Clinical study evaluating the effect of bevacizumab on the severity of zoledronic acid-related osteonecrosis of the jaw in cancer patients.

This study aimed to evaluate the effect of bevacizumab (BVZ) on the severity of osteonecrosis of the jaw (ONJ) in a cohort of cancer patients treated with intravenous zoledronic acid (ZA). We reviewed 42 oncologic patients with ONJ between 2007 and 2010. Only patients with solids tumors and who had received ZA were included. Data analyses included age, sex, underlying disease, ZA and BVZ dosages, dental history and ONJ characteristics. Of the 42 ONJ patients treated with ZA, 10 also received BVZ. In the 10 ZA/BVZ patients, the mean duration of ZA treatment at the time of ONJ diagnosis was 12.4 months (±6.8), compared to 22.9 months (±4.8) in the 32 patients who received ZA only (p<0.05). Cox's model analysis of the delay to ONJ diagnosis confirmed the impact of BVZ on ONJ diagnosis. In the ZA/BVZ-treated group, 7 (70%) patients developed spontaneous osteonecrosis. Multiple logistic regression analysis showed that ZA/BVZ is associated with increased risk of developing spontaneous ONJ (OR 6.07; 95% CI, [1.3-28.2], p<0.05). And finally, the number of ONJ lesions was increased in the ZA/BVZ-treated group compared to the ZA group (p<0.01). Other clinical conditions as type of tumor (prostate, breast…), cancer severity or other chemotherapy drugs also could be involved in ONJ evolution. However, this study demonstrates for the first time the potential negative influence of BVZ on the incidence and severity of ONJ in patients receiving ZA. Within the study limits, our results suggest that combination ZA/BVZ treatment may possibly predispose to the development of spontaneous and earlier ONJ.

High frequency of BRAF V600E mutations in ameloblastoma.

Ameloblastoma is a benign but locally infiltrative odontogenic neoplasm. Although ameloblastomas rarely metastasise, recurrences together with radical surgery often result in facial deformity and significant morbidity. Development of non-invasive therapies has been precluded by a lack of understanding of the molecular background of ameloblastoma pathogenesis. When addressing the role of ERBB receptors as potential new targets for ameloblastoma, we discovered significant EGFR over-expression in clinical samples using real-time RT-PCR, but observed variable sensitivity of novel primary ameloblastoma cells to EGFR-targeted drugs in vitro. In the quest for mutations downstream of EGFR that could explain this apparent discrepancy, Sanger sequencing revealed an oncogenic BRAF V600E mutation in the cell line resistant to EGFR inhibition. Further analysis of the clinical samples by Sanger sequencing and BRAF V600E-specific immunohistochemistry demonstrated a high frequency of BRAF V600E mutations (15 of 24 samples, 63%). These data provide novel insight into the poorly understood molecular pathogenesis of ameloblastoma and offer a rationale to test drugs targeting EGFR or mutant BRAF as novel therapies for ameloblastoma.

Osteonecrosis of the jaw and nonmalignant disease: is there an association with rheumatoid arthritis?

OBJECTIVE: To review cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) occurring in association with benign disease and to describe and compare the clinical course and outcome for patients with BRONJ and rheumatoid arthritis (RA) or osteoporosis. METHODS: We retrospectively reviewed observations of all patients referred for treatment and followup for BRONJ from January 2007 to December 2011. Only patients with malignant disease were excluded. Demographic data, medical history, maxillofacial findings, BRONJ treatment, and followup were reviewed for each case. RESULTS: Over a 5-year period, we diagnosed 112 patients with BRONJ. Among these patients, 15 received bisphosphonate (BP) treatment for nonmalignant disease (mean age 65.7 ± 19.8 yrs, 80% women). Patients received BP for a variety of reasons: 8 (53%) to prevent osteoporosis in association with underlying RA; 6 (40%) to prevent idiopathic osteoporosis; and 1 (7%) to treat ankle algodystrophy. The mean oral BP exposure period was 48.4 months (median 36 mo). In 13 cases (86.6%), BRONJ was diagnosed following dental extraction. Of the 8 patients with RA, 5 (62.5%) were taking prednisone at the time of the discovery of BRONJ. Major surgery, sequestrectomy, or alveolectomy was performed in 9 patients (60%), all of whom healed within 3 to 36 months (mean 11.5 mo). Comparative analysis of all the variables showed no statistically significant differences between patients with RA and others. CONCLUSION: ONJ is a rare adverse effect of BP therapy, especially when administered orally. Within the limits of our study, we were unable to demonstrate a difference in BRONJ disease spectrum, clinical course, or outcome between patients with and those without RA.

