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.

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.

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.

A comparison of airway dimensions, measured by acoustic reflectometry and ultrasound before and after general anaesthesia.

Changes in airway dimensions can occur during general anaesthesia and surgery for a variety of reasons. This study explored factors associated with postoperative changes in airway dimensions. Patient airway volume was measured by acoustic reflectometory and neck muscle diameter by ultrasound echography in the pre- and post-anaesthetic periods in a total of 281 patients. Neck circumference was also assessed during these periods. A significant decrease in median (IQR [range]) total airway volume (from 63.8 (51.8-75.7 [14.7-103]) ml to 45.9 (33.5-57.2 [6.4-96.3]) ml, p < 0.0001), and a significant increase in muscle diameter (from 4.3 (3.3-5.6 [2.2-9.0]) mm to 5.8 (4.7-7.3 [2.8-1.3]) mm, p < 0.0001) and neck circumference (from 34.0 (32.5-37.0 [29.5-49.0]) cm to 35.0 (33.5-38.0 [30.5-50.5]) cm, p < 0.0001) were observed. It may be possible that changes in airway volume and neck circumference were influenced by surgical duration or peri-operative fluid management (ρ) = -0.31 (95% CI -0.24 to -0.01), p = 0.0301, -0.17 (-0.23 to -0.06), p = 0.0038, 0.23 (0.12-0.34), p < 0.0001, and 0.16 (0.05-0.27), p = 0.0062, respectively). The intra-oral space can significantly decrease and neck thickness increase after general anaesthesia, and might increase the risk of difficult laryngoscopy and intubation if airway management is required after extubation following general anaesthesia.

Protumoral roles of melanoma inhibitory activity 2 in oral squamous cell carcinoma.

BACKGROUND: The role of melanoma inhibitory activity 2 (MIA2) was examined in human oral squamous cell carcinoma (OSCC). METHODS: MIA2 role was examined by immunohistochemistry of human OSCCs and knockdown studies using human 3 OSCC cell lines with MIA2 expression. RESULTS: MIA2 expression was observed in 62 (66.7%) of 93 OSCCs and was associated with tumour expansion and nodal metastasis. Melanoma inhibitory activity 2 expression was inversely correlated with intratumoral infiltration of lymphocytes. Invasion and anti-apoptotic survival were reduced by MIA2 knockdown in HSC3 cells. MOLT-3 lymphocytes infiltrating the HSC3 cell layer was enhanced by MIA2 knockdown or MIA2 depletion with the antibody. In HSC3 cells, MIA2 knockdown decreased the expressions of vascular endothelial growth factor (VEGF), VEGF-C, and VEGF-D. The downregulation of VEGF-C and -D was caused by inhibition of p38 and extracellular signal-regulated kinase (ERK)1/2, respectively. Melanoma inhibitory activity 2 was co-precipitated with integrin α4 andα5 in HSC3 cells. Integrin α4 knockdown decreased p38 phosphorylation and increased apoptosis, whereas integrin α5 knockdown decreased c-Jun N-terminal kinase (JNK) phosphorylation and apoptosis. Inhibition of JNK decreased apoptosis in the HSC3 cells. CONCLUSION: These findings suggest that the roles of MIA2 might be based on the variety of the integrins and the subtypes of mitogen-activated protein kinase.

Downregulation of miR-126 induces angiogenesis and lymphangiogenesis by activation of VEGF-A in oral cancer.

BACKGROUND: MicroRNA (miRNA)-126 (miR-126) is an endothelial-specific miRNA located within intron 7 of epidermal growth factor-like domain 7 (EGFL7). However, the role of miR-126 in cancer is controversial. METHODS: We examined the function of miR-126 in oral squamous cell carcinoma (OSCC) cells. Furthermore, a series of 118 cases with OSCC were evaluated for the expression levels of miR-126. RESULTS: MicroRNA-126 (miR-126) was associated with cell growth and regulation of vascular endothelial growth factor-A activity, and demethylation treatment increased expression levels of miR-126 and EGFL7 in OSCC cells. A significant association was found between miR-126 expression and tumour progression, nodal metastasis, vessel density, or poor prognosis in OSCC cases. In the multivariate analysis, decreased miR-126 expression was strongly correlated with disease-free survival. CONCLUSION: The present results suggest that miR-126 might be a useful diagnostic and therapeutic target in OSCC.

