Toshifumi Nakajima

Deep-heating characteristics of an RF capacitive heating device

An RF capacitive heating device was constructed and its deep-heating characteristics were studied using three mini-pigs. The deep-heating ability of RF capacitive heating was found to be improved by enlarging the electrodes, driving at 8 MHz, cooling the skin under the electrodes, inserting a bolus between the body and the electrodes and considering the anatomical structure of the body. The heating characteristics obtained were as follows. When applicators were placed on both sides of the abdomen of a mini-pig, 7 mm in fat layer thickness and 23 cm in lateral chest thickness, the increase in temperature of the deep part was greater than that of the fat layer. When applicators were placed on the posterior and anterior abdomen, overheating was noted in the fat and muscle near the back. The temperature was highest in a mock tumour, made by blocking blood flow to the spleen. The bio-heat equation revealed that RF capacitive heating accompanied by surface cooling at 10 degrees C could heat the deep portion of the body to 42 degrees C without excessive heating of a 1.6 cm thick fat layer.

Intraarterial infusion chemotherapy and radiotherapy with or without surgery for patients with locally advanced or recurrent breast cancer.

We analyzed response, side effects, and local control rates of a multimodal treatment consisting of intraarterial infusion chemotherapy (IAIC) and radiotherapy with or without surgery for patients with locally advanced or recurred breast cancer. Thirty-three patients, clinically diagnosed as stage IIB in 1, IIIA in 2, IIIB in 12, IV in 18, were treated from 1991 to 1998. Twenty-five were primary and eight were recurrent cases after surgery. IAIC started as initial treatment up to three times maximum. In most cases, doxorubicin 50 mg, cisplatin 50 mg, and mitomycin 10 mg were infused in the subclavian and/or internal mammary artery. After IAIC, patients in primary cases underwent radical mastectomy or breast conservation surgery, after radiotherapy at a total dose of 50 Gy/25 fractions/5 weeks with a boost of 10 Gy. In recurrent cases, a full dose of radiotherapy was delivered. Clinical objective and complete response rates were 78% and 9% after IAIC. Despite a high rate of residual positive margin (67%) or clinically residual carcinoma, local recurrence developed only in 2 patients (6%) and local control rates at 5 years were calculated as 89%. Bone marrow suppression was frequent, and skin vesiculation (15%) and ulceration (9%) were experienced after IAIC. Skin ulcer (6%), brachial plexus neuropathy (3%), and radiation pneumonitis (3%) occurred as late toxicity. IAIC was effective as an induction treatment and radiotherapy played a role of local control for patients with locally advanced or recurrent breast cancer.

Studies on in vitro effect of free fatty acids on water content and osmotic fragility of rabbit (lepus cuniculus) erythrocytes

The effects of free fatty acids in the blood on osmotic fragility and water content of erythrocytes when combined with hyperthermia were investigated. The isotonic buffer, containing the fatty acid, was added to the erythrocyte suspension to a final concentration of 200 microM/L. The samples were kept for one hour in an incubator at 37 degrees C or 42 degrees C. The osmotic fragility of erythrocytes was determined by coil planet centrifuge system and intracellular water content was measured by gas-liquid chromatography. A high concentration of unsaturated fatty acid and hyperthermia caused the increase in intracellular water and the decrease in osmotic resistance of the red blood cells compared to saturated fatty acid and the control. The present experiment demonstrated that unsaturated fatty acid was one of the principal chemical and metabolic factors which caused sports anemia.

Comparison of dosimetric parameters and acute toxicity after whole-pelvic vs prostate-only volumetric-modulated arc therapy with daily image guidance for prostate cancer.

OBJECTIVE To compare dosimetric parameters and acute toxicity rates between whole-pelvic (WP) and prostate-only (PO) volumetric-modulated arc therapy (VMAT) in patients with localized prostate cancer. METHODS A total of 224 consecutive patients treated with definitive VMAT to 78 Gy in 39 fractions were enrolled. Of these, 119 patients received initial WP VMAT at 46.8 Gy in 26 fractions using a simultaneous integrated boost technique, and 105 patients received PO VMAT. Image-guided radiotherapy was practised with daily cone beam CT. RESULTS The mean rectal dose, the rectal volume receiving ≥30 Gy (V30Gy), rectal V50Gy, the mean bladder dose, bladder V30Gy and bladder V50Gy were significantly increased in the WP group (p < 0.05 each); however, the rectal V70Gy did not differ between groups (p = 0.101), and the bladder V70Gy was significantly lower in the WP group (p = 0.029). The WP group experienced a significantly increased frequency of acute grade 2 diarrhoea relative to the PO group (5.9% vs 0%; p = 0.015). No differences were seen between the WP and PO groups in terms of acute grade 2 proctitis (10.1% vs 6.7%; p = 0.360) and genitourinary (GU) toxicity (12.6% vs 10.5%; p = 0.620). CONCLUSION Despite larger rectum and bladder volumes at low- and medium-dose levels, WP VMAT resulted in no significant increase in acute proctitis or GU toxicity when compared with PO VMAT. ADVANCES IN KNOWLEDGE This study demonstrates that whole-pelvic radiotherapy has comparable acute toxicity to those observed with prostate-only radiotherapy when VMAT with daily image guidance is used.

