Denosumab-related osteonecrosis of the jaw: A retrospective study.

BACKGROUND: Osteonecrosis of the jaw is a very delicate side effect of Denosumab. The aim of this retrospective study was to assess the occurrence rate of Denosumab-related osteonecrosis of the jaw (DRONJ) at the Cancer Institute of Lorraine (ICL) and to highlight necrosis risk factors. METHODS: To that purpose, we analyzed the medical records of 249 consecutive patients treated with Denosumab at the ICL during the past 5 years. Patients who received orofacial radiotherapy or a previous treatment with a bisphosphonate were excluded. The P-value was set at .005. RESULTS: A total of 141 patients treated at the ICL between January 2010 and December 2015 were included. All patients were treated with XGEVA® . Of the 141 patients included in the study, 10 developed DRONJ. The incidence of DRONJ increases with the duration of follow-up as follows: 3% at 1 year, 7% at 2 years, and 8% from 30 months on. No risk factor for necrosis could be identified except the realization of prior dental extraction (P = .025). CONCLUSION: Our results raise important questions about the dental management of these patients, in particular, concerning the healing period between dental extractions and the initiation of Denosumab.

Use of new targeted cancer therapies in children: effects on dental development and risk of jaw osteonecrosis: a review.

New targeted cancer therapies such as bisphosphonates, denosumab, and bevacizumab are routinely used in adult for the past decades. Their introduction into pediatric medicine is more recent that means there is a paucity of data on long-term effects on dental development and on the risk of osteonecrosis of jaw. This study aimed to outline adverse effects of new targeted cancer therapies on oral cavity including dental abnormalities observed in pediatric population treated with these molecules and the risk of osteonecrosis of the jaw (ONJ). The impact of bisphosphonates and denosumab on bone remodeling (inhibition of osteoclasts) could interfere with teeth exfoliation and eruption processes, causing a tooth eruption delay. This hypothesis was confirmed, bisphosphonate-treated rats presented tooth eruption delay, and bisphosphonate therapy was associated with a mean delay of 1.67 years in tooth eruption in children with osteogenesis imperfecta. Another study showed that the inhibition of RANK/RANKL by denosumab was associated with a lack of tooth eruption in animals. Several animal studies reported that bisphosphonate could also induce dental abnormalities including defective amelogenesis and dentinogenesis in rats, but there is no evidence of such effects in children; only one case of enamel hypoplasia in a child treated for idiopathic arterial calcification with bisphosphate was reported. To date, there has been no reported case of ONJ in children treated with bisphosphonates, denosumab, or bevacizumab.

Feasibility of treating irradiated bone with intramedullary delivered autologous mesenchymal stem cells.

BACKGROUND: We aimed to explore (i) the short-term retention of intramedullary implanted mesenchymal stem cells BMSCs and (ii) their impact on the bone blood flow and metabolism in a rat model of hindlimb irradiation. METHODS: Three months after 30 Gy irradiation, fourteen animals were referred into 2 groups: a sham-operated group (n = 6) and a treated group (n = 8) in which ¹¹¹In-labelled BMSCs (2 × 106 cells) were injected in irradiated tibias. Bone blood flow and metabolism were assessed by serial (99m)Tc-HDP scintigraphy and 1-wk cell retention by recordings of (99m)Tc/¹¹¹In activities. RESULTS: The amount of intramedullary implanted BMSCs was of 70% at 2 H, 40% at 48 H, and 38% at 168 H. Bone blood flow and bone metabolism were significantly increased during the first week after cell transplantation, but these effects were found to reduce at 2-mo followup. Conclusion. Short-term cell retention produced concomitant enhancement in irradiated bone blood flow and metabolism.

A Comparison of the Clinical and Radiological Extent of Denosumab (Xgeva®) Related Osteonecrosis of the Jaw: A Retrospective Study.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of antiresorptive medication. The aim of this study was to evaluate the incidence of denosumab-related osteonecrosis of the jaw and to compare the clinical and radiological extent of osteonecrosis. A retrospective study of patients who received Xgeva® at the Institut de Cancérologie de Lorraine (ICL) was performed. Patients for whom clinical and radiological (CBCT) data were available were divided into two groups: "exposed" for patients with bone exposure and "fistula" when only a fistula through which the bone could be probed was observed. The difference between clinical and radiological extent was assessed. The p-value was set at 0.05, and a total of 246 patients were included. The cumulative incidence of osteonecrosis was 0.9% at 6 months, 7% at 12 months, and 15% from 24 months. The clinical extent of MRONJ was significantly less than their radiological extent: in the "exposed" group, 17 areas (45%) were less extensive clinically than radiologically (p < 0.001) and respectively 6 (67%) for the "fistula" group (p < 0.031). It would seem that a CBCT is essential to know the real extent of MRONJ. Thus, it would seem interesting to systematically perform a CBCT during the diagnosis of MRONJ, exploring the entire affected dental arch.

Brain abscesses and intracranial empyema due to dental pathogens: Case series.

