B-cell infiltration is associated with survival outcomes following programmed cell death protein 1 inhibition in head and neck squamous cell carcinoma.

BACKGROUND: Programmed cell death protein 1 (PD-1) axis blockade has become the mainstay in the treatment of recurrent and/or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Programmed death-ligand 1 (PD-L1) is the only approved biomarker for patient selection; however, response rate is limited even among high expressors. Our primary objective was to investigate the association of immune cell-related biomarkers in the tumor and tumor microenvironment with PD-1 checkpoint inhibitors' outcomes in patients with R/M HNSCC. PATIENTS AND METHODS: NCT03652142 was a prospective study in nivolumab-treated platinum-refractory R/M HNSCC, aiming to evaluate biomarkers of response to treatment. Tumor biopsies and blood samples were collected from 60 patients at baseline, post-treatment, and at progression. Immune cells in the tumor and stromal compartments were quantified by immunofluorescence using a five-protein panel (CD3, CD8, CD20, FoxP3, cytokeratin). Tertiary lymphoid structures (TLSs), PD-L1 expression, and peripheral blood immune cell composition were also evaluated for associations with outcome. Our findings were validated by gene set enrichment analysis (GSEA) messenger RNA in situ expression data from the same patients, for B-cell- and TLS-associated genes. RESULTS: High pre-treatment density of stromal B cells was associated with prolonged progression-free survival (PFS) (P = 0.011). This result was validated by GSEA, as stromal enrichment with B-cell-associated genes showed association with response to nivolumab. PD-L1 positivity combined with high B-cell counts in stroma defined a subgroup with significantly longer PFS and overall survival (P = 0.013 and P = 0.0028, respectively). CONCLUSIONS: Increased B cells in pre-treatment HNSCC biopsy samples correlate with prolonged benefit from PD-1-based immunotherapy and could further enhance the predictive value of PD-L1 expression.

Management of recurrent localised bladder amyloid, has methotrexate helped?

Background: Amyloidosis of the bladder is a benign condition which can present with a multitude of symptoms including bladder mass, irritative voiding symptoms and haematuria. Case presentation: We report on the investigation and management of a patient with recurrent localised amyloidosis of the bladder, which appears to have been managed fortuitously by concurrent methotrexate prescribed for another indication. Conclusion: We provide further assessment and management with a focus on the possible benefit of methotrexate for management of localised bladder amyloidosis.

Perspectives for integrating human and environmental risk assessment and synergies with socio-economic analysis.

For more than a decade, the integration of human and environmental risk assessment (RA) has become an attractive vision. At the same time, existing European regulations of chemical substances such as REACH (EC Regulation No. 1907/2006), the Plant Protection Products Regulation (EC regulation 1107/2009) and Biocide Regulation (EC Regulation 528/2012) continue to ask for sector-specific RAs, each of which have their individual information requirements regarding exposure and hazard data, and also use different methodologies for the ultimate risk quantification. In response to this difference between the vision for integration and the current scientific and regulatory practice, the present paper outlines five medium-term opportunities for integrating human and environmental RA, followed by detailed discussions of the associated major components and their state of the art. Current hazard assessment approaches are analyzed in terms of data availability and quality, and covering non-test tools, the integrated testing strategy (ITS) approach, the adverse outcome pathway (AOP) concept, methods for assessing uncertainty, and the issue of explicitly treating mixture toxicity. With respect to exposure, opportunities for integrating exposure assessment are discussed, taking into account the uncertainty, standardization and validation of exposure modeling as well as the availability of exposure data. A further focus is on ways to complement RA by a socio-economic assessment (SEA) in order to better inform about risk management options. In this way, the present analysis, developed as part of the EU FP7 project HEROIC, may contribute to paving the way for integrating, where useful and possible, human and environmental RA in a manner suitable for its coupling with SEA.

