The purpose of the present study was to establish a non-surgical breast-conserving treatment (BCT) using KORTUC II radiosensitization treatment. A new radiosensitizing agent containing 0.5% hydrogen peroxide and 0.83% sodium hyaluronate (a CD44 ligand) has been developed for intra-tumoral injection into various tumors. This new method, named KORTUC II, was approved by our local ethics committee for the treatment of breast cancer and metastatic lymph nodes. A total of 72 early-stage breast cancer patients (stage 0, 1 patient; stage I, 23; stage II, 48) were enrolled in the KORTUC II trial after providing fully informed consent. The mean age of the patients was 59.7 years. A maximum of 6 mL (usually 3 mL for tumors of less than approximately 3 cm in diameter) of the agent was injected into breast tumor tissue twice a week under ultrasonographic guidance. For radiotherapy, hypofraction radiotherapy was administered using a tangential fields approach including an ipsilateral axillary region and field-in-field method; the energy level was 4 MV, and the total radiation dose was 44 Gy administered as 2.75 Gy/fraction. An electron boost of 3 Gy was added three times. Treatment was well tolerated with minimal adverse effects in all 72 patients. No patients showed any significant complications other than mild dermatitis. A total of 24 patients under 75 years old with stage II breast cancer underwent induction chemotherapy (EC and/or taxane) prior to KORTUC II treatment, and 58 patients with estrogen receptor-positive tumors also received hormonal therapy following KORTUC II. The mean duration of follow-up as of the end of September 2014 was 51.1 months, at which time 68 patients were alive without any distant metastases. Only one patient had local recurrence and died of cardiac failure at 6.5 years. Another one patient had bone metastases. For two of the 72 patients, follow-up ended after several months following KORTUC II treatment. In conclusion, non-surgical BCT can be performed using KORTUC II, which has three major characteristics: imaging guidance; enzyme-targeting; and targeting of breast cancer stem cells via the CD44 receptor.

Abstract. Animal studies have demonstrated that liver function parameters affect the degree of liver enhancement by gadolinium-ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA). The present study prospectively investigated whether liver function parameters and liver damage scores similarly correlate with the degree of liver enhancement by Gd-EOB-DTPA in humans with hepatocellular carcinoma (HCC). A total of 41 patients (32 males, 9 females; mean age, 71.9 years; range, 38-86 years) with suspected HCC provided written, informed consent to undergo a Gd-EOB-DTPA (30 µmol/kg of body weight)-enhanced T1-gradient-echo (GRE) magnetic resonance imaging (MRI) study. The signal intensity of the liver parenchyma was quantified at various time points following injection of Gd-EOB-DTPA. We investigated the correlations between maximal relative enhancement (RE) values and liver function parameters, and liver damage scores. Correlations between parameters and maximum RE values were determined using the Student's t-test and univariate regression analyses. The effect of potential confounding factors was controlled by multiple stepwise regression analysis. Two-tailed values of p<0.05 were considered to indicate a statistically significant difference. The RE values were maximal in 8 and 33 patients at 20 and 30 min, respectively, following Gd-EOB-DTPA injection and did not significantly differ between respective liver damage scores. Univariate analyses revealed that maximal RE values were associated with serum aspartate aminotransferase, total bilirubin, albumin and 15-min indocyanine green retention rates. Multiple stepwise regression analyses revealed that serum albumin and total bilirubin remained independently significant. The degree of liver parenchyma enhancement by Gd-EOB-DTPA depends on liver function parameters in humans, as in animals. The results from this study suggest that Gd-EOB-DTPA has potential for use as a liver function test, and for providing a short examination time for liver MRI results in patients with normal liver function.

Linear accelerator-based radiotherapy has little effect on the majority of locally advanced neoplasms. Thus, the novel radiosensitizer Kochi Oxydol Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II), which contains hydrogen peroxide and sodium hyaluronate, was developed. The effectiveness of KORTUC II for the treatment of chemotherapy-resistant supraclavicular lymph node metastases has been previously demonstrated. The present study evaluated the safety and effectiveness of KORTUC II in patients with recurrent breast cancer. A total of 20 patients (age range, 39–84 years) were enrolled in the study. The majority of patients underwent positron emission tomography (PET)-computed tomography (CT) examinations prior to and 1–7 months following KORTUC II treatment, and every 6 months thereafter when possible. The radiotherapy regimen was 2.75 Gy/fraction, 5 fractions/week, for 16–18 fractions, with a total radiation dose of 44.00–49.50 Gy (X-ray irradiation), or 4.00 Gy/fraction, 3 fractions/week, for 10–12 fractions, with a total radiation dose of 40.00–48.00 Gy (electron beam irradiation). The injection of 3–6 ml of the KORTUC II agent was initiated at the fifth radiotherapy fraction, and was performed twice/week under ultrasonographic guidance. The therapeutic effects were evaluated by PET-CT examinations prior and subsequent to KORTUC II treatment, which was observed to be well tolerated with minimal adverse effects. Of the 24 lesions presented by the 20 patients, 18 exhibited complete response, 5 partial response, 0 stable disease and 1 progressive disease. The overall survival rate was 100% at 1 year and 95% at 2 years. The mean duration of follow-up at the end of June 2014 was 51 months. Based on the results of the PET-CT studies conducted, KORTUC II treatment demonstrated marked therapeutic effects, with satisfactory treatment outcomes and acceptable adverse events.

