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Abstract: Introduction: Stroke is a severe complication of sickle cell anemia (SCA), with devastating sequelae. Transcranial Doppler (TCD) ultrasonography predicts stroke risk, but implementing TCD screening with suitable treatment for primary stroke prevention in low-resource environments remains challenging. SPHERE (NCT03948867) is a prospective phase 2 open-label hydroxyurea trial for SCA in Tanzania. Methods: After formal training and certification, local personnel screened children 2-16 years old; those with conditional (170-199 cm/sec) or abnormal (≥200 cm/sec) time-averaged mean velocities (TAMV) received hydroxyurea at 20 mg/kg/day with dose escalation to maximum tolerated dose (MTD). The primary study endpoint is change in TAMV after 12 months of hydroxyurea; secondary endpoints include SCA-related clinical events, splenic volume and function, renal function, infections, hydroxyurea pharmacokinetics, and genetic modifiers. Results: Between April 2019 and April 2020, 202 children (average 6.8±3.5 years, 53% female) enrolled and underwent TCD screening; 196 were deemed eligible by DNA testing. Most had numerous previous hospitalizations and transfusions, with low baseline hemoglobin (7.7±1.1 g/dL) and %HbF (9.3±5.4%). Palpable splenomegaly was present at enrollment in 49 (25%); average sonographic splenic volume was 103 mL (range 8-1045 mL). TCD screening identified 22% conditional and 2% abnormal velocities, with hydroxyurea treatment initiated in 96% (45/47) eligible children. Conclusion: SPHERE has built local capacity with high-quality research infrastructure and TCD screening for SCA in Tanzania. Fully enrolled, participants have a high prevalence of elevated baseline TCD velocities and splenomegaly. SPHERE will prospectively determine the benefits of hydroxyurea at MTD for primary stroke prevention, anticipating expanded access to hydroxyurea treatment across Tanzania.
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Abstract: Introduction: Mutated RUNX1 is considered a poor prognostic factor and usually is mutually exclusive with NPM1 mutations. Monitoring of molecular markers for minimal residual disease provides a powerful tool to assess remission and guide clinical decisions. Methods: Newly diagnosed RUNX1-mutated AML patients, designated to intensive chemotherapy-based treatment or non-intensive regimens, were monitored for mutated RUNX1 transcript levels by qPCR with patient-specific primers. Samples were obtained along the treatment course and follow-up.Results: A clear correlation was observed between mutated RUNX1 levels and response to treatment as observed by flow-cytometry and STR-based assessment. Conclusion: We demonstrate the feasibility of RUNX1-based MRD to correlate with the clinicopathological status of leukemia. We further suggest how RUNX1 qPCR monitoring can influence clinical decision-making and contribute to improved personalized patient care.
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Abstract: Introduction: To construct a pyroptosis-related risk score (RS) model for the prognosis of acute myeloid leukemia (AML).Methods: The TARGET (training) and E-MTAB-1216 (validation) datasets were downloaded. Pyroptosis-related genes with differences in expression were identified between the recurrent and non-recurrent samples of the training dataset. An RS prognostic model comprising seven pyroptosis-related genes was constructed using LASSO regression coefficients. The samples were classified into the high- and low-risk groups using the RS model; the differentially expressed genes (DEGs) between these groups were identified, followed by DEG functional analysis and the immunological evaluation of these groups.Results: Forty-nine pyroptosis-related genes, including 22 DEGs, were screened. WT1, NPM, FLT3/ITD, and CEBPA mutations were found in most pediatric AML samples. An RS prognostic model was constructed using seven pyroptosis-related genes. The two risk groups and prognostic data were significantly related. FLT3/ITD mutations, CEBPA mutations, and RS model status were identified as independent prognostic factors, using the clinical information. The DEGs between the two groups were correlated with immune-related pathways. Moreover, the immune cell distribution and occurrence of immune-related pathways were notably decreased in the high-risk group.Discussion/Conclusion: Seven pyroptosis-related genes, CHMP2A, PRKACA, CASP9, IRF2, CHMP3, HMGB1, and AIM2, can predict the prognosis and recurrence of childhood AML.
