NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma.

Background: A randomized, phase II, placebo-controlled, and blinded clinical trial (NCT01062425) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, versus placebo in combination with radiation and temozolomide in newly diagnosed glioblastoma. Methods: Patients with newly diagnosed glioblastoma were randomly assigned 2:1 to receive (1) cediranib (20 mg) in combination with radiation and temozolomide; (2) placebo in combination with radiation and temozolomide. The primary endpoint was 6-month progression-free survival (PFS) based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted MRI brain scans and was tested using a 1-sided Z test for 2 proportions. Adverse events (AEs) were evaluated per CTCAE version 4. Results: One hundred and fifty-eight patients were randomized, out of which 9 were ineligible and 12 were not evaluable for the primary endpoint, leaving 137 eligible and evaluable. 6-month PFS was 46.6% in the cediranib arm versus 24.5% in the placebo arm (P = .005). There was no significant difference in overall survival between the 2 arms. There was more grade ≥ 3 AEs in the cediranib arm than in the placebo arm (P = .02). Conclusions: This study met its primary endpoint of prolongation of 6-month PFS with cediranib in combination with radiation and temozolomide versus placebo in combination with radiation and temozolomide. There was no difference in overall survival between the 2 arms.

The artoriine wolf spiders of Australia: the new genus Kochosa and a key to genera (Araneae: Lycosidae).

A key to the six Australian genera of the wolf spider (Lycosidae Sundevall, 1833) subfamily Artoriinae Framenau, 2007 is provided, now including Artoria Thorell, 1877, Artoriopsis Framenau, 2007, Diahogna Roewer, 1960, Kangarosa Framenau, 2010, Kochosa gen. nov. and Tetralycosa Roewer, 1960. Kochosa gen. nov. is described to include 16 species: K. australia sp. nov. (type species; from New South Wales, Queensland, South Australia, Victoria, Western Australia), K. aero sp. nov. (Western Australia), K. asterix sp. nov. (New South Wales, Queensland, Tasmania and Victoria), K. confusa sp. nov. (Queensland), K. erratum sp. nov. (Queensland), K. fleurae sp. nov. (Victoria), K. mendum sp. nov. (Australian Capital Territory, New South Wales, Queensland), K. nigra sp. nov. (Queensland), K. obelix sp. nov. (Western Australia), K. queenslandica sp. nov. (Queensland), K. sharae sp. nov. (South Australia), K. tanakai sp. nov. (New South Wales, Queensland), K. tasmaniensis sp. nov. (Tasmania), K. timwintoni sp. nov. (Western Australia), K. tongiorgii sp. nov., (Queensland), and K. westralia sp. nov. (Western Australia). Kochosa gen. nov. differs distinctly from all other genera within the Artoriinae by somatic and genitalic morphology. Most conspicuous is a distinct off-white or yellowish-white cardiac mark on an otherwise generally uniformly dark abdomen. The cardiac mark is rendered by thick black setae, which are particularly dense posteriorly. The tegular apophysis of the male pedipalp is heavily reduced, generally forming a semi-transparent small lobe. In turn, the embolic division is often complex with a variety of apophyses. Kochosa gen. nov. generally inhabit mesic habitats such as temperate and tropical shrubs and forests along the eastern and south-eastern coast and in the south-western parts of Australia.

Germline polymorphisms in MGMT associated with temozolomide-related myelotoxicity risk in patients with glioblastoma treated on NRG Oncology/RTOG 0825.

Background: We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Methods: Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. Results: 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy (n = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in MGMT had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02-3.27) and being female (OR, 4.45; 95% CI, 2.45-8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43-1.89). Conclusions: Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.

Two new species in the orb-weaving spider genus Larinia Simon, 1874 (Araneae, Araneidae) from Western Australia.

Two new species in the orb-weaving spider genus Larinia Simon, 1874 are described, L. sexta n. sp. and L. tumulus n. sp. This elevates the Australian number of described species in the genus to seven. With the exception of two females of L. sexta n. sp. recorded from mainland Western Australia, both species have so far exclusively been found on Barrow Island, 50 km off the north-western Western Australian coast where a third species, L. montagui Hogg, 1914, also occurs. Both new species appear to favour spinifex (Triodia spp.) grassland, but specimen numbers in collections are too low to accurately characterize life history patterns and habitat preferences.