Microsurgical reconstruction of the jaw with fibular grafts and implants.

Reconstructive treatments for jaw defects are complex procedures that can combine multiple techniques including fibula free flap (FFF) grafting. The purpose of this retrospective study was to document and share our experience on mandibular and maxillar reconstruction with FFF followed by secondary dental rehabilitation using implant insertion.We reviewed 198 patients treated by FFF grafting for mandibular and/or maxillary defects in our department during the past 11 years (1996-2007). A selection of 30 patients (18 males and 12 females, mean age of 46 y) with adequate criteria (hygiene, motivation, and prognosis) received secondary placement of osseointegrated implants. The implant success was clinically and radiographically evaluated.A total of 105 osseointegrated implants were placed in the grafted fibulas 5 months to 3 years after the reconstruction surgery. Only 4 implants were lost because of peri-implantitis (3 patients) and fibular fracture (1 patient); this corresponds to a 96.2% implant success rate.During the mean follow-up of 76 months, patient's satisfaction and functional and aesthetic results were evaluated. Radiologic findings indicated a low crest resorption around the implants despite an unfavorable crown-to-root ratio.The main difficulties in the reconstructions were lack of FFF height, absence of a vestibular groove, limitation of mouth opening, skin paddle thickness, and the reconstruction of surrounding tissues including the lip. Our management strategy is discussed.Prosthetic choice is fundamental to achieving patient-specific solutions. The prostheses used included sealed or screwed bridge, resin-bonded bridge, tooled bar, implant-borne denture, or implant-stabilized dentures. Dental implants may be used even in situations involving an unfavorable crown-to-root ratio and implant position by using milled bar and overdenture. The FFF provides a consistent bone graft that allows a reliable and predictable restoration with dental implants, leading to a satisfactory functional and aesthetic restoration.

P27, SKP2, and extra-cellular signal-related kinase signalling in human salivary gland mucoepidermoid carcinoma.

Extra-cellular signal-related kinase (ERK) can modulate P27 in several ways. ERK is phosphorylated in a subset of salivary gland mucoepidermoid carcinoma (MEC). We determined immunohistochemical expression of P27, SKP2, cyclin A, Ki67, phospho-RB, and phospho-ERK in 43 MEC. SKP2 correlated with tumour size, microscopic grade, and a worse prognosis. Cyclin A and Ki67 also predicted prognosis, and were correlated with SKP2. P27 did not predict prognosis. P27 had no inverse relationship with SKP2, and correlated with neither Ki67 nor cyclin A. Instead, P27 high expressers had higher levels of phospho-ERK and phospho-RB. When highly expressed, P27 co-localized with cyclin D1 in the nuclei. Relationships of P27 with ERK and RB and its nuclear co-localization with cyclin D1 favour the hypothesis that P27 is in complexes with cyclin D1. This may explain why P27 in contrast to SKP2 and cyclin A does not correlate with tumour cell proliferation and prognosis.

Patterning of the hyoid cartilage depends upon signals arising from the ventral foregut endoderm.

Hyoid bone is a part of the visceral skeleton which arises from both Hox-expressing (Hox+) and Hox-nonexpressing (Hox-) cephalic neural crest cells. In a previous work, we have demonstrated that the Hox- neural crest domain behaves as a naïve entity to which the ventral foregut endoderm confers patterning cues to specify the shape and orientation of the nasal and mandibular skeleton. By using ablation and grafting approaches, we have extended our study to the formation of the hyoid bone and tested the patterning ability of more caudal levels of the lateroventral foregut endoderm in the chick embryo at the early neurula stage. In this study, endodermal stripes have first been delineated according to the projection of mid- and posterior rhombencephalic structures. The extirpation of endodermal transverse stripes along the anteroposterior axis selectively hampers the formation of the ceratobranchials and epibranchials. Thus defined, the patterning ability of the endodermal stripes was further explored in their medial and lateral parts. When homotopically engrafted on the migration pathway of cephalic neural crest cells, ventromedial zones of endoderm lead to the formation of supernumerary basihyal and basibranchial, while lateral zones generate additional cartilaginous pieces recognizable as ceratobranchial and epibranchial. Taken together, our data demonstrate that, early in development, the ventral foregut endoderm exerts a regionalized patterning activity on the cephalic neural crest to build up the primary facial and visceral skeleton in jaws and neck and enable a map of the endodermal skeletogenic areas to be drawn. This map reveals that a cryptic metamerization of the anterior foregut endoderm precedes the formation of the branchial arches.