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Abstract: IntroductionTreatment-free remission (TFR) is increasingly considered as treatment goal for patients with chronic myeloid leukemia (CML), but information on the disposition and outcome of TFR in clinical practice is scarce. Here we report the characteristics of patients with CML in deep molecular remission (DMR) and/or after an attempt of TFR reported by 33 German hematologists. MethodsData were collected retrospectively by means of a questionnaire. Patients were eligible if they had either discontinued tyrosine kinase inhibitor (TKI) therapy or had achieved DMR of at least MR4 (BCR-ABL ≤0.01%) prior to the time-point of data collection. Results797 patients were included in the analysis, out of which 281 patients had been discontinued from TKI treatment. TKI discontinuation rates among practices were variable, ranging from 0-36 patients. Mean time from TKI initiation to discontinuation was 7.2 years, mean duration of MR4 before TFR was 3.5 years. At the time of entering TFR, most patients (90.8%) had achieved a deep molecular response (≥MR4). BCR-ABL monitoring during TFR was performed heterogeneously: Within the first six months of TFR, 58.6% of the practices reported mean monitoring intervals of 8 weeks. After entering TFR, 53.2% of patients remained in MR4 or better. TKI treatment was re-initiated in 108 patients, mainly for loss of major molecular remission. ConclusionsThese clinical data from a German real-life population show that TKI discontinuation is feasible in clinical practice. Outcomes appear to be comparable to those reported in clinical trials, but molecular monitoring in TFR is rather variable.
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Abstract: Introduction: Data regarding the prevalence of paraproteinemia in patients with chronic myeloid leukemia (CML) are lacking.Methods: To evaluate for paraproteinemia prevalence we undertook this cross-sectional study among consecutive chronic-phase CML patients. Complete blood count, chemistry, immunoglobulins, serum-free light chains, serum-protein electrophoresis and immunofixation were collected. Further analyses evaluated whether various patient, disease and treatment-related variables are associated with paraproteinemia.Results: One hundred patients, median age 63.5 (IQR 48.1-72) years were recruited. Median time from CML diagnosis to enrollment was 6.3 (IQR 2.3-11.3) years.Monoclonal-protein was detected in eight patients (8%), diagnosed with: smoldering multiple myeloma (SMM, n=2) and low-risk monoclonal gammopathy of undetermined significance (MGUS, n=6). Six patients were on tyrosine kinase inhibitor treatment, two were in treatment-free-remission. The only covariate associated with paraproteinemia was the presence of anemia, albeit with borderline statistical significance in univariate analysis (p=0.053) and when adjusted for age (p=0.056).Conclusions: In this largest study so far describing the prevalence of paraproteinemia among CML patients, we found MGUS prevalence to be higher than the 3.2% expected prevalence in the general-population above 50 years and a non-negligible prevalence of SMM (2%). Screening for paraproteinemia in CML patients, especially in the presence of anemia, should be considered.
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Abstract: Progressive multifocal leukoencephalopathy (PML) is a rare neurological disease caused by the reactivation of latent John Cunningham polyomavirus. Hematological disorders associated with immunomodulatory monoclonal antibodies and hematopoietic stem cell transplantation (HSCT) are risk factors for PML. Blinatumomab is a novel anti-leukemic immunomodulatory agent and more effective for relapsed and refractory acute lymphoblastic leukemia (ALL) than conventional chemotherapy. But, blinatumomab suppresses humoral immunity due to long-lasting B-cell depletion during and after the treatment. The development of PML involves cellular immunity and impairment of humoral immunity. Although few cases of blinatumomab-related PML have been reported, the use of blinatumomab after allogeneic HSCT may increase the risk of developing PML. The current case report presents a patient of Philadelphia chromosome-positive ALL wherein PML developed after cord blood stem cell transplantation and administrating blinatumomab.
