Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial.

BACKGROUND: To evaluate potential synergistic effect of pembrolizumab with radiotherapy (RT) compared with a standard-of-care (SOC) cetuximab-RT in patients with locally advanced-squamous cell carcinoma of head and neck (LA-SCCHN). PATIENTS AND METHODS: Patients with nonoperated stage III-IV SCC of oral cavity, oropharynx, hypopharynx, and larynx and unfit for receiving high-dose cisplatin were enrolled. Patients received once-daily RT up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab-RT arm) or 200 mg Q3W pembrolizumab during RT (pembrolizumab-RT arm). The primary endpoint was locoregional control (LRC) rate 15 months after RT. To detect a difference between arms of 60%-80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at two-sided significance level of 0.20. RESULTS: Between May 2016 and October 2017, 133 patients were randomized to cetuximab-RT (n = 66) and pembrolizumab-RT (n = 67). Two patients (one in each arm) were not included in the analysis (a consent withdrawal and a progression before treatment start). The median age was 65 years (interquartile range 60-70 years), 92% were smokers, 60% were oropharynx (46% of oropharynx with p16+) and 75% were stage IV. Median follow-up was 25 months in both arms. The 15-month LRC rate was 59% with cetuximab-RT and 60% with pembrolizumab-RT ]odds ratio 1.05, 95% confidence interval (CI) 0.43-2.59; P = 0.91]. There was no significant difference between arms for progression-free survival (hazard ratio 0.85, 95% CI 0.55-1.32; P = 0.47) and for overall survival (hazard ratio 0.83, 95% CI 0.49-1.40; P = 0.49). Toxicity was lower in the pembrolizumab-RT arm than in the cetuximab-RT arm: 74% versus 92% patients with at least one grade ≥3 adverse events (P = 0.006), mainly due to mucositis, radiodermatitis, and rash. CONCLUSION: Compared with the SOC cetuximab-RT, pembrolizumab concomitant with RT did not improve the tumor control and survival but appeared less toxic in unfit patients with LA-SCCHN.

PET-based prognostic survival model after radiotherapy for head and neck cancer.

PURPOSE: The aims of this multicentre retrospective study of locally advanced head and neck cancer (LAHNC) treated with definitive radiotherapy were to (1) identify positron emission tomography (PET)-18F-fluorodeoxyglucose (18F-FDG) parameters correlated with overall survival (OS) in a training cohort, (2) compute a prognostic model, and (3) externally validate this model in an independent cohort. MATERIALS AND METHODS: A total of 237 consecutive LAHNC patients divided into training (n = 127) and validation cohorts (n = 110) were retrospectively analysed. The following PET parameters were analysed: SUVMax, metabolic tumour volume (MTV), total lesion glycolysis (TLG), and SUVMean for the primary tumour and lymph nodes using a relative SUVMax threshold or an absolute SUV threshold. Cox analyses were performed on OS in the training cohort. The c-index was used to identify the highly prognostic parameters. A prognostic model was subsequently identified, and a nomogram was generated. The model was externally tested in the validation cohort. RESULTS: In univariate analysis, the significant PET parameters for the primary tumour included MTV (relative thresholds from 6 to 83% and absolute thresholds from 1.5 to 6.5) and TLG (relative thresholds from 1 to 82% and absolute thresholds from 0.5 to 4.5). For the lymph nodes, the significant parameters included MTV and TLG regardless of the threshold value. In multivariate analysis, tumour site, p16 status, MTV35% of the primary tumour, and MTV44% of the lymph nodes were independent predictors of OS. Based on these four parameters, a prognostic model was identified with a c-index of 0.72. The corresponding nomogram was generated. This prognostic model was externally validated, achieving a c-index of 0.66. CONCLUSIONS: A prognostic model of OS based on primary tumour and lymph node MTV, tumour site, and p16 status was proposed and validated. The corresponding nomogram may be used to tailor individualized treatment.

Cetuximab, docetaxel, and cisplatin as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma: a multicenter, phase II GORTEC study.

