Boron neutron capture therapy using cyclotron-based epithermal neutron source and borofalan (10B) for recurrent or locally advanced head and neck cancer (JHN002): An open-label phase II trial.

BACKGROUND AND PURPOSE: Boron neutron capture therapy (BNCT) can be performed without reactors due to development of cyclotron-based epithermal neutron source (C-BENS), which is optimized for treatment for deeper-seated tumors. The purpose of this study was to evaluate efficacy and safety of cyclotron-based BNCT with borofalan (10B) for recurrent or locally advanced head and neck cancer. MATERIALS AND METHODS: In this open-label, phase II JHN002 trial of BNCT using C-BENS with borofalan (10B), patients with recurrent squamous cell carcinoma (R-SCC) or with recurrent/locally advanced non-squamous cell carcinoma (R/LA-nSCC) of the head and neck were intravenously administered 400 mg/kg borofalan (10B), followed by neutron irradiation. The tumor dose was determined passively as the mucosal maximum dose of 12 Gy-Eq. The primary endpoint was the objective response rate (ORR). Post-trial observational JHN002 Look Up study was planned for evaluating locoregional progression-free survival (LRPFS). RESULTS: Eight R-SCC and 13 R/LA-nSCC patients were enrolled. All R-SCC patients had prior radiotherapy with a median dose of 65.5 Gy (range, 59.4-76.0 Gy). The ORR for all patients was 71%, and complete response/partial response were 50%/25% in R-SCC and 8%/62% in R/LA-nSCC. The 2-year overall survival for R-SCC and R/LA-nSCC were 58% and 100%, respectively. The median LRPFS was 11.5 months for R-SCC. Frequently observed adverse events included alopecia (95%), hyperamylasemia (86%), and nausea (81%). CONCLUSION: These data suggest that BNCT using C-BENS with borofalan (10B) is a promising treatment option for patients with R-SCC or R/LA-nSCC of the head and neck.

Proton Beam Therapy in Combination with Intra-Arterial Infusion Chemotherapy for T4 Squamous Cell Carcinoma of the Maxillary Gingiva.

This study aimed to evaluate the therapeutic effect and toxicity of proton beam therapy in combination with intra-arterial infusion chemotherapy in patients with squamous cell carcinoma of the maxillary gingiva. Between December 2010 and March 2016, 30 patients with T4 squamous cell carcinoma of the maxillary gingiva were treated with radiotherapy and retrograde intra-arterial infusion chemotherapy using cisplatin (20⁻40 mg/m², 4⁻6 times). Radiotherapy was basically administered using boost proton beam therapy for primary tumor and neck lymph node tumors, following 36⁻40 Gy photon radiation therapy delivered to the prophylactic area, to a total dose of 70.4⁻74.8 Gy. The median follow-up was 33 months. The 3-year local control and overall survival rates were 69% and 59%, respectively. Major grade 3 or higher acute toxicities included mucositis, neutropenia, and dermatitis in 12 (40%), 5 (17%), and 3 (10%) patients, respectively. No grade 3 or higher late toxicities were observed. These results suggested that proton beam therapy in combination with intra-arterial infusion chemotherapy was not inferior to other treatment protocols and should be considered as a safe and effective option in patients with T4 squamous cell carcinoma of the maxillary gingiva.

Clinical results of proton beam therapy for hepatocellular carcinoma over 5 cm.

AIM: This study aimed to evaluate the safety and efficacy of proton beam therapy for large hepatocellular carcinoma (HCC). METHODS: Twenty-four patients with a HCC larger than 5.0 cm were treated with proton beam therapy at our institution between 2008 and 2015. RESULTS: The clinical stage was I in 2 patients, II in 9 patients, and IIIB in 13 patients. Ten of the 24 patients were not surgical candidates because of advanced HCC or old age. Median tumor size was 90 mm (range, 50-180 mm). Median total dose delivered was 72.6 Gray-equivalents (GyE) in 22 fractions (range, 60.8-85.8 GyE). Median follow-up period was 17.5 months (range, 3-70 months). Local control rate at 2 years was 87.0%. The 2-year overall survival rate was 52.4%. The predominant tumor progression pattern was new hepatic tumor development outside the irradiated field. No acute or late treatment-related toxicity of grade 3 or higher, other than dermatitis, was observed. CONCLUSIONS: These results show that proton beam therapy offers an effective and safe method for treating patients with large HCC. Proton beam therapy represents a promising method for treatment of large-volume HCC.

Sphingosine 1-phosphate acts as a signal molecule in ceramide signal transduction of TNF-alpha-induced activator protein-1 in osteoblastic cell line MC3T3-E1 cells.

We previously demonstrated that tumor necrosis factor (TNF)-alpha stimulated the production of activation protein (AP)-1, a transcriptional factor, in mouse osteoblastic MC3T3-E1 cells. Recent studies have shown the importance of ceramide and its metabolites as signal molecules for TNF-alpha-induced gene expression in several cell types. Therefore, our interest was to investigate whether sphingosine metabolites are involved in TNF-alpha-induced signaling in MC3T3-E1 cells. DL-threo-1-phenyl-2-hexadecanoyl-amino-3-pyrrolidino-1-propanol (PPPP), which causes accumulation of intracellular ceramide, stimulated the TNF-alpha-induced expression of the c-fos and c-jun genes. Gel shift assay clearly showed that PPPP increased the cytokine-induced specific binding of nuclear proteins to the 12-tetra-decanoyl phorbol 13-acetate-responsive element (TRE), a consensus sequence for AP-1. In addition, cell-permeable ceramide (N-acetylsphingosine, N-hexanoylsphingosine or N-octanoylsphingosine) stimulated expression of the c-fos and c-jun genes and nuclear protein binding to TRE. Interestingly, DL-threo-dihydrosphingosine (DHS), an inhibitor of sphingosine kinase, clearly blocked the ceramide analogue-induced stimulation. Sphingosine 1-phosphate (SPP) actually induced expression of these oncogenes and activated AP-1. Although TNF-alpha stimulated the AP-1-mediated expression of the monocyte chemoattractant JE/MCP-1, this stimulation was inhibited by DHS. SPP also stimulated JE/MCP-1 gene expression. The present study thus suggests that SPP acts as a signal molecule in ceramide-dependent signal transduction in TNF-alpha-induced AP-1 in osteoblastic MC3T3-E1 cells.