Antiresorptive agent-related osteonecrosis of the jaw risk in cancer patients before bone-modifying agent therapy: A retrospective study of 511 patients.

INTRODUCTION: Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a serious adverse event associated with therapies for advanced cancer involving bone-modifying agents (BMAs). Although many studies have investigated the risk factors for ARONJ, none have provided sufficient clarifications. We aimed to determine whether there is a correlation between tooth extraction before BMA therapy and the development of ARONJ. PATIENTS AND METHODS: We included 511 patients who were admitted to our department before BMA therapy. The incidence of ARONJ and its risk factors was retrospectively evaluated, focusing on tooth extraction before BMA therapy and radiological findings of the extracted tooth. RESULTS: Of the 511 patients, 135 underwent tooth extraction before undergoing BMA therapy. ARONJ was observed in 17.7 % and 7.2 % of patients in the extraction and non-extraction groups, respectively (p = 0.0002). Regarding the findings of panoramic radiographs before tooth extraction, the incidence of periapical disease was significantly higher in the ARONJ group than that in the non-ARONJ group (50 % and 27 %, respectively, p = 0.034), and the proportion of bone sclerotic changes in the surrounding teeth was significantly higher in the ARONJ group (58.3 %) than in the non-ARONJ group (24.4 %) (p = 0.0004). CONCLUSION: The presence of a hopeless tooth that requires extraction prior to BMA therapy is a risk factor for MRONJ. However, extraction of such teeth should be considered, as this is known to decrease the risk of MRONJ development after BMA therapy initiation. Moreover, the radiological findings of periapical disease and bone sclerotic changes in the extracted teeth identified in this study can be used as novel predictive factors for ARONJ.

Comparing the Efficacy of a Microperforated Titanium Membrane for Guided Bone Regeneration with an Existing Mesh Retainer in Dog Mandibles.

Acute-type lateral ridge defects (25 mm × 6 mm × 5 mm) were bilaterally created in the mandibles of four dogs (two defects per animal). The defects were reconstructed with particulate autologous bone and covered with a microperforated titanium membrane (Ti-honeycomb membrane, TiHM) or an existing conventional titanium mesh as control. The samples were dissected after 16 weeks postoperatively and processed for radiographic, histologic, and histomorphometric analyses. Regenerated tissue and bone volume were significantly larger in the TiHM group than in the control group (p = 0.05; p = 0.049). In contrast, bone mineral density was similar between the two groups. Histomorphometric analysis revealed that the regenerated bone area and calcific osseous area were larger in the TiHM group than in the control group; however, the differences were not significant. The efficacy of TiHM was generally satisfactory with the potential to become a standard tool for the GBR procedure; however, early membrane exposure will be a major problem to overcome.

Soluble JAM-C Ectodomain Serves as the Niche for Adipose-Derived Stromal/Stem Cells.

Junctional adhesion molecules (JAMs) are expressed in diverse types of stem and progenitor cells, but their physiological significance has yet to be established. Here, we report that JAMs exhibit a novel mode of interaction and biological activity in adipose-derived stromal/stem cells (ADSCs). Among the JAM family members, JAM-B and JAM-C were concentrated along the cell membranes of mouse ADSCs. JAM-C but not JAM-B was broadly distributed in the interstitial spaces of mouse adipose tissue. Interestingly, the JAM-C ectodomain was cleaved and secreted as a soluble form (sJAM-C) in vitro and in vivo, leading to deposition in the fat interstitial tissue. When ADSCs were grown in culture plates coated with sJAM-C, cell adhesion, cell proliferation and the expression of five mesenchymal stem cell markers, Cd44, Cd105, Cd140a, Cd166 and Sca-1, were significantly elevated. Moreover, immunoprecipitation assay showed that sJAM-C formed a complex with JAM-B. Using CRISPR/Cas9-based genome editing, we also demonstrated that sJAM-C was coupled with JAM-B to stimulate ADSC adhesion and maintenance. Together, these findings provide insight into the unique function of sJAM-C in ADSCs. We propose that JAMs contribute not only to cell-cell adhesion, but also to cell-matrix adhesion, by excising their ectodomain and functioning as a niche-like microenvironment for stem and progenitor cells.

Anti-VEGFR therapy is one of the healing inhibitors of antiresorptive-related osteonecrosis of the jaw.

