The epidermal growth factor receptor variant III deletion mutation, EGFRvIII, is expressed in ∼30% of primary glioblastoma and linked to poor long-term survival. Rindopepimut consists of the unique ...EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin. In previous phase II trials (ACTIVATE/ACT II), rindopepimut was well tolerated with robust EGFRvIII-specific immune responses and promising progression-free and overall survival. This multicenter, single-arm phase II clinical trial (ACT III) was performed to confirm these results.
Rindopepimut and standard adjuvant temozolomide chemotherapy were administered to 65 patients with newly diagnosed EGFRvIII-expressing (EGFRvIII+) glioblastoma after gross total resection and chemoradiation.
Progression-free survival at 5.5 months (∼8.5 mo from diagnosis) was 66%. Relative to study entry, median overall survival was 21.8 months, and 36-month overall survival was 26%. Extended rindopepimut vaccination (up to 3.5+ years) was well tolerated. Grades 1-2 injection site reactions were frequent. Anti-EGFRvIII antibody titers increased ≥4-fold in 85% of patients, and increased with duration of treatment. EGFRvIII was eliminated in 4/6 (67%) tumor samples obtained after >3 months of therapy.
This study confirms, in a multicenter setting, the preliminary results seen in previous phase II trials of rindopepimut. A pivotal, double-blind, randomized, phase III trial ("ACT IV") is under way.
Background
The sensitivity, specificity, and agreement of 4 diagnostic assays (SNAP canine pancreatic lipase (cPL), specific cPL (Spec cPL), VetScan cPL Rapid Test, and Precision PSL) for ...pancreatitis in dogs have not been directly compared.
Hypothesis/Objectives
To determine the level of agreement among each of the 4 assays and a clinical suspicion score, level of agreement among the assays, and sensitivity and specificity of each assay in a clinically relevant patient group.
Animals
Fifty client‐owned dogs with clinical signs of gastrointestinal disease.
Methods
Prospective study. History, physical examination, complete blood count, serum biochemistry, abdominal ultrasound examination, and the 4 diagnostic assays for pancreatitis were performed. Intraclass correlation coefficients (ICC) were used to determine the level of agreement between each assay and a clinical suspicion score determined by a panel of 5 board‐certified veterinary internists.
Results
The ICC between the clinical suspicion score and the 4 assays were SNAP cPL, 0.61; Spec cPL, 0.68; VetScan cPL Rapid Test, 0.68; and Precision PSL, 0.60. The sensitivities of the assays ranged from 73.9 to 100.0%, whereas the specificities were SNAP cPL, 71.1–77.8%; Spec cPL, 74.1–81.1%; VetScan cPL Rapid Test, 76.9–83.8%; and Precision PSL, 64.0–74.3%.
Conclusions and Clinical Importance
A good to excellent level of agreement was demonstrated among the 4 assays. The previously unreported sensitivity and specificity of the VetScan cPL Rapid Test were 73.9–83.3% and 76.9–83.8%, respectively. Results of any of the 4 diagnostic assays alone, in the absence of supporting clinical findings, are insufficient to establish a diagnosis of clinical pancreatitis in dogs.
The challenges posed by equine arboviruses Chapman, G. E.; Baylis, M.; Archer, D. ...
Equine veterinary journal,
July 2018, 2018-Jul, 2018-07-00, 20180701, Letnik:
50, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Summary
Equine populations worldwide are at increasing risk of infection by viruses transmitted by biting arthropods, including mosquitoes, biting midges (Culicoides), sandflies and ticks. These ...include the flaviviruses (Japanese encephalitis, West Nile and Murray Valley encephalitis), alphaviruses (eastern, western and Venezuelan encephalitis) and the orbiviruses (African horse sickness and equine encephalosis). This review provides an overview of the challenges faced in the surveillance, prevention and control of the major equine arboviruses, particularly in the context of these viruses emerging in new regions of the world.
