Basic concepts and directions in the radiation therapy quality assurance processes of clinical trials.

The radiation therapy quality assurance of clinical trials is internationally recognized as a key factor to control the quality of radiotherapy for its impact on clinical trial's goals. Quality assessment may be performed at different levels and by different means, which are now quite standardized. The optimal radiation therapy quality assurance of clinical trials trade-off to maintain accrual rates, radiotherapy quality and optimize clinical trial research processes is yet to be defined. This article addresses current definitions, processes, limitations and directions.

Voice modulation, self-perception and motor branch of the superior laryngeal nerve.

OBJECTIVES: Vocal morbidity resulting from damage to the motor branch of the superior laryngeal nerve (SLN) after endocrine surgery is well known, but diagnosis is often delayed. The present study aimed to quantify these vocal changes acoustically (main objective), and correlate this with the vocal complaints of patients with suspected SLN motor impairment (secondary objective). MATERIAL AND METHODS: Thirty females patients with suspected injury of the SLN cricothyroid branch (CT-) were compared to 30 patients without postoperative vocal impairment (CT+) and to 30 control subjects. Mean, minimal and maximal fundamental frequencies (F0mean, F0min and F0max) and vocal range were measured on /e/ at high frequency, sirens (glissandi), a reading text, and minimal intonation pairs. Subjective vocal impairment was evaluated on the Voice Handicap Index (VHI). RESULTS: A lowering of F0mean associated with vocal range reduction by one fifth (in the reading text) seemed to be specific to CT- patients. Production of questions was affected, with differences in melodic curve and attack. Thyroidectomy within 2 months in itself (without suspected SLN cricothyroid branch injury) also affected these parameters, but to a lesser degree. CT- patients reported greater voice impairment than CT+ patients or controls (P=0.0004). CONCLUSION: Alterations in speech intonation, quantified on minimal pair test, and self-assessed vocal handicap (VHI) are tools that can easily be used in daily practice to screen for SLN motor branch lesion.

Influence of land use and host species on parasite richness, prevalence and co-infection patterns.

Tropical forests are experiencing increasing impacts from a multitude of anthropogenic activities such as logging and conversion to agricultural use. These perturbations are expected to have strong impacts on ecological interactions and on the transmission dynamics of infectious diseases. To date, no clear picture of the effects of deforestation on vector-borne disease transmission has emerged. This is associated with the challenge of studying complex systems where many vertebrate hosts and vectors co-exist. To overcome this problem, we focused on an innately simplified system - a small oceanic island (São Tomé, Gulf of Guinea). We analyzed the impacts of human land-use on host-parasite interactions by sampling the bird community (1735 samples from 30 species) in natural and anthropogenic land use at different elevations, and screened individuals for haemosporidian parasites from three genera (Plasmodium, Haemoproteus, Leucocytozoon). Overall, Plasmodium had the highest richness but the lowest prevalence, while Leucocytozoon diversity was the lowest despite having the highest prevalence. Interestingly, co-infections (i.e. intra-host diversity) involved primarily Leucocytozoon lineages (95%). We also found marked differences between bird species and habitats. Some bird species showed low prevalence but harbored high diversity of parasites, while others showed high prevalence but were infected with fewer lineages. These infection dynamics are most likely driven by host specificity of parasites and intrinsic characteristics of hosts. In addition, Plasmodium was more abundant in disturbed habitats and at lower elevations, while Leucocytozoon was more prevalent in forest areas and at higher elevations. These results likely reflect the ecological requirements of their vectors: mosquitoes and black flies, respectively.

Hypofractionated stereotactic radiotherapy for challenging brain metastases using 36 Gy in six fractions.

PURPOSE: Stereotactic radiosurgery and hypofractionated stereotactic radiotherapy are standard treatments for brain metastases when they are small in size (at the most 3cm in diameter) and limited in number, in patients with controlled extracerebral disease and a good performance status. Large inoperable brain metastases usually undergo hypofractionated stereotactic radiotherapy while haemorrhagic brain metastases have often been contraindicated for both stereotactic radiosurgery or hypofractionated stereotactic radiotherapy. The objective of this retrospective study was to assess a six 6Gy-fractions hypofractionated stereotactic radiotherapy scheme in use at our institution for haemorrhagic brain metastases, large brain metastases (size greater than 15cm3) or brain metastases located next to critical structures. MATERIAL AND METHODS: Patients with brain metastases treated with the 6×6Gy scheme since 2012 to 2016 were included. Haemorrhagic brain metastases were defined by usual criteria on CT scan and MRI. Efficacy, acute and late toxicity were evaluated. RESULTS: Sixty-two patients presenting 92 brain metastases were included (32 haemorrhagic brain metastases). Median follow up was 10.1 months. One-year local control rate for haemorrhagic brain metastases, large brain metastases, or brain metastases next to critical structures were 90.7%, 73% and 86.7% respectively. Corresponding overall survival rates were 61.2%, 32% and 37.8%, respectively. Haemorrhagic complications occurred in 5.3% of patients (N=5), including two cases of brain metastases with pretreatment haemorrhagic signal. Tolerance was good with only one grade 3 acute toxicity. CONCLUSION: The 6×6Gy hypofractionated stereotactic radiotherapy scheme seems to yield quite good results in patients with haemorrhagic brain metastases, which must be confirmed in a prospective way.

