Odontogenic Myxomas Harbor Recurrent Copy Number Alterations and a Distinct Methylation Signature.

Odontogenic myxoma is a rare, benign, and locally aggressive tumor that develops in the tooth-bearing areas of the jaw. The molecular mechanisms underlying odontogenic myxomas are unknown and no diagnostic markers are available to date. The aim of this study was to analyze DNA methylation and copy number variations in odontogenic myxomas to identify new molecular signatures for diagnostic decision-making. We collected a cohort of 16 odontogenic myxomas from 2006 to 2021 located in the mandible (n = 10) and maxilla (n = 6) with available formalin-fixed paraffin-embedded or fresh frozen tumor tissue from a biopsy or resection material. Genome-wide DNA methylation and copy number variation data were generated from 12 odontogenic myxomas using the Illumina Infinium Methylation EPIC array, interrogating >850,000 CpG sites. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) revealed that odontogenic myxomas formed a distinct DNA methylation class. Copy number profiling showed recurrent whole-chromosome gains (trisomies) of chromosomes 5, 8, and 20 in all cases, and of chromosomes 10, 12, and 17 in all except one case. In conclusion, odontogenic myxomas harbor recurrent copy number patterns and a distinct DNA methylation profile, which can be used as an additional diagnostic tool in the appropriate clinical and radiologic context. Further research is needed to explain the genetic mechanisms caused by these alterations that drive these locally aggressive neoplasms.

Denosumab in Giant Cell Rich Tumors of Bone: An Open-Label Multicenter Phase II Study.

BACKGROUND: Since giant cell tumors of bone (GCTB) and other giant cell rich tumors of bone (GCRTB) share the histological presence of osteoclastic giant cells and expression of RANK/RANKL, we hypothesized that GCRTB will respond similarly to denosumab as GCTB. The primary objective of this study was to determine the efficacy of denosumab in patients with GCRTB that have recurred or require morbid surgery. METHODS: In this open-label, multicenter, phase II trial, patients with GCRTB were included (June 2018-March 2020). Recruitment was stopped because of low accrual. Patients received denosumab (120 mg) subcutaneously (SC) on day 1 of every 4-week cycle with a loading dose of 120 mg SC on days 8 and 15. RESULTS: Three patients were enrolled. One withdrew consent before start of study. The remaining patients had central giant cell granuloma of the jawbone (CGCG). Median treatment duration was 15 cycles (range 12-18). In both subjects, improvement in ossification of lesions was seen. Median follow-up was 28.5 months (range 20-37). One patient developed a recurrence for which surgery was performed. CONCLUSION: Due to critical emerging real-world data of denosumab in GCRTBs, the study was prematurely stopped and not supportive of use of denosumab for this indication. (ClinicalTrials.gov Identifier: NCT03605199).

A multidisciplinary care pathway improves quality of life and reduces pain in patients with fibrous dysplasia/McCune-Albright syndrome: a multicenter prospective observational study.

