Potentiation of Anticancer Activity of G2/M Blockers by Mild Hyperthermia.

BACKGROUND/AIM: Hyperthermia (HT), combined with chemotherapy, has been used to treat various types of cancer. This study aimed to investigate the HT-sensitivity of malignant and non-malignant cells, and then evaluate the combination effect of docetaxel (DTX) and a newly synthesized chromone derivative (compound A) with HT. MATERIALS AND METHODS: The number of viable cells was determined using the MTT method. Cell cycle distribution was analyzed using a cell sorter, and DNA fragmentation pattern was detected using agarose gel electrophoresis. RESULTS: Among 12 cultured cells, oral squamous cell carcinoma (OSCC), especially Ca9-22 cells, and myelogenous leukemia cells showed higher sensitivity to HT than lung carcinoma and glioblastoma cell lines, while normal oral cells were the most resistant. Cytotoxicity of DTX on Ca9-22 cells was maximum at 41-42°C and 45~60 min exposure to HT. DXT, compound A, and HT induced G2/M arrest of Ca-22 cells. Mild HT enhanced the DTX- and compound A-induced subG1 arrest, in a synergistic fashion. CONCLUSION: The combination G2/M blockers and mild-HT can potentially be used for the treatment of OSCC.

Thermochemoradiotherapy Using Superselective Intra-arterial Infusion for Patients With Oral Cancer With Cervical Lymph Node Metastases.

AIM: We aimed to retrospectively investigate the outcomes and pathological effects of retrograde superselective intra-arterial chemoradiotherapy (IACRT) combined with hyperthermia on metastatic lymph nodes of patients with oral squamous cell carcinoma. PATIENTS AND METHODS: Patients with lymph node metastasis from oral cancer were treated with IACRT using cisplatin plus docetaxel combined with hyperthermia prior to surgical removal 8 weeks after completion of IACRT and hyperthermia. The locoregional control and overall survival rates were calculated using the Kaplan-Meier method. RESULTS: A total of 35 patients received the combination therapy of whom 26 received it as definitive treatment and in the rest, it was administered as preoperative treatment. The 5-year locoregional control and overall survivaI rates were 95.6% and 80.2% in the definitive-treatment group, and 100% and 66.6% in the preoperative-treatment group, respectively. CONCLUSION: The combination therapy provided good outcomes in patients with lymph node metastases from advanced oral cancer.

Retrograde superselective intra-arterial chemoradiotherapy combined with hyperthermia and cetuximab for carcinoma of the buccal mucosa with N3 lymph node metastasis: a case report.

We herein report a case of squamous cell carcinoma of the buccal mucosa with N3 cervical lymph node metastasis in a 63-year-old man. The patient was treated with combination therapy comprising radiotherapy (2 Gy/day, total of 70 Gy), superselective intra-arterial chemotherapy via a superficial temporal artery (docetaxel, total of 70 mg/m2 and cisplatin, total of 175 mg/m2), cetuximab (initial dose of 400 mg/m2 with subsequent weekly doses of 250 mg/m2 intravenously), and four sessions of hyperthermia for cervical lymph node metastases. The patient responded well to the therapy, with a complete response of the primary tumor. Radical neck dissection was performed with reconstructive surgery, including resection of the overlying skin. A pathologic complete response was achieved for the N3 and all other cervical lymph node metastases. The patient showed no evidence of recurrence in the 3 years following treatment. Based on the findings in the present case, the use of retrograde superselective intra-arterial chemoradiotherapy combined with hyperthermia and cetuximab seems to be a promising modality for patients with N3 cervical lymph node metastasis of oral cancer.

Implant Stability Development of Photofunctionalized Implants Placed in Regular and Complex Cases: A Case-Control Study.

