Neuromuscular Adaptations in Endurance-Trained Male Adolescents Versus Untrained Peers: A 9-Month Longitudinal Study.

BACKGROUND: Neuromuscular function is considered as a determinant factor of endurance performance during adulthood. However, whether endurance training triggers further neuromuscular adaptations exceeding those of growth and maturation alone over the rapid adolescent growth period is yet to be determined. OBJECTIVE: The present study investigated the concurrent role of growth, maturation, and endurance training on neuromuscular function through a 9-month training period in adolescent triathletes. METHODS: Thirty-eight 13- to 15-year-old males (23 triathletes [~6 h/week endurance training] and 15 untrained [<2 h/week endurance activity]) were evaluated before and after a 9-month triathlon training season. Maximal oxygen uptake (V̇O2max) and power at V̇O2max were assessed during incremental cycling. Knee extensor maximal voluntary isometric contraction torque (MVCISO) was measured and the voluntary activation level (VAL) was determined using the twitch interpolation technique. Knee extensor doublet peak torque (T100Hz) and normalized vastus lateralis (VL) electromyographic activity (EMG/M-wave) were also determined. VL and rectus femoris (RF) muscle architecture was assessed using ultrasonography. RESULTS: Absolute V̇O2max increased similarly in both groups but power at V̇O2max only significantly increased in triathletes (+13.8%). MVCISO (+14.4%), VL (+4.4%), and RF (+15.8%) muscle thicknesses and RF pennation angle (+22.1%) increased over the 9-month period in both groups similarly (p < 0.01), although no changes were observed in T100Hz, VAL, or VL EMG/M-wave. No changes were detected in any neuromuscular variables, except for coactivation. CONCLUSION: Endurance training did not induce detectible, additional neuromuscular adaptations. However, the training-specific cycling power improvement in triathletes may reflect continued skill enhancement over the training period.

Can neuromuscular differences manifest by early adolescence in males between predominantly endurance and strength sports?

INTRODUCTION: Although neuromuscular function varies significantly between strength and endurance-trained adult athletes, it has yet to be ascertained whether such differences manifest by early adolescence. The aim of the present study was to compare knee extensor neuromuscular characteristics between adolescent athletes who are representative of strength (wrestling) or endurance (triathlon) sports. METHODS: Twenty-three triathletes (TRI), 12 wrestlers (WRE) and 12 untrained (CON) male adolescents aged 13 to 15 years participated in the present study. Maximal voluntary isometric contraction (MVIC) knee extensor (KE) torque was measured, and 100-Hz magnetic doublets were delivered to the femoral nerve during and after KE MVIC to quantify the voluntary activation level (%VA). The doublet peak torque (T100Hz) and normalized vastus lateralis (VL) and rectus femoris (RF) EMG (EMG/M-wave) activities were quantified. VL and RF muscle architecture was also assessed at rest using ultrasound. RESULTS: Absolute and relative (to body mass) KE MVIC torques were significantly higher in WRE than TRI and CON (p < 0.05), but comparable between TRI and CON. No significant differences were observed between groups for %VA, T100Hz or either VL or RF muscle thickness. However, VL EMG/M-wave was higher, RF fascicle length longer, and pennation angle smaller in WRE than TRI and CON (all p < 0.05). CONCLUSION: The wrestlers were stronger than triathletes and controls, potentially as a result of muscle architectural differences and a greater neural activation. Neuromuscular differences can already be detected by early adolescence in males between predominantly endurance and strength sports, which may result from selection bias and/or physical training.

Effects of a Cycling versus Running HIIT Program on Fat Mass Loss and Gut Microbiota Composition in Men with Overweight/Obesity.