Chlorine is ubiquitous on Mars, some of it in the form of oxy-chlorine salts. Chlorine-containing salts have been found at several landing sites, including that of Phoenix and Curiosity, in the form ...of perchlorates and chlorides. Several intermediate states also exist, of which chlorate is the most stable. While perchlorates have received much attention in the past few years, chlorate salts are much less studied. The ratio of perchlorate to chlorate on Mars is not well-defined but may be approximately 1:1. Chlorate salts have similar properties to perchlorates: high solubility, low eutectic temperatures, and likely low deliquescence relative humidities. Laboratory studies were performed to determine the ability of sodium and magnesium chlorate salts to take up water vapor at low temperatures (296 K to 237 K). These studies were performed using a Raman microscope equipped with an environmental chamber and a single particle optical levitator equipped with a Raman spectrometer. The deliquescence of sodium chlorate (NaClO3) was found to be temperature-dependent with the average relative humidity (RH) values ranging from 68% RH at 296 K to 80% RH at 237 K. Additionally, there was a slight deviation between experimental deliquescence values for this salt and those predicted by equilibrium thermodynamics. The observed efflorescence (recrystallization) of NaClO3 occurred at lower RH values ranging from 18% RH at 264 K to 24% RH at 249 K, demonstrating the hysteresis common to salt recrystallization. Several experiments were performed below the reported eutectic temperature of NaClO3 which resulted in supercooling of the brine and depositional ice nucleation. Based on the supercooling effects observed during our experiments, a revised metastable eutectic temperature of 237 K is suggested for NaClO3 compared to the previously reported value of 252 K. Two phases of magnesium chlorate (Mg(ClO3)2) were observed and exhibited different water uptake behavior. The most common form of Mg(ClO3)2 appeared to be a hydrated, amorphous phase, Mg(ClO3)2 • X H2O(a) that continuously took up water when the RH was increased. This water uptake behavior was even observed at very low humidity values, 5.0 (±1.9)% RH, with little temperature dependence. This detectable water persisted down to RH values close to 0%, averaging 0.5 (±0.6)% RH with no visible temperature dependence. The deliquescence relative humidity (DRH) of the hexahydrate, Mg(ClO3)2 • 6 H2O, was found to range from 50.9 (± 7.5)% at 227 K to 55.8 (± 6.6)% at 224 K and was consistent with thermodynamic calculations. Under conditions measured by the Remote Environmental Monitoring Station (REMS) instrument at Gale Crater and conditions modeled in the shallow subsurface, magnesium chlorate, if present, likely interacts with water vapor during some diurnal cycles.
•Water uptake and release by chlorate salts were studied at low temperatures.•Water uptake and release were independent of total pressure.•Sodium chlorate exhibits strong hysteresis between deliquescence and efflorescence.•Magnesium chlorate takes up water at single digit relative humidities.•Subsurface Mg(ClO3)2 is predicted to uptake water diurnally at Gale Crater on Mars.
There is growing concern about the increasing risk of disease outbreaks caused by arthropod‐borne viruses (arboviruses) in both human beings and animals. There are several mosquito‐borne viral ...diseases that cause varying levels of morbidity and mortality in horses and that can have substantial welfare and economic ramifications. While none has been recorded in the UK, vector species for some of these viruses are present, suggesting that UK equines may be at risk. The authors undertook, therefore, the first study of mosquito species on equine premises in the UK. Mosquito magnet traps and red‐box traps were used to sample adults, and larvae were collected from water sources such as tyres, buckets, ditches and pools. Several species that are known to be capable of transmitting important equine infectious arboviruses were trapped. The most abundant, with a maximum catch of 173 in 72 hours, was Ochlerotatus detritus, a competent vector of some flaviviruses; the highest densities were found near saltmarsh habitats. The most widespread species, recorded at >75 per cent of sites, was Culiseta annulata. This study demonstrates that potential mosquito vectors of arboviruses, including those known to be capable of infecting horses, are present and may be abundant on equine premises in the UK.
Abstract To determine if amputation increases survival when compared to limb salvage surgery in patients with a soft tissue sarcoma (STS) of the extremity when there is often a misconception among ...physicians and patients that ablative surgery eliminates local recurrence and increases overall survival. This retrospective cohort study assessed 278 patients with STS and compared 18 patients who had undergone amputations for soft tissue sarcomas of the extremities to a comparative cohort of 260 patients who underwent limb salvage surgery during the same time period. Our limb salvage surgery (LSS) rate was 94% overall for soft tissue sarcomas with a median follow-up of 3.1 years. Patients undergoing amputations either had tumors that involved a critical neurovascular bundle (in particular nerve rather than vessel resection was more responsible for a decision toward ablation), or underlying bone or had neoplasms whose large size would require such an enormous resection that a functional limb would not remain. In comparing prognostic effects, mainly death due to sarcoma, distant metastasis and local recurrence, it was found that there was no statistically significant difference between patients undergoing amputation to those undergoing limb salvage surgery ( p > 0.05). While amputations do not increase overall survival in soft tissue sarcomas of the extremity as compared to LSS, they are still a valuable option in a surgeon's arsenal. In particular, amputations can provide improved local control and symptomatic treatment in patients who might not be candidates for limb salvage surgery.
The principal argument in Gibraltar and Empire is that Gibraltarians constitute a separate and distinctive people, notwithstanding the political stance taken by the government of Spain.
Various ...factors - environmental, ethnic, economic, political, religious, linguistic, educational and informal - are adduced to explain the emergence of a sense of community on the Rock and an attachment to the United Kingdom. A secondary argument is that the British empire has left its mark in Gibraltar in various forms - such as militarily - and for a number of reasons. Gilbraltar and Empire's exploration of the manifold reasons why the Gibraltarians have bucked the trend in the history of decolonization comes at a time when the issues in question have come to the fore in diplomatic and political areas.