INTRODUCTION: Antiresorptive-related osteonecrosis of the jaw (ARONJ) is a rare but serious adverse event associated with bone-modifying agents (BMAs) and affects patients in the terminal stages of cancer. Molecular targeting drugs (MTDs), anti-vascular endothelial growth factor receptor (VEGFR), and anti-epidermal growth factor receptor (EGFR) drugs are essential in various cancer treatments, although MTDs are risk factors for ARONJ. However, the mechanism through which MTDs affect treatment prognosis of ARONJ remains unclear. Therefore, we investigated the potential inhibitory factors for healing in the conservative therapy of ARONJ with a focus on MTDs. MATERIALS AND METHODS: Sixty patients who were administered BMAs for the treatment of malignancies and who underwent conservative treatment for ARONJ were assessed. The healing rate of ARONJ for each risk factor was retrospectively evaluated. RESULTS: Among the 60 patients, 27 were male and 33 were female. The median age was 67 years, and the median follow-up period was 292 (range 91-1758) days. The healing rate was lower in those treated with both zoledronic acid (Za) and denosumab (Dmab) than in those treated with Za or Dmab alone (0% vs. 28.8%, p = 0.03). Regarding the administration of MTDs, the treatment rate with anti-VEGFR drugs was 7.1% (p = 0.04), anti-EGFR drugs was 12.5% (p = 0.18), and without MTDs was 36.8%. CONCLUSION: In the conservative treatment of ARONJ, the administration of several BMAs and anti-VEGFR drugs was the factor contributing to the inhibition of healing.

A novel technique of arterial blood flow modification in intra-arterial chemoradiotherapy of maxillary sinus squamous cell carcinoma.

OBJECTIVES: Intra-arterial chemoradiotherapy via a superficial temporal artery is reportedly a useful organ-preserving treatment for maxillary sinus squamous cell carcinoma. This study aimed to determine whether blood flow modification facilitates sufficient drug delivery to the entire carcinoma via the maxillary artery alone, even for advanced tumors. MATERIALS AND METHODS: A retrospective study of 10 patients who were diagnosed with locally advanced carcinoma (4 [40%] at stage T3, 5 [50%] at T4a, and 1 [10%] at T4b) from August 2016 to July 2018, with tumor blood flow from both the maxillary and facial arteries, was conducted. Patients underwent intra-arterial chemoradiotherapy, which involved chemotherapy with weekly cisplatin administration (40 mg/m2) and radiotherapy (70 Gy/35 fr), with facial artery ligation. The success rate of blood flow modification, as well as its therapeutic effects and safety, were evaluated, with a median follow-up period of 14.4 months (range: 12.3-35 months). RESULTS: The blood flow surrounding the tumor was changed from both the maxillary and facial arteries to the maxillary artery alone in all patients. A median of 9 chemotherapy courses (range: 8-10) were administered; the median total cisplatin dose was 350 mg/m2 (range: 320-360 mg/m2). Radiotherapy of 70 Gy/35 fr was used to treat all patients. Grade 3 oral mucositis (80%) and irradiation field dermatitis (40%) were observed. In all patients, complete response was achieved, and local recurrence was not observed for at least 1 year. CONCLUSION: Simplifying the blood flow around the tumor facilitates more standardized intra-arterial chemoradiotherapy via a superficial temporal artery procedure.

Evaluation of a Newly Designed Microperforated Titanium Membrane with Beta-Tricalcium Phosphate for Guided Bone Regeneration in Dog Mandibles.