Whole-pelvic volumetric-modulated arc therapy for high-risk prostate cancer: treatment planning and acute toxicity

The objectives of this study were to evaluate dosimetric quality and acute toxicity of volumetric-modulated arc therapy (VMAT) and daily image guidance in high-risk prostate cancer patients. A total of 100 consecutive high-risk prostate cancer patients treated with definitive VMAT with prophylactic whole-pelvic radiotherapy (WPRT) were enrolled. All patients were treated with a double-arc VMAT plan delivering 52 Gy to the prostate planning target volume (PTV), while simultaneously delivering 46.8 Gy to the pelvic nodal PTV in 26 fractions, followed by a single-arc VMAT plan delivering 26 Gy to the prostate PTV in 13 fractions. Image-guided RT was performed with daily cone-beam computed tomography. Dose–volume parameters for the PTV and the organs at risk (OARs), total number of monitor units (MUs) and treatment time were evaluated. Acute toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. All dosimetric parameters met the present plan acceptance criteria. Mean MU and treatment time were 471 and 146 s for double-arc VMAT, respectively, and were 520 and 76 s for single-arc VMAT, respectively. No Grade 3 or higher acute toxicity was reported. Acute Grade 2 proctitis, diarrhea, and genitourinary toxicity occurred in 12 patients (12%), 6 patients (6%) and 13 patients (13%), respectively. The present study demonstrated that VMAT for WPRT in prostate cancer results in favorable PTV coverage and OAR sparing with short treatment time and an acceptable rate of acute toxicity. These findings support the use of VMAT for delivering WPRT to high-risk prostate cancer patients.

Granulocyte-colony stimulating factor enhances anti-tumour effect of hyperthermia.

The combined effect of granulocyte-colony stimulating factor (GCSF) and hyperthermia in the treatment of experimental tumours was studied to examine the possible involvement of activated granulocytes in the antitumour effect of hyperthermia. Two weeks after transplantation of SCC VII cells (1 x 105) into the instep of the left leg of C3H/HeJ male mice, the mice were given subcutaneous injections of GCSF (0.2mg/kg) for 4 days. On day 4, hyperthermia was applied locally at 43 C for 40min. Hyperthermia inhibited the tumour growth, and this effect was enhanced by pre-treating the animals with GCSF. The numbers of circulating neutrophils in control and GCSF-treated mice were 2728 +/- 517/mul and 3124 +/- 194/mul, respectively ( p = 0.53). Hyperthermia increased the number of neutrophils to 4409 +/- 700/mul ( p < 0.05). Hyperthermia combined with GCSF significantly increased the number of netrophils to 5479 +/- 691/mul ( p < 0.01). Chemiluminescence analysis using L-012 revealed that GCSF enhanced the generation of reactive oxygen species by about 10-fold. Glutathione contents in tumours 24h after hyperthermia decreased by about 50% in both the hyperthermia groups with or without GCSF, as compared to those in the control. The GCSF-enhanced anti-tumour activity of hyperthermia was markedly inhibited by administration of a long-acting superoxide dismutase derivative (SM-SOD). These results suggest that GCSF activates the ability to generate active oxygen species by neutrophils and, thereby, enhances the anti-tumour effect of hyperthermia.

A dosimetric comparison of RapidArc and IMRT with hypofractionated simultaneous integrated boost to the prostate for treatment of prostate cancer