A new Monte Carlo model of a Cyberknife® system for the precise determination of out-of-field doses.

In a previous work, a PENELOPE Monte Carlo model of a Cyberknife system equipped with fixed collimator was developed and validated for in-field dose evaluation. The aim of this work is to extend it to evaluate peripheral doses and to determine the precision of the treatment planning system (TPS) Multiplan in evaluating the off-axis doses. The Cyberknife® head model was completed with surrounding components based on manufacturer drawings. The contribution of the different head parts on the out-of-field dose was studied. To model the attenuation and the modification of particle energy caused by components not modelled, the photon transport was modified in one of the added components. The model was iteratively adjusted to fit dose profiles measured with EBT3 films and an ionization chamber for several collimator sizes. Finally, dose profiles were calculated using the two Multiplan TPS algorithms and were compared to our simulations. The contributions to out-of-field dose were identified as scattered radiation from the phantom and head leakage and scatter originating at the secondary collimator level. Particle transport in the additional pieces was modified to model this radiation. The maximum differences between simulated and measured doses are of 20.4%. Regarding the detector responses away from axis, EBT3 films and the Farmer chamber give similar response (less than 20% difference). The TPS Monte Carlo algorithm underestimates the doses away from axis more importantly for the smaller field sizes (up to 98%). Besides, RayTracing simplifies peripheral dose to a constant value with no inclusion of particle transport. A Monte Carlo model of a Cyberknife system for the determination of out-of-field doses up to 14 cm off-axis was successfully developed and validated for different depths and field sizes in comparison with measurements. This study also confirms that TPS algorithms do not model peripheral dose properly.

[Digital applicator by 3D printing in contact brachytherapy]. / Applicateur numérique par impression tridimensionnelle en curiethérapie de contact.

Brachytherapy of skin tumours uses custom applicators that are manufactured manually. The integration of 3D printing customization of applicators during hidh dose rate brachytherapy planning could allow a better skin conformation and a better reproducibility of the positioning and treatment. We present the technical implementation of this method for our first two patients. A provisional planning scanner was carried out to create a digital applicator. The creation of the digital applicator used successively several software programs. The first, commercial, was RhinocerosR 3D used via Grasshopper, an integrated open source plug-in. The 3D applicator was then exported to the commercial software Simplify3DR. A g-code format file was generated for the printer. A second scanner was made with a 3D applicator in place to plan the final treatment. The treatment was planned by reverse optimization. The applicator could be designed within 15 days. For patient A, it was noted that 95 % of the clinical target volume received at least 35.4Gy (63Gy EQD2). For patient B, 95 % of the clinical target volume received at least 36Gy (64.8Gy EQD2). The forecast and actual planimetry met the coverage criteria of D95. Contact brachytherapy with 3D bioimpression is feasible, after software training, for complex treatment lesions. This technique could be extended to other indications.

Increased CXCR3+ T Cells Impairs Recruitment of T-Helper Type 17 Cells via Interferon γ and Interleukin 18 in the Small Intestine Mucosa During Treated HIV-1 Infection.

The restoration of CD4+ T cells, especially T-helper type 17 (Th17) cells, remains incomplete in the gut mucosa of most human immunodeficiency virus type 1 (HIV-1)-infected individuals despite sustained antiretroviral therapy (ART). Herein, we report an increase in the absolute number of CXCR3+ T cells in the duodenal mucosa during ART. The frequencies of Th1 and CXCR3+ CD8+ T cells were increased and negatively correlated with CCL20 and CCL25 expression in the mucosa. In ex vivo analyses, we showed that interferon γ, the main cytokine produced by Th1 and effector CD8+ T cells, downregulates the expression of CCL20 and CCL25 by small intestine enterocytes, while it increases the expression of CXCL9/10/11, the ligands of CXCR3. Interleukin 18, a pro-Th1 cytokine produced by enterocytes, also contributes to the downregulation of CCL20 expression and increases interferon γ production by Th1 cells. This could perpetuate an amplification loop for CXCR3-driven Th1 and effector CD8+ T cells recruitment to the gut, while impairing Th17 cells homing through the CCR6-CCL20 axis in treated HIV-1-infected individuals.