PURPOSE: High-intensity interval training (HIIT) can efficiently decrease total and (intra-)abdominal fat mass (FM); however, the effects of running versus cycling HIIT programs on FM reduction have not been compared yet. In addition, the link between HIIT-induced FM reduction and gut microbiota must be better investigated. The aim of this study was to compare the effects of two 12-wk HIIT isoenergetic programs (cycling vs running) on body composition and fecal microbiota composition in nondieting men with overweight or obesity. METHODS: Sixteen men (age, 54.2 ± 9.6 yr; body mass index, 29.9 ± 2.3 kg·m -2 ) were randomly assigned to the HIIT-BIKE (10 × 45 s at 80%-85% of maximal heart rate, 90-s active recovery) or HIIT-RUN (9 × 45 s at 80%-85% of maximal heart rate, 90-s active recovery) group (3 times per week). Dual-energy x-ray absorptiometry was used to determine body composition. Preintervention and postintervention fecal microbiota composition was analyzed by 16S rRNA gene sequencing, and diet was controlled. RESULTS: Overall, body weight, and abdominal and visceral FM decreased over time ( P < 0.05). No difference was observed for weight, total body FM, and visceral FM between groups (% change). Conversely, abdominal FM loss was greater in the HIIT-RUN group (-16.1% vs -8.3%; P = 0.050). The α-diversity of gut microbiota did not vary between baseline and intervention end and between groups, but was associated with abdominal FM change ( r = -0.6; P = 0.02). The baseline microbiota profile and composition changes were correlated with total and abdominal/visceral FM losses. CONCLUSIONS: Both cycling and running isoenergetic HIIT programs improved body composition in men with overweight/obesity. Baseline intestinal microbiota composition and its postintervention variations were correlated with FM reduction, strengthening the possible link between these parameters. The mechanisms underlying the greater abdominal FM loss in the HIIT-RUN group require additional investigations.

A long-duration race induces a decrease of left ventricular strains, twisting mechanics and myocardial work in trained adolescents.

We investigated the acute cardiac consequences of a long-duration (>5 h) adventure race in adolescent athletes from evaluations of left ventricular (LV) strains and myocardial work. Twenty trained male adolescents (i.e. 8 ± 4 h·week-1 of endurance sports) aged 14-17 years participated in a competitive long-duration adventure race. Blood samples were collected before, immediately and 24 h after the race to determine the time course of troponin I (cTnI) considered a myocardial damage biomarker. Resting echocardiography was conducted before and after the race to assess myocardial regional strains, LV twisting mechanics and myocardial work using speckle tracking echocardiography. The mean completion time of the race was 05:38 ± 00:20 h, with a mean heart rate (HR) of 83 ± 5% of maximal HR. cTnI concentration significantly increased in 16/20 participants after the race (pre: 0.001 ± 0.002 vs. post: 0.244 ± 0.203 ng·dL-1, p < .001) and returned to baseline within 24 h. Stroke volume, ejection fraction and global longitudinal strains remained unchanged after the race, while LV twist and global myocardial work significantly decreased (8.6 ± 3.3 vs. 6.3 ± 3.3 deg and 2080 ± 250 vs. 1781 ± 334 mmHg%, p < .05). Diastolic function, indexes of myocardial relaxation and LV untwisting rate (-91.0 ± 19.0 vs. -56.4 ± 29.1 deg·s-1, p < .001) were affected after the race. We demonstrated that in trained adolescents, a high-intensity endurance exercise of several hours induced an increase of the cTnI concentration associated with an alteration of myocardial function.HighlightsThis is the first study to explore the acute cardiac consequences of a very-long duration and high-intensity race in trained adolescentsThe cardiac evaluations before and immediately after the race were conducted using up-to-date advances in echocardiography, including not only regional left ventricular strains, rotations and twists, but also global myocardial work to consider changes in loading conditions that occur after such exercises.We observed exercise-induced cardiac fatigue in the adolescents, characterized by a drop in myocardial work, associated with an increase of cardiac troponin I in 16/20 participants.The cardiac alterations were principally observed at the apical level of the heart: the apical strains and rotations were decreased and delayed. Consequently, left ventricular twist and twisting rates were also delayed, which probably affected the diastolic function after the race.

