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Abstract Background A significant genetic component has been described for idiopathic pulmonary fibrosis (IPF). The R131H (rs1801274) polymorphism of the IgG receptor FcγRIIa determines receptor affinity for IgG subclasses and is associated with several chronic inflammatory diseases. We investigated whether this polymorphism is associated with IPF susceptibility or progression. Methods In a case-control study, we compared the distribution of FcγRIIa R131H genotypes in 142 patients with IPF and in 218 controls using allele-specific PCR amplification. Results No differences in the frequency of FcγRIIa genotypes were evident between IPF patients and control subjects. However, significantly impaired pulmonary function at diagnosis was observed in HH compared to RR homozygotes, with evidence of more severe restriction (reduced forced vital capacity (FVC)) and lower diffusing capacity for carbon monoxide (DLCO). Similarly, increased frequency of the H131 allele was observed in patients with severe disease (DLCO < 40% predicted) (0.53 vs. 0.38; p = 0.03). Furthermore, the H131 allele was associated with progressive pulmonary fibrosis as determined by > 10% drop in FVC and/or > 15% fall in DLCO at 12 months after baseline (0.48 vs. 0.33; p = 0.023). Conclusions These findings support an association between the FcγRIIa R131H polymorphism and IPF severity and progression, supporting the involvement of immunological mechanisms in IPF pathogenesis.

Approximately one-third of patients with chronic myeloid leukaemia will fail to achieve or maintain responses to imatinib. Changes in solute carrier family 22 (organic cation transporter), member 1 ( SLC22 A1, also termed OCT1), the main transporter for imatinib, have been proposed as a possible predictive factor. We analysed SLC22A1 m RNA levels and single nucleotide polymorphisms ( SNPs) located in exon 7 in 153 diagnostic whole blood samples from two patient cohorts. The level of SLC22A1 expression did not significantly correlate with imatinib failure or achievement of molecular remission. The SNP 408V>M (g.1222G>A) was present in 65% of patients and was associated in all cases with an eight base-pair insertion (8+ allele) at the 3′ end of exon 7. The latter generates an alternative splice site, leading to a premature stop codon. M420del was found in 33% of patients and never in cis with 8+ (the 3− allele). Significantly longer times to 1% and 0·1% molecular responses (by quantitative reverse transcription polymerase chain reaction) were seen in patients with 8+8+ or 8+N compared to those with the remaining four genotypes (N = no insertion or deletion). Patients lacking 8+ and 3− (NN, 18%) showed the best outcomes overall. Thus, while SLC22 A1 expression does not appear to affect response, alterations in its splicing or amino acid sequence may do so. [ABSTRACT FROM AUTHOR]

Somatic mutations in the endoplasmic reticulum chaperone calreticulin (CALR) are detected in approximately 40% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Multiple different mutations have been reported, but all result in a +1-bp frameshift and generate a novel protein C terminus. In this study, we generated a conditional mouse knockin model of the most common CALR mutation, a 52-bp deletion. The mutant novel human C-terminal sequence is integrated into the otherwise intact mouse CALR gene and results in mutant CALR expression under the control of the endogenous mouse locus. CALRdel/+ mice develop a transplantable ET-like disease with marked thrombocytosis, which is associated with increased and morphologically abnormal megakaryocytes and increased numbers of phenotypically defined hematopoietic stem cells (HSCs). Homozygous CALRdel/del mice developed extreme thrombocytosis accompanied by features of MF, including leukocytosis, reduced hematocrit, splenomegaly, and increased bone marrow reticulin. CALRdel/+ HSCs were more proliferative in vitro, but neither CALRdel/+ nor CALRdel/del displayed a competitive transplantation advantage in primary or secondary recipient mice. These results demonstrate the consequences of heterozygous and homozygous CALR mutations and provide a powerful model for dissecting the pathogenesis of CALR-mutant ET and PMF. [ABSTRACT FROM AUTHOR]