A taxonomic revision of the tube-web spiders of the genus Ariadna (Araneae: Segestriidae) in Tasmania.

The genus Ariadna Audouin, 1826 is revised for Tasmania to include 13 species, ten of which are described as new: Ariadna abbreviata sp. nov., A. alta sp. nov., A. amabilia sp. nov., A. crypticola sp. nov., A. ferrogrisea sp. nov., A. fragilis sp. nov., A. gonzo sp. nov., A. muscosa Hickman, 1929, A. segmentata Simon, 1893, A. subnubilum sp. nov., A. thylacinus sp. nov. and A. tigrina sp. nov.. The species described in this manuscript exhibit high levels of sympatry.

Revision of the new Australasian orb-weaving spider genus Salsa (Araneae, Araneidae).

A new Australasian genus in the orb-weaving spider family Araneidae Clerck, 1757 is described to include seven species: Salsafuliginata (L. Koch, 1871) comb. nov. (type species; = Epeirarubicundula Keyserling, 1887) syn. nov.) (Australia, introduced to New Zealand); S.brisbanae (L. Koch, 1867) comb. nov. (Australia); S.canalae (Berland, 1924) comb. nov. (New Caledonia); S.neneba sp. nov. (Papua New Guinea); S.recherchensis (Main, 1954) comb. nov. (Australia); S.rueda sp. nov. (Australia); and S.tartara sp. nov. (Australia; Lord Howe Island endemic). Salsa gen. nov. belongs to the Australasian informal backobourkiine clade and differs from other genera of this clade by a distinct abdominal shape (single posterior abdominal tubercle) and ventral colouration (pale lateral spindle-shaped bands), male pedipalp morphology (C-shaped median apophysis that has teeth-like tubercles inside the basal arch) and the shape of the female epigyne scape (partially translucent and generally shorter than the epigyne plate). Based mainly on male pedipalp morphology within the backobourkiines, Salsa gen. nov. has closest morphological affinities with Acroaspis Karsch, 1878 and Socca Framenau, Castanheira & Vink, 2022.

The Mean Vertigo Score (MVS) Outcome Scale and Its Use in Clinical Research for Quantifying Vestibular Disorders.

Introduction: The Mean Vertigo Score (MVS) is a composite score for defining the burden of disease of patients suffering from vestibular disorders. It has been used in clinical research for about 30 years. This study investigates discriminant validity of the MVS and describes structural relationships of the 12 single criteria used for construction of the MVS. Materials and Methods: The statistical analyses are based on the raw data of an earlier conducted randomized, doubleblind, placebo-controlled clinical trial, which compared the following four randomized treatment groups: a fixed combination of cinnarizine and dimenhydrinate (Arlevert), two groups with only one of the two study drugs, and a group with placebo. The method used for the statistical calculations is the Wei-Lachin procedure, a multivariate generalization of the Mann-Whitney test, which takes into account correlations among the 12 single symptoms of the composite score. Results: All 12 single symptoms of the composite endpoint proved to be useful for detecting differences (Mann-Whitney effect size measures: 0.58-0.73) and thus for discriminating between treatment groups. Their Pearson product-moment correlations are all positive (range 0.07-0.71) and point to the same direction, which indicates one-dimensionality and good internal consistency of the composite index MVS. Furthermore, our statistical calculations revealed that successively increasing the number of single items of the MVS to up to twelve enhances its reliability (R 12 = 0.923), which leads to a substantially higher test power and reduction of the number of patients needed (sample size) in a clinical trial. Conclusion: The use of the multivariate Wei-Lachin procedure provides further evidence of the validity of the 12-item composite score MVS, based on the efficacy data of its 12 single vertigo symptoms. The present findings demonstrate that the MVS is a powerful tool, which can be used to adequately describe the patients' self-perceived vertigo complaints, both qualitatively and quantitatively. It may therefore be regarded as a clinically meaningful alternative to other questionnaires that are presently used in vestibular research.

A ghost in the salt: A new species of halotolerant tube-web spider in the genus emAriadna/em (Araneae: Segestriidae).

