Case report: golimumab-related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw is an uncommon but highly morbid adverse event of certain medical therapies. Although classically induced by bisphosphonates, the recent advent of monoclonal antibodies is contributing to a rise in cases. In this case report, we present a rare case of golimumab-associated medication-related osteonecrosis of the jaw and discuss the possible mechanisms of pathogenesis.

DNA methylation profile discriminates sporadic giant cell granulomas of the jaws and cherubism from their giant cell-rich histological mimics.

Sporadic giant cell granulomas (GCGs) of the jaws and cherubism-associated giant cell lesions share histopathological features and microscopic diagnosis alone can be challenging. Additionally, GCG can morphologically closely resemble other giant cell-rich lesions, including non-ossifying fibroma (NOF), aneurysmal bone cyst (ABC), giant cell tumour of bone (GCTB), and chondroblastoma. The epigenetic basis of these giant cell-rich tumours is unclear and DNA methylation profiling has been shown to be clinically useful for the diagnosis of other tumour types. Therefore, we aimed to assess the DNA methylation profile of central and peripheral sporadic GCG and cherubism to test whether DNA methylation patterns can help to distinguish them. Additionally, we compared the DNA methylation profile of these lesions with those of other giant cell-rich mimics to investigate if the microscopic similarities extend to the epigenetic level. DNA methylation analysis was performed for central (n = 10) and peripheral (n = 10) GCG, cherubism (n = 6), NOF (n = 10), ABC (n = 16), GCTB (n = 9), and chondroblastoma (n = 10) using the Infinium Human Methylation EPIC Chip. Central and peripheral sporadic GCG and cherubism share a related DNA methylation pattern, with those of peripheral GCG and cherubism appearing slightly distinct, while central GCG shows overlap with both of the former. NOF, ABC, GCTB, and chondroblastoma, on the other hand, have distinct methylation patterns. The global and enhancer-associated CpG DNA methylation values showed a similar distribution pattern among central and peripheral GCG and cherubism, with cherubism showing the lowest and peripheral GCG having the highest median values. By contrast, promoter regions showed a different methylation distribution pattern, with cherubism showing the highest median values. In conclusion, DNA methylation profiling is currently not capable of clearly distinguishing sporadic and cherubism-associated giant cell lesions. Conversely, it could discriminate sporadic GCG of the jaws from their giant cell-rich mimics (NOF, ABC, GCTB, and chondroblastoma).

Alterations in macrophage polarization in the craniofacial and extracranial skeleton after zoledronate application and surgical interventions - an in vivo experiment.

Purpose: Medication-related osteonecrosis occurs exclusively in the jaw bones. However, the exact pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) and the unique predisposition of the jaw bones have not been elucidated, making its treatment a challenge. Recent evidence indicates that macrophages might play a pivotal role in MRONJ pathogenesis. The aim of the present study was to compare the macrophage populations between the craniofacial and extracranial skeleton and to investigate the changes induced by zoledronate (Zol) application and surgical interventions. Materials and methods: An in vivo experiment was performed. 120 wistar rats were randomized to 4 groups (G1, G2, G3, G4). G1 served as an untreated control group. G2 and G4 received Zol injections for 8 weeks. Afterwards, the right lower molar of the animals from G3 and G4 was extracted and the right tibia osteotomized followed by osteosynthesis. Tissue samples were taken from the extraction socket and the tibia fracture at fixed time points. Immunohistochemistry was conducted to determine the labeling indexes of CD68+ and CD163+ macrophages. Results: Comparing the mandible and the tibia, we observed a significantly higher number of macrophages and a heightened pro-inflammatory environment in the mandible compared to the tibia. Tooth extraction caused an increase of the overall number of macrophages and a shift toward a more pro-inflammatory microenvironment in the mandible. Zol application amplified this effect. Conclusion: Our results indicate fundamental immunological differences between the jaw bone and the tibia, which might be a reason for the unique predisposition for MRONJ in the jaw bones. The more pro-inflammatory environment after Zol application and tooth extraction might contribute to the pathogenesis of MRONJ. Targeting macrophages might represent an attractive strategy to prevent MRONJ and improve therapy. In addition, our results support the hypothesis of an anti-tumoral and anti-metastatic effect induced by BPs. However, further studies are needed to delineate the mechanisms and specify the contributions of the various macrophage phenotypes.

Radiologic findings of osteonecrosis, osteoradionecrosis, osteomyelitis and jaw metastatic disease with cone beam CT.