BACKGROUND: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) may cause pain, impaired ambulation and decreased quality of life (QoL). International guidelines advocate management of FD/MAS in a tertiary multidisciplinary care pathway, but no longitudinal data are available to support this recommendation. This multicenter prospective observational study aimed to evaluate effects of 1 year of treatment in the FD/MAS care pathway in 2 tertiary clinics on QoL and pain, assessed by change in Short Form 36 and Brief Pain Inventory between baseline and follow-up. Patients completing baseline questionnaires < 1 year after intake were classified as new referrals, others as under chronic care. RESULTS: 92 patients were included, 61 females (66%). 22 patients (24%) had monostotic disease, 16 (17%) isolated craniofacial FD, 27 (40%) polyostotic FD and 17 (19%) MAS. 26 were new referrals (28%) and 66 chronic patients (72%). Median age at baseline was 47 years (Q1-Q3 36-56). Skeletal burden correlated with baseline Physical Function (rs = - 0.281, p = 0.007). QoL was in all domains lower compared to the general population. New referrals reported clinically important differences (CID) over time in domains Physical Function (mean 67 ± SD24 to 74 ± 21, effect size (ES) 0.31, p = 0.020), Role Physical (39 ± 41 to 53 ± 43, ES 0.35, p = 0.066), Social Functioning (64 ± 24 to 76 ± 23, ES 0.49, p = 0.054), and Health Change (39 ± 19 to 53 ± 24, ES 0.76, p = 0.016), chronic patients in Physical Function (52 ± 46 to 66 ± 43, ES 0.31, p = 0.023) and Emotional Wellbeing (54 ± 27 to 70 ± 15, ES 0.59, p < 0.001). New referrals reported a CID of 1 point in maximum pain, average pain and pain interference, chronic patients reported stable scores. Change in pain interference and Role Physical were correlated (rs = - 0.472, p < 0.001). Patients with limited disease extent improved more than patients with severe disease. Patients receiving FD-related therapy had lower baseline scores than patients not receiving therapy and reported improvements in QoL after 1 year. Yet also patients without FD-related therapy improved in Physical Function. CONCLUSIONS: All FD-subtypes may induce pain and reduced QoL. A multidisciplinary care pathway for FD/MAS may improve pain and QoL, mainly in new referrals without MAS comorbidities with low baseline scores. Therefore, we recommend referral of patients with all subtypes of FD/MAS to specialized academic centers.

Bisphosphonate therapy in chronic diffuse sclerosing osteomyelitis/tendoperiostitis of the mandible: Retrospective case series.

This study aims to evaluate short-term and long-term results of bisphosphonate therapy in patients with diffuse sclerosing osteomyelitis/tendoperiostitis (DSO/TP) of the mandible. Eighteen patients (12 female, 6 male) aged 34.8 ± 22.2 years with DSO/TP of the mandible that were treated with bisphosphonates were included. In 16 patients, the bisphosphonate treatment led to remission with decrease of symptoms (pain, swelling of the cheek, trismus, tenderness of masticatory muscles) with a follow-up period of 4.5 (0.8-11.9) years between start of bisphosphonate treatment and latest follow-up consult. Of these, three patients were still in need of regular bisphosphonate therapy. Two patients were lost to follow-up. Bisphosphonate therapy is a treatment option for DSO/TP of the mandible that is associated with a high chance of remission of symptoms. Within the limitations of the study it seems that this treatment might be an effective second step in DSO/TP refractory to conservative treatment.

A comparison of the cone beam computed tomography findings in medication-related osteonecrosis of the jaws related to denosumab versus bisphosphonates: an observational pilot study.

OBJECTIVE: The aim of this study was to compare the radiographic abnormalities on cone beam computed tomography (CBCT) in patients with medication-related osteonecrosis of the jaws (MRONJ) related to denosumab use versus bisphosphonate use. STUDY DESIGN: The study included 34 consecutive patients with MRONJ who had a history of exclusive use of denosumab (n = 17) or bisphosphonates (n = 17) and had undergone CBCT for determination of extent of disease. Demographic data of the patients were collected. Differences in radiologic characteristics between patients with denosumab-related osteonecrosis of the jaws (DRONJ) and those with bisphosphonate-related osteonecrosis of the jaws (BRONJ) were scored and studied on CBCT. RESULTS: In patients with DRONJ, sequestra (P = .015) and lysis of the cortical border of the jaw (P = .033) were significantly less common than in patients with BRONJ. Subperiosteal bone formation did not differ between the groups (P = .545). There was no association between stage of disease and duration of drug therapy or duration of symptoms for either medication group. CONCLUSIONS: The radiologic features of DRONJ may be different from those of BRONJ with regard to the presence of sequestra and cortical lysis and might, therefore, be improperly diagnosed. Underestimation and undertreatment of DRONJ may potentially lead to progression of disease and, thus, make treatment more difficult.

