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Neoadjuvant BRAF-targeted therapy for ameloblastoma of the mandible: an organ preservation approach.Journal of the National Cancer Institute Apr 2024Ameloblastoma is a rare odontogenic neoplasm frequently located in the mandible. Standard treatment involves radical bone resection and immediate reconstruction, causing...
BACKGROUND
Ameloblastoma is a rare odontogenic neoplasm frequently located in the mandible. Standard treatment involves radical bone resection and immediate reconstruction, causing functional, aesthetic, and psychological impairments. The BRAF V600E mutation is present in approximately 80% of mandible ameloblastomas, and BRAF inhibitors have demonstrated sustained responses in unresectable cases.
METHODS
We identified ameloblastoma patients planned for ablative surgery and screened them for BRAF V600E mutation. Neoadjuvant BRAF inhibitors were offered to facilitate jaw preservation surgery. Retrospective data collection encompassed treatment regimens, tolerability, tumor response, and conversion to mandible preservation surgery.
RESULTS
Between 2017 and 2022, a total of 11 patients received dabrafenib (n = 6) or dabrafenib with trametinib (n = 5). The median age was 19 (range = 10-83) years. Median treatment duration was 10 (range = 3-20) months. All (100%) patients achieved a radiological response. Ten (91%) patients successfully converted to mandible preservation surgery with residual tumor enucleation. One patient attained complete radiological response, and surgery was not performed. Among the 10 surgically treated patients, all exhibited a pathological response, with 4 achieving near complete response and 6 partial response. At a median follow-up of 14 (range = 7-37) months after surgery, 1 case of recurrence was observed. Grade 1-2 adverse effects were reported in 8 (73%) patients, with a single case of grade 3 (hepatitis). Dose modification was necessary for 3 patients, and 4 experienced treatment interruptions, while 1 patient permanently discontinued therapy.
CONCLUSIONS
Neoadjuvant BRAF inhibition may offer a safe and effective strategy for organ preservation in mandible ameloblastoma treatment.
Topics: Humans; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Ameloblastoma; Proto-Oncogene Proteins B-raf; Neoadjuvant Therapy; Retrospective Studies; Organ Preservation; Mutation; Protein Kinase Inhibitors; Mandible; Imidazoles; Oximes
PubMed: 37966914
DOI: 10.1093/jnci/djad232 -
Journal of Oral Biosciences Jun 2024Odontogenic tumors arise in the jawbone and originate from cells associated with tooth development. Therefore, understanding odontogenic tumors requires knowledge of all... (Review)
Review
BACKGROUND
Odontogenic tumors arise in the jawbone and originate from cells associated with tooth development. Therefore, understanding odontogenic tumors requires knowledge of all aspects of dental research, including tooth development and eruption. Ameloblastoma is the most common odontogenic tumor.
HIGHLIGHT
Although a benign tumor, ameloblastoma progresses with marked jawbone resorption. Because of its locally aggressive features, it can be treated surgically by resecting the surrounding bone. From a molecular pathology perspective, several genetic mutations and dysregulated signaling pathways involved in ameloblastoma tumorigenesis have been identified. Histopathologically, ameloblastomas consist of peripheral ameloblast-like cells and an inner stellate reticulum. The stromal region consists of fibrovascular connective tissue, showing a characteristic sparse myxoid histology. In general, the tumor microenvironment, including the surrounding non-tumor cells, contributes to tumorigenesis and progression. In this review, we focus on the tumor microenvironment of ameloblastomas. In addition, we present some of our recent studies on osteoclastogenesis, tubulin acetylation-induced cell migration, and hypoxia-induced epithelial-mesenchymal transition in ameloblastomas.
CONCLUSION
Further research on ameloblastomas can lead to the development of new treatments and improve patients' quality of life.