PURPOSE: The purpose of this study was to assess CBCT scans of patients with medication related osteonecrosis of the jaws (MRONJ), osteoradionecrosis (ORN), osteomyelitis (OM) and jaw metastatic disease (JM), evaluate the presence and extent of radiologic findings, identify radiologic parameters that may distinguish the four entities and last, introduce a new modified radiographic index (CRIm), in order to contribute to the diagnosis of these conditions. METHODS: Τwo major databases were retrospectively searched for fully documented and diagnosed CBCT scans of MRONJ, ORN, OM and JM from 2006 to 2019. 335 CBCT scans met the inclusion criteria and were assessed under standardized viewing conditions blindly by 2 observers. The CRIm index proposed in this study evaluates: lytic changes, sclerosis, periosteal bone formation, sequestration, non-healing extraction sockets and other findings which included: sinus implication, inferior alveolar canal implication and jaw fracture. Lytic changes, sclerosis, periosteal bone formation, sequestration and non-healing extraction sockets were scored as: absent (0), localized/single (1) and extensive/multiple (2). Each one of other findings were scored individually as: absent (0) and present (1). For statistical analysis t-test, Pearson's r correlation coefficient, one-way ANOVA and Bonferonni were performed. RESULTS: Extensive lytic changes were the most common finding, especially for ORN, where it occurred in all CBCT scans (100%). The mean value of the CRIm index differs significantly between CBCT scans with MRONJ and JM, as well as between those with OM and JM (Bonferroni p < 0.001). CONCLUSIONS: The new modified Composite Radiographic Index introduced in this study, appears to have improved an objective approach to the previously used Composite Radiographic Index by means of cumulative radiologic features. Τhe predominance of certain radiologic features in one or more of these entities may lead the diagnostician towards the correct diagnosis.

Immune microenvironment: novel perspectives on bone regeneration disorder in osteoradionecrosis of the jaws.

Osteoradionecrosis of the jaws (ORNJ) is a severe complication that occurs after radiotherapy of head and neck malignancies. Clinically, conservative treatments and surgeries for ORNJ exhibited certain therapeutic effects, whereas the regenerative disorder of the post-radiation jaw remains a pending problem to be solved. In recent years, the recognition of the role of the immune microenvironment has led to a shift from an osteoblasts (OBs) or bone marrow mesenchymal stromal cells (BMSCs)-centered view of bone regeneration to the concept of a complicated microecosystem that supports bone regeneration. Current advances in osteoimmunology have uncovered novel targets within the immune microenvironment to help improve various regeneration therapies, notably therapies potentiating the interaction between BMSCs and immune cells. However, these researches lack a thorough understanding of the immune microenvironment and the interaction network of immune cells in the course of bone regeneration, especially for the post-operative defect of ORNJ. This review summarized the composition of the immune microenvironment during bone regeneration, how the immune microenvironment interacts with the skeletal system, and discussed existing and potential strategies aimed at targeting cellular and molecular immune microenvironment components.

Radiological aspects of lymphomas and leukaemias affecting the jaws: A systematic review.

BACKGROUND: This systematic review aimed to investigate the radiological features of lymphomas and leukaemias affecting the jaws. METHODS: A systematic literature review was conducted using the electronic databases of PubMed, Web of Science and Scopus. Articles that contained sufficient radiographic examinations (periapical, panoramic or computed tomography images) for individual cases were included. Additionally, either immunohistochemical or molecular confirmation was required prior to inclusion. Three authors evaluated and described the image quality and radiological features. RESULTS: From an initial 1079 articles screened, 129 cases were included, containing 88 tomographic, 76 panoramic and 26 periapical examinations. The quality of the majority of images was sufficient for evaluation. Diffuse large B-cell lymphoma, Burkitt lymphoma, leukemic infiltration, plasmablastic lymphoma and extranodal Natural killer (NK)/T-cell lymphoma, nasal type were the most common subtypes. Involved teeth presented with mobility in 37.2% of the cases and a provisional diagnosis of inflammatory/infectious dental disease was considered in 49.2% of cases. Computed tomography exams were available for 76% of the cases, with most presented with an osteolytic lesion with ill-defined borders. Periosteal reactions were uncommon. CONCLUSION: Lymphoma/leukaemia infiltrates of the jaw bones are usually of high-grade subtypes and rarely present with periosteal reactions.

The clinical importance of marsupialization treatment of the cystic lesion of the jaws: Analysis of the dental pulp vitality.