Retrospective evaluation of blood copper stable isotopes ratio 65 Cu/63 Cu as a biomarker of cancer in dogs.

Previous studies in humans with breast, colorectal or liver cancer showed that neoplasia was associated with a modification of the blood ratio between 65 Cu and 63 Cu (∂Cu). The aim of the present study was to compare the blood ∂Cu of dogs with cancer to healthy controls or dogs with non-oncologic disease. One hundred and seventeen dogs were included in the study (35 dogs with cancer, 33 dogs with non-neoplastic disease, and 49 healthy controls). The ∂Cu of dogs with cancer was significantly lower than the ratio of healthy controls (P < 0.0001) but not significantly different from dogs with non-oncologic disease. Six dogs with lymphoma were also evaluated after they achieved clinical remission and five out of six had an increase of ∂Cu. Further studies are warranted but these results suggest that ∂Cu could help in the diagnosis of cancer in a controlled clinical context, and may be a potential biomarker for the follow-up of cancer.

CCR6(-) regulatory T cells blunt the restoration of gut Th17 cells along the CCR6-CCL20 axis in treated HIV-1-infected individuals.

The gut CD4(+) T cells, particularly the T helper type 17 (Th17) subset, are not completely restored in most HIV-1-infected individuals despite combined antiretroviral therapy, when initiated at the chronic phase of infection. We show here that the CCR6-CCL20 chemotactic axis is altered, with reduced CCL20 production by small intestine epithelial cells in treated HIV-1-infected individuals. This leads to impaired CCR6(+)CD4(+) T-cell homing, particularly Th17 cells, to the small intestine mucosa. In contrast, the frequency of gut FoxP3(+) T regulatory (Treg) cells, specifically the CCR6(-) subset, was increased. The resulting imbalance in the Th17/CCR6(-) Treg ratio and the associated shift from interleukin (IL)-17 to IL-10 and transforming growth factor-ß (TGF-ß) blunts CCL20 production by enterocytes, perpetuating a negative feedback for the recruitment of CCR6(+)CD4(+) T cells to the small intestine in treated HIV-1-infected individuals.

Spatially explicit predictions of blood parasites in a widely distributed African rainforest bird.

Critical to the mitigation of parasitic vector-borne diseases is the development of accurate spatial predictions that integrate environmental conditions conducive to pathogen proliferation. Species of Plasmodium and Trypanosoma readily infect humans, and are also common in birds. Here, we develop predictive spatial models for the prevalence of these blood parasites in the olive sunbird (Cyanomitra olivacea). Since this species exhibits high natural parasite prevalence and occupies diverse habitats in tropical Africa, it represents a distinctive ecological model system for studying vector-borne pathogens. We used PCR and microscopy to screen for haematozoa from 28 sites in Central and West Africa. Species distribution models were constructed to associate ground-based and remotely sensed environmental variables with parasite presence. We then used machine-learning algorithm models to identify relationships between parasite prevalence and environmental predictors. Finally, predictive maps were generated by projecting model outputs to geographically unsampled areas. Results indicate that for Plasmodium spp., the maximum temperature of the warmest month was most important in predicting prevalence. For Trypanosoma spp., seasonal canopy moisture variability was the most important predictor. The models presented here visualize gradients of disease prevalence, identify pathogen hotspots and will be instrumental in studying the effects of ecological change on these and other pathogens.

Cost-effectiveness of pneumococcal vaccination for prevention of invasive pneumococcal disease in the elderly: an update for 10 Western European countries.

Pneumococcal vaccine is effective in preventing invasive pneumococcal disease in adults >or=65 years of age, but it is not widely used in Western Europe. In this study, data from an earlier (1995) cost-effectiveness study on Belgium, France, Scotland, Spain, and Sweden are updated, and data on five new countries--Denmark, the UK (specifically, England and Wales), Germany, Italy and The Netherlands--are added. Epidemiological and economic variables specific for each country were used, and it was assumed that pneumococcal and influenza vaccines would both be administered during the same physician visit. In the base-case analyses, the cost-effectiveness ratios ranged from euro 9239 to euro 23,657 per quality-adjusted life-year. Because the incidence and mortality of invasive pneumococcal disease were underestimated in most countries, a country-by-country analysis was performed, assuming an incidence of 50 cases per 100,000 population and mortality rates of 20, 30 and 40%. For a mortality of 20%, the cost-effectiveness ratios ranged from euro 4,778 to euro 17,093, and for a mortality of 30%, they ranged from euro 3,186 to euro 11,395. Pneumococcal vaccination to prevent invasive pneumococcal disease in elderly adults was very cost-effective in all 10 countries. This evidence justifies the wider use of the vaccine in Western Europe.

