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OBJECTIVE: This study aimed to longitudinally assess the risk of facial nerve injury (FNI) in the surgical repair of mandibular condylar neck and subcondylar fractures (CN/SCFs) and to explore its predictors. MATERIALS AND METHODS: In a retrospective cohort study, the outcome was defined as FNI at 1 week and 1, 3, and 6 months postoperatively. Potential predictors included age, sex, etiology, fracture site and pattern (dislocation/non-dislocation), concomitant facial fractures, interval to surgery, surgeons' experience, plate types, and the marginal mandibular branch-traversing approach (deep/superficial group). We employed generalized estimating equations (GEEs) for repeated measurements throughout the 6-month follow-up period. RESULTS: Among 102 patients with 114 fractures, 27 patients (26.5%) developed FNI within 1 week. Prolonged FNI (≥ 1 month) occurred in 19 (19.2%) of 99 patients. Multivariate GEE analyses revealed that deep surgical approaches (i.e., traditional submandibular and retroparotid approaches; odds ratio [OR], 18.90; p = 0.011), fractures with dislocation (OR, 3.60; p = 0.025), and female gender (OR, 2.71; p = 0.040) were independently associated with the overall FNI risk. Additionally, the deep approaches (OR, 15.91; p = 0.014) and female gender (OR, 3.41; p = 0.035) were correlated with a prolonged FNI risk. Sensitivity analyses for the outcomes identified the same predictors. CONCLUSION: The predictors longitudinally associated with FNI in CN/SCF surgeries included a deep MMB-traversing approach, dislocated fracture, and female gender. CLINICAL RELEVANCE: The superficial surgical approaches (i.e., transparotid, transmasseteric anteroparotid, and high perimandibular approaches) should be adopted for CN/SCF treatment to minimize postoperative morbidity, especially for female patients with dislocated condyles.
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Traumatismos del Nervio Facial/etiología , Fijación Interna de Fracturas/efectos adversos , Fracturas Mandibulares/cirugía , Adulto , Anciano , Nervio Facial , Femenino , Humanos , Estudios Longitudinales , Masculino , Cóndilo Mandibular , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Adulto JovenRESUMEN
Boron neutron capture therapy (BNCT) is radiotherapy in which a nuclear reaction between boron-10 (10B) in tumor cells and neutrons produces alpha particles and recoiling 7Li nuclei with an extremely short range, leading to the destruction of the tumor cells. Although the neutron source has traditionally been a nuclear reactor, accelerators to generate neutron beams have been developed and commercialized. Therefore, this treatment will become more widespread. Recurrent head and neck cancer (HNC) close to the body surface is considered a candidate for BNCT using the boron compound boronophenylalanine (BPA) and has been found to be highly responsive to this treatment. However, some cases recur early after the completion of the treatment, which needs to be addressed. Ultrasound is a highly safe diagnostic method. Ultrasound with microbubbles is expected to promote the uptake of BPA into tumor cells. Ultrasound also has the ability to improve the sensitivity of tumor cells to radiotherapy. In addition, high-intensity focused ultrasound may improve the efficacy of BNCT via its thermal and mechanical effects. This review is not systematic but outlines the current status of BPA-based BNCT and proposes plans to reduce the recurrence rate of HNC after BNCT in combination with ultrasound.
