A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ?

Root amputation, extraction of a single tooth, bone loss or severe tooth mobility, and an unclosed wound were significantly associated with increased risk of developing medication-related osteonecrosis of the jaw (MRONJ). We recommend a minimally traumatic extraction technique, removal of any bone edges, and mucosal wound closure as standard procedures in patients receiving bisphosphonates. INTRODUCTION: Osteonecrosis of the jaws can occur following tooth extraction in patients receiving bisphosphonate drugs. Various strategies for minimizing the risk of MRONJ have been advanced, but no studies have comprehensively analyzed the efficacy of factors such as primary wound closure, demographics, and drug holidays in reducing its incidence. The purpose of this study was to retrospectively investigate the relationships between these various risk factors after tooth extraction in patients receiving oral bisphosphonate therapy. METHODS: Risk factors for MRONJ after tooth extraction were evaluated using univariate and multivariate analysis. All patients were investigated with regard to demographics; type and duration of oral bisphosphonate use; whether they underwent a discontinuation of oral bisphosphonates before tooth extraction (drug holiday), and the duration of such discontinuation; and whether any additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. RESULTS: We found that root amputation (OR = 6.64), extraction of a single tooth (OR = 3.70), bone loss or severe tooth mobility (OR = 3.60), and an unclosed wound (OR = 2.51) were significantly associated with increased risk of developing MRONJ. CONCLUSIONS: We recommend a minimally traumatic extraction technique, removal of any bone edges, and mucosal wound closure as standard procedures in patients receiving bisphosphonates. We find no evidence supporting the efficacy of a pre-extraction short-term drug holiday from oral bisphosphonates in reducing the risk of MRONJ.

Predictors of obstructive sleep apnoea-hypopnea severity and oral appliance therapy efficacy by using lateral cephalometric analysis.

Obstructive sleep apnoea-hypopnea (OSAH) is a common disorder characterised by repetitive complete or partial closure of the upper airway during sleep, which results in sleep fragmentation and oxygen desaturation. There is growing interest in the use of oral appliances (OAs) to treat OSAH. The purpose of this study was to clarify the cephalometric factors that are associated with OSAH severity and that predict the outcome of OA therapy. Two hundred nine patients with OSAH were recruited and analysed retrospectively. They had a polysomnographically documented apnoea-hypopnea index (AHI) of more than five respiratory events per hour. Lateral skull radiographs were used for cephalometric analysis. Only 67 of the 209 recruited patients underwent a second polysomnography (PSG) to evaluate the efficacy of OA therapy. In all recruited patients, the angle formed by the subspinal point (A) to the nasion (N) to the supramental point (B) (i.e. ANB angle) and the distance between the mandibular plane and hyoid bone (MP-H) were predictive factors of OSAH severity. In only 67 patients underwent PSG with an OA, the mean rate of decrease in the AHI was 47·8 ± 29·1%. OA therapy effectively treated OSAH in some patients with a very severe form of OSAH. However, patients who had a high position of the hyoid bone had a poor response to OA therapy. This study suggested that cephalometric analysis is useful for predicting OSAH severity and OA therapy efficacy.

Reconstruction using a submental island flap combined with mylohyoid muscle as a reliable surgical strategy after rim mandibulectomy for the management of stage 3 medication-related osteonecrosis of the mandible.

The purpose of this study was to evaluate the clinical outcomes of patients with stage 3 mandibular medication-related osteonecrosis of the jaw (MRONJ) treated using a submental island flap in combination with mylohyoid muscle reconstruction after rim mandibulectomy. The medical records of 12 patients treated between January 2019 and April 2022 were analysed retrospectively. Primary wound healing was assessed as the maintenance of full mucosal coverage without signs of infection at 6 months postoperatively. The follow-up period ranged from 7 to 38 months, with an average of 21.8 months. All 12 patients (100%) experienced primary wound healing, with normal mouth opening and occlusion, and without pathological mandibular fracture or facial aesthetic problems during the follow-up period. Postoperative panoramic images revealed new bone formation in the treated areas of the mandible in four patients. During the follow-up period, one patient continuing bevacizumab and zoledronate administration for the primary cancer developed MRONJ in the same area at 13 months postoperatively and finally died. Hence the total success rate was 91.7%. In summary, for patients with stage 3 mandibular MRONJ treated with rim mandibulectomy, the submental island flap combined with mylohyoid muscle is an effective reconstructive option for wound-healing and possible bone regeneration of denuded bone.