PURPOSE: The objective of this study was to compare the rate of implant stability development of as-received and photofunctionalized dental implants in regular and complex cases. MATERIALS AND METHODS: Forty-nine implants (24 as-received and 25 photofunctionalized) placed in regular or complex cases (simultaneous guided bone regeneration, sinus elevation, or fresh extraction sockets) were studied. Photofunctionalization was performed by ultraviolet (UV) treatment of implants for 15 minutes using a photo device immediately prior to placement, and the generation of superhydrophilicity was confirmed. Implant stability was evaluated by measuring the implant stability quotient (ISQ) at placement (ISQ1) and at stage-two surgery (ISQ2). The rate of implant stability development was evaluated by calculating the osseointegration speed index (OSI), defined as the ISQ increase per month ([ISQ2-ISQ1]/healing time in months). The percentage of innate bone support at placement was evaluated clinically and radiographically. RESULTS: The average OSI was considerably greater for photofunctionalized implants (3.7 ± 2.9) than for as-received implants (0.0 ± 1.0). The OSI in complex cases was 4.2 ± 3.2 for photofunctionalized implants and 0.2 ± 0.9 for as-received implants. The OSI in cases with simultaneous sinus elevation was 5.5 ± 3.5 for photofunctionalized implants and 0.2 ± 1.1 for as-received implants. Photofunctionalized implants showed significantly higher ISQ2 values than as-received implants. Photofunctionalized implant ISQ2 values were greater than 60, regardless of primary stability and innate bone support at placement. In multivariate analysis including the effects of photofunctionalization, age and sex of patients, and diameter and length of implants, photofunctionalization showed the strongest influence on the OSI for both regular and complex cases, while other factors influenced the OSI only in certain conditions. CONCLUSION: Photofunctionalization accelerated the rate and enhanced the final level of implant stability development compared with as-received implants, particularly for implants placed into poor-quality bone and other complex cases. Photofunctionalization was a stronger determinant of implant stability than all the other tested implant- and host-related factors.

Simultaneous hyperthermia-chemotherapy with controlled drug delivery using single-drug nanoparticles.

We previously investigated the utility of µ-oxo N,N'- bis(salicylidene)ethylenediamine iron (Fe(Salen)) nanoparticles as a new anti-cancer agent for magnet-guided delivery with anti-cancer activity. Fe(Salen) nanoparticles should rapidly heat up in an alternating magnetic field (AMF), and we hypothesized that these single-drug nanoparticles would be effective for combined hyperthermia-chemotherapy. Conventional hyperthermic particles are usually made of iron oxide, and thus cannot exhibit anti-cancer activity in the absence of an AMF. We found that Fe(Salen) nanoparticles induced apoptosis in cultured cancer cells, and that AMF exposure enhanced the apoptotic effect. Therefore, we evaluated the combined three-fold strategy, i.e., chemotherapy with Fe(Salen) nanoparticles, magnetically guided delivery of the nanoparticles to the tumor, and AMF-induced heating of the nanoparticles to induce local hyperthermia, in a rabbit model of tongue cancer. Intravenous administration of Fe(Salen) nanoparticles per se inhibited tumor growth before the other two modalities were applied. This inhibition was enhanced when a magnet was used to accumulate Fe(Salen) nanoparticles at the tongue. When an AMF was further applied (magnet-guided chemotherapy plus hyperthermia), the tumor masses were dramatically reduced. These results indicate that our strategy of combined hyperthermia-chemotherapy using Fe(Salen) nanoparticles specifically delivered with magnetic guidance represents a powerful new approach for cancer treatment.

U-shaped Osteotomy Around the Descending Palatine Artery to Prevent Posterior Osseous Interference for Superior/Posterior Repositioning of the Maxilla in Le Fort I Osteotomy.

In maxillary orthognathic surgery, superior repositioning of the maxilla is sometimes difficult, and removal of bony interference, especially around the descending palatine artery (DPA), is very time-consuming in cases of severe maxillary impaction. Posterior repositioning of the maxilla for removal of bony interference between the posterior maxilla and the pterygoid process is also technically difficult. Because the most common site of hemorrhage in Le Fort I osteotomy is the posterior maxilla, this bone removal is a source of frustration for surgeons in DPA injury. When the DPA is injured during bone removal and ligation is performed, aseptic necrosis of the maxilla may occur. Therefore, a simple and safe method for maxillary superior/posterior repositioning is required to remove osseous interference around the DPA. The authors describe here U-shaped osteotomy around the DPA to prevent posterior osseous interference for superior/posterior repositioning of the maxilla in Le Fort I osteotomy.

Hyperthermia generated with ferucarbotran (Resovist®) in an alternating magnetic field enhances cisplatin-induced apoptosis of cultured human oral cancer cells.

Hyperthermia is a promising anti-cancer treatment in which the tissue temperature is increased to 42-45 °C, and which is often used in combination with chemotherapy or radiation therapy. Our aim in the present work was to examine the feasibility of combination therapy for oral cancer with cisplatin and hyperthermia generated with ferucarbotran (Resovist(®); superparamagnetic iron oxide) in an alternating magnetic field (AMF). First, we established that administration of ferucarbotran at the approved dosage for magnetic resonance imaging provides an iron concentration sufficient to increase the temperature to 42.5 °C upon exposure to AMF. Then, we examined the effect of cisplatin combined with ferucarbotran/AMF-induced hyperthermia on cultured human oral cancer cells (HSC-3 and OSC-19). Cisplatin alone induced apoptosis of cancer cells in a dose-dependent manner, as is well known. However, the combination of cisplatin with ferucarbotran/AMF was significantly more effective than cisplatin alone. This result suggests that it might be possible to reduce the clinically effective dosage of cisplatin by administering it in combination with ferucarbotran/AMF-induced hyperthermia, thereby potentially reducing the incidence of serious cisplatin-related side effects. Further work seems justified to evaluate simultaneous thermo-chemotherapy as a new approach to anticancer therapy.

