Multiple Schwannomas Arising in the Midline Space Between the Bilateral Genioglossus Muscles and Left Submandibular Space.

Schwannomas mostly occur as solitary tumors, and multiple schwannomas are very rare. Schwannomas in the submandibular space are extremely rare. Furthermore, schwannomas in the midline space between the bilateral genioglossus muscles are even rarer. We report multiple schwannomas arising in the midline space between the bilateral genioglossus muscles and left submandibular space. Because the common differential diagnosis of the midline deep sublingual lesions does not include schwannoma for the rarity, surgeons should consider schwannoma in the differential diagnosis.

A Novel Orthognathic Surgery With a Half-Millimeter Accuracy for the Maxillary Positioning Using Prebent Plates and Computer-Aided Design and Manufacturing Osteotomy Guide.

This retrospective study aimed to assess the accuracy of prebent plates and computer-aided design and manufacturing osteotomy guide for orthognathic surgery. The prebent plates correspondent to the planning model were scanned with a 3-dimensional printed model for guide design and used for fixation. Forty-two patients who underwent bimaxillary orthognathic surgery using computer-aided design and manufacturing intermediate splint with the guide (guided group: 20 patients) or with conventional fixation under straight locking miniplates (SLMs) technique (SLM group: 20 patients) were analyzed. A deviation of the maxilla between the planned and postoperative positions was evaluated using computed tomography, which was taken 2 weeks before and 4 days after the surgery. The surgery time and the infraorbital nerve paranesthesia were also evaluated. The mean deviations in the mediolateral ( x ), anteroposterior ( y ), and vertical directions ( z ) were 0.25, 0.50, and 0.37 mm, respectively, in the guided group, while that in the SLM group were 0.57, 0.52, and 0.82 mm, respectively. There were significant differences in x and z coordinates ( P <0.001). No significant difference in the surgery duration and paranesthesia was seen, suggesting the present method offers a half-millimeter accuracy for the maxillary repositioning without increasing the risk of extending surgery duration and nerve complication.

Synergistic Enhancement of Protein Recruitment and Retention via Implant Surface Microtopography and Superhydrophilicity in a Computational Fluid Dynamics Model.

The exact mechanisms by which implant surface properties govern osseointegration are incompletely understood. To gain insights into this process, we examined alterations in protein and blood recruitment around screw implants with different surface topographies and wettability using a computational fluid dynamics (CFD) model. Compared with a smooth surface, a microrough implant surface reduced protein infiltration from the outer zone to the implant thread and interface zones by over two-fold. However, the microrough implant surface slowed blood flow in the interface zone by four-fold. As a result, compared with the smooth surface, the microrough surface doubled the protein recruitment/retention index, defined as the mass of proteins present in the area per unit time. Converting implant surfaces from hydrophobic to superhydrophilic increased the mass of protein infiltration 2-3 times and slowed down blood flow by up to two-fold in the implant vicinity for both smooth and microrough surfaces. The protein recruitment/retention index was highest at the implant interface when the implant surface was superhydrophilic and microrough. Thus, this study demonstrates distinct control of the mass and speed of protein and blood flow through implant surface topography, wettability, and their combination, significantly altering the efficiency of protein recruitment. Although microrough surfaces showed both positive and negative impacts on protein recruitment over smooth surfaces, superhydrophilicity was consistently positive regardless of surface topography.

Multicenter retrospective study of nivolumab for recurrent/metastatic oral squamous cell carcinoma.

OBJECTIVES: Immunotherapy with nivolumab for patients with recurrent/metastatic oral squamous cell carcinoma has not been evaluated. Here, we aimed to examine the efficacy, safety, and prognostic factors of nivolumab in these patients. MATERIALS AND METHODS: This multicenter retrospective observational study involved patients who received nivolumab between April 2017 and June 2019. The patient characteristics were evaluated for association with progression-free and overall survival. Progression-free and overall survival rates were calculated; parameters that were significant in the univariate analysis were used as explanatory variables. Independent factors for progression-free and overall survival were identified using multivariate analysis. RESULTS: Totally, 143 patients were included. The overall response and disease control rates were 27.3% and 46.2%, respectively. The median, 1- and 2-year progression-free survival rates were 2.7 months, 25.4%, and 19.2%, respectively; those for overall survival were 11.2 months, 47.3%, and 33.6%, respectively. The independent factors affecting progression-free survival were performance status and immune-related adverse event occurrence, whereas those affecting overall survival were performance status, target disease, and number of previous lines of systemic cancer therapy. Eight patients reported grade ≥3 immune-related adverse events. CONCLUSION: Nivolumab was effective for recurrent/metastatic oral squamous cell carcinoma treatment and was well tolerated by patients.

