Citations

In patients not meeting the required hematocrit (HCT) or hemoglobin (Hb) thresholds according to BCSH and the WHO diagnostic criteria, the diagnosis of masked polycythemia vera (mPV) has been proposed. A comparison of HCT or Hb values with the expression of JAK2V617F, JAK2 exon 12, and CALR mutations in strictly WHO‐defined 257 overt PV and 140 mPV (59 mPV according to BCSH) and 397 patients with essential thrombocythemia (ET) was performed. Hb and HCT thresholds of mPV patients were significantly higher than JAK2V617F ET (P < 0.0001). The best cut‐off for Hb to discriminate JAK2‐mutated ET from PV was 16.5 g/dL for males and 16.0 g/dL for females. For HCT, this was 49% in males and 48% in females. The proportion of patients correctly classified as ET or PV when regarding Hb or HCT levels was 95% in males and 93% in females and 94% in both males and females, respectively. Am. J. Hematol. 89:588–590, 2014. © 2014 Wiley Periodicals, Inc.

Background— Ejection fraction (EF) as a marker of left ventricular (LV) dysfunction and the appropriate thresholds for diagnosing severe or mild/moderate LV dysfunction in mitral regurgitation are doubted and poorly followed in clinical practice. We aimed at assessing the role of EF in a large registry of organic mitral regurgitation to objectively establish thresholds for various degrees of LV dysfunction and to analyze whether mitral surgery remains beneficial in those subsets of patients. Methods and Results— We investigated the relation between EF and mortality in 1875 patients with mitral regurgitation due to flail leaflets in sinus rhythm (65±13 years; median EF, 66% [60%–71%]) enrolled in the Mitral Regurgitation International Database (MIDA) registry. With EF <60%, mortality after diagnosis increased precipitously under medical management (adjusted hazard ratio [HR], 1.59 [1.19–2.12]) and during the entire follow-up (adjusted HR, 1.51 [1.22–1.87]). Severe LV dysfunction, if defined by EF <30%, would affect a minuscule number of patients (0.3%). Conversely, EF <45% was more frequent (2.9%) and was associated with considerable mortality under medical management (adjusted HR, 2.43 [1.50–3.95]) and during the entire follow-up (adjusted HR, 2.46 [1.67–3.61]). The group with EF of 45% to 60% represented a large proportion of patients (23%), exhibited rarely overt symptoms, and had higher mortality compared with EF >60%. Above 60%, no EF threshold further determined survival. The benefit of surgery remained considerable in the groups with EF <45% (adjusted HR, 0.28 [0.17–0.56]) and with EF of 45% to 60% (adjusted HR, 0.34 [0.21–0.64]). Conclusions— EF is valuable in defining presence and severity of LV dysfunction in organic mitral regurgitation. Patients with EF <45% have severe LV dysfunction, catastrophic outcome under medical management, and should not be denied surgery. Although there is no survival gain with EF ranges >60%, with EF dropping <60%, mortality increases precipitously and prompt surgical referral is critical to outcome.

Polycythemia vera (PV) is currently diagnosed by the World Health Organization (WHO) criteria regarding hemoglobin (HB) levels and JAK2V617F and related mutations or by the British Committee for Standards in Haematology (BCSH) guidelines predominantly based on hematocrit (HCT) values (>52% in men and >48% in women) in JAK2 mutated patients. We examined clinical features at diagnosis and outcome in 397 mutated PV patients showing a bone marrow (BM) morphology conforming with the WHO descriptions but including also cases with a HB level <18.5 g/dL in males (range 16.0–18.4) and <16.5 g/dL in females (range 15.0–16.4). These patients were regarded as masked PV (mPV) comprising 140 (35%) cases of our cohort. A comparison with the BCSH criteria based on HCT levels revealed a decrease of mPV patients to 59 (15%). In both classification systems, mPV patients were more males, presented more frequently with higher platelet counts, and increased BM reticulin fibrosis. A worsening of overall survival was documented in mPV patients in comparison with overt PV following the WHO (P = 0.011) as well as the BCSH (P = 0.0019) criteria. Risk factors for inferior survival in mPV were age >65 years and white blood cell count >15 × 109/L. Without these risk factors mPV patients had the same survival as overt PV suggesting that a fraction of patients with HB lower than that required for WHO diagnosis should still be considered as overt PV. This study has established the existence of mPV by two different classification systems based on either HB or HCT threshold values. Am. J. Hematol. 89:199–202, 2014. © 2013 Wiley Periodicals, Inc.

We examined the baseline features and clinical outcomes of 140 patients presenting with JAK2V617F positivity and a bone marrow morphology conforming with WHO criteria of polycythemia vera (PV), but a hemoglobin level of <18.5 g/dL in males (range 16.0–18.4) and <16.5 g/dL in females (range 15.0–16.4). This cohort operationally referred to as masked PV (mPV) was compared with 257 patients with overt PV and displayed male predominance, a more frequent history of arterial thrombosis and thrombocytosis. Incidence of thrombosis was similar between the two groups but mPV displayed significantly higher rates of progression to myelofibrosis and acute leukemia and inferior survival. In multivariable analysis mPV diagnosis was an independent predictor of poor survival along with age >65 years and leukocyte count >10 × 109/L. Our data suggest that mPV is a heterogeneous myeloproliferative neoplasia and not necessarily an early/ pre‐polycythemic form of classical PV that at onset in a small fraction of patients clinically may mimic essential thrombocythemia. On the other hand, the majority mPV may have a longer prodrome of undiagnosed PV or a disease biology akin to primary myelofibrosis‐post PV myelofibrosis that could explain the worsening of outcome in comparison to overt/classical manifestations. Am. J. Hematol. 89:52–54, 2014. © 2013 Wiley Periodicals, Inc.

The glucagon-like peptide-1 receptor (GLP-1R) controls the physiological responses to the incretin hormone glucagon-like peptide-1 and is a major therapeutic target for the treatment of type 2 diabetes, owing to the broad range of effects that are mediated upon its activation. These include the promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of β-cell mass, improved peripheral insulin action, and promotion of weight loss. Regulation of GLP-1R function is complex, with multiple endogenous and exogenous peptides that interact with the receptor that result in the activation of numerous downstream signaling cascades. The current understanding of GLP-1R signaling and regulation is limited, with the desired spectrum of signaling required for the ideal therapeutic outcome still to be determined. In addition, there are several single-nucleotide polymorphisms (used in this review as defining a natural change of single nucleotide in the receptor sequence; clinically, this is viewed as a single-nucleotide polymorphism only if the frequency of the mutation occurs in 1% or more of the population) distributed within the coding sequence of the receptor protein that have the potential to produce differential responses for distinct ligands. In this review, we discuss the current understanding of GLP-1R function, in particular highlighting recent advances in the field on ligand-directed signal bias, allosteric modulation, and probe dependence and the implications of these behaviors for drug discovery and development.