Standard versus hypofractionated intensity-modulated radiotherapy for prostate cancer: assessing the impact on dose modulation and normal tissue effects when using patient-specific cancer biology.

Hypofractionation of prostate cancer radiotherapy achieves tumour control at lower total radiation doses, however, increased rectal and bladder toxicities have been observed. To realise the radiobiological advantage of hypofractionation whilst minimising harm, the potential reduction in dose to organs at risk was investigated for biofocused radiotherapy. Patient-specific tumour location and cell density information were derived from multiparametric imaging. Uniform-dose plans and biologically-optimised plans were generated for a standard schedule (78 Gy/39 fractions) and hypofractionated schedules (60 Gy/20 fractions and 36.25 Gy/5 fractions). Results showed that biologically-optimised plans yielded statistically lower doses to the rectum and bladder compared to isoeffective uniform-dose plans for all fractionation schedules. A reduction in the number of fractions increased the target dose modulation required to achieve equal tumour control. On average, biologically-optimised, moderately-hypofractionated plans demonstrated 15.3% (p-value: <0.01) and 23.8% (p-value: 0.02) reduction in rectal and bladder dose compared with standard fractionation. The tissue-sparing effect was more pronounced in extreme hypofractionation with mean reduction in rectal and bladder dose of 43.3% (p-value: < 0.01) and 41.8% (p-value: 0.02), respectively. This study suggests that the ability to utilise patient-specific tumour biology information will provide greater incentive to employ hypofractionation in the treatment of localised prostate cancer with radiotherapy. However, to exploit the radiobiological advantages given by hypofractionation, greater attention to geometric accuracy is required due to increased sensitivity to treatment uncertainties.

Automatic oxygen administration and weaning in patients following mechanical ventilation.

PURPOSE: To evaluate efficacy of FreeO2 device in oxygen weaning of patients after being liberated from mechanical ventilation (MV). METHODS: Prospective crossover cohort study in patients admitted to ICU and after MV weaning. FreeO2 curves were recorded during constant flow and FreeO2 modes. Oxygenation parameters and O2 consumption were assessed. RESULTS: Fifty one records were obtained in 51 patients (median age, 62 years, 54.9% had COPD, admission for acute respiratory failure in 96%). NIV was used initially in 68.6%. For a median records duration of 2.04 h, the time spent within target SpO2 range was significantly higher with FreeO2 mode compared to constant O2 flow mode [86.92% (77.11-92.39) vs 43.17% (5.08-75.37); p < 0.001]. Time with hyperoxia was lower with FreeO2 mode: 8.68% (2.96-15.59) vs 38.28% (2.02-86.34). Times with hypoxaemia, and with severe desaturation, were similar. At the end of FreeO2 mode, O2 flow was lower than 1 l/min in 28 patients (54.9%), with a median of 0.99 l/min. CONCLUSIONS: For the purpose of oxygen weaning in patients recovering from MV, automatic O2 titration with FreeO2 was associated with a substantial reduction in O2 delivery and better oxygenation parameters in comparison with constant O2 flow.

Voxel-level biological optimisation of prostate IMRT using patient-specific tumour location and clonogen density derived from mpMRI.

AIMS: This study aimed to develop a framework for optimising prostate intensity-modulated radiotherapy (IMRT) based on patient-specific tumour biology, derived from multiparametric MRI (mpMRI). The framework included a probabilistic treatment planning technique in the effort to yield dose distributions with an improved expected treatment outcome compared with uniform-dose planning approaches. METHODS: IMRT plans were generated for five prostate cancer patients using two inverse planning methods: uniform-dose to the planning target volume and probabilistic biological optimisation for clinical target volume tumour control probability (TCP) maximisation. Patient-specific tumour location and clonogen density information were derived from mpMRI and geometric uncertainties were incorporated in the TCP calculation. Potential reduction in dose to sensitive structures was assessed by comparing dose metrics of uniform-dose plans with biologically-optimised plans of an equivalent level of expected tumour control. RESULTS: The planning study demonstrated biological optimisation has the potential to reduce expected normal tissue toxicity without sacrificing local control by shaping the dose distribution to the spatial distribution of tumour characteristics. On average, biologically-optimised plans achieved 38.6% (p-value: < 0.01) and 51.2% (p-value: < 0.01) reduction in expected rectum and bladder equivalent uniform dose, respectively, when compared with uniform-dose planning. CONCLUSIONS: It was concluded that varying the dose distribution within the prostate to take account for each patient's clonogen distribution was feasible. Lower doses to normal structures compared to uniform-dose plans was possible whilst providing robust plans against geometric uncertainties. Further validation in a larger cohort is warranted along with considerations for adaptive therapy and limiting urethral dose.