Postoperative adjuvant therapy for patients with loco-regionally advanced oral squamous cell carcinoma who are at high risk of recurrence.

Extranodal extension (ENE) of lymph node metastasis and the presence of a positive or close margin (PCM) are major risk factors for head and neck squamous cell carcinoma recurrence. This retrospective multicentre cohort study compared the prognostic impact of postoperative radiotherapy (RT) and concurrent chemoradiotherapy (CCRT) in oral squamous cell carcinoma (OSCC) patients at high risk of recurrence. One hundred and eighteen patients with PCM and/or ENE who underwent definitive surgery plus either adjuvant RT or CCRT using cisplatin for OSCC were investigated. The cohort-wide 5-year loco-regional control (LRC), disease-free survival (DFS), and overall survival (OS) rates (the main outcome measures) were 54.3%, 35.8%, and 43.2%, respectively. Multivariate analysis showed that age ≥64 years (hazard ratio (HR) 0.584), cT3-4 stage (HR 1.927), ≥4 metastatic lymph nodes (HR 1.912), and PCM (HR 2.014) were significant independent predictors of OS. Moreover, postoperative CCRT with cisplatin was associated with a significantly improved LRC rate, but not with improved DFS or OS rates, compared to postoperative RT (HR 0.360). Given that CCRT with cisplatin does not significantly improve survival, additional clinical trials will be required to validate new regimens that further improve the outcomes of patients with loco-regionally advanced OSCC going forward.

A Targeted Genetic Association Study of the Rare Type of Osteomyelitis.

Chronic nonbacterial osteomyelitis is a rare bone disorder that can be found in the jaw. It is often associated with systemic conditions, including autoimmune deficiencies. However, little is known about how the genetic and immunologic background of patients influences the disease. Here, we focus on human leukocyte antigen (HLA), killer cell immunoglobulin-like receptors (KIRs), and their specific combinations that have been difficult to analyze owing to their high diversity. We employed a recently developed technology of simultaneous typing of HLA alleles and KIR haplotype and investigated alleles of the 35 HLA loci and KIR haplotypes composed of centromeric and telomeric motifs in 18 cases and 18 controls for discovery and 472 independent controls for validation. We identified an amino acid substitution of threonine at position 94 of HLA-C in combination with the telomeric KIR genotype of haplotype tA01/tB01 that had significantly higher frequency (>20%) in the case population than in both control populations. Multiple logistic regression analysis based on a dominant model with adjustments for age and sex revealed and validated its statistical significance and high predictive accuracy (C-statistic ≥0.85). Structure-based analysis revealed that the combination of the amino acid change in HLA-C and the telomeric genotype tA01/tB01 could be associated with lower stability of HLA-C. This is the first case-control study of a rare disease that employed the latest sequencing technology enabling simultaneous typing and investigated amino acid polymorphisms at HLA loci in combination with KIR haplotype.

Overexpression of metastasis-associated MTA1 in oral squamous cell carcinomas: correlation with metastasis and invasion.

Metastasis-associated protein 1 (MTA1) is physiologically expressed at low levels in human tissues. Its expression is associated with progression of solid cancers and is common in cancer cell lines. This study investigated whether MTA1 was expressed in squamous cell carcinoma (SCC) and would be a useful metastatic marker. Specimens from 38 patients with oral SCC were stained using the avidin-biotin-peroxidase technique with polyclonal antibodies against MTA1. Human SCC cell lines SAS, HSC2, OSC19 and OSC20 were analysed for MTA1 mRNA expression. MTA1 expression in control tissues was significantly lower than in carcinomas. MTA1 protein expression was detected in 33 of 38 SCC tissues from patients. Histologically, MTA1 protein production was strongly associated with cancer cell invasion, and clinically there was a correlation between lymph node metastasis and MTA1 protein production. Among the cancer cell lines, HSC2 showed the lowest mRNA expression, and OSC20 showed the highest MTA1 mRNA expression. In the Matrigel invasion assay, the HSC2 cell line showed the lowest invasion and the OSC20 cell line showed the highest invasion. RNAi-mediated MTA1 silencing in the OSC20 cells decreased the invasion index. MTA1 expression in oral SCC may be associated with increased invasive ability, which may cause lymph node metastasis.

