The role of M1 and M2 macrophage polarization in progression of medication-related osteonecrosis of the jaw.

OBJECTIVES: The aim of this study was to investigate the relationship between M1 and M2 macrophage polarization and clinical stage in patients with medication-related osteonecrosis of the jaw (MRONJ) who underwent treatment with bisphosphonates or denosumab. MATERIALS AND METHODS: M1 and M2 macrophage density and expression of interleukin (IL)-6 and IL-10 were assessed on biopsies of mucosal tissues surrounding necrotic bone in 30 MRONJ patients with stages 1-3 and controls. For identification of M1 and M2 macrophages, double CD68/iNOS and CD68/CD206 immunofluorescence staining was conducted, respectively. Computer-assisted immunofluorescence quantification of markers was performed. RESULTS: Early stage 1 MRONJ patients showed a switch toward the M2 phenotype, as indicated by the higher density of M2 macrophages, the decreased M1/M2 ratio, and the upregulation of IL-10. MRONJ patients with advanced stages 2 and 3 showed a shift toward M1-polarized macrophages, as suggested by the higher density of M1 macrophages, the increased M1/M2 ratio, and the overexpression of IL-6. The macrophage density of both M1 and M2 subsets was significantly enhanced in patients receiving bisphosphonates compared with those receiving denosumab. CONCLUSIONS: The M1-M2 macrophage polarization status in mucosal tissues bordering necrotic bone correlates with clinical stage of MRONJ. Patients with early-stage MRONJ show a switch toward M2-polarized macrophages, while MRONJ patients with advanced stage demonstrate a shift toward the M1 phenotype. CLINICAL RELEVANCE: Therapeutic molecules targeting the inflammatory microenvironment via the regulation of either M1 or M2 macrophage polarization may represent a novel strategy for treatment of MRONJ.

The use of crevicular fluid to assess markers of inflammation and angiogenesis, IL-17 and VEGF, in patients with solid tumors receiving zoledronic acid and/or bevacizumab.

PURPOSE: Crevicular fluid was used to assess interleukin-17 (IL-17) and vascular endothelial growth factor (VEGF) in cancer patients receiving zoledronic acid and/or bevacizumab. The markers were also assessed in the serum. METHODS: Twenty-five patients were included and comprised three groups: patients who received zoledronic acid (n = 9), patients who received bevacizumab (n = 9), and patients who received zoledronic acid combined with bevacizumab (n = 5). One patient received zoledronic acid and everolimus and another received zoledronic acid, bevacizumab, and temsirolimus. IL-17 and VEGF were measured by standard quantitative ELISA kits and assessed in two study points. RESULTS: Twenty-four patients maintained good periodontal health; one had asymptomatic osteonecrosis of the jaw. First assessment: 44 samples were collected; 21 from serum and 23 from crevicular fluid. Second assessment, 6 months later: 11 samples were collected; 6 from serum and 5 from crevicular fluid. IL-17 was detected in all samples, in serum and crevicular fluid, and remained unchanged at both time points. Serum VEGF in patients with bevacizumab alone or combined with zoledronic acid was significantly lower compared with that of patients who received zoledronic acid alone. VEGF was not detected in the crevicular fluid. CONCLUSIONS: Crevicular fluid might be an easy, non-invasive means to assess IL-17. The stable values of IL-17 in crevicular fluid and serum and the lack of VEGF in the crevicular fluid could be related to the good periodontal health of our patients. Further studies are needed to assess IL-17 and VEGF in the crevicular fluid in patients with and without periodontal disease.

Alveolar bone histological necrosis observed prior to extractions in patients, who received bone-targeting agents.