Purpose: Cytoreductive therapy is beneficial in patients with essential thrombocythemia (ET) at high risk of thrombosis. However, its value in those lacking high-risk features remains unknown. This open-label, randomized trial compared hydroxycarbamide plus aspirin with aspirin alone in patients with ET age 40 to 59 years and without high-risk factors or extreme thrombocytosis., Patients and Methods: Patients were age 40 to 59 years and lacked a history of ischemia, thrombosis, embolism, hemorrhage, extreme thrombocytosis (platelet count ≥ 1,500 × 10 9 /L), hypertension, or diabetes requiring therapy. In all, 382 patients were randomly assigned 1:1 to hydroxycarbamide plus aspirin or aspirin alone. The composite primary end point was time to arterial or venous thrombosis, serious hemorrhage, or death from vascular causes. Secondary end points were time to first arterial or venous thrombosis, first serious hemorrhage, death, incidence of transformation, and patient-reported quality of life., Results: After a median follow-up of 73 months and a total follow-up of 2,373 patient-years, there was no significant difference between the arms in the likelihood of patients reaching the primary end point (hazard ratio, 0.98; 95% CI, 0.42 to 2.25; P = 1.0). The incidence of significant vascular events was low, at 0.93 per 100 patient-years (95% CI, 0.61 to 1.41). There were also no differences in overall survival; in the composite end point of transformation to myelofibrosis, acute myeloid leukemia, or myelodysplasia; in adverse events; or in patient-reported quality of life., Conclusion: In patients with ET age 40 to 59 years and lacking high-risk factors for thrombosis or extreme thrombocytosis, preemptive addition of hydroxycarbamide to aspirin did not reduce vascular events, myelofibrotic transformation, or leukemic transformation. Patients age 40 to 59 years without other clinical indications for treatment (such as previous thrombosis or hemorrhage) who have a platelet count < 1,500 × 10 9 /L should not receive cytoreductive therapy.

The myeloproliferative neoplasms are a heterogeneous group of clonal disorders characterized by the overproduction of mature cells in the peripheral blood, together with an increased risk of thrombosis and progression to acute myeloid leukemia. The majority of patients with Philadelphia-chromosome negative myeloproliferative neoplasms harbor somatic mutations in Janus kinase 2, leading to constitutive activation. Acquired mutations in calreticulin or myeloproliferative leukemia virus oncogene are found in a significant number of patients with essential thrombocythemia or myelofibrosis, and mutations in numerous epigenetic regulators and spliceosome components are also seen. Although the cellular and molecular consequences of many of these mutations remain unclear, it seems likely that they interact with germline and microenvironmental factors to influence disease pathogenesis. This review will focus on the determinants of specific myeloproliferative neoplasm phenotypes as well as on how an improved understanding of molecular mechanisms can inform our understanding of the disease entities themselves., (Copyright© Ferrata Storti Foundation.)

Sevelamer (Renagel and Renvela), is an orally administered weakly basic anion exchange resin that binds dietary phosphate in the gastrointestinal tract, and is approved for use in the US, Europe and many other countries for the treatment of hyperphosphatemia in adult patients on hemodialysis or peritoneal dialysis. Clinical evidence shows that sevelamer is at least as effective as calcium-based oral phosphate binders in controlling serum phosphate, but with a lower incidence of hypercalcemia. Whilst sevelamer hydrochloride is associated with mild acidosis, sevelamer carbonate does not have this drawback. Use of sevelamer and avoidance of calcium-based binders may slow the progression of vascular calcification in hemodialysis patients, and it also reduces serum low-density lipoprotein-cholesterol levels. There was no between-group difference in all-cause mortality between sevelamer and calcium-based phosphate binder therapy in the primary efficacy analysis of the large (n >2100), 3-year DCOR trial. In the smaller (n = 109) nonblind RIND trial in patients new to hemodialysis, data suggest there may be an overall survival benefit with sevelamer versus calcium-based phosphate binder treatment but the evidence on the efficacy of sevelamer in reducing mortality and hospitalization is not strong. The balance of evidence, however, does not strongly support the use of sevelamer over the much less costly calcium-based binders except in patients at risk of hypercalcemic episodes. Further research into cardiovascular and all-cause mortality over a longer time period would be needed to settle this issue, and the relative survival benefits and cost effectiveness of all phosphate binder therapies remains to be fully determined. Despite the relative paucity of data available, sevelamer has established itself as the most widely used binder in the United States and the most widely used noncalcium-based binder worldwide. However, affordability is a major issue for most health economies and in the light of recent economic events is likely to become more prominent.