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Abstract. Linear accelerator-based radiotherapy has little effect on tumors such as malignant melanoma, various types of sarcoma, and most locally-advanced neoplasms that have grown to several centimeters or more. These tumors contain many hypoxic cancer cells or large amounts of anti-oxidative enzymes, and are therefore resistant to low linear energy transfer radiation. Therefore, it was necessary to develop a new radiosensitizer to overcome these situations. We previously developed a new enzyme-targeting radiosensitization treatment named KORTUC I, which uses 3% w/v hydrogen peroxide solution-soaked gauze. We developed a new radiosensitizer for intratumoral injection (KORTUC II), comprising a combination of hydrogen peroxide and sodium hyaluronate. After providing a fully informed written consent, 52 patients with unresectable or recurrent neoplasms (53 lesions) were enrolled in the KORTUC II trial. The present study of 52 patients with unresectable or recurrent neoplasms showed that KORTUC II is safe when injected intratumorally, well tolerated, and can efficiently exert a radiation sensitizing effect. Because this radiosensitizer is safe and less expensive than other methods, and can be applied for almost every type of low-LET radioresistant neoplasm, it has potential for worldwide and immediate use. IntroductionRadiotherapy is second to surgery as a local treatment method for malignant tumors. Because it can be applied to elderly patients and also enables normal organs and tissues to be conserved, its use has spread rapidly in recent years. However, linear 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 therefore have a relatively weak biological effect. Accordingly, linear accelerator based radiotherapy has little effect on tumors such as malignant melanoma, various types of sarcoma, and glioblastoma multiforme. Further, because locally advanced neoplasms that have grown to several centimeters or more contain many hypoxic cancer cells or large amounts of anti-oxidative enzymes, and are therefore resistant to low-LET radiation, they are not amenable to linear accelerator based radiotherapy.Heavy particle beam therapy is a method used to improve the radiotherapeutic effect in these situations. However, the widespread use of this therapy is hampered by the cost of the equipment, which involves an investment of several tens of billions of yen.In the past 40 years, various radiosensitizers (such as metronidazole, misonidazole, etanidazole, and nimorazole) have been developed to increase the radiotherapeutic effect (1-3). However, these agents have not yet been approved for clinical practice because their effects are uncertain and they have side effects such as peripheral neuropathy.When pre-treating cancer tissue for immunohistochemical staining, peroxidase blockade is usually an essential step to avoid non-specific staining of the tissue. Most cancer tissues contain abundant peroxidase/catal...

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. The decision to repeat transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) is based on correct evaluation of response to therapy. The purpose of this study was to investigate whether apparent diffusion coefficient (ADC), a quantitative parameter of diffusionweighted imaging (DWI), can predict early HCC recurrence after TACE. Results obtained using this method were compared with those using iodized-oil computed tomography (CT). DWI was performed on 25 patients with 36 HCCs before and 5-7 days after TACE to calculate the ADC of HCC. Patients were also evaluated with iodized-oil CT immediately after TACE. Contrast-enhanced CT was performed 3 months after TACE to confirm early relapse of HCC lesion. After TACE, the percent change in ADC (%ADC) from before to after therapy was significantly increased in non-relapsed lesions (85.2±12.4%) compared to relapsed lesions (8.0±56.7%, p=0.0004). However, no difference in area under the curve was seen for receiver operating characteristic analysis to predict early relapse after TACE between %ADC from DWI (95% confidence interval, 0.743-1.026) and iodized-oil CT (95% confidence interval, 0.703-1.016). ADC from DWI can evaluate the efficacy of TACE for HCC as effectively as iodized-oil CT, and may help in deciding whether to repeat TACE.

Neoadjuvant chemotherapy (NACT) is a widely accepted therapeutic option for patients with breast cancer. Although NACT produces good results for breast cancer patients, it has the potential to delay effective treatment in patients with chemotherapy-resistant breast cancer. The purpose of the present study was to evaluate the utility of the pretreatment apparent diffusion coefficient (ADC), which is calculated from diffusion-weighted imaging (DWI), the change in ADC after first administration of NACT, and the change in tumor greatest diameter on ultrasonography in the early prediction of the tumor response to NACT. The response rate of breast tumors to NACT was calculated by the greatest diameter measured by contrast-enhanced MRI obtained before and after NACT. Only the change in ADC was significantly correlated with the response rate. The area under the curve of the change in ADC was sufficiently high (0.90, 95% confidence interval, 0.760–1.040) to discriminate between responders and non-responders. Calculation of the ADC from DWI-MRI was found to be useful for predicting breast tumor response to NACT. Further studies are required to investigate the benefit of changing systemic therapy for breast cancer based on the prediction of the response to NACT by DWI-MRI.