INTRODUCTION: Spontaneous brain abscess and intracranial empyema are rare but life-threatening diseases. They can result from potential complications of oral chronic infections. Given the similarity between most of the germs commonly found both in cerebral abscess and in oral cavity and its anatomic proximity, the oral cavity represents a major source of cerebral infections. PRESENTATION OF CASES: We report here a series of seven cases of intracranial abscesses and empyema due to dental pathogens that occurred in the neurosurgery department of our institute. Five of those seven cases were then cared in the oral surgery department of our institute. DISCUSSION: Bacteriological examination of the brain abscesses identified an oral commensal bacterium belonging to streptococci group in six patients (85.7%) and Porphyromonas Gingivalis, a pathogen oral germ involved in periodontal diseases in the seventh patient. For all patients examined, oral status and oral health were poor or moderate with the presence of dental caries, missing teeth and abundant dental plaque. Except the oral cavity, no other front door or infectious site were found. CONCLUSION: This rare series of cases highlights the importance of systematically explore the oral cavity in presence of intracranial infection and to radically eradicate the potential infectious foci.

Oral management in a patient with Gardner-Diamond Syndrome: A case report.

INTRODUCTION: Gardner-Diamond Syndrome (GDS) is rare. It is characterized by the spontaneous formation of painful erythematous skin lesions that develop into ecchymoses within 24 h and then disappear progressively over days to weeks. The complications can be serious. PRESENTATION OF CASE: A 35-year-old man with GDS was admitted to the oral surgery department for dental infectious focus eradication. Clinical and radiological examinations indicated extraction of tooth 17. It was performed with local anaesthesia, cardiac monitoring, and verbal reassurance therapy. After delivering anaesthesia, two intra-oral hematomas and a bruise quickly developed. Cardiovascular manifestations and a spontaneous painful right temporal erythematous skin lesion appeared in the next 24 h. The patient was briefly hospitalized in the cardiovascular medicine department. Over the next 21 days, some haematomas regressed, another expanded, and a new cervico-thoracic ecchymosis developed. DISCUSSION: The surgical and post-surgical complications in this clinical case raise several points concerning the oral management of patients with GDS. We propose to apply: verbal reassurance therapy during surgery; presurgical haematological evaluation and postsurgical daily haematological follow-up; and atraumatic surgery with intra- and post-surgical haemostatic precautions. Systematic antibiotic prophylaxis and non-steroidal anti-inflammatory drugs may also be useful. Other possibilities include desmopressin acetate, corticosteroids, antihistamines, plasmapheresis, and immunosuppressive agents; however, few cases have been treated with these strategies. CONCLUSION: This case highlights the difficult management of patients with GDS who require oral surgery. Further studies are needed to improve the oral surgical procedures in these patients and to establish a systematic management algorithm.

Experimental model of naturally occurring post-radiation sarcoma: interest of positron emission tomography (PET) for early detection.

Radiotherapy is an integral part of overall cancer therapy. One of the most serious adverse effects of irradiation concern, for long-term survivors, the development of post-radiation sarcoma (PRS) in healthy tissues located within the irradiated area. PRS have bad prognosis and are often detected at a late stage. Therefore, it is obvious that the early detection PRS is a key-point and the development of preclinical models is worthy to evaluate innovative diagnostic and therapeutic procedures. The aim of this study was to develop a spontaneous rodent model of PRS and to evaluate the potency of Positron Emission Tomography (PET) for early detection. Fifteen Wistars rats were irradiated unilateraly on the hindlimb with a single dose of 30 Gy. Sequential analysis was based on observational staging recordings, Computerized Tomography (CT) scanning and PET. Tumors were removed and, histopathological and immunochemistry analyses were performed. Among the irradiated rats, 12 sarcomas (80%) were detected. All tumors occurred naturallty within the irradiated hindlimb and were highly aggressive since most tumors (75%) were successfully transplanted and maintained by serial transplantation into nude mice. Upon serial staging recordings, using PET, was found to enable the detection of PRS earlier after irradiation than with the other methods (i.e. 11.9 ± 1.8 vs 12.9 ± 2.6 months). These results confirmed the interest of experimental models of PRS for the preclinical evaluation of innovative diagnostic strategies and confirmed the potency of PET for early detection of PRS. This preclinical model of PRS can also be proposed for the evaluation of therapeutic strategies.

[Salvage surgery for upper aerodigestive tract tumours]. / Chirurgie de rattrapage dans les tumeurs des VADS.

Salvage surgeries of head and neck tumors are considered as poor satisfactory either for disease control results or for aesthetic and functional outcomes. Several improvements have been made possible since few years in all fields of oncologic treatments. A new approach must be initiated in that context, moreover since take in charge for head and neck region (exclusive initial medical treatment) let us consider an increasement of clinical situations for which a salvage therapy could be performed. The new surgery techniques have to be considered, reconstructive and guided by systems, which can improve surgical skills (navigation, robotic, sentinel node procedure, nervous detection and so on), the help of reirradiation techniques, the use of medical therapy during surgical procedure, the photodynamic therapy and all the help provided by new medical imaging and modern biology, which can determine more precisely the status of the cancer when it is taken in charge. The mastery of those techniques improvements must follow on an evolution of the concepts in the field of combined salvage treatments performed by multidisciplinary teams. Those treatments have to be realized in structures, which have the techniques and the multiple skills for allowing increasement of outcomes of those severe diseases.