Huge Submandibular Gland Mucocele With Diagnostic Difficulties.

ABSTRACT: Submandibular gland mucoceles, which are very rare cystic lesions, make differentiation from other cystic neck masses such as plunging ranula and cystic lymphatic malformation difficult. The authors report a rare huge submandibular gland mucocele with diagnostic difficulties. A 39-year-old woman with painless swelling in the left submandibular region underwent OK-432 injection therapy with a diagnosis of plunging ranula at another hospital. However, she was referred to our department for recurrent swelling. Computed tomography showed a well-circumscribed, multilocular, low-density lesion in the left submandibular region. Fine needle aspiration was performed, and the content of the cystic lesion was yellowish-brown serous fluid. After the fine needle aspiration, computed tomography was performed. The cystic lesion was radiologically diagnosed as submandibular gland mucocele. Therefore, the patient underwent endoscopically-assisted intraoral removal of the sublingual and submandibular glands under general anesthesia. The pathological diagnosis was submandibular gland mucocele.

Anatomical Relationship Between the Lingual Nerve and Submandibular Duct.

ABSTRACT: The purpose of this study was to investigate the anatomical relationship between the lingual nerve and submandibular duct. This study included 1403 patients with submandibular or sublingual gland diseases who underwent intraoral removal of submandibular gland sialoliths, submandibular glands, or sublingual glands. Of all patients, 33 patients underwent bilateral surgeries. All surgeries were performed a single surgeon, and the anatomical relationship between the lingual nerve and submandibular duct was always identified intraoperatively and recorded in the operation recorded. The anatomical relationship was investigated based on the intraoperative findings. The lingual nerve which crosses above the submandibular duct was detected in 8 of 1436 sides (0.6%). There were 4 in the right sides and 4 in the left sides. The lingual nerve below the submandibular gland was seen in 99.4%. Although the lingual nerve crosses above the submandibular duct with a rarer incidence, surgeons should beware of injuring the lingual nerve during intraoral salivary gland surgery.

Intraoral Styloidectomy Using an Endoscope With Tissue Retractor.

ABSTRACT: The extraoral approach with the risk of facial nerve injury and the visible scar is commonly performed for an elongated styloid process, because intraoral styloidectomy is challenging for the deep and limited surgical field. The authors report minimally invasive intraoral styloidectomy using an endoscope with tissue retractor. A 57-year-old female was referred to our department with a left pharyngeal foreign body sensation and pharyngeal pain after head turning and neck compression. Clinical and radiological diagnosis was an elongated styloid process (Eagle syndrome). Because the styloid process could be palpated intraorally, the patient underwent endoscopically-assisted intraoral styloidectomy without tonsillectomy under general anesthesia as minimally invasive surgery. The styloid process was resected safely with a piezoelectric surgical device under endoscopic guidance. The postoperative course was uneventful without complications.

Clinical Anatomy of Feeding Artery of the Submandibular Gland.

ABSTRACT: The purpose of this study was to investigate the clinical anatomy of the feeding artery of the submandibular gland (SMG). A total of 199 SMG removals were performed in extraoral or intraoral approach with/without endoscopic assistance by a single surgeon. The feeding artery of the SMG was always identified intraoperatively and recorded in the operation record. The clinical anatomy of the feeding artery of the SMG was investigated based on the intraoperative findings. The facial artery was ligated and transected for the involvement of tumor or severe inflammation in 16 (8.0%) procedures. The feeding artery was investigated in the remaining 183 procedures. The mean number of the glandular branch was 1.5. There were 1 branch in 98 procedures (53.6%), 2 branches in 80 procedures (43.7%), and 3 branches in 5 procedures (2.7%). Detailed anatomical knowledge of the feeding artery of the SMG is useful for proper dissection of the SMG and preservation of the facial artery.

A 3-Dimensional Finite Element Analysis of Resected Mandibular Bone to Determine the Most Stable Implant Positions for a Fixed Prosthesis.