A new species of halotolerant Ariadna Audouin, 1826 is described from Western Australia, based on morphological features of both the male and female, and elevating the total number of described species of Ariadna in Australia to 14. This is the first record of the tube-web spider family Segestriidae Simon, 1893 inhabiting salt lakes, where they construct burrows in to the lake surface. The species is likely to be of conservation importance, due to its specialised habitat requirements and the many threats posed to the salt lake ecosystem. We provide recommendation for Ariadna phantasma sp. nov. to be considered for inclusion in the IUCN Red List.

A further study on the wolf spider subfamily Artoriinae from China (Araneae: Lycosidae).

The further collection and study of Chinese wolf spiders, family Lycosidae Sundevall, 1833, expand the known distribution of the subfamily Artoriinae Framenau, 2007 from Yunnan to Guangxi, Guizhou, and Sichuan Provinces of South China. Sinartoria gen. nov. is described to include two new species, S. damingshanensis sp. nov. (type species) and S. zhuangius sp. nov. In addition, a new Artoria species, A. hamata sp. nov. is described and new distribution records for A. ligulacea (Qu, Peng Yin, 2009) and A. parvula Thorell, 1877 are provided. Within the Artoriinae, Sinartoria gen. nov. appears to be most similar to the South American Lobizon Piacentini Grismado, 2009, but their relationship will remain contentious without a comprehensive phylogenetic analysis of artoriine genera.

A multicomponent intervention to decrease sedentary time during hospitalization: a quasi-experimental pilot study.

OBJECTIVE: The aim of this study was to evaluate the feasibility and preliminary effects of a multicomponent intervention to decrease sedentary time during and shortly after hospitalization. DESIGN: This is a quasi-experimental pilot study comparing outcomes in patients admitted before and after the implementation of the intervention. SETTING: The study was conducted in a university hospital. SUBJECTS: Participants were adult patients undergoing elective organ transplantation or vascular surgery. INTERVENTIONS: In the control phase, patients received usual care, whereas in the intervention phase, patients also received a multicomponent intervention to decrease sedentary time. The intervention comprised eight elements: paper and digital information, an exercise movie, an activity planner, a pedometer and Fitbit Flex™, a personal activity coach and an individualized digital training program. MEASURES: Measures of feasiblity were the self-reported use of the intervention components (yes/no) and satisfaction (low-high = 0-10). Main outcome measure was the median % of sedentary time measured by an accelerometer worn during hospitalization and 7-14 days thereafter. RESULTS: A total of 42 controls (mean age = 59 years, 62% male) and 52 intervention patients (58 years, 52%) were included. The exercise movie, paper information and Fitbit Flex were the three most frequently used components, with highest satisfaction scores for the fitbit, paper information, exercise movie and digital training. Median sedentary time decreased from 99.6% to 95.7% and 99.3% to 91.0% between Days 1 and 6 in patients admitted in the control and intervention phases, respectively. The difference at Day 6 reached statistical significance (difference = 41 min/day, P = 0.01). No differences were seen after discharge. CONCLUSION: Implementing a multicomponent intervention to reduce sedentary time appeared feasible and may be effective during but not directly after hospitalization.

Cognitive impairment appears progressive in the mdx mouse.

Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease caused by mutations in the DMD gene, which encodes the large cytoskeletal protein dystrophin. Approximately one-third of DMD patient's exhibit cognitive problems yet it is unknown if cognitive impairments worsen with age. The mdx mouse model is deficient in dystrophin demonstrates cognitive abnormalities, but no studies have investigated this longitudinally. We assessed the consequences of dystrophin deficiency on brain morphology and cognition in male mdx mice. We utilised non-invasive methods to monitor CNS pathology with an aim to identify changes longitudinally (between 4 and 18 months old) which could be used as outcome measures. MRI identified a total brain volume (TBV) increase in control mice with ageing (p < 0.05); but the mdx mice TBV increased significantly more (p < 0.01). Voxel-based morphometry (VBM) identified decreases in grey matter volume, particularly in the hippocampus of the mdx brain, most noticeable from 12 months onwards, as were enlarged lateral ventricles in mdx mice. The caudate putamen of older mdx mice showed increases in T2- relaxometry which may be considered as evidence of increased water content. Hippocampal spatial learning and memory was decreased in mdx mice, particularly long-term memory, which progressively worsened with age. The novel object recognition (NOR) task highlighted elevated anxiety-related behaviour in older mdx mice. Our studies suggest that dystrophin deficiency causes a progressive cognitive impairment in mice (compared to ageing control mice), becoming evident at late disease stages, and may explain why progressive CNS symptoms are not obvious in DMD patients.