PURPOSE: This study evaluated the efficacy of newly designed, laser-perforated pure titanium membranes for guided bone regeneration using beta-tricalcium phosphate (ß-TCP), and compared them with the existing membrane. MATERIALS AND METHODS: Bilateral acute lateral ridge defects were created in the mandibles of 12 dogs (four defects per animal), which were then randomly divided into two groups (six dogs each). The twenty-four bone defects in each group were then further divided into five groups. The groups were as follows: (1) F001M0, a prototype membrane without a frame plus ß-TCP (n = 5); (2) F001M1, a prototype membrane with a frame plus ß-TCP (n = 5); (3) FBS, an existing control membrane plus ß-TCP (n = 5); (4) control 1, ß-TCP without membrane and with covering flap only (n = 5); and (5) control 2, no treatment (no ß-TCP and no membrane) (n = 4). In all groups where ß-TCP was used, it was mixed with peripheral blood. The animals were necropsied at 6 or 12 weeks postoperatively (six dogs each), and samples were collected and processed for radiographic, histologic, and histomorphometric analyses. RESULTS: Among the three membrane groups, regenerated tissue and bone volume was greatest in the F001M1 group at both 6 and 12 weeks postoperatively, although differences among groups were not statistically significant. Bone mineral density was similar among the membrane groups. Histologic analysis revealed that immature fibroblasts were present on the laser-perforated portion at 6 weeks, which induced vascularization. In addition, more calcified bone was replaced beneath the prototypes than beneath the FBS membrane at 12 weeks. Histomorphometric analyses revealed that the calcific osseous areas at 12 weeks after surgery were significantly greater in the F001M1 and F001M0 groups than in the FBS group (P = .021, P = .032). Furthermore, the fibrous tissue areas beneath the membrane at 12 weeks postoperatively were significantly smaller in the prototype groups than in the FBS group (P = .02, P = .02). CONCLUSION: The efficacies of both prototype membranes were not inferior to that of the FBS membrane, indicating that they may facilitate bone regeneration and maturation when ß-TCP mixed with autologous blood is employed.

Evaluation of a Newly Designed Microperforated Pure Titanium Membrane for Guided Bone Regeneration.

PURPOSE: This study aimed to evaluate the safety and efficacy of newly designed, laser-perforated pure titanium membranes for guided bone regeneration and to compare them with an existing product, the FRIOS BoneShield (FBS). MATERIALS AND METHODS: Acute-type lateral ridge defects were bilaterally created in the mandibles of 13 dogs (two defects per animal). The defects were randomly divided into three groups and were reconstructed with particulate autologous bone (PAB) in combination with three different titanium membranes: (1) F001M0 (prototype without a frame), (2) F001M1 (prototype with a frame), and (3) FBS as a standard membrane. All animals were observed periodically and sacrificed 26 or 27 weeks postoperatively. At 26 weeks, approximately half of the dogs in each group underwent membrane removal to examine the postoperative condition of the titanium membranes. The samples were dissected and processed for radiographic, histologic, and histomorphometric analyses. RESULTS: Membrane exposure was not found in the F001M0 or F001M1 groups, and their membranes were removed easily without adhesion to the surrounding tissue. Regenerated bone tissue volume was largest in the F001M1 group, followed by the F001M0 and FBS groups. A significant difference was observed only between the F001M1 and FBS groups (P = .047). In contrast, bone mineral density was similar among the three groups. Histologically, a layer of fibrous tissue was present underneath the titanium membrane, overlying the regenerated cortical bone in all the groups. Notably, the tissue was highly vascular in the F001M1 and F001M0 groups compared with the FBS group. In addition, there was little difference in the semiquantitative soft tissue evaluation and histologic findings of bone regeneration among the three groups. The histomorphometric analysis revealed that the regenerated bone area was larger in the F001M1 and F001M0 groups than in the FBS group, and a significant difference was observed only between the F001M1 and FBS groups (P = .045). Calcific osseous area was similar among the three groups. CONCLUSION: The safety and efficacy of both F001M0 and F001M1 were equivalent to or greater than those of FBS, thereby indicating their potential for future clinical applications.

Liver X receptor reduces proliferation of human oral cancer cells by promoting cholesterol efflux via up-regulation of ABCA1 expression.

Liver X receptors (LXRs) contribute not only to maintain cholesterol homeostasis but also to control cell growth. However, the molecular mechanisms behind the LXR-mediated anti-proliferative effects are largely unknown. Here we show, by immunohistochemistry, that LXRα and LXRß are differentially distributed in oral stratified squamous epithelia. By immunohistochemical and Western blot analyses, we also reveal that LXRα is abundantly expressed in human oral squamous cell carcinoma (HOSCC) tissues and cell lines. Cell counting, BrdU labeling and cell cycle assay indicated that LXR stimulation led to significant reduction of proliferation in HOSCC cells. Importantly, our study highlights, by using RNA interference, that the ATP-binding cassette transporter A1 (ABCA1)-accelerated cholesterol efflux is critical for the growth inhibitory action of LXRs in HOSCC cells. Moreover, we demonstrate that LXR activation reduces the growth of xenograft tumour of HOSCC cells in mice accompanied by the upregulation of ABCA1 expression and the decline of cholesterol levels in the tumour. These findings strongly suggested that targeting the LXR-regulated cholesterol transport, yielding in lowering intracellular cholesterol levels, could be a promising therapeutic option for certain types of cancers.