[Awake intubation using Pentax Airway Scope as an alternative to awake fiberoptic intubation in management of anticipated difficult tracheal intubation in major burn patients]. / Le glottiscope AWS-Pentax™, alternative à la fibroscopie dans deux cas d'intubation difficile prévue du brûlé grave.

Intubating patients with facial burn is difficult to most anesthesiologists. Awake flexible fiberoptic intubation is the gold standard for management of anticipated difficult tracheal intubation. However, serious facial burn and dysmorphic syndrome can make fiberoptic intubation more difficult or impossible. We report the use of awake oral intubation using the Pentax-Airway Scope (AWS) in two major burn patients with facial injury, in whom awake fiberoptic intubation was impossible. As shown in morbidly obese patient and in patients with unstable necks, AWS could be useful to facilitate tracheal intubation in awake, facial burn patients presenting with a potentially difficult airway. Awake AWS intubation seems as a potential alternative to awake fiberoptic intubation.

Comparison of models to analyze mortality data and derive concentration-time response relationship of inhaled chemicals.

The derivation of thresholds for lethal effects for inhaled chemicals is a key issue in accidental risk management because they largely determine the outcome of land use planning, among which localization of habitations in the vicinity of a factory. This derivation is generally performed on the basis of rodent lethality data analyzed by statistical models able to extrapolate effects for different times and concentrations of exposure. A model commonly used in France is the standard probit model. In this model, effects is related to exposure concentration and duration according to the Haber's law and considers that individual thresholds, corresponding to the maximum tolerated effects before dying, are log-normally distributed among the population. This approach has been criticized for its lack of biological parameters and its inability to treat data characterized by only one time of exposure. In order to improve the current state of modeling, we proposed three alternative models. Two of them (DEBtox and Haber-TKTD models) incorporate the kinetics of the chemicals. The third one (Loguniform model) is a linearization of the standard probit model. We evaluated their performance by analyzing real data and simulated data generated with each model. For data characterized by several times of exposure, the standard probit model outperformed all other models in terms of goodness of fits and estimation of parameters. For data characterized by only one time of exposure, only DEBtox model was able to fit the data and estimate parameters, provided we dispose of several observation times, typically just after exposure and a long period afterwards.

Decrease in ovalbumin-induced pulmonary allergic response by benzaldehyde but not acetaldehyde exposure in a Guinea pig model.

The pulmonary effects of two environmentally relevant aldehydes were investigated in nonsensitized or ovalbumin (OA)-sensitized guineapigs (GPs). Four-week-old male Hartley GPs, weighing about 400 g, were intraperitoneally injected with 1 ml of an NaCl solution containing 100 microg OA and 100 mg Al(OH)(3). They were then exposed to either acetaldehyde (200 ppb) or benzaldehyde (500 ppb) for 4 wk (6 h/d, 5 d/wk). At the end of exposure, GPs were challenged with an OA aerosol (0.1% in NaCl) and pulmonary functions were measured. The day after, guinea pigs were anesthetized and several endpoints related to inflammatory and allergic responses were assessed in blood, whole-lung histology, and bronchoalveolar lavage (BAL). Sensitized nonexposed GPs showed bronchial hyperresponsiveness to OA and an increased number of eosinophils in blood and BAL, together with a rise in total protein and leukotrienes (LTB(4) and LTC(4)/D(4)/E(4)) in BAL. In nonsensitized GPs, exposure to acetaldehyde or benzaldehyde did not induce any change in the tested parameters, with the exception of irritation of the respiratory tract as detected by histology and an increased number of alveolar macrophages in animals exposed to acetaldehyde. In sensitized GPs, exposure to acetaldehyde induced a moderate irritation of the respiratory tract but no change in biological parameters linked to the inflammatory and allergic responses. In contrast, exposure to benzaldehyde induced a decrease both in OA-induced bronchoconstriction and in eosinophil and neutrophil numbers in BAL, an increase in the bronchodilatator mediator prostaglandin E(2) (PGE(2)), and a decrease in the bronchoconstrictor mediators LTC(4)/D(4)/E(4). Further investigations are needed to determine if the attenuated response observed in sensitized GPs exposed to benzaldehyde is due to an alteration of the mechanism of sensitization or to a more direct effect on various mechanisms of the allergic response.

