Association between CDK4/6 inhibitors and drug-related osteonecrosis of the jaw: A pharmacoepidemiological study using the FDA Adverse Events Reporting System.

The most common toxicities associated with cyclin-dependent kinase (CDK) 4/6 inhibitor therapy include decreased leukopenia and neutropenia due to the inhibition of CDK6 of leukocyte and neutrophil precursors in bone marrow. These hematological toxicities are more commonly observed with palbociclib administration than with abemaciclib administration, which is approximately 13 times more selective against CDK4 than CDK6. Thus, even though both successfully inhibit CDK4/6, the side effects of palbociclib and abemaciclib differ due to differences in selectivity. Recent reports have suggested an association between palbociclib and medication-related osteonecrosis of the jaw; however, reports on this association are inconsistent. This study investigated the potential association of palbociclib and abemaciclib with MRONJ using the FAERS. Signals of "Osteonecrosis of jaw" were detected only in females using palbociclib (cROR025: 2.08). Other signals detected included stomatitis-related adverse events with abemaciclib and intraoral soft tissue damage and infection with palbociclib. As previous exploratory studies have reported MRONJ signals for bisphosphonates and denosumab, we calculated the aROR for palbociclib-induced osteonecrosis of the jaw using concomitant bisphosphonates and denosumab as covariates. A signal was detected even after adjusting for sex, age, and concomitant medications as covariates (aROR0025: 5.74). A proper understanding of the differences in CDK selectivity is necessary for the appropriate use of CDK4/6 inhibitors. To the best of our knowledge, this is the first report on CDK4/6 inhibitors and drug-related osteonecrosis of the jaw. We believe that these results will offer new insights into adverse events related to the use of CDK4/6 inhibitors, and may aid in the proper use of CDK4/6 inhibitors.

Medication-related osteonecrosis of the jaw: evolving research for multimodality medical management.

PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating side effect of antiresorptive and antiangiogenic agents that can lead to progressive bone destruction in the maxillofacial region. Dental surgery, including tooth extractions, commonly trigger the onset of MRONJ. While guidelines suggest avoiding extraction when possible, complete avoidance is not always feasible, as necrosis can develop from dental and periodontal disease without dental procedures. The goal of this article is to provide an update review of current preventive and therapeutic approaches for MRONJ. METHODS: A comprehensive electronic search was conducted on PubMed/MEDLINE, Embase, and Scopus databases. All English articles encompassing randomized controlled trials, systematic reviews, observational studies, and case studies were reviewed. The current medical treatments and adjuvant therapies for managing MRONJ patients were critically assessed and summarized. RESULTS: Pentoxifylline and alpha tocopherol (PENT-E), teriparatide, photobiomodulation (PBM), photodynamic therapy (PDT), and the use of growth factors have shown to enhance healing in MRONJ patients. Implementing these methods alone or in conjunction with surgical treatment has been linked to reduced discomfort and improved wound healing and increased new bone formation. DISCUSSION: While several adjuvant treatment modalities exhibit promising results in facilitating the healing process, current clinical practice guidelines predominantly recommend antibiotic therapy as a non-surgical approach, primarily addressing secondary infections in necrotic areas. However, this mainly addresses the potential infectious complication of MRONJ. Medical approaches including PENT-E, teriparatide, PBM, and PDT can result in successful management and should be considered prior to taking a surgical approach. Combined medical management for both preventing and managing MRONJ holds potential for achieving optimal clinical outcomes and avoiding surgical intervention, requiring further validation through larger studies and controlled trials.

Deep learning in the diagnosis for cystic lesions of the jaws: a review of recent progress.

