Contemporary risk models in primary myelofibrosis (PMF) include the mutation (MIPSS70) and mutation/karyotype enhanced (MIPSS70 plus/v2.0) international prognostic scoring systems. High molecular risk (HMR) mutations incorporated in one or both of these models include ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1Q157; the current study examines additional prognostic contribution from more recently described HMR mutations, including CBL, NRAS, KRAS, RUNX1, and TP53. In a cohort of 363 informative cases (median age 58 years; 60% males), mutations included JAK2 61%, CALR 24%, MPL 6%, ASXL1 29%, SRSF2 10%, U2AF1Q157 5%, EZH2 10%, IDH1/2 4%, TP53 5%, CBL 5%, NRAS 7%, KRAS 4%, and RUNX1 4%. At a median follow-up of 4.6 years, 135 (37%) deaths and 42 (11.6%) leukemic transformations were recorded. Univariate analysis confirmed significant survival impact from the original MIPSS70/plus/v2.0 HMR mutations as well as CBL (HR 2.8; p < .001), NRAS (HR 2.4; p < .001), KRAS (HR 2.1; p = .01), and TP53 (HR 2.4; p = .004), but not RUNX1 mutations (HR 1.8; p = .08). Multivariate analysis (MVA) that included both the original and more recently described HMR mutations confirmed independent prognostic contribution from ASXL1 (HR 1.8; p = .007), SRSF2 (HR 4.3; p < .001), U2AF1Q157 (HR 2.9, p = .004), and EZH2 (HR 2.4; p < .001), but not from IDH1/2 (p = .3), TP53 (p = .2), CBL (p = .3), NRAS (p = .8) or KRAS (p = .2) mutations. The lack of additional prognostic value from CBL, NRAS, KRAS, RUNX1, and TP53 was further demonstrated in the setting of (i) MVA of mutations and karyotype, (ii) MVA of MIPSS70/plus/v2.0 composite scores and each one of the recently described HMR mutations, except TP53, and iii) modified MIPSS70/plus/plus v2.0 that included CBL, NRAS, KRAS, and TP53 as part of the HMR constituency, operationally referred to as "HMR+" category. Furthermore, "HMR+" enhancement of MIPSS70/plus/plus v2.0 did not result in improved model performance, as measured by C-statistics. We conclude that prognostic integrity of MIPSS70/plus/plus v2.0, as well as their genetic components, was sustained and their value not significantly upgraded by the inclusion of more recently described HMR mutations, including CBL, NRAS, KRAS, and RUNX1. Additional studies are needed to clarify the apparent additional prognostic value of TP53 mutation and its allelic state.

THC triggers a pronounced entry of Ca2+ , which may be deleterious, into sickle cell red blood cells via activation of the TRPV2 channel.

Graphical representation of increasing percentage of female patients seen at HTCs, percentage of females by diagnosis, number of clinics in existence, and absolute number of female patients seen over a 10-year period (top left then clockwise).

AbstractLow‐count monoclonal B‐cell lymphocytosis (MBLlo) has been associated with an underlying immunodeficiency and has recently emerged as a new risk factor for severe COVID‐19. Here, we investigated the kinetics of immune cell and antibody responses in blood during COVID‐19 of MBLlo versus non‐MBL patients. For this study, we analyzed the kinetics of immune cells in blood of 336 COVID‐19 patients (74 MBLlo and 262 non‐MBL), who had not been vaccinated against SARS‐CoV‐2, over a period of 43 weeks since the onset of infection, using high‐sensitivity flow cytometry. Plasma levels of anti‐SARS‐CoV‐2 antibodies were measured in parallel by ELISA. Overall, early after the onset of symptoms, MBLlo COVID‐19 patients showed increased neutrophil, monocyte, and particularly, plasma cell (PC) counts, whereas eosinophil, dendritic cell, basophil, and lymphocyte counts were markedly decreased in blood of a variable percentage of samples, and with a tendency toward normal levels from week +5 of infection onward. Compared with non‐MBL patients, MBLlo COVID‐19 patients presented higher neutrophil counts, together with decreased pre‐GC B‐cell, dendritic cell, and innate‐like T‐cell counts. Higher PC levels, together with a delayed PC peak and greater plasma levels of anti‐SARS‐CoV‐2‐specific antibodies (at week +2 to week +4) were also observed in MBLlo patients. In summary, MBLlo COVID‐19 patients share immune profiles previously described for patients with severe SARS‐CoV‐2 infection, associated with a delayed but more pronounced PC and antibody humoral response once compared with non‐MBL patients.