Phylogeny of the orb-weaving spider family Araneidae (Araneae: Araneoidea).

We present a new phylogeny of the spider family Araneidae based on five genes (28S, 18S, COI, H3 and 16S) for 158 taxa, identified and mainly sequenced by us. This includes 25 outgroups and 133 araneid ingroups representing the subfamilies Zygiellinae Simon, 1929, Nephilinae Simon, 1894, and the typical araneids, here informally named the "ARA Clade". The araneid genera analysed here include roughly 90% of all currently named araneid species. The ARA Clade is the primary focus of this analysis. In taxonomic terms, outgroups comprise 22 genera and 11 families, and the ingroup comprises three Zygiellinae and four Nephilinae genera, and 85 ARA Clade genera (ten new). Within the ARA Clade, we recognize ten informal groups that contain at least three genera each and are supported under Bayesian posterior probabilities (≥ 0.95): "Caerostrines" (Caerostris, Gnolus and Testudinaria), "Micrathenines" (Acacesia, Micrathena, Ocrepeira, Scoloderus and Verrucosa), "Eriophorines" (Acanthepeira, Alpaida, Eriophora, Parawixia and Wagneriana), "Backobourkiines" (Acroaspis, Backobourkia, Carepalxis, Novakiella, Parawixia, Plebs, Singa and three new genera), "Argiopines" (Arachnura, Acusilas, Argiope, Cyrtophora, Gea, Lariniaria and Mecynogea), "Cyrtarachnines" (Aranoethra, Cyrtarachne, Paraplectana, Pasilobus and Poecilopachys), "Mastophorines" (Celaenia, Exechocentrus and Mastophora,), "Nuctenines" (Larinia, Larinioides and Nuctenea), "Zealaraneines" (Colaranea, Cryptaranea, Paralarinia, Zealaranea and two new genera) and "Gasteracanthines" (Augusta, Acrosomoides, Austracantha, Gasteracantha, Isoxya, Macracantha, Madacantha, Parmatergus and Thelacantha). Few of these groups are currently corroborated by morphology, behaviour, natural history or biogeography. We also include the large genus Araneus, along with Aculepeira, Agalenatea, Anepsion, Araniella, Cercidia, Chorizopes, Cyclosa, Dolophones, Eriovixia, Eustala, Gibbaranea, Hingstepeira, Hypognatha, Kaira, Larinia, Mangora, Metazygia, Metepeira, Neoscona, Paraplectanoides, Perilla, Poltys, Pycnacantha, Spilasma and Telaprocera, but the placement of these genera was generally ambiguous, except for Paraplectanoides, which is strongly supported as sister to traditional Nephilinae. Araneus, Argiope, Eriophora and Larinia are polyphyletic, Araneus implying nine new taxa of genus rank, and Eriophora and Larinia two each. In Araneus and Eriophora, polyphyly was usually due to north temperate generic concepts being used as dumping grounds for species from southern hemisphere regions, e.g. South-East Asia, Australia or New Zealand. Although Araneidae is one of the better studied spider families, too little natural history and/or morphological data are available across these terminals to draw any strong evolutionary conclusions. However, the classical orb web is reconstructed as plesiomorphic for Araneidae, with a single loss in "cyrtarachnines"-"mastophorines". Web decorations (collectively known as stabilimenta) evolved perhaps five times. Sexual dimorphism generally results from female body size increase with few exceptions; dimorphic taxa are not monophyletic and revert to monomorphism in a few cases.

Tumor treating fields and maintenance temozolomide for newly-diagnosed glioblastoma: a cost-effectiveness study.

