Summary Background The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas. Methods This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0–2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150–200 mg/m2 temozolomide given on days 1–5); or to receive radiotherapy with concurrent temozolomide 75 mg/m2 per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). This trial is registered with ClinicalTrials.gov, number NCT00626990. Findings At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 (99·145% CI 0·45–0·93). Overall survival at 5 years was 55·9% (95% CI 47·2–63·8) with and 44·1% (36·3–51·6) without adjuvant temozolomide. Grade 3–4 adverse events were seen in 8–12% of 549 patients assigned temozolomide, and were mainly haematological and reversible. Interpretation Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed. Funding Schering Plough and MSD.

Abstract Background Depatuxizumab mafodotin (Depatux-M) is a tumor-specific antibody–drug conjugate consisting of an antibody (ABT-806) directed against activated epidermal growth factor receptor (EGFR) and the toxin monomethylauristatin-F. We investigated Depatux-M in combination with temozolomide or as a single agent in a randomized controlled phase II trial in recurrent EGFR amplified glioblastoma. Methods Eligible were patients with centrally confirmed EGFR amplified glioblastoma at first recurrence after chemo-irradiation with temozolomide. Patients were randomized to either Depatux-M 1.25 mg/kg every 2 weeks intravenously, or this treatment combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, or either lomustine or temozolomide. The primary endpoint of the study was overall survival. Results Two hundred sixty patients were randomized. In the primary efficacy analysis with 199 events (median follow-up 15.0 mo), the hazard ratio (HR) for the combination arm compared with the control arm was 0.71 (95% CI = 0.50, 1.02; P = 0.062). The efficacy of Depatux-M monotherapy was comparable to that of the control arm (HR = 1.04, 95% CI = 0.73, 1.48; P = 0.83). The most frequent toxicity in Depatux-M treated patients was a reversible corneal epitheliopathy, occurring as grades 3–4 adverse events in 25–30% of patients. In the long-term follow-up analysis with median follow-up of 28.7 months, the HR for the comparison of the combination arm versus the control arm was 0.66 (95% CI = 0.48, 0.93). Conclusion This trial suggests a possible role for the use of Depatux-M in combination with temozolomide in EGFR amplified recurrent glioblastoma, especially in patients relapsing well after the end of first-line adjuvant temozolomide treatment. (NCT02343406)

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Gousiekte, a cardiac syndrome of ruminants in southern Africa, is caused by the ingestion of plants containing the polyamine pavettamine. All the six known gousiekte-causing plants are members of the Rubiaceae or coffee family and house endosymbiotic Burkholderia bacteria in their leaves. It was therefore hypothesized that these bacteria could be involved in the production of the toxin. The pavettamine level in the leaves of 82 taxa from 14 genera was determined. Included in the analyses were various nodulated and non-nodulated members of the Rubiaceae. This led to the discovery of other pavettamine producing Rubiaceae, namely Psychotria kirkii and Ps. viridiflora. Our analysis showed that many plant species containing bacterial nodules in their leaves do not produce pavettamine. It is consequently unlikely that the endosymbiont alone can be accredited for the synthesis of the toxin. Until now the inconsistent toxicity of the gousiekte-causing plants have hindered studies that aimed at a better understanding of the disease. In vitro dedifferentiated plant cell cultures are a useful tool for the study of molecular processes. Plant callus cultures were obtained from pavettamine-positive species. Mass spectrometric analysis shows that these calli do not produce pavettamine but can produce common plant polyamines.

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