Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group

BACKGROUND AND PURPOSE: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005). CONCLUSION: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer

A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck

BACKGROUND: Former meta-analyses have shown a survival benefit for the addition of chemotherapy (CHX) to radiotherapy (RT) and to some extent also for the use of hyperfractionated radiation therapy (HFRT) and accelerated radiation therapy (AFRT) in locally advanced squamous cell carcinoma (SCC) of the head and neck. However, the publication of new studies and the fact that many older studies that were included in these former meta-analyses used obsolete radiation doses, CHX schedules or study designs prompted us to carry out a new analysis using strict inclusion criteria. METHODS: Randomised trials testing curatively intended RT (≥60 Gy in >4 weeks/>50 Gy in <4 weeks) on SCC of the oral cavity, oropharynx, hypopharynx, and larynx published as full paper or in abstract form between 1975 and 2003 were eligible. Trials comparing RT alone with concurrent or alternating chemoradiation (5-fluorouracil (5-FU), cisplatin, carboplatin, mitomycin C) were analyzed according to the employed radiation schedule and the used CHX regimen. Studies comparing conventionally fractionated radiotherapy (CFRT) with either HFRT or AFRT without CHX were separately examined. End point of the meta-analysis was overall survival. RESULTS: Thirty-two trials with a total of 10 225 patients were included into the meta-analysis. An overall survival benefit of 12.0 months was observed for the addition of simultaneous CHX to either CFRT or HFRT/AFRT (p < 0.001). Separate analyses by cytostatic drug indicate a prolongation of survival of 24.0 months, 16.8 months, 6.7 months, and 4.0 months, respectively, for the simultaneous administration of 5-FU, cisplatin-based, carboplatin-based, and mitomycin C-based CHX to RT (each p < 0.01). Whereas no significant gain in overall survival was observed for AFRT in comparison to CFRT, a substantial prolongation of median survival (14.2 months, p < 0.001) was seen for HFRT compared to CFRT (both without CHX). CONCLUSION: RT combined with simultaneous 5-FU, cisplatin, carboplatin, and mitomycin C as single drug or combinations of 5-FU with one of the other drugs results in a large survival advantage irrespective the employed radiation schedule. If radiation therapy is used as single modality, hyperfractionation leads to a significant improvement of overall survival. Accelerated radiation therapy alone, especially when given as split course radiation schedule or extremely accelerated treatments with decreased total dose, does not increase overall survival

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe

The motor control of aimed limb movements in an insect

Page KL, Zakotnik J, Dürr V, Matheson T. The motor control of aimed limb movements in an insect. Journal of Neurophysiology. 2008;99(2):484-499.Limb movements that are aimed toward tactile stimuli of the body provide a powerful paradigm with which to study the transformation of motor activity into context-dependent action. We relate the activity of excitatory motor neurons of the locust femoro-tibial joint to the consequent kinematics of hind leg movements made during aimed scratching. There is posture-dependence of motor neuron activity, which is stronger in large amplitude (putative fast) than in small (putative slow and intermediate) motor neurons. We relate this posture dependency to biomechanical aspects of the musculo-skeletal system and explain the occurrence of passive tibial movements that occur in the absence of agonistic motor activity. There is little recorded co-activation of antagonistic tibial extensor and flexor motor neurons, and there is differential recruitment of proximal and distal flexor motor neurons. Large-amplitude motor neurons are often recruited soon after a switch in joint movement direction. Motor bursts containing large-amplitude spikes exhibit high spike rates of small-amplitude motor neurons. The fast extensor tibiae neuron, when recruited, exhibits a pattern of activity quite different to that seen during kicking, jumping, or righting: there is no co-activation of flexor motor neurons and no full tibial flexion. Changes in femoro-tibial joint angle and angular velocity are most strongly dependent on variations in the number of motor neuron spikes and the duration of motor bursts rather than on firing frequency. Our data demonstrate how aimed scratching movements result from interactions between biomechanical features of the musculo-skeletal system and patterns of motor neuron recruitment

Co-contraction and passive forces facilitate load compensation of aimed limb movements.

Vertebrates and arthropods are both capable of load compensation during aimed limb movements, such as reaching and grooming. We measured the kinematics and activity of individual motoneurons in loaded and unloaded leg movements in an insect. To evaluate the role of active and passive musculoskeletal properties in aiming and load compensation, we used a neuromechanical model of the femur–tibia joint that transformed measured extensor and flexor motoneuron spikes into joint kinematics. The model comprises three steps: first, an activation dynamics module that determines the time course of isometric force; second, a pair of antagonistic muscle models that determine the joint torque; and third, a forward dynamics simulation that calculates the movement of the limb. The muscles were modeled in five variants, differing in the presence or absence of force–length–velocity characteristics of the contractile element, a parallel passive elastic element, and passive joint damping. Each variant was optimized to yield the best simulation of measured behavior. Passive muscle force and viscous joint damping were sufficient and necessary to simulate the observed movements. Elastic or damping properties of the active contractile element could not replace passive elements. Passive elastic forces were similar in magnitude to active forces caused by muscle contraction, generating substantial joint stiffness. Antagonistic muscles co-contract, although there was no motoneuronal coactivation, because of slow dynamics of muscle activation. We quantified how co-contraction simplified load compensation by demonstrating that a small variation of the motoneuronal input caused a large change in joint torque

Activation dynamics data for locust hind leg extensor muscle

Clare AJ, Blackburn LML, Harischandra N, Zakotnik J, Dürr V, Matheson T. Activation dynamics data for locust hind leg extensor muscle. Bielefeld University; 2019.This data set has been acquired and analysed in association with a computational modelling project that compared and evaluated five muscle activation dynamics models for application to insect muscle. The data was acquired in experiments on the extensor tibiae muscle of the locust hind leg (*Schistocerca gregaria*). The zip-archive comprises mostly MATLAB files. Two data files contain original isometric force measurements with controlled stimulation of either the slow (SETI) or the fast (FETI) extensor tibiae motoneurons. Moreover, it contains four files with parameter sets for two non-linear muscle activation models, as proposed by *Zakotnik et al.* [1] and *Wilson et al.* [2], respectively. Finally, a readme file and Matlab script for demonstration of the experimental data are supplied for general information. All data are referred to in the manuscript “Evaluation of linear and non-linear activation dynamics models for insect muscle” by Harischandra et al., that is currently under revision. Data may be used in conjunction with a Matlab toolbox IMADSim that is available from the Matlab Central repository. **References:** [1] Zakotnik J, Matheson T, Dürr V (2006) Co-contraction and passive forces facilitate load compensation of aimed limb movements. J Neurosci 26: 4995-5007. [2] Wilson E, Rustighi E, Newland PL, Mace BR (2013) Slow motor neuron stimulation of locust skeletal muscle: model and measurement. Biomech Model Mechanobiol 12: 581-596