopoietic genes and shifts differentiation towards erythroid progenitors.
NANOG can block generation of megakaryocyte‐erythroid progenitors in the adult bone marrow.
Tal1, a key regulator of erythroid fate, is directly repressed by NANOG during gastrulation.
NANOG regulates the transition from mesoderm to primitive hematopoietic system by directly repressing erythroid lineage specification.
In cases of treatment failure in acute myeloid leukemia (AML), the utility of mutational profiling in primary refractoriness and relapse is not established. We undertook a perspective study using ...next-generation sequencing (NGS) of clinical follow-up samples (n=91) from 23 patients with AML with therapeutic failure to cytarabine plus idarubicin or fludarabine. Cases of primary refractoriness to treatment were associated with a lower number of DNA variants at diagnosis than cases of relapse (median 1.67 and 3.21, respectively, p=0.029). The most frequently affected pathways in patients with primary refractoriness were signaling, transcription and tumor suppression, whereas methylation and splicing pathways were mainly implicated in relapsed patients. New therapeutic targets, either by an approved drug or within clinical trials, were not identified in any of the cases of refractoriness (0/10); however, 8 potential new targets were found in 5 relapsed patients (5/13) (p=0.027): 1 IDH2, 3 SF3B1, 2 KRAS, 1 KIT and 1 JAK2. Sixty-five percent of all variants detected at diagnosis were not detected at complete response (CR). Specifically, 100% of variants in EZH2, RUNX1, VHL, FLT3, ETV6, U2AF1, PHF6 and SF3B1 disappeared at CR, indicating their potential use as markers to evaluate minimal residual disease (MRD) for follow-up of AML. Molecular follow-up using a custom NGS myeloid panel of 32 genes in the post-treatment evaluation of AML can help in the stratification of prognostic risk, the selection of MRD markers to monitor the response to treatment and guide post-remission strategies targeting AML, and the selection of new drugs for leukemia relapse.
Acute T-cell lymphoblastic leukaemia (T-ALL) is an aggressive disorder derived from immature thymocytes. The variability observed in clinical responses on this type of tumours to treatments, the high ...toxicity of current protocols and the poor prognosis of patients with relapse or refractory make it urgent to find less toxic and more effective therapies in the context of a personalized medicine of precision.
Whole exome sequencing and RNAseq were performed on DNA and RNA respectively, extracted of a bone marrow sample from a patient diagnosed with tumour primary T-ALL and double negative thymocytes from thymus control samples. We used PanDrugs, a computational resource to propose pharmacological therapies based on our experimental results, including lists of variants and genes. We extend the possible therapeutic options for the patient by taking into account multiple genomic events potentially sensitive to a treatment, the context of the pathway and the pharmacological evidence already known by large-scale experiments.
As a proof-of-principle we used next-generation-sequencing technologies (Whole Exome Sequencing and RNA-Sequencing) in a case of diagnosed Pro-T acute lymphoblastic leukaemia. We identified 689 disease-causing mutations involving 308 genes, as well as multiple fusion transcript variants, alternative splicing, and 6652 genes with at least one principal isoform significantly deregulated. Only 12 genes, with 27 pathogenic gene variants, were among the most frequently mutated ones in this type of lymphoproliferative disorder. Among them, 5 variants detected in CTCF, FBXW7, JAK1, NOTCH1 and WT1 genes have not yet been reported in T-ALL pathogenesis.
Personalized genomic medicine is a therapeutic approach involving the use of an individual's information data to tailor drug therapy. Implementing bioinformatics platform PanDrugs enables us to propose a prioritized list of anticancer drugs as the best theoretical therapeutic candidates to treat this patient has been the goal of this article. Of note, most of the proposed drugs are not being yet considered in the clinical practice of this type of cancer opening up the approach of new treatment possibilities.
The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which were CALR‐mutated. ...In low risk patients, time from diagnosis to cytoreduction was shorter in CALR‐positive than in the other genotypes (2·8, 3·2, 7·4 and 12·5 years for CALR, MPL, JAK2V617F and TN, respectively, P < 0·0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% in CALR and JAK2V617F genotypes, respectively. Median time to CR was 192 days for JAK2V617F, 343 for TN, 433 for MPL, and 705 for CALR genotypes (P < 0·0001). Duration of CR was shorter in CALR‐mutated ET than in the remaining patients (P = 0·003). In CALR‐positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration. CALR‐mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% for JAK2V617F, CALR, MPL and TN, respectively; P < 0·0001). In conclusion, conventional cytoreductive agents are less effective in CALR‐mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype.
The current status of the use of optical nanoparticles for imaging of the cardiovascular system is reviewed in detail. The different types of optical (luminescent, photoacoustic, and scattering) ...nanoparticles capable of vessel imaging and diagnosis are described, paying special attention to the use of optical nanoparticles for atherosclerosis detection and diagnosis, for advanced imaging of blood perfusion and, finally, for the detection and diagnosis of ischemic tissues. The advantages and disadvantages of different optical nanoparticles and related techniques for cardiovascular imaging are discussed in detail.
This review summarizes the latest advances regarding the use of optical nanoparticles for advanced optical imaging of the cardiovascular system. The different types of optical (luminescent, photoacoustic, and scattering) nanoparticles capable of vessel imaging and diagnosis are described; the advantages and disadvantages of their use are discussed in detail.
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