Cystic lesions of the gnathic bones present challenges in differential diagnosis. In recent years, artificial intelligence (AI) represented by deep learning (DL) has rapidly developed and emerged in the field of dental and maxillofacial radiology (DMFR). Dental radiography provides a rich resource for the study of diagnostic analysis methods for cystic lesions of the jaws and has attracted many researchers. The aim of the current study was to investigate the diagnostic performance of DL for cystic lesions of the jaws. Online searches were done on Google Scholar, PubMed, and IEEE Xplore databases, up to September 2023, with subsequent manual screening for confirmation. The initial search yielded 1862 titles, and 44 studies were ultimately included. All studies used DL methods or tools for the identification of a variable number of maxillofacial cysts. The performance of algorithms with different models varies. Although most of the reviewed studies demonstrated that DL methods have better discriminative performance than clinicians, further development is still needed before routine clinical implementation due to several challenges and limitations such as lack of model interpretability, multicentre data validation, etc. Considering the current limitations and challenges, future studies for the differential diagnosis of cystic lesions of the jaws should follow actual clinical diagnostic scenarios to coordinate study design and enhance the impact of AI in the diagnosis of oral and maxillofacial diseases.

Osteonecrosis of the jaw after radiation followed by bevacizumab.

Osteonecrosis of the jaw is a recognized complication associated with bevacizumab. Here, we present a patient with squamous cell carcinoma of the tonsil who experienced minimal skin fibrosis following intensity-modulated radiation therapy. Subsequently, the patient developed rectal adenocarcinoma and encountered osteonecrosis of the jaw after receiving two cycles of bevacizumab. Close monitoring, accompanied by thorough examination to detect early signs of osteonecrosis of the jaw, should be considered for patients who have undergone radiation therapy in the head and neck region and are receiving bevacizumab or other medications known to be associated with osteonecrosis of the jaw.

[Medication-related osteonecrosis of the jaws associated with the use of bone-modifying agents]. / Medikamentoznyi osteonekroz chelyustei, svyazannyi s priemom osteomodifitsiruyushchikh preparatov.

The relevance of the study is associated with the widespread use of osteomodifying agents in patients with bone metastases and osteoporosis. Bisphosphonates and other osteo-modifying agents are widely used in oncology and prevention of age-related changes in the human bone system. The use, therapeutic effects and complications of therapy with osteo modifying agents are being investigated all over the world. However, the etiology and pathogenesis of drug-induced osteonecrosis of the jaws (MONCH) have not been fully studied, in this regard, the study of risk factors and mechanisms of its development remains relevant. New data on the etiology and pathogenesis of drug-induced osteonecrosis are presented. The literature review is carried out on the electronic resource PubMed.

Mechanisms underlying the adaptive pulp and jaw bone trabecular changes in sickle cell anemia.

OBJECTIVE: Mechanisms underlying the oral outcomes in sickle cell anemia (HbSS) have been less explored. This study aimed to investigate the association of morbimortality indicators and hydroxyurea use with adaptive pulp and jaw bone trabecular changes in HbSS. METHODS: This cross-sectional study included 123 individuals with HbSS. The exposures were the morbimortality indicators of HbSS (number of vaso-occlusive crises, organ damage, hemoglobin level, and leukocyte count) and the use of hydroxyurea for HbSS treatment. The outcomes were adaptive pulp and jaw bone trabecular changes confirmed by radiographic examination. Associations were estimated by Poisson regression in crude and adjusted analyses for sex, skin color, socioeconomic class, and age. RESULTS: The vaso-occlusive crises (mean ratio (MR) = 3.5, p = 0.045), lower hemoglobin (MR = 2.4, p = 0.037), and higher leukocyte count (MR = 2.17, p = 0.036) were risk factors, while the use of hydroxyurea was inversely associated with adaptive pulp changes (MR = 0.23, p = 0.024). The vaso-occlusive crises were associated with jaw bone trabecular changes (MR = 1.33, p = 0.02). CONCLUSION: Adaptive pulp changes may be a potential clinical marker of chronic vasculopathy in HbSS. The use of hydroxyurea may reduce the frequency of adaptive pulp changes.

Prevalence of Oral Exostoses in Northern China During the Past Six Millennia-From a Sex and Age Perspective.

