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.

Appropriateness of Antibiotic Prescription During Teleconsultation.

Teleconsultation has become a new means of using care which has taken off significantly since the COVID crisis, The pooling of the technological environment within the TC makes it possible to set up practice reviews by reusing the data collected. Our aim was to evaluate the relevance of antibiotic therapy during teleconsultations carried out on the national teleconsultation platform "Qare" in 4 common infections. 143,428 TCs with structured prescriptions were analyzed, with an appropriate prescription in more than 82% of cases, higher than in the literature. The use of data makes it possible to quickly assess practices and inform doctors to improve their practices.

A new ER-specific photosensitizer unravels (1)O2-driven protein oxidation and inhibition of deubiquitinases as a generic mechanism for cancer PDT.

Photosensitizers (PS) are ideally devoid of any activity in the absence of photoactivation, and rely on molecular oxygen for the formation of singlet oxygen ((1)O2) to produce cellular damage. Off-targets and tumor hypoxia therefore represent obstacles for the use of PS for cancer photodynamic therapy. Herein, we describe the characterization of OR141, a benzophenazine compound identified through a phenotypic screening for its capacity to be strictly activated by light and to kill a large variety of tumor cells under both normoxia and hypoxia. This new class of PS unraveled an unsuspected common mechanism of action for PS that involves the combined inhibition of the mammalian target of rapamycin (mTOR) signaling pathway and proteasomal deubiquitinases (DUBs) USP14 and UCH37. Oxidation of mTOR and other endoplasmic reticulum (ER)-associated proteins drives the early formation of high molecular weight (MW) complexes of multimeric proteins, the concomitant blockade of DUBs preventing their degradation and precipitating cell death. Furthermore, we validated the antitumor effects of OR141 in vivo and documented its highly selective accumulation in the ER, further increasing the ER stress resulting from (1)O2 generation upon light activation.

Yrast 6⁺ seniority isomers of (136,138)Sn.

Delayed γ-ray cascades, originating from the decay of (6⁺) isomeric states, in the very neutron-rich, semimagic isotopes (136,138)Sn have been observed following the projectile fission of a ²³8U beam at RIBF, RIKEN. The wave functions of these isomeric states are proposed to be predominantly a fully aligned pair of f(7/2) neutrons. Shell-model calculations, performed using a realistic effective interaction, reproduce well the energies of the excited states of these nuclei and the measured transition rates, with the exception of the B(E2;6⁺→4⁺) rate of ¹³6Sn, which deviates from a simple seniority scheme. Empirically reducing the νf(7/2)(2) orbit matrix elements produces a 41⁺ state with almost equal seniority 2 and 4 components, correctly reproducing the experimental B(E2;6⁺→4⁺) rate of ¹³6Sn. These data provide a key benchmark for shell-model interactions far from stability.

1p3/2 proton-hole state in 132Sn and the shell structure along N = 82.

A low-lying state in 131In82, the one-proton hole nucleus with respect to double magic 132Sn, was observed by its γ decay to the Iπ=1/2- ß-emitting isomer. We identify the new state at an excitation energy of Ex=1353 keV, which was populated both in the ß decay of 131Cd83 and after ß-delayed neutron emission from 132Cd84, as the previously unknown πp3/2 single-hole state with respect to the 132Sn core. Exploiting this crucial new experimental information, shell-model calculations were performed to study the structure of experimentally inaccessible N=82 isotones below 132Sn. The results evidence a surprising absence of proton subshell closures along the chain of N=82 isotones. The consequences of this finding for the evolution of the N=82 shell gap along the r-process path are discussed.

[Hodgkin's Lymphoma]. / Lymphome de Hodgkin.