Purpose: The EF-14 trial demonstrated that adding tumor treating fields (TTFields) to maintenance temozolomide (TMZ) significantly extends progression-free survival (PFS) and overall survival (OS) for newly-diagnosed glioblastoma (GBM) patients. This study assessed the cost-effectiveness of TTFields and TMZ for newly-diagnosed GBM from the US healthcare system perspective. Methods and materials: Outcomes for newly-diagnosed GBM patients were estimated over a lifetime horizon using an area under the curve model with three states: stable disease, progressive disease, or death. The survival model integrated the 5-year EF-14 trial results with long-term GBM epidemiology data and US background mortality rates. Adverse event rates were derived from the EF-14 trial data. Utility values to determine quality-adjusted life-years, adverse event costs, and supportive care costs were obtained from published literature. A 3% discount rate was applied to future costs and outcomes. One-way and probabilistic sensitivity analyses were performed to assess result uncertainty due to parameter variability. Results: Treatment with TTFields and TMZ was estimated to result in a mean increase in survival of 1.25 life years (95% credible range [CR] = 0.89-1.67) and 0.96 quality-adjusted life years (QALYs) (95% CR = 0.67-1.30) compared to treatment with TMZ alone. The incremental total cost was $188,637 (95% CR = $145,324-$225,330). The incremental cost-effectiveness ratio (ICER) was $150,452 per life year gained and $197,336 per QALY gained. The model was most sensitive to changes in the cost of TTFields treatment. Conclusions: Adding TTFields to maintenance TMZ resulted in a substantial increase in the estimated mean lifetime survival and quality-adjusted survival for newly-diagnosed GBM patients. Treatment with TTFields can be considered cost-effective within the reported range of willingness-to-pay thresholds in the US.

The scorpion-tailed orb-weaving spiders (Araneae, Araneidae, Arachnura) in Australia and New Zealand.

The scorpion-tailed orb-weaving spiders in the genus Arachnura Vinson, 1863 (Araneidae Clerck, 1757) are revised for Australia and New Zealand. Arachnura higginsii (L. Koch, 1872) only occurs in Australia and A. feredayi (L. Koch, 1872) only in New Zealand. A single female collected in south-eastern Queensland (Australia) is here tentatively identified as A. melanura Simon, 1867, but it is doubtful that this species has established in Australia. Two juveniles from northern Queensland do not conform to the diagnoses of any of the above species and are illustrated pending a more thorough revision of the genus in South-East Asia and the Pacific region. An unidentified female from Westport (New Zealand) does not conform to the diagnoses of A. feredayi and A. higginsii, but is not described due to its poor preservation status. Arachnura caudatella Roewer, 1942 (replacement name for Epeira caudata Bradley, 1876), originally described from Hall Sound (Papua New Guinea) and repeatedly catalogued for Australia, is considered a nomen dubium.

Peptide-conjugated phosphodiamidate oligomer-mediated exon skipping has benefits for cardiac function in mdx and Cmah-/-mdx mouse models of Duchenne muscular dystrophy.

Cardiac failure is a major cause of mortality in patients with Duchenne muscular dystrophy (DMD). Antisense-mediated exon skipping has the ability to correct out-of-frame mutations in DMD to produce truncated but functional dystrophin. Traditional antisense approaches have however been limited by their poor uptake into cardiac muscle. The addition of cell-penetrating peptides to antisense molecules has increased their potency and improved their uptake into all muscles, including the heart. We have investigated the efficacy of the Peptide-conjugated phosphodiamidate morpholino oligomer (P-PMO) Pip6a-PMO, for restoration of cardiac dystrophin and functional rescue in DMD mice- the mdx mouse and the less well characterised Cmah-/-mdx mouse (which carry a human-like mutation in the mouse Cmah gene as well as a mutation in DMD). In our first study male mdx mice were administered Pip6a-PMO, i.v, fortnightly from 12 to 30 weeks of age alongside mock-injected age-matched mdx and C57BL10 controls. Mice received 4 doses of 18 mg/kg followed by 8 doses of 12.5 mg/kg. The cardiac function of the mice was analysed 2 weeks after their final injection by MRI followed by conductance catheter and their muscles were harvested for dystrophin quantification. In the second study, male Cmah-/-mdx mice, received 12.5 mg/kg Pip6a-PMO, i.v fortnightly from 8 to 26 weeks and assessed by MRI at 3 time points (12, 18 and 28 weeks) alongside mock-injected age-matched mdx, C57BL10 and Cmah-/-mdx controls. The mice also underwent MEMRI and conductance catheter at 28 weeks. This allowed us to characterise the cardiac phenotype of Cmah-/-mdx mice as well as assess the effects of P-PMO on cardiac function. Pip6a-PMO treatment resulted in significant restoration of dystrophin in mdx and Cmah-/-mdx mice (37.5% and 51.6%, respectively), which was sufficient to significantly improve cardiac function, ameliorating both right and left ventricular dysfunction. Cmah-/-mdx mice showed an abnormal response to dobutamine stress test and this was completely ameliorated by PIP6a-PMO treatment. These encouraging data suggest that total restoration of dystrophin may not be required to significantly improve cardiac outcome in DMD patients and that it may be realistic to expect functional improvements with modest levels of dystrophin restoration which may be very achievable in future clinical trials.

