Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Multi-criteria analysis of strategies towards sustainable recycling of phosphorus from sewage sludge in Austria.

To promote optimal phosphorus (P) recovery from municipal wastewater and sewage sludge with viable legal instruments, it is imperative to understand the regional and national consequences of different legal requirements for recycling. In this study we develop a scenario-based analysis to assess the environmental and economic impact of different national P recovery strategies in the context of a detailed representation of the existing Austrian wastewater infrastructure. This assessment combines material flow analysis, life cycle assessment and life cycle costing and includes the indicators P recycling rate, P utilization degree, heavy metal removal rate, share of heavy metals' content in wastewater redirected to agricultural soils, global warming potential, cumulated energy demand, terrestrial acidification potential, volume of freight transport and annual costs. The following main conclusions can be drawn. P recovery from ash shows the highest potential regarding the utilization of P from wastewater. A high P utilization from wastewater should rely on recovery technologies that decontaminate products, otherwise pollutant loads to agricultural soils might increase. P recovery to the extent of 60-85 % of P in WWTPs influent can be achieved by savings/costs of -0.8 to +4.7 EUR inhabitant-1 yr-1 in addition to current cost of the wastewater treatment/sludge disposal system. Key factors to be considered for costs are the choice of recovery process, revenues from products, and the use of existing incineration infrastructure. P recovery can lead to the reduction of greenhouse gas emissions in Austria if nitrous oxide emissions from sludge incineration are limited and efficient heat utilization strategies are implemented. There is a trade-off in terms of environmental and economic costs in choosing a more centralized or decentralized mono-incineration strategy.

Motor deficit in a Drosophila model of mucolipidosis type IV due to defective clearance of apoptotic cells.

Disruption of the Transient Receptor Potential (TRP) mucolipin 1 (TRPML1) channel results in the neurodegenerative disorder mucolipidosis type IV (MLIV), a lysosomal storage disease with severe motor impairments. The mechanisms underlying MLIV are poorly understood and there is no treatment. Here, we report a Drosophila MLIV model, which recapitulates the key disease features, including abnormal intracellular accumulation of macromolecules, motor defects, and neurodegeneration. The basis for the buildup of macromolecules was defective autophagy, which resulted in oxidative stress and impaired synaptic transmission. Late-apoptotic cells accumulated in trpml mutant brains, suggesting diminished cell clearance. The accumulation of late-apoptotic cells and motor deficits were suppressed by expression of trpml(+) in neurons, glia, or hematopoietic cells. We conclude that the neurodegeneration and motor defects result primarily from decreased clearance of apoptotic cells. Since hematopoietic cells in humans are involved in clearance of apoptotic cells, our results raise the possibility that bone marrow transplantation may limit the progression of MLIV.

The longitudinal loss of islet autoantibody responses from diagnosis of type 1 diabetes occurs progressively over follow-up and is determined by low autoantibody titres, early-onset, and genetic variants.

The clinical usefulness of post-diagnosis islet autoantibody levels is unclear and factors that drive autoantibody persistence are poorly defined in type 1 diabetes (T1D). Our aim was to characterise the longitudinal loss of islet autoantibody responses after diagnosis in a large, prospectively sampled UK cohort. Participants with T1D [n = 577] providing a diagnosis sample [range -1.0 to 2.0 years] and at least one post-diagnosis sample (<32.0 years) were tested for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A). Select HLA and non-HLA SNPs were considered. Non-genetic and genetic factors were assessed by multivariable logistic regression models for autoantibody positivity at initial sampling and autoantibody loss at final sampling. For GADA, IA-2A, and ZnT8A, 70.8%, 76.8%, and 40.1%, respectively, remained positive at the final sampling. Non-genetic predictors of autoantibody loss were low baseline autoantibody titres (P < 0.0001), longer diabetes duration (P < 0.0001), and age-at-onset under 8 years (P < 0.01--0.05). Adjusting for non-genetic covariates, GADA loss was associated with low-risk HLA class II genotypes (P = 0.005), and SNPs associated with autoimmunity RELA/11q13 (P = 0.017), LPP/3q28 (P = 0.004), and negatively with IFIH1/2q24 (P = 0.018). IA-2A loss was not associated with genetic factors independent of other covariates, while ZnT8A loss was associated with the presence of HLA A*24 (P = 0.019) and weakly negatively with RELA/11q13 (P = 0.049). The largest longitudinal study of islet autoantibody responses from diagnosis of T1D shows that autoantibody loss is heterogeneous and influenced by low titres at onset, longer duration, earlier age-at-onset, and genetic variants. These data may inform clinical trials where post-diagnosis participants are recruited.