Clonidine for major vascular surgery in hypertensive patients: a double-blind, controlled, randomized study.

The utility of clonidine for hypertensive patients presenting for major vascular procedures remains debatable. Twenty-one hypertensive patients presenting for aortic surgery were given clonidine (n = 11) or placebo (n = 10) in a double-blind, randomized manner. Clonidine was administered 6 micrograms/kg per os 120 min before induction of anesthesia and 3 micrograms/kg intravenously (i.v.) over 60 min from aortic declamping to skin closure. Anesthesia was induced with alfentanil 20 micrograms/kg, midazolam, and atracurium and maintained with nitrous oxide 70%, an alfentanil infusion (0.25 microgram.kg-1. min-1), and isoflurane. Anesthetic requirements, circulatory variables, interventions, and isoproterenol dose-response curves (pre- and postoperatively) were determined. Plasma concentrations of clonidine, alfentanil, and vasoactive hormones were measured. When the clonidine group was compared with the placebo group, (a) isoflurane, alfentanil, and midazolam requirements were reduced by 38%, 42%, and 41%, respectively (P = 0.04, 0.03, 0.0002, respectively); (b) supplemental circulatory and anesthetic adjustments were reduced by 51% (P = 0.0006); (c) interventions with vasopressors were not significantly increased (placebo: two; clonidine: five); (d) systolic and mean arterial pressures and heart rate were reduced; (e) increases in norepinephrine, epinephrine, and plasma renin activity were suppressed, whereas vasopressin surge was attenuated; and (f) chronotropic response to isoproterenol was unaffected. Clonidine was effective in reducing anesthetic requirements and in improving circulatory stability in hypertensive patients presenting for major vascular procedures.

Effects of a continuous lipid infusion on glucose metabolism in critically ill patients.

The effects of lipid administration on carbohydrate oxidation rate remain controversial, particularly in critically ill patients. The aim of this study was to determine the effects of these patients of a continuous lipid infusion on glucose metabolism using indirect calorimetry and stable isotopes. We studied seven patients, mechanically ventilated, during two consecutive 24-h periods. Throughout the first period they received a continuous infusion of glucose (2 mg.kg-1.min-1) and amino acids. During the second period, in addition to the glucose, they received a continuous infusion of 1 mg.kg-1.min-1 of long-chain triglycerides emulsion. Substrate oxidation rates were calculated from pulmonary gas exchange and nitrogen excretion measurements. Glucose kinetic parameters were measured using primed constant infusions of [6,6-2H2]glucose and [1-13C]glucose. The lipid infusion did not modify the glucose metabolism parameters; 45% of the lipid supply was stored.

Clinical validation of the Deltatrac monitoring system in mechanically ventilated patients.

OBJECTIVE: To evaluate a monitor of pulmonary gas exchange (Deltatrac, Datex) in a clinical setting. DESIGN: After in vitro evaluation, comparison over 2 min between VO2 and VCO2 values measured by the Deltatrac and the Douglas bag technique. Comparisons were also achieved over 8 h periods between the Deltatrac and a system using a mass-spectrometer. SETTING: Polyvalent intensive care unit (ICU 15 beds) in a 1200 bed general hospital. PATIENTS: Comparison with the Douglas bag technique in 10 patients undergoing controlled ventilation. Comparison with the mass-spectrometer system in 25 other patients undergoing controlled or pressure support ventilation. MEASUREMENTS AND RESULTS: Compared to the results obtained by the Douglas bag technique, the bias (+/- 2 SD) for VO2 and VCO2 was -3.5 +/- 26.6 and 6.1 +/- 12.7 ml.min-1, respectively. By comparison with the mass-spectrometer system, the bias for VO2 and RQ was -5.8 +/- 16.0 ml.min-1 and 0.018 +/- 0.048, respectively. No drift between the two systems was observed over time. CONCLUSIONS: The Deltatrac appears suitable for VO2 and VCO2 measurements in ventilated patients and equivalent to a mass-spectrometer system for long term measurements.