The water uptake and release by perchlorate salts have been well studied since the first in situ identification of such salts in the Martian soil by the Phoenix mission in 2008. However, there have ...been few studies on the effect of the insoluble regolith minerals on the interaction of perchlorate with water vapor. In this work, we investigate the impact of a Mars‐relevant mineral, montmorillonite, and a Mars soil analog, Mojave Mars Simulant (MMS), on the deliquescence (transition from dry crystalline to aqueous via water vapor absorption), ice formation, and efflorescence (transition from aqueous to dry crystalline via loss of water) of pure magnesium perchlorate. We studied mixtures of magnesium perchlorate hexahydrate with either montmorillonite or MMS. Although montmorillonite and MMS are materials that may serve as nuclei for either ice nucleation or salt efflorescence, we find that these soil analogs did not affect the phase transitions of magnesium perchlorate. The salt‐mineral mixture behaved similarly, within estimated uncertainties, to pure magnesium perchlorate in all cases. Experiments were performed in both N2 and CO2 atmospheres, with no detectable difference. We use data from the Mars Science Laboratory Rover Environmental Monitoring Station instrument and the Phoenix Thermal and Electrical Conductivity Probe, as well as modeling of the shallow subsurface, to determine the likelihood of these perchlorate phase transitions occurring at Gale Crater and the northern arctic plains (Vastitas Borealis). We find that aqueous solutions are predicted in the shallow subsurface of the Phoenix landing site, but not predicted at Gale Crater.
Plain Language Summary
Most previous studies on Mars‐relevant salts have looked at the water uptake and release of the pure salts, but few have looked at the effect that insoluble minerals might have on the water uptake and release. This is an important potential effect because the surface of Mars is mainly composed of (~99%) mineral dust and we might not be accurately predicting if liquid solutions are possible on Mars today. However, this study shows that a Mars‐relevant mineral (montmorillonite) and a Mars surface analog (Mojave Mars Simulant) did not have a significant effect on the water uptake of magnesium perchlorate. In addition, the Phoenix landing site is more favorable to support liquid solutions of magnesium perchlorate, rather than Gale Crater (Curiosity's current site).
Key Points
This paper discusses the water uptake and release of Martian salts, mixed with regolith analogs
The DRH, ERH, and ice RH of magnesium perchlorate were not affected by Mars‐relevant regolith analogs
Brines are predicted in the subsurface at PHX site, but not at Gale Crater
Attrition is a ubiquitous problem in randomized controlled clinical trials (RCT) of psychotropic agents that can cause biased estimates of the treatment effect, reduce statistical power, and restrict ...the generalizability of results. The extent of the problem of attrition in central nervous system (CNS) trials is considered here and its consequences are examined. The taxonomy of missingness mechanisms is then briefly reviewed in order to introduce issues underlying the choice of data analytic strategies appropriate for RCTs with various forms of incomplete data. The convention of using last observation carried forward to accommodate attrition is discouraged because its assumptions are typically inappropriate for CNS RCTs, whereas multiple imputation strategies are more appropriate. Mixed-effects models often provide a useful data analytic strategy for attrition as do the pattern-mixture and propensity adjustments. Finally, investigators are encouraged to consider asking participants, at each assessment session, the likelihood of attendance at the subsequent assessment session. This information can be used to eliminate some of the very obstacles that lead to attrition, and can be incorporated in data analyses to reduce bias, but it will not eliminate all attrition bias.
Immunosuppression is frequently associated with malignancy and is particularly severe in patients with malignant glioma. Anergy and counterproductive shifts toward T(H)2 cytokine production are ...long-recognized T-cell defects in these patients whose etiology has remained elusive for >30 years. We show here that absolute counts of both CD4(+) T cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+) T cells (T(regs)) are greatly diminished in patients with malignant glioma, but T(regs) frequently represent an increased fraction of the remaining CD4 compartment. This increased T(reg) fraction, despite reduced counts, correlates with and is sufficient to elicit the characteristic manifestations of impaired patient T-cell responsiveness in vitro. Furthermore, T(reg) removal eradicates T-cell proliferative defects and reverses T(H)2 cytokine shifts, allowing T cells from patients with malignant glioma to function in vitro at levels equivalent to those of normal, healthy controls. Such restored immune function may give license to physiologic antiglioma activity, as in vivo, T(reg) depletion proves permissive for spontaneous tumor rejection in a murine model of established intracranial glioma. These findings dramatically alter our understanding of depressed cellular immune function in patients with malignant glioma and advance a role for T(regs) in facilitating tumor immune evasion in the central nervous system.
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