Preoperative underweight is associated with adverse postoperative events in patients undergoing microvascular reconstruction surgery for oral and maxillofacial cancer.

We aimed to describe the prevalence of postoperative complications and evaluate its relationship with underweight, obesity, preoperative nutritional status, and systemic inflammation status in patients undergoing microvascular reconstruction for oral and maxillofacial cancer. Patients who were ≥20 years old and underwent microvascular reconstruction surgery between January 2009 to June 2019 were investigated. Patient demographics including body mass index, prognostic nutritional status, and neutrophil-lymphocyte ratio were collected. Logistic regression analysis was applied to evaluate these impacts on postoperative complications. A postoperative complication was defined as a Clavien-Dindo classification more than or equal to II. Of the 145 patients included in the analysis, 83 patients (57.2%) experienced postoperative complications, belonging to a Clavien-Dindo classification Ⅱ (n=71), Ⅲb (n=11), and Ⅳa (n=1). Multiple logistic regression revealed that a body mass index less than 18.5 kg/m2 (odds ratio 6.19, 95% confidential interval 1.34-28.6, P=0.02) was related to postoperative complications. Another multiple logistic regression model including all explanatory factors found that underweight (P=0.03) was related to postoperative complications. This retrospective study showed that preoperative underweight was associated with postoperative complications as evaluated by the Clavien-Dindo classification.

Assessment of facial symmetry by three-dimensional stereophotogrammetry after mandibular reconstruction: A comparison with subjective assessment.

INTRODUCTION: The assessment of facial symmetry, after mandibular reconstruction, currently relies on subjective esthetic assessment by an evaluator. The present study aimed to compare conventional subjective assessment with quantitative evaluation by three-dimensional (3D) stereophotogrammetry of facial cosmetic symmetry. METHODS: This retrospective study enrolled 20 patients who underwent mandibular reconstruction with free fibula flap after segmental resection between 2014 and 2018. Subjective assessments were performed by seven clinicians at 6-12 months after surgery. Simultaneously, lower face symmetry was measured by 3D stereophotogrammetry with the VECTRA H1 system and recorded as the root mean square deviation (RMSD). Data from the subjective and quantitative evaluations were compared using Spearman's rank correlation coefficient. RESULTS: The results showed that subjective assessments were strongly and negatively correlated with RMSD (P=0.00000128). This confirmed that RMSD, obtained by 3D stereophotogrammetry, reflected the subjective assessment of symmetry in our cohort. CONCLUSIONS: Three-dimensional stereophotogrammetry of facial cosmetic symmetry will be an available quantitative method for patients with head and neck cancer after mandibular reconstruction.

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.

MMP-3 activation is a hallmark indicating an early change in TMJ disorders, and is related to nitration.

Recent studies on temporomandibular joint (TMJ) disorders have suggested that matrix metalloproteinases (MMPs) are closely involved in the pathophysiological progression of the internal derangement (ID) of TMJ. The aim of this study was to investigate MMPs in synovial fluid (SF) at different stages of ID. To examine the relationship between MMP activation and ID progression, 54 SF samples from ID patients were classified based on the criteria of Wilkes and were assayed for MMP activity. It was found that MMP-3 activity was transiently increased in the intermediate stage. This increase in the active form of MMP-3 was also confirmed by Western blotting. When the 54 samples were classified into two groups based on the presence or absence of inflammatory findings, the intensity of MMP-3 activity correlated with the inflammatory symptoms. These findings suggest that MMP-3 activation is a hallmark of early degenerative changes in ID. The tylosin nitration by the peroxynitrite can regulate the enzyme activity. To elucidate the activating pathway of MMPs in vivo, nitrated proteins in SF were analysed by immunoprecipitation. Some nitrated proteins in SF were identified as MMP-2 and -3, and the nitration of MMP-3 rendered them active in vitro.

