Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: a multicenter retrospective study.

Pre-existing inflammation, corticosteroid therapy, periapical periodontitis, longer duration of denosumab therapy, and female sex were significantly associated with an increased risk of denosumab-related osteonecrosis of the jaw after tooth extraction in patients with cancer on oncologic doses of denosumab. A short drug holiday did not protect against this complication. INTRODUCTION: This study retrospectively investigated the relationship between various risk factors, including brief discontinuation of denosumab, and development of denosumab-related osteonecrosis of the jaw (DRONJ) after tooth extraction in patients with cancer who were receiving oncologic doses of this agent. METHODS: Data were collected on demographic characteristics, duration of denosumab therapy, whether or not denosumab was discontinued before tooth extraction (drug holiday), duration of discontinuation, presence of pre-existing inflammation, and whether or not additional surgical procedures were performed. Risk factors for DRONJ after tooth extraction were evaluated by univariate and multivariate analyses. RESULTS: A total of 136 dental extractions were performed in 72 patients (31 men, 41 women) with cancer who were receiving oncologic doses of denosumab. Post-extraction DRONJ was diagnosed in 39 teeth (28.7%) in 25 patients. Tooth extraction was significantly associated with development of DRONJ only in patients with pre-existing inflammation (odds ratio [OR] 243.77), those on corticosteroid therapy (OR 73.50), those with periapical periodontitis (OR 14.13), those who had been taking oncologic doses of denosumab for a longer period (OR 4.69), and in women (OR 1.04). There was no significant difference in the occurrence of DRONJ between patients who had a drug holiday before tooth extraction and those who did not. CONCLUSIONS: These findings suggest that inflamed teeth should be extracted immediately in patients with cancer who are receiving oncologic doses of denosumab. Drug holidays have no significant impact on the risk of DRONJ.

A clinical investigation of the association between perioperative oral management and prognostic nutritional index in patients with digestive and urinary cancers.

Background: The prognostic nutritional index (pni) is a simple metric calculated using serum albumin and the peripheral lymphocyte count. It was reported that a low pni score is significantly associated with major postoperative complications and poor prognosis. The purpose of the present study was to investigate the effects of perioperative oral management (pom) on the perioperative pni profiles of patients with digestive system or urinary cancers. Study Design: The medical records of 181 patients with cancer who underwent surgery and for whom a pni could be calculated were retrospectively reviewed. Results: The intervention rate with pom was 34.8%. The median preoperative pni score was 48.25 in all patients with a pom intervention [25% to 75% interquartile range (iqr): 44.38-54.13] and 47.25 in those without an intervention (iqr: 42.0-53.5). Compared with patients not receiving pom, those who received pom had significantly higher pni scores from the early postoperative period (p < 0.05). Notably, of patients who could resume oral intake within 3 days after surgery, those who received pom intervention, compared with those who did not, had significantly higher pni scores from the early postoperative period (p < 0.05). Conclusions: Perioperative oral management interventions might have positive effects on the postoperative pni scores of patients with cancer.

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.

Nuclear protein of the testis midline carcinoma in the oral cavity: retrospective review of those initially diagnosed as poorly differentiated squamous cell carcinoma using an anti-C52B1 antibody.

Nuclear protein of the testis (NUT) midline carcinomas (NMC) are malignant epithelial tumours that have chromosomal rearrangements of the gene encoding NUT at 15q14. NMC is typically an aggressive fatal cancer, clinically overlaps with other carcinomas, and differential diagnosis is difficult. The purpose of this study was to investigate NMC in poorly differentiated oral squamous cell carcinoma (OSCC) with a retrospective analysis based on anti-C52B1 immunohistochemical staining. An anti-C52B1 antibody was used for immunohistochemical staining in all 27 primary tumours, and the prevalence and pathological features of NMC in the oral cavity were examined. Only two of 27 cases (7.4%) were C52B1 immunopositive. Both positive patients were women aged 38 and 43 years - younger than the other C52B1-negative patients, whose average age was 65.6 years (range 41-83). The primary sites were the right side of the floor of the mouth and the left side of the tongue. They had a poor prognosis and died within 8 months postoperation compared with the median overall survival time of 60.2 months for patients with other poorly differentiated squamous cell carcinoma. The pathological findings of their primary tumours were similar to typical poorly differentiated OSCC.

Effectiveness of a comprehensive oral management protocol for the prevention of severe oral mucositis in patients receiving radiotherapy with or without chemotherapy for oral cancer: a multicentre, phase II, randomized controlled trial.