Effects of glucose-to-lipid ratio and type of lipid on substrate oxidation rate in patients.

This study is an investigation into the effects of different carbohydrate-to-lipid ratios on CO2 production in postoperative patients and the determination of the substrate oxidation rates induced by long-chain triglycerides (LCT) or a mixture of long- and medium-chain triglycerides (MCT/LCT) at various carbohydrate-to-lipid ratios. Two groups of eight patients randomly received either LCT or MCT/LCT emulsions. Total caloric intake was set at the measured energy expenditure provided at three different glucose-to-lipid ratios (70:30, 50:50, 30:70). We used long-term indirect calorimetry with a mass spectrometer system and measurement of natural enrichment in 13C of expired CO2 and plasma glucose. The carbon dioxide production and minute ventilation were not different among the different glucose-to-lipid ratios, whatever the type of lipid. Increasing the lipid supply up to 70% of nonprotein caloric intake led to an only minor increase in lipid oxidation rate and thus to a net fat deposit. We conclude that large amounts of lipid (LCT or MCT/LCT) were not of interest in such patients.

Metabolic effects of hemodialysis with and without glucose in the dialysate.

This study was conducted in eight acute renal failure patients undergoing mechanical ventilation to test if the addition of glucose in the dialysate prevents metabolic and hormonal changes induced by hemodialysis. Hemodialysis was performed with a bicarbonate dialysate, a polyacrilonitrile membrane and a continuous heparinization. Two four-hour hemodialysis sessions were performed in each patient: one without glucose (GFD) and one with glucose (GD) in the dialysate at a concentration close to each patient's initial plasma glucose concentration. Oxygen consumption and carbon dioxide elimination, glucose insulin, aceto-acetate and free fatty acids were measured before, during and after the sessions. Oxygen consumption and carbon dioxide elimination were measured with a system using a mass spectrometer. Hemodynamic state and temperature remained constant. Before hemodialysis, respiratory quotient (RQ) values were the same in both groups. There was no change in RQ during GD. There was a decrease in RQ during GFD. Glucose and insulin concentrations decreased during GFD and remained unchanged during GD. Aceto-acetate concentration remained constant under both conditions. Free fatty acids concentration increased to the same extent during GD and GFD. The authors conclude that the addition of glucose in the dialysate prevents the decrease in RQ induced by hemodialysis. This effect is most likely related to a decreased mobilization of non-glucidic fuels.

Recovery of [13C]bicarbonate as respiratory 13CO2 in mechanically ventilated patients.

Measurement of the nutrient oxidation rate with 13C as a tracer requires knowledge of the value of its coefficient of fractional recovery in the expired gas (FR). We measured FR in nine intensive care patients who were mechanically ventilated and received total parenteral nutrition. NaH13CO3 was administered at a priming dose (3.75 mumol.kg-1.min-1) followed by a continuous infusion (0.05 mumol.kg-1.min-1). Metabolic rate and pulmonary carbon dioxide elimination (VCO2) were measured by using a mass-spectrometer system. The 13C-12C ratio was measured in the expired gas with an isotopic-ratio mass spectrometer and FR was calculated by using standard equations. The average value of FR was 0.899 +/- 0.026 (means +/- SE) and remained stable for each patient on 2 consecutive days. Between patients, the coefficient of variation of FR was 8.6%. Metabolic rate was the only physiological factor found to affect the FR value.

Use of a new gas chromatograph isotope ratio mass spectrometer to trace exogenous 13C labelled glucose at a very low level of enrichment in man.