Compliance with the European trauma guidelines: An observational single centre study.

OBJECTIVES: The European trauma guidelines were developed to assist clinicians in the early phase of trauma management to diagnose and treat coagulopathy and bleeding. This study aimed to determine compliance with these European trauma guidelines in a French referral trauma centre. METHODS: Medical charts of trauma patients with an injury severity score≥16 admitted between January 2013 and December 2014 were reviewed. Compliance with 21 recommendations in the first 24-hours of patient management was assessed. RESULTS: There were 145 patients with median ISS of 34 [IQR 25-41]. A good level of compliance (i.e. applied in≥80% of patients) was identified for nine recommendations, inconsistent compliance (i.e. applied in 50 to 79% of patients) for six recommendations, including fibrinogen levels at hospital admission and achievement of a target mean arterial blood pressure (MAP)>80mmHg in patients with major bleeding and TBI (55.5%), and poor compliance (i.e. applied in<50% of patients) for another six recommendations. Poorly applied recommendations included early measurement of lactate or base deficit (32%), early administration of tranexamic acid (18%), and achievement of normocapnia in patients with TBI undergoing invasive ventilation (3%). CONCLUSIONS: In a referral trauma centre, nine of the 21 evaluable recommendations in the European trauma guidelines were applied in≥80% of patients. Early diagnosis and treatment of trauma-related coagulopathy was identified as an area for significant practice improvement. In patients with TBI, efforts should be made to achieve the targeted MAP and to maintain normocapnia.

Radiobiological parameters in a tumour control probability model for prostate cancer LDR brachytherapy.

To provide recommendations for the selection of radiobiological parameters for prostate cancer treatment planning. Recommendations were based on validation of the previously published values, parameter estimation and a consideration of their sensitivity within a tumour control probability (TCP) model using clinical outcomes data from low-dose-rate (LDR) brachytherapy. The proposed TCP model incorporated radiosensitivity (α) heterogeneity and a non-uniform distribution of clonogens. The clinical outcomes data included 849 prostate cancer patients treated with LDR brachytherapy at four Australian centres between 1995 and 2012. Phoenix definition of biochemical failure was used. Validation of the published values from four selected literature and parameter estimation was performed with a maximum likelihood estimation method. Each parameter was varied to evaluate the change in calculated TCP to quantify the sensitivity of the model to its radiobiological parameters. Using a previously published parameter set and a total clonogen number of 196 000 provided TCP estimates that best described the patient cohort. Fitting of all parameters with a maximum likelihood estimation was not possible. Variations in prostate TCP ranged from 0.004% to 0.67% per 1% change in each parameter. The largest variation was caused by the log-normal distribution parameters for α (mean, [Formula: see text], and standard deviation, σ α ). Based on the results using the clinical cohort data, we recommend a previously published dataset is used for future application of the TCP model with inclusion of a patient-specific, non-uniform clonogen density distribution which could be derived from multiparametric imaging. The reduction in uncertainties in these parameters will improve the confidence in using biological models for clinical radiotherapy planning.

Impact of the humidification device on intubation rate during noninvasive ventilation with ICU ventilators: results of a multicenter randomized controlled trial.

