Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer.

Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in patients who received ≤1 line of therapy for advanced BTC was conducted after determination of the maximum tolerated dose in this Phase 1 trial. Patients received binimetinib 60 mg twice daily. The primary objectives were to characterize the safety profile and pharmacokinetics of binimetinib in advanced BTC. Secondary objectives included assessment of clinical efficacy, changes in weight and lean body mass, and pharmacodynamic effects. Tumor samples were assessed for mutations in relevant genes. Results Twenty-eight patients received binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea (54%) being most common. Two patients experienced grade 4 AEs, one generalized edema and the other pulmonary embolism. The pharmacokinetics in this patient population were consistent with those previously reported (Bendell JC et al., Br J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and two had objective responses (1 complete response, 1 partial response) per Response Evaluation Criteria in Solid Tumors and stable metabolic disease by positron emission tomography/computed tomography. Most patients (18/25; 72%) did not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation between mutation status and response. The average non-fluid weight gain was 1.3% for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the potential for binimetinib to promote muscle gain in patients with BTC.

Management of adverse events from the treatment of encorafenib plus cetuximab for patients with BRAF V600E-mutant metastatic colorectal cancer: insights from the BEACON CRC study.

Colorectal cancer is the second leading cause of cancer deaths worldwide, with a 5-year relative survival of 14% in patients with metastatic colorectal cancer (mCRC). Patients with BRAF V600E mutations, which occur in ∼10%-15% of patients with mCRC, have a poorer prognosis compared with those with wild-type BRAF tumours. The combination of the BRAF inhibitor encorafenib with the epidermal growth factor receptor inhibitor cetuximab currently represents the only chemotherapy-free targeted therapy approved in the USA and Europe for previously treated patients with BRAF V600E-mutated mCRC. As a class, BRAF inhibitors are associated with dermatologic, gastrointestinal, and renal events, as well as pyrexia and secondary skin malignancies. Adverse event (AE) profiles of specific BRAF inhibitors vary, however, and are affected by the specific agents given in combination. In patients with mCRC, commonly reported AEs of cetuximab monotherapy include infusion reactions and dermatologic toxicities. Data from the phase III BEACON CRC study indicate that the combination of encorafenib with cetuximab has a distinct safety profile. Here we review the most frequently reported AEs that occurred with this combination in BEACON CRC and best practices for managing and mitigating AEs that require more than standard supportive care.

Heat debt as an index for cold adaptation in men.

Several types of cold adaptation in men have been described in the literature (metabolic, insulative, hypothermic). The aim of this study is to show that the decrease of heat debt can be considered as a new index for cold adaptation. Ten male subjects were acclimated by water immersions (temperature 10-15 degrees C, 4 immersions/wk over 2 mo). Thermoregulatory responses before and after acclimation were tested by a standard cold test in a climatic chamber for 2 h at rest [dry bulb temperature (Tdb): 10 degrees C; relative humidity (rh): 25%]. After adaptation, four thermoregulatory modifications were observed: an increase in the delay for the onset of shivering (32.7 +/- 7.99 instead of 14.1 +/- 5.25 min); a decrease of body temperature levels for the onset of shivering [rectal temperature (Tre): 37.06 +/- 0.08 instead of 37.31 +/- 0.06 degrees C; mean skin temperature (Tsk): 24.83 +/- 0.56 instead of 26.86 +/- 0.46 degrees C; mean body temperature (Tb): 33.03 +/- 0.20 instead of 34.16 +/- 0.37 degrees C); a lower level of body temperatures in thermoneutrality (Tre = 37.16 +/- 0.08 instead of 37.39 +/- 0.06 degrees C; Tsk = 31.29 +/- 0.21 instead of 32.01 +/- 0.22 degrees C; Tb = 35.92 +/- 0.08 instead of 36.22 +/- 0.05 degrees C); a decrease of heat debt calculated from the difference between heat gains and heat losses (5.66 +/- 0.08 instead of 8.33 +/- 0.38 kJ/kg). The different types of cold adaptation observed are related to the physical characteristics of the subjects (percent body fat content) and the level of physical fitness (VO2max).(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of heat debt in the cold: partitional calorimetry vs. conventional methods.