The aim of this phase II, multicentre, randomized controlled trial was to evaluate the effectiveness of a comprehensive oral management protocol for the prevention of severe oral mucositis in patients with oral cancer receiving radiotherapy alone or chemoradiotherapy. In total, 124 patients with oral cancer were enrolled from five institutions. Of these, 37 patients undergoing radiotherapy were randomly divided into an intervention group (n=18) and a control group (n=19). The remaining 87 patients, who were undergoing chemoradiotherapy, were also randomized into an intervention group (n=42) and a control group (n=45). During radiotherapy, patients in the control group received only oral care, while those in the intervention group additionally received spacers to cover the entire dentition, pilocarpine hydrochloride, and topical dexamethasone ointment for oral mucositis. The primary endpoint was the incidence of severe oral mucositis. The intervention was significantly associated with a decreased incidence of severe oral mucositis in patients receiving radiotherapy alone (P=0.046), but not in those receiving chemoradiotherapy (P=0.815). These findings suggest that an oral management protocol can prevent severe oral mucositis in patients with oral cancer undergoing radiotherapy without concurrent chemotherapy.

Medication-related osteonecrosis of the jaw after tooth extraction in cancer patients: a multicenter retrospective study.

Root amputation, immunosuppressive therapy, mandibular tooth extraction, pre-existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents. INTRODUCTION: No studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure-related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab. METHODS: Risk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. RESULTS: We found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (≥ 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ. CONCLUSIONS: Tooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation.

Treatment modalities and risk factors associated with refractory neurosensory disturbances of the inferior alveolar nerve following oral surgery: a multicentre retrospective study.

Little research has been conducted into hypoesthesia, and no studies have elucidated the risk factors for refractory hypoesthesia and compared treatment modalities. The purpose of this multicentre retrospective cohort study was to investigate the relationships between various risk factors, treatment modalities, and refractory hypoesthesia. Risk factors for refractory hypoesthesia after oral surgery were evaluated using univariate and multivariate analysis. To minimize the selection bias associated with a retrospective data analysis, a propensity score analysis was performed between the medication and non-medication groups (65 sites in each group). Moderate or severe hypoesthesia (odds ratio 13.42) and no or late administration of ATP/vitamin B12 (odds ratio 2.28) were significantly associated with refractory hypoesthesia. In the propensity score analysis, the incidence rate of refractory hypoesthesia in the medication group was lower than that in the non-medication group (P<0.001). This study demonstrated the multivariate relationships between various risk factors, treatment modalities, and refractory hypoesthesia. Moderate or severe hypoesthesia and no or late administration of ATP/vitamin B12 were significantly associated with refractory hypoesthesia. Therefore, clinicians should consider these risk factors and initiate early oral administration of ATP/vitamin B12 in cases of hypoesthesia.

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.

Estimation of the width of free margin with a significant impact on local recurrence in surgical resection of oral squamous cell carcinoma.

The purpose of this study was to estimate the width of free margin with a significant impact on local recurrence in surgical resection of oral squamous cell carcinoma (OSCC). Clinical and pathological data of 127 consecutive patients who underwent radical resection of OSCC were analyzed retrospectively. The local control rate was compared between patients with clear, close, and involved surgical margins, changing the required width of free margin for the definition of 'close surgical margin' (from 1 to 5mm). If a free margin of within 1, 2, or 4mm was judged a close margin, the risk of local recurrence was significantly different among the patients with clear, close, and involved surgical margins. If the definition of close margin was within 5mm of the resection margin, the difference between clear and close margin did not reach statistical significance. The results of this study suggest that 5mm of clearance at the surgical resection margin should be the index of oncological surgery. More than 5mm of histological free margin around OSCC is not justified in terms of the risk management of local recurrence and the resultant morbidity.

Nosocomial transmission of methicillin-resistant Staphylococcus aureus via the surfaces of the dental operatory.

OBJECTIVE: We assess the possibility of methicillin-resistant Staphylococcus aureus (MRSA) transmission via the surfaces of the dental operatory. METHODS: A survey of MRSA contamination on the surfaces of the dental operatory, and an analysis of MRSA transmission via the dental operatory between patients was carried out in the department of special dental care and oral surgery. RESULTS: MRSA was observed on the surfaces of dental operatory including the air-water syringe and reclining chair. Nosocomial infection or colonisation of MRSA occurred in eight out of 140 consecutive patients who had no evidence of MRSA at admission. Antibiograms of 30 antibiotics revealed that the isolates from the eight patients were of the same strain as those from the surface of dental operatory. After treating the patients under a revised infection control (IC) protocol including a single use of barrier covers, MRSA was not detected on the surfaces of the dental operatory, and no nosocomial infection or colonisation occurred during hospitalisation (0/117 patients). CONCLUSIONS: These results suggest that MRSA contaminates the surfaces of the dental operatory, and therefore the dental operatory should be considered a possible reservoir of MRSA.

Young adult-specific hyperphagia in diabetic Goto-kakizaki rats is associated with leptin resistance and elevation of neuropeptide Y mRNA in the arcuate nucleus.

