Variation of plate fixation for mandibular advancement with intraoral vertical ramus osteotomy using endoscopically assisted intraoral rigid or semi-rigid internal fixation: Case series study: Postoperative condylar seating control for mandibular advancement.

The purpose of the present study was to evaluate the safety and efficacy associated with mandibular advancement by intraoral vertical ramus osteotomy (IVRO) with endoscopically assisted intraoral rigid or semi-rigid internal fixation. The study sample included all patients who had undergone an mandibular advancement by IVRO procedure with endoscopically assisted intraoral plate fixation from September 2008 to May 2012. An mandibular advancement by IVRO with endoscopically assisted intraoral rigid or semi-rigid internal fixation was used for mandibular advancement. The patients were analyzed prospectively, with more than 2 years of follow-up, and were evaluated in terms of functional results, postoperative complications, and skeletal stability. A total of 14 patients (bilateral, 7 patients with class II; unilateral, 7 patients with asymmetry) were included in the present study. The average degree of mandibular advancement was 5.5 ± 1.9 mm (range, 3-9 mm). Both the occlusal relationship and facial appearance in all patients were significantly improved by the surgical-orthodontic treatment, with no major harmful clinical symptoms. In addition, one-screw semi-rigid fixation could control postoperative passive condylar seating. This study showed that mandibular advancement by IVRO with endoscopically assisted, intraoral semi-rigid internal fixation offers a promising treatment alternative for patients with skeletal class II malocclusion or facial asymmetry.

Combination of Mandibular Constriction and Intraoral Vertical Ramus Osteotomies for a Transverse Jaw Discrepancy.

BACKGROUND: The aim of the present study was to evaluate the treatment of patients developing a transverse jaw width discrepancy who exhibited class III malocclusion and/or facial asymmetry by a combination of mandibular constriction (MC) and intraoral vertical ramus osteotomies (IVROs). SUBJECTS AND METHODS: In a retrospective study, functional results, postoperative complications, and skeletal stability were analyzed for all the patients who had undergone MC and IVRO, with more than 2 years of follow-up. A mandibular midline osteotomy for constriction with lag screw technique and IVROs was used for MC and setback. RESULTS: Sixteen patients were included in the present study. The average degree of MC was 6.34 mm. Both the occlusal relationship and facial appearance in all patients were significantly improved by the surgical orthodontic treatment, with no harmful clinical symptoms. In addition, our original MC using lag screw technique provided the most reliable results in terms of skeletal stability. CONCLUSIONS: This study showed that MC using lag screw technique gives a very stable mandibular width constriction, and the combination of MC and IVROs offers a promising treatment alternative for patients with mandibular prognathism developing a transverse jaw width discrepancy.

Identification of Akt1 as a potent therapeutic target for oral squamous cell carcinoma.

Oncogene addiction can provide therapeutic opportunities in human malignancies. In this study, we aimed to identify critical oncogenes for oral squamous cell carcinoma (OSCC) development and progression. We determined gene expression profiles in 10 primary OSCCs and 10 human OSCC cell lines using Applied Biosystems Human Genome Survey Arrays. Akt1 was the only gene identified that was expressed in all OSCC tissues and cultured cells, but not in non-neoplastic tissues and cells. Subsequently, western blot analysis showed that Akt1 protein was overexpressed in OSCC tissues and cell lines. Immunohistochemistry also showed Akt1 protein expression in 59 of 63 (94%) primary OSCCs. To clarify the oncogenic function of Akt1 in human OSCC cells, we used RNA interference. We designed and synthesized 5 small interfering RNAs specific for Akt1 (siAkt1). Transfecting human OSCC cells with siAkt1 in vitro markedly suppressed their expression of Akt1 protein and significantly reduced their growth rate. Furthermore, the growth of human OSCC tumors which had been subcutaneously xenografted in athymic nude mice lacking interferon responses was markedly inhibited by atelocollagen-mediated systemic siAkt1 administration. We also found that synthetic siAkt1 had an inhibitory effect on the growth of primary cultured OSCC cells. Finally, we investigated the molecular mechanisms involved in the growth inhibitory effect of Akt1 suppression using microarray analysis of human OSCC cells transfected with siAkt1. Knockdown of Akt1 induced the expression of CDKN2B, a tumor suppressor gene, and reduced the expression of TGFBR1, which supports malignant phenotypes. These results suggest that Akt1 functions as a critical oncogene in human OSCC cells and may therefore be an appropriate target for novel OSCC therapies.

Computer-aided design provisionalization and implant insertion combined with optical scanning of plaster casts and computed tomography data.

