Clinical outcomes under hydroxyurea treatment in polycythemia vera: a systematic review and meta-analysis

Hydroxyurea is the standard treatment in high risk patients with polycythemia vera. Yet, estimates of its effect in terms of clinical outcomes (thrombosis, bleeding, hematological transformations and mortality) are lacking. We performed a meta-analysis to determine the absolute risk of events in contemporary patients under hydroxyurea treatment. We searched for relevant articles or abstracts in the following databases: Medline, EMBASE, clinicaltrials.gov, WHO International Clinical Trials Registry, LILACS. Sixteen studies published from 2008 to 2018 reporting number of events using WHO diagnosis for polycythemia vera were selected. Through a random effect logistic model, incidences, study heterogeneity and confounder effects were estimated for each outcome at different follow-ups. Overall, 3,236 patients were analyzed. While incidences of thrombosis and acute myeloid leukemia were stable over time, mortality and myelofibrosis varied depending on follow-up duration. Thrombosis rates were 1.9, 3.6 and 6.8% persons/year at median ages 60, 70 and 80 respectively. Higher incidence of arterial events was predicted by previous cardiovascular complication. Leukemic transformation incidence was 0.4% persons/year. Incidence of transformation to myelofibrosis and mortality were significantly dependent on age and follow-up duration. For myelofibrosis, rates were 5.0 at 5 year and 33.7% at 10 years; overall mortality was 12.6% and 56.2% at 5 and 10 years respectively. In conclusion, we provide reliable risk estimates for the main outcomes in polycythemia vera patients under hydroxyurea treatment. These findings can help design comparative clinical trials with new cytoreductive drugs and prove the feasibility of using hard endpoints for efficacy, such as major thrombosis

Hydroxyurea prevents arterial and late venous thrombotic recurrences in patients with myeloproliferative neoplasms but fails in the splanchnic venous district. Pooled analysis of 1500 cases

We collected 1500 patients with myeloproliferative neoplasms (MPN) and arterial or venous thrombosis (935/565), pooling three independent cohorts previously reported. Long-term treatment with antiplatelet drugs or vitamin K-antagonists (VKA) was given to 1391 (92.7%) patients; 975 (65%) patients received hydroxyurea (HU). We recorded 348 recurrences (venous in 142 cases) over 6075 patient-years, with an incidence rate of 5.7 per 100 pt-years (95% CI 5.1-6.4). The site of the first thrombosis predicted the site of recurrence. Independent factors influencing the rate of novel arterial thrombosis were HU (HR 0.67, 95% CI 0.46-0.98), antiplatelet treatment (HR 0.54, 95% CI 0.35-0.82), and VKA (HR 0.58, 95% CI 0.35-0.96). On the contrary, the recurrence of venous thromboses was significantly diminished only by VKA (HR 0.60, 95% CI 0.37-0.95), while HU prevented late but not early recurrences after venous thrombosis at common sites. Of note, we failed to demonstrate a positive effect of HU in the prevention of recurrent splanchnic vein thrombosis. In conclusion, in MPN patients, HU plays a role in the prevention of arterial thrombosis, together with aspirin and VKA, whereas its action in the prevention of recurrent venous thrombosis is uncertain. Such findings call for future studies to optimize and personalize secondary prophylaxis after MPN-related thrombosis

Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera

BACKGROUND: The driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs) and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs. METHODS: We evaluated 305 with essential thrombocythemia (ET) and 172 polycythemia vera (PV) patients diagnosed according to the 2016 WHO criteria and with full molecular characterization for driver mutations. RESULTS: PTX3 levels were significantly increased in carriers of homozygous JAK2V617F mutation compared to all the other genotypes and triple negative ET patients, while hs-CRP levels were independent of the mutational profile. The risk of haematological evolution and death from any cause was about 2- and 1.5-fold increased in individuals with high PTX-3 levels, while the thrombosis rate tended to be lower. High hs-CRP levels were associated with risk of haematological evolution, death and also major thrombosis. After sequential adjustment for potential confounders (age, gender, diagnosis and treatments) and the presence of JAK2V617F homozygous status, high hs-CRP levels remained significant for all outcomes, while JAK2V617F homozygous status as well as treatments were the factors independently accounting for adverse outcomes among patients with high PTX3 levels. CONCLUSIONS: These results provide evidence that JAK2V617F mutation influences MPN-associated inflammation with a strong correlation between allele burden and PTX3 levels. Plasma levels of hs-CRP and PTX3 might be of prognostic value for patients with ET and PV, but their validation in future prospective studies is needed

Magnetic Resonance vs. Intraoral Ultrasonography in the Preoperative Assessment of Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis

Background: Preoperative assessment is critical to decide the most adequate surgical strategy for oral squamous cell carcinoma (SCC). Magnetic resonance (MR) and intraoral ultrasonography (US) have been reported to be of great value for preoperative estimation of depth of invasion (DOI) and/or tumor thickness (TT). This review aims to analyze the accuracy of MR and intraoral US in determining DOI/TT in oral SCC, by assuming histological evaluation as the reference method. Methods: The procedure was conducted following the modified 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We performed a systematic search of papers on PubMed, Scopus, Web of Science, and Cochrane Library databases until July 31st, 2019. For quantitative synthesis, we included nine studies (487 patients) focused on MR, and 12 (520 patients) focused on intraoral US. The Pearson correlation coefficient (r) between DOI/TT evaluated with MR or intraoral US was assumed as effect size. A meta-analysis (MA) for each study group (MR and US) was performed by using the random-effects models with the DerSimonian\u2013Laird estimator and r-to-z transformation. Results: In the MA for MR studies, a high heterogeneity was found (I2 = 94.84%; Q = 154.915, P < 0.001). No significant risk of bias occurred by evaluating funnel plot asymmetry (P = 0.563). The pooled (overall) r of the MR studies was 0.87 (95% CI from 0.82 to 0.92), whereas the pooled r-to-z transformed was 1.44 (95% CI from 1.02 to 1.85). In the MA for US studies a high heterogeneity was found (I2 = 93.56%; Q = 170.884, P < 0.001). However, no significant risk of bias occurred (P = 0.779). The pooled r of the US studies was 0.96 (95% CI from 0.94 to 0.97), whereas the pooled r-to-z transformed was 1.76 (95% CI from 1.39 to 2.13). These outputs were confirmed in additional MA performed by enrolling only MR (n = 8) and US (n = 11) studies that evaluated TT. Conclusions: MR and intraoral US seem to be promising approaches for preoperative assessment of DOI/TT in oral SCC. Remarkably, a higher pooled r and r-to-z transformed were observed in the intraoral US studies, suggesting that this approach could be more closely related to histopathological findings