With approximately 1500 cases per year in France, Hodgkin's lymphoma (HL) represents only 10 to 15 % of new cases of lymphomas, and 0.5 to 1 % of new cases of cancers. The management of this lymphoproliferative disease has undergone profound conceptual changes over time, allowing at present to obtain a cure rate of 75 to 80 % of all confused stage, and up to 90 % in case of early stage HL. If initial treatment consisted in an exclusive extensive (total or sub-total lymphoid) irradiation whatever the stage may be, the place of radiotherapy in the management of HL has evolved over time but remains today one of the cornerstones of the treatment. It becomes integrated within the framework of combined modality therapies associating chemotherapy then irradiation for the early stage HL, and stays a therapeutic alternative in all situations (in advanced stage and\or recurrent disease) which raises the issue of increasing the locoregional tumor control. Despite the undeniable contribution of radiotherapy in controlling the disease, delayed side effects of treatments are not negligible. So the long-term monitoring of treated patients is essential, mainly because of an increased risk of morbi-mortality due to cardiovascular events and/or secondary cancers. It is important to remember that even today the "Involved Field" irradiation type remains the gold standard, even if we witness at present the emergence of new types of irradiation, which aim to reduce the amount of irradiated tissues to try to limit the risks of delayed radio-induced complications. The purpose of this article is to clarify the specific aspects (epidemiological, radio-anatomical and prognostic characteristics) of HL, as well as the practical modalities of the irradiation (illustrated by a clinical case record) when an indication of radiotherapy is placed for its treatment.

[Non-hodgkin's lymphomas]. / Lymphomes malins non hodgkiniens.

With approximately 10000 cases per year in France, non-Hodgkin's lymphoma (NHL) represents the most frequent hematological malignancy, and 5 to 10 % of new cases of cancers. NHLs constitute a heterogeneous group of lymphoproliferative diseases, including entities with very different epidemiological and evolutive characteristics, as well as prognosis and treatments. Several classifications exist, but in practice, we individualize aggressive NHL including Diffuse Large B-Cell Lymphomas (DLBCL) which is the most common lymphoma, and indolent NHL including follicular lymphomas and mucosa-associated lymphoid tissue (MALT) lymphomas. The role of the radiotherapy in the management of NHLs varies according to the specific sub-type of lymphoma, but it has become increasingly limited over time. Overall it finds indications with curative intent only in situations of localized LMNH: either associated with chemotherapy as part of a combined modality therapy as for the treatment of localized DLBCL, or as exclusive treatment specially in the rare situations of localized follicular lymphomas. Moreover, lymphocytes being extremely radiosensitive cells, radiotherapy retains excellent indications with palliative intent for the management of symptomatic bulky tumor masses, and that whatever the sub-type of NHLs may be. It is important to remember that even today the "Involved Field" irradiation type remains the gold standard for the treatment of nodal NHLs, even if we witness at present the emergence of new types of irradiation, which aim to reduce the amount of irradiated tissues to try to limit the risks of delayed radio-induced complications. The purpose of this article is to clarify the specific aspects (epidemiological, radio-anatomical and prognostic characteristics) of each NHLs'sub-types (except primary central nervous system lymphomas), as well as the practical modalities of the irradiation (illustrated by a clinical case record) when an indication of radiotherapy is placed for their treatment.

[Normal tissue tolerance to external beam radiation therapy: bone marrow]. / Dose de tolérance à l'irradiation des tissus sains: la moelle osseuse.

Bone marrow is one of the major dose-limiting tissue for radiotherapy. It is composed of many sub-units with complex regulatory mechanisms implying cytokines and growth factors, dispersed throughout the skeleton, each acting with a semi-autonomy but are unified into an integrated system that responds to ionizing radiations as one critical organ. A better knowledge of the complexity of this tissue's distribution and physiology is fundamental to understanding and forecasting the consequences of radiation-induced bone marrow injury. According to cancer characteristics, the volume of hematopoietic bone marrow included within radiation fields and the dose it receives vary in a very significant way, and finally the impact on blood cell count varies in widely different ranges. Furthermore, to predict the overall risk of therapy-induced hematological toxicities, it is necessary to take into account the possible contemporary administration of other cytotoxic drugs (before and/or during radiation therapy). Conversely, the hematological toxicity of usually well-tolerated chemotherapies can be increased, if the patient has a history of radiotherapy. Although the importance of minimizing the volume of active bone marrow exposed to ionizing radiations is well established, so far, no consensual recommendation exists about the dose-volume relationship between bone marrow irradiation and hematological tolerance. Data have recently emerged from trials studying the interest of IMRT for treatment of pelvic malignancies which confirm that reducing bone marrow exposure to irradiation prevents the rise of hematological toxicities during and after radiation therapy, even if some questions remain unanswered on how to define the contours of bone marrow volume.

[Normal tissue tolerance to external beam radiation therapy: spinal cord]. / Tolérance à l'irradiation des tissus sains: moelle épinière.