PURPOSE: The use of heat and moisture exchangers (HME) during noninvasive ventilation (NIV) can increase the work of breathing, decrease alveolar ventilation, and deliver less humidity in comparison with heated humidifiers (HH). We tested the hypothesis that the use of HH during NIV with ICU ventilators for patients with acute respiratory failure would decrease the rate of intubation (primary endpoint) as compared with HME. METHODS: We conducted a multicenter randomized controlled study in 15 centers. After stratification by center and type of respiratory failure (hypoxemic or hypercapnic), eligible patients were randomized to receive NIV with HH or HME. RESULTS: Of the 247 patients included, 128 patients were allocated to the HME group and 119 to the HH group. Patients were comparable at baseline. The intubation rate was not significantly different: 29.7% in the HME group and 36.9% in the HH group (p = 0.28). PaCO2 did not significantly differ between the two arms, even in the subgroup of hypercapnic patients. No significant difference was observed for NIV duration, ICU and hospital LOS, or ICU mortality (HME 14.1 vs. HH 21.5%, p = 0.18). CONCLUSIONS: In this study, the short-term physiological benefits of HH in comparison with HME during NIV with ICU ventilators were not observed, and no difference in intubation rate was found. The physiologic effects may have been obscured by leaks or other important factors in the clinical settings. This study does not support the recent recommendation favoring the use of HH during NIV with ICU ventilators.

The semi-seated position slightly reduces the effort to breathe during difficult weaning.

PURPOSE: The influence of posture on breathing effort in patients with difficult weaning is unknown. We hypothesized that posture could modulate the breathing effort in difficult-to-wean patients. METHODS: A prospective, crossover, physiologic study was performed in 24 intubated patients breathing with pressure support who had already failed a spontaneous breathing trial or an extubation episode. Their median duration of mechanical ventilation before measurements was 25 days. Breathing pattern, occlusion pressure (P (0.1)), intrinsic PEEP (PEEP(i)), and inspiratory muscle effort evaluated by the pressure-time product of the respiratory muscles and the work of breathing were measured during three postures: the seated position in bed (90°LD), simulating the position in a chair, the semi-seated (45°), and the supine (0°) positions consecutively applied in a random order. A comfort score was obtained in 17 cooperative patients. The influence of position on chest wall compliance was measured in another group of 11 sedated patients. RESULTS: The 45° position was associated with the lowest levels of effort (p ≤ 0.01) and occlusion pressure (p < 0.05), and tended to be more often comfortable. Respiratory effort was the lowest at 45° in 18/24 patients. PEEP(i) and PEEP(i)-related work were slightly higher in the supine position (p ≤ 0.01), whereas respiratory effort, heart rate, and P (0.1) values were increased in the seated position (p < 0.05). CONCLUSION: A 45° position helps to unload the respiratory muscles, moderately reduces PEEP(i), and is often considered as comfortable. The semi-seated position may help the weaning process in ventilator-dependent patients.

[Current trends in plasma transfusion for patients with severe hemorrhage]. / Plasma thérapeutique dans les hémorragies sévères.

Recent changes in plasma transfusion practices for severe hemorrhage are largely related to the recognition of an early endogenous coagulopathy associated with traumatic injury. Observational and mostly retrospective data suggest improved survival rates with high-dose plasma therapy, up to a 1:1 ratio of fresh frozen plasma to packed red blood cells, but the quality of evidence is limited. Putting it into practice raises many issues (early identification of patients at risk of massive bleeding, extrapolation to non-trauma settings, alternative or adjunctive treatments, among others) that are discussed in this brief review.

Optical analysis of developmental changes in synaptic potentiation in the neonatal rat corticostriatal projection.