Comparison of osseous healing after sagittal split ramus osteotomy and intraoral vertical ramus osteotomy.

The sagittal split ramus osteotomy (SSRO) is generally associated with greater postoperative stability than the intraoral vertical ramus osteotomy (IVRO); however, it entails a risk of inferior alveolar nerve damage. In contrast, IVRO has the disadvantages of slow postoperative osseous healing and projection of the antegonial notch, but inferior alveolar nerve damage is believed to be less likely. The purposes of this study were to compare the osseous healing processes associated with SSRO and IVRO and to investigate changes in mandibular width after IVRO in 29 patients undergoing mandibular setback. On computed tomography images, osseous healing was similar in patients undergoing SSRO and IVRO at 1year after surgery. Projection of the antegonial notch occurred after IVRO, but returned to the preoperative state within 1year. The results of the study indicate that IVRO is equivalent to SSRO with regard to both bone healing and morphological recovery of the mandible.

Natriuretic peptide receptor A is related to the expression of vascular endothelial growth factors A and C, and is associated with the invasion potential of tongue squamous cell carcinoma.

Natriuretic peptide receptor A (NPRA) is one of the natriuretic peptide receptors. NPRA has been reported to play a role in the carcinogenesis of various tumours, as well as functional roles in renal, cardiovascular, endocrine, and skeletal homeostasis. The clinicopathological significance of NPRA in tongue squamous cell carcinoma (TSCC) was examined in this study. The overexpression of NPRA was more frequent in TSCC (21/58, 36.2%) than in the normal oral epithelium (0/10, 0%) (P<0.05). It was also more frequently observed in cancers with higher grades according to the pattern of invasion (grades 1-2 vs. grades 3-4, P<0.01). Additionally, there was a tendency towards an association between the N classification and NPRA expression (N0 vs. N1-2, P=0.06). Significant correlations were also observed between the expression of NPRA and that of VEGF-A (P<0.001) and VEGF-C (P<0.001). The high-NPRA expression group had a significantly poorer prognosis, with a 5-year disease-specific survival rate of 39.7%, compared to 97.0% in the low-expression group (P<0.001). Multivariate analysis suggested that the overexpression of NPRA may also be an independent prognostic factor (P<0.05). In conclusion, NPRA is associated with VEGF expression levels, invasion, and metastasis, and may be a prognostic factor in TSCC patients.

Evaluation of the level of progression of extracapsular spread for cervical lymph node metastasis in oral squamous cell carcinoma.

Only a few reports on the level of progression of extracapsular spread (ECS) have been published. The aim of this study was to evaluate the efficacy of the level of progression of ECS in identifying those patients with oral squamous cell carcinoma (OSCC) at a high risk of recurrence who would benefit most from the intensification of adjuvant therapy. The level of progression of ECS for cervical lymph node metastasis in OSCC was divided into three types (A-C), and their relationships with patient prognosis were examined. ECS was observed in 87 of 441 patients with OSCC. The recurrence rate in patients with type C, which was defined as macroscopic tumour invasion into perinodal fat or muscle tissue, was high (69.8%), with 13 cases of death due to distant metastasis. The 3-year disease-specific survival rate for patients with type C was 49.0% and these patients also had a significantly poorer prognosis (P<0.01). The results of the multivariate analysis suggested that the prognosis of ECS in OSCC patients was associated with the level of progression of ECS, especially type C (P<0.01). Overall, the results of this study suggest that the level of progression of ECS is a useful prognostic factor in OSCC patients.