Islet autoantibody profiles associated with higher diabetes risk in Lithuanian compared with English schoolchildren.

During a 15-year period, the incidence of type 1 diabetes has doubled in Lithuania, while increasing by a third in England; however, England still has a higher incidence. Analysis of sera collected from non-diabetic schoolchildren from Lithuania and England more than 20 years ago showed a similar number of multiple autoantibody-positive schoolchildren between the populations, but a higher prevalence of islet antigen-2 autoantibodies (IA-2A) in English schoolchildren. We aimed to use recently developed, more specific islet autoantibody tests to characterize differences in humoral autoimmunity between these two general population cohorts in greater detail. Samples from 88 Lithuanian and 133 English schoolchildren previously found islet autoantibody-positive were selected for measurement of additional islet autoantibodies by radioimmunoassay. Samples were tested for autoantibodies to zinc transporter 8 (ZnT8A), GAD (96-585), the protein tyrosine phosphatase region of islet antigen-2 (PTPA) and the related IA-2ßA, while autoantibodies to IA-2A were reassayed using the current harmonized method. IA-2-related autoantibodies PTPA (0·13 versus 0·45%, P = 0·027) and IA-2ßA (0 versus 0·35%, P < 0·001), but not IA-2A measured using the harmonized method, were less common in Lithuanian compared to English schoolchildren. Lithuanian schoolchildren who were islet autoantibody-positive were positive for fewer biochemical autoantibodies compared with English schoolchildren (P = 0·043). Background rates of islet autoimmunity in childhood differ subtly between countries, which have different incidences of type 1 diabetes. The optimal screening strategy (age and combination of markers) for detection of islet autoimmunity may vary between countries, dependent upon the pattern of autoantibodies found in the general population.

A quarter of patients with type 1 diabetes have co-existing non-islet autoimmunity: the findings of a UK population-based family study.

Individuals with type 1 diabetes (T1D) are at increased risk of coeliac disease (CD), autoimmune thyroiditis and autoimmune gastritis, but the absolute risks are unclear. The aim of this study was to investigate the prevalence of autoantibodies to tissue transglutaminase (TGA), thyroid peroxidase (TPOA) and gastric H+ /K+ -ATPase (ATPA) and their genetic associations in a well-characterized population-based cohort of individuals with T1D from the Bart's-Oxford family study for whom islet autoantibody prevalence data were already available. Autoantibodies in sera from 1072 patients (males/females 604/468; median age 11·8 years, median T1D duration 2·7 months) were measured by radioimmunoassays; HLA class II risk genotype was analysed in 973 (91%) using polymerase chain reaction with sequence specific primers (PCR-SSP). The prevalence of TGA (and/or history of CD), TPOA and ATPA in patients was 9·0, 9·6 and 8·2%, respectively; 3·1% had two or more autoantibodies. Females were at higher risk of multiple autoimmunity; TGA/CD were associated with younger age and TPOA with older age. ATPA were uncommon in patients under 5 years, and more common in older patients. Anti-glutamate decarboxylase autoantibodies were predictive of co-existing TPOA/ATPA. TGA/CD were associated with human leucocyte antigen (HLA) DR3-DQ2, with the DR3-DQ2/DR3-DQ2 genotype conferring the highest risk, followed by DR4-DQ8/DR4-DQ8. ATPA were associated with DR3-DQ2, DRB1*0404 (in males) and the DR3-DQ2/DR4-DQ8 genotype. TPOA were associated with the DR3-DQ2/DR3-DQ2 genotype. Almost one-quarter of patients diagnosed with T1D aged under 21 years have at least one other organ-specific autoantibody. HLA class II genetic profiling may be useful in identifying those at risk of multiple autoimmunity.

