Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial.

Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-based intralesional oncolytic immunotherapy approved for the treatment of unresectable melanoma. The present, ongoing study aimed to estimate the treatment effect of neoadjuvant T-VEC on recurrence-free survival (RFS) of patients with advanced resectable melanoma. An open-label, phase 2 trial (NCT02211131) was conducted in 150 patients with resectable stage IIIB-IVM1a melanoma who were randomized to receive T-VEC followed by surgery (arm 1, n = 76) or surgery alone (arm 2, n = 74). The primary endpoint was a 2-year RFS in the intention-to-treat population. Secondary and exploratory endpoints included overall survival (OS), pathological complete response (pCR), safety and biomarker analyses. The 2-year RFS was 29.5% in arm 1 and 16.5% in arm 2 (overall hazard ratio (HR) = 0.75, 80% confidence interval (CI) = 0.58-0.96). The 2-year OS was 88.9% for arm 1 and 77.4% for arm 2 (overall HR = 0.49, 80% CI = 0.30-0.79). The RFS and OS differences between arms persisted at 3 years. In arm 1, 17.1% achieved a pCR. Increased CD8+ density correlated with clinical outcomes in an exploratory analysis. Arm 1 adverse events were consistent with previous reports for T-VEC. The present study met its primary endpoint and estimated a 25% reduction in the risk of disease recurrence for neoadjuvant T-VEC plus surgery versus upfront surgery for patients with resectable stage IIIB-IVM1a melanoma.

Investigation of quality of life and family burden issues during insulin pump therapy in children with Type 1 diabetes mellitus--a large-scale multicentre pilot study.

AIMS: To investigate psychosocial aspects of continuous subcutaneous insulin infusion (CSII) therapy in children with Type 1 diabetes and to identify relevant and sensitive measures. METHODS: We performed a multi-centre prospective pre-/post-study with children (53 girls, 64 boys, age 10.5 +/- 3.7 years, mean +/- sd) with Type 1 diabetes and their main carer from 18 German diabetic centres. Twenty-five children aged 8-11 years and 63 adolescents aged 12-16 years and their parents, plus 29 parents of children aged 4-7 years completed standardized questionnaires on generic and diabetes-specific quality of life (QOL), generic parenting stress, mealtime behaviour, fear of hypoglycaemia and family conflict immediately before and 6 months after transition to CSII. RESULTS: After transition to CSII, diabetes-specific QOL of children increased significantly (P < 0.001) in all age groups, with moderate to large effect sizes (children aged 4-7 years: Cohen's effect sized = 1.3; 8-11 years: d = 0.9, adolescents 12-16 years: d = 0.6). Parents reported reduced frequency (P < 0.01, d = 0.4-0.7) and difficulty (P < 0.01, d = 0.3-0.6) of overall parenting stress and decreased worries about hypoglycaemia (P < 0.01, d = 0.4-0.6). Parents of younger children (4-7 years) reported reduced problems with nutrition management (frequency: P < 0.001, d = 1.1; difficulty: P < 0.05, d = 0.7). CONCLUSIONS: CSII may have substantial psychosocial benefits. Controlled studies are needed.

Occurrence and changes of proline content in plants in the southern Namib Desert in relations to increasing and decreasing drought.

Over a period of seven years (1977-1983) the proline content and its responses to climatic changes were investigated in plants - especially Mesembryanthemaceae - in the southern Namib Desert (South Africa). Among 95 species in 26 families, 61 had detectable amounts of proline. In several of these species the proline content increased considerably in years with insufficient rainfall but decreased when the rainfall was abundant again. When individuals of the same species were grown at different sites, water availability in the soil determined their proline content. Many of the investigated species showed a clear diurnal fluctuation in their proline content with a remarkable proline accumulation during times of highest evaporative demand. In general, the higher the proline content the more pronounced were the changes, indicating that in these species-predominantly annual plants - proline was most probably involved in drought tolerance. The observation that proline accumulation and degradation reacted sensitively to changing climatic conditions over many years confirmed the correlation of proline synthesis to increasing water stress as postulated by the results of laboratory experiments with Mesembryanthemaceae.

The activity and malate inhibition/stimulation of phosphoenolpyruvate-carboxylase in crassulacean-acid-metabolism plants in their natural environment.

The effect of environmental conditions, temperature, relative humidity, and light, together with the regulation of PEPC (phosphoenolpyruvate-carboxylase) activity by malate and pH on CAM (crassulacean acid metabolism), was studied in members of the Mesembryanthemaceae in their natural environment, the southern Namib desert. It was found that during a 24 h period the characteristics of PEPC change. Before sunrise the activity is higher when measured at pH 7 than 8. With bright sunlight the activity measured at pH 7 drops to 20% of its pre-sunrise value, the activity only recovers gradually after malate disappearance and stays constant throughout the night. When measured at pH 8, PEPC shows an opposite behavior, i.e., activity increases in bright sunlight and declines as the pH 7 activity increases. A day-night oscillation in the capacity of malate to stimulate or inhibit PEPC was found. During the day malate inhibits about 90% of the PEPC activity at both pH 7 and 8. After sunset there is a sudden decrease in this inhibition and, at pH 8, malate stimulates the activity by 50%. At pH 7 the stimulation was less.Both stomatal conductance and malate formation were found to increase only when the relative humidity at night rose to 80%. Changes in the properties of the PEPC coincided with the exposure to bright sunlight and changes in leaf temperature. The importance of these metabolic and environmental controls on the regulation of CAM in the Mesembryanthemaceae will be discussed.