The differentiation of prehypertrophic into hypertrophic chondrocytes drives an OA-remodeling program and IL-34 expression.

OBJECTIVES: We hypothesize that chondrocytes from the deepest articular cartilage layer are pivotal in maintaining cartilage integrity and that the modification of their prehypertrophic phenotype to a hypertrophic phenotype will drive cartilage degradation in osteoarthritis. DESIGN: Murine immature articular chondrocytes (iMACs) were successively cultured into three different culture media to induce a progressive hypertrophic differentiation. Chondrocyte were phenotypically characterized by whole-genome microarray analysis. The expression of IL-34 and its receptors PTPRZ1 and CSF1R in chondrocytes and in human osteoarthritis tissues was assessed by RT-qPCR, ELISA and immunohistochemistry. The expression of bone remodeling and angiogenesis factors and the cell response to IL-1ß and IL-34 were investigated by RT-qPCR and ELISA. RESULTS: Whole-genome microarray analysis showed that iMACs, prehypertrophic and hypertrophic chondrocytes each displayed a specific phenotype. IL-1ß induced a stronger catabolic effect in prehypertrophic chondrocytes than in iMACs. Hypertrophic differentiation of prehypertrophic chondrocytes increased Bmp-2 (95%CI [0.78; 1.98]), Bmp-4 (95%CI [0.89; 1.59]), Cxcl12 (95%CI [2.19; 5.41]), CCL2 (95%CI [3.59; 11.86]), Mmp 3 (95%CI [10.29; 32.14]) and Vegf mRNA expression (95%CI [0.20; 1.74]). Microarray analysis identified IL-34, PTPRZ1 and CSFR1 as being strongly overexpressed in hypertrophic chondrocytes. IL-34 was released by human osteoarthritis cartilage; its receptors were expressed in human osteoarthritis tissues. IL-34 stimulated CCL2 and MMP13 in osteoblasts and hypertrophic chondrocytes but not in iMACs or prehypertrophic chondrocytes. CONCLUSION: Our results identify prehypertrophic chondrocytes as being potentially pivotal in the control of cartilage and subchondral bone integrity. Their differentiation into hypertrophic chondrocytes initiates a remodeling program in which IL-34 may be involved.

[Risk of radionecrosis after hypofractionated stereotactic radiotherapy targeting the postoperative resection cavity of brain metastases]. / Risque de radionécrose après radiothérapie hypofractionnée en conditions stéréotaxiques du lit opératoire de métastases cérébrales.

PURPOSE: To investigate the factors that potentially lead to brain radionecrosis after hypofractionated stereotactic radiotherapy targeting the postoperative resection cavity of brain metastases. METHODS AND MATERIALS: A retrospective analysis conducted in two French centres, was performed in patients treated with trifractionated stereotactic radiotherapy (3×7.7Gy prescribed to the 70% isodose line) for resected brain metastases. Patients with previous whole-brain irradiation were excluded of the analysis. Radionecrosis was diagnosed according to a combination of criteria including clinical, serial imaging or, in some cases, histology. Univariate and multivariate analyses were performed to determine the predictive factors of radionecrosis including clinical and dosimetric variables such as volume of brain receiving a specific dose (V8Gy-V22Gy). RESULTS: One hundred eighty-one patients, with a total of 189 cavities were treated between March 2008 and February 2015. Thirty-five patients (18.5%) developed radionecrosis after a median follow-up of 15 months (range: 3-38 months) after hypofractionated stereotactic radiotherapy. One third of patients with radionecrosis were symptomatic. Multivariate analysis showed that infra-tentorial location was predictive of radionecrosis (hazard ratio [HR]: 2.97; 95% confidence interval [95% CI]: 1.47-6.01; P=0.0025). None V8Gy-V22Gy was associated with appearance of radionecrosis, even if V14Gy trended toward significance (P=0.059). CONCLUSION: Analysis of patients and treatment variables revealed that infratentorial location of brain metastases was predictive for radionecrosis after hypofractionated stereotactic radiotherapy for postoperative resection cavities.

[Orodental status before radiation therapy of the head and neck area: A prospective analysis on 48 patients]. / État buccodentaire des patients avant radiothérapie des voies aérodigestives supérieures : analyse prospective de 48 patients.

PURPOSE: The treatment by irradiation of tumours of the upper head and neck tract cause many complications on the oral sphere, such as mucositis, dysphagia, asialia and tooth decay. Associated manifestations are frequent and their severity has been poorly studied. However, the patient's quality of life is directly correlated with their oral health. PATIENTS AND METHODS: We carried out an evaluation of the oral health of 48 patients with an upper head and neck tract cancer treated by irradiation at the Paul-Strauss Centre in Strasbourg. The inclusion criteria of this study concerned the localization of the tumour in the upper head and neck tract and a treatment by irradiation associated or not to chemotherapy. RESULTS: The patients of the study were concerned by alcohol and smoking intoxication, on average, 22.2 pack-year and 2.2 glasses of alcohol per day. They received an irradiation of 60.9Gy on average. Their oral health was characterized by a DMFT (decayed, missing, filled teeth) index of 16.1, with, in mean, eight missing teeth and eight filling teeth and, by the presence of dental plaque in 70% of cases. Along the treatment by irradiation, the oral complications evaluation showed that on average, patients developed mucositis 18 days after the beginning of radiotherapy, xerostomia after 20 days, and dysphagia after 17 days. At the end of the treatment, we noted an oral hygiene improvement, with teeth brushing more frequent (two to three per day), mouthwash use, and daily fluoride prophylaxis. CONCLUSION: This study provides insights of the dental status of patients irradiated in the oral cavity. This series lays the groundwork for the study of prosthesis requirement and dosimetry calculation.