[Immune-related adverse events]. / Les manifestations indésirables liées à l'immunothérapie.

Immunotherapy has revolutionized cancer management in recent years and is affecting more and more patients. Immunotherapy side effects are specific, immune-related, and their early recognition and management are essential. Here we describe the main adverse effects of immunotherapy and their general principles of management.

L'immunothérapie a révolutionné la prise en charge des cancers ces dernières années et concerne de plus en plus de patients. Les manifestations indésirables de l'immunothérapie sont spécifiques, de type dysimmunitaire, et leur reconnaissance et prise en charge précoces sont primordiales. Dans cet article, nous décrivons les principaux effets secondaires de l'immunothérapie et leurs principes généraux de prise en charge.

[Immunotherapy for head and neck squamous cell carcinoma]. / Place de l'immunothérapie dans le traitement des carcinomes épidermoïdes de la tête et du cou.

Current recommendations for systemic treatments of head and neck squamous cell carcinoma have been significantly modified with the advent of immunotherapy for a majority of these cancers. Indeed, immune checkpoint inhibitors are now recommended in metastatic disease and in locoregional recurrence not amenable to a local treatment. PD-L1 positive tumours are eligible for immunotherapy in first line and immunotherapy is also available in second line, after failure of platinum based chemotherapy, regardless of PD-L1 expression. Ongoing clinical trials are exploring the role of immune checkpoint inhibitors in the adjuvant setting as well as with radiotherapy as definitive treatment. Immunotherapy has changed the treatment landscape and has improved the prognosis of patients with head and neck squamous cell carcinoma.

Les recommandations actuelles concernant les traitements systémiques des carcinomes épidermoïdes de la tête et du cou ont été largement modifiées avec l'avènement de l'immunothérapie pour une majorité de ces cancers. En effet, les inhibiteurs de points de contrôle immunitaire sont maintenant recommandés en situation métastatique ou en cas de récidive locorégionale inaccessible à un traitement local et ce, dès la première ligne pour les tumeurs exprimant le PD-L1. L'immunothérapie est également accessible en deuxième ligne, après échec d'une chimiothérapie par sels de platine, quelle que soit l'expression du PD-L1. Des études cliniques étudiant leur place en situation adjuvante ou concomitante à la radiothérapie sont également en cours. Ces traitements d'immunothérapie ont élargi les possibilités thérapeutiques et amélioré le pronostic des patients présentant un carcinome épidermoïde de la tête et du cou.

[Evolution of systemic anti-cancer therapies]. / Evolution des thérapies anti-cancéreuses systémiques.

Before the advent of chemotherapy in the 1940s, cancer treatment was dominated by surgery and radiation therapy. The developments of targeted anti-cancer therapies in the 2000s followed by immunotherapy have largely changed the treatment landscape in particular in the metastatic setting. Here we provide a history of these advances.

Avant l'avènement de la chimiothérapie dans les années 1940, le traitement du cancer était dominé par la chirurgie et la radiothérapie. Il a fallu attendre les années 2000 pour voir apparaître le développement des thérapies anti-cancéreuses ciblées, puis de l'immunothérapie. Ces traitements systémiques ont fortement modifié la prise en charge des patients en oncologie et, en particulier, au stade métastatique. Nous dressons ici un historique de ces avancées.

[Hepatosplenic lesions due to a systemic bartonellosis in an immunocompetent patient]. / Atteinte hépato-splénique et bartonellose systémique chez une patiente immunocompétente.

We describe a case of a young healthy patient who presents a lot of hepato-splenic lesions caused by a systemic cat scratch disease. This case allows us to discuss the uncommon manifestations of the cat scratch disease and to describe the two types of hepatic lesions caused by a systemic bartonella infection : the granulomatosis and peliosis.

Nous rapportons le cas d'une jeune patiente immunocompétente présentant de multiples lésions hépato-spléniques secondaires à une infection systémique à bartonella. L'opportunité nous est ainsi donnée de discuter des manifestations rares de la maladie des griffes du chat ainsi que de décrire les deux types d'atteintes hépatiques causées par cette infection : la granulomatose et la péliose.

[Cancer therapy-induced cardiotoxicity]. / La cardiotoxicité des traitements anti-cancéreux.

The incidence of cancer is raising and the treatments are increasingly aggressive. Consequently, physicians are regularly facing side effects of cytotoxic therapies. Cancer- therapy-induced cardiotoxicity is a serious complication because it can be fatal and causes a temporary or permanent cessation of the treatment. In this article, we summarize the mechanisms, the monitoring and the multidisciplinary management of patients with cancer-therapy induced cardiotoxicity.

Les cancers sont de plus en plus fréquents et leurs traitements de plus en plus agressifs. En conséquence, les médecins se trouvent régulièrement confrontés aux effets secondaires des traitements cytotoxiques. La cardiotoxicité induite par les traitements anti-cancéreux est une complication gravissime, car elle peut être mortelle et provoque un arrêt temporaire, voire définitif, des traitements. Dans cet article, nous décrivons les mécanismes, le dépistage et la prise en charge multidisciplinaire de la cardiotoxicité des agents anti-cancéreux.

[BREAST CANCER: FROM TARGETED THERAPY TO PRECISION MEDICINE]. / CANCER DU SEIN : DE LA THÉRAPIE CIBLÉE À LA MÉDECINE PERSONNALISÉE.