Topics: Ameloblastoma; Humans; Tumor Microenvironment; Cell Transformation, Neoplastic; Cell Movement; Jaw Neoplasms; Osteogenesis; Epithelial-Mesenchymal Transition; Osteoclasts
PubMed: 38734178
DOI: 10.1016/j.job.2024.05.002 -
Indian Journal of Otolaryngology and... Dec 2023Hypoxia-inducible factor-1α is a transcriptional protein that has been extensively researched in human cancers whose overexpression is found to be associated with...
Hypoxia-inducible factor-1α is a transcriptional protein that has been extensively researched in human cancers whose overexpression is found to be associated with unfavorable prognosis. Contemporary studies have proved its vital role in ameloblastoma by correlating its expression with the aggressiveness of the tumor. Therefore, an attempt was made to explore its significance in the malignant transformation and prognosis of ameloblastoma. The present systematic review aimed to understand the impact of HIF-1α in AMB which might lead to favorable outcomes in the treatment. An electronic search was carried out using PubMed, Scopus, Google scholar, Cochrane library, and EMBASE databases. Original articles from all languages involving HIF-1α in AMB were scrutinized by two independent authors. Data were compiled and tabulated in Microsoft Excel and the Risk of bias was analyzed using the JBI tool. Twelve eligible articles were included for the quantitative analysis comprising 305 cases of AMB in which HIF-1α expression was studied for various characteristics like pattern, intensity, and site of immunoexpression which were found to be increased with an increase in the aggressiveness of AMB. It was concluded that HIF-1α is proven to have a crucial role in the progression and aggressiveness of AMB. Extended research regarding the crucial role of HIF-1α in the initiation of tumors and therapies aiming at HIF-1α in AMB cases might show promising outcomes in the future.
PubMed: 37974737
DOI: 10.1007/s12070-023-03928-6 -
Oral Diseases Oct 2023BRD4, belonging to the bromodomain extra-terminal (BET) protein family, plays a unique role in tumor progression. However, the potential impact of BRD4 in ameloblastoma...
BACKGROUND
BRD4, belonging to the bromodomain extra-terminal (BET) protein family, plays a unique role in tumor progression. However, the potential impact of BRD4 in ameloblastoma (AM) remains largely unknown. Herein, we aimed to assess the expression and functional role of BRD4 in AM.
METHODS
The expression level of BRD4 was assessed by immunohistochemistry. The proliferation, migration, invasion, and tumorigenic abilities of AM cells were assessed by a series of assays. To explore the molecular expression profile of BRD4-depleted AM cells, RNA sequencing (RNA-seq) was performed. Bioinformatic analysis was performed on AM expression matrices obtained from the Gene Expression Omnibus (GEO). The therapeutic efficacy of BET-inhibitors (BETi) was assessed with AM patient-derived organoids.
RESULTS
Upregulation of BRD4 was observed in conventional AMs, recurrent AMs, and ameloblastic carcinomas. Depletion of BRD4 inhibited proliferation, invasion, migration, and tumorigenesis in AM. Administration of BETi attenuated the aggressiveness of AM and the growth of AM patient-derived organoids. Bioinformatic analysis indicated that BRD4 may promote AM progression by regulating the Wnt pathway and stemness-associated pathways.
CONCLUSION
BRD4 increases the aggressiveness and promotes the recurrence of ameloblastoma by regulating the Wnt pathway and stemness-associated pathways. These findings highlight BRD4 as a promising therapeutic target in AM management.
PubMed: 37798926
DOI: 10.1111/odi.14762 -
Oral Diseases Oct 2023Although benign, ameloblastoma is a locally aggressive lesion in some patients and the development of additional treatments is needed. Verteporfin (VP) is a...
OBJECTIVE
Although benign, ameloblastoma is a locally aggressive lesion in some patients and the development of additional treatments is needed. Verteporfin (VP) is a photosensitizer exhibiting considerable photocytotoxicity in various tumor cells. We aimed to investigate the effects of verteporfin photodynamic therapy (VP PDT) on ameloblastoma.