Efficacy of topical antibiotic administration on the inhibition of perioperative oral bacterial growth in oral cancer patients: a preliminary study.

Parenteral antibiotic prophylaxis is the current standard of therapy in clean-contaminated oral cancer surgery. Nevertheless, the incidence of surgical site infection (SSI) in oral oncological surgery is relatively high, especially in major surgery with reconstruction and tracheotomy. The aims of this study were to investigate the perioperative condition related to microorganisms in the oral cavity and to examine the efficacy of the topical administration of tetracycline in reducing the number of bacteria in the oropharyngeal fluid during intubation. The number of oral bacteria was measured during intubation in patients undergoing major oral cancer surgery. The efficacy of the topical administration of tetracycline or povidone iodine gel in reducing the bacteria was then investigated. Bacteria in the oropharyngeal fluid grew from 10(6)CFU/ml to 10(8)CFU/ml during the 3h after intubation (CFU, colony-forming units). When tetracycline was applied to the dorsum of the tongue, oral bacteria decreased immediately to 10(5)CFU/ml, and the number of bacteria in the oropharyngeal fluid was maintained below 10(7)CFU/ml for 7h. The concentration of tetracycline in the oropharyngeal fluid was extremely high for several hours after topical administration. The topical administration of tetracycline could reduce oral bacteria in patients undergoing clean-contaminated oral cancer surgery. This method is expected to be effective in the prevention of SSI.

A clinicopathological study of perineural invasion and vascular invasion in oral tongue squamous cell carcinoma.

The risk factors for recurrence of head and neck cancer are classified as being of high or intermediate risk. Those of intermediate risk include multiple positive nodes without extracapsular nodal spread, perineural/vascular invasion, pT3/T4 primary tumours, and positive level IV/V nodes. However, little evidence is available to validate these intermediate risk factors. We analyzed perineural/vascular invasion in 89 patients who underwent radical surgery for oral tongue squamous cell carcinoma, whose records were reviewed retrospectively. Perineural invasion was found in 27.0% of cases and vascular invasion in 23.6%; both had a strong relationship with histopathological nodal status (P = 0.005). The 5-year disease-specific survival (DSS) and overall survival rates of patients with perineural invasion were significantly lower than those of patients without perineural invasion (P < 0.001 and P = 0.002, respectively). The 5-year DSS of UICC stage I and II cases with perineural/vascular invasion was significantly lower than those without (P < 0.001 and P = 0.008, respectively). Perineural invasion and vascular invasion are risk factors for regional metastasis and a poor prognosis. We recommend elective neck dissection when perineural/vascular invasion is found in clinical stage I and II cases. The accumulation of further evidence to consider intermediate risks is required.

Juvenile hyaline fibromatosis complicated with oral squamous cell carcinoma: a case report.

A 45-year-old woman was referred because of swelling of the palate, gingival hypertrophy, and multiple cutaneous tumors. She had many cutaneous tumors, which covered most of her body, and she also displayed contractures of the major joints. Maxillary and mandibular gingival hypertrophy, malposition of the teeth, and swelling of the hard palate were the oral findings. The histopathologic features of the cutaneous and gingival tumors were consistent with hyaline fibromatosis, and the swelling of the palate proved to be a squamous cell carcinoma. The carcinoma was treated with tegafur/uracil and seemed to respond to this therapy.

Effects of postoperative chemotherapy and radiotherapy on patients with squamous cell carcinoma of the oral cavity and multiple regional lymph node metastases.

