Adjunctive Volasertib in Patients With Acute Myeloid Leukemia not Eligible for Standard Induction Therapy : A Randomized, Phase 3 Trial

In this phase 3 trial, older patients with acute myeloid leukemia ineligible for intensive chemotherapy were randomized 2:1 to receive the polo-like kinase inhibitor, volasertib (V; 350 mg intravenous on days 1 and 15 in 4-wk cycles), combined with low-dose cytarabine (LDAC; 20 mg subcutaneous, twice daily, days 1-10; n = 444), or LDAC plus placebo (P; n = 222). Primary endpoint was objective response rate (ORR); key secondary endpoint was overall survival (OS). Primary ORR analysis at recruitment completion included patients randomized >= 5 months beforehand; ORR was 25.2% for V+LDAC and 16.8% for P+LDAC (n = 371; odds ratio 1.66 [95% confidence interval (CI), 0.95-2.89]; P = 0.071). At final analysis (>= 574 OS events), median OS was 5.6 months for V+LDAC and 6.5 months for P+LDAC (n = 666; hazard ratio 0.97 [95% CI, 0.8-1.2]; P = 0.757). The most common adverse events (AEs) were infections/infestations (grouped term; V+LDAC, 81.3%; P+LDAC, 63.5%) and febrile neutropenia (V+LDAC, 60.4%; P+LDAC, 29.3%). Fatal AEs occurred in 31.2% with V+LDAC versus 18.0% with P+LDAC, most commonly infections/infestations (V+LDAC, 17.1%; P+LDAC, 6.3%). Lack of OS benefit with V+LDAC versus P+LDAC may reflect increased early mortality with V+LDAC from myelosuppression and infections.Peer reviewe

Real-World Insights on the Management of Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP) With Caplacizumab

peer reviewe

Adjunctive volasertib in patients with acute myeloid leukemia not eligible for standard induction therapy: a randomized, phase 3 trial

In this phase 3 trial, older patients with acute myeloid leukemia ineligible for intensive chemotherapy were randomized 2:1 to receive the polo-like kinase inhibitor, volasertib (V; 350 mg intravenous on days 1 and 15 in 4-wk cycles), combined with low-dose cytarabine (LDAC; 20 mg subcutaneous, twice daily, days 1–10; n = 444), or LDAC plus placebo (P; n = 222). Primary endpoint was objective response rate (ORR); key secondary endpoint was overall survival (OS). Primary ORR analysis at recruitment completion included patients randomized ≥5 months beforehand; ORR was 25.2% for V+LDAC and 16.8% for P+LDAC (n = 371; odds ratio 1.66 [95% confidence interval (CI), 0.95–2.89]; P = 0.071). At final analysis (≥574 OS events), median OS was 5.6 months for V+LDAC and 6.5 months for P+LDAC (n = 666; hazard ratio 0.97 [95% CI, 0.8–1.2]; P = 0.757). The most common adverse events (AEs) were infections/infestations (grouped term; V+LDAC, 81.3%; P+LDAC, 63.5%) and febrile neutropenia (V+LDAC, 60.4%; P+LDAC, 29.3%). Fatal AEs occurred in 31.2% with V+LDAC versus 18.0% with P+LDAC, most commonly infections/infestations (V+LDAC, 17.1%; P+LDAC, 6.3%). Lack of OS benefit with V+LDAC versus P+LDAC may reflect increased early mortality with V+LDAC from myelosuppression and infections

Dense network of wet bulb globe temperature observations to assess the effect of diverse micro-environments on heat stress

There is an urgent need for governments to know which measures effectively decrease heat stress and how to adapt urban environments to keep our cities livable in a climate with more, and more extreme, heatwave days. To answer this question, an observational campaign took place in the urban fringe of Ghent (Belgium), a maritime mid-latitude city, during the summer of 2023, including a heatwave in June. This campaign employed diverse in-situ weather stations (2 Campbell stations, 2 Hobo devices and a station from the Flemish MOCCA and VLINDER networks) complemented by 16 AT-HTS01 devices, specifically designed to measure heat stress. Combined, the stations are equipped with black globe thermometers, anemometers, humidity sensors, short-wave radiation pyranometers and actively and passively ventilated air temperature sensors. Based on these variables the wet bulb globe temperature (WBGT) is computed and from this, the influence of different suburban micro-environments on heat stress is derived. In particular, the effects of the surface type, neighboring buildings, trees and forest patches on WBGT are investigated. Some air temperature sensors are installed in actively ventilated shields to detect air temperature differences in different forest patches excluding any radiation-induced measurement errors. Additionally, drone infrared measurements were conducted to estimate the surface temperature of the different surface types during the day and the night. A forest patch decreases the maximum air temperature during the heatwave to up to 1.5 °C. At night, the unpaved surface decreases the globe temperature to up to 1.5 °C compared to paved surfaces. During daytime shadow effects of buildings and trees have the largest impact on decreasing the globe temperature (by 10 °C) and consequently strongly lowers the actual WBGT (up to 4 °C). Future research will focus on validating meter-scale numerical models with these observations

Integrin engagement-induced inhibition of human myelopoiesis is mediated by proline-rich tyrosine kinase 2 gene products