BACKGROUND: Cetuximab in combination with platinum and 5-fluorouracil is the standard of care in the first-line treatment of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab and taxane combinations have shown promising activity. This study evaluated the efficacy and safety of four cycles of docetaxel associated with cisplatin and cetuximab (TPEx), followed by maintenance with cetuximab every 2 weeks. PATIENTS AND METHODS: Patients with a histologically confirmed HNSCC with metastasis or recurrence unsuitable for locoregional curative treatment received docetaxel and cisplatin (75 mg/m(2) both) at day 1 and weekly cetuximab 250 mg/m(2) (loading dose of 400 mg/m(2)), repeated every 21 days for four cycles, followed by maintenance cetuximab 500 mg/m(2) every 2 weeks until progression or unacceptable toxicity. Prophylactic administration of granulocyte colony-stimulating factor was done systematically after each chemotherapy cycle. Patients had a good general status (performance status ≤1) and were under 71 years. Prior total doses of cisplatin exceeding 300 mg/m(2) were not allowed. The primary end point was objective response rate (ORR) after four cycles. RESULTS: Fifty-four patients were enrolled. The primary end point was met with an ORR of 44.4% (95% CI 30.9-58.6). Median overall and progression-free survivals were, respectively, 14 months (95% CI 11.3-17.3) and 6.2 months (95% CI 5.4-7.2). The most common grade 3/4 adverse events were skin rash (16.6%) and non-febrile neutropenia (20.4%). There were one pulmonary embolism and two infectious events leading to death. CONCLUSIONS: The TPEx regimen showed promising activity as first-line treatment in fit patients with recurrent/metastatic HNSCC. Further studies are needed to compare the TPEx versus EXTREME regimen in this population. CLINICALTRIALGOV: NCT01289522.

[Informed consent in radiotherapy care]. / Consentement aux soins en radiothérapie.

Obtaining consent to care requires the radiation oncologist to provide loyal information and to ensure that the patient understands it. Proof of such an approach rests with the practitioner. The French Society for Radiation Oncology (SFRO) does not recommend the signature of a consent form by the patient but recommends that the radiation oncologist be able to provide all the elements demonstrating the reality of a complete information circuit.

A data-driven method for reconstructing and modelling social interactions in moving animal groups.

Group-living organisms that collectively migrate range from cells and bacteria to human crowds, and include swarms of insects, schools of fish, and flocks of birds or ungulates. Unveiling the behavioural and cognitive mechanisms by which these groups coordinate their movements is a challenging task. These mechanisms take place at the individual scale and can be described as a combination of interactions between individuals and interactions between these individuals and the physical obstacles in the environment. Thanks to the development of novel tracking techniques that provide large and accurate datasets, the main characteristics of individual and collective behavioural patterns can be quantified with an unprecedented level of precision. However, in a large number of studies, social interactions are usually described by force map methods that only have a limited capacity of explanation and prediction, being rarely suitable for a direct implementation in a concise and explicit mathematical model. Here, we present a general method to extract the interactions between individuals that are involved in the coordination of collective movements in groups of organisms. We then apply this method to characterize social interactions in two species of shoaling fish, the rummy-nose tetra (Hemigrammus rhodostomus) and the zebrafish (Danio rerio), which both present a burst-and-coast motion. From the detailed quantitative description of individual-level interactions, it is thus possible to develop a quantitative model of the emergent dynamics observed at the group level, whose predictions can be checked against experimental results. This method can be applied to a wide range of biological and social systems. This article is part of the theme issue 'Multi-scale analysis and modelling of collective migration in biological systems'.

Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma.

BACKGROUND: We designed a randomized clinical trial to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV (i.e., advanced oropharynx carcinoma). METHODS: A total of 226 patients have been entered in a phase III multicenter, randomized trial comparing radiotherapy alone (arm A) with radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions. In arm B, patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin (70 mg/m(2) per day) and 5-fluorouracil (600 mg/m(2) per day) by continuous infusion. The two arms were equally balanced with regard to age, sex, stage, performance status, histology, and primary tumor site. RESULTS: Radiotherapy compliance was similar in the two arms with respect to total dose, treatment duration, and treatment interruption. The rate of grades 3 and 4 mucositis was statistically significantly higher in arm B (71%; 95% confidence interval [CI] = 54%-85%) than in arm A (39%; 95% CI = 29%-56%). Skin toxicity was not different between the two arms. Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level. Three-year overall actuarial survival and disease-free survival rates were, respectively, 51% (95% CI = 39%-68%) versus 31% (95% CI = 18%-49%) and 42% (95% CI = 30%-57%) versus 20% (95% CI = 10%-33%) for patients treated with combined modality versus radiation therapy alone (P =.02 and.04, respectively). The locoregional control rate was improved in arm B (66%; 95% CI = 51%-78%) versus arm A (42%; 95% CI = 31%-56%). CONCLUSION: The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx.

[Nocardia brasiliensis leg ulcer and nodular lymphangitis in France]. / Ulcère de jambe et lymphangite nodulaire à Nocardia brasiliensis en France métropolitaine.