The authors review the principles of systemic therapy in breast cancer. They analyze the degree of treatment individualization in our current approach. New technologies allow the detection of genomic alterations in cancer cells. Unfortunately, we do not know yet how to best use this knowledge for routine patient care. Most genomic alterations are rare events complicating further drug development. Temporal and spatial heterogeneity in tumors also has to be taken into account. An intense international collaboration is ongoing to try and demonstrate that precision medicine will really improve treatment outcome.

Characteristics of EPI-hNE4 aerosol: a new elastase inhibitor for treatment of cystic fibrosis.

The purpose of this study was to define nebulization conditions providing delivery of aerosols of EPI-hNE4, an inhibitor of human neutrophil elastase (HNE). EPI-hNE4 was nebulized with Pari LC Star and tested at three concentrations (2.5, 5, and 10 mg/mL). The inhaled mass was measured over 15 min. Particle size distribution was measured by cascade impaction. The effect was also tested of mixing EPI-hNE4 with a (99m)Tc human serum albumin (HSA) tracer on the aerodynamic properties of the aerosol. The inhibitory activity of EPI-hNE4 after nebulization was assessed on purified HNE. The inhaled mass was 32.3 +/- 3.5% (mean +/- SD) after 10 min and 44.2 +/- 3.8% (mean +/- SD) after 15 min. Mass median aerodynamic diameter ranged between 1.2 and 1.8 microm. The (99m)Tc HSA EPI-hNE4 aerosol was similar in terms of particle size distribution (y = 1.0338x - 0.003, r = 0.83). (99m)Tc activity was predictive of EPI-hNE4 mass distribution (y = 1.0278x - 1.6991, r = 0.89). The inhibitory capacity of aerosolized samples remained unchanged after up to 10 min of nebulization. EPI-hNE4 can be nebulized efficiently without decrease in its activity. Mixing this inhibitor with (99m)Tc HSA should allow quantification of its deposition in CF patients.

Direct micro-radioimmunoassay of the new renin inhibitor CGP 60536.

A solid phase method for direct radioimmunoassay in plasma of the new renin inhibitor CGP 60536 has been developed which does not require the extraction of the parent drug with organic solvents. The assay showed a good reproducibility down to plasma concentrations of 0.15 ng/ml (LOQ) with intra- and inter-assay coefficients of variation < or = 20%. The procedure, which requires only small volumes of plasma (25 microl), is simple to use and well suited for routine analysis. The method allows the investigation of the pharmacokinetics of CGP 60536 in animals and man given low oral doses of the drug.

Second-generation octarellins: two new de novo (beta/alpha)8 polypeptides designed for investigating the influence of beta-residue packing on the alpha/beta-barrel structure stability.

The sequence of octarellin I, the first de novo (beta/alpha)8 polypeptide, was revised according to several criteria, among others the symmetry of the sequence, beta-residue volume and hydrophobicity, and charge distribution. These considerations and the overall conclusions drawn from the first design led to two new sequences, corresponding to octarellins II and III. Octarellin II retains perfect 8-fold symmetry. Octarellin III has the same sequence as octarellin II, except for the beta-strands which exhibit a 4-fold symmetry. The two proteins were produced in Escherichia coli. Infrared and CD spectral analyses of octarellins II and III reveal a high secondary structure content. Non-denaturing gel electrophoresis, molecular sieve chromatography and analytical ultracentrifugation suggest that both of these second-generation artificial polypeptides exist as a mixture of a monomer and a dimer form. Octarellins II and III are at least 10 times more soluble than octarellin I. Urea-induced unfolding followed by fluorescence emission suggests that the tryptophan residues, designed to be buried in the (beta/alpha)8, are indeed packed in the hydrophobic core of both proteins. However, octarellin III displays a higher stability towards urea denaturation, indicating that introducing 4-fold symmetry into the beta-barrel might be important for stability of the overall folding.

Evolution of some biochemical characteristics of the intestinal mucosa during the first postnatal weeks in C57 mice. Effects of thyroxine and putrescine.

In C57 mice, during the third week after birth, there is a rapid conversion of the intestinal epithelium from fetal to mature adult status. Some characteristics (lactase, maltase, diamine oxidase, and sucrase activity; putrescine, spermine and spermidine concentrations; mitotic index) have been analyzed for the proximal, middle, and distal parts of the intestine in mice of different ages: 8, 15, 19, and 60 days. The most important observations recorded were as follows: (a) sucrase- and maltase-specific activities as well as spermine and spermidine contents increased abruptly on the 19th postnatal day and then decreased; (b) decrease of lactase and diamine oxidase-specific activity was recorded between the 15th and 19th postnatal days, (c) later, diamine oxidase-specific activity increased, whereas putrescine content decreased in the proximal part of the intestine; and (d) mitotic index was not significantly different when estimated for the crypts on days 11 and 19. No similar variations of these biochemical parameters were observed over a period of 3 days when mice were injected with thyroxine on the 8th day or when mice received putrescine per os on the 9th day, as explained in the text. Only a slight but significant variation in sucrase- or maltase-specific activity with thyroxine and a variation of the lactase or DAO-specific activity of the distal part of the intestine with putrescine were recorded.