OBJECTIVE: Hematopoietic progenitor proliferation and differentiation are inhibited by integrin engagement of fibronectin (FN). Focal adhesion kinases have been shown to mediate intracellular signaling from integrins, and we recently demonstrated that gene expression and pre-mRNA splicing of the focal adhesion kinase, PYK2, is abnormal in CD34(+) cells from chronic myelogenous leukemia (CML) patients. Here we investigated whether PYK2 gene products mediate integrin signaling in hematopoietic stem and progenitor cells. METHODS: Cord blood CD34(+) cells were retrovirally transduced with vectors encoding Pyk2H, Pyk2, or the dominant negative-acting, kinase-deficient, C-terminal PYK2 fragment, PRNK, and myeloid proliferation and differentiation was assessed using colony-forming cell (CFC), long-term culture-initiating cell (LTC-IC), and liquid culture assays. RESULTS: CD34(+) cells overexpressing Pyk2H or Pyk2 generated 50% less colony-forming unit granulocyte/macrophage (CFU-GM) than eGFP-transduced controls. Although the number of CFC generated by PRNK-expressing cells was unchanged, LTC-IC were significantly reduced. Culture of CD34(+) cells on FN significantly reduced the generation of mature myeloid cells vs those cultured on BSA-coated wells, and could be overcome by addition of SCF. As is observed when integrins are engaged, overexpression of either Pyk2H or Pyk2 decreased committed myeloid progenitor proliferation and differentiation; however, SCF could not override this inhibition. Finally, as is observed when integrins are not engaged, PRNK-mediated inhibition of endogenous Pyk2H resulted in integrin-nonresponsive proliferation and differentiation of myeloid precursors and accelerated differentiation of primitive hematopoietic progenitors. CONCLUSION: These studies indicate that PYK2 gene products mediate integrin-induced signals that regulate myelopoiesis.status: publishe

Prenatal markers of neonatal fat mass: A systematic review

Background: Environmental influences during pregnancy are able to affect off spring phenotype with lifelong effects. Clinical applicable markers are needed to identify foetuses at risk for neonatal adiposity. This systematic review aims to 1) review the current literature on prenatal markers of neonatal fat mass, and 2) appraise the clinical applicability of the assessed markers. Methods: A systematic literature search was conducted to identify studies meeting the following inclusion criteria: 1) original research papers in English; 2) research on dynamic and measurable prenatal markers of neonatal fat mass; 3) neonatal fat mass measurement within one month after birth, using the four-compartment model, magnetic resonance imaging, dual-energy X-ray absorptiometry or air displacement plethysmography. Two reviewers independently performed study selection, assessment of methodological (QUADAS-II) and statistical quality and appraisal of clinical applicability. Results: Of 2333 studies primarily identified by the search strategy, 16 studies were included. Four of these were both methodologically and statistically of moderate or high quality. Prenatal markers investigated were ultrasound parameters, maternal biochemical markers and maternal characteristics. Markers of predefined interest were maternal pre-pregnancy body mass index, fasting glucose and HbA1c, showing varying results. A meta-analysis was not possible due to substantial methodological heterogeneity. Clinically applicability of all markers was rated poor. Conclusions: Although associations were found, no useful marker was identified, due to lack of methodological and statistical quality, inconsistent results and poor clinical applicability. No markers were investigated in the periconceptional and embryonic period. (C) 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved

Disease and treatment characteristics of polycythemia vera patients in Belgium: Results from a scientific survey

Objective: The current survey aimed to gather predefined disease parameters and treatment strategies to characterize the polycythemia vera (PV) patient population in Belgium. Methods: Cross-sectional data from PV patients, seen at least once between May 2014 and May 2015 at 10 sites in Belgium, were collected in aggregated form and analyzed descriptively and quantitatively. Results: Data from 343 PV patients were collected. Of these, 174 (50.7%) were male and 256 (74.6%) were ≥60 years of age. Ninety-two (26.8%) had a prior history of thrombotic events. Considerable proportions of patients had increased hematological parameters (hematocrit > 45% [31.2%], leukocytes > 10 × 109/L [33.3%], and platelet > 400 × 109/L [38.2%]). Most patients had non-palpable spleen (284, 87.7%) and no phlebotomies during the past 6 months (197, 57.4%). Low-dose aspirin was given as thrombosis prophylaxis in 249 (72.6%) patients, while 232 (67.6%) received hydroxyurea (HU) as cytoreductive treatment. Forty-one patients (12.0%) were reported as resistant and/or intolerant to HU. Seventeen patients (5.0%) received ruxolitinib in the context of clinical trials. Conclusion: This survey provides better insight into the characteristics of Belgian PV patients and currently used treatment strategies. It shows that 232 (67.6%) PV patients continue to receive HU despite being potentially HU-resistant.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Non-Hodgkin Lymphoma after Treatment with Extended Dosing Temozolomide and Radiotherapy for a Glioblastoma: A Case Report

Temozolomide (TMZ) is an alkylating agent, used for the treatment of high-grade gliomas. This case report describes the development of a non-Hodgkin lymphoma in a patient treated with extended-dose temozolomide and radiotherapy. In addition to the possible mutagenic effect of temozolomide – as described for all alkylating agents – there might have been an immunosuppressive effect of TMZ. The pathological appearance of the lymphoma as well as the presence of a grade 3 lymphopenia early in treatment supports this hypothesis. As the use of TMZ increases, the awareness that TMZ may induce secondary malignancies should increase as well