The present study aimed to examine whether hyperphagia, which is frequently observed in type 1 diabetic patients and model animals, also occurs in type 2 diabetic Goto-Kakizaki (GK) rats and, if so, to explore underlying abnormalities in the hypothalamus. GK rats at postnatal weeks 6-12, compared to control Wistar rats, exhibited hyperphagia, hyperglycaemia, hyperleptinemia and increased visceral fat accumulation, whereas body weight was unaltered. The ability of leptin to suppress feeding was reduced in GK rats compared to Wistar rats of these ages. In GK rats, leptin-induced phosphorylation of signal transducer and activator of transcription 3 was significantly reduced in the cells of the hypothalamic arcuate nucleus (ARC), but not of the ventromedial hypothalamus, whereas the mRNA level of functional leptin receptor was unaltered. By real-time polymerase chain reaction and in situ hybridisation, mRNA levels of neuropeptide Y, but not pro-opiomelanocortin and galanin-like peptide, were significantly increased in the ARC of GK rats at 11 weeks, but not 26 weeks. Following i.c.v. injection of a NPY Y1 antagonist, 1229U91, the amount of food intake in GK rats was indistinguishable from that in Wistar rats, thus eliminating the hyperphagia of GK rats. These results demonstrate that young adult GK rats display hyperphagia in association with leptin resistance and increased NPY mRNA level in the ARC.

A long-term follow-up study of radiographically evident degenerative changes in the temporomandibular joint with different conditions of disk displacement.

The purpose of this retrospective study is to assess the relationship between an initial and persisting condition of disk displacement (DD) and the long-term course of radiographically evident degenerative changes of the temporomandibular joint (TMJ). Nineteen patients agreed to a radiographic follow-up examination of 29 joints and were included in this study. The joints were radiographically assessed at the first visit and at least 46 months after the first visit (mean 89.3 months). At the time of the follow-up, all subjects had a good clinical course after a favorable response to the treatments. There were significant relationships between the initial diagnosis of DD and the interval change in the morphology of the articular eminence. The articular eminence became flattened or deformed only in the joints with persistent DD without reduction. And there was a tendency that the condyle became smaller in the joints initially with permanent DD and in the joints which show a progression in the disk-condylar relationship. The results of this study suggested that, in the joints with persisting non-reducing disk displacement, flattening and deformation of the articular eminence and regression of the condylar size were likely to happen even after symptoms and signs of TMJ disorders were resolved or reduced.

Resorption of the postero-superior corner of the lateral part of the mandibular condyle correlates with progressive TMJ internal derangement.

The purpose of this study was to test the hypothesis that resorption of postero-superior corner of lateral part of the mandibular condyle (RLC) occurs with the advancement of TMJ internal derangement (ID). One hundred and sixty-seven TMJs in 122 patients were studied. RLC was assessed on plane radiographs of frontal oblique projection. The correlation between the prevalence of RLC and radiological stage of ID was analysed and clinical correlations to the radiological stage of ID and the prevalence of RLC were discussed. The higher prevalence of RLC in joints with advanced ID was statistically significant (Mann-Whitney U-test, P< 0.05). There was no correlation between the prevalence of RLC and neither OA on the articular surface of the condyle nor clinical symptoms/signs. The result of this study suggests that RLC appears to occur in joints with advanced ID as a result of remodelling changes secondary to ID.

Two-dimensional thick-slice MR digital subtraction angiography in the assessment of small to medium-size intracranial arteriovenous malformations.

Assessment of intracranial arteriovenous malformations (AVMs) by conventional catheter angiography carries risks; moreover, this invasive procedure is often repeated for follow-up. We investigated the clinical applicability of two-dimensional thick-slice, contrast-enhanced magnetic resonance digital subtraction angiography (2D MRDSA) with high temporal resolution in the assessment of AVMs. We performed 78 2D MRDSA studies of treated or untreated small to medium-size AVMs on a 1.5 tesla imager. Two observers independently evaluated demonstration of nidus flow void on T2-weighted images and each component of the AVM on 2D MRDSA employing a three-point grading scale. In 55 patients with AVMs, the mean ratings of nidus flow voids, feeding vessels, nidi, draining vessels and early venous filling on MRI were 2.8, 2.4, 2.6, 2.8 and 2.8, respectively. sensitivity, specificity, positive and negative predictive values for an AVM using 2D MRDSA were 87, 100, 100 and 78%, respectively and for nidus flow voids on T2-weighted images 80, 91, 96 and 66%, respectively. 2D MRDSA can thus demonstrate haemodynamic features of AVMs. It can be employed as a less invasive, dynamic angiographic tool for follow-up of AVMs previously delineated by catheter angiography.

Relationship between alteration of horizontal size and bony morphological change in the mandibular condyle.

OBJECTIVE: To analyse the relationship between horizontal size and morphological changes on the articular surface and the lateral part of the mandibular condyle. METHODS: The study group comprised 139 joints in 88 women aged over 18 years. Horizontal condylar size was measured in the anteroposterior (AP) and mediolateral (ML) dimensions using axial MR images. Bony morphological change on the articular surface (sagittal change) was assessed on the sagittal MR image, and resorption of the lateral part of the condyle (RLC) was assessed on a plane radiograph in the AP projection. RESULTS: There was no significant relationship between horizontal condylar size and sagittal change. However, condyles with RLC were smaller than those without RLC in the ML dimension. CONCLUSIONS: The results of this study suggest a possible relationship between decreased horizontal condylar size and RLC. It is also suggested that sagittal bone changes do not influence the horizontal size of the condyle.