Measurements of core temperature (Tc) at different sites produce on some occasions different cooling curves in cold-exposed humans, suggesting that the corresponding thermometric heat debts (HD) could be equally different when calculated by conventional methods [via the change in either Tc or mean body temperature (Tb)]. The present study also compared these thermometric HD values with the calorimetric HD obtained by partitional calorimetry (S). Nine subjects who showed similar initial but different final Tc [rectal (Tre) and auditory canal temperatures (Tac)] during nude cold exposure (2 h at 1 degrees C at rest) were used. Tc-derived HD corresponded to a heat gain of 12 +/- 21 kJ and an HD of 78 +/- 20 kJ with use of Tre and Tac, respectively, whereas the Tb-derived HD varied from 266 +/- 35 to less than or equal to 1,479 +/- 71 kJ with the use of various well-known Tb weighing coefficients. In contrast, S corresponded to 504 +/- 79 kJ, a level that could have been obtained only if the thermoneutral/cold Tb weighing coefficients had been 0.818/0.818 for Tre and 0.865/0.865 for Tac. The results demonstrate that calculation by conventional methods can markedly overestimate or underestimate HD. These differences could not be explained by the site chosen to represent Tc, inasmuch as about the same effect was observed with use of either Tre or Tac. It is concluded that the thermometric value of HD in the cold is not, at least under the present conditions, as accurate and reliable as S.

Thyroid hormone changes in a cold air environment after local cold acclimation.

Serum thyroid hormones (TH) and internal temperatures were investigated in 8 euthyroid men during a general standard cold air test (SCAT) (dry bulb temperature = 1 degree C, 2 h, nude, at rest) performed both before and after a local cold acclimation. Serum total thyroxin (TT4), total triiodothyronine (TT3), free thyroxin (FT4), free triiodothyronine (FT3), and thyrotropin (TSH) were studied during the SCT. The TH values were corrected following the plasmatic volume reduction (delta PV) calculated with Dill and Costill's formula. During SCAT, delta PV reached -9 to -11% (P < 0.05) without any effect of local cold acclimation. Slight TH changes were observed according to delta PV: TT4, TT3, and TSH increased during SCAT (P < 0.05) only before correction. FT4 and FT3 did not vary before correction but increased after correction (P < 0.05). After acclimation, a slightly decreased TT3 was observed both before and after correction (-18% and -11.7%, respectively; P < 0.05). Decreased internal temperatures after local cold acclimation suggested a hypothermic general cold adaptation. It was concluded that TH changes during SCAT differed if correction due to delta PV was applied and that the slight decrease in TT3 observed after local cold acclimation could suggest the presence of a "T3 polar syndrome."

Physical fitness and thermoregulatory reactions in a cold environment in men.

The relationship between the physical fitness level (maximal O2 consumption, VO2max) and thermoregulatory reactions was studied in 17 adult males submitted to an acute cold exposure. Standard cold tests were performed in nude subjects, lying for 2 h in a climatic chamber at three ambient air temperatures (10, 5, and 1 degrees C). The level of physical fitness conditioned the intensity of thermoregulatory reactions to cold. For all subjects, there was a direct relationship between physical fitness and 1) metabolic heat production, 2) level of mean skin temperature (Tsk), 3) level of skin conductance, and 4) level of Tsk at the onset of shivering. The predominance of thermogenic or insulative reactions depended on the intensity of the cold stress: insulative reactions were preferential at 10 degrees C, or even at 5 degrees C, whereas colder ambient temperature (1 degree C) triggered metabolic heat production abilities, which were closely related to the subject's physical fitness level. Fit subjects have more efficient thermoregulatory abilities against cold stress than unfit subjects, certainly because of an improved sensitivity of the thermoregulatory system.

Individuality of breathing patterns during hypoxia and exercise.