METHODS
Eighteen patients who underwent surgery for ameloblastoma were randomly selected. We performed an immunohistochemical assessment to investigate the expression of low-density lipoprotein receptor (LDLR) and Yes-associated protein (YAP), targets of VP, in human ameloblastoma tissues and cultured human ameloblastoma cell line (HAM1). The effect of VP PDT on cell proliferation and apoptosis in HAM1 was analyzed.
RESULTS
The expression of LDLR and YAP were detected in human ameloblastoma tissues and HAM1. LDLR expression was significantly higher in patients who had previously undergone surgery than in patients who were receiving it for the first time. The cytotoxic effect of the combination of low-concentration VP administration and laser irradiation was comparable to high-concentration VP administration with and without laser irradiation. The addition of laser irradiation to VP administration significantly accelerated apoptotic bleb formation compared with VP administration alone.
CONCLUSION
VP PDT has the potential to become an additional treatment for large-sized ameloblastoma.
PubMed: 37890051
DOI: 10.1111/odi.14775 -
Journal of Oral Pathology & Medicine :... Aug 2023Unicystic ameloblastoma is an encapsulated odontogenic neoplasm with a single cyst cavity. The conservative or aggressive surgical approaches used to treat the tumor...
BACKGROUND
Unicystic ameloblastoma is an encapsulated odontogenic neoplasm with a single cyst cavity. The conservative or aggressive surgical approaches used to treat the tumor directly affect recurrence rates. However, there is a lack of a standard protocol that can guide its management.
STUDY DESIGN
We retrospectively reviewed the clinicopathological findings and therapeutical procedures of 12 unicystic ameloblastoma cases treated by the same surgeon during the past 20 years.
METHODS
All cases of unicystic ameloblastoma diagnosed by biopsy and treated by the same surgeon between 2002 and 2022 were reviewed. Eligibility criteria were patients with completely filled-out charts containing the follow-up period and confirmation of the diagnoses based on the microscopic findings of the whole excised specimens. Data collected were categorized into clinical, radiographic, histological, surgical, and recurrence aspects.
RESULTS
There was a female predilection (2:1), and ages ranged between 18 and 61 years (mean: 27.25, ±12.45). Almost all (92%) affected the posterior mandible. Radiographically, the mean length of the lesions was 46.14 mm ± 14.28 mm which 92% were unilocular and 8.3% multilocular. Root resorption (n = 7, 58%), tooth displacement (n = 9, 75%), and cortical perforation (n = 5, 42%) were also observed. The mural histological subtype corresponded to 9 (75%) of the cases. The same conservative protocol was performed in all cases. The follow-up period ranged between 12 and 240 months (~62 ± 65) and recurrence occurred in only one patient (8%).
CONCLUSION
Our findings suggest a conservative approach should be the first option for unicystic ameloblastoma treatment, even for those with mural proliferation.
Topics: Humans; Female; Adolescent; Young Adult; Adult; Middle Aged; Ameloblastoma; Retrospective Studies; Mandible; Odontogenic Tumors; Biopsy
PubMed: 37224237
DOI: 10.1111/jop.13453 -
Medicina (Kaunas, Lithuania) Dec 2023Ameloblastoma is a benign epithelial tumor that has aggressive, destructive and unlimited growth potential, having the capacity for recurrence and malignant...
Ameloblastoma is a benign epithelial tumor that has aggressive, destructive and unlimited growth potential, having the capacity for recurrence and malignant transformation. Regarding the symptoms and clinical signs, the presentation of ameloblastoma is poor. In children and young people, ameloblastoma can be difficult to diagnose, because it mimics other benign lesions. Its diagnosis requires a combination of imaging data, histopathological analysis and molecular tests. The methods of treatment consist of radical surgery (segmental resection) and conservative treatments (enucleation with bone curettage). The particularity of the presented case is represented by the late request for medical consultation, a direct consequence of the measures implemented to prevent and control the spread of COVID-19.
