NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma.

BACKGROUND: There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older. METHODS: NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm. RESULTS: A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events. CONCLUSIONS: Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations

Economic evaluation of multiplex ligation-dependent probe amplification and karyotyping in prenatal diagnosis: a cost-minimization analysis

textabstractPurpose: To assess the cost-effectiveness of Multiplex Ligation-dependent Probe Amplification (MLPA, P095 kit) compared to karyotyping. Methods: A cost-minimization analysis alongside a nationwide prospective clinical study of 4,585 women undergoing amniocentesis on behalf of their age (≥36 years), an increased risk following first trimester prenatal screening or parental anxiety. Results: Diagnostic accuracy of MLPA (P095 kit) was comparable to karyotyping (1.0 95% CI 0.999-1.0). Health-related quality of life did not differ between the strategies (summary physical health: mean difference 0.31, p = 0.82; summary mental health: mean difference 1.91, p = 0.22). Short-term costs were lower for MLPA: mean difference €315.68 (bootstrap 95% CI €315.63-315.74; -44.4%). The long-term costs were slightly higher for MLPA: mean difference €76.42 (bootstrap 95% CI €71.32-81.52; +8.6%). Total costs were on average €240.13 (bootstrap 95% CI €235.02-245.23; -14.9%) lower in favor of MLPA. Cost differences were sensitive to proportion of terminated pregnancies, sample throughput, individual choice and performance of tests in one laboratory, but not to failure rate or the exclusion of polluted samples. Conclusion: From an economic perspective, MLPA is the preferred prenatal diagnostic strategy in women who undergo amniocentesis on behalf of their age, following prenatal screening or parental anxiety

A randomized phase II trial of veliparib (V), radiotherapy (RT) and temozolomide (TMZ) in patients (pts) with unmethylated MGMT (uMGMT) glioblastoma (GBM)

2011 Background: TMZ offers minimal benefit in uMGMT GBM pts. V is synergistic with both RT and TMZ in preclinical models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated. This study examined a novel approach to patients with uMGMT GBM. Methods: VERTU is a randomized Phase 2 trial comparing Arm A (Standard of care) = RT (60Gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150–200mg/m2D 1–5) every 28 days for 6 cycles vs Arm B (experimental arm) = RT (60Gy/30 fractions) + V (200mg PO BID) followed by TMZ (150–200mg/m2D 1–5) + V (40mg bid, D 1–7) every 28 days for 6 cycles in pts with newly diagnosed centrally determined uMGMT GBM. The study aims to randomize 120 pts (2:1 to the experimental arm). The primary endpoint was 6 months progression free survival (6mPFS) with multiple secondary and tertiary endpoints. Evaluation of feasibility and safety was planned after completion of RT in the first 60 pts (Stage 1). (ANZCTR #ACTRN12615000407594). Tumor tissue and serial bloods were collected for translational research. Results: 125 pts were randomized (41 Arm A, 84 Arm B). Mean (range) age 58 (22–78) years, 70% male, 61% ECOG 0, 86% macroscopic resection, 14% biopsy. At the time of analysis (cut-off date: 04/Feb/2019), median follow up was 16.5 months, 76 pts had died. 6mPFS (95% CI, Kaplan-Meier estimate) was 37% (22–52) in Arm A and 53% (41–63) in Arm B, and median PFS was 4.4m (95% CI 4.0–6.0) for Arm A and 6.2m (95% CI 4.9–7.1) for Arm B (HR = 0.81, 95%CI 0.54–1.21). 50% of pts in Arm A and 53% in Arm B experienced ≥ G3 adverse events (AEs). The most common G 3/4 AEs were decreased platelets, seizures, hyperglycemia and diarrhea (each 5%) in Arm A and decreased platelets (13%) and seizures (11%) in Arm B. Conclusions: In this multicenter, randomized study, the experimental therapy was feasible and well tolerated. The observed 6mPFS appeared longer in Arm B, but at the time of submitting the abstract, this result did not meet the prespecified primary endpoint. More mature results will be presented at the annual meeting. QoL in VERTU is reported separately. Central MR review, biomarker analyses, including DNA repair and methylation signature analyses are ongoing. Clinical trial information: ACTRN12615000407594. </jats:p

Citizenship and enterprise: Issues from an investigation of teachers' perceptions in England and Hungary.

We explore the perceptions of teachers concerning citizenship and enterprise in Hungary and England. Contextual matters are described and research methods outlined prior to a discussion of emerging issues. We argue that citizenship in both countries is understood broadly in terms of what it means to be human. The English teachers emphasized community issues and being socially active more often than those in Hungary. Hungarian teachers were less positive about state and civil society and more patriotic about their country. In both countries those in provincial towns (rather than those in capital cities) suggested a belief in the need for a greater adherence to rules. There was greater enthusiasm for citizenship education in primary rather than secondary schools in both countries. All teachers seemed wary about a form of enterprise education that relates directly to the economy and this was especially true for the Hungarian sample. Teachers in both countries, while recognizing the current emphasis on competition between and within schools, tended to characterize citizenship education as a constructive social enterprise (rather than an economic enterprise), in which young people are encouraged to explore problems and develop their initiative and capacity for action. All teachers favoured a collaborative and broad-based pedagogical approach in which young people are allowed to explore social and political issues through dilemmas