The use of 13C labelled glucose in human metabolic studies has been limited by the high cost of the tracer and the problems of measuring low 13C isotopic abundance in plasma glucose. In the present work we describe a new gas chromatograph-isotope ratio mass spectrometer allowing the measurement of a 0.001 atom % increase in 13C abundance over baseline, on a nanomole glucose sample. Studies were performed in rats and in human subjects. The rate of glucose appearance in 24 h fasted rats using D-[1-13C] glucose as tracer and analysed by this new method was found to be 10.4 +/- 0.7 mg.kg-1.min-1, a value 21% lower than that found using D-[6,6-2H2] glucose as tracer (13.1 +/- 1.1 mg.kg-1.min-1) analysed by classic gas chromatography-mass spectrometry. The new method was also used to trace, in combination with D-[6,6 2H2] glucose, the metabolic fate in human subjects of two oral glucose loads (0.5 g.kg.-1,1 g.kg.-1) labelled with 0.1% D-[U-13C] glucose. During the six hours following the glucose load, it was found that total glucose appearance was 0.97 +/- 0.04 g.kg.-1 and 1.2 +/- 0.04 g.kg.-1, exogenous glucose appearance was 0.51 +/- 0.02 g.kg.-1 and 0.84 +/- 0.04 g.kg.-1, endogenous glucose production was 0.44 +/- 0.04 g.kg.-1 and 0.35 +/- 0.06 g.kg.-1 after the 0.5 and 1 g.kg.-1 load respectively. These values are similar to those reported using glucose labelled with radioactive isotopes.(ABSTRACT TRUNCATED AT 250 WORDS)

Mass spectrometric measurements of oxygen uptake during epidural analgesia combined with general anesthesia.

Oxygen uptake was measured using a mass spectrometer system in 12 patients scheduled for abdominal surgery who intraoperatively were mechanically ventilated with 50% nitrous oxide and given continuous intravenous infusions of methohexital (3.5 mg.kg-1.h-1) plus repeated epidural injections of lidocaine. At the end of the surgical procedure, meperidine (0.7 mg/kg) was epidurally injected in six patients (group A). The other six patients (group B) received no epidural injections during the first 2 h after surgery. Intraoperatively, oxygen uptake decreased in both groups by an average of 28%. Within the first two postoperative hours, clear-cut differences among the two groups arose. Patients in group A had smoother increases in oxygen uptake and core temperatures, greater cardiovascular stability as reflected by the rate-pressure product, and no visible shivering. We suggest that epidural meperidine given immediately at the end of a surgical procedure might be beneficial, especially, perhaps, in patients with impaired cardiac function.

The effects of norepinephrine infusion on oxygen consumption in a patient with septic shock.

A 65-year-old man developed postsurgical septic shock, unresponsive to plasma volume expansion and administration of dopamine and dobutamine. A continuous norepinephrine infusion was then started and the dose increased to 0.62 micrograms.kg-1.min-1 until the mean arterial pressure was 70 mmHg. Prior to and during the norepinephrine infusion, oxygen consumption was continuously measured with a mass spectrometer system. There was a parallel increase in mean arterial pressure and oxygen consumption (+ 35%). There was also an increase in cardiac index and oxygen delivery. Systemic vascular resistance was only transiently increased. In this case with septic shock, norepinephrine infusion improved hemodynamic variables with an associated increase in oxygen consumption.

[Measurement of gas exchange in anesthesia and during resuscitation: principles and applications]. / Mesure des échanges gazeux en anesthésie et en réanimation: principes de mesure et applications.

Pulmonary gas exchange measurements can be performed in ICU with commercially available devices. During open-circuit anaesthesia, measurement of VO2 and VCO2 requires the acquisition of fractional concentration of inspired and expired nitrogen, the appropriate calibration of sensors according to the use of anaesthetic gases and to take into account the unsteady state of nitrogen body stores after a change in FiN2. This technique can be readily used to measure energetic expenditure or to specific applications as oxygen cost of breathing, respiratory effects of parenteral nutrition or the metabolic effects of various anaesthetic procedures in man.