Topics: Child; Female; Humans; Adolescent; Ameloblastoma; Mandible; Aggression; COVID-19; Conservative Treatment
PubMed: 38256328
DOI: 10.3390/medicina60010066 -
Zhonghua Kou Qiang Yi Xue Za Zhi =... Aug 2023Ameloblastoma (AM) is a benign odontogenic tumor with unknown etiology. It is prone to recurrence and has a potential for malignant transformation. Patients often show... (Review)
Review
Ameloblastoma (AM) is a benign odontogenic tumor with unknown etiology. It is prone to recurrence and has a potential for malignant transformation. Patients often show high rates of relapse after curettage, or suffer from structural and functional damage of jaw after partial resection. Whole-genome sequencing data revealed that BRAF mutations and SMO mutations were common and likely to be mutually exclusive in AM. It was also reported that BRAF inhibitors were effective in several patients carrying BRAF mutation. However, reliable preclinical models are urgently needed for exploring targeted therapy as it's so difficult to conduct large clinical trials in this tumor. Patient-derived cell models in vitro and xenograft models in vivo are frequently used preclinical models. In fact, benign tumor cells generally showed a finite proliferative capacity in two-dimensional culture, and most likely, they could exhibit altered cellular phenotype after immortalization. Moreover, this benign tumor presented low chances of subcutaneous engraftment in nude mice. Accordingly, humanized mouse xenograft model needs more exploration. Yet, it is worth mentioning that a three-dimensional organoid model presents a high potential in culturing stem-cell-like epithelial cells in AM, and it would further be used in recapitulating corresponding tumors and developing targeted medicines. In this paper, we review research progress in preclinical models and the genetic variations of AM, and raise drug screening prospect of the current organoid models, which may pave the way for the possible personalized medicine in AM.
Topics: Humans; Animals; Mice; Ameloblastoma; Proto-Oncogene Proteins B-raf; Mice, Nude; Neoplasm Recurrence, Local; Odontogenic Tumors; Mutation
PubMed: 37550047
DOI: 10.3760/cma.j.cn112144-20230703-00264 -
Journal of Oral Pathology & Medicine :... Nov 2023Odontogenic tumors (OT) are composed of heterogeneous lesions, which can be benign or malignant, with different behavior and histology. Within this classification,...
BACKGROUND
Odontogenic tumors (OT) are composed of heterogeneous lesions, which can be benign or malignant, with different behavior and histology. Within this classification, ameloblastoma and ameloblastic carcinoma (AC) represent a diagnostic challenge in daily histopathological practice due to their similar characteristics and the limitations that incisional biopsies represent. From these premises, we wanted to test the usefulness of models based on artificial intelligence (AI) in the field of oral and maxillofacial pathology for differential diagnosis. The main advantages of integrating Machine Learning (ML) with microscopic and radiographic imaging is the ability to significantly reduce intra-and inter observer variability and improve diagnostic objectivity and reproducibility.
METHODS
Thirty Digitized slides were collected from different diagnostic centers of oral pathology in Brazil. After performing manual annotation in the region of interest, the images were segmented and fragmented into small patches. In the supervised learning methodology for image classification, three models (ResNet50, DenseNet, and VGG16) were focus of investigation to provide the probability of an image being classified as class0 (i.e., ameloblastoma) or class1 (i.e., Ameloblastic carcinoma).
RESULTS
The training and validation metrics did not show convergence, characterizing overfitting. However, the test results were satisfactory, with an average for ResNet50 of 0.75, 0.71, 0.84, 0.65, and 0.77 for accuracy, precision, sensitivity, specificity, and F1-score, respectively.
CONCLUSIONS
The models demonstrated a strong potential of learning, but lack of generalization ability. The models learn fast, reaching a training accuracy of 98%. The evaluation process showed instability in validation; however, acceptable performance in the testing process, which may be due to the small data set. This first investigation opens an opportunity for expanding collaboration to incorporate more complementary data; as well as, developing and evaluating new alternative models.