Linac-based radiotherapy has a negligible effect on the majority of advanced neoplasms. Therefore, a novel radiosensitization treatment Kochi Oxydol Radiation Therapy for Unresectable Carcinomas II (KORTUC II), which utilizes hydrogen peroxide and sodium hyaluronate was developed. The effectiveness of KORTUC II for the treatment of chemotherapy-resistant supraclavicular lymph node metastases and recurrent breast cancers has previously been demonstrated. The present study evaluated the safety and efficacy of KORTUC II in patients with stage IV primary breast cancer. Seven patients (age range, 36–65 years) were enrolled. All patients received induction chemotherapy prior to KORTUC II treatment and underwent positron emission tomography-computed tomography (PET-CT) examinations prior to and 2–7 months following KORTUC II treatment, and every six months thereafter where possible. The radiotherapy regimen (x-ray irradiation) was 2.75 gray (Gy)/fraction, 5 fractions/week for 16–18 fractions with a total radiation dose of 44–49.5 Gy. Administration of the KORTUC II agent (3–6 ml: 3 ml for a lesion <3 cm in diameter and 6 ml for a lesion ≥3 cm) was initiated from the sixth radiotherapy fraction, and was conducted twice a week under ultrasonographic guidance. The therapeutic effects were evaluated by PET-CT examinations prior to and following KORTUC II treatment. Of the seven lesions from the seven patients, five exhibited complete responses, two exhibited partial responses and none exhibited stable disease or progressive disease. The overall survival rate was determined to be 100% at 1 and 86% at 2 years post-treatment. The mean duration of follow-up by December 2014 was 51 months. The results of the PET-CT studies indicated that KORTUC II treatment demonstrated marked therapeutic effects with satisfactory treatment outcomes and acceptable adverse effects.

IntroductionLinear accelerator (Linac)-generated high-energy X-rays and electron beams that are generally used for radiotherapy are low-linear energy transfer (LET) forms of radiation, and have a relatively weak biological effect. High-energy X-rays and electron beams have minimal effects on tumors that contain many hypoxic cancer cells and/or large amounts of antioxidative enzymes. Examples of such tumors include malignant melanoma, various types of sarcomas, glioblastoma multiforme, and most relatively large tumors more than several centimeters in their long diameter. Thus, effective treatment of these tumors requires strategies to re-oxygenate hypoxic tumor cells and to inhibit antioxidative enzymes. Therapeutic response to a new enzyme-targeting radiosensitization treatment (KORTUC-SC) for patients with chemotherapy-resistant supraclavicular lymph node metastasis AbstractWe have developed a new radiosensitizer containing hydrogen peroxide and sodium hyaluronate, part of a method we call "KORTUC II". This study aimed to evaluate the safety and effectiveness of KORTUC II specifically for patients with chemotherapy-resistant supraclavicular lymph node metastasis (KORTUC-SC). Twelve patients were enrolled after providing fully informed written consent. Most of the patients underwent PET-CT examinations prior to and 3-8 months after KORTUC-SC, and every 6 months thereafter if possible. The patients' age ranged from 58 to 77. The radiotherapy regimen was 4 Gy/ fraction, 3 fractions/ week, for 4 weeks, and the total dose was 48 Gy. The injection of 3 to 6 mL of the agent was started from the fifth radiotherapy fraction, and it was performed twice a week under ultrasonographic guidance. Therapeutic effects were evaluated by PET-CT examinations performed before and after KORTUC-SC treatment. The patients were well tolerated with minimal adverse effects. Of the 12 patients, 4, 5, 2 and 1 patient showed complete response, partial response, stable disease and progressive disease, respectively. The overall survival rate was 83% at 1 year and 75% at 2 years. The mean duration of follow-up at the end of February 2011 was 35.1 months. Based on the PET-CT studies, remarkable therapeutic effects of the KORTUC II treatment were clearly identified. The treatment outcomes were satisfactory. Welldesigned, prospective, randomized, clinical trials are needed to confirm the therapeutic efficacy of KORTUC-SC.