Long-term alterations of cytokines and growth factors expression in irradiated tissues and relation with histological severity scoring.

PURPOSE: Beside its efficacy in cancer treatment, radiotherapy induces degeneration of healthy tissues within the irradiated area. The aim of this study was to analyze the variations of proinflammatory (IL-1α, IL-2, IL-6, TNF-α, IFN-γ), profibrotic (TGF-ß1), proangiogneic (VEGF) and stem cell mobilizing (GM-CSF) cytokines and growth factors in an animal model of radiation-induced tissue degeneration. MATERIALS AND METHODS: 24 rats were irradiated unilaterally on the hindlimb at a monodose of 30 Gy. Six weeks (n=8), 6 months (n=8) and 1 year (n=8) after irradiation the mediators expression in skin and muscle were analyzed using Western blot and the Bio-Plex® protein array (BPA) technology. Additional histological severity for fibrosis, inflammation, vascularity and cellularity alterations scoring was defined from histology and immnunohistochemistry analyses. RESULTS: A significant increase of histological severity scoring was found in irradiated tissue. Skin tissues were more radio-sensitive than muscle. A high level of TGF-ß1 expression was found throughout the study and a significant relation was evidenced between TGF-ß1 expression and fibrosis scoring. Irradiated tissue showed a chronic inflammation (IL-2 and TNF-α significantly increased). Moreover a persistent expression of GM-CSF and VEGF was found in all irradiated tissues. The vascular score was related to TGF-ß1 expression and the cellular alterations score was significantly related with the level of IL-2, VEGF and GM-CSF. CONCLUSION: The results achieved in the present study underline the complexity and multiplicity of radio-induced alterations of cytokine network. It offers many perspectives of development, for the comprehension of the mechanisms of late injuries or for the histological and molecular evaluation of the mode of action and the efficacy of rehabilitation techniques.

Re-assessment of chronic radio-induced tissue damage in a rat hindlimb model.

Radiotherapy is successfully used to treat neoplastic lesions, but may adversely affect normal tissues within the irradiated volume. However, additional clinical and para-clinical data are required for a comprehensive understanding of the pathogenesis of this damage. We assessed a rat model using clinical records and medical imaging to gain a better understanding of irradiation-induced tissue damage. The hindlimbs of the rats in this model were irradiated with a single dose of 30 or 50 Gy. Sequential analysis was based on observation records of stage and planar scintigraphy. Additional radiography, radiohistology and histology studies were performed to detect histological alterations. All animals developed acute and late effects, with an increased severity after a dose of 50 Gy. The bone uptake of (99m)Tc-HDP was significantly decreased in a dose- and time-dependent manner. Histologically, significant tissue damage was observed. After the 50 Gy irradiation, the animals developed lesions characteristic of osteoradionecrosis (ORN). Radiographic and histological studies provided evidence of lytic bone lesions. Our rat model developed tissue damage characteristic of radiation injury after a single 30 Gy irradiation and tissue degeneration similar to that which occurs during human ORN after a 50 Gy irradiation. The development of this animal model is an essential step in exploring the pathogenesis of irradiation-induced tissue damage, and may be used to test the efficacy of new treatments.

Rehabilitation of irradiated head and neck tissues by autologous fat transplantation.

BACKGROUND: Treatment of head and neck cancers allows good carcinologic results but induces aesthetic and functional sequelae. Autologous fat transplants have been used to correct aesthetic defects since the past century and exhibit many of the qualities of the ideal filler. Results reported here stem from experiences from 2000, with abdominal fat grafting in 11 patients who were referred to the authors' center for aesthetic subcutaneous or submucous head and neck reconstruction after radiotherapy. METHODS: Abdominal fat tissues were harvested, and injection into host sites was performed in a manner similar to that of the lipostructure technique described by Coleman. The postoperative follow-up periods ranged from 2 to 88 months (mean, 39.9 months). Clinical monitoring of the patients was carried out. Additional pathologic study was performed on irradiated tissues surrounding the scar and on abdominal fat and treated tissues. RESULTS: No surgical procedure complications occurred. For all cases, except for one patient, the rehabilitation was aesthetic and functional. The quality of life of the patients was improved. The pathologic data highlighted a decrease in irradiated morphologic patterns characterized by an absence of necrotic areas and a high vascular network density associated with a normal histologic structure. CONCLUSIONS: Fat tissues can be successfully transplanted into irradiated areas, inducing both aesthetic and functional improvement. The cellular and/or tissular mechanisms underlying these changes need further investigation.