Antiplatelet therapy versus observation in low-risk essential thrombocythemia with CALR mutation

The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 low-risk essential thrombocythemia patients (CALR-mutated n=271, JAK2V617F-mutated n=162) who were on antiplatelet therapy or observation only. After a 2215 person-years follow-up free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 vs. 1.8 x1000 patient-years, p=0.03). In JAK2V617F-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2V617F-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3-42.3; p=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated than in JAK2V617F-mutated essential thrombocythemia (median time 5 years and 9.8 years, respectively; p=0.0002) usually to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.

HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.

BACKGROUND: HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT±cetuximab in the EXPERT-C trial. PATIENTS AND METHODS: Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio ≥2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. RESULTS: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated±cetuximab. CONCLUSIONS: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. TRIAL REGISTRATION: ISRCTN Register: 99828560.

Phonic skills mediate improved literacy outcomes in at-risk primary school children: results from the Ready-to-Learn Programme

Background
Learning to read is a key goal during primary school: reading difficulties may curtail children’s learning trajectories. Controversy remains regarding what types of interventions are effective for children at risk for academic failure, such as children in disadvantaged areas. We present data from a complex intervention to test the hypothesis that phonic skills and word recognition abilities are a pivotal and specific causal mechanism for the development of reading skills in children at risk for poorer literacy outcomes.
Method
Over 500 pupils across 16 primary schools took part in a Cluster Randomised Controlled Trial from school year 1 to year 3. Schools were randomly allocated to the intervention or the control arm. The intervention involved a literacy-rich after-school programme. Children attending schools in the control arm of the study received the curriculum normally provided. Children in both arms completed batteries of language, phonic skills, and reading tests every year. We used multilevel mediation models to investigate mediating processes between intervention and outcomes.
Findings
Children who took part in the intervention displayed improvements in reading skills compared to those in the control arm. Results indicated a significant indirect effect of the intervention via phonics encoding.
Discussion
The results suggest that the intervention was effective in improving reading abilities of children at risk, and this effect was mediated by improving children’s phonic skills. This has relevance for designing interventions aimed at improving literacy skills of children exposed to socio-economic disadvantage. Results also highlight the importance of methods to investigate causal pathways from intervention to outcomes.

Territoriality and Migration in a Divided Society: Lay Theories of Citizenship and Place in Northern Ireland

The study of citizenship has increasingly focused on the ways in which spatialized understandings of the concept can be used to marginalise and exclude social groups: exclusive constructions of national boundaries, local neighbourhoods and public spaces can deny marginalised groups their social and political rights. Less attention has been paid to how constructions of place can accommodate different groups’ rights and promote peaceful coexistence. This is particularly important in locations where migration disrupts existing understandings (‘lay theories’) of the relationship between residency, identity and collective rights. The present research examines how spatialized understandings of citizenship shape perceptions of intergroup mixing in previously segregated areas of a post-conflict society. Critical Discursive Social Psychological (CDSP) analysis of 30 interviews with long-term residents and recent migrants to increasingly mixed areas of Belfast shows that, while all pa
rticipants acknowledged Northern Ireland’s territorialisation, different lay theories of citizenship underpin the possibility and desirability of intergroup coexistence. Long-term residents drew upon understandings of the negative citizenry of the outgroup to argue against the possibility of peaceful coexistence within their locale, while recent incomers gave evidence of their own experiences of good citizenship within the shared spaces of neighbourhood to demonstrate that this could and should be achieved. The implications of lay theories of citizenship for the study of residential migration and mixing are discussed

Importance of risk factor management in diabetic patients and reduction in Stage B heart failure

BACKGROUND: A number of studies have demonstrated the presence of a diabetic cardiomyopathy, increasing the risk of heart failure development in this population. Improvements in present-day risk factor control may have modified the risk of diabetes-associated cardiomyopathy.

AIM: We sought to determine the contemporary impact of diabetes mellitus (DM) on the prevalence of cardiomyopathy in at-risk patients with and without adjustment for risk factor control.

DESIGN: A cross-sectional study in a population at risk for heart failure.

METHODS: Those with diabetes were compared to those with other cardiovascular risk factors, unmatched, matched for age and gender and then matched for age, gender, body mass index, systolic blood pressure and low density lipoprotein cholesterol.

RESULTS: In total, 1399 patients enrolled in the St Vincent's Screening to Prevent Heart Failure (STOP-HF) cohort were included. About 543 participants had an established history of DM. In the whole sample, Stage B heart failure (asymptomatic cardiomyopathy) was not found more frequently among the diabetic cohort compared to those without diabetes [113 (20.8%) vs. 154 (18.0%), P = 0.22], even when matched for age and gender. When controlling for these risk factors and risk factor control Stage B was found to be more prevalent in those with diabetes [88 (22.2%)] compared to those without diabetes [65 (16.4%), P = 0.048].

CONCLUSION: In this cohort of patients with established risk factors for Stage B heart failure superior risk factor management among the diabetic population appears to dilute the independent diabetic insult to left ventricular structure and function, underlining the importance and benefit of effective risk factor control in this population on cardiovascular outcomes.

Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C).

PURPOSE: To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. PATIENTS AND METHODS: Patients with operable magnetic resonance imaging-defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. RESULTS: One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. CONCLUSION: Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.