Effects of deep sedation under mechanical ventilation on cognitive outcome in patients undergoing surgery for oral and maxillofacial cancer and microvascular reconstruction.

OBJECTIVE: Cognitive impairment after intensive care unit (ICU) admission is becoming increasingly recognized. High-dose deep sedation has been suggested to play an important role in the development of cognitive impairment. However, the impact of heavy sedation as a single cause in the development of cognitive impairment in ICU patients remains unclear. In this study we investigated whether a three-day deep sedation protocol could reduce cognitive function in mechanically ventilated non-critical patients. DESIGN: A prospective observational study was carried out. PATIENTS: A total of 17 surgical patients were studied. INTERVENTION: None. VARIABLES OF INTEREST: Cognitive function before and after ICU admission. RESULTS: Thirty-one patients requiring three days of sedation after microvascular reconstruction were initially enrolled in the study. Sedation in the ICU was maintained with propofol and dexmedetomidine combined with fentanyl. Cognitive function was assessed using a battery of 6 neuropsychological tests two days before surgery and three weeks after surgery. Finally, a total of 17 patients were included in the analysis. Cognitive impairment (defined as a decline of >20% from the pre-admission cognitive evaluation scores in at least two of 6 tests) was observed in 5 of the 17 patients (29%). However, there were no significant differences between the pre- and post-admission cognitive evaluations in 6 tests. CONCLUSIONS: Middle-term cognitive function can be impaired in some patients subjected to deep sedation during several days following maxillary-mandibular oral surgery with microvascular reconstruction.

Reg IV expression is associated with cell growth and prognosis of adenoid cystic carcinoma in the salivary gland.

AIMS: Regenerating islet-derived family, member 4 (Reg IV) is associated with the progression of various cancers. The aim was to examine Reg IV expression in adenoid cystic carcinomas (ACCs) in salivary glands. METHODS AND RESULTS: Reg IV expression was detected by immunohistochemistry and compared with clinicopathological parameters. Expression of phosphorylated epidermal growth factor receptor (pEGFR), phosphorylated AKT (pAKT) and MUC2 was examined by immunohistochemistry. Reg IV function was assessed with Reg IV antisense S-oligodeoxynucleotides (AS) in ACC3 human ACC cells. Reg IV was expressed by salivary duct epithelia and acinus myoepithelia, but not in squamous epithelia. Reg IV expression was found in 41% (17/41) of ACCs, but in none of 40 oral squamous cell carcinomas (OSCCs) and was associated with nodal metastasis (P = 0.047) and poor prognosis (P = 0.012) in ACCs. Reg IV expression was associated with pEGFR (14/17, 82%) in Reg IV+ ACCs, but had no relationship with pAKT or MUC2 expression in ACCs. Cell growth was inhibited by AS treatment in Reg IV+ ACC3 cells, but not in HSC-4 OSCC cells, whereas in vitro invasion of neither cell types was affected by AS treatment. CONCLUSIONS: These results suggest that Reg IV might accelerate cell growth and disease progression of ACCs.

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.

The effects of the sympathetic nerves on lumbar radicular pain: a behavioural and immunohistochemical study.

A rat model of lumbar root constriction with an additional sympathectomy in some animals was used to assess whether the sympathetic nerves influenced radicular pain. Behavioural tests were undertaken before and after the operation. On the 28th post-operative day, both dorsal root ganglia and the spinal roots of L4 and L5 were removed, frozen and sectioned on a cryostat (8 microm to 10 microm). Immunostaining was then performed with antibodies to tyrosine hydroxylase (TH) according to the Avidin Biotin Complex method. In order to quantify the presence of sympathetic nerve fibres, we counted TH-immunoreactive fibres in the dorsal root ganglia using a light microscope equipped with a micrometer graticule (10 x 10 squares, 500 mm x 500 mm). We counted the squares of the graticule which contained TH-immunoreactive fibres for each of five randomly-selected sections of the dorsal root ganglia. The root constriction group showed mechanical allodynia and thermal hyperalgesia. In this group, TH-immunoreactive fibres were abundant in the ipsilateral dorsal root ganglia at L5 and L4 compared with the opposite side. In the sympathectomy group, mechanical hypersensitivity was attenuated significantly. We consider that the sympathetic nervous system plays an important role in the generation of radicular pain.