Impact of long-duration adventure racing on hydration status, blood electrolytes and biomarkers of kidney function in trained adolescent athletes.

BACKGROUND: Little is known about the biochemical consequences of endurance activities in adolescents. The present study aimed to examine the impact of a long-duration adventure race (>5 h) on hydration status, blood electrolytes and biomarkers of kidney function in adolescent athletes. METHODS: Twenty male adolescents aged 14 to 17 y (mean±SD; body mass: 59.7±9.1 kg and maximal O2 uptake: 56.2±4.6 mL∙kg-1∙min-1) volunteered to participate in a competitive adventure race of 68.5 km. Volunteers could drink ad libitum and fluid intake was monitored throughout the race. Blood samples were collected before, within 15 minutes after, and 24 hours after the race to monitor blood electrolytes (sodium, potassium, chloride), creatinine and blood urea nitrogen (BUN). Body mass and urine specific gravity (USG) were also measured across the same time points. RESULTS: The race was completed on average in 05:38±00:20 h:min under cold and rainy conditions (10-15 °C and 83-93% of relative humidity). Fluid intake was 1.45±0.66 L and body mass decreased by 1.2% compared to before the race (P<0.001). Blood sodium concentrations remained stable after the race (140.4±2.1 mmol∙L-1) despite an expansion in the plasma volume of 8.9±15.6%. No significant variations in BUN or BUN-to-creatinine ratio occurred. A significant increase in creatinine (+13.5%, P=0.003) was observed immediately after the race but remained within the reference range. CONCLUSIONS: The long-duration race completed under cold and humid conditions seems not to have exposed adolescents to hypohydration, hyponatremia or clinically significant alterations in kidney function.

Effect of Concurrent Training on Body Composition and Gut Microbiota in Postmenopausal Women with Overweight or Obesity.

PURPOSE: Menopause tends to be associated with an increased risk of obesity and abdominal fat mass (FM) and is associated with lower intestinal species diversity. The aim of this study was to determine the effects of a high-intensity interval training and resistance training (HIIT + RT) program on body composition and intestinal microbiota composition in overweight or obese postmenopausal women. METHODS: Participants (n = 17) were randomized in two groups: HIIT + RT group (3× per week, 12 wk) and control group without any training. Dual-energy x-ray absorptiometry was used to measure whole-body and abdominal/visceral FM and fat-free mass. Intestinal microbiota composition was determined by 16S rRNA gene sequencing at baseline and at the study end, and the diet was controlled. RESULTS: Compared with sedentary controls, physical fitness (maximal oxygen consumption, peak power output) increased, total abdominal and visceral FM decreased, and segmental muscle mass increased in the training group. Although the HIIT + RT protocol did not modify α-diversity and taxonomy, it significantly influenced microbiota composition. Moreover, various intestinal microbiota members were correlated with HIIT + RT-induced body composition changes, and baseline microbiota composition predicted the response to the HIIT + RT program. CONCLUSIONS: HIIT + RT is an effective modality to reduce abdominal/visceral FM and improve physical capacity in nondieting overweight or obese postmenopausal women. Training modified intestinal microbiota composition, and the response to training seems to depend on the initial microbiota profile. More studies are needed to determine whether microbiota composition could predict the individual training response.

Changes in Pulmonary Function After Long-duration Adventure Racing in Adolescent Athletes.

The present study investigated the acute effects of a mixed-modality, long-duration adventure race on pulmonary function in adolescent athletes. Twenty male adolescents aged 14 to 17 years volunteered to participate in a wilderness adventure race of 68.5-km. Expiratory function was evaluated before, immediately after, and 24 h after race completion. Measurements included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and peak expiratory flow (PEF). Maximal inspiratory and expiratory mouth static pressures (MIP and MEP, respectively) were also measured using a portable hand-held mouth pressure meter across the same time points. The mean completion time of the race was 05:38±00:20 hours. A significant post-race decrease in FVC was observed immediately after the race (-5.2%, p=0.01). However, no significant changes were observed for FEV1, PEF and the FEV1/FVC and FEV1/PEF ratios. In addition, estimates of respiratory muscle strength (MIP and MEP) were unaffected by the race. The long-duration adventure race induced no marked reduction in expiratory pulmonary function and this response was associated with no apparent respiratory muscle fatigue. Therefore, the pulmonary system of trained adolescent athletes was sufficiently robust to sustain the mixed-modality, long-duration adventure race of ~ 5-6 h.

