Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients.

Key Points: JAK2 (V617F)-mutated essential thrombocythemia and polycythemia vera are different phenotypes in the evolution of a single neoplasm. CALR-mutated essential thrombocythemia is a distinct disease entity not only at the molecular level, but also with respect to clinical outcomes.

Key Points: Patients with PMF may carry JAK2 (V617F), a CALR exon 9 indel, an MPL exon 10 mutation, or none of these genetic lesions. The genetic subtypes of PMF differ substantially as regards clinical course, disease progression, and overall survival.

A quarter of patients with essential thrombocythemia or primary myelofibrosis carry a driver mutation of CALR, the calreticulin gene. A 52-bp deletion (type 1) and a 5-bp insertion (type 2 mutation) are the most frequent variants. These indels might differentially impair the calcium binding activity of mutant calreticulin. We studied the relationship between mutation subtype and biological/clinical features of the disease. Thirty-two different types of CALR variants were identified in 311 patients. Based on their predicted effect on calreticulin C-terminal, mutations were classified as: (i) type 1-like (65%); (ii) type 2-like (32%); and (iii) other types (3%). Corresponding CALR mutants had significantly different estimated isoelectric points. Patients with type 1 mutation, but not those with type 2, showed abnormal cytosolic calcium signals in cultured megakaryocytes. Type 1-like mutations were mainly associated with a myelofibrosis phenotype and a significantly higher risk of myelofibrotic transformation in essential thrombocythemia. Type 2-like CALR mutations were preferentially associated with an essential thrombocythemia phenotype, low risk of thrombosis despite very-high platelet counts and indolent clinical course. Thus, mutation subtype contributes to determining clinical phenotype and outcomes in CALR-mutant myeloproliferative neoplasms. CALR variants that markedly impair the calcium binding activity of mutant calreticulin are mainly associated with a myelofibrosis phenotype.

Background: Short-term exposure to air pollution has adverse effects among patients with asthma, but whether long-term exposure to air pollution is a cause of adult-onset asthma is unclear. Objective: We aimed to investigate the association between air pollution and adult onset asthma. Methods: Asthma incidence was prospectively assessed in six European cohorts. Exposures studied were annual average concentrations at home addresses for nitrogen oxides assessed for 23,704 participants (including 1,257 incident cases) and particulate matter (PM) assessed for 17,909 participants through ESCAPE land-use regression models and traffic exposure indicators. Meta-analyses of cohort-specific logistic regression on asthma incidence were performed. Models were adjusted for age, sex, overweight, education, and smoking and included city/area within each cohort as a random effect. Results: In this longitudinal analysis, asthma incidence was positively, but not significantly, associated with all exposure metrics, except for PMcoarse. Positive associations of borderline significance were observed for nitrogen dioxide [adjusted odds ratio (OR) = 1.10; 95% CI: 0.99, 1.21 per 10 μg/m3; p = 0.10] and nitrogen oxides (adjusted OR = 1.04; 95% CI: 0.99, 1.08 per 20 μg/m3; p = 0.08). Nonsignificant positive associations were estimated for PM10 (adjusted OR = 1.04; 95% CI: 0.88, 1.23 per 10 μg/m3), PM2.5 (adjusted OR = 1.04; 95% CI: 0.88, 1.23 per 5 μg/m3), PM2.5absorbance (adjusted OR = 1.06; 95% CI: 0.95, 1.19 per 10–5/m), traffic load (adjusted OR = 1.10; 95% CI: 0.93, 1.30 per 4 million vehicles × meters/day on major roads in a 100-m buffer), and traffic intensity (adjusted OR = 1.10; 95% CI: 0.93, 1.30 per 5,000 vehicles/day on the nearest road). A nonsignificant negative association was estimated for PMcoarse (adjusted OR = 0.98; 95% CI: 0.87, 1.14 per 5 μg/m3). Conclusions: Results suggest a deleterious effect of ambient air pollution on asthma incidence in adults. Further research with improved personal-level exposure assessment (vs. residential exposure assessment only) and phenotypic characterization is needed. Citation: Jacquemin B, Siroux V, Sanchez M, Carsin AE, Schikowski T, Adam M, Bellisario V, Buschka A, Bono R, Brunekreef B, Cai Y, Cirach M, Clavel-Chapelon F, Declercq C, de Marco R, de Nazelle A, Ducret-Stich RE, Ferretti VV, Gerbase MW, Hardy R, Heinrich J, Janson C, Jarvis D, Al Kanaani Z, Keidel D, Kuh D, Le Moual N, Nieuwenhuijsen MJ, Marcon A, Modig L, Pin I, Rochat T, Schindler C, Sugiri D, Stempfelet M, Temam S, Tsai MY, Varraso R, Vienneau D, Vierkötter A, Hansell AL, Krämer U, Probst-Hensch NM, Sunyer J, Künzli N, Kauffmann F. 2015. Ambient air pollution and adult asthma incidence in six European cohorts (ESCAPE). Environ Health Perspect 123:613–621; http://dx.doi.org/10.1289/ehp.1408206

Regression of hepatitis C virus (HCV)–associated lymphoma with interferon (IFN)-based antiviral treatment supports an etiological link between lymphoma and HCV infection. In addition, a favorable impact of antiviral treatment on overall survival of patients with HCV-related lymphoma has been reported. Data on IFN-free regimens combining direct-acting antivirals (DAAs) in HCV-associated lymphoproliferative disorders are scanty. We analyzed the virological and lymphoproliferative disease response (LDR) of 46 patients with indolent B-cell non-Hodgkin lymphomas (NHLs) or chronic lymphocytic leukemia (CLL) and chronic HCV infection treated with DAAs. The histological distribution was 37 marginal zone lymphomas (MZLs), 2 lymphoplasmacytic lymphomas, 2 follicular lymphomas, 4 CLL/small lymphocytic lymphomas (CLL/SLLs), and 1 low-grade NHL not otherwise specified. Thirty-nine patients received a sofosbuvir-based regimen and 7 patients received other DAAs. The median duration of DAA therapy was 12 weeks (range, 6-24 weeks). A sustained virological response at week 12 after finishing DAAs was obtained in 45 patients (98%); the overall LDR rate was 67%, including 12 patients (26%) who achieved a complete response. The LDR rate was 73% among patients with MZL, whereas no response was observed in CLL/SLL patients. Seven patients cleared cryoglobulins out of 15 who were initially positive. After a median follow-up of 8 months, 1-year progression-free and overall survival rates were 75% (95% confidence interval [CI], 51-88] and 98% [95% CI, 86-100], respectively. DAA therapy induces a high LDR rate in HCV-associated indolent lymphomas. These data provide a strong rationale for prospective trials with DAAs in this setting. Publisher9s Note: There is an Inside Blood Commentary on this article in this issue. Key Points Direct-acting antiviral agents are able to induce lymphoma response in patients with HCV-associated indolent non-Hodgkin lymphoma. The highest rate of lymphoma response (73%) was observed in patients with marginal zone lymphoma.