Radiographic characteristics of chronic diffuse sclerosing osteomyelitis/tendoperiostitis of the mandible: A comparison with chronic suppurative osteomyelitis and osteoradionecrosis.

Diffuse sclerosing osteomyelitis (DSO) of the mandible is a poorly understood chronic disease. It is assumed to be a form of chronic osteomyelitis. Other forms of chronic osteomyelitis are chronic suppurative osteomyelitis (CSO) and osteoradionecrosis (ORN). This study aimed to investigate radiographic characteristics of DSO and compare these findings with the radiographic characteristics of CSO and ORN in order to radiographically distinguish these three diseases. In this retrospective study, 33 patients were clinically diagnosed with DSO (13), CSO (6), or ORN (14). The panoramic radiographs, computed tomography images, and magnetic resonance images of these patients were evaluated. Osseous and soft tissue changes were analysed. Patients with DSO showed extensive cortical and medullary sclerosis combined with subperiosteal bone formation, condylar process deformation, and hypertrophy and oedema of the masseter muscle. DSO patients showed no pathological fractures or sequestra, which were observed in patients with CSO and ORN. The radiographic characteristics that differentiate DSO from CSO and ORN include subperiosteal bone formation, condylar process deformation, masticatory muscle changes, and the absence of sequestra and pathological fractures.

Treatment of pathologic fractures of the mandible in stage III medication-related osteonecrosis of the jaw-an observational study.

PURPOSE: The treatment of pathologic fractures in stage III medication-related osteonecrosis of the jaw (MRONJ) remains challenging. The treatment in the literature is controversial, varying from extensive and aggressive surgery with resections and musculocutaneous free flap reconstruction to conservative treatment with only mouth rinses and/or antimicrobial treatment. The purpose of this study was to analyse the results of the treatment protocol in the Leiden University Medical Center in the Netherlands. MATERIALS AND METHODS: Between 2003 and 2017, a total of 15 consecutive patients were seen with pathologic fractures in stage III MRONJ. Patient characteristics and treatment were studied. RESULTS: Seven patients were dentate, and were all surgically treated according to protocol, with 3 additionally undergoing intermaxillary fixation. Eight patients were edentulous of whom 6 were surgically treated: 2 with osteosynthesis and the rest with a soft diet post-operatively for several weeks. One patient showed healing in a later stage and was not treated. Two patients were treated with antimicrobial treatment and a soft diet. Eleven patients (73%) showed complete healing of the fracture or a pseudarthrosis and were free of complaints and able to function. CONCLUSION: These results show that a relatively simple (surgical and/or antimicrobial) approach, combined with intermaxillary fixation on occasion, can lead to consolidation and/or a pseudarthrosis with a remaining and acceptable function of the jaw.

Bisphosphonate-related osteonecrosis of the jaws: Cohort study of surgical treatment results in seventy-four stage II/III patients.

INTRODUCTION: Bisphosphonates are used in the treatment of osteoporosis and bone metastases. They inhibit osteoclast function, thereby decreasing bone resorption. A side effect of these drugs is bisphosphonate-related osteonecrosis of the jaw (BRONJ), which can be difficult to treat. The purpose of this study was to evaluate the surgical treatment protocol used in our hospital for BRONJ patients. The patients were retrospectively analyzed and followed-up at the Leiden University Medical Center. METHODS: All patients who were referred to our hospital with therapy-resistant BRONJ between 2003 and 2014 were seen. At first presentation, the clinical features, medical and dental history, bisphosphonate use, and the use of other medications were recorded. Patients underwent surgical intervention, performed by senior surgeons, following the principles of our previously published protocol. RESULTS: Seventy-four patients were followed-up for 6-96 months. Curation was successful with this surgical approach in 93.2% of the patients. DISCUSSION: All the patients were cured with our surgical protocol, for up to 5 years after surgery. We conclude that this treatment protocol has a high success rate in treating all stages of BRONJ.

Evaluation of a surgical treatment of denosumab-related osteonecrosis of the jaws.