Thermochemoradiation therapy using superselective intra-arterial infusion via superficial temporal and occipital arteries for oral cancer with N3 cervical lymph node metastases.

PURPOSE: To evaluate the therapeutic results and histopathological effects of treatment with thermochemoradiation therapy using superselective intra-arterial infusion via the superficial temporal and occipital arteries for N3 cervical lymph node metastases of advanced oral cancer. METHODS AND MATERIALS: Between April 2005 and September 2010, 9 patients with N3 cervical lymph node metastases of oral squamous cell carcinoma underwent thermochemoradiation therapy using superselective intra-arterial infusion with docetaxel (DOC) and cisplatin (CDDP). Treatment consisted of hyperthermia (2-8 sessions), superselective intra-arterial infusions (DOC, total 40-60 mg/m(2); CDDP, total 100-150 mg/m(2)) and daily concurrent radiation therapy (total, 40-60 Gy) for 4-6 weeks. RESULTS: Six of 9 patients underwent neck dissection 5-8 weeks after treatment. In four of these 6 patients, all metastatic lymph nodes, including those at N3, were grade 3 (non-viable tumor cells present) or grade 4 (no tumor cells present) tumors, as classified by the system by Shimosato et al (Shimosato et al Jpn J Clin Oncol 1971;1:19-35). In 2 of these 6 patients, the metastatic lymph nodes were grade 2b (destruction of tumor structures with a small amount of residual viable tumor cells). The other 3 patients did not undergo neck dissection due to distant metastasis after completion of thermochemoradiation therapy (n=2) and refusal (n=1). The patient who refused neck dissection underwent biopsy of the N3 lymph node and primary sites and showed grade 3 cancer. During follow-up, 5 patients were alive without disease, and 4 patients died due to pulmonary metastasis (n=3) and noncancer-related causes (n=1). Five-year survival and locoregional control rates were 51% and 88%, respectively. CONCLUSIONS: Thermochemoradiation therapy using intra-arterial infusion provided good histopathologic effects and locoregional control rates in patients with N3 metastatic lymph nodes. However, patients with N3 metastatic lymph nodes experienced a high rate of distant metastases.

Hydroxyapatite coating for titanium fibre mesh scaffold enhances osteoblast activity and bone tissue formation.

This study investigated the bone regeneration properties of titanium fibre mesh as a tissue engineering material. A thin hydroxyapatite (HA) coating on the titanium fibre web was created using the developed molecular precursor method without losing the complex interior structure. HA-coated titanium fibre mesh showed apatite crystal formation in vitro in a human osteoblast culture. Titanium fibre mesh discs with or without a thin HA coating were implanted into rat cranial bone defects, and the animals were killed at 2 and 4 weeks. The in vivo experience revealed that the amount of newly formed bone was significantly higher in the HA-coated titanium fibre mesh than in the non-coated titanium fibre mesh 2 weeks after implantation. These results suggest that thin HA coating enhances osteoblast activity and bone regeneration in the titanium fibre mesh scaffold. Thin HA-coating improved the ability of titanium fibre mesh to act as a bone regeneration scaffold.

Optimization of hyperthermia and dendritic cell immunotherapy for squamous cell carcinoma.

The aims of this study were to explore the feasibility of a novel combination therapy comprising hyperthermia (HT) and dendritic cell (DC) application for squamous cell carcinoma (SCC), and to optimize the conditions of this therapy. In vitro, the correlation between maturation of DCs by co-culture with SCCVII cells and HT was investigated. DCs did not mature in simple HT (43 °C for 30 min) with SCCVII cells. On the other hand, DC maturation occurred in additional mild HT (mHT: 41 °C for 30 min) with simple HT. To assess whether additional mHT was effective, in vivo combined treatment was performed using tumor-bearing C3H/HeJ mice. A more suppressive effect of tumor growth was observed, and cytotoxic T cell infiltration was significantly increased by adding mHT compared to conventional only simple HT with DCs. These phenomena also occurred in non-treated contralateral tumors as well as treated ones. Our data suggest that the combination of 43 °C preheated simple HT SCCVII tumors and additional 41 °C heat mHT promotes DC maturation, resulting in suppression of tumor growth systemically and lifetime prolongation in mice. A three-step process of additional mHT after local HT and intratumoral immature DC (iDC) injection could be a more effective and novel method for the treatment of SCC.

