Objective: To systematically review and summarize the current available literature on prognostic variables relating to upper limb recovery following stroke. To identify which, if any variables ...predict upper limb recovery following stroke.
Data sources: We completed searches in MEDLINE, EMBASE, AMED, CINAHL and Cochrane CENTRAL databases. Searches were completed in November 2010.
Review methods: Studies were included if predictor variables were measured at baseline and linked to an outcome of upper limb recovery at a future time point. Exclusion criteria included predictor variables relating to response to treatment and outcome measurements of very specific upper limb impairments such as spasticity or pain. Two independent reviewers completed data extraction and assessed study quality.
Results: Fifty-eight studies met the inclusion criteria. Predictor variables which have been considered within these studies include; age, sex, lesion site, initial motor impairment, motor-evoked potentials andsomatosensory-evoked potentials. Initial measures of upper limb impairment and function were found to be the most significant predictors of upper limb recovery; odds ratio 14.84 (95% confidence intervals (CI) 9.08–24.25) and 38.62 (95% CI 8.40–177.53), respectively.
Conclusions: Interpretation of these results is complicated by methodological factors including variations in study populations, upper limb motor outcome scales, timing of baseline and outcome assessments and predictors selected. The most important predictive factors for upper limb recovery following stroke appears to the initial severity of motor impairment or function.
The assessment of data quality is a crucial element in many disciplines such as predictive toxicology and risk assessment. Currently, the reliability of toxicity data is assessed on the basis of ...testing information alone (adherence to Good Laboratory Practice (GLP), detailed testing protocols, etc.). Common practice is to take one toxicity data point per compound — usually the one with the apparently highest reliability. All other toxicity data points (for the same experiment and compound) from other sources are neglected. To show the benefits of incorporating the “less reliable” data, a simple, independent, statistical approach to assess data quality and reliability on a mathematical basis was developed. A large data set of toxicity values to Aliivibrio fischeri was assessed. The data set contained 1813 data points for 1227 different compounds, including 203 identified as non-polar narcotic. Log KOW values were calculated and non-polar narcosis quantitative structure–activity relationship (QSAR) models were built. A statistical approach to data quality assessment, which is based on data outlier omission and confidence scoring, improved the linear QSARs. The results indicate that a beneficial method for using large data sets containing multiple data values per compound and highly variable study data has been developed. Furthermore this statistical approach can help to develop novel QSARs and support risk assessment by obtaining more reliable values for biological endpoints.
•A statistical approach for the quality of data with multiple values was developed.•Confidence scores were assigned to toxicity data for individual compounds.•Confidence scores were related to the number of entries and their variability.•Using higher quality data allowed for the development of more robust QSARs.
Olaparib combined with paclitaxel has previously shown a significant improvement in overall survival versus placebo plus paclitaxel as second-line therapy in a phase 2 study in Asian patients with ...advanced gastric cancer, especially in those with ataxia-telangiectasia mutated protein (ATM)-negative tumours. Here, we report the primary efficacy and safety analyses from a subsequent phase 3 trial.
This double-blind, randomised, placebo-controlled, phase 3 study (GOLD) recruited Asian patients aged 18 years or older (≥20 years if Japanese) with advanced gastric cancer that had progressed following, or during, first-line chemotherapy. Patients were randomly assigned (1:1) to receive oral olaparib (100 mg twice daily) plus paclitaxel (80 mg/m2 intravenously) or matching placebo plus paclitaxel. Randomisation was done through an interactive voice response system and no stratification factors were used. Patients and investigators were masked to treatment allocation. Two co-primary populations were assessed: the overall population of all patients and patients whose tumours were ATM-negative (identified after randomisation, before the data cutoff date, March 28, 2016). The primary endpoint in both populations was overall survival (defined as the time from the date of randomisation until death from any cause before data cutoff); a significant difference was defined as p<0·025. Efficacy was assessed in the intention-to-treat populations and safety in patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01924533 (study ID, D081BC00004), and is ongoing but no longer recruiting participants.
Between Sept 3, 2013, and March 28, 2016, 643 patients were enrolled from 58 study sites in hospitals and medical centres in China, Japan, South Korea, and Taiwan. 525 eligible patients were randomly assigned: 263 to receive olaparib plus paclitaxel and 262 to receive placebo plus paclitaxel. 94 patients were determined to have ATM-negative tumours before unmasking for the primary analysis (48 in the olaparib plus paclitaxel group and 46 in the placebo plus paclitaxel group). Overall survival did not differ between treatment groups in the overall patient population (median overall survival 8·8 months 95% CI 7·4–9·6 in the olaparib group vs 6·9 months 6·3–7·9 in the placebo group; HR 0·79 97·5% CI 0·63–1·00; p=0·026) or in the ATM-negative population (12·0 months 7·8–18·1 vs 10·0 months 6·4–13·3; 0·73 0·40–1·34; p=0·25). In the overall patient population, the most common grade 3 or worse adverse events in the olaparib plus paclitaxel group were neutropenia (78 30% of 262 patients), leucopenia (42 16%), and decreased neutrophil count (40 15%); in the placebo plus paclitaxel group, they were neutropenia (59 23% of 259 patients), leucopenia (27 10%), and decreased white blood cell count (21 8%). Adverse events with an outcome of death causally related to study treatment (according to investigator assessment) were reported in two patients: liver injury in one patient (<1%) in the olaparib plus paclitaxel group and cardiac failure in one patient (<1%) in the placebo plus paclitaxel group.