The first 142 amino acids of glutamate decarboxylase do not contribute to epitopes recognized by autoantibodies associated with Type 1 diabetes.

AIMS: Glutamate decarboxylase (GAD) antibodies are the most widely used predictive marker for Type 1 diabetes, but many individuals currently found to be GAD antibody-positive are unlikely to develop diabetes. We have shown previously that radioimmunoassays using N-terminally truncated 35 S-GAD65 (96-585) offer better disease specificity with similar sensitivity to full-length 35 S-GAD65 (1-585). To determine whether assay performance could be improved further, we evaluated a more radically truncated 35 S-GAD65 (143-585) radiolabel. METHODS: Samples from people with recent-onset Type 1 diabetes (n = 157) and their first-degree relatives (n = 745) from the Bart's-Oxford family study of childhood diabetes were measured for GAD antibodies using 35 S-labelled GAD65 (143-585). These were screened previously using a local radioimmunoassay with 35 S-GAD65 (1-585). A subset was also tested by enzyme-linked immunosorbent assay (ELISA), which performs well in international workshops, but requires 10 times more serum. Results were compared with GAD antibody measurements using 35 S-GAD65 (1-585) and 35 S-GAD65 (96-585). RESULTS: Sensitivity of GAD antibody measurement was maintained using 35 S-GAD65 (143-585) compared with 35 S-GAD65 (1-585) and 35 S-GAD65 (96-585). Specificity for Type 1 diabetes was improved compared with 35 S-GAD65 (1-585), but was similar to 35 S-GAD65 (96-585). Relatives found to be GAD antibody-positive using these truncated labels were at increased risk of diabetes progression within 15 years, compared with those positive for GAD(1-585) antibody only, and at similar risk to those found GAD antibody-positive by ELISA. CONCLUSIONS: The first 142 amino acids of GAD65 do not contribute to epitopes recognized by Type 1 diabetes-associated GAD antibodies. Low-volume radioimmunoassays using N-terminally truncated 35 S-GAD65 are more specific than those using full-length GAD65 and offer practical alternatives to the GAD antibody ELISA for identifying children at increased risk of Type 1 diabetes.

Chair based exercise in community settings: a cluster randomised feasibility study.

BACKGROUND: Some older people who find standard exercise programmes too strenuous may be encouraged to exercise while remaining seated - chair based exercises (CBE). We previously developed a consensus CBE programme (CCBE) following a modified Delphi process. We firstly needed to test the feasibility and acceptability of this treatment approach and explore how best to evaluate it before undertaking a definitive trial. METHODS: A feasibility study with a cluster randomised controlled trial component was undertaken to 1. Examine the acceptability, feasibility and tolerability of the intervention and 2. Assess the feasibility of running a trial across 12 community settings (4 day centres, 4 care homes, 4 community groups). Centres were randomised to either CCBE, group reminiscence or usual care. Outcomes were collected to assess the feasibility of the trial parameters: level of recruitment interest and eligibility, randomisation, adverse events, retention, completion of health outcomes, missing data and delivery of the CCBE. Semi- structured interviews were conducted with participants and care staff following the intervention to explore acceptability. RESULTS: 48% (89 out of 184 contacted) of eligible centres were interested in participating with 12 recruited purposively. 73% (94) of the 128 older people screened consented to take part with 83 older people then randomised following mobility testing. Recruitment required greater staffing levels and resources due to 49% of participants requiring a consultee declaration. There was a high dropout rate (40%) primarily due to participants no longer attending the centres. The CCBE intervention was delivered once a week in day centres and community groups and twice a week in care homes. Older people and care staff found the CCBE intervention largely acceptable. CONCLUSION: There was a good level of interest from centres and older people and the CCBE intervention was largely welcomed. The trial design and governance procedures would need to be revised to maximise recruitment and retention. If the motivation for a future trial is physical health then this study has identified that further work to develop the CCBE delivery model is warranted to ensure it can be delivered at a frequency to elicit physiological change. If the motivation for a future trial is psychological outcomes then this study has identified that the current delivery model is feasible. TRIAL REGISTRATION: ISRCTN27271501 . Date registered: 30/01/2018.