We applied voltage-sensitive dye imaging to neonatal rat cortical slice preparations and analyzed developmental changes in synaptic plasticity, long-term potentiation (LTP), in the corticostriatal projection. Coronal slice preparations were dissected from postnatal 1- to 21-day (P1-P21) rats, and the transmembrane voltage-related optical signals evoked by cortical stimulation were recorded using a 464ch optical recording system with the voltage-sensitive absorption dye. In the striatum, the optical signal was composed of a fast spike-like signal followed by a slow signal, which corresponded to an action potential and an excitatory postsynaptic potential (EPSP), respectively. The slow signal could be detected at the P1 stage, suggesting that the EPSP is already expressed in the corticostriatal projection at least at early stages after birth. On the other hand, the slow signal was potentiated with a single shot of tetanic stimulation and the potentiation lasted at least 1 h, which is considered to correspond to long-term potentiation. With ontogenetic examinations, we found that (1) the EPSP could be potentiated with tetanic stimulation from the P9 stage and that (2) after the LTP induction, the potentiation was maintained for a longer time in the postnatal 3W stage than in the 2W stage. These results suggest that characteristics of LTP change dynamically during postnatal development.

Camellia japonica suppresses immunoglobulin E-mediated allergic response by the inhibition of Syk kinase activation in mast cells.

BACKGROUND: Novel approaches are being explored to develop new therapies for various allergic diseases. Complementary and alternative medicines are considered to be promising avenues for the development of such new therapies. OBJECTIVES: To investigate the effect of many Korean plants on the IgE-mediated allergic response in mast cells and in vivo, and its mechanism of action. MATERIALS AND METHODS: The anti-allergic activity was tested by evaluating effects on degranulation of mast cells in culture and passive cutaneous anaphylaxis (PCA) in vivo. Its mechanism of action was investigated by immunoblotting analysis, immunoprecipitation, RT-PCR, and other molecular biological approaches in mast cells. RESULTS: We screened approximately 100 natural plant extracts collected in Korea for in vitro anti-allergic activity. The leaf extract of Camellia japonica (LECJ) exhibited the most potent effect on degranulation in antigen-stimulated rodent and human mast cells. LECJ reversibly inhibited degranulation in a dose-dependent manner, with IC(50) values of approximately 50 microg/mL for the mast cells, and it also suppressed the expression and secretion of TNF-alpha and IL-4 in rat basophilic leukaemia-2H3 mast cells. In agreement with its in vitro activity, LECJ significantly inhibited mast cell-mediated PCA in an animal model. LECJ inhibited activating phosphorylation of tyrosine Y371 on Syk kinase, indicating that LECJ inhibits the activity of Src-family kinases in mast cells. In the in vitro kinase assay, LECJ directly inhibited Lyn kinase, the major Src-family kinase in the cells. It also suppressed Akt and MAP kinases, which are critical for the production of various pro-inflammatory cytokines in mast cells. In high-performance liquid chromatography analysis, quercetin-3-beta-D-glucoside and eugenol were identified as the major active components. CONCLUSION: The present results strongly suggest that the anti-allergic activity of LECJ is mediated through inhibiting degranulation and allergic cytokine secretion by inhibition of Src-family kinase in mast cells and it may be useful for the treatment of mast cell-related immediate and delayed allergic diseases.

[Indications and practical issues concerning oxygen therapy]. / Intérêts et modalités pratiques de mise en route d'une oxygénothérapie.

INTRODUCTION: The initiation of oxygen therapy for acute or chronic respiratory failure is a common medical intervention, both for hospital in-patients and in out-of-hospital emergency settings. Oxygen therapy is also frequently initiated by paramedics or nurses, without any initial medical prescription, in acutely ill patients. STATE OF THE ART/PERSPECTIVES: It is important to remember that oxygen is a pharmaceutical drug, and its prescription should therefore be considered within treatment guidelines. Two main pathological situations may be encountered: tissue hypoxia and acute/chronic hypoxemia. CONCLUSION: Physicians should be aware of the clinical signs that may indicate the presence of hypoxia and the pathological situations that may lead to hypoxemia. They must also be aware of the potential complications, in particular CO(2) retention in patients with chronic type II respiratory failure as well as the overall indications, and practical issues concerning oxygen therapy.

[Revision of the 3rd Consensus Conference in Intensive Care and Emergency Medicine in 1988: management of acute asthmatic crisis in adults and chidren (excluding infants)]. / Révision de la troisième conférence de consensus en réanimation et médecine d'Urgence de 1988: prise en charge des crises d'asthme aiguës graves de l'adulte et de l'enfant (à l'exclusion du nourrisson).