OBJECTIVE: We reported the alveolar bone histology prior to dental extractions in cancer patients, who received bone-targeting agents (BTA). SUBJECTS AND METHODS: Fifty-four patients were included. Patients underwent extractions, and bone biopsies were taken. RESULTS: Extractions were performed due to pain, swelling, purulence, fistula, and numbness, not responding to treatment, in 40 patients (group A); extractions due to asymptomatic, non-restorable teeth, were performed in 14 patients (group B). Complete alveolar jaw bone histological necrosis was observed in 28 of 40 (70%) patients of group A and none of group B (p < .001). The development of clinical osteonecrosis (MRON) was assessed in 44 patients; 10 patients, who were also treated with Low Level Laser Treatments-LLLT, were excluded from this analysis, as the alternative therapies were a confounding factor. Twelve patients, with alveolar bone histological necrosis prior to extraction, developed medication-related osteonecrosis of the jaw (MRONJ) compared with two patients with vital or mixed vital/non-vital bone (p < .0007). BTAs >1 year and concurrent targeted therapy were also significantly associated with MRONJ (p = .016 and p = .050). CONCLUSION: Pain, swelling, purulence, fistula, and numbness were significantly associated with complete bone histological necrosis prior to extractions and increased MRONJ development. Research is justified to explore whether histological necrosis represents an early stage of osteonecrosis.

Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review.

INTRODUCTION: The reporting of osteonecrosis of the jaw (ONJ) related to anticancer agents without known antiresorptive properties (non-antiresorptives), such as antiangiogenics, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, immune checkpoint inhibitors, and cytotoxic chemotherapy is increasing. OBJECTIVE: To review characteristics of ONJ in cancer patients receiving non-antiresorptives. METHODS: A systematic review of the literature between 2009 and 2017 was conducted by the Bone Study Group of MASCC/ISOO. RESULTS: Of 6249 articles reviewed and from personal communication, 42 ONJ cases related to non-antiresorptives were identified. No gender predilection was noted. Median age was 60 years and ONJ stage 2 was most common, with predilection for posterior mandible. Exposed bone, pain, and infection were common at diagnosis. In comparison to bone targeting agents (BTAs), radiology, histology, and management were similar, with medication often discontinued. Delayed diagnosis (median 8 weeks) was noted. Important differences included earlier time to ONJ onset (median 20 weeks), absence of trigger event (40%), and greater likelihood of healing and shorter healing time (median 8 weeks) as compared to BTA-related ONJ. Gastrointestinal cancers predominated, followed by renal cell carcinomas compared to breast, followed by prostate cancers in BTA-related ONJ, reflecting different medications. CONCLUSIONS: Data about non-antiresorptive-related ONJ is sparse. This type of ONJ may have better prognosis compared to the BTA-related ONJ, suggested by greater likelihood of healing and shorter healing time. However, the delay in diagnosis highlights the need for more education. This is the first attempt to characterize ONJ associated with different non-antiresorptives, including BRAF and immune checkpoint inhibitors.

A systematic review of dental disease management in cancer patients.

INTRODUCTION: This systematic review aims to update on the prevalence of odontogenic-related infections and the efficacy of dental strategies in preventing dental-related complications in cancer patients since the 2010 systematic review. REVIEW METHOD: A literature search was conducted in the databases MEDLINE/PubMed and EMBASE for articles published between 1 January 2009 and 30 June 2016. Each study was assessed by 2 reviewers and the body of evidence for each intervention was assigned an evidence level. RESULTS: After examination of the abstracts and full-text articles, 59 articles satisfied the inclusion criteria. The weighted prevalence of dental infections and pericoronitis during cancer therapy was 5.4 and 5.3%, respectively. The frequency of dental-related infections during intensive chemotherapy after complete, partial, and minimal pre-cancer dental evaluation/treatment protocols ranged from 0 to 4%. Protocols involving third molars extractions had the highest complications (40%). CONCLUSIONS: In view of the low prevalence of infections and the potential for complications after third molar extractions, it is suggested that partial dental evaluation/treatment protocols prior to intensive chemotherapy; whereby minor caries (within dentin), asymptomatic third molars or asymptomatic teeth without excessive probing depth (<8 mm), mobility (mobility I or II) or with periapical lesions of <5 mm were observed; is a viable option when there is insufficient time for complete dental evaluation/treatment protocols. The use of chlorhexidine, fluoride mouth rinses as well as composite resin, resin-modified glass ionomer cement (GIC), and amalgam restorations over conventional GIC in post head and neck radiation patients who are compliant fluoride users is recommended.

Impact of COVID-19 Disease on the Development of Osteomyelitis of Jaws: A Systematic Review.