Climate drives shifts in grass reproductive phenology across the western USA.

The capacity of grass species to alter their reproductive timing across space and through time can indicate their ability to cope with environmental variability and help predict their future performance under climate change. We determined the long-term (1895-2013) relationship between flowering times of grass species and climate in space and time using herbarium records across ecoregions of the western USA. There was widespread concordance of C3 grasses accelerating flowering time and general delays for C4 grasses with increasing mean annual temperature, with the largest changes for annuals and individuals occurring in more northerly, wetter ecoregions. Flowering time was delayed for most grass species with increasing mean annual precipitation across space, while phenology-precipitation relationships through time were more mixed. Our results suggest that the phenology of most grass species has the capacity to respond to increases in temperature and altered precipitation expected with climate change, but weak relationships for some species in time suggest that climate tracking via migration or adaptation may be required. Divergence in phenological responses among grass functional types, species, and ecoregions suggests that climate change will have unequal effects across the western USA.

Combination of red cell distribution width and American Society of Anesthesiologists score for hip fracture mortality prediction.

UNLABELLED: The prognostic value of red cell distribution width (RDW) and a combination of RDW and the American Society of Anesthesiologists (ASA) score for long-term hip fracture mortality remains unknown. Our data showed that both RDW and ASA were independent risk predictors. A combination of these two parameters may provide a more powerful strategy for the prediction of hip fracture mortality. INTRODUCTION: Red cell distribution width (RDW) has recently been suggested as an independent predictor of prognosis in a variety of disorders. The American Society of Anesthesiologists (ASA) system has been widely used to stratify patients for outcome evaluations. However, the prognostic value of RDW and a combination of RDW and the ASA score for long-term hip fracture mortality has yet to be studied. METHODS: This prospective cohort study included 1402 subjects from 2000 to 2011 with a follow-up study over a 2 year period. Cox proportional hazards models with a bootstrap validation were used to evaluate associations of RDW, ASA, and a combination of both with long-term mortality. The global fit and the area under the receiver operating characteristic (ROC) curve (AUC) for model discrimination were further analyzed. RESULTS: Both RDW and ASA exhibited as independent risk predictors of 2-year mortality. The population with elevation of either RDW or ASA increased the risk of mortality (bootstrap validated hazard ratio (HR) 1.971 95 % confidence interval (CI) [1.336-3.005] p < 0.01) while those with an increase in both assessments (bootstrap validated HR 2.667 95 % CI [1.526-4.515] p < 0.01) were at the highest risk for mortality. The addition of the combination of ASA and RDW improved the discrimination power of risk prediction models (AUC increased from 0.700 to 0.723, p < 0.05). CONCLUSION: Both RDW and ASA exhibited as independent risk predictors of 2-year hip fracture mortality. The combination of these two readily available parameters may provide a more powerful and effective strategy for the assessment of all-cause mortality in hip fracture patients.

Clinical characteristics and risk factors of postoperative pneumonia after hip fracture surgery: a prospective cohort study.

