[Oligometastatic breast cancer : therapeutic implications of a new paradigm]. / Cancer du sein oligométastatique : implications thérapeutiques d'un nouveau paradigme.

INTRODUCTION: Oligometastatic breast cancer incidence is recently increasing thanks to screening and imaging improvements. Unlike patients with metastatic disease, a small number of oligometastatic patients may expect a definitive remission, in case of aggressive management performed with intent to cure. We report the atypical evolution of an oligometastatic breast cancer patient, who lately relapsed with a different Her2 status. RESULTS: A 46 year old women was treated for an infiltrating duct breast carcinoma, initially diagnosed with oligometastases and an Her2- negative status. Treatments were performed in intent to cure but the patient relapsed 5 years later with a solitary Her2-positive liver metastasis. The aggressive local and systemic (using an anti- Her2 targeted therapy) management induced a still complete remission at last follow-up. CONCLUSION: Prognosis of breast oligometastatic cancer is unpredictable, but an aggressive with intent-to-cure management may bring benefits to patients. However very rare, the switch of Her2 status between initial diagnosis and relapse highlights tumor heterogeneity, and the fact that a cell population featuring targetable characteristics may appear due to anticancer drug induced-cell selection.

INTRODUCTION: L'incidence des cancers du sein oligométastatiques est en augmentation, grâce aux progrès du dépistage et de l'imagerie. Au contraire de la maladie métastatique, un faible pourcentage de ces patientes peut espérer une guérison définitive en cas de prise en charge menée en intention curative sur toutes les cibles. Nous rapportons le cas de l'évolution atypique d'une patiente oligométastatique, avec une récidive tardive d'un cancer du sein, aux caractéristiques génétiques transformées. Résultats : Une patiente de 46 ans a été prise en charge initialement pour un adénocarcinome mammaire d'emblée oligo-métastatique ne surexprimant pas Her2. Après un traitement à visée curative, la patiente a rechuté 5 ans plus tard avec une métastase hépatique unique, surexprimant Her2. La prise en charge locale curative et systémique avec une thérapie ciblant Her2 a permis la rémission complète persistante après 3 ans de suivi. CONCLUSION: Le pronostic de la maladie oligométastatique du sein doit être abordé avec prudence, mais un traitement réalisé en intention curative peut apporter un bénéfice aux patientes. Le changement de statut Her2 entre le diagnostic primitif et la récidive -fait très rare- souligne l'hétérogénéité de la population tumorale, dont une fraction présentant des caractéristiques génétiques particulières peut émerger, sous la pression de sélection des drogues anticancéreuses.

Regulation of osteoprotegerin pro- or anti-tumoral activity by bone tumor microenvironment.

Tumor development in bone is often associated with fractures, bone loss and bone pain, and improvement is still needed in therapeutic approaches. Bone tumors are related to the existence of a vicious cycle between bone resorption and tumor proliferation in which the molecular triad osteoprotegerin (OPG)/receptor activator of NF-kappaB (RANK)/RANK ligand (RANKL) plays a pivotal role. RANKL, a member of the TNF superfamily, is one of the main inducers of bone resorption. Its soluble receptor OPG represents a promising therapeutic candidate as it prevents bone lesions and inhibits associated tumor growth. However, its therapeutic use in bone tumors remains controversial due to its ability to bind and inhibit another member of the TNF superfamily, TNF related apoptosis inducing ligand (TRAIL), which is a potent inducer of tumor cell apoptosis. Through its heparin binding domain, OPG is also able to bind proteoglycans present in the bone matrix. This paper is an overview of the involvement of the micro-environment, as represented by the balance of RANKL/TRAIL and the presence of proteoglycans in the regulation of OPG biological activity in bone tumors.

Preventing healthcare-associated infections: Residents and attending physicians need better training in advanced isolation precautions.

OBJECTIVE: Compliance with advanced isolation precautions (IPs) is crucial to reduce healthcare-associated infections. Our aim was to evaluate physician's knowledge and attitudes related to IPs. METHODS: An online questionnaire was sent to our hospital's physicians (attending physicians and residents). RESULTS: A total of 111 physicians completed the questionnaire: 60 (54%) attending physicians and 51 (46%) residents. Overall, respondents had a poor knowledge of the three types of IPs, especially droplet precautions (13 correct answers, 11.7%) and airborne IP (17 correct answers, 16.3%). We observed a statistically significant difference between attending physicians and residents for the type of IP to prescribe to a patient presenting with multidrug-resistant urinary infection: 44 residents (86%) gave the correct answer vs 42 attending physicians (70%), P=0.04. Physicians (both residents and attending physicians) who were already familiar with the dedicated webpage available on the hospital's intranet (n=40) obtained a score of 4.75/10 (±2.0) compared with 4.03/10 (±1.7) for those who had never used that tool (n=71). The difference was statistically significant (P=0.04). The average score for both residents and attending physicians was 4.3/10 (±1.9, range: 1-10). Attending physicians' and residents' scores were 4/10 (±1.8) and 4.5/10 (±1.9), respectively, but the difference was not statistically significant (P=0.14). CONCLUSION: Physicians' knowledge of IPs was insufficient. Improvement in medical training is needed. The use of a dedicated webpage on hospitals' intranet could help physicians acquire better knowledge on that matter.