Background/Objectives: Osteomyelitis is characterized by an inflammatory process affecting both bone and bone marrow, leading to cell death and the formation of bone sequestrum. Recent literature from the past five years has documented instances of osteomyelitis following infections of SARS-CoV-2. This systematic review explores the link between osteomyelitis of the jaw (OMJ) and COVID-19 infections. Methods: This review adhered to the PRISMA guidelines, systematically analyzing literature from 2020 to 2024 sourced from databases including Medline, Embase, Scopus, and Web of Science. PROSPERO ID: CRD42024526257. Results: The review selected 42 articles, detailing 201 cases of osteomyelitis of the jaw related to COVID-19 (COMJ). The demographic breakdown included 195 male (74.4%) and 67 female patients (25.6%), with a median age of 52.7 years, ranging from 24 to 71 years. A significant portion of COMJ patients (41.5%) were hospitalized due to COVID-19, and 58.5% received corticosteroid therapy. Diabetes mellitus was a common comorbidity among COMJ patients (65.1%). Most cases involved maxilla (182 cases; 90.5%), with nearly half showing sinus involvement (49.4%). The mandible was affected in 19 cases (9.5%). Mucormycosis and aspergillosis emerged as the predominant fungal infections, identified in 103 (51.2%) and 50 (24.9%) cases, respectively. Conclusions: Individuals with pre-existing health conditions such as diabetes mellitus who have been treated for COVID-19 are at an increased risk of developing OMJ, particularly maxillary fungal osteomyelitis. COMJ poses a significant diagnostic and therapeutic challenge for dental and maxillofacial professionals, who are often the first to encounter these cases.

Orthodontic treatment as triggering factor of Medication Related Osteonecrosis of the Jaw in a breast cancer patient. Report of a rare case.

Background: Orthodontic treatment in adult patient is widely accepted nowadays. Therefore, orthodontists are needed to interact with more complex medical histories that may interfere with the orthodontic treatment. Antiresorptive medication is a widely used treatment for osteoporosis or malignancies that may affect the orthodontic movement and planning. Case presentation: A 53-year-old patient diagnosed with MRONJ one year after she started orthodontic treatment. Patients' medical history includes breast cancer and treatment with high doses of denosumab for over 2 years. The patient had a drug holiday period in the start of orthodontic treatment and then resumed antiresorptive medication until extreme tooth mobility was observed during the orthodontic treatment. After a long absence from denosumab and failure of conservative means to control the established MRONJ we proceeded in surgical management of the affected area. After two relapse the patient is now stable and prosthetically rehabilitated. Discussion: The affected area was the only one treated orthodontically and in lack of other triggering factors such as extraction or acute inflammation we consider the orthodontic movement as triggering factor of MRONJ. BPs are widely known to affect orthodontic treatment as they suppress bone remodeling but there is a lack of literature as far as patients treated with denosumab or high doses of antiresorptive medication concern. Conclusions: Patients treated with high doses of antiresorptive medication should considered at high risk of developing MRONJ during orthodontic movement. Although, more studies are needed to establish a protocol for the patients seeking orthodontic treatment and treated with denosumab. Key words:Medication Related Osteonecrosis of the Jaw, MRONJ, orthodontic treatment, bisphosphonates, denosumab, antiresorptive medication, surgical management.

Co-existence of Congenital Epidermoid Cyst and Ranula in a Newborn. Report of a Unique Case.

Background: Congenital cystic swellings involving the floor of the mouth include various lesions such as developmental cysts (e.g., dermoid and epidermoid cysts), ranulas, vascular malformations etc. However, coexistence of such conditions, possibly with a cause-and-effect- relationship, is rare. The purpose of this case report is to present a rare case of a congenital epidermoid cyst associated with a mucous retention cyst in a newborn. Methods: A 6-month-old female infant was referred to an Oral Medicine Clinic in Athens, Greece on October 2019 for evaluation of a swelling at the floor of the mouth, first noticed by her paediatrician just after birth. Clinically, a yellowish "pearly" nodule in close association with the orifice of the left submandibular duct, posteriorly transitioning to a diffuse bluish cystic swelling of the left floor of the mouth was observed. With a provisional diagnosis of a dermoid cyst and/or ranula, a surgical excision was performed under general anaesthesia. Results: Histopathologically, a well-defined, keratin-filled, cystic cavity lined by orthokeratinized stratified squamous epithelium was observed in the anterior aspect while posteriorly and in close proximity, a dilated salivary duct lined by cylindrical, cuboidal or pseudostratified epithelium was noted. A final diagnosis of an epidermoid cyst intimately associated with a mucus retention cyst (ranula) of the submandibular duct was rendered. Conclusions: The coexistence of two cystic lesions in the floor of the mouth with features of epidermoid and mucous retention cyst, respectively, is rare and its pathogenesis intriguing, especially in a newborn.