UNLABELLED: In this study, we attempt to determine the clinical characteristic and risk factors of postoperative pneumonia (POP) after hip fracture surgery in a well-defined hip fracture cohort. We find that intrinsic factors as well as major clinical interventions were all important risk factors of POP. INTRODUCTION: Postoperative pneumonia (POP) is one of the major complications following hip fractures surgery. However, the risk factors of POP are not well studied in hip fracture cohorts. We attempt to determine the clinical characteristic and risk factors of POP after hip fracture surgery in a well-defined hip fracture cohort. METHODS: Datasets from a prospective hip fracture cohort study with a 2-year follow-up period, from 2000 to 2011, were reanalyzed for characteristics of POP. Multivariate Cox proportional regression was used to evaluate the association between the incidence of POP and all-cause mortality. Multivariate logistic regression was used to screen for potential risk factors of POP by analyzing demographic factors, comorbidities, major clinical interventions, and hematological parameters. RESULTS: In 1429 patients who underwent hip surgery, the incidence of POP was 4.9 % (n = 70). All-cause mortality of patients with POP was significantly higher than that of patients without POP at 30 days (hazard ratio (HR) 3.05, 95 % confidence intervals (CI) 1.88-4.94), 1 year (HR 1.87, 95 % CI 1.41-2.48), and 2 years (HR 1.57, 95 % CI 1.23-1.99) postoperatively. Multivariate logistic regression showed that intrinsic factors (advanced age, anemia, diabetes, prior stroke, number of comorbidities, ASA score ≥III, and some laboratory biomarkers) as well as major clinical interventions were all significant risk factors for POP. CONCLUSION: Intrinsic factors and major clinical interventions were all important risk factors of POP in patients after hip fracture surgery. Targeted preventive measures to mitigate the above risk factors may help in reducing the incidence of POP.

A multicentre study of the precision and accuracy of the TruSlice and TruSlice Digital histological dissection devices.

BACKGROUND: Five key factors enabling a good surgical grossing technique include a flat uniformly perpendicular specimen cutting face, appropriate immobilisation of the tissue specimen during grossing, good visualisation of the cutting tissue face, sharp cutting knives and the grossing knife action. TruSlice and TruSlice Digital are new innovative tools based on a guillotine configuration. The TruSlice has plastic inserts whilst the TruSlice Digital has an electronic micrometre attached: both features enable these dissection factors to be controlled. The devices were assessed in five hospitals in the UK. MATERIAL AND METHODS: A total of 267 fixed tissue samples from 23 tissue types were analysed, principally the breast (n = 32) skin (30), rectum (28), colon (27) and cervix (17). Precision and accuracy were evaluated by measuring the defined thickness, and the consistency of achieving the defined thickness of tissue samples taken respectively. Both parameters were expressed as a total percentage of compliance for the cohort of samples accessed. RESULTS: Overall, the mean (standard deviation) score for precision was 81 (11) % whilst the accuracy score was 82 (11) % (both p < 0.05, chi-squared test), although this varied with type of tissue. Accuracy and precision were strongly correlated (rp = 0.83, p < 0.001). CONCLUSION: The TruSlice Digital devices offer an assured precision and accuracy performance which is reproducible across an assortment of tissue types. The use of a micrometre to set tissue slice thickness is innovative and should comply with laboratory accreditation requirements, alleviating concerns of how to tackle issues such as the 'measurement of uncertainty' at the grossing bench.

[Expression and significance of miR-210 in the epididymis in rats with varicocele and following varicocelectomy].

Objective: To investigate the expression of microRNA 210 (miR-210) in the epididymis of rats with varicocele and changes in miR-210 expression following high spermatic vein ligation, so as to explore the significance of the surgery in treating varicocele. Methods: A total of 21 male Sprague-Dawley (SD) rats aged 7 weeks were randomly divided into control group (n=7), experimental group (n=7), and surgical group (n=7). Varicocele model was established in both the experimental and surgical groups, while only vein isolation was performed in the control group. After 8 weeks, spermatic vein diameter were measured in the control and experimental rats, and collected the left epididymis (fixed in formaldehyde and frozen in refrigerator at -80 ℃). In the surgical group, left high spermatic vein ligation was performed, and the left epididymis was collected after 4 weeks as in the control and the experimental groups. The fixed epididymis tissues were treated with HE staining for observation of tissue injuries. The miR-210 expression in the epididymis was detected with reverse transcription-polymerase chain reaction (RT-PCR). At last every group had 5 rats. Results: The pathological examination showed that the number and distribution of mature sperms in epididymal duct in the experimental group were lower and less even compared to the control group, while the two indicators in the surgical group were better than those in the experimental group. The diameter of the left spermatic vein in the experimental group and pre-treatment surgical group were significantly enlarged than in the control group (P<0.01). The expression of miR-210 in the left epididymis in the experimental group was significantly higher compared with the control group(1.32±0.06 vs 0.98±0.14, P<0.01), while the expression of miR-210 in the left epididymis in the surgical group was significantly decreased compared with the experimental group (0.96±0.16 vs 1.32±0.06, P<0.01); the difference between the control group and the surgical group was not statistically significant (P>0.05). Conclusion: The expression of miR-210 in the epididymis may be increased by varicocele and reduced after high ligation of the affected spermatic vein.

EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma.

BACKGROUND: We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. RESULTS: We recruited 55 eligible participants from September 2010 to August 2012. DEMOGRAPHICS: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. CONCLUSIONS: The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12609000643279.

Factor XII: a novel target for safe prevention of thrombosis and inflammation.

Plasma protein factor XII (FXII) activates the procoagulant and proinflammatory contact system that drives both the kallikrein-kinin system and the intrinsic pathway of coagulation. When zymogen FXII comes into contact with negatively charged surfaces, it auto-activates to the serine proteaseactivated FXII (FXIIa). Recently, various in vivo activators of FXII have been identified including heparin, misfolded protein aggregates, polyphosphate and nucleic acids. Murine models have established a central role of FXII in arterial and venous thrombosis. Despite its central function in thrombosis, deficiency in FXII does not impair haemostasis in animals and humans. In a preclinical cardiopulmonary bypass system in large animals, the FXIIa-blocking antibody 3F7 prevented thrombosis; however, in contrast to traditional anticoagulants, bleeding was not increased. In addition to its function in thrombosis, FXIIa initiates formation of the inflammatory mediator bradykinin. This mediator increases vascular leak, causes vasodilation, and induces chemotaxis with implications for septic, anaphylactic and allergic disease states. Therefore, targeting FXIIa appears to be a promising strategy for thromboprotection without associated bleeding risks but with anti-inflammatory properties.

First Direct Measurement of (12)C((12)C,n)(23)Mg at Stellar Energies.

Neutrons produced by the carbon fusion reaction (12)C((12)C,n)(23)Mg play an important role in stellar nucleosynthesis. However, past studies have shown large discrepancies between experimental data and theory, leading to an uncertain cross section extrapolation at astrophysical energies. We present the first direct measurement that extends deep into the astrophysical energy range along with a new and improved extrapolation technique based on experimental data from the mirror reaction (12)C((12)C,p)(23)Na. The new reaction rate has been determined with a well-defined uncertainty that exceeds the precision required by astrophysics models. Using our constrained rate, we find that (12)C((12)C,n)(23)Mg is crucial to the production of Na and Al in pop-III pair instability supernovae. It also plays a nonnegligible role in the production of weak s-process elements, as well as in the production of the important galactic γ-ray emitter (60)Fe.

Measurement of maximum diameter of native abdominal aortic aneurysm by angio-CT: reproducibility is better with the semi-automated method.

OBJECTIVES: We sought to identify the technique yielding the best reproducibility from among various measures of native maximum abdominal aortic aneurysm (AAA) diameter with computed tomography angiography (CTA). METHODS: Ten parameters of maximum diameter in 68 native AAA were measured double-blind by three radiologists on orthogonal planes, curved multiplanar reconstructions, and, finally, using semi-automated software. The semi-automated software creates the AAA lumen centreline and automatically provides cross sections perpendicular to this centreline. The maximum diameter in any direction is automatically calculated once the slice of interest has been selected. Intra- and inter-observer reproducibility and discordance >5 mm were analysed. RESULTS: Intra-observer reproducibility was high. The limits of agreement were within the clinically accepted range [-5; +5 mm] in 27/30 (90%) comparisons. The method common to all three observers that yielded the lowest values was the semi-automated method. Inter-observer reproducibility was poorer. The limits were outside the clinically accepted range in 26/30 (87%) comparisons. The semi-automated method led to lower intra- (0%) and inter-observer (5.88%) discordances rates. CONCLUSION: Even using precise methodology, the reproducibility of maximum diameter measurements of native AAA on CTA may exceed recommended thresholds. The semi-automatic method yielded the lower discordance rates and provided a more relevant anatomical approach for measuring the maximum diameter of an AAA.