This study was conducted to determine the most secure implant positioning on the marginally resected mandible to support a fixed complete denture through finite element analysis. Three or 4 implants were placed at near, middle, or far positions from the resected margin in a simulation model with a symmetrical marginal defect in the mandibular symphysis. The height of the residual bone was 5, 10, or 15 mm. The 4 possible implant patterns for 3 or 4 implants were defined as (1) asymmetrically isolated position 1 to position 2, (2) asymmetrically isolated position 1 to position 3, (3) asymmetrically isolated with greater-length position 1 to position 2, and (4) 2 implants symmetrically positioned on each side of the defect. The von Mises stress in the resected and peri-implant bone with respect to the occlusal force was calculated. Initially, because the peri-implant bone stress around the isolated implant at the near position was greater than at the middle and far positions regardless of the residual bone height, the near position was excluded. Second, the von Mises stress in the resected bone region was >10 MPa when the isolated implant was at the far position, and it increased inversely depending on the bone height. However, the stress was <10 MPa when the isolated implant was placed at the middle position regardless of the bone height, and it was significantly lower compared with the far position and equivalent to the symmetrically positioned implants. Furthermore, the use of a greater-length implant reduced peri-implant bone stress, which was even lower than that of the symmetrically positioned implants. These results suggest that the asymmetrically positioned 3-implant-supported fixed denture, using a greater-length isolated implant, placed neither too close to nor too far from the resected margin, can be an effective alternative to the symmetrically positioned 4-implant-supported fixed denture.

Prostaglandin E2 receptor EP4 regulates cell migration through Orai1.

The EP4 prostanoid receptors are one of four receptor subtypes for prostaglandin E2 (PGE2 ). Therefore, EP4 may play an important role in cancer progression. However, little information is available regarding their function per se, including migration and the cellular signaling pathway of EP4 in oral cancer. First, we found that mRNA and protein expression of EP4 was abundantly expressed in human-derived tongue squamous cell carcinoma cell lines HSC-3 and OSC-19. The EP4 agonist (ONO-AE1-437) significantly promoted cell migration in HSC-3 cells. In contrast, knockdown of EP4 reduced cell migration. Furthermore, we confirmed that knockdown of EP4 suppressed metastasis of oral cancer cells in the lungs of mice in vivo. Therefore, we focused on the mechanism of migration/metastasis in EP4 signaling. Interestingly, EP4 agonist significantly induced intracellular Ca2+ elevation not in only oral cancer cells but also in other cells, including normal cells. Furthermore, we found that EP4 activated PI3K and induced Ca2+ influx through Orai1 without activation of store depletion and stromal interaction molecule 1 (STIM1). Immunoprecipitation showed that EP4 formed complexes with Orai1 and TRPC1, but not with STIM. Moreover, the EP4 agonist ONO-AE1-437 phosphorylated ERK and activated MMP-2 and MMP-9. Knockdown of Orai1 negated EP4 agonist-induced ERK phosphorylation. Taken together, our data suggested that EP4 activated PI3K and then induced Ca2+ influx from the extracellular space through Orai1, resulting in ERK phosphorylation and promoting cell migration. Migration is regulated by EP4/PI3K/Orai1 signaling in oral cancer.

Impact of superselective intra-arterial and systemic chemoradiotherapy for gingival carcinoma; analysis of treatment outcomes and prognostic factors.

BACKGROUND: We compared outcomes and toxicities between concurrent retrograde super-selective intra-arterial chemoradiotherapy (IACRT) and concurrent systemic chemoradiotherapy (SCRT) for gingival carcinoma (GC). METHODS: We included 84 consecutive patients who were treated for non-metastatic GC ≥ stage III, from 2006 to 2018, in this retrospective analysis (IACRT group: n = 66; SCRT group: n = 18). RESULTS: The median follow-up time was 24 (range: 1-124) months. The median prescribed dose was 60 (6-70.2) Gy (IACRT: 60 Gy; SCRT: 69 Gy). There were significant differences between the two groups in terms of 3-year overall survival (OS; IACRT: 78.8, 95% confidence interval [CI]: 66.0-87.6; SCRT: 50.4, 95% CI: 27.6-73.0; P = 0.039), progression-free survival (PFS; IACRT: 75.6, 95% CI: 62.7-85.2; SCRT: 42.0, 95% CI: 17.7-70.9; P = 0.028) and local control rates (LC; IACRT: 77.2, 95% CI: 64.2-86.4; SCRT: 42.0, 95% CI: 17.7-70.9; P = 0.015). In univariate analysis, age ≥ 65 years, decreased performance status (PS) and SCRT were significantly associated with worse outcomes (P < 0.05). In multivariate analysis, age ≥ 65 years, clinical stage IV, and SCRT were significantly correlated with a poor OS rate (P < 0.05). Patients with poorer PS had a significantly worse PFS rate. Regarding acute toxicity, 22 IACRT patients had grade 4 lymphopenia, and osteoradionecrosis was the most common late toxicity in both groups. CONCLUSIONS: This is the first report to compare outcomes from IACRT and SCRT among patients with GC. ALL therapy related toxicities were manageable. IACRT is an effective and safe treatment for GC.