Neuromuscular Fatigue After Long-Duration Adventure Racing in Adolescent Athletes.

PURPOSE: To characterize the acute effects of a long-duration adventure race on knee extensor (KE) fatigue and the knee functional ratio in adolescent athletes. METHODS: Twenty trained male adolescents (aged 14-17 y) performed an adventure race of 68.5 km. Maximal voluntary isometric contraction (MVIC) KE and knee flexor torques were measured before and immediately after the race. Central and peripheral components of neuromuscular fatigue were quantified from the maximal voluntary activation level and the doublet peak torque (Tw100), respectively. The peak eccentric knee flexor torque to concentric KE torque ratio was also measured to determine functional ratio. RESULTS: The race completion time was 05:38 (00:20) hours. Significant reductions in MVICKE (-14.7%, P < .001) and MVICKF (-17.0%, P < .01) were observed after the race. Voluntary activation level decreased by 8.3% (P < .001) while Tw100 remained unchanged. Peak eccentric knee flexor torque decreased 16.0% (P < .001) while peak concentric KE torque did not change. This resulted in a significant reduction in functional ratio (-12.0%, P < .01). CONCLUSION: The adventure race induced a moderate fatigue, which was mainly explained by central factors without significant peripheral fatigue. However, particular attention should be paid to the knee muscular imbalance incurred by the race, which could increase the risk of ligament injury in adolescent athletes.

Acute metabolic responses after continuous or interval exercise in post-menopausal women with overweight or obesity.

This pilot study compared the effects of acute high-intensity intermittent exercise (HIIE) and moderate-intensity continuous exercise (MICE) on post-exercise VO2 , fat utilization, and 24-hours energy balance to understand the mechanism of higher fat mass reduction observed after high-intensity interval training in post-menopausal women with overweight/obesity. 12 fasted women (59.5 ± 5.8 years; BMI: 28.9 ± 3.9 kg·m-2 ) completed three isoenergetic cycling exercise sessions in a counterbalanced, randomized order: (a) MICE [35 minutes at 60%-65% of peak heart rate, HRmax ], (b) HIIE 1 [60 × (8-s cycling-12-s recovery) at 80%-90% of HRmax ], and (c) HIIE 2 [10 × 1min at 80%-90% of HRmax  - 1-min recovery]. Then, VO2 and fat utilization measured at rest and during the 2 hours post-exercise, enjoyment, perceived exertion, and appetite recorded during the session and energy intake (EI) and energy expenditure (EE) assessed over the next 24 hours were compared for the three modalities. Overall, fat utilization increased after exercise. No modality effect or time-modality interaction was observed concerning VO2 and fat oxidation rate during the 2 hours post-exercise. The two exercise modalities did not induce specific EI and EE adaptations, but perceived appetite scores at 1 hour post-exercise were lower after HIIE 1 and HIIE 2 than MICE. Perceived exertion was higher during HIIE 1 and HIIE 2 than MICE, but enjoyment did not differ among modalities. The acute HIIE responses did not allow explaining the greater fat mass loss observed after regular high-intensity interval training in post-menopausal women with overweight/obesity. More studies are needed to understand the mechanisms involved in such adaptations.

Moderate-Intensity Continuous Training or High-Intensity Interval Training with or without Resistance Training for Altering Body Composition in Postmenopausal Women.

