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Introduction: Lymph node metastasis caused by migration of oral cancer cells is an important prognostic factor. We previously reported that EP4, a prostaglandin E2 (PGE2) receptor, regulates the cell migration in oral cancer cells via Ca2+ signaling. However, how Ca2+ signaling regulates cell migration remains unclear. The intracellular Ca2+ regulates a variety of signaling pathways, either directly or by forming complexes with proteins such as calmodulin (CaM), and then phosphorylates calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Furthermore, Ca2+ signaling is directly or indirectly involved in cancer cell proliferation and migration. Therefore, we hypothesized that EP4 regulates the cell migration via CaMKK2 and its downstream signaling in oral cancer. Materials and Methods: Human gingival fibroblasts, HGnF and Human tongue squamous cell carcinoma cell lines, HSC-3 were used. EP4 agonist (ONO-AE1-437) and CaMKK2 inhibitor (STO-609) were used. HSC-3 cells were transduced with CaMKK2 shRNA, and scramble control shRNA using lentivirus. The protein expressions were evaluated by western blotting. The intracellular calcium concentrations were measured using Fura-2, the Fluorescent Ca2+ Indicator. The cell migration ability was evaluated by scratch assay. Immunocytochemistry was performed to evaluate the lamellipodium. The mRNA transcriptions of the mitochondrial associated genes were evaluated by real-time qPCR. The intracellular adenosine triphosphate (ATP) production and the reactive oxygen species (ROS) production were also evaluated by luciferase activity assay and DCFH-DA staining. Results: EP4 protein expression of HSC-3 cells was higher than that of HGnF cells (n=4, p Conclusion: EP4/CaMKK2/AMPK pathway is a novel signal transduction in oral cancer and may be a new target for oral cancer therapy. Citation Format: Soichiro Ishikawa, Masanari Umemura, Rina Nakakaji, Akane Nagasako, Kagemichi Nagao, Yuto Mizuno, Fumina Suzuki, Kohei Osawa, Mitomu Kioi, Kenji Mitsudo, Yoshihiro Ishikawa. EP4 promoted cell migration via mitochondrial biogenesis in oral cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3619.

Background: It is not well-known that contralateral vertebral artery dissecting aneurysms (VADA) may be newly revealed after parental artery occlusion for unilateral VADA. However, the optimal treatment strategies and perioperative management have not been established. In this report, we present the case of a patient who required reconstructive embolization in the subacute stage for contralateral VADA developed after endovascular internal trapping of the ruptured VADA. Case Description: A 61-year-old man developed subsequent disturbance of consciousness. Head CT showed a diffuse and symmetrical SAH. 3DCT revealed a fusiform aneurysm of the left intracranial vertebral artery with bleb formation. We performed emergency endovascular parent artery occlusion of the left vertebral artery. A digital subtraction angiography on postoperative day 16 showed continued occlusion of the left VA, and a fusiform aneurysm was noted at the right VA. We performed reconstructive embolization and the patient eventually recovered with minimal persistent symptoms. Conclusion: Since the outcomes of contralateral VAD complicated by infarction or hemorrhage are poor, and most cases develop within 7–14 days after endovascular internal trapping for unilateral VAD, performing bilateral radiographic reinspection within this time frame is recommended for early detection and preventive treatment of possible contralateral VADs.

Cerebral bypass surgery, such as the superficial temporal artery-middle cerebral artery bypass, is one of the essential procedures for cerebral revascularization. However, very narrow or thin blood vessels will increase the risk of anastomotic problems, such as occurs in Moyamoya disease. For such vessels, we have devised a "lifting method" in the recipient arteriotomy. In the present study, we have introduced this novel optional technique and evaluated its effects.The lifting method is a procedure of lifting the incision edge of a linear incision on the recipient vessel to widen the ostium. We attempted the lifting method in 23 consecutive patients (41 arteries) and, as a historical control, compared the results with those from the conventional method in 25 consecutive patients (37 arteries) for the previous 3 years. We compared patient age, years of surgical experience, recipient vessel diameter, anastomotic events, and final patency. As a subanalysis, the same evaluations were performed separately for patients with Moyamoya disease. Furthermore, the time required for the lifting procedure was measured retrospectively.The incidence of anastomotic events with the conventional method was 13.5% overall and 19% in those with Moyamoya disease. No adverse events occurred with the lifting method (P0.05). No statistically significant differences were found for the other factors, including final patency between the 2 groups. The time required for the lifting procedure averaged 1 minute, 15 seconds.Use of the lifting method widens and secures the ostium in a recipient vessel and greatly facilitates operability. We have found it to be a foolproof method enabling safe and reliable anastomosis even with narrow or thin vessels.

Primary central nervous system lymphoma(PCNSL)is a primary brain tumor, which appears commonly and occupies around 4.6% of all primary brain tumors. The standard therapy for this tumor is high-dose methotrexate chemotherapy(HD-MTX)and whole-brain irradiation. No salvage therapies for HD-MTX therapy-refractory or recurrent PCNSLs have been standardized. In our institution, ESHAP therapy(high-dose cytarabine:2,000mg, cisplatin:25mg/mWe administered ESHAP therapy as secondary chemotherapy for patients with refractory/recurrent PCNSL after HD-MTX therapy. Patients with PCNSL who were diagnosed and treated at our institute since 1996 were retrospectively studied. Clinical evaluations were performed based on Karnofsky Performance Status and overall survival, and the effect of ESHAP therapy was evaluated using the Response Assessment in Neuro-Oncology criteria.The number of patients with refractory/recurrent PCNSLs were 18(28-77 years of age, median age of 58.5 years). The response rate(RR)after the first course of salvage ESHAP therapy was 77.8%(14 cases), and complete response(CR)was achieved in 6 cases. The RR after the final course of ESHAP therapy was as high as 61.1%(11 cases), and 4 patients retained CR status. In patients with refractory PCNSL who were treated with HD-MTX, the RR in the final course of salvage ESHAP therapy was as high as 77.8%(7 cases), and 3 patients retained CR status during the periods. The occurrence rate of Grade 3 or higher adverse events, according to the Common Terminology Criteria for Adverse Events version 4.0, was 66.7%(12 cases);all events that were associated with blood and lymphatic system disorders were quickly alleviated, and no fatal adverse events occurred.In this study, we retrospectively examined the efficacy of ESHAP therapy as a secondary chemotherapy for patients with refractory/recurrent PCNSL after receiving HD-MTX therapy. Based on our findings, we suggest that ESHAP therapy should be considered as an encouraging secondary chemotherapy for patients with refractory/recurrent PCNSL.