BACKGROUND: Jaw cyst is the most common pathology in the oral and maxillofacial region. The management of the teeth involved in cystic lesions is highly controversial. However, if the teeth involved in the cystic lesion could be preserved with their pulp vitality, the life span of these teeth will be considerably lengthened to improve the masticatory function of these patients after surgery. The present retrospective study over 10 years; with 92 patients that had cystic lesions of the jaws aimed to evaluate the effect of marsupialization on the preservation of the vitality teeth involved in the cystic lesion before and after treatment taking. MATERIAL AND METHODS: clinical retrospective study between January 2013 and January 2022, included 92 patients with a cystic lesion of jaw treated by marsupialization were carried out. The clinical data were collected; the number of teeth involved in the cystic lesion, the vitality of these teeth before and after marsupialization, the number of teeth that have undergone root canal treatment, the number of cases of failure (teeth that were extracted during surgery to open the cystic lesion and teeth that were extracted after surgery) as well as the duration of treatment for each patient were assessed. RESULTS: Of 92 patients, 54 were men and 38 women with ages ranged from 7 years to 62 years were enrolled in this study.380 teeth were involved in the cystic lesion of that 352 teeth were positive and 28 teeth were negative before marsupialization. 28 teeth underwent root canal treatment before surgery. After surgery, 338 teeth were positive and 42 were negative. Among the 42 negative teeth, 31 teeth failed (extracted) and 11 teeth recovered their vitality before the end of the treatment.321 teeth were saved and preserved their pulp vitality. CONCLUSION: The effect of marsupialization is good; it saves and preserves the vitality of the teeth involved in the cystic lesion and it reduces the cost of treatment for the patients.

Post-COVID steroid induced avascular necrosis of the jaw: Emerging challenge in India.

The COVID-19 pandemic continues to evolve and spread with new variants of SARS-CoV-2 across the globe, as well as bring to clinical attention several post-COVID conditions. We report a post-COVID condition observed at our tertiary care center: spontaneous de novo development of steroid induced avascular necrosis in patients who have recently recovered from COVID-19 following high dose steroid usage in a short span of time. Pre-COVID published literature indicates that these lesions were seen very rarely in the jaws and were related to long-term usage of steroids and recent tooth extraction. They were considered under the broad spectrum of medication-related osteonecrosis of the jaws. Present authors believe that the post-COVID-19 steroid-induced avascular necrosis of the jaws is a distinct new entity. It is analogous to the avascular necrosis noticed in the femoral head of individuals recuperating from COVID-19, a condition conventionally known to be strongly associated with steroid therapy. Rapid progression, associated morbidity and mortality, and its possible differential diagnosis require pathologists to be vigilant regarding the chance encounter of such cases in jaws. Further reporting of such cases is required to gain additional insight into its features.

A new TRPV4 mutation in a case of multiple central giant cell granulomas of the jaws.

Sporadic central giant cell granulomas of the jaws (GCGJ) are often solitary lesions, characterized by KRAS, FGFR1, and TRPV4 somatic mutations. Multifocal lesions may occur and are associated with hyperparathyroidism or underlying syndromes such as cherubism, which is marked by SH3BP2 mutations, and RASopathies, which are caused by mutations in the FGFR-RAS-RAF-MEK-ERK signaling cascade. The diagnosis of multiple GCGJ can be challenging. The present case reports a 14-year-old boy with multiple central GCGJ and no obvious syndromic trait. Sanger sequencing-based analysis revealed wild-type sequences for SH3BP2 (exon 9), KRAS (exons 2-4), and FGFR1 (exons 9 and 10) genes. A rare TRPV4 somatic mutation (p.Val708Met) was detected in the lesion on the right side of the mandible, whereas the other tumor and the normal oral mucosa revealed wild-type TRPV4 sequences. This report expands the spectrum of TRPV4 somatic mutations in central GCGJ.

Temporomandibular joint anatomy, function and clinical relevance.

The articulatory system comprises the temporomandibular joints (TMJs), intra-articular discs, mandibular/jaw muscles and occlusion. In the simplest terms, the TMJ is the articulation between the upper and lower jaws. The teeth form the contacts between the upper and lower jaws and the muscles are the motors that move the mandible. This system is unique in that the TMJs are paired; any stimulus that affects one joint or any other single part of the articulatory system can have a 'knock-on effect' in the rest of the system.It is important to have a good understanding of anatomy, not only to be able to differentiate between what is physiological and what is pathological, but also to understand the objectives of some treatment options. Sound knowledge of anatomy is essential and an appreciation of the anatomical features associated with the TMJ can serve as a foundation for understanding the clinical management of temporomandibular disorders.This article reviews the functional anatomical features of the articulatory system with a look at the clinical significance of this anatomy.