Breathing was recorded via a pulsed ultrasonic flowmeter in 11 healthy subjects, at rest and during steady-state exercise (at 50% of their maximal O2 consumption) at both sea level (200 m) and simulated altitude (4,500 m in a hypobaric chamber). The pattern of breathing was quantified breath by breath in terms of classical respiratory variables (tidal volume and inspiratory and expiratory times), and the shape of the entire airflow profile was quantified by harmonic analysis. Statistical tests were used to compare the within-individual with the between-individual variations. In comparing the sea level vs. altitude rest (16% increase in ventilation) and sea level vs. altitude exercise (40% increase in ventilation) airflow profiles, we found a significantly greater resemblance within the individual than between individuals. Comparisons of sea level rest and exercise (295% increase in ventilation) and altitude rest and exercise (375% increase in ventilation) revealed no similarity within individuals. Despite airflow profile changes between rest and exercise, it is still possible to attest to a diversity of flow profile between individuals during exercise. Hypoxia at rest or during exercise does not alter the phenomenon of the individuality of breathing patterns.

Multiple-dose, placebo-controlled, phase I study of oral dolasetron.

STUDY OBJECTIVES: To evaluate the safety, tolerability, and pharmacokinetics of increasing dose levels of oral dolasetron mesylate, a new 5-HT3 antagonist. DESIGN: Double-blind, placebo-controlled, dose-ranging phase I study. SETTING: A clinical research center. PATIENTS: Forty healthy male volunteers. INTERVENTIONS: Eight subjects at each dose level were randomized in a ratio of 3:1 to receive either dolasetron mesylate 25, 50, 100, 150, or 200 mg in a single oral dose on days 1 and 9, and twice/day on days 2-8, or placebo for 9 days. MEASUREMENTS AND MAIN RESULTS: Dolasetron was well tolerated at all dose levels. The adverse event rates for dolasetron- and placebo-treated subjects who experienced at least one adverse event were 80% and 50%, respectively. Most frequently reported by subjects receiving dolasetron were headache, constipation, flatulence, and lightheadedness. They generally were mild, and none was severe. No dose-response relationship was apparent for any adverse event. There were no clinically significant changes in mean laboratory values or vital signs. Asymptomatic treatment-related electrocardiographic changes were consistent with the drug's electrophysiologic properties. These changes have been well characterized and have thus far been clinically unimportant. Pharmacokinetics of the reduced metabolite were dose independent, and multiple-dose exposure of this metabolite can be predicted from its single-dose values. CONCLUSION: Oral dolasetron mesylate was well tolerated when administered in doses up to 200 mg/day for 9 days in healthy volunteers.

Determination of the velocity associated with VO2max.

PURPOSE: The theoretical velocity associated with VO2max (vVO2max) defined by Daniels (1985) is extrapolated from the submaximal VO2-velocity relationship. VO2 is generally determined by assuming that the aerobic response reacts like a linear first-order system at the beginning of square-wave exercise with a steady-state reached by the 4th minute. However, at supra-ventilatory threshold work rates, the steady state in VO2 is delayed or not attained. METHODS: The present study was carried out to compare three values for vVO2max determined with Daniels' method, but with VO2 either measured at the 4th minute (vVO2max4), the 6th minute (vVO2max6), or after the attainment of the true steady-state (vVO2maxSS). The metabolic response during square-wave exercise at each of the three vVO2max were also assessed. RESULTS: These velocities were significantly different (P < 0.05), but vVOmaxSS and vVO2max6 were highly correlated (r = 0.98; P < 0.05). Blood lactate concentrations measured after exercise at velocities very close to the three vVO2max were similar and the end-exercise VO2 were not different from VO2max, but the time required to elicit 95% VO2max during these three square-wave tests were significantly different. CONCLUSION: Therefore, when vVO2max is determined by extrapolation from the submaximal VO2-velocity relationships, submaximal VO2 should be measured beyond the 6th minute of square-wave exercise (at least if it takes 30 s to reach the desired velocity) to ensure that all vVO2max reported in future studies describe a similar quantitative index.

Influence of hyperthermia on cochlear micromechanical properties in humans.