Experimental study of a novel thermotherapy for hepatocellular carcinoma using a magnesium ferrite complex powder that produces heat under a magnetic field.

BACKGROUND/AIMS: The anti-cancerous effect on hepatocellular carcinoma of a newly established form of thermotherapy, which uses an implant heating system, was evaluated. As a new material for application in hyperthermia, the authors developed a powder type Mg-ferrite complex that produces heat under a relatively low-power magnetic field. METHODOLOGY: This material suspended in Lipiodol was injected into tumors on the backs of mice that consisted of human hepatocellular carcinoma cells. Hyperthermia was performed by directing a magnetic charge on tumor-bearing mice that contained the Mg-ferrite complex. The temperature of the tumor was kept at 42-43 degrees C, while the magnetic field power ranged from 50 to 80G. RESULTS: A 10-min hyperthermia treatment was insufficiently effective against tumor growth. Systemic injection of doxorubicin (ADM) before hyperthermia appeared to enhance the anti-cancerous effect, but the difference was little and did not reach a statistically significant level (repeated measure analysis of variance). The anticancerous effect of hyperthermia for 15 minutes, in contrast, was marked. The nodules had almost completely disappeared by the end of the experiment. CONCLUSIONS: In conclusion, it is suggested that hyperthermotherapy using this newly developed Mg-ferrite complex might become an option for low-invasive therapy for advanced hepatocellular carcinoma in humans.

Selective hyperthermia using magnetoliposomes to target cervical lymph node metastasis in a rabbit tongue tumor model.

The effect of hyperthermia on cervical lymph node metastasis of VX7 tongue cancer in female Japanese white rabbits was investigated. Magnetoliposomes (MLs) with a neutral surface charge and a size of 94.1 nm were used as heating mediators. MLs were injected into the tongue 20 days after tumor transplantation, and we examined whether they reached the metastatic deep cervical lymph node. The highest magnetite concentration 24 h after ML injection was detected in the lymph node, followed by tongue, spleen, blood, and liver. Rabbits were separated into three groups: group I as the control; group II with ML injection alone; and group III with ML injection and hyperthermia 24 h after ML injection, generated by applying an alternating magnetic field (118 kHz, 384 Oe) to the neck region. The hyperthermic effect was evaluated in terms of the percentage of necrosis in proportion to the metastatic tumor and the apoptotic index (AI), defined as the ratio of TUNEL-positive cells. The temperature of lymph nodes in group III reached over 44 degrees C. The mean area of necrosis in group III was 58.0%, which was significantly higher than that in group I (19.6%) or group II (20.4%). The AI in group III was 22.9%, significantly higher than in group I (1.67%) or II (1.42%). The difference between group I and II was not statistically significant. Group III tumor sites around MLs showed necrosis or apoptosis-positive cells induced by hyperthermia. These results indicate that MLs injected into the tongue can target cervical lymph node metastases and accumulate there at concentrations sufficient to generate therapeutically effective temperatures.

Prognostic evaluation of preoperative thermochemoradiotherapy for N(3) cervical lymph node metastases of oral cancer.

OBJECTIVE: The purpose of this study was to evaluate the clinical efficacy, histopathological efficacy, and response to preoperative thermochemoradiotherapy for N(3) cervical lymph node metastases of oral cancer. METHODS: Preoperative thermochemoradiotherapy was performed in 8 patients with oral cancer and N(3) cervical lymph node metastasis. These patients underwent four-weekly sessions of hyperthermia, combined with radiotherapy (40 Gy) as well as chemotherapy with cisplatin (CDDP; 100 mg/m2), all prior to surgery. Radical neck dissection was performed 4 weeks after completion of preoperative thermochemoradiotherapy. RESULTS: The preoperative treatment of cervical lymph node metastases yielded a partial response in 6 patients, while 2 patients demonstrated no change. Histopathologically, grade III was detected in 1, grade IIb in 4 and grade IIa in 3 patients after surgery, according to the criteria of Shimosato. The follow-up period ranged from 13 to 64 months (mean 34). Of the 8 patients, 2 died (1 of lymph node metastasis and 1 had metastasis to a distant site), and 6 patients were alive at the last follow-up, with the longest postoperative disease-free survival being 63 months. The 5-year cumulative survival rate was 70.0%. CONCLUSION: These results indicate that preoperative thermochemoradiotherapy is a promising modality for patients with N(3) cervical lymph node metastasis of oral cancer.