PURPOSE: This study aimed to compare body composition changes induced by moderate-intensity continuous training (MICT), high-intensity interval training (HIIT), or HIIT + resistance training (RT) programs (3 d·wk, 12 wk) in overweight/obese postmenopausal women, and to determine whether fat mass reduction is related to greater fat oxidation (FatOx). METHODS: Participants (n = 27) were randomized in three groups: MICT (40 min at 55%-60% of peak power output), HIIT (60 × 8 s at 80%-90% of peak HR, 12 s active recovery), and HIIT + RT (HIIT + 8 whole-body exercises: 1 set of 8-12 repetitions). Dual-energy x-ray absorptiometry was used to measure whole-body and abdominal/visceral fat mass (FM) and fat-free mass. FatOx was determined at rest, during a moderate-intensity exercise (40 min at 50% of peak power output), and for 20 min postexercise, before and after training. RESULTS: Overall, energy intake and physical activity levels did not vary from the beginning to the end of the intervention. Body weight and total FM decreased in all groups over time, but significant abdominal/visceral FM losses were observed only in HIIT and HIIT + RT groups. When expressed in percentage, total FM, fat-free mass, and muscle mass were significantly modified only by HIIT + RT training. FatOx did not change at rest but increased similarly in the three groups during and after exercise. Therefore, the HIIT-induced greater FM loss was not related to higher FatOx during or after exercise. CONCLUSIONS: MICT or HIIT ± RT could be proposed to nondieting postmenopausal women who are overweight/obese to decrease weight and whole-body FM. The HIIT programs were more effective than MICT in reducing abdominal/visceral FM. RT addition did not potentiate this effect but increased the percentage of muscle mass.

Immune gene expression in head and neck squamous cell carcinoma patients.

BACKGROUND: Nivolumab and pembrolizumab targeting programmed cell death protein 1 (PD-1) have recently been approved among patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) who failed platinum therapy. We aimed to evaluate the prognostic value of selected immune gene expression in HNSCC. PATIENTS AND METHODS: We retrospectively assessed the expression of 46 immune-related genes and immune-cell subpopulation genes including immune checkpoints by real-time polymerase chain reaction among 96 patients with HNSCC who underwent primary surgery at Institut Curie between 1990 and 2006. Univariate and multivariate analyses were performed to assess the prognostic value of dysregulated genes. RESULTS: The Median age of the population was 56 years [range: 35-78]. Primary tumour location was oral cavity (45%), oropharynx (21%), larynx (18%) and hypopharynx (17%). Twelve patients (13%) had an oropharyngeal human papillomavirus-positive tumour. Most significantly overexpressed immune-related genes were TNFRSF9/4-1BB (77%), IDO1 (75%), TNFSF4/OX40L (74%) and TNFRSF18/GITR (74%), and immune-cell subpopulation gene was FOXP3 (62%). Eighty-five percent of tumours analysed overexpressed actionable immunity genes, including PD-1/PD-L1, TIGIT, OX40/OX40L and/or CTLA4. Among the immune-related genes, high OX40L mRNA level (p = 0.0009) and low PD-1 mRNA level (p = 0.004) were associated with the highest risk of recurrence. Among the immune-cell subpopulation genes, patients with high PDGFRB mRNA level (p < 0.0001) and low CD3E (p = 0.0009) or CD8A mRNA levels (p = 0.004) were also at the highest risk of recurrence. CONCLUSIONS: OX40L and PDGFRB overexpression was associated with poor outcomes, whereas PD-1 overexpression was associated with good prognosis in patients with HNSCC treated with primary surgery, suggesting their relevance as potential prognostic biomarkers and major therapeutic targets.

Comparative Analysis of Durable Responses on Immune Checkpoint Inhibitors Versus Other Systemic Therapies: A Pooled Analysis of Phase III Trials.