INTRODUCTION: Nocardia brasiliensis is a very rarely reported cause of chronic phagedenic ulcerations. We report the case of an elderly woman who developed such an infection after falling on her right leg on the road in the Bresse country (an essentially agricultural and bovine-cattle breading region) and developed a chronic phagedenic ulcer secondarily complicated by nodular lymphangitis of the thigh. CASE REPORT: A 75 year-old woman fell on her right leg on the side of the main road outside her hamlet in the Bresse country and secondarily developed a chronique phagedenic ulceration. We first considered her as suffering from pyoderma gangrenosum. A complete scanning only revealed an autoimmune thyroiditis and a rapidly healing gastric ulceration, and none of the treatments, either local or systemic, helped the skin condition to heal. After 3 weeks of application of a local corticoid ointment, the patient developed fever, general malaise, an exacerbation of her wound and an infiltration of the skin round her knee, together with nodular lymphangitic dissemination. A supplementary bacterial swab disclosed massive proliferation of a slow-growing Gram-positive bacillus, which proved to be Nocardia brasiliensis, together with a methicillino-sensitive Staphylococcus aureus. The treatment with sulfamethoxazole-trimetoprim gave a rash after 12 hours and was changed to amoxicillin and clavulanic acid, which rapidly proved to be permanently effective. DISCUSSION: The revelation of this particular slow-growing bacteria is difficult and requires bacterial swabs. Nocardia brasiliensis is relatively rare in primary skin ulcerations and we discuss the reasons why an elderly women should find this bacteria on the road outside her hamlet in the French countryside. This particular infectious condition requires general scanning, to make sure that the primary skin condition does not extend to other organs. We review the therapeutical options for patients who exhibit allergic reactions to the classically effective antibiotic drugs.

Concomitant radiochemotherapy or accelerated radiotherapy: analysis of two randomized trials of the French Head and Neck Cancer Group (GORTEC).

In the early 1990s, when conventional radiotherapy (RT) was the standard of care in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), two main options were being tested to improve the efficacy and the therapeutic ratio of RT. The first approach evaluated the effect of adding chemotherapy (CT) simultaneously to RT (RT-CT), while the second approach assessed the effect of modified fractionated RT. To answer these two questions, in 1994, the French Group for Head and Neck Oncology Radiotherapy (GORTEC) initiated two randomized trials. A total of 494 patients were entered in these two parallel phase III multicenter trials comparing conventional RT (70 Gy in 35 fractions) either with concomitant RT-CT (226 patients; 70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and 5-fluorouracil [5FU]) or with very accelerated RT (268 patients) delivering 64 Gy in 3 weeks. The 5-year overall survival (OS), specific disease-free survival (DFS), and local-regional control rates were improved in favor of simultaneous RT-CT, whereas local-regional control was significantly improved with accelerated RT, along with a marginal effect on OS and DFS. This increased antitumor efficacy was in both cases associated with a marked increase in acute RT-induced toxicity, which was more pronounced with accelerated RT, whereas late effects were marginally increased with the addition of CT and not influenced by accelerated RT. We conclude that both concomitant RT-CT and accelerated RT improved tumor control rates, as compared to conventional RT, along with increased but manageable toxicity. The two regimens are currently being tested in an ongoing randomized study and also being compared to moderately accelerated RT and concomitant CT.

Genetic diversity of Schistosoma mansoni within and among individual hosts (Rattus rattus): infrapopulation differentiation at microspatial scale.

The distribution of genetic diversity in a local population of the trematode Schistosoma mansoni was determined within and between individual wild rats at a microspatial geographic scale of a standing water transmission site. Using RAPD markers, molecular variance and canonical correspondence analysis were performed to test the significance of genetic differentiation between infrapopulations. Of total gene diversity, 8 and 11% was partitioned between hosts trapped at few metres distance from each other. Significant temporal differentiation (2%) was also detected among schistosomes sampled at 6 month intervals with more infrapopulation pairs differentiated during the dry season of parasite transmission than during the rainy season (45 and 12%, respectively). A combination of factors such as restricted displacement of rats, patchy spatial aggregation of infected snails and limited cercarial dispersion in standing water are likely to promote the genetic differentiation observed between infrapopulations at this microgeographic scale.

Estimate of blow-up and relaxation time for self-gravitating Brownian particles and bacterial populations.

We determine an exact asymptotic expression of the blow-up time t(coll) for self-gravitating Brownian particles or bacterial populations (chemotaxis) close to the critical point in d=3. We show that t(coll) = t(*) (eta- eta(c) )(-1/2) with t(*) =0.917 677 02..., where eta represents the inverse temperature (for Brownian particles) or the mass (for bacterial colonies), and eta(c) is the critical value of eta above which the system blows up. This result is in perfect agreement with the numerical solution of the Smoluchowski-Poisson system. We also determine the exact asymptotic expression of the relaxation time close to but above the critical temperature and derive a large time asymptotic expansion for the density profile exactly at the critical point.

