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.

Diagnostic Value of Model-Based Iterative Reconstruction Combined with a Metal Artifact Reduction Algorithm during CT of the Oral Cavity.

BACKGROUND AND PURPOSE: Metal artifacts reduce the quality of CT images and increase the difficulty of interpretation. This study compared the ability of model-based iterative reconstruction and hybrid iterative reconstruction to improve CT image quality in patients with metallic dental artifacts when both techniques were combined with a metal artifact reduction algorithm. MATERIALS AND METHODS: This retrospective clinical study included 40 patients (men, 31; women, 9; mean age, 62.9 ± 12.3 years) with oral and oropharyngeal cancer who had metallic dental fillings or implants and underwent contrast-enhanced ultra-high-resolution CT of the neck. Axial CT images were reconstructed using hybrid iterative reconstruction and model-based iterative reconstruction, and the metal artifact reduction algorithm was applied to all images. Finally, hybrid iterative reconstruction + metal artifact reduction algorithms and model-based iterative reconstruction + metal artifact reduction algorithm data were obtained. In the quantitative analysis, SDs were measured in ROIs over the apex of the tongue (metal artifacts) and nuchal muscle (no metal artifacts) and were used to calculate the metal artifact indexes. In a qualitative analysis, 3 radiologists blinded to the patients' conditions assessed the image-quality scores of metal artifact reduction and structural depictions. RESULTS: Hybrid iterative reconstruction + metal artifact reduction algorithms and model-based iterative reconstruction + metal artifact reduction algorithms yielded significantly different metal artifact indexes of 82.2 and 73.6, respectively (95% CI, 2.6-14.7; P < .01). The latter algorithms resulted in significant reduction in metal artifacts and significantly improved structural depictions(P < .01). CONCLUSIONS: Model-based iterative reconstruction + metal artifact reduction algorithms significantly reduced the artifacts and improved the image quality of structural depictions on neck CT images.

Interleukin-4 Restores Insulin Sensitivity in Insulin-Resistant Osteoblasts by Increasing the Expression of Insulin Receptor Substrate 1.

Obesity and latent inflammation can give rise to insulin resistance and type 2 diabetes. Here we established an insulin resistance model of osteoblasts to explore the restoration effect of anti-inflammatory interleukin-4 (IL-4) on insulin sensitivity and its mechanism. We found that IL-4 inhibited cell proliferation in a concentration- and time-dependent manner. Insulation resistance significantly reduced the phosphorylation levels of the insulin receptor substrate 1 (IRS1; Tyr612), Akt (Ser473), and AS160 (Ser318) proteins. The addition of IL-4 to the insulin resistance model led to a dose-dependent stimulation of the phosphorylation of IRS1, Akt, and AS160. IL-4 fully restored the activation of the insulin cascade in insulin-resistant cells at the concentration of 50 ng/ml. Additionally, IL-4 promoted the expression of IRS1 in a time-dependent manner. We conjecture that IL-4 restores insulin sensitivity in osteoblasts by upregulating the expression of IRS1. It was also found that IL-4 promoted the expression of osteoprotegerin depending on the time of exposure. This effect may play an important role in the regulation of the energy metabolism in the whole body.

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 Case of Feline T-cell Lymphoma with Tropism for Striated Muscle and Peripheral Nerve.

An 11-year-old female American shorthair cat was presented with a 3-month history of hindlimb ataxia and knuckling of the left forelimb. Clinical abnormalities included weight loss, hyperaesthesia of the neck and back, cardiac murmur and systemic muscle atrophy. The cat died 10 days after the initial presentation and a necropsy examination was performed. Grossly, extensive pale lesions were seen in the wall of the left ventricle and the septum of the heart. There were no detectable masses in the heart, skeletal muscles or peripheral nerves. Histopathological examination revealed diffuse, extensive infiltration of atypical lymphoid cells in the heart; the cardiac muscles were markedly degenerate and atrophic and were replaced by the neoplastic cells. Neoplastic cells with similar morphology were seen in all specimens of the skeletal muscles and peripheral nerves. Clonality analysis of the paraffin wax-embedded heart tissue revealed a monoclonal rearrangement of the gene encoding the T-cell receptor γ chain. Based on these findings, the case was diagnosed as T-cell lymphoma with tropism for striated muscle and peripheral nerve.

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.

Nodular fasciitis involving the palm.

Nodular fasciitis (NF) is a self-limiting fibrous neoplasm that can be mistaken for a soft tissue sarcoma. It is characterised by rapid growth, slight pain and local tenderness. Although it is frequently found in the forearm, a lesion distal to the wrist is quite rare. We present two unusual cases of NF involving the palm, supported by detecting ubiquitin specific protease 6 gene rearrangement. The first patient had non-intraneural NF presenting as peripheral neuropathy affecting the digital nerve while the second patient suffered from painless, non-tender NF in the palm, which had not regressed spontaneously during the five months prior to surgery.