OBJECTIVE: Denosumab, a monoclonal antibody, is a relatively new antiresorptive agent that has recently shown a serious adverse effect: denosumab-related osteonecrosis of the jaws (DRONJ). The purpose of this study was to retrospectively observe the efficacy of the combined surgical and antimicrobial treatment of DRONJ. STUDY DESIGN: In this case series, all patients with osteonecrosis that occurred after starting treatment with denosumab, were treated with surgery and antimicrobial treatment and followed up. The primary outcome was healing of the jaw. For patient characterization, secondary variables, such as clinical features, denosumab use, dental history (including luxation), and duration of complaints, were studied. RESULTS: Eleven patients met the criteria to be included in this study. Nine patients experienced healing within 4 weeks after surgery. Two patients were not cured and died as a result of their underlying disease. In all patients, a dental focus was found. Six patients had been treated only with denosumab, and five had also been treated with bisphosphonates. CONCLUSIONS: We were able to achieve healing in 9 of the 11 patients with DRONJ. Our treatment protocol showed promising results; however, further research is needed.

'Autoreconstruction' of the Mandible-Report of a Case.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) was first mentioned in the literature in 2003. Since then, several reports have been published referring to this disease. The etiology of BRONJ still remains unclear. The treatment of BRONJ also remains a topic of discussion between those who are in favor of a conservative treatment and those who are convinced that surgical treatment gives the best results. In this case report, a patient is presented with BRONJ in the mandible which has been treated surgically in combination with antibiotic treatment. During surgery it appeared that a large part of the jaw was sequestrated full-thickness with, at the same time, formation of a substantial amount of subperiosteal bone that was formed around the BRONJ, supporting the sequestrated part of the mandible and, after sequestrectomy, serving as a neo-mandible. This case shows the capacity of the jawbone despite bisphosphonate use to regenerate itself.

Bisphosphonate related osteonecrosis of the jaws: spontaneous or dental origin?

OBJECTIVE(S): Bisphosphonates are frequently used worldwide mostly in osteoporosis and skeletal bone metastases. However, a serious side-effect is bisphosphonate related osteonecrosis of the jaws (BRONJ). The mechanism behind BRONJ remains unclear. In literature several origins are suggested. Presence of the teeth in the jaws may play an important role. Therefore in this study 45 patients were analyzed retrospectively. STUDY DESIGN: Files of 45 patients with a diagnosis of BRONJ were analyzed, meaning clinical features, bisphosphonate use, dental history including luxating moment and (previous) treatment. RESULTS: In 97.5% (n = 44) a certain or presumable dental focus, such as extractions, a previous dental treatment or prosthesis complaints were found as initiating factor of BRONJ. CONCLUSION: In contrast to findings in literature, in our group of patients a dental focus was found in 44 of 45 cases. This implies a dentoalveolar start of BRONJ with subsequent spreading into the jaws in nearly all cases.

Denosumab osteonecrosis of the mandible: a new entity? A case report.

In the treatment of osteoporosis, M. Kahler and bone metastases from prostate and breast cancer bisphosphonates play a major role. Not all patients respond well to bisphosphonate treatment. Since a few years adverse effects of these drugs have been reported. A new drug, denosumab, a fully human monoclonal antibody to RANKL, has recently been developed. This case reports a 74-year-old male patient with a medical history of diabetes mellitus, angina pectoris, coronary bypasses, hypertension, and prostate cancer with multiple metastases to lymph nodes, bone and lungs. The prostate cancer was treated according to the protocol. But he was never treated with bisphosphonates. Instead he was included in a phase III randomized double blind multicenter trial, testing the efficacy of denosumab compared to zoledronic acid in the treatment of bone metastases of hormone resistant prostate cancer. Only 7 months after start of denosumab infectious symptoms developed, followed by infestation of the mandible. Despite surgical treatment fistula and exposed bone remained. This case illustrates that use of denosumab can lead to a type of osteonecrosis resembling bisphosphonate related osteonecrosis of the jaws.