PURPOSE: Immune checkpoint inhibitors (ICIs) have been demonstrated to improve overall survival (OS) in several tumor types. Durable responses have been reported with these agents in patients with melanoma and lung cancer. We aimed to quantify the proportion of patients who experience durable responses on ICIs and to compare it with other drug classes. PATIENTS AND METHODS: We retrieved published phase III randomized trials that included at least one ICI arm in the recurrent and/or metastatic setting. A durable response to treatment was defined as a progression-free survival that exceeded three times the median progression-free survival of the whole population. The proportion of patients who experienced an OS that exceeded two times the median OS of the whole patient population also was estimated. RESULTS: Nineteen studies involving 11,640 patients treated in 42 treatment arms (26 ICI and 16 non-ICI arms) were included. The mean proportion of patients who experienced a durable response was 2.3 times higher in those treated with an ICI compared with those treated in the control arms (25% v 11%). Durable responses were more frequent in patients treated with anti-PD-1/PD-L1 agents than in patients treated with anti-CTLA-4 agents (28% v 18%). The mean proportion of patients who had an OS that exceeded two times the median OS was also higher in those treated with ICIs than in those treated in the control arms (30% v 23%). In multivariable analysis, the effects of treatment with anti-PD-1/PD-L1 agents and of first-line treatment were statistically associated with a higher mean proportion of durable responses. CONCLUSION: Durable responses were more frequent in patients treated with ICIs, although they also occurred in patients treated with other drug classes.

Short-term pain evolution in chronic low back pain with Modic type 1 changes treated by a lumbar rigid brace: A retrospective study.

BACKGROUND: Blocking the lumbar or lumbosacral spine with a custom-made rigid lumbar brace, based on the mechanical origin of active discopathy, is a therapeutic option for low back pain, but no study has yet defined its applicability in low back pain. OBJECTIVE: To assess the pain evolution of individuals with non-specific chronic low back pain associated with Modic type 1 changes treated with custom-made rigid lumbar brace. METHODS: This was a retrospective observational study conducted in the Physical Medicine and Rehabilitation unit at Clermont-Ferrand University Hospital, France, between January 2014 and December 2016. Inclusion criteria were adults with non-specific chronic low back pain associated with Modic type 1 changes on the lumbar or lumbosacral spine confirmed by MRI. Patients had 4 consultations with the physician (baseline, 5 weeks, 3 months, and 5 months). The brace was progressively withdrawn at 3 months. The main outcome was pain improvement of at least 30% at 3 months (visual pain scale). The secondary outcome was an improvement of at least 50%. We also studied the association between pain improvement at the 2 thresholds (30 and 50%) and clinical data, level of Modic type 1 changes, and pain recurrence after withdrawal of the brace. RESULTS: Among the 174 patients who wore the brace, 62 were included in the study; 49/62 (79%) showed improvement of at least 30% at 3 months. Two months after brace withdrawal, pain recurred for 30/46 patients (16 missing data). No sociodemographic, clinical or radiographic criteria were associated with pain evolution. CONCLUSION: In the present study, a rigid lumbar brace worn for 3 months was associated with a 30% reduction in pain for 79% of patients with chronic low back pain and active discopathy. However, the retrospective open and uncontrolled design of our study limits our interpretation about a specific treatment effect. A prospective randomized controlled trial is needed to clarify the effect of a rigid lumbar brace in this condition.

Walking Speed Is Correlated With the Isokinetic Muscular Strength of the Knee in Patients With Charcot-Marie-Tooth Type 1A.

Charcot-Marie-Tooth disease type 1A is the most common hereditary neuropathy. Affected individuals have a distal motor deficit, initially affecting the lower limbs and impairing walking performance. Isokinetic dynamometry can be used to objectively assess muscle strength of patients with neuromuscular disorders. No studies have evaluated the effect of muscle strength deficits of knee extensors and flexors on walking parameters for patients with Charcot-Marie-Tooth disease type 1A. The purpose of this study was to determine correlations between the isokinetic muscular strength of knee flexors and knee extensors and walk parameters for patients with Charcot-Marie-Tooth disease type 1A. isokinetic muscular strength of the knee was assessed on an isokinetic dynamometer (Cybex) and walking by instrumented walkway analysis (GaitRite). We included 33 patients (23 females, mean ± SD age 46.7 ± 13.3 yrs, mean ± SD body mass index 25.7 ± 4.6 kg/m). We found a correlation between walking speed and isokinetic muscular strength of knee extensors for the entire population and between walking speed and isokinetic muscular strength of knee extensors and knee flexors for patients younger than 50 yrs. Isokinetic dynamometry can provide objective measures of knee muscle strength, which is correlated with walking speed but not cadence or step/stride length of patients with Charcot-Marie-Tooth disease.