We investigated the effect of body temperature on transient evoked otoacoustic emissions (TEOAEs) in humans. Hyperthermic conditions were obtained in adults in a climatic chamber. During hyperthermia up to an average temperature of 38.4 degrees C, significant falls were found in total amplitude and peak values of TEOAEs: by 1.3 dB SPL/degree C and 2.3 dB/degree C, respectively. This inhibition affected all spectrum components equally. These findings indicate that the outer hair cell micromechanical activity that is presumed to be measured by TEOAEs is not independent of variations in body temperature. The reduction found in hyperthermia suggests that temperature-dependent mechanisms are involved in the generation of TEOAEs.

Factors enhancing cardiac output in resting subjects during cold exposure in air environment.

Six young males, in semi-nude conditions, resting in dorsal reclining position, were exposed successively to a thermoneutral environment (30 min), a cold environment (1 degree C) (Cold) or thermoneutrality (Control) (120 min), and during 60 min recovery in thermoneutral conditions. Cardiac output has been measured using a Dual Beam Doppler. During cold stress a significant increase of heart rate (66.4 +/- 6.4 to 91.0 +/- 14.9 beats.min-1), systolic blood pressure (119.5 +/- 7.8 to 218.7 +/- 18.7 mmHg), diastolic blood pressure (68.1 +/- 11.7 to 114.3 +/- 28.3 mmHg) and cardiac output (5.42 +/- 0.96 to 8.08 +/- 1.28 l.min-1) were observed. On the contrary initial systolic aorta flow acceleration is significantly lowered (1130 +/- 120 to 840 +/- 170 cm.s-2). Systolic ejection volume remained unchanged throughout the whole experiment. Increase in cardiac output during cold air (1 degree C) exposure is thus only imputed to the higher heart rate partly due to hypersecretion of catecholamines. The diminution of the blood flow acceleration could be related to a lesser arterial compliance and/or to the cold induced hemoconcentration. Enhanced heart's mechanical work due to sympathetic stimulation, seems thus to be absorbed by the increase in the peripheral resistance.

Comparison of indirect calorimetry and direct heat flow discs results in measuring R+C heat loss in burned patients.

This study was carried out on 17 burned patients. Metabolic heat production, rectal and skin temperatures, and heat exchanges by R+C were measured. It was found that R+C heat loss takes into account 60 to 80% of the increased metabolic heat production. Two methods were used to measure R+C heat loss: calculation by indirect calorimetry and direct measurements by using heat flow discs. The direct relationship which exists between the results of these two methods showed the reliability of the use of heat flow discs for measuring R+C heat loss. This fast-responding techniques may allow the elaboration of a thermal setting system which could modulate ambient air temperature, thus limiting exagerated heat loss due to the skin lesions.

Thermal strain resulting from protective clothing of an armored vehicle crew in warm conditions.

The purpose of the study is to define a method of evaluation of physiological strain resulting from protective garments worn in warm conditions by the armored vehicle crew. A technique is developed evaluating evaporative transfer through clothing by continuous weighing of the active man (accuracy +/- 3/g). An index is defined (Iw) as the ratio of steady-state evaporating rate in clothed conditions to steady-state evaporation of nude subject in the same conditions of work and heat stress. The Iw index is significantly related to physiological strain determined by increased body heat content and reduced tolerance time. The results are compared to other previous findings concerning evaporative transfer through clothing and physiological strain indexes. The technique shows that evaporation through heavy clothing is not negligible. It is suggested that usual static measurements using physical models underestimate the evaporative heat transfer through clothing layers.

Are the laboratory and field conditions observations of acute mountain sickness related?

