A phase 1/2 study of the oral FLT3 inhibitor pexidartinib in relapsed/refractory FLT3-ITD-mutant acute myeloid leukemia.

FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have activity in acute myeloid leukemia (AML) patients with FLT3 internal tandem duplication (ITD) mutations, but efficacy is limited by resistance-conferring kinase domain mutations. This phase 1/2 study evaluated the safety, tolerability, and efficacy of the oral FLT3 inhibitor PLX3397 (pexidartinib), which has activity against the FLT3 TKI-resistant F691L gatekeeper mutation in relapsed/refractory FLT3-ITD-mutant AML. Ninety patients were treated: 34 in dose escalation (part 1) and 56 in dose expansion (part 2). Doses of 800 to 5000 mg per day in divided doses were tested. No maximally tolerated dose was reached. Plasma inhibitory assay demonstrated that patients dosed with ≥3000 mg had sufficient levels of active drug in their trough plasma samples to achieve 95% inhibition of FLT3 phosphorylation in an FLT3-ITD AML cell line. Based on a plateau in drug exposure, the 3000-mg dose was chosen as the recommended phase 2 dose. The most frequently reported treatment-emergent adverse events were diarrhea (50%), fatigue (47%), and nausea (46%). Based on modified response criteria, the overall response rate to pexidartinib among all patients was 21%. Twenty-three percent of patients treated at ≥2000 mg responded. The overall composite complete response rate for the study was 11%. Six patients were successfully bridged to transplantation. Median overall survival (OS) of patients treated in dose expansion was 112 days (90% confidence interval [CI], 77-150 days), and median OS of responders with complete remission with or without recovery of blood counts was 265 days (90% CI, 170-422 days). This trial was registered at www.clinicaltrials.gov as #NCT01349049

MASked-unconTrolled hypERtension management based on office BP or on ambulatory blood pressure measurement (MASTER) Study: a randomised controlled trial protocol

INTRODUCTION: Masked uncontrolled hypertension (MUCH) carries an increased risk of cardiovascular (CV) complications and can be identified through combined use of office (O) and ambulatory (A) blood pressure (BP) monitoring (M) in treated patients. However, it is still debated whether the information carried by ABPM should be considered for MUCH management. Aim of the MASked-unconTrolled hypERtension management based on OBP or on ambulatory blood pressure measurement (MASTER) Study is to assess the impact on outcome of MUCH management based on OBPM or ABPM. METHODS AND ANALYSIS: MASTER is a 4-year prospective, randomised, open-label, blinded-endpoint investigation. A total of 1240 treated hypertensive patients from about 40 secondary care clinical centres worldwide will be included -upon confirming presence of MUCH (repeated on treatment OBP <140/90 mm Hg, and at least one of the following: daytime ABP ≥135/85 mm Hg; night-time ABP ≥120/70 mm Hg; 24 hour ABP ≥130/80 mm Hg), and will be randomised to a management strategy based on OBPM (group 1) or on ABPM (group 2). Patients in group 1 will have OBP measured at 0, 3, 6, 12, 18, 24, 30, 36, 42 and 48 months and taken as a guide for treatment; ABPM will be performed at randomisation and at 12, 24, 36 and 48 months but will not be used to take treatment decisions. Patients randomised to group 2 will have ABPM performed at randomisation and all scheduled visits as a guide to antihypertensive treatment. The effects of MUCH management strategy based on ABPM or on OBPM on CV and renal intermediate outcomes (changing left ventricular mass and microalbuminuria, coprimary outcomes) at 1 year and on CV events at 4 years and on changes in BP-related variables will be assessed. ETHICS AND DISSEMINATION: MASTER study protocol has received approval by the ethical review board of Istituto Auxologico Italiano. The procedures set out in this protocol are in accordance with principles of Declaration of Helsinki and Good Clinical Practice guidelines. Results will be published in accordance with the CONSORT statement in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT02804074; Pre-results

Characteristics and outcome of patients with core-binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study

