Phenotypic subtypes of leukaemic transformation in chronic myelomonocytic leukaemia

Chronic myelomonocytic leukaemia (CMML) is a haematological disorder with high risk of transformation to acute myeloid leukaemia (AML). To characterize the phenotypic and genomic patterns of CMML progression, we evaluated a cohort of 189 patients with AML evolving from CMML. We found that transformation occurs through distinct trajectories characterized by genomic profiles and clonal evolution: monocytic (Mo-AML, 53%), immature myeloid (My-AML, 43%) or erythroid (Ery-AML, 2%). Mo-AML, characterized by expansion of monoblasts and promonocytes (low CD34, CD117 expression; high CD14, CD33, CD56 and CD64 expression), were defined by SRSF2, TET2 and RAS pathway mutation co-dominance and were more likely to evolve from SRSF2-TET2 co-mutant CMML through emergence/expansion of RAS pathway mutant clones. Conversely, My-AML, characterized by expansion of immature myeloid blasts (high frequency of CD34, CD38, CD117; low frequency of CD14, CD64 and CD56 expression) were less likely to exhibit SRSF2-TET2 co-mutations or RAS pathway mutations and had higher frequency of CEBPA mutations. Ery-AML was defined by complex karyotypes and TP53 mutations. A trend towards improved OS and EFS with hypomethylating agent-venetoclax combination was observed in My-AML, but not Mo-AML. These findings define distinct progression of CMML and set the basis for future studies evaluating the role of phenotype-specific therapeutics.     

Routine sequencing in CLL has prognostic implications and provides new insight into pathogenesis and targeted treatments

Chronic lymphocytic leukaemia (CLL) is a genetically heterogeneous disease characterised by genomic alterations and gene mutations that may portend worse survival or resistance to treatments. A total of 680 blood or bone marrow samples underwent targeted sequencing of 29 genes previously identified as being mutated in CLL, which were correlated to known prognostic clinical characteristics. Overall, 400 (59%) patients were treatment-naïve (TN) and 280 (41%) were relapsed/refractory (R/R). Most patients (70%) had ≥1 mutation, with TP53 (22%), SF3B1 (18%), NOTCH1 (13%) and ATM (13%) being the most commonly mutated genes. A higher proportion of R/R patients had mutations in SF3B1 (P = 0·01) and TP53 (P < 0·001). Patients with mutated IGHV CLL more often had mutations in KLHL6 (P = 0·001) and MYD88 (P < 0·001). Pairwise associations showed mutational co-occurrences in the TN group including SF3B1/ATM [false discovery rate (FDR) < 0·05] and NOTCH1/POT1 (FDR < 0·01). Recurrent mutations resulting in premature truncation prior to the ubiquitination domains of NOTCH1 in its PEST domain and BIRC3 in its RING domain can produce proteins that constitutively activate CLL. Frequent missense mutations, such as K700E in SF3B1 and E571K in XPO1, have unknown function but are most likely to be activating mutations. Future directions include using these mutations to identify pathways for therapeutic targeting and rational drug design.     

Analyses of the facilitatory effect of orexin on eating and masticatory muscle activity in rats

The orexins (orexin-A and orexin-B) are neuropeptides that are secreted from neurons in the lateral hypothalamus and that participate in the regulation of feeding behavior. It remains to be determined, however, how the orexins exert their effects on feeding behavior, including masticatory movements. To this end, we analyzed food intake behavior and masticatory muscle activity using video analysis and electromyography (EMG) recording methods. The results showed that the cumulative food intake over 4 h was larger in rats intraventricularly injected with either orexin-A or orexin-B than in saline-injected control rats. The latency to eating and the feeding time for a fixed amount of pellets were shortened by injections of orexins in a dose-dependent manner, with a more potent effect by orexin-A than orexin-B. The shorter feeding time corresponded to a decreased number of chewing cycles. EMG recordings from both the digastric and masseter muscles showed two distinct patterns of bursts corresponding to the gnawing and chewing phases. After the injection of orexin-A, the magnitude of the bursts became larger in both phases in the masseter muscle, the burst duration became longer in the chewing phase in the masseter muscle, and the interburst interval became shortened in the gnawing phase in both muscles. Consequently, the burst frequency in the chewing phase was increased in the digastric muscle and, conversely, reduced in the masseter muscle. These results suggest that the orexin-A-induced facilitatory feeding behavior is characterized by a dynamic jaw-opener activity that opens the mouth rapidly and a powerful jaw-closer activity for crushing the increased amount of food taken into the mouth. The possible involvement of orexin-A in binge eating disorder is discussed.     

Is the oral contraceptive pill associated with fracture in later life? New evidence from the Royal College of General Practitioners Oral Contraception Study

Background

Several studies, including an earlier analysis from the Royal College of General Practitioners (RCGP) Oral Contraception Study, have suggested that ever users of oral contraceptives have an increased risk of fracture when compared with never users. In this paper, we examined a subset of women in the RCGP study living in Scotland to determine whether this risk has persisted.

Study Design

A nested case-control study was carried out using data collected prospectively for the RCGP Oral Contraception Study. Cases were women with a first ever diagnosis of fracture (n=651), age-matched to two controls (n=1302). Adjustments were made for smoking, social class and parity.

Results

There was not a significant association between ever use of oral contraception and fracture (adjusted odds ratio 1.05, 95% confidence interval 0.86–1.29), compared with never users. Neither were significant associations found between fracture and smoking, social class and parity. The findings did not vary materially with age or type of fracture.

Conclusion

Ever use of oral contraception was not associated with fracture in this study.     

Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

Although generally considered a clinically indolent neoplasm, CLL/SLL may undergo transformation to a clinically aggressive lymphoma. The most common form of transformation, to DLBCL, is also known as Richter syndrome. Transformation determines the course of the disease and is associated with unfavorable patient outcome. Precise detection of transformation and identification of predictive biomarkers and specific molecular pathways implicated in the pathobiology of transformation in CLL/SLL will enable personalized therapeutic approach and provide potential avenues for improving the clinical outcome of patients. In this review, we present an overview of the pathologic features, risk factors, and pathogenic mechanisms of CLL/SLL transformation. Am. J. Hematol. 91:1036–1043, 2016. © 2016 Wiley Periodicals, Inc.