Integrated proteomics, phosphoproteomics and metabolomics analyses reveal similarities among giant cell granulomas of the jaws with different genetic mutations.

BACKGROUND: Giant cell granuloma of the jaws are benign osteolytic lesions of the jaws. These lesions are genetically characterized by mutually exclusive somatic mutations at TRPV4, KRAS, and FGFR1, and a fourth molecular subgroup which is wild-type for the three mutations. Irrespective of the molecular background, giant cell granulomas show MAPK/ERK activation. However, it remains unclear if these mutations lead to differences in their molecular signaling in giant cell granulomas. METHODS: Metabolomics, proteomics, and phosphoproteomics analyses were carried out in formalin-fixed paraffin-embedded samples of giant cell granuloma of the jaws. The study cohort consisted of five lesions harboring mutations in FGFR1, six in KRAS, five in TRPV4, and five that were wild-type for these mutations. RESULTS: Lesions harboring KRAS or FGFR1 mutations showed overall similar proteomics and metabolomics profiles. In all four groups, metabolic pathways showed similarity in apoptosis, cell signaling, gene expression, cell differentiation, and erythrocyte activity. Lesions harboring TRPV4 mutations showed a greater number of enriched pathways related to tissue architecture. On the other hand, the wild-type group presented increased number of enriched pathways related to protein metabolism compared to the other groups. CONCLUSION: Despite some minor differences, our results revealed an overall similar molecular profile among the groups with different mutational profile at the metabolic, proteic, and phosphopeptidic levels.

Are Bacteria Just Bystanders in the Pathogenesis of Inflammatory Jaw Conditions?

PURPOSE: It is unclear whether certain bacteria initiate the development of inflammatory jaw conditions, or whether these diseases create a milieu for dysbiosis and secondary colonization of indigenous flora. At present, there are no comparative studies on the types of bacteria that colonize different inflammatory jaw conditions. Accordingly, this study aims to identify and compare the types of bacteria isolated in osteomyelitis, osteoradionecrosis, and MRONJ. METHODS: This is a retrospective cohort study of patients diagnosed with inflammatory jaw conditions. The predictor variables were classification of bacteria as oral flora, categorized herein as resident bacteria, non-resident bacteria, or opportunistic organisms. The outcome variables were a diagnosis of osteomyelitis, osteoradionecrosis, and MRONJ. Covariates were age, sex, penicillin allergy, a diagnosis of diabetes and a history of smoking. Data analysis was performed using ANOVA and chi-squared tests. RESULTS: A total of 105 patients with inflammatory jaw conditions were enrolled. The final sample size was 69 subjects of which 16 were diagnosed with osteomyelitis, 20 with osteoradionecrosis, and 33 with MRONJ. There was no difference in the frequency that resident bacteria were isolated. Non-resident bacteria, which included Staphylococcus and Enterococcus among others, were isolated more frequently at 75% in osteomyelitis compared to 60% in osteoradionecrosis and 48% in MRONJ cases. There is weak evidence of significant difference when comparing osteomyelitis and MRONJ cases (P = .08). Opportunistic organisms, which included Mycobacterium and Candida, were isolated more frequently in osteoradionecrosis at 30% compared to 12.5% in osteomyelitis and 12.12% in MRONJ cases. There is weak evidence of significant difference when comparing osteoradionecrosis and MRONJ cases (P = .1). CONCLUSION: Non-resident bacteria including Staphylococcus and Enterococcus may be more frequently isolated in patients with osteomyelitis, while opportunistic organisms like Mycobacterium and Candida may be more frequently found in patients diagnosed with osteoradionecrosis.

Manifestations of hyperparathyroidism in the jaws: Concepts, mechanisms, and clinical aspects.

Hyperparathyroidism is one of the most common endocrine disorders worldwide. In countries where routine biochemical screening is not common, symptomatic hyperparathyroidism predominates. Its manifestations include skeletal alterations, calcification of soft tissues, kidney stones, and functional alterations in other systems. Notably, jaw alterations can be the first clinical sign of hyperparathyroidism, including brown tumor, renal osteodystrophy, osteitis fibrosa, and leontiasis ossea, and knowing such conditions is of core importance for the multidisciplinary diagnosis and management of hyperparathyroidism. We aimed to perform a concise review, systematizing the concepts and mechanisms underlying hyperparathyroidism and associated gnathic alterations. In addition, a detailed description of the clinical aspects of the jaw manifestations is presented.

Clinicopathological and genetic study of a rare occurrence: Malignant transformation of fibrous dysplasia of the jaws.