Relevance of a molecular tumour board (MTB) for patients' enrolment in clinical trials: experience of the Institut Curie.

BACKGROUND: High throughput molecular screening techniques allow the identification of multiple molecular alterations, some of which are actionable and can be targeted by molecularly targeted agents (MTA). We aimed at evaluating the relevance of using this approach in the frame of Institut Curie Molecular Tumor Board (MTB) to guide patients with cancer to clinical trials with MTAs. PATIENTS AND METHODS: We included all patients presented at Institut Curie MTB from 4 October 2014 to 31 October 2017. The following information was extracted from the chart: decision to perform tumour profiling, types of molecular analyses, samples used, molecular alterations identified and those which are actionable, and inclusion in a clinical trial with matched MTA. RESULTS: 736 patients were presented at the MTB. Molecular analyses were performed in 442 patients (60%). Techniques used included next-generation sequencing, comparative genomic hybridisation array and/or other techniques including immunohistochemistry in 78%, 51% and 58% of patients, respectively. Analyses were performed on a fresh frozen biopsy in 91 patients (21%), on archival tissue (fixed or frozen) in 326 patients (74%) and on both archival and fresh frozen biopsy in 25 patients (6%). At least one molecular alteration was identified in 280 analysed patients (63%). An actionable molecular alteration was identified in 207 analysed patients (47%). Forty-five analysed patients (10%) were enrolled in a clinical trial with matched MTA and 29 additional patients were oriented and included in a clinical trial based on a molecular alteration identified prior to the MTB analysis. Median time between date of specimen reception and molecular results was 28 days (range: 5-168). CONCLUSIONS: The implementation of an MTB at Institut Curie enabled the inclusion of 10% of patients into a clinical trial with matched therapy.

Revisited analysis of a SHIVA01 trial cohort using functional mutational analyses successfully predicted treatment outcome.

It still remains to be demonstrated that using molecular profiling to guide therapy improves patient outcome in oncology. Classification of somatic variants is not straightforward, rendering treatment decisions based on variants with unknown significance (VUS) hard to implement. The oncogenic activity of VUS and mutations identified in 12 patients treated with molecularly targeted agents (MTAs) in the frame of SHIVA01 trial was assessed using Functional Annotation for Cancer Treatment (FACT). MTA response prediction was measured in vitro, blinded to the actual clinical trial results, and survival predictions according to FACT were correlated with the actual PFS of SHIVA01 patients. Patients with positive prediction had a median PFS of 5.8 months versus 1.7 months in patients with negative prediction (P < 0.05). Our results highlight the role of the functional interpretation of molecular profiles to predict MTA response.

Exploitation of Precision Medicine Trials Data: Examples of Long Responders From the SHIVA01 Trial.