Topics: Humans; Ameloblastoma; Artificial Intelligence; Deep Learning; Reproducibility of Results; Odontogenic Tumors; Carcinoma
PubMed: 37712132
DOI: 10.1111/jop.13481 -
The Journal of Craniofacial SurgeryAmeloblastoma is a benign neoplasm composed of epithelial tissue with invasive and infiltrative behavior at the local level and a high recurrence rate, with various...
BACKGROUND
Ameloblastoma is a benign neoplasm composed of epithelial tissue with invasive and infiltrative behavior at the local level and a high recurrence rate, with various histopathologic patterns and clinical forms. Approximately 85% of conventional ameloblastomas occur in the mandible, most often in the body, angle, and ascending ramus area. The treatment modalities include both conservative and radical treatments. Postoperative follow-up is most important in the treatment of ameloblastoma.
AIMS AND OBJECTIVES
To describe the clinicopathologic profile of mandibular ameloblastoma in patients undergoing different surgical modalities. The primary objective was to describe the clinicopathologic profile and surgical management of mandibular ameloblastoma in patients aged ≥18 years, who had reported to a tertiary dental care center for follow-up during the study period. The secondary objective was to describe the distribution of comorbidities associated with different surgical modalities and reconstructive methods.
SUBJECTS AND METHODS
A total of 34 patients with mandibular ameloblastoma who underwent various surgical modalities between 2011 and 2021 were studied. Information was collected using a predesigned proforma and statistically analyzed.
RESULTS
Thirty-four review cases of ameloblastoma were included in the study. The patients were analyzed concerning age, sex, site, size, clinical presentation, radiographic pattern, histopathologic subtype, type of surgery, and associated comorbidities. Most cases of mandibular ameloblastoma involve the age of 16 to 55 years. The mean age of occurrence was found to be 35.5±13.2. A female preponderance, a tumor size range of 2 to 4 cm, a multicystic variant, involvement of the mandibular body in the premolar-molar area, root resorption, cortical perforation, and a follicular type of histopathologic pattern were the common presentations. Isolated anterior tumors restricted to the incisor/canine region were not found. The common surgical modalities undertaken were conservative methods such as enucleation, and chemical cauterization, and radical methods such as marginal mandibulectomy and segmental resection. Reconstruction using a titanium plate or free fibular graft was performed in the indicated cases. The common comorbidities included difficulty in chewing and loss of facial contour. Recurrence after surgical treatment was rare. Only 9% of cases developed a recurrence within 5 years. No recurrence was noted in cases treated with radical treatment, whereas 50% of cases treated with conservative methods showed recurrence.
CONCLUSION
The age of occurrence, site, and size of the tumor, cortical perforation, root resorption, histopathologic type, and radiographic patterns are widely considered factors in devising a treatment plan for mandibular ameloblastoma. However, there may be rare instances where these tumors behave differently regardless of their innocuous clinicopathologic presentation. Surgical procedures such as segmental resection and marginal mandibulectomy were found to be promising for the eradication of the tumor, and prevention of recurrences and metastasis. However, conservative measures such as enucleation and chemical cauterization were fraught with an increased risk of tumor recurrence and metastasis. Future studies with a larger sample size should focus on the clinicopathologic characteristics of ameloblastoma to elucidate its varied behavior and develop newer and advanced treatment modalities that would provide better surgical and postsurgical outcomes in affected patients.
Topics: Humans; Female; Adolescent; Adult; Young Adult; Middle Aged; Ameloblastoma; Mandibular Neoplasms; Root Resorption; Mandible; Mandibular Osteotomy; Neoplasm Recurrence, Local; Retrospective Studies
PubMed: 37691573
DOI: 10.1097/SCS.0000000000009706