The GOLD study did not meet its primary objective of showing a significant improvement in overall survival with olaparib in the overall or ATM-negative population of Asian patients with advanced gastric cancer. The study generated informative efficacy and safety data regarding the use of olaparib in combination with a chemotherapeutic agent and provides a foundation for future studies in this difficult-to-treat patient population.
AstraZeneca.
In the Phase III PAOLA-1/ENGOT-ov25 (NCT02477644) trial, the addition of the PARP inhibitor olaparib to bevacizumab maintenance therapy led to a significant progression-free survival (PFS) benefit in ...patients with newly diagnosed advanced ovarian cancer (hazard ratio HR 0.59; 95% confidence interval CI 0.49-0.72), particularly in patients who were homologous recombination deficiency (HRD) positive, both including patients with BRCA1 and/or BRCA2 mutations (BRCAm; HR 0.33; 95% CI 0.25-0.45) and patients without a BRCAm (HR 0.43; 95% CI 0.28-0.66; Ray-Coquard et al. NEJM 2019). We explored the role of mutations in genes involved in homologous recombination repair (HRRm) excluding BRCAm as a predictive biomarker in patients with newly diagnosed advanced ovarian cancer who received olaparib + bevacizumab maintenance therapy in PAOLA-1.
Patients with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer were randomized (2:1) to olaparib + bevacizumab maintenance or placebo + bevacizumab maintenance following response to platinum-based chemotherapy + bevacizumab. In an exploratory analysis, PFS was assessed in patients harboring a tumor mutation in a wide range of HRR gene panels (excluding tumor BRCAm tBRCAm): a panel with 13 pre-defined genes involved in HRR, an expanded panel with five additional genes involved in HRR, a restricted panel using five selected genes with the highest median genomic instability scores, and three published panels (Table). Tumors were analyzed using the Myriad myChoice HRD plus assay.
Of the 806 patients randomized in PAOLA-1, 235/806 (29.2%) had a tBRCAm. The percentage of patients harboring deleterious mutations involved in HRR excluding tBRCAm ranged from 3.7% to 9.8% depending on the HRR gene panel (Table). For each gene panel, the number of patients with an HRRm in each treatment arm and HRD status are shown in the Table. PFS using different gene panels for HRRm is summarized in the Table; using the 13-gene panel, in patients with an HRRm excluding tBRCAm (n=54), the HR for PFS was 0.95 (95% CI 0.49-1.94). Expansion of this panel to include five other genes (n=72) demonstrated an HR (95% CI) for PFS of 1.01 (0.55-1.95). Consistent results were seen in patients with HRRm excluding tBRCAm using the three other published HRR gene panels (Table).
Acknowledging limitations of small subgroup sizes, HRRm (excluding tBRCAm) was not predictive of PFS benefit with maintenance olaparib in combination with bevacizumab, compared with bevacizumab alone, in PAOLA-1, regardless of the gene panel used. Mutation analysis using HRRm gene panels did not have utility beyond tBRCAm for selecting patients who may benefit from maintenance olaparib plus bevacizumab in PAOLA-1 and should not be considered a substitute for HRD determined by BRCA and/or genomic instability testing. Display omitted
Abstract
Twenty-eight genotypes (bred diploids, seed-fertile triploids and tetraploid
hybrids) of Musa spp. were evaluated in pot tests in Honduras for resistance
and tolerance to Radopholus similis ...through comparison with reference
genotypes (Grand Nain as susceptible and Pisang Jari Buaya and Yangambi Km5
as resistant). Eleven tests were carried out, each with seven to 12 Musa
genotypes. Tissueculture plants (TC) or plants grown from a corm (Co) were
inoculated with 1000 or 3500 nematodes per plant, respectively. Data on
nematode population densities, fresh root weight, percentages dead roots,
root necrosis and root bases on the corm with lesions were taken 13-23 weeks
after inoculation. In most tests, Gros Michel and Highgate were as
susceptible to R. similis as Grand Nain. Resistance was shown by both TC and
Co plants of SH-3142, SH-3362, SH-3648 and SH-3723, and by Co plants of
SH-2095, SH-3624, the female parents Calcutta 4 and Prata Enana, and the
hybrid FHIA-01. Moderate resistance was shown by TC plants of SH-3624 and Co
plants of SH-3437, the female parent Pelipita and the hybrids FHIA-18 and
FHIA-23. The other genotypes were susceptible to R. similis although the
male parents SH-3386 and SH-3640, and the hybrid FHIA-21 had some degree of
resistance. FHIA-03 was susceptible but showed tolerance to R. similis.
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