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The protein kinase C (PKC) inhibitor safingol increased rounding and detachment of human oral squamous cell carcinoma (SCC) cells in monolayer cultures. When dissociated cells were incubated in the presence of safingol, cell adhesion was prevented and cell viability was lost gradually, while most cells survived in the absence of safingol even if their attachment was blocked by coating the culture plates with polyhydroxyethyl methacrylate. Flow cytometric analysis and agarose gel electrophoresis of cellular DNA revealed an increase in the proportion of sub-G(1) cells and DNA fragmentation, indicating that safingol induced apoptosis of dissociated cells. During the induction of apoptosis in cell suspensions by safingol, there was an increase of the pro-apoptotic BH-3 only protein Bim and decrease of pro-survival Bcl-2 family proteins Bcl-xL and mitochondrial pro-apoptogenic factor endonuclease G translocated to the nucleus. The level of phosphorylated focal adhesion kinase (FAK) required for cell survival also rapidly decreased, followed by a decrease in the protein level. The introduction of siRNA against PKCalpha into SAS cells resulted in an increase of Bim, a decrease of Bcl-xL, the translocation of endonuclease G, and a decrease in the phosphorylation of FAK. These results suggest that Bim, Bcl-xL, FAK and endonuclease G are involved in safingol-induced apoptosis of detached oral SCC cells. Safingol can be used to induce apoptosis with cell detachment, anoikis, of oral SCC cells.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis/fisiología , Carcinoma de Células Escamosas/metabolismo , Endodesoxirribonucleasas/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Proteínas de la Membrana/metabolismo , Neoplasias de la Boca/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/metabolismo , Esfingosina/análogos & derivados , Anoicis/fisiología , Proteína 11 Similar a Bcl2 , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , Ciclo Celular/fisiología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Citocromos c/efectos de los fármacos , Citocromos c/metabolismo , Fragmentación del ADN/efectos de los fármacos , Endodesoxirribonucleasas/antagonistas & inhibidores , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Humanos , ARN Interferente Pequeño/genética , Esfingosina/farmacologíaRESUMEN
PURPOSE: The effects of boronophenylalanine (BPA)-mediated boron neutron capture therapy (BNCT) on the growth potential and cell cycle of human oral squamous cell carcinoma (SCC) cells were examined. MATERIALS AND METHODS: SAS cells expressing a functional wild-type p53 were exposed to neutron beams in the presence of BPA and growth potential was measured by colony formation assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell cycle and cell cycle-related proteins were examined by flow cytometry and immunoblot analysis. RESULTS: BNCT affected the colony-forming ability and viability of SAS cells. In the flow-cytometric analysis of BNCT-treated cells, the cell cycle was arrested at the G1 and G2 checkpoints, and sub-G1 cells appeared. Apoptotic cells were detected by nuclear DNA staining. Immunoblot analysis revealed the phosphorylation of p53, up-regulation of p21, and down-regulation of retinoblastoma (Rb) gene protein at 6 h after BNCT. Twelve hours after BNCT, the up-regulation of Wee1, phosphorylation of cdc2, and up-regulation of cyclin B1 were observed. Cleavage of poly (ADP-ribose) polymerase (PARP) occurred from 6 h after BNCT. CONCLUSION: These results indicate that the early inhibitory effect of BNCT on the growth of human oral SCC cells can be ascribed to arrest at the G1 and G2 checkpoints and apoptosis associated with G1 arrest.
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Terapia por Captura de Neutrón de Boro , Carcinoma de Células Escamosas/patología , Neoplasias de la Boca/patología , Compuestos de Boro/farmacología , Carcinoma de Células Escamosas/metabolismo , Ciclo Celular/efectos de la radiación , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Humanos , Neoplasias de la Boca/metabolismo , Fenilalanina/análogos & derivados , Fenilalanina/farmacología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
PURPOSE: To clarify the role of p53 in boron neutron capture therapy (BNCT) for oral squamous cell carcinoma (SCC), the effect of BNCT on oral SCC xenografts with either wild-type or mutant-type p53 was examined. MATERIALS AND METHODS: Oral SCC cells expressing either wild-type (SAS/neo) or mutant-type p53 (SAS/mp53) were used to produce nude mouse tumours. Tumour-bearing mice received boronophenylalanine (BPA) at a dose of 250 mg/kg and tumours were exposed to neutron irradiation. RESULTS: After BNCT, the growth of SAS/neo and SAS/mp53 tumours was suppressed remarkably and all tumours became undetectable within two weeks. However, three of six SAS/mp53 tumours showed regrowth in two months. Histological examination of BNCT-treated tumours revealed chromosomal condensation, micronucleation, nuclear segmentation and intra- and intercelluar vacuolation. Notably, multinucleated giant cells appeared in SAS/mp53 tumours early after BNCT, suggesting mitotic catastrophe. In SAS/mp53 tumours treated with BNCT, a rapid decrease in phosphorylated cell division cycle 2 (cdc2) and a high level of cyclin B1, required for premature mitosis, were observed. CONCLUSION: These results indicate that BNCT suppressed oral SCC xenografts in nude mice efficiently, but cells survived in mutant-type p53 tumours. BNCT induces multinucleation which represents prestage of apoptosis or necrosis in oral SCC with mutant-type p53, but it may be also associated with the recurrence of BNCT-treated tumours.