BACKGROUND: Malignant transformation of fibrous dysplasia (FD) is very rare and little is known about this occurrence. METHODS: We present the detailed clinical course of three cases of osteosarcoma arising from FD of the jaws and explore the genetic aberrations by Sanger sequencing, whole-exome sequencing (WES) and immunohistochemistry (IHC). A literature review of important topics related to this occurrence was also performed. RESULTS: It was observed that patients with secondary sarcoma from FD showed a wide range of ages, with most during the third decade. Female and males were equally affected. Craniofacial bones and femurs were the most affected sites. High-risk factors for this occurrence included polyostotic FD, McCune-Albright syndrome and excess growth hormone. Notably, a potential relationship between thyroid hormones and sarcoma development was suggested in one patient, who began to show malignant features after hypothyroidism correction. Sanger sequencing revealed GNAS mutations of FD retained in all malignant tissues. Additionally, abnormal TP53 was demonstrated in all three cases by WES and IHC. WES also revealed two other driver mutations, ROS1 and CHD8, and large amounts of somatic copy number alterations (CNAs) where various oncogenes and tumour suppressors are located. CONCLUSION: This study demonstrated and reviewed the clinical features and risk factors for a rare occurrence, secondary sarcoma from FD, and provided important new knowledge about its genetics.

Radiological evaluation of the periosteal reactions in the jaws: a retrospective CBCT study.

OBJECTIVES: The objective of this study is to evaluate the relationship between the radiological features of periosteal reactions (PR) and histopathological features of the lesions. METHODS: A total of 4605 CBCT images were evaluated and they were classified according to their radiological differential diagnosis. Images with pathologies were listed according to their histopathological examinations as cystic lesions, benign tumours, malignant tumours, fibro-osseous lesions and osteonecrosis, while images without pathologies were listed as traumas and others. All groups were reclassified as with or without the presence of detected PR. RESULTS: Pathologies and traumas were detected in 1801 of 4605 patients. There were 3 PR in 1140 cystic lesions, 4 PR in 102 benign tumours, 16 PR in 43 malignant tumours, 67 PR in 156 osteonecrosis/osteomyelitis cases and 3 PR in 262 trauma cases. As a result of the chi-square test between groups, there was a significant relationship between histopathologic diagnoses and periosteal reaction patterns (p = 0.000). CONCLUSIONS: Although there is a significant overlap between the patterns of PRs, PRs can be used to narrow the possibilities in the differential diagnosis. However, PRs alone are not sufficient variables for differential diagnosis in the absence of cortical bone destruction, localization, clinical and systemic findings.

[Bilateral giant cell central granuloma of the jaws in a Noonan syndrome: About one case with emphasizing on bone giant cell lesions of the jaws]. / Granulome central à cellules géantes des maxillaires bilatéral dans le cadre d'un syndrome de Noonan : à propos d'un cas avec mise au point sur les lésions osseuses riches en cellules géantes des maxillaires.

We report the case of a 10-year-old child with bilateral mandibular localization of a central giant cell granuloma occurring in the setting of Noonan syndrome. The histological appearance was classic with two intermigled components, one fibrous with non-atypical mononuclear cells, the other consisting of numerous osteoclast-like giant cells. This aspect is similar to that observed in the brown tumor as well as that of cherubism, which can also give multiple bone lesions. We will discuss the other lesions to consider in case of benign giant cell bone lesions affecting the jawbones, sometimes multiple and part of which falls within the scope of RASopathies.

Osteonecrosis of the Jaws in Patients with Hereditary Thrombophilia/Hypofibrinolysis-From Pathophysiology to Therapeutic Implications.

Osteonecrosis of the jaws (ONJ) usually has a clear etiology. Local infection or trauma, radiotherapy and drugs that disrupt the vascular supply or bone turnover in the jaws are its major contributors. The thrombotic occlusion of the bone's venous outflow that occurs in individuals with hereditary thrombophilia and/or hypofibrinolysis has a less known impact on jaw health and healing capability. Our research provides the most comprehensive, up-to-date and systematized information on the prevalence and significance of hereditary thrombophilia and/or hypofibrinolysis states in ONJ. We found that hereditary prothrombotic abnormalities are common in patients with ONJ refractory to conventional medical and dental treatments. Thrombophilia traits usually coexist with hypofibrinolysis traits. We also found that frequently acquired prothrombotic abnormalities coexist with hereditary ones and enhance their negative effect on the bone. Therefore, we recommend a personalized therapeutic approach that addresses, in particular, the modifiable risk factors of ONJ. Patients will have clear benefits, as they will be relieved of persistent pain and repeated dental procedures.