The conventional implant prosthesis planning process currently involves confirmation of two-dimensional anatomical findings or the quantity and quality of bones using panoramic X-ray images. The introduction of computed tomography (CT) into the field has enabled the previously impossible confirmation of three-dimensional findings, making implant planning in precise locations possible. However, artifacts caused by the presence of metal prostheses can become problematic and can result in obstacles to diagnosis and implant planning. The most updated version of SimPlant(®) Pro has made it possible to integrate plaster cast images with CT data using optical scanning. Using this function, the obstacles created by metal prostheses are eliminated, facilitating implant planning at the actual intraoral location. Furthermore, a SurgiGuide(®) based on individual patient information can be created on plaster casts, resulting in easier and more precise implant insertion.

Risk of maxillary artery injury during an intraoral vertical ramus osteotomy in Japanese patients is high--is it enough just to avoid damaging the inferior alveolar nerve?

PURPOSE: Since managing a case in which the maxillary artery was injured during intraoral vertical ramus osteotomy (IVRO) with intraoperative transcatheter arterial embolization, we have conducted preoperative vascular computed tomography (CT) evaluations of the maxillary artery course in patients scheduled to undergo mandibular bone osteotomy. The aim of the present study was to describe the anatomy of the maxillary artery in the infratemporal artery in Japanese patients. MATERIALS AND METHODS: The study design was a prospective case series. The study sample included all patients who had undergone IVRO from October 2009 to December 2012. We evaluated the positional relationship between the maxillary artery and the mandible using CT vascular imaging before surgery. The primary outcome variable was the requirement for subperiosteal dissection on the medial surface of the mandible from the perspective of the intersection of the route of the maxillary artery with the IVRO osteotomy line. RESULTS: A total of 156 sides from 78 patients who had undergone mandibular bone osteotomy were included in the present study. The maxillary artery course was positioned directly below the mandibular notch in approximately one half of the cases, necessitating subperiosteal dissection on the medial surface of the mandible. CONCLUSIONS: IVRO is a common surgical procedure that can be safely and easily conducted in conjunction with endoscopy. However, improved maxillary artery damage prevention methods are recommended, such as subperiosteal dissection on the medial surface of the mandible and filling the medial surface of the mandibular ramus with gauze.

Three-dimensional virtual operations can facilitate complicated surgical planning for the treatment of patients with jaw deformities associated with facial asymmetry: a case report.

This article describes a case we experienced in which good postsurgical facial profiles were obtained for a patient with jaw deformities associated with facial asymmetry, by implementing surgical planning with SimPlant OMS. Using this method, we conducted LF1 osteotomy, intraoral vertical ramus osteotomy (IVRO), sagittal split ramus osteotomy (SSRO), mandibular constriction and mandibular border genioplasty. Not only did we obtain a class I occlusal relationship, but the complicated surgery also improved the asymmetry of the frontal view, as well as of the profile view, of the patient. The virtual operation using three-dimensional computed tomography (3D-CT) could be especially useful for the treatment of patients with jaw deformities associated with facial asymmetry.

Clinical approach for mandibular advancement by intraoral vertical ramus osteotomy with endoscopically assisted intraoral fixation of an L-shaped compact lock plate.

Intraoral vertical ramus osteotomy (IVRO) is widely used as a surgical corrective method to treat patients with skeletal class III malocclusion with mandibular setback. However, the conventional surgical method applied for mandibular advancement has induced such complications as condylar luxation caused by the instability of the placement of the proximal segment. To avoid this complication, it has been necessary to use the fixation of the proximal and distal segments with an L-shaped compact lock plate via an extraoral approach. This has made surgeons hesitate to propose this osteotomy for patients with skeletal class II malocclusions. We herein report a new surgical approach for the IVRO for mandibular corrective advancement with endoscopically assisted fixation of an L-shaped compact lock plate and good positioning of the condyle via an intraoral approach.The osteotomized mandibular segments were fixed with an L-shaped compact lock plate using right-angled burs and right-angled screwdrivers. Seven patients were included in this study. The average degree of mandibular advancement was 6.1 mm (range, 3.5-9 mm). Our results suggest that mandibular advancement by IVRO with endoscopically assisted intraoral fixation of an L-shaped compact lock plate in patients with skeletal class II malocclusion might be useful to improve the occlusion and facial aesthetics by maintaining good positioning of the condyle.

Endoscopically assisted intraoral modified Le Fort II type midfacial advancement using piezoelectric surgery and an intraoperative RED system.