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.

Cost Analysis of Transplantation in Japan, Performed With the Use of the National Database.

BACKGROUND: When assessing the cost of transplants in Japan, earlier studies have been limited to case series that investigated inpatient cost alone. Few studies have evaluated total cost, which includes inpatient, outpatient, and pharmaceutical costs, or compared costs before and after transplantation. Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), we investigated the total cost of major transplantation and contributing factors. METHODS: We analyzed the cost and complications of patients who underwent a cadaveric renal transplantation (CRT), living renal transplantation (LRT), living-donor liver transplantation (LDLT), allogeneic bone marrow transplantation, autologous bone marrow transplantation, allogeneic peripheral blood stem cell transplantation, or autologous peripheral blood stem cell transplantation (auto-PBSCT) from April 2009 to March 2010. RESULTS: The highest total cost of the month of transplantation was 4.95 million yen (JPY) for LDLT. Among renal transplantations, the cost of CRT was higher than LRT (3.69 vs 3.55 million JPY). Recipients of auto-PBSCT complicated by graft-versus-host disease, urinary tract infection, sepsis, or pneumonia had a significantly higher average total cost during the month of transplantation and the 2 following months than patients without it, as well as statistically longer total treatment days. CONCLUSIONS: In Japan, almost all medical services are covered by national health insurance, and the Japan government has begun to allow the use of the NDB for research activities. This is the first study to use the NDB to analyze the cost of transplantation, with technical and institutional limitations.

Survival of Brånemark System Mk III implants and analysis of risk factors associated with implant failure.

The purpose of this study was to retrospectively investigate the outcomes of Brånemark System Mk III TiUnite/Groovy implants placed in patients at Kobe University Hospital. Various risk factors for implant failure, including mechanical coupling, were investigated by univariate and multivariate analysis. The predictive variables investigated included age, sex, smoking habit, general health, history of radiation therapy, application of a dentomaxillary prosthesis, type of prosthesis, use of alveolar bone augmentation, site of implant insertion, mechanical coupling between implants, and the length and diameter of the implants. Of the 907 implants investigated, only 23 were unsuccessful; the overall survival rate was 96.7%. Increased age, radiation therapy, application of a removable prosthesis or dentomaxillary prosthesis, lack of mechanical coupling between implants, and shorter implants (≤8.5mm) were significant risk factors for implant failure according to univariate analysis (P<0.05). Multivariate analysis identified a significant association (P<0.05) between dental implant failure and a lack of mechanical coupling between implants (odds ratio 6.88) and shorter implants (≤8.5mm) (odds ratio 3.43). The findings of this study demonstrated multivariate relationships between various risk factors and dental implant failure.

Proteinuria selectivity index as a prognostic biomarker in lupus nephritis.

Objectives The selectivity index has been proposed in predicting the response to immunosuppressive therapy in nephrotic syndrome and other primary kidney disorders. The aim of this study was to elucidate the predictive value of the selectivity index for the treatment response and renal outcome in patients with lupus nephritis. Methods Forty-four patients with lupus nephritis with selectivity index available at the time of renal biopsy were divided into two groups according to the cut-off value of the selectivity index determined by a receiver operating characteristics curve to differentiate treatment responders from non-responders. The baseline characteristics, overall response rate and renal functional outcome were studied retrospectively, and compared between the two groups. Prognostic factors for achieving remission were identified. Results The cut-off value of the selectivity index was 0.167. The low selectivity index (<0.167) and the high selectivity index (≥0.167) group included 24 and 20 patients, respectively. The overall response rate was significantly higher (88% vs. 50%, P = 0.007) and the rate of progression to end-stage renal disease was lower in the low selectivity index group (0% vs. 15%, P = 0.049). More patients in the high selectivity index group had chronic lesions on renal biopsy ( P = 0.002). The selectivity index was the prognostic factor for achieving overall response based on a multivariate analysis ( P = 0.020). Conclusions A selectivity index ≥0.167 was a strong predictor for a poor treatment response and the presence of chronic lesions on renal biopsy. Further exploration with a larger cohort and longer follow-up period is warranted.

A multi-centre retrospective study of mandibular fractures: do occlusal support and the mandibular third molar affect mandibular angle and condylar fractures?