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Terapia por Captura de Neutrón de Boro/efectos adversos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Genes p53 , Neoplasias de la Boca/genética , Neoplasias de la Boca/radioterapia , Mutación , Animales , Compuestos de Boro/farmacología , Línea Celular Tumoral , Proliferación Celular , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitosis , Trasplante de Neoplasias , Fenotipo , Fenilalanina/análogos & derivados , Fenilalanina/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacologíaRESUMEN
BACKGROUND: Boron neutron capture therapy (BNCT) is a selective radiotherapy, being effective for the treatment of even advanced malignancies in head and neck regions as well as brain tumors and skin melanomas. To clarify the role of p53 gene, the effect of BNCT on oral squamous cell carcinoma (SCC) cells showing either wild- (SAS/neo) or mutant-type (SAS/mp53) p53 was examined. METHODS: Cells were exposed to neutron beams in the presence of boronophenylalanine (BPA) at Kyoto University Research Reactor. Treated cells were monitored for modulations in colony formation, proliferation, cell cycle, and expression of cell cycle-associated proteins. RESULTS: When SAS/neo and SAS/mp53 cells were subjected to BNCT, more suppressive effects on colony formation and cell viability were observed in SAS/neo compared with SAS/mp53 cells. Cell cycle arrest at the G1 checkpoint was observed in SAS/neo, but not in SAS/mp53. Apoptotic cells increased from 6 h after BNCT in SAS/neo and 48 h in SAS/mp53 cells. The expression of p21 was induced in SAS/neo only, but G2 arrest-associated proteins including Wee1, cdc2, and cyclin B1 were altered in both cell lines. CONCLUSION: These results indicate that oral SCC cells with mutant-type are more resistant to BNCT than those with wild-type p53, and that the lack of G1 arrest and related apoptosis may contribute to the resistance. At a physical dose affecting the cell cycle, BNCT inhibits oral SCC cells in p53-dependent and -independent manners.
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Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Neoplasias de la Boca/genética , Neoplasias de la Boca/radioterapia , Proteína p53 Supresora de Tumor/genética , Apoptosis/efectos de la radiación , Terapia por Captura de Neutrón de Boro , Línea Celular Tumoral , Proliferación Celular/efectos de la radiación , Separación Celular , Citometría de Flujo , Humanos , Immunoblotting , Mutación , Tolerancia a Radiación/genéticaRESUMEN
It is necessary to explore new treatments for recurrent head and neck malignancies (HNM) to avoid severe impairment of oro-facial structures and functions. Boron neutron capture therapy (BNCT) is tumor-cell targeted radiotherapy that has significant superiority over conventional radiotherapies in principle. We have treated with BNCT 42 times for 26 patients (19 squamous cell carcinomas (SCC), 4 salivary gland carcinomas and 3 sarcomas) with a recurrent and far advanced HNM since 2001. Results of (1) (10)B concentration of tumor/normal tissue ratios (T/N ratio) of FBPA-PET studies were SCC: 1.8-5.7, sarcoma: 2.5-4.0, parotid tumor: 2.5-3.7. (2) Therapeutic effects were CR: 12 cases, PR: 10 cases, PD: 3 cases NE (not evaluated): 1 case. Response rate was 85%. (3) Improvement of QOL such as a relief of severe pain, bleeding, and exudates at the local lesion, improvement of PS, disappearance of ulceration, covered with normal skin and preserved oral and maxillofacial functions and tissues. (4) Survival periods after BNCT were 1-72 months (mean: 13.6 months). Six-year survival rate was 24% by Kaplan-Meier analysis. (5) Adverse-events were transient mucositis and alopecia in most of the cases; three osteomyelitis and one brain necrosis were recognized. These results indicate that BNCT represents a new and promising treatment approach for advanced HNM.