Suppression of hematopoietic cell kinase ameliorates the bone destruction associated with inflammation.

Objectives: To investigate the role of non-receptor tyrosine kinases (NRTKs) in inflammation-induced osteoclastogenesis.Methods: Microarray analyses of global mRNA expression during receptor activator of NF-κB ligand (RANKL) and RANKL plus tumor necrosis factor (TNF)-α-induced osteoclast differentiation were performed. The inhibitory effect on TNF-α-induced osteoclast differentiation of A-419259, a potent inhibitor of hematopoietic cell kinase (Hck), was examined. The in vivo therapeutic effect of A-419259 treatment on lipopolysaccharide (LPS)-induced inflammatory bone destruction was evaluated.Results: We confirmed that Hck expression was selectively increased among the NRTKs during the osteoclast differentiation induced by RANKL and TNF-α, but not by RANKL alone. RANKL and TNF-α-induced osteoclast differentiation and they were dose-dependently inhibited by A-419259 treatment through inhibition of the expression of key regulators of osteoclastogenesis, including Prdm1 and Nfatc1. Notably, LPS-induced inflammatory bone loss in murine calvarial bones was ameliorated by the administration of A-419259.Conclusions: Our results demonstrate that the administration of A-419259 is effective for the inhibition of osteoclast differentiation induced by TNF-α in the presence of RANKL. Therefore, an inhibitor of Hck may be useful as a potent anti-osteoclastogenic agent for the treatment of inflammatory bone destruction.

Stiffness as measured with strain elastography is a prognostic factor for pT1/T2 tongue squamous cell carcinoma with muscle-layer invasion.

OBJECTIVE: The objective was to evaluate stiffness as a prognostic factor for tongue squamous cell carcinoma (TSCC). STUDY DESIGN: This retrospective study included 55 patients with pathologic stage pT1 or T2 TSCC with muscle-layer invasion who underwent preoperative strain elastography of the tongue, followed by surgery, as the primary treatment modality at our cancer center. The stiffness of TSCC was semi-quantified as the ratio of the strain value of a non-tumor site to the strain value of the tumor site (strain ratio [SR]) using ultrasound strain elastography findings. RESULTS: SR cutoff values that maximized the significance of the difference for prognosis of delayed cervical lymph node metastasis (DCLNM) and overall survival (OS) were 7.10 and 7.49, respectively. In univariate analysis, SR, age, depth of invasion, pT stage, and perineural invasion were significant risk factors for DCLNM, whereas SR, sex, and DCLNM were identified as having an association with OS. In multivariate analysis, SR was a significant risk factor for DCLNM (hazard ratio [HR] = 3.102; P = .021) and a non-significant but relevant risk factor for OS (HR = 8.774; P = .073). Age also had an association with OS (HR = 0.382; 95% CI 0.127-1.152; P = .088). CONCLUSION: Tongue stiffness is a prognostic factor in patients with pT1/T2 TSCC with muscle-layer invasion. SR values >7.10 indicate a poor prognosis, thereby warranting a strict follow-up regimen in these cases.

Stiffness of tongue squamous cell carcinoma measured using strain elastography correlates with the amount of collagen fibers in the tumor.

OBJECTIVES: To evaluate the stiffness of tongue squamous cell carcinoma (TSCC) using ultrasound strain elastography, a relatively new sonographic imaging technique, and to identify the factors that affect this stiffness. METHODS: We treated 62 patients diagnosed with muscle invasive TSCC, who were treated at the department of oral surgery of our institution. Each patient's tumor stiffness was semi-quantified according to the ratio of cancer to tongue muscle strain measured using ultrasound strain elastography (the strain ratio). Histopathological diagnosis was made on the same section as the ultrasound strain elastography. We set the following histopathological parameters: cancer cell content in the tumor area (%CCC), collagen fiber content in the tumor area (%CFC), and tumor-infiltrating inflammatory cell content in the stromal compartment (%TIIC). Spearman's rank correlation (rs) was used to assess correlations, and P values < 0.05 were considered significant. RESULTS: The mean strain ratio was 9.7 ± 9.8. The mean %CCC was 38.4 ± 11.3%, and % CFC was 31.1 ± 7.8%, % TIICs was 19.9 ± 8.9%. Log (strain ratio) by ultrasound strain elastography was positively correlated with %CFC (rs = 0.379, P = 0.024). %CFC was negatively correlated with %TIICs (rs = - 0.318, P = 0.012). No correlations were observed between other clinico-histopathological factors and either strain ratio, or %CFC. CONCLUSION: The strain ratio of the cancer to the strain of the tongue muscle measured through ultrasound strain elastography positively correlates with the collagen fiber content of the tumor area.

Potential factors influencing the development of oral tongue squamous cell carcinoma in young mature patients: Lingual position of the mandibular second molar and narrow tongue space.

The lingual position of the mandibular second molar and narrow tongue space are associated with oral tongue squamous cell carcinoma (OTSCC) development in young mature patients. The present study aimed to assess the role of the mandibular second molar position and tongue space in young mature patients with OTSCC. The medical records of 21 patients with OTSCC aged <50 years, who had an intact mandibular second molar and had undergone computed tomography (CT) imaging between April 2009 and December 2015 at the Section of Maxillofacial Surgery in Tokyo Medical and Dental University, were retrospectively examined. As controls, 21 sex-matched patients of a similar age to the patients in the OTSCC group, and with a height and weight within 5% of those of the OTSCC group, were collected. The location of the mandibular second molar on the affected side and area of the tongue space were determined using coronal and axial CT images. Mann-Whitney U test analysis revealed that the location of the mandibular second molar and the area of the tongue space differed significantly between young mature patients with OTSCC and the controls. The present study thus revealed that the lingual position of the mandibular second molar and the narrow tongue space may be potential factors influencing OTSCC development in young maturity.