This study is intended to investigate oral exostoses of 5 sample populations, spanning over 6000 years, from the same region of Northern China, to determine the significance of sex and age on the development of oral exostoses during each time period. The samples analyzed were 306 dry jaws from human skeletons, which were excavated from 4 archeological sites: Banpo (6700-5600 y BP), Shaolingyuan (3000 y BP), Shanren (2200 y BP), and Chang'an (1000-1300 y BP), as well as the modern Xi'an district. The sex and the age of the samples at death were estimated. The degree of buccal exostosis (BE), torus mandibularis (TM), and torus palatinus (TP) and the TP shape were recorded. The results showed BEs in the Banpo and Chang'an regions, TMs in the Banpo region were more often diagnosed in males than in females. Conversely, females in Shaolingyuan showed a higher prevalence and severity of TM than that in males. The occurrence of BEs in the Shanren and Xi'an regions, TMs in the Banpo, Chang'an, and Xi'an regions, as well as TPs in the Banpo region significantly increased with age at death. In conclusion, sex differences and increasing trends with age in relation to oral exostoses were found in samples from Northern China during the past six millennia.

Avoid the Phrase "No Drainable Fluid Collection" When Interpreting Examinations for Suspected Odontogenic Infection.

The phrase "no drainable fluid collection" harbors implicit management guidelines that may be inappropriate in regard to acute odontogenic infection. For many emergency department physicians, these words trigger a treatment plan involving antibiotics without drainage. However, many odontogenic infections require immediate drainage even when an abscess is not visible on imaging. As such, the phrase "no drainable fluid collection" should not be used when reporting on imaging performed for odontogenic infection.

Vaso-occlusive Pain Crisis Mimicking Mandibular Abscess in an Adolescent with Sickle Cell Disease.

In people with sickle cell disease (SCD), oral abscesses are concerning clinical conditions and carry a high risk of postoperative sickle cell complications. We present an unusual case of a 14-year-old girl with SCD whose initial presentation of facial swelling, headaches, jaw pain, and paresthesia mimicked an odontogenic abscess. She was diagnosed with vaso-occlusive crisis in the mandibular bone and successfully managed noninvasively. This is among the youngest cases of paresthesia in the lower lip in SCD, which provided a clue that postponing invasive aspiration or biopsy was possible under empiric antibiotics and close observation.

Radiographic and Clinical Analysis of Cranio-Maxillofacial Complications of Cavernous Sinus Thrombosis Among 256 COVID-19 Patients.

BACKGROUND: A heavy burden of cranio-maxillofacial complications may be encountered in corona virus disease-2019 patients due to the associated coagulopathy and inflammatory consequences of the disease. This study aims to describe clinical and radiographic features of these complications in 256 patients who developed 1 or more of the following complications: cavernous sinus thrombosis, osteomyelitis or necrosis of the jaws. METHODS: Clinical assessment of cranial nerve function and general clinical assessment were performed. Imaging techniques used were multi-slice computed tomography, magnetic resonance imaging, and MRI with contrast enhancement. RESULTS: Thromboembolism of brain and facial blood vessels were associated with inflammation and necrosis. Multi-slice computed tomography/MR angiography showed thrombotic occlusions of the internal carotid artery in the area of the cavernous sinus, and in the ophthalmic veins. Cavernous sinus thrombosis was attributed to coagulopathy and, inflammation of the paranasal sinuses, especially sphenoiditis. A noticeable increase in the size of the cavernous sinus was detected. Compression of the cranial nerves in the cavernous sinus (CS) region causes dysfunction and pathology in the corresponding regions.

Role of dendritic cell-mediated immune response in oral homeostasis: A new mechanism of osteonecrosis of the jaw.