Radiation myelopathy is one of the most dreadful complications of radiation therapy. Despite multiple animal experiments and human autopsic series, its pathogenesis remains largely unknown. In most instances, the classical aspect of myelomalacy combines glial and vascular injuries in various sequences. Recent studies point out the role of oligodendrocytes and their precusors, as well as of intercellular mediators (cytokines and stress molecules). The clinical presentation comprises a spectrum of non specific neurological symptoms whose evolution is sometimes regressive but more commonly progressive and life-threatening. Usually, it occurs following a latent period of six months to two years after irradiation of the cervical, thoracic or upper lumbar spine to a dose in excess of 50 Gy, conventionally fractionated. Nonetheless, these typical features can be altered by extrinsic factors, such as hypofractionation/acceleration of the dose, multiple surgical procedures, chemotherapy especially megatherapy, or neurotoxic drugs. Conversely, hyperfractionated regimens that take into account protracted half-time repair of sublethal damages to the CNS, as well as sophisticated estimates of the dose to the cord and QA programs during the treatment course minimize such risks.

[Changes in plasma parameters in rabbit does as a function of their physiological state and feed rationing]. / Evolution de paramètres plasmatiques chez des lapines reproductrices en fonction de l'état physiologique et du rationnement alimentaire.

We followed the evolution of hematocrit and of plasma Na, K, Cl, total protein, creatinine, Pi, alkaline phosphatases, triglycerides, cholesterol, glucose and GPT. The amount of feed given to the rabbit does was restricted to 75 percent of the quantity eaten ad libitum, in similar conditions to those of intensive breeding. This had a slight effect on the values obtained for plasmatic components in healthy rabbits. This was not dependent on the timing of blood collection, nor on the physiological state of the animal. The changes in biochemical composition of the plasma due to pregnancy in healthy rabbit does are: a fall in total plasma protein and cholesterol levels, alkaline phosphatases activity, hematocrit, and a rise followed by a marked fall in plasma triglycerides level. During lactation, these levels return progressively to the values obtained in non-pregnant, non-lactating rabbits.

[The pathology of ther reproducing female rabbit: a comparative, descriptive study of morbidity phenomena observed during the reproduction o purebred strains of rabbit]. / Pathologie des lapines reproductrices: étude descriptive comparative des phénomènes morbides observés lors de la reproduction de deux souches pures de lapin.

We analysed the working life of purebred New Zealand, and Californian rabbit breeding does kept in identical conditions. Our study notes the health of the does as well as various factors affecting the survival rate of baby rabbits until weaning. After the first six months of rearing the productivity and the health of the two breeds were very different. The Californian females came through their first two gestations and lactations very well but more than half of them showed signs of respiratory ailments, and many had to be eliminated. Their first two litters were characterised by a low number of baby rabbits weaned as well as a large number of whole litters dead before weaning. The females of the New Zealand breed were in good health but then died suddenly at the end of gestation or in the middle of lactation; the surviving females raised practically their whole litter until weaning. The loss of animals is numerically fairly similar in the two breeds but takes on different farms. This comparative study of the elimination of the does, of their mortality, or of that of the baby rabbits during lactation leads us to the hypothesis that these three phenomena are probably different manifestations of the same pathological phenomena occurring early on, probably from the first gestation onwards.

[Pathology among breeding does. Evolution of several plasma parameters among primiparous rabbit does]. / Pathologie des reproductrices. Evolution de quelques paramètres plasmatiques chez des lapines primipares.

One of the most important limiting factors of rabbit production is reproductive pathology. This pathology has two aspects: livestock reduction (elimination and death of rabbit does) and mortality of young rabbits before weaning. We studied alterations of hematocrit and of plasma Na, K, Ca, Mg, Pi, total proteins, prolactin, during gestation and lactation of primiparous rabbit does. In females which were going to die the first results showed a fall in plasma NaK, Ca concentrations and a rise in plasma Mg. We think that these alterations are only consequences of anterior metabolic alterations and are indicators or secondary causes of the animal's proximate death. We noticed a deep fall in plasma prolactin concentration before death; its signification is discussed. In the females which did not wean their whole litter, average prolacting levels during gestation and at the beginning of lactation were lower than in females weaning their whole litter. These first results would confirm the hypothesis that youngs' mortality is a pathology linked with dams' state.