Experts designated by the "référentiels" committee of the SRLF analyzed the numerous articles published after the French consensus conference on the severe acute asthma of 1988. From their work, a revision of this consensus conference has been performed. The pediatric specificity has been added in this revision. There is no severity score able to predict the severity of acute asthma on admission. In every case, the nebulization of beta-2 agonists represents the priority treatment. The nebulization of anticholinergic associated with the beta-2 agonists induces a moderate additional effect. In the absence of response to nebulizations, the usefulness of the beta-2 agonists associated intravenous. Administration is not demonstrated. Corticosteroids should be administered using a 1 to 2 mg per kg dosage, but their efficacy is delayed. In adult patients, aminophylline should not be prescribe, but it is still used by some pediatricians. Other associated treatments (adrenaline, magnesium sulfate, helium-oxygen mixture) did not demonstrate their efficacy as adjunctive therapies. The therapeutic response should be evaluated using the peak flow determination.

Prospective evaluation and outcome of patients admitted for syncope over a 1 year period.

AIMS: Syncope is a frequent and potentially dangerous symptom. The epidemiological data are based on series mainly collected 20 years ago in the U.S.A. and do not adequately assist in the management of patients admitted now for this symptom in Europe. METHODS AND RESULTS: To evaluate prospectively the epidemiological aspects and the management of the patients admitted in the emergency department of an adult university hospital for a 'verified' syncope, charts of all the patients consecutively admitted between June 1999 and June 2000 were systematically reviewed by a member of the cardiology staff. Those with a loss of consciousness were selected and those with a definite syncope were included in the study group and followed until they were discharged from the hospital. Among the 37,475 patients who presented to the emergency department, 454 (1.21%) had a definite syncope. For 296 it was the first episode and 169 (mean age 43+/-23 years) were discharged straight away; 285 (mean age 66+/-19 years; P<0.0001) were admitted to internal medicine (n=151), cardiology (n=65), neurology (n=44), endocrinology (n=14) and surgery (n=11) services. In 75.7% of all the patients a diagnosis was reported but it was inadequate to explain a syncopal episode in 56 cases (16.3%). Management differed by department: 36% of the patients had 'neurological' investigations mainly in internal medicine and neurology. Except in cardiology very few had 'cardiological' investigations particularly tilt test and electrophysiological studies (5%). CONCLUSION: Syncope is a frequent symptom but its cause often remains unknown partly due to inadequate management. Precise and simple guidelines are urgently needed.

A global approach to energy metabolism in an experimental model of sepsis.

Disturbances in energy metabolism during sepsis are not clearly understood. The aim of the study was to globally assess the energy drive in septic rat myocytes, studying both glycolysis rates and mitochondrial maximal activities together, using recent in vitro techniques. Measurements were assessed before (H0) and 4 h after sepsis induction (H4). Hyperlactatemia was observed in all septic animals ([lactate] = 1.2 +/- 0.3 mmol/L at H0 versus 3.3 +/- 0.6 mmol/L at H4; p < 0.001). An enhanced glycolysis rate was observed in both aerobic ( J(A) = 7.2 +/- 0.9 at H0 versus 18.2 +/- 4.1 nmol glucose/min/g at H4; p < 0.05) and anaerobic ( J(B) = 7.5 +/- 1.2 at H0 versus 15.4 +/- 3.4 micromol glucose/min/g at H4; p < 0.05) fluxes, associated with a selective significant pyruvate-malate-dependent oxygen consumption rate decrease (V O(2)-PM = 0.144 +/- 0.008 at H0 versus 0.113 +/- 0.007 micromol O(2)/h/mg at H4; p < 0.05). This oxygen consumption decrease can be interpreted either as a complex I and/or a complex I-ubiquinone relation alteration. Our results are consistent with the hypothesis that an altered mitochondrial function during sepsis is responsible, at least in part, for hyperlactatemia, which is thus a consequence of an increased glycolysis rate.