Experimental study of the effect of autologous platelet-rich plasma on the early phases of osteoinduction by allogenic demineralized bone matrix.

PURPOSE: To evaluate the effect of autologous platelet-rich plasma (PRP) on the early phases of osteoinduction by allogenic demineralized bone matrix (DBM) in rabbit intramuscular positions. MATERIALS AND METHODS: Allogenic DBM was produced from bones of 3 healthy rabbits. In each of 6 experimental animals, 0.3 mL autologous PRP was prepared and 2 muscle pouches were created, where 250 mg DBM + PRP (experimental sites) and 250 mg DBM without PRP (control sites) were randomly implanted. Animals were euthanized 3 weeks postoperatively. RESULTS: Histologic examination revealed uneventful healing in all cases, whereas remineralization of the periphery of the bone graft particles was a constant finding. In both control and experimental sites, fibroblasts and other mesenchymal cells (probably osteoprogenitor cells and preosteoblasts) were observed. The main histological difference was the recolonization of the empty lacunae of the bone graft particles by osteocytes at the control sites. The degradation of the graft at the control sites was statistically significantly quicker, although a statistically significant difference regarding the amount of the newly formed fibrous connective tissue was not observed. CONCLUSION: The present study demonstrated that in this experimental model, the addition of PRP to DBM had a negative effect on the early phases of osteoinduction at 3 weeks of observation.

Aplasia of the Major and Minor Salivary Glands: Report of a Rare Case.

Background: Aplasia of the salivary glands, either partial or involving all the major and possibly the minor salivary glands, is a very rare cause of hyposalivation. The aim of this case report is to present a case of aplasia of the major and minor salivary glands and discuss the relevant literature. Methods: A 23-year-old woman, with a non-contributory medical and family history was referred due to rampant caries, that could not be attributed to any obvious aetiology. No sicca symptoms, previous parotid gland swelling or general symptoms were reported. Clinically, oral mucosa dryness and extended dental erosions and caries were observed, while the orifices of the excretory ducts of the parotid and submandibular salivary glands were not evident. Unstimulated and stimulated saliva flow rates were severely diminished, while a diagnostic biopsy of the lower lip revealed absence of minor salivary glands. Detailed hematologic and immunological investigations to exclude systemic disorders were also within normal limits. Ultrasound and magnetic resonance imaging revealed the absence of all major salivary glands, confirming the clinical diagnosis of congenital aplasia of the salivary glands. Results: Oral hygiene instructions and dietary advice were given while dental products with fluoride and saliva substitutes were administered and appropriate dental treatment was implemented. Regular dental follow-up was also advised. Conclusions: Timely diagnosis of aplasia of the salivary glands is important, considering the detrimental effects of the absence of saliva on oral health. Management consists of the use of saliva substitutes, nutritional adaptation, maintenance of oral health and regular dental follow-ups.

Oral Side Effects in Patients with Metastatic Renal Cell Carcinoma Receiving the Antiangiogenic Agent Pazopanib-Report of Three Cases.

Pazopanib is a potent multi-kinase inhibitor that hinders angiogenesis and blocks tumor growth. It has been approved for the treatment of metastatic renal cell carcinoma (mRCC) and advanced soft tissue sarcoma. There is emerging evidence that bleeding is a common adverse effect of pazopanib and other targeted therapies in patients with mRCC. In addition, jaw osteonecrosis related to pazopanib was recently described in the literature. We report three cases of patients with mRCC who developed adverse oral events related to pazopanib. The first patient, treated with pazopanib as monotherapy, presented with gingival bleeding and oral burning sensation. The other two patients receiving pazopanib as monotherapy and pazopanib followed by sunitinib, respectively, presented complaining about mandibular pain; a diagnosis of medication-related osteonecrosis of the jaw (MRONJ) was rendered in both cases. Gingival bleeding and MRONJ may develop as oral side effects of pazopanib use. The cases presented here aim to alert and inform health care professionals about the risk of adverse oral events in patients with mRCC receiving the antiangiogenic agent pazopanib.