The aim of this study was to evaluate the prognostic impact of FLT3-ITD in core-binding factor acute myeloid leukemia (CBFAML) in an international, multicenter survey of 97 patients of whom 52% had t(8;21)(q22;q22) and 48% had inv(16)(p13q22)/t(16;16)(p13;q22). The median age of the patients was 53 years (range, 19-81). Complete remission after anthracycline-based induction (n=86) and non-intensive therapy (n=11) was achieved in 97% and 36% of the patients, respectively. The median follow-up was 4.43 years (95% confidence interval [95% CI]: 3.35-7.39 years). The median survival after intensive and non-intensive treatment was not reached and 0.96 years, respectively. Among intensively treated patients, inv(16) with trisomy 22 (n=11) was associated with a favorable 4-year relapse-free survival rate of 80% (95% CI: 59-100%) as compared to 38% (95% CI: 27-54%; P=0.02) in all other patients with CBFAML/ FLT3-ITD (n=75). Overall, 24 patients underwent allogeneic hematopoietic cell transplantation (HCT), 12 in first complete remission and 12 after relapse. Allogeneic HCT in first complete remission was not beneficial (P=0.60); however, allogeneic HCT seemed to improve median survival in relapsed patients compared to that of patients treated with chemotherapy (not reached vs. 0.6 years, respectively; P=0.002). Excluding patients with inv(16) with trisomy 22, our data indicate that compathe outcome of CBF-AML patients with FLT3-ITD may be inferior to that of patients without FLT3-ITD (based on previously published data), suggesting that prognostically CBF-AML patients with FLT3-ITD should not be classified as favorable-risk. FLT3-inhibitors may improve the outcome of these patients

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension

Aims Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk

Promotoranalyse des gehirnspezifisch exprimierten Gens 83.5

In unserem Arbeitskreis wurde auf der Suche nach Blut-Hirn-Schranke spezifischen Expressionsprodukten zwei bisher noch nicht beschriebene mRNA-Sequenzen (tmp 83.5 und sp 83.5) isoliert. In situ Hybridisierungen und immunhistochemische Untersuchungen zeigten, dass beide Transkripte in unterschiedlichen Neuronentypen der Groß- und Kleinhirnrinde des Schweins gebildet werden. Die Transkripte codieren höchstwahrscheinlich für ein noch nicht beschriebenes potenzielles Transmembranprotein (TMP 83.5) sowie für dessen lösliche Isoform (SP 83.5). Die mRNA-Sequenzen werden von einem 21,7 kb langen Gen (Gen 83.5) unter der Nutzung alternativer Promotoren gebildet. Interessanterweise existiert zu dem porcinen Gen 83.5 eine humane Genvariante sowie eine korrespondierende mRNA tmp 83.5. Das humane Gen HTMP10 ist auf Chromosom 10 in einem Bereich lokalisiert, der im engen Zusammenhang mit neuronalen Fehlfunktionen steht. In der vorliegenden Arbeit wurde zunächst der Transkriptionsstartpunkt des Transkripts sp 83.5 in Primer Extension Analysen bestimmt. Die computergestützte Sequenzanalyse der resultierenden Promotorregion ergab, das diese zahlreiche Bindungsstellen neuronaler und gehirnspezifischer Transkriptionsfaktoren enthält. Im zweiten Teil der Arbeit wurde der Promotor tmp 83.5 analysiert. Zum Nachweis funktioneller regulatorischer Sequenzelemente im Promotor tmp 83.5 sowie in der 5`-nichttranslatierten Region (5`-UTR) wurde eine Serie von Promotortestplasmiden mit zunehmenden 5`-Deletionen des Wildtyp-Promotors tmp 83.5 generiert. Die Expressionsraten dieser Promotorvarianten wurden in neuronalen Zellinien sowie im Vergleich hierzu in einer nichtneuronalen Zellinie untersucht. Mit den Ergebnissen dieser Deletionsstudien konnten verschiedene funktionelle Bereiche im Promotor eingegrenzt werden, die für eine zellspezifische bzw. allgemeine Aktivierung respektive Repression des Gens 83.5 verantwortlich sind. Mit DNase I Footprinting- und Band Shift-Analysen konnten in vitro sequenzspezifische Protein-Bindungen im Bereich des Kern- und proximalen Promotors tmp 83.5 nachgewiesen werden. Anhand der erhaltenen Ergebnisse wurde ein Modell für die Regulation des Promotors tmp 83.5 aufgestellt. Es umfasst neben einen ubiquitären Enhancer in der 5’-nichttranslatierten Region einen neuronspezifischen Aktivator und Repressor im distalen Promotor sowie Bindungsstellen für induzierbare und neuronspezifische Transkriptionsfaktoren im proximalen Promotor

Transnational moralities: the politics of ir/responsibility of and against the EU border regime

The death of Alan Kurdi, the boy washed ashore in Turkey in September 2015, provoked a global moral outcry. The pictures of the toddler went viral across social networks and in the media. Following these images across borders, we analyse moral and political responses to the ‘EU refugee crisis’ by illuminating the circumstances under which people feel, take on, and demand responsibility. Considering EU policies and their lethal consequences as mechanisms of an organised irresponsibility, we show how the circulation and modification of the images played on moral sentiments and on political demands in Europe and across the Mediterranean. The anthropological engagement with transnational moralities contributes to the analysis of politics of ir/responsibility of and against the EU border regime