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Abstract: Objectives: Three variations including a novel F11 gene variation were detected in two unrelated Chinese families with coagulation factor XI deficiency and their possible pathogenesis were elucidated. Methods: The genomic DNA of the probands’ pedigrees was extracted, and all exons and flanking sequences of F11 gene were subjected to PCR amplification and Sanger sequencing. ClustalX-2.1-win, Mutation Taster and Swiss-Pdb Viewer software were used to analyze the conservation and impact of the variations on protein function and structure. Results: DNA sequencing showed that the proband one had p.Gly350Glu and p.Trp501stop complex heterozygous variations, while the proband two took p.Pro338Leu and p.Trp501stop compound heterozygous variations. Conservation, structural and functional analysis of variant amino acids indicated that these three variations were harmful and probably affected the structure and function of the variable protein. Conclusions: Three variations including p.Pro338Leu, p.Gly350Glu and p.Trp501stop responsible for the reduction of the FXI activities were herein detected. Notably, the p.Pro338Leu variation was discovered for the first time in the world. Furthermore, the p.Gly350Glu was first reported in China.
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Abstract: The diagnosis of polycythemia, particularly the secondary forms, can be challenging. The distinction between primary and secondary polycythemia is relevant and has management implications. A systematic diagnostic work-up algorithm and a good anamnesis are of paramount relevance. More than one cause may be involved in the development of polycythemia, identifying all of them will be the key to better understanding and eventually solving the polycythemia. We describe a case of a 53-year-old Swiss woman with polycythemia and a high level of carboxyhemoglobin. Her medical story included obesity and obstructive sleep apnea. The anamnesis ruled out the habit of smoking cigarettes, however, the patient reported that she was on a trip to Egypt 10 years before and bought herself a shisha, since then she used to smoke shisha daily, at home, alone. After drastically reducing and then stopping the shisha smoking, 7 months later her blood count and carboxyhemoglobin completely normalized.
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Abstract: Hereditary spherocytosis (HS) is a congenital disease in which erythrocyte membranes are abnormal, with ANK1 defects as the main cause. The diagnosis of neonatal HS is difficult due to poor phenotypic specificity. Therefore, a detailed inquiry into family history may be helpful for diagnosis. Here, we describe a familial case of HS caused by a novel mutation in ANK1. The proband is a premature infant of Chinese Han ethnicity, characterized by progressive aggravation of anemia and jaundice. The disease was caused by a frameshift mutation (c.3392delT/p.Leu1131Argfs*15) of ANK1 that was identified by genetic testing. In vitro functional experiments showed that this variant may seriously affect the protein expression, and further expanded the mutation spectrum of ANK1-HS. In this case, we emphasize the diagnostic value of early-intervention genetic testing for neonatal hemolytic anemia with a family history.
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Abstract: BackgroundThe safety and efficacy of blinatumomab, a CD19/CD3 BiTE® (bispecific T-cell engager) molecule, was evaluated in an expansion cohort of the phase 1b/2 study (NCT02412306) in Japanese adult (n=14) and pediatric (n=17) patients with relapsed/refractory Philadelphia-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). MethodsGlobally recommended blinatumomab doses were administered to adult (9–28 μg/day) and pediatric (5–15 μg/m2/day) patients. Primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs. ResultsAll adult and pediatric patients experienced ≥1 TEAE. Grade ≥3 TEAEs were observed in 11 (79%) adult and 15 (88%) pediatric patients. Blinatumomab was discontinued in one (6%) pediatric patient due to treatment-related grade 4 cytokine release syndrome. Fatal AEs such as disease progression and multiple organ dysfunction syndrome, which were not treatment-related, were reported in two (12%) pediatric patients. Eleven (79%) adults achieved complete remission (CR)/CR with partial hematological recovery (CRh) within the first two blinatumomab cycles. Nine of 10 adult patients with CR/CRh and evaluable minimal residual disease (MRD) achieved MRD response. CR/CRh was achieved by five (29%) pediatric patients, of which two had MRD response. ConclusionIn conclusion, blinatumomab was safe and efficacious in Japanese patients with relapsed/refractory BCP ALL.
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