In order to study relationships between acute mountain sickness (AMS) observations done both during a short-term hypoxic exposure in a hypobaric chamber, and in field conditions during a high altitude expedition, nine subjects were submitted to a 9-h hypoxic exposure in a hypobaric chamber. Then, they experienced a high altitude expedition in the Himalayas. The Lake Louise AMS scoring system was used to assess AMS in both conditions, especially the self report questionnaire. During the expedition, the mean self report score of each subject, defined as the ratio between the sum of daily self report scores and the duration of the expedition, appears to be correlated not only to the maximal self report score observed in altitude (r = +0.77, p < 0.05) but also to the self report and self report+clinical assessment scores observed at the end of the hypobaric chamber sojourn (r = +0.81, p < 0.01 and r = +0.75, p < 0.05, respectively). In conclusion, the Lake Louise AMS scoring system, especially the self report questionnaire, is relevant to assess AMS with simplicity and rapidity both in laboratory and in field conditions. Our study also suggests that AMS induced by a short term sojourn in a hypobaric chamber is related to AMS observed in field conditions.

Cognitive performance during short acclimation to severe hypoxia.

BACKGROUND: Exposure to high altitudes requires acclimation or acclimatization, to prevent the negative effects of severe hypoxia. Among several methods, short acclimation with intermittent exposure to severe hypoxia in a hypobaric chamber triggers efficient physiological pre-adaptation mechanisms (11-13). However, we have little knowledge about the cognitive repercussions of such an acclimation protocol. METHODS: Four mountaineers were tested daily in the course of a short acclimation protocol (5 d). After their SaO2 (arterial oxyhemoglogin saturation) were recorded, they carried out a choice reaction time task (Manikin test) twice every day; first at ground level (250 m, control sessions), second at the highest altitude of the day (D1 = 5000 m, D2 = 5500 m, D3 = 6000 m, D4 = 6500 m, D5 = 7000 m). RESULTS: High altitude SaO2 level decreased during the first 3 d, then stabilized around 72-73%. Despite a slight and transient increase at the highest altitude relative to the ground level in D4, the error rate remained low throughout the protocol. Further, response time to the Manikin task did not show significant changes among the days during the acute stage of hypoxia relative to ground level up to 7000 m. CONCLUSIONS: On the whole, it seems that a short acclimation protocol based on intermittent exposure to simulated high altitudes triggered adaptive processes without major impairment in a choice reaction time task during the acute stages of severe hypoxia.

Evaluation of the Lake Louise acute mountain sickness scoring system in a hypobaric chamber.

This study evaluated the relevance of the Lake Louise acute mountain sickness (AMS) scoring system in comparison with other AMS scoring systems. To achieve this objective nine subjects were submitted to a 9-hr exposure to hypoxia in a hypobaric chamber (altitude 4500-5500 m) that led to the development of AMS. AMS was scored at the end of this exposure period both by questionnaires (Hackett AMS questionnaire, Lake Louise AMS self-report questionnaire, Environmental Symptoms Questionnaire ESQ II and ESQ IV) and by a clinical investigation following the Lake Louise AMS clinical and functional AMS assessment. The AMS scores were between 0 and 9 for the Hackett AMS score, 0 and 38 for the ESQ II AMS score, 0 and 13.7 for the ESQ IV AMS score, 0 and 10 for the Lake Louise AMS self-report, 0 and 2 for the Lake Louise AMS clinical assessment score, and between 0 and 2 for the Lake Louise functional score. All the AMS questionnaire scores were related to the clinical AMS assessment score (p < 0.05) without significant differences between them. The Lake Louise AMS self-report score appeared highly correlated to other AMS scoring systems (Hackett, ESQ II and ESQ IV) (p < 0.05). Suggestions were proposed to improve the sensitivity and the specificity of the Lake Louise AMS scoring questionnaire but also the Lake Louise AMS clinical assessment. In conclusion, this study suggests the relevance of the Lake Louise AMS self-report questionnaire to assess and score AMS with simplicity and rapidity.

Short hypobaric hypoxia and breathing pattern: effect of positive end expiratory pressure.