Diagnostic challenges in a diffuse large B-cell lymphoma of the maxilla presenting as exposed necrotic bone.

Lymphoma is the second most common malignancy in the head and neck area, affecting both nodal and extranodal sites, including oral soft and hard tissues, usually in the form of non-Hodgkin's lymphoma (NHL). However, lymphomas of the jaws, including diffuse large B-cell lymphoma (DLBCL), the most common type of NHL, are very rare and may cause significant diagnostic challenges resembling common jaw pathologies, such as periapical lesions, osteomyelitis and osteonecrosis. The aim of this paper is to present a rare case of DLBCL in an 84-years-old diabetic male patient on methylprednisolone treatment for autoimmune hemolytic anemia. The lesion appeared clinically as exposed necrotic bone of the maxilla with surrounding soft tissue ulceration and radiographically as an extensive osteolytic lesion with ill-defined borders. Despite the resemblance of the lesion with osteonecrosis or osteomyelitis that could be theoretically related to diabetes and/or systemic use of corticosteroids, histopathologic examination, necessitating a repeat biopsy in order to acquire sufficient tissue, revealed the final diagnosis of lymphoma. The need for increased clinical awareness and vigilance of this possible diagnostic conundrum is emphasized. Key words:Diffuse large B-cell lymphoma, exposed bone, oral, malignancy, maxilla, jaw osteonecrosis, differential diagnosis.

Three-Dimensional Analysis of Posterior Mandibular Displacement in Rats.

Mandibular protrusion and its treatment is challenging for the orthodontist. The aim of the present research was to identify macroscopic changes in the mandible, based on three-dimensional Cone Beam Computed Tomography analysis. Seventy-two male Wistar rats were divided into two equal groups, experimental (group A) and control (group B). Each consisted of three equal subgroups of 12 rats (A1, A2, A3, B1, B2, B3). Full-cast orthodontic intraoral devices were attached to the maxillary incisors of the experimental animals, and effected functional posterior mandibular displacement. Throughout the experimental period, all animals were fed with mashed food. Animals were sacrificed at 30 days (A1, B1), 60 days (A2, B2) and 90 days (A3, B3). At the 60th day of the experiment, the orthodontic devices were removed from the remaining experimental subgroup A3. Measurements revealed significant differences in the anteroposterior dimensions between experimental and control subgroups. However, the observed changes in the vertical dimensions, Condylion/Go'-Menton and the Intercondylar distance proved insignificant. Posterior mandibular displacement of the mandible in growing rats affects the morphology of the mandible and culminates in the development of a smaller mandible at a grown age.

Histological and Biochemical Analysis after Posterior Mandibular Displacement in Rats.

The present study aimed to investigate any biochemical and histological changes of the rat condyle and mandible in animals that had sustained mandibular growth restriction. Seventy-two male Wistar rats were divided into two equal groups, experimental and control. Each group consisted of three equal subgroups. The animals were sacrificed 30, 60, and 90 days after the start of the experiment. Blood samples were collected from the eye, and the osteoprotegerin (OPG), Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL), and Macrophage Colony-Stimulating factor (MCSF)concentrations were measured by using enzyme-linked immunosorbent assay (ELISA) kits. A histological analysis was performed on the mandibular condyles. The blood serum values of OPG, RANKL, and MCSF did not exhibit any statistically significant difference between groups or subgroups. However, significant histological changes became evident after a histomorphometric condylar examination was performed. The Bone Surface/Total Surface ratio appeared reduced in the anterior and posterior regions of the condyle. In addition, the Posterior Condylar Cartilage Thickness was measured and determined to be significantly diminished. The present intervention that employed orthodontic/orthopedic devices did not prove to have any significant effect on the circulating proteins under study. Posterior displacement of the mandible may culminate only in local histological alterations in condylar cartilage thickness and its osseous microarchitecture.

Intraosseous mandibular venous malformation.

