Dysfunctions and cosmetic disturbance after surgery for oral cancer are major problem. I focused hyperthermia as non-invasive therapy for oral cancer. Magnetic induction interstitial hyperthermia using ferromagnetic implant needle (Implant heating system: IHS) has been developed, and the antitumor effectiveness was studied experimentally and clinically for tongue cancer. The effectiveness of hyperthermia tended to extend gradually toward the peripheral side of the tongue tumor inoculated VX7. Eight patients with primary cancer of the oral cavity were treated using hyperthermia combined with chemotherapy. As a result, the thermal distribution was good, and complete response was observed in all patients.
The antitumor effectiveness of interstitial hyperthermia using magnetic liposomes was studied experimentally. The primary tongue tumor was disappeared due to good thermal distribution. Magnetic liposomes were delivered selectively to the cervical lymph node metastasis. Then, necrosis and apoptosis were observed in the cervical lymph node metastasis under alternating magnetic field. Ferucarbotran of existing drugs was heated under alternating magnetic field. Combination of cisplatin with ferucarbotran under alternating magnetic field induced apoptosis of cancer cells more effectively than cisplatin alone with significant differences. A new anti-cancer agent for magnet-guided delivery with anti-cancer activity (Fe (Salen)) was studied experimentally in terms of antitumor effectiveness. Fe (Salen) alone inhibited the growth of tongue tumor. The heat was confirmed in Fe (Salen) under alternating magnetic field, and tongue tumor was disappeared with interstitial hyperthermia using Fe (Salen).
The combined therapy with superselective intra-arterial chemoradiotherapy and RF hyperthermia was effective therapy for advanced oral cancer with cervical lymph node metastasis (N3). This therapy is promising as a new strategy of non-invasive therapy for advanced oral cancer.

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Radio-hyperthermo-chemotherapy (RHC), which combines radiotherapy, hyperthermia, and chemotherapy, for malignant soft-tissue tumors was introduced with the aim of decreasing local recurrence after surgery. We performed various experiments to apply this trimodal therapy to soft-tissue sarcomas, and herein review progress at our institution.
In vitro application of hyperthermia (42-43°C) resulted in apoptosis and selectively decreased the number of cells in the G1 phase, which are thought to exhibit radioresistance. Moreover, simultaneous administration of hyperthermia (42°C) with cisplatin increased the concentration of the anti-tumor agent within the cells, resulting in significant inhibition of DNA synthesis. These findings reinforced the synergic effects of hyperthermia and chemotherapy/radiotherapy.
We began using RHC combination therapy for highly malignant soft-tissue tumors in the early 1990s. Between 1990-1999, we treated 44 patients (21 cases of undifferentiated pleomorphic sarcoma; 7 cases of high grade lipoasarcoma; among others). The local control rate was 97.6% (29 cases were marginal resection; 5 cases were intralesional resection).
Regarding histological analysis, we reviewed 20 cases from 2004-2013. Total necrosis occurred in 15% of patients, while 30% of patients were considered to exhibit over 90% necrosis, and 45% of patients exhibited 50-90% necrosis.
Moreover, we performed a matched control analysis with a nationwide database to yield more objective evidence by eliminating selective bias. Overall survival at 5 years was 81.2% and 79.3% in the RHC and database groups, respectively (p=0.52). There was a significant difference in local control rate at 5 years between the two groups (97.3% vs. 87.1% in the RHC and database groups, respectively; p=0.04), despite patients in the RHC group undergoing surgery with closer margins.
Thus, RHC neoadjuvant therapy inhibits local recurrence, demonstrating a new strategy for treating soft-tissue sarcoma following less invasive surgery, potentially resulting in limb preservation and averting amputation.

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Hikeshi is a protein that mediates the heat stress-induced nuclear import of heat shock protein 70 (HSP70: HSPA1 and HSPA8). Dysfunction of Hikeshi in humans can cause serious hereditary diseases, but the cellular function of Hikeshi is not fully understood. Previously, we reported that depletion of Hikeshi resulted in different effects in two human cell lines following proteotoxic stress. Depletion of Hikeshi reduced the survival of HeLa cancer cells after proteotoxic stress. However, Hikeshi-knockout (KO) hTERT-RPE1 cells, immortalized with telomerase reverse transcriptase, acquired resistance against proteotoxic stress, which was accompanied by increased p21 (WAF1/CIP1, CDKN1A) expression. p21 is a cell-cycle inhibitor and a direct p53-regulated target gene. Here, we investigated the effect of Hikeshi depletion and inhibition of HSP70 molecular chaperone function on cellular signaling in HeLa and hTERT-RPE1 cells. Functional modulation of HSP70 with the inhibitor YM-1 caused cell death in the HeLa cells but resulted in growth arrest of the hTERT-RPE1 cells. Further, YM-1 treatment dramatically up-regulated p53 and p21 proteins in hTERT-RPE1 cells and down-regulated FoxM1 and survivin, which are regulators of cell cycle progression, in both hTERT-RPE1 cells and HeLa cells. Our results showed that regardless of the presence or absence of Hikeshi, the p53-p21 pathway becomes active when hTERT-RPE1 non-cancer cells are treated with YM-1, which contributes to protection against cell death. Hikeshi might function as an upstream regulator of HSP70, which affects activation of the p53-p21 pathway, especially during and after proteotoxic stress.

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