Straight Locking Miniplate Technique Achieves Submillimeter Accuracy of Condylar Positional Change During Bimaxillary Orthognathic Surgery for Patients With Skeletal Class III Malocclusion.

PURPOSE: The straight locking miniplate (SLM) technique is a straightforward method to accurately reposition the maxilla during bimaxillary orthognathic surgery. The present study evaluated the accuracy of the SLM technique in maintaining the condylar position during surgery without the use of a cutting guide. PATIENTS AND METHODS: The present prospective, single-center study was conducted at Yokohama City University between 2016 and 2017 and included patients with skeletal Class III malocclusion. The patients were divided into 2 groups according to the fixation method used for the mandibular segments. The mandibular segments were fixed with miniplates either manually (manual group) or using the SLM technique (SLM group). Computed tomography was performed before and 3 days after surgery to compare the condylar position. The bodily and rotational movements of the condyle were analyzed. RESULTS: The subjects were 18 Japanese patients (36 condyles) who had undergone bilateral set back surgery with Le Fort I osteotomy. The amount of bodily movements in the manual and SLM groups were 1.44 and 0.62 mm, respectively. The degree of rotational movement in the sagittal plane in the manual and SLM groups was 3.33° and 0.23°, respectively. The bodily and rotational movements in the SLM group were significantly smaller than those in the manual group (P < .05 and P < .01, respectively). CONCLUSIONS: These results suggest that use of the SLM technique reduces the risk of condylar positional changes to less than 1 mm during orthognathic surgery without the use of any complex devices or a cutting guide.

Computational Fluid Simulation of Fibrinogen around Dental Implant Surfaces.

Ultraviolet treatment of titanium implants makes their surfaces hydrophilic and enhances osseointegration. However, the mechanism is not fully understood. This study hypothesizes that the recruitment of fibrinogen, a critical molecule for blood clot formation and wound healing, is influenced by the degrees of hydrophilicity/hydrophobicity of the implant surfaces. Computational fluid dynamics (CFD) implant models were created for fluid flow simulation. The hydrophilicity level was expressed by the contact angle between the implant surface and blood plasma, ranging from 5° (superhydrophilic), 30° (hydrophilic) to 50° and 70° (hydrophobic), and 100° (hydrorepellent). The mass of fibrinogen flowing into the implant interfacial zone (fibrinogen infiltration) increased in a time dependent manner, with a steeper slope for surfaces with greater hydrophilicity. The mass of blood plasma absorbed into the interfacial zone (blood plasma infiltration) was also promoted by the hydrophilic surfaces but it was rapid and non-time-dependent. There was no linear correlation between the fibrinogen infiltration rate and the blood plasma infiltration rate. These results suggest that hydrophilic implant surfaces promote both fibrinogen and blood plasma infiltration to their interface. However, the infiltration of the two components were not proportional, implying a selectively enhanced recruitment of fibrinogen by hydrophilic implant surfaces.

Daily Cisplatin and Weekly Docetaxel versus Weekly Cisplatin Intra-Arterial Chemoradiotherapy for Late T2-3 Tongue Cancer: A Pilot and Feasibility Trial.

Background and objectives: The aim of present study was to compare the treatment results of daily cisplatin (CDDP), weekly docetaxel (DOC) intra-arterial infusion chemotherapy combined with radiotherapy (DIACRT) regimen and weekly CDDP intra-arterial infusion chemotherapy combined with radiotherapy (WIACRT) for patients with tongue cancer. Materials and Methods: Between January 2007 and December 2016, a total of 11 patients treated with WIACRT and 45 patients treated with DIACRT were enrolled in the present study. In the DIACRT group, 25 patients had late T2, and 20 patients had T3. A total of nine patients had late T2 and two had T3 in WIACRT (p = NS). In DIACRT, the treatment schedule consisted of intra-arterial chemotherapy (DOC, total 60 mg/m²; CDDP, total 150 mg/m²) and daily concurrent radiotherapy (RT) (total, 60 Gy). In WIACRT, the treatment schedule consisted of intra-arterial chemotherapy (CDDP, total 360 mg/m²) and daily concurrent RT (total, 60 Gy). Results: The median follow-up periods for DIACRT and WIACRT were 61 and 66 months, respectively. The five-year local control (LC) and overall survival (OS) rate were 94.5% and 89.6% for the DIACRT group, and 60.6% and 63.6% for the WIACRT group, respectively. The LC rate and OS of the DIACRT group were significantly higher than those of the WIACRT group. As regards toxicities, no treatment-related deaths were observed during the follow-up periods in both groups. Conclusions: DIACRT was found to be feasible and effective for patients with tongue cancer and could become a new treatment modality.