Dendritic cells are an important link between innate and adaptive immune response. The role of dendritic cells in bone homeostasis, however, is not understood. Osteoporosis medications that inhibit osteoclasts have been associated with osteonecrosis, a condition limited to the jawbone, thus called medication-related osteonecrosis of the jaw. We propose that disruption of the local immune response renders the oral microenvironment conducive to osteonecrosis. We tested whether zoledronate (Zol) treatment impaired dendritic cell (DC) functions and increased bacterial load in alveolar bone in vivo and whether DC inhibition alone predisposed the animals to osteonecrosis. We also analyzed the role of Zol in impairment of differentiation and function of migratory and tissue-resident DCs, promoting disruption of T-cell activation in vitro. Results demonstrated a Zol induced impairment in DC functions and an increased bacterial load in the oral cavity. DC-deficient mice were predisposed to osteonecrosis following dental extraction. Zol treatment of DCs in vitro caused an impairment in immune functions including differentiation, maturation, migration, antigen presentation, and T-cell activation. We conclude that the mechanism of Zol-induced osteonecrosis of the jaw involves disruption of DC immune functions required to clear bacterial infection and activate T cell effector response.

Actinomycosis in a gray four-eyed opossum (Philander opossum) caused by a novel species of Schaalia.

BACKGROUND: Infective lesions of the jaws and adjacent tissues (lumpy jaw disease, LJD) have been recognized as one major cause of death of captive macropods. Fusobacterium necrophorum and Actinomyces species serve as the main source of LJD in kangaroos and wallabies. Currently, little is reported about LJD or similar diseases in opossums. CASE PRESENTATION: Here we report a case of actinomycosis resembling the entity lumpy jaw disease in a gray four-eyed opossum, caused by a novel species of Schaalia. A 2.8 year old male Philander opossum was presented with unilateral swelling of the right mandible. After an initial treatment with marbofloxacin, the opossum was found dead the following day and the carcass was submitted for necropsy. Postmortem examination revealed severe mandibular skin and underlying soft tissue infection with subsequent septicemia as the cause of death. Histological examination demonstrated Splendore-Hoeppli phenomenon, typically seen in classical cases of actinomycosis. Bacteriology of liver and mandibular mass yielded a previously undescribed species of Schaalia, whose 16 S rRNA gene sequence was 97.0 % identical to Schaalia canis. Whole genome sequencing of the opossum isolate and calculation of average nucleotide identity confirmed a novel species of Schaalia, for which no whole genome sequence is yet available. CONCLUSIONS: The herewith reported Schaalia infection in the gray four-eyed opossum resembling classical actinomycosis gives a novel insight into new exotic animal bacterial diseases. Schaalia species may belong to the normal oral microbiome, as in macropods, and may serve as a contributor to opportunistic infections. Due to the lack of current literature, more insights and improved knowledge about Schaalia spp. and their pathogenicity will be useful to choose appropriate therapy regimens and improve the treatment success rate and outcome in exotic and endangered species.

Osteonecrosis of the jaw: a rare but possible side effect in thyroid cancer patients treated with tyrosine-kinase inhibitors and bisphosphonates.

Osteonecrosis of the jaw (ONJ) is a rare but very serious disease that can affect both jaws. It is defined as exposed bone in the maxillofacial region that does not heal within 8 weeks after a health care provider identification. ONJ can occur spontaneously or can be due to drugs like bisphosphonates (BPS) and anti-RANK agents, in patients with no history of external radiation therapy in the craniofacial region. Although in phase 3 trials of tyrosine kinase inhibitors (TKIs) used in thyroid cancer (TC) the ONJ was not reported among the most common side effects, several papers reported the association between ONJ and TKIs, both when they are used alone and in combination with a bisphosphonate. The appearance of an ONJ in a patient with metastatic radio-iodine refractory differentiated TC, treated with zoledronic acid and sorafenib, has put us in front of an important clinical challenge: when a ONJ occurred during TKIs treatment, it really worsens the patients' quality of life. We should consider that in the case of ONJ a TKI discontinuation becomes necessary, and this could lead to a progression of neoplastic disease. The most important aim of this review is to aware the endocrinologists/oncologists dealing with TC to pay attention to this possible side effect of BPS and TKIs, especially when they are used in association. To significantly reduced the risk of ONJ, both preventive measures before initiating not only antiresorptive therapy but also antiangiogenic agents, and regular dental examinations during the treatment should always be proposed.