[Formulation and stability study of sucred solutions for a clinical trial in neonates]. / Fabrication et étude de stabilité de solutions sucrées pour un essai clinique chez le nouveau-né

A randomized, double blind clinical trial have been initiated in the neonatology unit of CHRU in Lille to compare the analgesic effect of two oral solutions (25% dextrose and 30% glucose) after heel prick sampling. As part of this trial, the pharmacy was asked to perform the preparation and the randomization. In agreement with good clinical practices and good manufacturing practices, we have valided manufacturing processes, and performed microbiological tests, chromatography control and polarimetric dosage. The stability study of solutions (six months), allows preparation of only one batch in accordance with good manufacturing practice for 25% sucrose and 30% glucose. The participation of hospital pharmacist in the preparation of investigational products is becoming more and more frequent. This enhances his involvement in the quality control of clinical trials.

Cost-effectiveness of pneumococcal vaccination of older people: a study in 5 western European countries.

Pneumococcal vaccination of older persons is thought to be cost-effective in preventing pneumococcal pneumonia, but evidence of clinical protection is uncertain. Because there is better evidence of vaccination effectiveness against invasive pneumococcal disease, we determined the cost-effectiveness of pneumococcal vaccination of persons aged > or =65 years in preventing hospital admission for both invasive pneumococcal disease and pneumococcal pneumonia in 5 western European countries. In the base case analyses, the cost-effectiveness ratios for preventing invasive disease varied from approximately 11,000 to approximately 33,000 European currency units (ecu) per quality-adjusted life year (QALY). Assuming a common incidence (50 cases per 100,000) and mortality rate (20%-40%) for invasive disease, the cost-effectiveness ratios were <12,000 ecu per QALY in all 5 countries. For preventing pneumococcal pneumonia, vaccinating all elderly persons would be highly cost-effective to cost saving. Public health authorities should consider policies for encouraging pneumococcal vaccination for all persons aged > or =65 years.

Influence of Zn2+ on the kinetic events that contribute to the 500-kDa dextran-sulfate-dependent activation of factor XII (Hageman factor).

The effect of zinc ions on kinetic and equilibrium steps that may contribute to the activation and subsequent autoactivation of human blood coagulation factor XII in the presence of 500-kDa dextran sulfate was studied. To analyze the results, the expression of the overall autoactivation constant that had been established from the model presented in a previous study was used. Comparison of the kinetics obtained at different levels of zinc, which included amounts lower than the residual concentration introduced by NaCl in the incubation mixture, suggested that the addition of Zn2+ up to 5 microM lowered the mean number of sites available for the binding of factor XII to the surface from 220 to 172 and increased the rate of the first-order activation of factor XII by one order of magnitude, from (1.6 +/- 0.4) x 10(-4) s(-1) to (8.0 +/- 0.4) x 10(-4) s(-1) in the presence of 550 nM dextran sulfate. Neither the factor XII/surface dissociation constant (1 microM), the apparent catalytic constant, nor the apparent Michaelis-Menten constant associated with the postulated multi-stage kinetic sequence were affected by the presence of zinc. Most experimental trends induced by the presence of zinc could be successfully interpreted by using the model, thus reinforcing its reliability under different conditions.

Explicit constants for the dextran-sulfate-mediated activation and autoactivation of purified human factor XII (Hageman factor).

The autoactivation kinetics of purified factor XII (FXII) in the presence of dextran sulfate of 500000 Da was reexamined assuming the existence of two preceding activation steps. Kinetics were numerically simulated by using rate and equilibrium constants related to surface-bound species. Relevant feature parameters related to the polymer (number of binding sites and concentration, dissociation constant of FXII from the surface) and the zymogen (concentration. Michaelis-Menten constant of the autoactivation reaction, catalytic rate constant) were accordingly introduced in the mechanisms. Depending on the rate-limiting step i.e. whether the polymer or FXII predominates, numerical simulation analysis led to obtain for the observed autoactivation rate constant (kobs) two explicit expressions which included the contributing variables. One of the two proposed models was in good accordance with the experimental data obtained in this study and with others published previously. We were able to estimate the mean number of the FXII-activating sites supported by the polymer chains (220) and the equilibrium dissociation constant of FXII from the surface (1 microM). Further treatment led us to determine surface-concentration-independent constants (K(m) = 2510 nM and kcat = 0.01 s-1), as well as the rate constant (k1 = 1.6 x 10(-4) s-1) of the postulated first-order activation rate aimed at explaining the formation of the first trace amounts of FXIIa via an intramolecular mechanism. Overall, the treatment applied to the dextran sulfate case offers a quantitative tool by which data determined in the presence of other activating materials can be rationalized.