OBJECTIVE To compare the dosimetric results and treatment delivery efficiency among RapidArc® (Varian Medical Systems, Palo Alto, CA), 7-field intensity-modulated radiotherapy (7-f IMRT) and 9-field IMRT (9-f IMRT) with hypofractionated simultaneous integrated boost to the prostate. METHODS RapidArc, 7-f IMRT and 9-f IMRT plans were created for 21 consecutive patients treated for high-risk prostate cancer using the Eclipse™ treatment planning system (Varian Medical Systems). All plans were designed to deliver 70.0 Gy in 28 fractions to the prostate planning target volume (PTV) while simultaneously delivering 50.4 Gy in 28 fractions to the pelvic nodal PTV. Target coverage and sparing of organs at risk (OARs) were compared across techniques. The total number of monitor units (MUs) and the treatment time were used to assess treatment delivery efficiency. RESULTS RapidArc resulted in slightly superior conformity and homogeneity of prostate PTV, whereas all plans were comparable with respect to dose to the nodal PTV. Although OARs sparing for RapidArc and 7-f IMRT plans were almost equivalent, 9-f IMRT achieved better sparing of the rectum and bladder than RapidArc and 7-f IMRT. RapidArc provided the highest treatment delivery efficiency with the lowest MUs and shortest treatment time. CONCLUSION RapidArc resulted in similar OAR sparing to 7-f IMRT, whereas 9-f IMRT provided the best OAR sparing. Treatment delivery efficiency is significantly higher for RapidArc. ADVANCES IN KNOWLEDGE This study validated the feasibility and limitations of RapidArc in the treatment of high-risk prostate cancer with complex pelvic target volumes.

Effect of lactic acid in tumours on antitumour activity of hyperthermia

The change of lactic acid concentration in the tumour after intraperitoneal administration of 5 g/kg glucose, and the effect of the lactic acid concentration on antitumour activity of hyperthermia were studied in an experimental murine tumour. The lactic acid concentration in SCC VII tumours transplanted into the legs of C3H/HeJ male mice was measured by gas chromatography. Local hyperthermic treatment to the tumour was performed with a water bath at 43 degrees C for 40 min. Antitumour effects were evaluated by measuring tumour volume doubling time (DT) as an index. The mean concentration of lactic acid in the tumour was 10.4 mumol/g in the no-treatment group. The lactic acid concentration gradually increased after glucose administration, reaching a significantly high concentration of 20.0 mumol/g at 90 min later. The DTs in the no-treatment group and hyperthermia alone group were 2.4 and 3.7 days respectively. The DTs in the glucose administration groups shortly before, 30 and 60 min before the hyperthermia were 3.6, 3.6 and 5.6 days respectively. The DT in the 60 min group was significantly extended (p < 0.0001). Hyperthermia during the period of increased lactic acid concentration significantly prolonged the DT of the tumour. These results clearly showed that an increase of lactic acid concentration in the tumour improved the effect of local hyperthermia.

In vivo radiosensitizing effect of nitroimidazole derivative KIN-804.

PURPOSE In vivo characteristics of 2-nitroimidazole-1-methylacetohydroxamate (KIN-804), which is a newly developed hypoxic cell radiosensitizer, are presented. METHODS AND MATERIALS The toxicity, pharmacokinetics, and radiosensitizing effect of KIN-804 were studied by in vivo experiments using C3H/He mice bearing the SCC-VII tumor. Results were compared with misonidazole (MISO). RESULTS LD50(7) of KIN-804 and MISO were 3200 mg/kg and 2000 mg/kg, respectively. The peak of concentrations of KIN-804 in the tumor occurred 20 min after intraperitoneal injection and reached about 62% of the maximum concentration in the blood. The concentrations in brain and sciatic nerve were very low and clearance from sciatic nerve was rapid. Enhancement ratios of KIN-804 calculated using the growth delay method were 1.22, 1.50 and 1.71 at doses of 50, 100, and 200 mg/kg, respectively, compared with 1.36 for MISO at a dose of 100 mg/kg. In the TCD50 assay, enhancement ratios at a dose of 200 mg/kg were 1.69 for KIN-804 and 1.52 for MISO, respectively. CONCLUSION KIN-804 is a promising radiosensitizer since it shows less toxicity and higher radiosensitizing activity than MISO.

Synergistic Effect of Irradiation and Hyperthermia on Established Cell Lines Derived from Maxillary Carcinoma Report I

Cultured tumor cells of an established cell line derived from cancer of the head and neck (maxillary and lingual cancer) were irradiated with X-rays (5 or 10 Gy). This treatment inhibited cell proliferation in a dose-dependent way. Cell cycle analysis showed that the ratio of cells in the S phase to the population of viable cells was higher than that in a non-irradiated control group. Thus, the S phase was prolonged by exposure to X-rays. Cell proliferation was also inhibited by 1 h of heat treatment at 43 degrees C. However, movement through the cell cycle was slowed down overall and no cell aggregation in any phase of the cell cycle was found. Proliferation of not only radioresistant but also radiosensitive cells was inhibited by this treatment. Hyperthermia at 43 degrees C for 1 h did not affect cell proliferation, nor did it influence the pattern of cell cycle distribution. However, it caused a decrease in intracellular polyamine amount. The combination of irradiation and hyperthermia caused a stronger inhibition than either treatment alone. The synergistic effect of the two treatments probably arose from the S-phase cells being heat-labile although radioresistant.