Therapeutic alternatives in the management of osteoradionecrosis of the jaws. Systematic review.

BACKGROUND: to systematically review the literature, comparing the healing of osteoradionecrosis (ORN) among the therapeutic alternatives: surgical, pharmacological and combined. MATERIAL AND METHODS: The review was organized according to the PRISMA protocol with regards to the following PICO question: patients with ORN of the jaws (P=Patient); all interventions reported (I = intervention); between all therapies (C=Comparison); healing of lesions (O=outcome). RESULTS: Surgical treatment was the most common choice (46.3%) followed by pharmacological treatment, exclusively (25.9%) or combined (26.9%). Treatment exclusively by surgical intervention seems to be most effective option, with 51.2% of the lesions healed, OR for healing of 5.7 (CI95% 1.9-16.9, p=0.002). Only 1 case (0.9%) corresponded to low level laser therapy. CONCLUSIONS: It seems clear that early intervention with conservative surgical combined with pharmacological methods improves the prognosis of ORN.

Differential expression of nicotinamide N-methyltransferase in primary and recurrent ameloblastomas and odontogenic keratocysts.

BACKGROUND: Odontogenic tumours are a group of rare heterogeneous diseases that range from hamartomatous tissue proliferations to benign and malignant neoplasms. Recurrences can occur after 10 years, so long-term clinical and radiological follow-up is required. The study of the molecular mechanisms involved in the development of these lesions is necessary to identify new prognostic markers. In this study, we evaluate the possible role of nicotinamide N-methyltransferase (NNMT) in ameloblastomas (AM) and odontogenic keratocysts (OKC). MATERIALS AND METHODS: A total of 105 surgical specimens of primary and recurrent lesions were obtained from 55 patients (25 AM, 30 OKC). In particular, 50 AMs (25 primary, 25 recurrences) and 55 OKCs (30 primary, 25 recurrences) were retrieved. We carried out immunohistochemical analyses to evaluate the cytoplasmic expression of NNMT, measuring the percentage of positive cells and the value of NNMT expression intensity. RESULTS: NNMT expression was significantly higher in recurrent than primary AMs (P = .0430). This result was confirmed by staining intensity, showing more cases with moderate/intense staining in recurrent AMs (P = .0470). NNMT expression was significantly lower in recurrent than primary OKC (P = .0014). Staining intensity showed more cases with moderate/intense staining in primary OKCs (P = .0276). CONCLUSIONS: This report is the first to evaluate NNMT expression in odontogenic lesions and to demonstrate a differential expression in recurrent AMs and OKCs, suggesting that there is potential for use of NNMT as prognostic marker.

Imaging of Mixed and Radiopaque Jaw Lesions.

Radiopaque lesions and lesions of mixed density are less frequent than radiolucent lesions of the jawbones. They comprise a spectrum of odontogenic and non-odontogenic lesions. The latter group includes inherited and developmental disorders, osteomyelitis, and benign and malignant primary bone tumors and metastases. Most odontogenic radiopaque or mixed lesions are either related to the apex or more rarely to the crown of the tooth, although there are exceptions to this rule. Some lesions, such as a torus mandibularis and torus palatinus, have a characteristic location, whereas others show no relationship to the dentition. This article describes the most characteristic and prevalent radiopaque and mixed lesions of the jaws and their imaging characteristics. Paget's disease, fibrous dysplasia, and rare sclerotic bone diseases of the maxillofacial bones are discussed elsewhere in this issue. Careful correlation of clinical presentation, panoramic radiographs, cone beam computed tomography, and histopathology are the cornerstones for appropriate lesion characterization.

Imaging of Radiolucent Jaw Lesions.