A Ferromagnetic Foreign Body at the Lateral Aspect of the Mandibular Ramus in a Medically Compromised Patient.

A case of a ferromagnetic foreign body in a medically compromised patient was reported. The patient was a 45-year-old male who consulted our department complaining of a foreign body accidentally impacted in the right cheek. X-ray examination revealed a foreign body at the lateral aspect of the right mandibular ramus. The removal of the foreign body was scheduled, but the patient did not return for the procedure. After 8 years he revisited our department for the removal of the foreign body, because it had been found to be ferromagnetic and a barrier to MRI examination. X-ray examination confirmed the foreign body was located at the same site as 8 years prior. Although the patient was suffering from liver cirrhosis with thrombocytopenia and leukopenia, the foreign body was successfully removed under general anesthesia. The foreign body was 12 × 5 × 1 mm, weighed 0.48 g, and was ferromagnetic. The patient's postoperative course was uneventful. X-ray examination confirmed the removal of the foreign body. Since the surgery, the patient has been in generally stable condition with no complications. This case was a rare example of a foreign body that needed to be removed for medical examination.

A patient with untreated tongue carcinoma surviving for 15 years.

A rare case of untreated tongue carcinoma survived for 15 years is presented. A 43-year-old Japanese woman was referred to our department with a 1.8 cm x 1.0 cm white and red non-indurated lesion of the left border of the tongue. The histological examination showed a diagnosis of well-differentiated squamous cell carcinoma. We informed the patient and her family that she had a Stage I tongue carcinoma and needed to receive treatment immediately. However, they refused treatment. Fifteen years later, the patient presented again, complaining of a 55 mm x 40 mm painful gradual-growth swelling of the same site as before, and the clinical stage was T3N2aM0 (Stage IV). The patient agreed to receive radical surgery following preoperative chemoradiotherapy this time. Currently the patient has been free of recurrence for 4 years. Clinical and immunohistochemical features of this rare case are presented and discussed.

Epigenetic alterations in methylation in oral squamous cell carcinoma cell lines detected by two-dimensional gel electrophoresis.

It has been described that DNA alterations in human oral squamous cell carcinomas were successfully demonstrated as 6 spots being commonly reduced in more than 50% of 10 lesions using the restriction landmark genomic scanning (RLGS) method. In the present study, the question of whether the DNA alterations involve not only genetic but also epigenetic change was examined with the use of cell lines Ca9-22, HO-1-u-1, HSC-2 and KB and treatment with a demethylating agent 5-aza-2'-deoxycytidine (5-AzaCDR). Intensities of two of the reduced spots were amplified in the cell lines by the 5-AzaCDR treatment, showing that they were due to altered DNA methylation. Our study provides clear evidence that epigenetic changes, like the methylation are related to carcinogenesis in human oral squamous cell epithelium.

Genomic alterations in oral squamous cell carcinoma cell lines detected by two-dimensional gel analysis.

To initially analyze the genomic abnormalities in human oral squamous cell carcinoma, DNA extracted from each of four oral carcinoma cell lines (Ca9-22, HO-1-u-1, HSC-2, KB) was examined using restriction landmark genomic scanning (RLGS), a method especially conducive to detection of amplifications and rearrangements of genomic DNA. Isolated cell line and normal oral epithial DNAs were sequentially cleaved with specific restriction enzymes, radiolabelled and separated in two-dimensional gel electrophoreses. Thirteen distinct fragments were commonly amplified in the oral cancer cell lines, six of which were evident in all samples. These results suggest genetic alterations characteristic of oral squamous cell carcinogenesis.