Scaling laws and vortex profiles in two-dimensional decaying turbulence.

We use high resolution numerical simulations over several hundred of turnover times to study the influence of small scale dissipation onto vortex statistics in 2D decaying turbulence. A scaling regime is detected when the scaling laws are expressed in units of mean vorticity and integral scale, like predicted in Carnevale et al., Phys. Rev. Lett. 66, 2735 (1991), and it is observed that viscous effects spoil this scaling regime. The exponent controlling the decay of the number of vortices shows some trends toward xi=1, in agreement with a recent theory based on the Kirchhoff model [C. Sire and P. H. Chavanis, Phys. Rev. E 61, 6644 (2000)]. In terms of scaled variables, the vortices have a similar profile with a functional form related to the Fermi-Dirac distribution.

Genetic diversity and recruitment pattern of Schistosoma mansoni in a Biomphalaria glabrata snail population: a field study using random-amplified polymorphic DNA markers.

Random-amplified polymorphic DNA markers have been used to assess the amount and the distribution of the genetic diversity of Schistosoma mansoni within a natural population of Biomphalaria glabrata at a transmission site of the murine schistosomiasis focus of Guadeloupe. Despite high infection rate and heavy schistosome load within the definitive hosts (Ratus rattus), prevalences within intermediate snails ranged from 0.2 to 4.8%. Whatever the transmission season may be (rainy vs. dry), most of the infected snails were spatially aggregated and 88.4% of them harbored a single parasite genotype indicative of a monomiracidial infection; 4.7% had dual sex infections and a parasite intensity not exceeding 3 miracidia per snail. A substantial resistance level toward the parasite and recruitment regulatory process within snails may explain in part the observed low parasite prevalences and intensities. Considering such a distribution pattern of larval S. mansoni genetic diversity among B. glabrata, mobility of the definitive hosts, or rapid turnover of infected snails, or both, are required to maintain genetic heterogeneity within adult schistosome populations.

[Stage III and IV cancers of the oropharynx: results of a randomized study of Gortec comparing radiotherapy alone with concomitant chemotherapy]. / Cancers de l'oropharynx de stades III et IV: résultats d'une étude randomisée du Gortec comparant radiothérapie exclusive et radiothérapie avec chimiothérapie concomitante.

The aim of the study was to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV oropharynx carcinoma. A total of 226 patients have been entered in a phase III multicentric randomized trial comparing radiotherapy alone (arm A) to radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions. In arm B patients received simultaneously 3 cycles of a four-day regimen containing carboplatin (70 mg/m2/d) and 5 fluorouracil (600 mg/m2/d) continuous infusion. The two arms were equally balanced regarding to age, gender, stage, performance status, histology, and primary tumor site. Radiotherapy compliance was similar in the two arms regarding to total dose, treatment duration and treatment interruption. Grade 3 and 4 mucositis rate was significantly higher in arm B (67% versus 36%). Skin toxicity was not different. Haematologic toxicity was higher in arm B on neutrophil count and hemoglobin level. Three-year overall actuarial survival and disease-free survival rates were respectively 51% versus 31% and 42% versus 20% for patients treated with combined modality versus radiation alone (p = 0.022 and 0.043). Local and regional control rate has been improved in arm B (66% versus 42%). The statistically significant improvement in overall survival obtained support the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx.

[Advances in head and neck cancers on behalf of the French Intergroup ORL and GORTEC]. / Évolution des concepts dans les cancers des voies aérodigestives supérieures, sous l'égide de l'Intergroupe ORL (GORTEC, GETTEC, GERCOR).

Head and neck cancers are the fifth among the most common cancers in France. Two thirds of cases occur at an advanced stage. For advanced disease, progression-free survival, despite undeniable progress, remains below 50% at three years. The last 20 years have been marked by the necessity to identify situations where less intense surgery and/or radiotherapy and/or chemotherapy is possible without jeopardizing the prognosis, and situations where a therapeutic intensification is necessary and results in a gain in survival while better preserving function with less toxicity. French cooperative groups gathering radiation oncologists (GORTEC), surgeons (GETTEC) and medical oncologists or physicians involved in the management of systemic treatments in head and neck cancers (GERCOR) are now belonging to the INCa-labelled Intergroup ORL to deal with the challenges of head and neck cancers.