Nodal metastasis in oral squamous cell carcinoma (OSCC) is considered to be a predictor of a poor prognosis. The aim of this study was to investigate the relationship between the number of positive lymph nodes and the prognosis in OSCC patients with nodal metastases and to assess the effects of postoperative radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) on this patient group. A retrospective investigation of 98 patients with OSCC who underwent radical neck dissection and had at least three pathologically positive lymph nodes was performed. The 5-year disease-specific survival rate was 66.7% for patients with 3 positive nodes, while it was significantly lower for those with 4 positive nodes and those with ≥ 5 positive nodes (21.5% and 46.1%, respectively; P < 0.01). The loco-regional control and disease-specific survival rates for the surgery alone, surgery plus RT, and surgery plus CCRT groups were 46.2% and 40.5%, 66.3% and 54.4%, and 81.7% and 52.4%, respectively. For patients with ≥ 4 positive nodes, the loco-regional control rate after surgery plus CCRT was better than that observed after surgery alone (77.5% vs. 32.6%, P = 0.01). Postoperative RT and CCRT have positive impacts on the prognosis of OSCC patients with advanced stage neck disease.

Benefits of maxillectomy with internal dissection of the masticator space by transmandibular approach in the surgical management of malignant tumours of the upper gingiva and hard palate: a clinical review of 10 cases.

The aim of this study was to review patients with tumours extending to the posterior portion of the upper gingiva and hard palate, and to evaluate the postoperative outcomes. Ten consecutive patients with tumours in the upper gingiva and hard palate, who underwent maxillectomy with internal dissection of the masticator space by the transmandibular approach, were reviewed retrospectively. Among the 10 patients, the pathological diagnosis was squamous cell carcinoma in seven, adenoid cystic carcinoma in one, malignant melanoma in one, and osteosarcoma in one. Loco-regional control was achieved in eight of nine patients (88.9%). Three patients had residual moderate trismus. Cosmetic issues were not noted in any patient. En bloc resection of the maxilla with the internal portion of the masticator space and neck through the parapharyngeal space by the transmandibular approach is a useful and satisfactory technique for the excision of a tumour with involvement of the posterior portion of the upper gingiva and hard palate.

Clinicopathological risk factors for local recurrence in oral squamous cell carcinoma.

Local recurrence of oral squamous cell carcinoma (OSCC) after primary surgery has been considered to be a poor prognostic entity in terms of survival rate. The purpose of this study is to evaluate the incidence of local recurrence and to identify significant risk factors for the local recurrence in OSCC. The authors retrospectively reviewed records for 187 patients who underwent radical surgery for OSCC. The local recurrence rate was 16.0% (30/187 patients) in this study. The survival rate of patients with local recurrence was 33.3%, which was significantly lower than that (94.3%) of patients without local recurrence. Pattern of invasion (POI), neoadjuvant chemotherapy (NAC), and the status of the surgical margin were identified as factors influencing local recurrence. In particular, NAC and the status of the surgical margin were independent risk factors by multivariate analysis. The deep margin was resected at a close site in many NAC-treated patients, suggesting that NAC may lead to local recurrence and poor outcomes. No efficacy of NAC was observed, suggesting that the standard treatment of oral cancers is surgery alone.

RNAi-mediated down-regulation of alpha-actinin-4 decreases invasion potential in oral squamous cell carcinoma.

alpha-actinin-4, originally identified as an actin-binding protein associated with cell motility, invasion, and metastasis of cancer cells, appears to be overexpressed in various human epithelial carcinomas, including colorectal, breast, esophageal, ovarian, and non-small cell lung carcinomas. The authors evaluated whether alpha-actinin-4 might be appropriate as a molecular target for cancer gene therapy. In 64 primary oral squamous cell carcinomas (OSCCs) and 10 normal oral mucosal specimens, and in seven human OSCC cell lines, alpha-actinin-4 expression was evaluated immunologically and correlations with clinicopathologic factors were examined. Overexpression of alpha-actinin-4 was detected in 38 of 64 oral squamous cell carcinomas (70%); significantly more frequently than in normal oral mucosa. The expression of alpha-actinin-4 was significantly associated with invasion potential defined by the Matrigel invasion assay. Cancer cell lines with higher alpha-actinin-4 expression had greater invasive potential. An RNAi-mediated decrease in alpha-actinin-4 expression reduced the invasion potential. These results indicated that the overexpression of alpha-actinin-4 was associated with an aggressive phenotype of OSCC. The study indicated that alpha-actinin-4 could be a potential molecular target for gene therapy by RNAi targeting for OSCC.