[Assessing Patient Factors Influencing the Discontinuation of Opioids after Intra-Arterial Chemotherapy for Oral Cancer - A Retrospective Study].

Superselective intra-arterial chemoradiation therapy for oral cancer induces the complication of mucositis. Although the associated pain is controlled using opioids, major questions from patients in clinical practice are as follows:(1)the mean number of days from the completion of superselective intra-arterial chemoradiation therapy to the discontinuation of opioid administration, and(2)patient factors enabling the discontinuation of opioids. The purpose of this study was to clarify these points. A retrospective follow-up study was conducted from April 2016 to March 2017 on patients who underwent superselective intra-arterial chemoradiation therapy at our department of oral surgery. The patients were divided into 2 groups:one who discontinued opioids, and the other who did not. Clinical backgrounds and data were compared between the 2 groups. The mean number of days from the completion of superselective intra-arterial chemoradiation therapy to the discontinuation of opioid administration was 51±34.4 days. The absence of diabetes and deliria during treatment were determined as factors contributing to the discontinuation of opioids.

[Patient Factors Enabling the Decannulation of the Gastrostomy Tube after Superselective Intra-Arterial Chemoradiation Therapy for Locally Advanced Oral Cancer - A Retrospective Study].

Superselective intra-arterial chemoradiation therapy for locally advanced oral cancer induces complications such as mucositis, which impedes oral intake. Thus, at our hospital, a gastrostomy is performed in almost all patients during the treatment period to ensure the presence of an alternative administration route for nutrition and drugs. The purpose of this study was to calculate the mean number of days from completion of superselective intra-arterial chemoradiation therapy to the decannulation of gastrostomy, and extract patient factors for the decannulation. A retrospective follow-up study was conducted from April 2016 to March 2017 on patients who underwent superselective intra-arterial chemoradiation therapy at our department of oral surgery. The patients were divided into 2 groups:one who was decannulated and the other who did not. Clinical backgrounds and data were compared between the 2 groups. In the group with the decannulation, the mean period from treatment completion to the decannulation was 132±51.6 days. Heavy alcohol consumption, absence of haphalgesia before treatment, and possible securement of the opening with the breadth of 3 fingers, were determined as factors contributing to the decannulation of gastrostomy tube.

Computational fluid dynamics study of intra-arterial chemotherapy for oral cancer.

BACKGROUND: Intra-arterial chemotherapy (IAC) for oral cancer can deliver a higher concentration of anticancer agent into a tumor-feeding artery than intravenous systemic chemotherapy. However, distribution of anticancer agent into several branches of the external carotid artery (ECA) in IAC has not demonstrated sufficient treatment efficacy. To improve the effectiveness of IAC, the flow distribution of anticancer agent into the branches of the ECA in several IAC methods was investigated using computational fluid dynamics (CFD). METHODS: Patient-specific three-dimensional vessel models were created from CT images of 2 patients with tongue cancer. Catheter models were combined with the vessel models. Thirty-two models were generated with varying vertical and horizontal positions of the catheter tip. With the use of a zero-dimensional resistance model of the peripheral vessel network, conventional IAC and superselective IAC were simulated in 30 and 2 models, respectively. The flow distribution of anticancer agent into the branches of the ECA was investigated in 32 models. Additionally, the blood streamline was traced from the inlet of the common carotid artery toward each outlet to examine the flow of anticancer agent in all models, and the wall shear stress of the vessel was calculated for some models. RESULTS: The CFD simulations could be conducted within a reasonable computational time. In several models, the anticancer agent flowed into the target artery only when the catheter tip was located below the bifurcation of the ECA and each target artery. Furthermore, the anticancer agent tended to flow into the target artery when the catheter tip was shifted toward the target artery. In all ECA branches that had flow of anticancer agent, the blood streamlines to the target arteries contacted the catheter tip. Anticancer agent flowed into only the target artery in patients' models for superselective IAC. However, high wall shear stress was observed at the target artery in one patient's model. CONCLUSIONS: This CFD study showed that location of the catheter tip was important in controlling the anticancer agent in conventional IAC. The distribution rate of anticancer agent into the tumor-feeding artery tended to increase when the catheter tip was placed below and toward the target artery. Although superselective IAC can reliably supply anticancer agent to the target artery, high wall shear stress at the target artery can occur, depending on vessel geometry of the patient, which may cause serious complications during the treatment.