PURPOSE: The Le Fort II midfacial advancement appears to be an effective surgical method for the treatment of severe midfacial-nose hypoplasia with a skeletal class III malocclusion, which is usually combined with syndromic midfacial anomalies. However, the conventional surgical method requires the coronal approach, including a coronal incision, together with other surgical approaches, such as an intraoral incision. Therefore, surgeons often hesitate to propose this type of osteotomy, even for patients who develop severe nonsyndromic midfacial-nose hypoplasia. This report presents a new surgical approach for performing a safe Le Fort II osteotomy for nasomaxillary, midfacial corrective advancement via a solely intraoral approach. MATERIALS AND METHODS: Surgery was performed with endoscopically assisted piezoelectric surgery. The osteotomized nasomaxillary Le Fort II segment was successfully protracted without aggressive down-fracture procedures with the sole intraoperative use of a rigid external distraction (RED) system, followed by internal rigid fixation, and the subsequent removal of the RED system. Seven patients (all patients were nonsyndromic, but 2 had cleft lip and palate, and an average age of 19.9 years) were included in this study. RESULTS: The degrees of midfacial advancement at the base of nasal bone (the top edge of the modified Le Fort II segment) that was osteotomized and at maxillary point A was 8.3 mm (range 5.8 mm to 10.5mm) and 8.5 mm (range 5.9 mm to 9.8 mm), respectively. CONCLUSION: This new method less invasively facilitates safe, secure, and ideal nasomaxillary midfacial protraction to yield a satisfactory resultant facial profile and favorable occlusion in patients with severe midfacial-nose hypoplasia and skeletal class III malocclusions.

Bone transport and bone graft using auto-tooth bone for alveolar cleft repair.

We herein report the application of a combination of maxillary bone transport and auto-tooth bone grafting for alveolar cleft repair using autogenous extracted teeth developed in Korea.A 9-year-old female patient suffering from unilateral cleft lip and palate was treated with this method. After sagittal interdental right-sided maxillary osteotomy was performed completely between #11 and #12 to the nasal floor, alveolar maxillary bone (#11, 21) was transported in the planned direction and the alveolar cleft was closed. At the end of the transporter activation period, soft tissue in the cleft was removed during so-called "docking surgery" using an electric knife for close bone contact at the docking site. We performed bone transporter removal and simultaneous auto-tooth bone grafting of the patient's supernumerary teeth to the docking site.Maxillary bone transport allowed for simultaneous correction of the nasal septal deviation, maxillary arch deformities, and malocclusion since the dental arch was expanded without donor sacrifice or soft tissue expansion. Auto-tooth bone grafting to the docking site allowed for repair of the bone defects of the nasal floor and alveolar cleft and resulted in a superior bone connection.A combination of maxillary bone transport and auto-tooth bone grafting to the docking site appears to be an effective approach for alveolar cleft repair.

Knockdown of Akt isoforms by RNA silencing suppresses the growth of human prostate cancer cells in vitro and in vivo.

The serine/threonine kinase Akt has three highly homologous isoforms in mammals: Akt1, Akt2, and Akt3. Recent studies indicate that Akt is often constitutively active in many types of human malignancy. Here we investigated the expression and function of Akt isoforms in human prostatic carcinoma cells. Initially, we used Western blotting to examine Akt expression in four human prostate cancer cell lines. Next, small-interfering RNAs (siRNAs) specific for Akt isoforms were used to elucidate their role on the in vitro and in vivo growth of prostate cancer cells. Expression of Akt1 and Akt2 was detected in all cells tested, but Akt3 was expressed only in cancer cells that did not express androgen receptors. All synthetic siRNAs against Akt isoforms suppressed their expression and inhibited the growth of cancer cells in vitro. Furthermore, atelocollagen-mediated systemic administration of siRNAs significantly reduced the growth of tumors that had been subcutaneously xenografted. These results suggest that targeting Akt isoforms could be an effective treatment for prostate cancers.

Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma.

Hypoxia promotes the invasive and metastatic potential of tumour cells. A recent study has shown that the activation of the chemokine receptor CXCR4 by lack of oxygen in breast cancer is HIF-1-dependent. We have previously demonstrated that CXCR4 signalling is involved in the establishment of lymph node metastasis in oral squamous cell carcinoma (OSCC). In this study, we investigated a correlation between CXCR4 and HIF-1alpha expression in OSCC. Immunohistochemistry showed that CXCR4 was expressed in 20 of 85 OSCC tissues, while HIF-1alpha was expressed in 51 of 85 samples. There was a significant correlation between the expression of CXCR4 and HIF-1alpha. In human OSCC cells, hypoxia markedly enhanced the expression of both HIF-1alpha and CXCR4. Furthermore, synthetic small interfering RNA specific for HIF-1alpha significantly suppressed the expression of this protein, and also attenuated the induction of CXCR4 expression under hypoxic conditions. These results indicated that HIF-1alpha regulated hypoxia-induced CXCR4 expression in OSCC.