This retrospective study was performed to investigate the influence of occlusal support and the presence, state, and position of mandibular third molars on the incidence of mandibular angle and condylar fractures. The following variables were investigated: age, sex, cause of fracture, presence and state (impaction, angulation, and the number of roots) of the mandibular third molars, site of the mandibular fracture, presence of occlusal support, duration of intermaxillary fixation, and postoperative complications. Various risk factors for mandibular angle and condylar fractures were investigated by univariate analysis. The risk of mandibular angle fracture was significantly higher in patients with occlusal support and mandibular third molars. The risk of condylar fracture was significantly higher in patients without occlusal support or mandibular third molars. The position and angulation of the mandibular third molars were not significant risk factors in mandibular angle and condylar fractures. This study demonstrated the influence of occlusal support and the presence of mandibular third molars on the incidence of mandibular angle and condylar fractures. The presence of occlusal support may be a more important factor affecting mandibular angle or condylar fractures than the position of the mandibular third molars.

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.

Bone marrow-derived stromal cells are associated with gastric cancer progression.

BACKGROUND: The aim of this study was to clarify the role of bone marrow-derived stromal cells (BM-SCs) expressing CD271 in the development of gastric cancer. METHODS: The effect of human BM-SCs on the proliferation and motility of six gastric cancer cell lines, OCUM-2M, OCUM-2MD3, OCUM-12, KATO-III, NUGC-3, and MKN-74, was examined. CD271 expression levels in BM-SCs were analysed by flow cytometry. We also generated a gastric tumour model by orthotopic inoculation of OCUM-2MLN cells in mice that had received transplantation of bone marrow from the CAG-EGFP mice. The correlation between the clinicopathological features of 279 primary gastric carcinomas and CD271 expression in tumour stroma was examined by immunohistochemistry. RESULTS: Numerous BM-SCs infiltrated the gastric tumour microenvironment; CD271 expression was found in ∼25% of BM-SCs. Conditioned medium from BM-SCs significantly increased the proliferation of gastric cancer cell lines. Furthermore, conditioned medium from gastric cancer cells significantly increased the number of BM-SCs, whereas migration of OCUM-12 and NUGC-3 cells was significantly increased by conditioned medium from BM-SCs. CD271 expression in stromal cells was significantly associated with macroscopic type-4 cancers, diffuse-type tumours, and tumour invasion depth. The overall survival of patients (n=279) with CD271-positive stromal cells was significantly worse compared with that of patients with CD271-negative stromal cells. This is the first report of the significance of BM-SCs in gastric cancer progression. CONCLUSIONS: Bone marrow-derived stromal cells might have an important role in gastric cancer progression, and CD271-positive BM-SCs might be a useful prognostic factor for gastric cancer patients.

Sequential evaluation for bone union of transferred fibula flaps in reconstructed mandibles: panoramic X-ray versus computed tomography.

The purpose of this study was to sequentially evaluate bone union of fibular grafts in mandibular reconstruction. Patients who underwent routine follow-up computed tomography (CT) and panoramic X-ray imaging during a period of ≥2 years were enrolled. On panoramic X-ray images, bone union was scored as 0 (absent callus formation) or 1 (complete callus formation). On CT images, a scale of 0 to 2 was used (0, absent callus formation; 1, complete callus formation only on the labial side; 2, complete callus formation on both the labial and lingual side). A total of 56 bone junctions were evaluated in 20 patients. Five of 56 junctions (9%) in four of 20 patients (20%) showed radiological non-union (panoramic X-ray score=0, CT score=0 or 1) at 2 years after surgery. All bone junctions with radiological non-union were located at the mandibular angle. No categorical values, including diabetes mellitus and radiation therapy, were significantly associated with radiological non-union. In conclusion, assessing at least two sides (i.e. labial and lingual sides) on CT images is adequate to evaluate bone union in transferred fibula flaps. Careful fixation at the mandibular angle may improve the rate of bone union.

Determining the location of the internal maxillary artery on ultrasonography and unenhanced magnetic resonance imaging before orthognathic surgery.

The purpose of this study was to examine the efficacy of ultrasonography (US) and unenhanced magnetic resonance imaging (MRI) to determine the location of the internal maxillary artery (IMA) before orthognathic surgery. The study subjects were 19 patients (seven males and twelve females) with mandibular prognathism seen at the authors' institution between March 2012 and April 2013. The distance from the skin to the IMA (S-IMA) and the distance from the mandibular notch to the IMA (MN-IMA) were measured. Using the US and coronal MRI images, S-IMA(cl) and MN-IMA(cl) in the closed position and S-IMA(op) and MN-IMA(op) in the open position were measured at a total of four points in each cross-section. There were significant correlations between the distances measured on coronal MRI and US for all groups (P<0.05). A total of 35 (92%) IMAs were classified as clear and three (8%) as unclear based on the US findings. Regarding the location of the IMA, 37 of the 38 sides studied (97%) were of the lateral type, while only one (3%) was of the medial type. The results of this study indicate that US can be used effectively to determine the location of the IMA.