Investigation of blood flow in the external carotid artery and its branches with a new 0D peripheral model.

BACKGROUND: Patient-specific modelling in clinical studies requires a realistic simulation to be performed within a reasonable computational time. The aim of this study was to develop simple but realistic outflow boundary conditions for patient-specific blood flow simulation which can be used to clarify the distribution of the anticancer agent in intra-arterial chemotherapy for oral cancer. METHODS: In this study, the boundary conditions are expressed as a zero dimension (0D) resistance model of the peripheral vessel network based on the fractal characteristics of branching arteries combined with knowledge of the circulatory system and the energy minimization principle. This resistance model was applied to four patient-specific blood flow simulations at the region where the common carotid artery bifurcates into the internal and external carotid arteries. RESULTS: Results of these simulations with the proposed boundary conditions were compared with the results of ultrasound measurements for the same patients. The pressure was found to be within the physiological range. The difference in velocity in the superficial temporal artery results in an error of 5.21 ± 0.78 % between the numerical results and the measurement data. CONCLUSIONS: The proposed outflow boundary conditions, therefore, constitute a simple resistance-based model and can be used for performing accurate simulations with commercial fluid dynamics software.

Diameters of lingual, facial, and maxillary arteries measured according to an objective protocol on 3D computed tomography angiography images.

PURPOSE: Retrograde superselective intra-arterial chemoradiotherapy is a radical treatment for advanced oral cancer. The catheter tip is placed into tumor-feeding arteries-the lingual, facial, or maxillary arteries. The diameter of the tumor-feeding arteries newly bifurcated from the external carotid artery is crucial for determining the requirement of a catheter navigation system. This study aimed to measure the diameter and distribution of the tumor-feeding artery according to an objective protocol using 3D computed tomography angiography images reproducibly. METHODS: Angiographic data of 20 noncatheterized carotid arteriesof 10 randomly selected patients were analyzed. We followed the external carotid artery to the entrance of each feeding artery to determine the center point where the artery diameter was measured. The diameter of the optimum circle measured at the adopted center point was taken as the diameter of each tumor-feeding artery. RESULTS: The diameters (mean ± standard deviation) were 3.5 ± 0.45, 2.9 ± 0.56, and 3.5 ± 0.56 mm for the maxillary, lingual, and facial arteries, respectively. The diameters of the maxillary and facial arteries were similar (p = 0.877), whereas the diameter of the lingual artery was smaller than that of the maxillary and facial arteries (p < 0.001). CONCLUSION: The findings of this study will be beneficial in determining the need of a new catheter navigation system and diameter of catheters to be used in the clinical practice. From the viewpoint of measurement automation and reproducibility, 3DCTA vessel measurement taken according to the proposed protocol was considered to be effective.

EP4-induced mitochondrial localization and cell migration mediated by CALML6 in human oral squamous cell carcinoma.

Lymph node metastasis, primarily caused by the migration of oral squamous cell carcinoma (OSCC) cells, stands as a crucial prognostic marker. We have previously demonstrated that EP4, a subtype of the prostaglandin E2 (PGE2) receptor, orchestrates OSCC cell migration via Ca2+ signaling. The exact mechanisms by which EP4 influences cell migration through Ca2+ signaling, however, is unclear. Our study aims to clarify how EP4 controls OSCC cell migration through this pathway. We find that activating EP4 with an agonist (ONO-AE1-473) increased intracellular Ca2+ levels and the migration of human oral cancer cells (HSC-3), but not human gingival fibroblasts (HGnF). Further RNA sequencing linked EP4 to calmodulin-like protein 6 (CALML6), whose role remains undefined in OSCC. Through protein-protein interaction network analysis, a strong connection is identified between CALML6 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), with EP4 activation also boosting mitochondrial function. Overexpressing EP4 in HSC-3 cells increases experimental lung metastasis in mice, whereas inhibiting CaMKK2 with STO-609 markedly lowers these metastases. This positions CaMKK2 as a potential new target for treating OSCC metastasis. Our findings highlight CALML6 as a pivotal regulator in EP4-driven mitochondrial respiration, affecting cell migration and metastasis via the CaMKK2 pathway.