CD151 regulates HGF-stimulated morphogenesis of human breast cancer cells.

We previously demonstrated that CD151 forms a functional complex with c-Met and integrin alpha3/alpha6 in human salivary gland cancer cells. In the current study, we investigated the involvement of CD151, c-Met, and integrin alpha3/alpha6 in the cellular morphogenesis of human breast cancer cells. Knockdown of CD151, integrin alpha3, or integrin alpha6 expression abolished branching morphogenesis. Decreased c-Met expression in these cells led to the formation of rudimentary networks and prevented their conversion. Furthermore, hepatocyte growth factor (HGF) promoted cellular morphogenesis by accelerating network reorganization. Immunoprecipitation revealed a specific association between CD151 and c-Met. The involvement of CD151 and integrin alpha3/alpha6 in HGF-dependent signaling was confirmed by the decreased Akt phosphorylation in cells lacking CD151, integrin alpha3, or integrin alpha6. Hence, the regulation of CD151 expression might contribute to changes in HGF/c-Met signaling and thereby modulate the phenotypic characteristics of cancer cells.

Stat3 as a molecular target in RNA interference-based treatment of oral squamous cell carcinoma.

Constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been observed in many human malignancies. Using the sequence-specific RNA interference (RNAi) method to switch off Stat3 expression, it may be possible to arrest cancer growth. In this study, we aimed to identify the most effective sequence of a synthetic small interfering RNA (siRNA) specific for Stat3 (Stat3-siRNA) and the effect of Stat3 suppression on the growth of oral squamous cell carcinoma cells. Ten designed siRNAs with known sequences were screened for the best RNAi effect at the working concentrations of 1 and 10 nM. The range of reduction of Stat3 expression varied from 21 to 67% for 10 nM siRNAs, and from 13 to 73% for 1 nM siRNAs. Three out of the 10 screened siRNAs reduced Stat3 expression to lower levels compared with the GFP-siRNA control. The interferon response of some siRNAs was observed at a concentration of 10 nM. However, at 1 nM, the mRNA levels of interferon response genes (OAS1, OAS2, MX1 and ISFG3gamma) remained unchanged. The growth of GFP-SAS, HSC-3, HSC-4 and KB cells was strongly inhibited by the use of three effective Stat3-siRNAs in comparison with other Stat3-siRNAs and GFP-siRNA. Moreover, the mRNA levels of genes for which transcription is activated by Stat3 were markedly suppressed. These results suggest that targeting Stat3 using siRNA may constitute a useful approach for the treatment of oral squamous cell carcinoma.

Role of Akt isoforms in HGF-induced invasive growth of human salivary gland cancer cells.

The expression of hepatocyte growth factor (HGF) and c-Met is associated with tumor progression in many human malignancies. A recent study demonstrated HGF and c-Met expression in human salivary gland cancer tissues. Here, we investigated the role of the HGF/c-Met system in the invasive growth of two human salivary gland cancer cell lines: green fluorescent protein-adenoid cystic carcinoma 2 (GFP-ACC2) and GFP-ACCM. HGF enhanced the invasive growth of the two cell lines by activating PI3K/Akt signaling. All Akt isoforms (Akt1, Akt2, and Akt3) were detected in both cell types by Western blot analysis. Knockdown of any of the Akt isoforms using isoform-specific synthetic small-interfering RNAs largely abrogated the invasive growth induced by HGF. Our findings suggest that all of the Akt isoforms are required for the HGF-stimulated invasive growth of human salivary gland cancer cells, and that targeting a single Akt isoform could be effective in treating salivary gland cancers.

Inactivation of AR activates HGF/c-Met system in human prostatic carcinoma cells.

Clinical studies with prostate cancer tissue indicate that alterations in androgen receptor (AR) or c-Met overexpression are associated with androgen-independent progression. We investigated the interaction between AR and c-Met signaling in human prostate cancer cells. Androgen withdrawal or AR-specific small interfering RNA significantly reduced the growth rate while each maneuver induced the expression of c-Met. Knockdown of both AR and c-Met expression markedly inhibited the cell growth. Furthermore, microarray analysis indicated that the activation of c-Met down-regulated the expression of DNA repair-related genes including 8-oxoguanine DNA glycosylase. Exogenous hepatocyte growth factor also induced the production of intracellular reactive oxygen species and resulted in the accumulation of DNA damages. These results suggested that the activation of c-Met signaling may lead to induction of spontaneous mutations or genomic instability, which may lead to the progression of androgen-independent state. Thus, c-Met signaling is utilized for survival and growth under the androgen-depleted condition.

Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells.

Hypoxia increases the invasive and metastatic potential of tumor cells. Increased expression of c-Met/hepatocyte growth factor (HGF)-receptor protein in response to hypoxia in thyroid papillary carcinomas is hypoxia-inducible factor-1 (HIF-1) dependent. Both HGF and c-Met are expressed in human salivary gland cancers. In the current study, we tested whether c-Met expression was regulated by hypoxia and HIF-1alpha using two human salivary gland cancer cell lines: GFP-ACC2 and GFP-ACCM. Hypoxia enhanced the expression of HIF-1alpha in both cell lines, whereas c-Met was markedly induced only in the GFP-ACCM cells, which have metastatic potential. In the latter, hypoxia also promoted HGF-induced invasiveness. Synthetic small-interfering RNA specific for HIF-1alpha inhibited HIF-1alpha expression in the GFP-ACCM cells, and also suppressed the increase in c-Met expression and HGF-induced invasiveness under hypoxic conditions. These results suggest that hypoxia activates the HGF/c-Met system via HIF-1alpha in human salivary gland cancers and might be involved in their metastasis.

CXCR4 expression is associated with lymph-node metastasis of oral squamous cell carcinoma.

The support mechanisms that are involved in lymph-node metastasis of oral squamous cell carcinoma (OSCC) remain largely unknown. Recent studies have demonstrated that tumor cells express chemokine receptors and use chemokines to metastasize to the target organ in many malignancies in humans. In this study, we examined the expression and function of chemokines and their receptors in OSCC. The expression of chemokine receptors was assessed in eight OSCC cell lines. CXCR3 mRNA and protein were expressed in all the OSCC cell lines examined, while CXCR4 mRNA and protein were expressed only in HSC2, HSC3, and Ca9-22 cells. Treatment with the ligand for CXCR4, stromal cell-derived factor-1 (SDF-1), enhanced the motility and invasiveness of OSCC cells expressing CXCR4. However, the CXCR3 ligand, Mig, did not affect the migration or invasiveness of CXCR3-positive cells. We also evaluated the clinical significance of CXCR4 expression immunohistochemically. CXCR4 expression was detected in 27 (30%) of the 90 OSCC tissues tested, and was localized in the membrane and cytoplasm of cancer cells. There was a highly significant correlation between CXCR4 expression and lymph-node metastasis (P=0.0035). Collectively, these findings suggest that CXCR4 might be involved in the lymph-node metastasis of OSCC.

CD151 forms a functional complex with c-Met in human salivary gland cancer cells.

In this study, we have attempted to elucidate the expression and function of CD151 in human salivary gland cancer cells. CD151 expression was detected in Acc2 and AccM cells, but not in normal tissues and primary cultured epithelial cells derived from human salivary gland. CD151 has been found to function as a molecular linker in the formation of complexes between c-Met/hepatocyte growth factor (HGF) receptor and integrin alpha3/alpha6. Knockdown of CD151 or integrin alpha3/alpha6 expression almost completely abrogated HGF-stimulated cell growth and migration. In contrast, forced expression of CD151 in Acc2 cells resulted in the increase of the HGF-dependent biological effects. These results suggest that CD151 forms a structural and functional complex with c-Met and integrin alpha3/alpha6, and exerts its oncogenic functions through excessive activation of the HGF/c-Met signalling pathway.

Phenotypic switch from paracrine to autocrine role of hepatocyte growth factor in an androgen-independent human prostatic carcinoma cell line, CWR22R.

Support mechanisms involved in growth of androgen-independent prostate cancer are primarily unknown. Hepatocyte growth factor (HGF)/Met has been suggested to be one of them based primarily on immunohistochemical studies. We conducted a series of experiments to assess the role of the HGF/Met system in an androgen-dependent human prostate carcinoma, CWR22 and its androgen-independent derivative, CWR22R. We found that action of HGF changed from paracrine to autocrine in progression to androgen-independent state. CWR22 tumors did not express HGF but expressed Met, whereas prostate stromal cells expressed HGF at a high level. Growth of CWR22 was stimulated either by addition of HGF to the culture or by the presence of prostate stromal cells. On the other hand, CWR22R cells expressed both HGF and Met. Knockdown of Met expression by RNA interference method suppressed the growth of CWR22R cells. Our data suggest that HGF is intimately involved in growth of human prostate cancer and that progression from the androgen-dependent to the androgen-independent state is associated with an adaptive switch in support mechanism from paracrine to autocrine. Our data offer one mechanism to account for androgen-independent human cancer growth.