[Carcinomatous meningitis: The radiation therapist's point of view]. / Méningite carcinomateuse: le point de vue de l'oncologue radiothérapeute.

Carcinomatous meningitis complicates 5 to 10% of cancers, essentially with breast cancers, lung cancers and melanomas. The incidence probably increased because of therapeutic advances in oncology. Treatment is based on external beam radiotherapy, systemic treatment, intrathecal chemotherapy and supportive care. The aim of this work was to review data on external radiation therapy and carcinomatous meningitis. There are few evidences on the subject, but it is a major topic of interest. A whole brain radiation therapy is indicated in case of brain metastases or clinical encephalitis. Focal radiation therapy is recommended on symptomatic, bulky or obstructive sites. The dose depends on performance status (20 to 40 Gy in five to 20 fractions), volume to treat and available techniques (classic fractionation or hypofractionation via stereotactic radiosurgery). The objective of radiation therapy is to improve quality of life. Association with systemic therapy improves overall survival. Administration of sequential intrathecal chemotherapy may also improve overall survival, but induces more toxicity. The use of new radiotherapy techniques and development of radiosensitizing molecules in patients with good performance status could improve survival in this frequent complication of cancer.

Pharmacological blocking of the osteoclastic biocorrosion of surgical stainless steel in vitro.

In vitro studies suggest that human osteoclasts (OC) are able to corrode surgical stainless steel 316L (SS). The aim of this study was to investigate whether osteoclastic biocorrosion can be blocked pharmacologically. Human OCs were generated in vitro from peripheral blood monocytic cells (PBMCs) in the presence of OC differentiation cytokines. The osteoclastic viability, differentiation, and resorptive function (on both bone and SS) were assessed using standard colorimetric cell viability assay 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenil)-2H-tetrazolium, inner salt (MTS), fluorescence microscopy, tartrate-resistant acid phosphatase expression (flow cytometry), and scanning electron microscopy. OCs cultured on SS were exposed to nontoxic concentrations of bafilomycin A1, amiloride hydrochloride, or zoledronic acid. The extent of biocorrosion was quantified using atomic emission spectrometry (to measure the concentration of metal ions released into the supernatant) and scanning electron microscopy. PBMCs differentiated into mature and functional OC in the presence of all the drugs used. Osteoclastic resorption of SS was noted with differences in the resorption pattern for all drug treatments. Under the drug treatments, single areas of osteoclastic resorption were larger in size but less abundant when compared with positive controls. None of the drugs used were able to inhibit osteoclastic biocorrosion of SS.

Therapeutic approach of primary bone tumours by bisphosphonates.

Bone tumours can be dissociated in two main categories: i) primary bone tumours (benign or malignant) including mainly osteosarcoma and other sarcomas.ii)and giant cell tumour and bone metastases originate from others cancer (Breast, prostate, kidney cancer, etc). These tumours are able to destroy or/and induce a new calcified matrix. However, the first step of bone tumour development is associated with an induction of bone resorption and the establishment of a vicious cycle between the osteoclasts and the tumour growth. Indeed, bone resorption contributes to the pathogenesis of bone tumour by the release of cytokines (IL6, TNFα) which govern the bone tumour's development and which are trapped into the bone matrix. Bisphosphonates (BPs) are chemical compounds of P-C-P structure with a high affinity for bone hydroxyapatite crystals. Thus, they have been used as a carrier for radio nucleotides to develop novel approaches of bone imaging. BPs exert also indirect anti-tumour activities in vivo. Indeed, BPs directly interfere with the bone microenvironment and target osteoclasts, endothelial cells and immune cells (tumour-associated macrophages, γ9δ2 T cells). BPs induce tumour cell death in vitro and same activity is suspected in vivo. The present review summarizes the mechanisms of actions of BPs as well as their clinical interests in bone primary tumours.

Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells.

We recently demonstrated original anti-tumor effects of zoledronic acid (Zol) on osteosarcoma cell lines independently of their p53 and Rb status. The present study investigated the potential Zol-resistance acquired by osteosarcoma cells after prolonged treatment. After 12 weeks of culture in the presence of 1 microm Zol, the effects of high doses of Zol (10-100 microm) were compared between the untreated rat (OSRGA, ROS) and human (MG63, SAOS2) osteosarcoma cells and Zol-pretreated cells in terms of cell proliferation, cell cycle analysis, migration assay and cytoskeleton organization. Long-term treatment with 1 microm Zol reduced the sensitivity of osteosarcoma cells to high concentrations of Zol. Furthermore, the Zol-resistant cells were sensitive to conventional anti-cancer agents demonstrating that this resistance process is independent of the multidrug resistance phenotype. However, as similar experiments performed in the presence of clodronate and pamidronate evidenced that this drug resistance was restricted to the nitrogen-containing bisphosphonates, we then hypothesized that this resistance could be associated with a differential expression of farnesyl diphos-phate synthase (FPPS) also observed in human osteosarcoma samples. The transfection of Zol-resistant cells with FPPS siRNA strongly increased their sensitivity to Zol. This study demonstrates for the first time the induction of metabolic resistance after prolonged Zol treatment of osteosarcoma cells confirming the therapeutic potential of Zol for the treatment of bone malignant pathologies, but points out the importance of the treatment regimen may be important in terms of duration and dose to avoid the development of drug metabolic resistance.