Thermodynamically accessible titanium clusters TiN, N = 2-32.

We have performed a genetic algorithm search on the tight-binding interatomic potential energy surface (PES) for small TiN (N = 2-32) clusters. The low energy candidate clusters were further refined using density functional theory (DFT) calculations with the PBEsol exchange-correlation functional and evaluated with the PBEsol0 hybrid functional. The resulting clusters were analysed in terms of their structural features, growth mechanism and surface area. The results suggest a growth mechanism that is based on forming coordination centres by interpenetrating icosahedra, icositetrahedra and Frank-Kasper polyhedra. We identify centres of coordination, which act as centres of bulk nucleation in medium sized clusters and determine the morphological features of the cluster.

A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913.

Background: This phase II study was designed to determine the efficacy of the mammalian target of rapamycin (mTOR) inhibitor everolimus administered daily with conventional radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma. Methods: Patients were randomized to radiation therapy with concurrent and adjuvant temozolomide with or without daily everolimus (10 mg). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS) and treatment-related toxicities. Results: A total of 171 patients were randomized and deemed eligible for this study. Patients randomized to receive everolimus experienced a significant increase in both grade 4 toxicities, including lymphopenia and thrombocytopenia, and treatment-related deaths. There was no significant difference in PFS between patients randomized to everolimus compared with control (median PFS time: 8.2 vs 10.2 mo, respectively; P = 0.79). OS for patients randomized to receive everolimus was inferior to that for control patients (median survival time: 16.5 vs 21.2 mo, respectively; P = 0.008). A similar trend was observed in both O6-methylguanine-DNA-methyltransferase promoter hypermethylated and unmethylated tumors. Conclusion: Combining everolimus with conventional chemoradiation leads to increased treatment-related toxicities and does not improve PFS in patients with newly diagnosed glioblastoma. Although the median survival time in patients receiving everolimus was comparable to contemporary studies, it was inferior to the control in this randomized study.

Safety and efficacy of Cerebrolysin in early post-stroke recovery: a meta-analysis of nine randomized clinical trials.

This meta-analysis combines the results of nine ischemic stroke trials, assessing efficacy of Cerebrolysin on global neurological improvement during early post-stroke period. Cerebrolysin is a parenterally administered neuropeptide preparation approved for treatment of stroke. All included studies had a prospective, randomized, double-blind, placebo-controlled design. The patients were treated with 30-50 ml Cerebrolysin once daily for 10-21 days, with treatment initiation within 72 h after onset of ischemic stroke. For five studies, original analysis data were available for meta-analysis (individual patient data analysis); for four studies, aggregate data were used. The combination by meta-analytic procedures was pre-planned and the methods of synthesis were pre-defined under blinded conditions. Search deadline for the present meta-analysis was December 31, 2016. The nonparametric Mann-Whitney (MW) effect size for National Institutes of Health Stroke Scale (NIHSS) on day 30 (or 21), combining the results of nine randomized, controlled trials by means of the robust Wei-Lachin pooling procedure (maximin-efficient robust test), indicated superiority of Cerebrolysin as compared with placebo (MW 0.60, P < 0.0001, N = 1879). The combined number needed to treat for clinically relevant changes in early NIHSS was 7.7 (95% CI 5.2 to 15.0). The additional full-scale ordinal analysis of modified Rankin Scale at day 90 in moderate to severe patients resulted in MW 0.61 with statistical significance in favor of Cerebrolysin (95% CI 0.52 to 0.69, P = 0.0118, N = 314). Safety aspects were comparable to placebo. Our meta-analysis confirms previous evidence that Cerebrolysin has a beneficial effect on early global neurological deficits in patients with acute ischemic stroke.

Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for Limited Brain Metastases: A Secondary Analysis of the North Central Cancer Treatment Group N0574 (Alliance) Randomized Controlled Trial.

PURPOSE: To determine whether whole-brain radiation therapy (WBRT) is associated with improved overall survival among non-small cell lung cancer (NSCLC) patients with favorable prognoses at diagnosis. METHODS AND MATERIALS: In the N0574 trial, patients with 1 to 3 brain metastases were randomized to receive stereotactic radiosurgery (SRS) or SRS plus WBRT (SRS + WBRT), with a primary endpoint of cognitive deterioration. We calculated diagnosis-specific graded prognostic assessment (DS-GPA) scores for NSCLC patients and evaluated overall survival according to receipt of WBRT and DS-GPA score using 2 separate cut-points (≥2.0 vs <2.0 and ≥2.5 vs <2.5). RESULTS: A total of 126 NSCLC patients were included for analysis, with median follow-up of 14.2 months. Data for DS-GPA calculation were available for 86.3% of all enrolled NSCLC patients. Overall, 50.0% of patients had DS-GPA score ≥2.0, and 23.0% of patients had DS-GPA scores ≥2.5. The SRS and SRS + WBRT groups were well balanced with regard to prognostic factors. The median survival according to receipt of WBRT was 11.3 months (+WBRT) and 17.9 months (-WBRT) for patients with DS-GPA ≥2.0 (favorable prognoses, P=.63; hazard ratio 0.86; 95% confidence interval 0.47-1.59). Median survival was 3.7 months (+WBRT) and 6.6 months (-WBRT) for patients with DS-GPA <2.0 patients (unfavorable prognoses, P=.85; hazard ratio 0.95; 95% confidence interval 0.56-1.62). Outcomes according to the receipt of WBRT and DS-GPA remained similar utilizing DS-GPA ≥2.5 as a cutoff for favorable prognoses. There was no interaction between the continuum of the DS-GPA groups and WBRT on overall survival (P=.53). CONCLUSIONS: We observed no significant differences in survival according to receipt of WBRT in favorable-prognosis NSCLC patients. This study further supports the approach of SRS alone in the majority of patients with limited brain metastases.

Safety and efficacy of Cerebrolysin in motor function recovery after stroke: a meta-analysis of the CARS trials.

This meta-analysis combines the results of two identical stroke studies (CARS-1 and CARS-2) assessing efficacy of Cerebrolysin on motor recovery during early rehabilitation. Cerebrolysin is a parenterally administered neuropeptide preparation approved for the treatment of stroke. Both studies had a prospective, randomized, double-blind, placebo-controlled design. Treatment with 30 ml Cerebrolysin once daily for 3 weeks was started 24-72 h after stroke onset. In addition, patients participated in a standardized rehabilitation program for 21 days that was initiated within 72 h after stroke onset. For both studies, the original analysis data were used for meta-analysis (individual patient data analysis). The combination of these two studies by meta-analytic procedures was pre-planned, and the methods were pre-defined under blinded conditions. The nonparametric Mann-Whitney (MW) effect size of the two studies on the ARAT score on day 90 indicated superiority of Cerebrolysin compared with placebo (MW 0.62, P < 0.0001, Wei-Lachin pooling procedure, day 90, last observation carried forward; N = 442). Also, analysis of early benefit at day 14 and day 21 by means of the National Institutes of Health Stroke Scale, which is regarded as most sensitive to early improvements, showed statistical significance (MW 0.59, P < 0.002). The corresponding number-needed-to-treat (NNT) for clinically relevant changes in early NIHSS was 7.1 (95% CI: 4 to 22). Cerebrolysin had a beneficial effect on motor function and neurological status in early rehabilitation patients after acute ischemic stroke. Safety aspects were comparable to placebo, showing a favourable benefit/risk ratio.