Radiolucent lesions in the jaw bones comprise a whole spectrum of odontogenic and nonodontogenic lesions. Although the imaging appearance is not always specific, careful radiologic analysis may contribute to characterization of these lesions. A useful approach is to first analyze the absence or presence of a relationship of the lesion to the teeth. The relation may be either near the tooth apex or crown of the tooth. Other lesions may or may not show any specific anatomical location. After analysis of the primary location of the lesion, additional criteria that may help in further imaging characterization are lesion demarcation and morphology, involvement of the cortex and periosteum, and soft tissue changes. This article describes the most characteristic and prevalent radiolucent lesions of the jaws at each location. In routine clinical practice, cone beam computed tomography is sufficient for appropriate lesion characterization, although magnetic resonance imaging may be useful in selected cases.

Central giant cell granuloma: A clinicopathological and immunohistochemical study of macrophages, blood vessels, lymphatic vessels and regulatory proteins.

OBJECTIVE: This study seeks to investigate immunohistochemical parameters that could distinguish non-aggressive Central giant cell granuloma (CGCG) from aggressive CGCG, two groups of lesions which differ in their clinical and radiographic features and prognosis. MATERIAL AND METHODS: 12 cases of non-aggressive CGCG and 11 cases of aggressive CGCG were investigated and associated the immunohistochemical expression of macrophages (CD68 and CD163), blood vessels (CD34 and CD105), lymphatic vessels (D2-40) and regulator proteins (p63 and Ki-67). Clinical and radiographic features were also studied. RESULTS: Associations between all proteins in non-aggressive and aggressive CGCG were not significant (p > 0.05). With respect to non-aggressive CGCG, there were no significant correlations, while in aggressive CGCG there was a significant positive correlation between CD68 and CD163 (p = 0.031), between CD34 and D2-40 proteins (p = 0.04), whereas a significant negative correlation was observed between CD105 and CD68 (p = 0.040). However, regardless of aggressiveness of CGCG, there was a significant positive correlation between CD68 and CD163 (p = 0,04). Among the clinical and immunohistochemical aspects, only the symptomatology was a significant risk factor for the occurrence of aggressive CGCG (OR = 12.00/p = 0.016). CONCLUSION: Macrophages and angiogenesis contribute to their maintenance and development of CGCG. In addition, immunohistochemistry used here was not able to differentiate their aggressiveness. However, symptomatology was proved to be a risk factor for the occurrence of aggressive CGCG. It is possible that clinical features, particularly symptomatology, represent the most appropriate parameter to attempt to distinguish GCCG.

Educational Resources in Craniofacial Surgery: The Case for User-Friendly Digital Simulators.

INTRODUCTION: Digital simulators are potential solutions to challenges facing surgical education. The authors sought to evaluate the reach and utilization of a freely-accessible craniofacial surgery digital educational simulator. More importantly, we compare usage patterns between web-based and mobile-based platforms. METHODS: A 3-way collaboration between academic, non-profit (myFace, New York, NY), and biotechnology (Biodigital, New York, NY) stakeholders in 2015 produced the Craniofacial Interactive Virtual Assistant Pro (CIVA-Pro). CIVA-Pro is a freely-accessible craniofacial surgery digital educational simulator. In addition to the web-based platform, a mobile-based platform was launched in 2017. Usage analytics were collected and analyzed. RESULTS: Since its launch, 751 registered users from 117 countries had accessed CIVA-Pro. The total number of sessions was 9531, including 7500 web and 2031 mobile sessions. The total screen time was 403.9 hours, 290.3 for the web and 113.6 for the mobile platform. Comparison of the mean monthly screen time and number of monthly sessions between platforms since 2017 demonstrated a significantly higher mean monthly screen time (60.1 ±â€Š33.2 versus 29.4 ±â€Š16.5 hours; P = 0.002) and number of sessions (110.2 ±â€Š36.1 versus 58.1 ±â€Š31.9; P < 0.0001) for the mobile-based platform. The mean screen time per session was comparable (P = 0.86). CONCLUSION: A freely available digital craniofacial surgery educational simulator designed for surgical trainees can achieve significant global reach. Significantly higher utilization of the mobile-based platform of the simulator as compared to the web-based platform reinforces the need to invest in user-friendly, easily accessible, and widely available digital educational resources by key stakeholders to ensure optimal plastic surgery trainee education.