The ventilatory effects of a 5-cm H2O positive end expiratory pressure (PEEP) and its influence on the breathing pattern during short hypoxic exposure both at rest and during physical exercise were studied. There were 22 healthy subjects who were submitted to normoxia and to 4-h of hypoxia in a hypobaric chamber (4500 m, PB = 589 hPa) both at rest and during an 8-min cycle ergometer exercise (100 W) without and with a 5 cm H2O PEEP. The results show that hypoxia compared with normoxia induces increases in tidal volume (VT) (+28.5%, p < 0.05 at rest; and +19.4%, p < 0.01 at 100 W) and in respiratory frequency (f) at 100 W (p < 0.05), and significant decreases in inspiratory (tI) (p < 0.05 at rest and at 100 W), and expiratory (tE) durations (p < 0.05 at 100 W). However, the breathing pattern expressed as duty cycle (tI/tt) is unchanged, whereas an increased mean inspiratory flow (VT/tI) is observed (p < 0.01 at rest and at 100 W). This study also demonstrates that PEEP during a 4-h hypobaric hypoxia significantly increases VT (+22.2% p < 0.01 at rest, +8.9% p < 0.05 at 100 W), tI, and tE at rest (p < 0.05), but not during exercise and tends to decrease f (p = 0.06 at rest and at 100 W). However, PEEP does not alter the breathing pattern in hypoxia since VT/tI and tI/tt are unchanged. Heart rate and arterial O2 saturation are also unaffected by PEEP. In conclusion, this study shows that a 4-h hypoxia modifies ventilatory parameters and mean inspiratory flow (VT/tI) at rest and during exercise (100 W), whereas a 5-cm H2O PEEP does not alter the breathing pattern despite changes in ventilatory parameters are observed.

Positive end expiratory pressure (PEEP) slightly modifies ventilatory response during incremental exercise.

To clarify the ventilatory effects of a 5-cm H2O positive end expiratory pressure (PEEP) in healthy men during incremental exercise in normoxic conditions, 22 subjects were subjected to a constant workload (0 W, 50 W, 100 W, 150 W and 200 W) on a cycle ergometer for periods of 8 min each, both with and without 5-cm H2O PEEP. Results show that PEEP increases inspiratory (TI) and expiratory (TE) duration and tidal volume (VT) and decreases breathing frequency (fB) at rest (p < 0.05). During exercise, TI is higher at 50 W and 100 W (p < 0.05), but not at 150 and 200 W. TE only increases at 50 W (p < 0.05). An increased VT (p < 0.05 at 50, 100 and 150 W) and a decreased fB (p < 0.05 throughout the experiment) were observed. However, mean inspiratory flow (VT/T1) and duty cycle (TI/TT) were unaffected by PEEP. In conclusion, this study shows that a 5-cm H2O PEEP slightly modifies the ventilatory parameters in healthy subjects during incremental exercise in normoxic conditions.

[Circadian analysis of sleep, rectal temperature and immunological and endocrinological variables in sleeping sickness: preliminary study]. / Analyse circadienne du sommeil, de la température rectale et de variables immunologiques et endocrinologiques dans la maladie du sommeil: etude préliminaire.

A multidisciplinary study was conducted in 8 patients with neurological Human African Trypanosomiasis. The sleep-wake cycle followed an ultradian pattern which was more pronounced in patients with more severe symptoms. The EEG trace was consistently interrupted by numerous cyclic activation patterns with K complexes, rapid low amplitude elements and slow high voltage elements. Circadian rhythmicity was also disturbed in other physiological (rectal temperature), immunological (interleukins) or hormonal (cortisol, prolactin) variables, the disturbance being greater in severely hit patients.

[Travelers exposed to extreme temperatures]. / Les voyageurs exposés aux températures extrêmes.

Sudden introduction of the unadapted human into extreme environments can result in serious, sometimes fatal, reactions. Most complications are due either to failure of thermoregulatory system or consecutive to the physiological responses to those environmental conditions. In addition to a number of minor diseases, cold can cause two major accidents, i.e., hypothermia and frostbite which can be enhanced at altitude. Moreover, the main disease in altitude conditions is represented by the acute mountain sickness which can lead to acute pulmonary and cerebral edema. Heat can cause heatstroke, dehydration, syncope, and other minor disorders. Prevention of these manifestations during stays in inhospitable climatic conditions for which the body is not suited requires knowledge of the environment and its dangers. Implementation of suitable measures can greatly reduces the incidence of adverse effects.