The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600

In the present study, we have provided clinical evidence of the predictive and prognostic relevance of tumoral PD-L1 expression and density of immune cell infiltration in BRAFV600-mutated metastatic melanoma patients treated with BRAF inhibitor

Unraveling the developmental roadmap toward human brown adipose tissue

Increasing brown adipose tissue (BAT) mass and activation is a therapeutic strategy to treat obesity and complications. Obese and diabetic patients possess low amounts of BAT, so an efficient way to expand their mass is necessary. There is limited knowledge about how human BAT develops, differentiates, and is optimally activated. Accessing human BAT is challenging, given its low volume and anatomical dispersion. These constraints make detailed BAT-related developmental and functional mechanistic studies in humans virtually impossible. We have developed and characterized functionally and molecularly a new chemically defined protocol for the differentiation of human pluripotent stem cells (hPSCs) into brown adipocytes (BAs) that overcomes current limitations. This protocol recapitulates step by step the physiological developmental path of human BAT. The BAs obtained express BA and thermogenic markers, are insulin sensitive, and responsive to β-adrenergic stimuli. This new protocol is scalable, enabling the study of human BAs at early stages of development

SREBP1-induced fatty acid synthesis depletes macrophages antioxidant defences to promote their alternative activation

Macrophages exhibit a spectrum of activation states ranging from classical to alternative activation1. Alternatively, activated macrophages are involved in diverse pathophysiological processes such as confining tissue parasites2, improving insulin sensitivity3 or promoting an immune tolerant microenvironment that facilitates tumour growth and metastasis4. Recently, the role of metabolism regulating macrophage function has come into focus as both the classical and alternative activation programmes require specific regulated metabolic reprogramming5. While most of the studies regarding immunometabolism have focussed on the catabolic pathways activated to provide energy, little is known about the anabolic pathways mediating macrophage alternative activation. In this study, we show that the anabolic transcription factor sterol regulatory element binding protein 1 (SREBP1) is activated in response to the canonical Th2 cytokine interleukin 4 (IL-4) to trigger the de novo lipogenesis (DNL) programme, as a necessary step for macrophage alternative activation. Mechanistically, DNL consumes NADPH, partitioning it away from cellular antioxidant defences and raising ROS levels. ROS serves as a second messenger, signalling sufficient DNL, and promoting macrophage alternative activation. The pathophysiological relevance of this mechanism is validated by showing that SREBP1/DNL is essential for macrophage alternative activation in vivo in a helminth infection model.This work was supported by the British Heart Foundation (RG/18/7/33636), the MRC (MC_UU_00014/2) and the FP7 MITIN (223450). K.P. was a recipient of a fellowship from the Wellcome Trust. A.N.J.M. and E.J. are supported by the Wellcome Trust (100963/Z/13/Z) and the MRC (U105178805). J.L. is a recipient fellowship of the British Heart Foundation. A.D. was a Marie-Curie Early-Stage Researcher supported by the European Union’s Horizon 2020 research and innovation programme (675585 Marie-Curie ITN ‘SymBioSys’) to J.S.-R. A.K. is supported by the Wellcome Trust (106260/Z/14/Z) and an ERC award (648889). P.F. is supported by the Science Foundation Ireland (10/IN.1/B3004). The IMS Genomics and Transcriptomics and Histology cores (B.M.-A., B.Y.H.L. and M.K.M.) are funded by the UK MRC Metabolic Disease Unit (MRC_MC_UU_12012/5) and a Wellcome Trust Strategic Award (100574/Z/12/Z). The Disease Model Core is part of the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5) and Wellcome Trust Strategic Award (100574/Z/12/Z)

Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera

Background: The driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs) and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs. Methods: We evaluated 305 with essential thrombocythemia (ET) and 172 polycythemia vera (PV) patients diagnosed according to the 2016 WHO criteria and with full molecular characterization for driver mutations. Results: PTX3 levels were significantly increased in carriers of homozygous JAK2V617F mutation compared to all the other genotypes and triple negative ET patients, while hs-CRP levels were independent of the mutational profile. The risk of haematological evolution and death from any cause was about 2- and 1.5-fold increased in individuals with high PTX-3 levels, while the thrombosis rate tended to be lower. High hs-CRP levels were associated with risk of haematological evolution, death and also major thrombosis. After sequential adjustment for potential confounders (age, gender, diagnosis and treatments) and the presence of JAK2V617F homozygous status, high hs-CRP levels remained significant for all outcomes, while JAK2V617F homozygous status as well as treatments were the factors independently accounting for adverse outcomes among patients with high PTX3 levels. Conclusions: These results provide evidence that JAK2V617F mutation influences MPN-associated inflammation with a strong correlation between allele burden and PTX3 levels. Plasma levels of hs-CRP and PTX3 might be of prognostic value for patients with ET and PV, but their validation in future prospective studies is needed