Intraosseous venous malformations are rare benign lesions that account for approximately 0.5% to 1% of all osseous tumors. Involvement of the facial skeleton is rather uncommon, with the mandible and maxilla most frequently involved. In the current study, we report a case of an intraosseous venous malformation in a 52-year-old male patient with a history of mandibular keratocystic odontogenic tumor. The patient presented with an asymptomatic bony lesion in the mandible. Treatment involved surgical excision. Histopathologic examination of the excised specimen revealed an intraosseous venous malformation. Twelve months postoperatively, there was no evidence of recurrence.

Uprighting an Impacted Permanent Mandibular First Molar Associated with a Dentigerous Cyst and a Missing Second Mandibular Molar-A Case Report.

The purpose of this paper is to present a case of an impacted mandibular first molar associated with a dentigerous cyst and a missing mandibular second molar in an 11-year-old girl that was treated with combined surgical and orthodontic procedures. After clinical and radiographic evaluation, marsupialization of the cyst was decided, and a molar attachment was bonded on the buccal side of the impacted molar as a part of a full orthodontic treatment with fixed appliances. After 18 months of orthodontic traction, the molar was moved to a more advantageous position, and new bone apposition was observed on the site of the cystic lesion. Histological examination confirmed a dentigerous cyst. The molar was left to erupt spontaneously for 14 more months. A functional occlusion was finally achieved. An interdisciplinary approach proved to be an effective modality in treating a large dentigerous cyst associated with a deeply impacted first mandibular molar, presenting many advantages, such as new bone apposition and patient comfort.

Generalized Aggressive Periodontitis Associated With a Plasma Cell Gingivitis Lesion: A Case Report and Non-Surgical Treatment.

INTRODUCTION: Plasma cell gingivitis (PCG) is an unusual inflammatory condition characterized by dense, band-like polyclonal plasmacytic infiltration of the lamina propria. Clinically, it appears as gingival enlargement with erythema and swelling of the attached and free gingiva and is not associated with any loss of attachment. The aim of this report is to present a rare case of severe generalized aggressive periodontitis (GAgP) associated with a PCG lesion that was successfully treated and maintained non-surgically. CASE PRESENTATION: A 32-year-old white male with a non-contributory medical history presented with gingival enlargement with diffuse erythema and edematous swelling, predominantly around teeth #5 through #8. Clinical and radiographic examination revealed generalized severe periodontal breakdown. A complete blood count and biochemical tests were within normal limits. Histologic and immunohistochemical examination were consistent with PCG. A diagnosis of severe GAgP associated with a PCG lesion was assigned. Treatment included elimination of possible allergens and non-surgical periodontal treatment in combination with azithromycin. Clinical examination at reevaluation revealed complete resolution of gingival enlargement, erythema, and edema and localized residual probing depths of 5 mm. One year after treatment, the clinical condition was stable. Radiographs indicated improved bone levels and formation of crestal lamina dura. CONCLUSION: This case report highlights the unusual coexistence of GAgP and PCG, in which non-surgical treatment with elimination of all possible causes in combination with antimicrobials resulted in elimination of the gingival enlargement and significant improvement of periodontal parameters.

A retrospective analysis of the characteristics, treatment and follow-up of 26 odontomas in Greek children.

Odontomas represent the most common type of odontogenic jaw tumors among patients younger than 20 years of age. Clinically, they are often associated with eruption failure of adjacent permanent teeth, and are classified as compound and complex. The aim of the present retrospective study was to present the characteristics, treatment approach and outcome of odontomas in Greek children, over a ten-year period. Twenty six patients, 2 to 14 years of age (mean 9.3 years), with odontomas treated during the years 1999-2008 at the Department of Oral & Maxillofacial Surgery of a Children's Hospital, were included in the study. Data from patients' files were retrieved and they were recalled for review. Odontomas were equally distributed in the maxilla and mandible and 42.3% of them were located in the anterior maxilla. Of the odontomas, 80.7% were related to disturbances in tooth eruption. Bone expansion was observed in 65.3% of the cases. All odontomas were surgically removed, and related impacted permanent teeth were either left to erupt spontaneously, orthodontically guided into occlusion or were removed. Orthodontic intervention appeared to be necessary in older children, while in younger children spontaneous eruption was frequent. In the present study, odontomas were associated with unerupted or impacted teeth. Radiographic examination was essential to verify the presence of the tumor and early removal prevented tooth eruption failure and disturbances in a majority of the cases.