PURPOSE: Precision medicine trials constitute a precious source of molecular data with prospective clinical annotations allowing the exploration of patients' subpopulations according to specific clinical or biological questions. Using the SHIVA01-the first randomized trial comparing molecularly targeted therapy on the basis of tumor molecular profiling versus conventional chemotherapy in metastatic cancer patients who failed standard of care therapy-annotated database, we report cases of patients treated in the trial with targeted therapy who experienced an objective response or prolonged disease stabilization in light of patients' molecular alterations. PATIENTS AND METHODS: We selected all patients included in SHIVA01 treated with a molecularly targeted agent (MTA) who experienced an objective response or disease stabilization that lasted longer than 6 months according to Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Among the 170 patients who received MTAs in the SHIVA01 trial, 15 patients (9%) experienced an objective response (n = 3) or disease stabilization that lasted longer than 6 months (n = 12). The most frequent histologic subtypes were breast cancer (27%) and cervical cancer (20%). Six patients, including three patients with breast cancer, were treated with abiraterone on the basis of androgen receptor protein overexpression. Five patients were treated with everolimus on the basis of a PTEN heterozygous deletion with loss of protein expression, PIK3CA mutation, or both alterations. The remaining four patients were treated with tamoxifen, erlotinib, imatinib, and vemurafenib on the basis of progesterone receptor expression, EGFR amplification, KIT mutation, and BRAF mutation, respectively. TP53 mutations were absent in responder patients. CONCLUSION: Analysis of patients who experienced objective responses or disease stabilization that lasted longer than 6 months allowed the identification of potential biomarkers of sensitivity and resistance to MTAs.

Efficacy of two injection-site localisation techniques for botulinum toxin injections: a single-blind, crossover, randomised trial protocol among adults with hemiplegia due to stroke.

INTRODUCTION: Botulinum toxin injections are an effective treatment for limb spasticity following stroke. Different tracking techniques are used for this purpose: palpation, electrostimulation, electromyography and ultrasound. Yet very few studies have compared these different techniques, and none has successfully proved the superior efficacy of ultrasound-guided injections compared to another tracking method. The primary objective of our study was therefore to compare the efficacy of botulinum toxin injections depending on the tracking technique used: ultrasound versus electrostimulation. METHODS AND ANALYSIS: This is a clinical, single-centre, prospective, interventional, single-blind, crossover, randomised trial. In total, 30 patients aged between 18 and 80 years presenting with triceps surae spasticity (evaluated >1 on the modified Ashworth scale) associated with hemiplegia sequelae due to stroke will be included. The patients will be selected among those who attend for consultation the Physical Medicine and Rehabilitation Department of the Clermont-Ferrand University Hospital. One group will receive the abobotulinumtoxinA (BoNT-A) injection guided by electrostimulation then ultrasound, and the second group's botulinum toxin injections will be guided by ultrasound then electrostimulation. For each patient, the duration of study participation is 5 months. The primary end point is variation in passive ankle dorsiflexion range of motion at slow and high speeds (Tardieu scale) with the knee straight. ETHICS AND DISSEMINATION: This study received ethics approval form the CPP of Rhônes-Alpes region. Results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT01935544; pre-results.

Effect of muscle length on voluntary activation of the plantar flexors in boys and men.

PURPOSE: The aim of the present study was to compare the effect of muscle length on the maximal voluntary activation level (VA) of the plantar-flexors between children and adults. METHODS: Fourteen boys (10.0 ± 1.0 years) and fifteen men (24.6 ± 4.2 years) performed 5-s maximal isometric voluntary contractions (MVC) of the plantar-flexor muscles at seven ankle angles [from 10° in dorsi-flexion (DF) to 20° in plantar-flexion (PF); 0° = reference position; the angle between the plantar surface and leg is a right angle]. Single magnetic stimulations were delivered to the posterior tibial nerve during MVCs to determine VA. RESULTS: Results showed a higher absolute torque of the plantar-flexor muscles at long (10° DF) than at short muscle length (20° PF) in men (89.4 ± 19.4 vs. 46.8 ± 17.0 N m, P < 0.001) and boys (44.9 ± 18.5 vs. 26.6 ± 12.8 N m, P < 0.001). On average, VA was significantly higher in men than in boys (92.4 ± 1.7 vs. 87.6 ± 1.6 %, P < 0.05). However, no significant main effect of the ankle angle was observed on VA. CONCLUSIONS: The VA partly accounts for the plantar-flexors MVC torque difference between children and adults but is not affected by the muscle length changes in both groups. Therefore, VA cannot account for the shape of the torque-angle relationship on the plantar-flexor muscles.