Development of a novel enzyme-targeting radiosensitizer (KORTUC) containing hydrogen peroxide for intratumoral injection for patients with low linear energy transfer-radioresistant neoplasms.

The therapeutic effect of radiotherapy using linear accelerators for relatively large tumors of more than several centimeters in diameter is reduced to one third due to a large number of hypoxic tumor cells and a significant amount of anti-oxidative enzymes including peroxidase/catalase. The most effective method by which to inject hydrogen peroxide into tumor tissue was examined. This proved difficult as 3% w/v hydrogen peroxide solution (Oxydol) is an antiseptic agent for skin lesions. Thus, injection into an affected lesion may result in hydrogen peroxide soaking into a body cavity, possibly causing an intra-arterial oxygen embolism. This study aimed to identify the most effective combination of drugs containing hydrogen peroxide in order to relieve local pain at the injection site and preserve high intratumoral oxygen concentration. Hyaluronate-hydrogen peroxide was identified as the most effective combination of drugs containing hydrogen peroxide for the preservation of high intratumoral oxygen concentration for 24 h following intratumoral injection with the agent. Based on the results, the clinical application of a novel enzyme-targeting radiosensitization treatment, Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas (KORTUC), was initiated for malignant tumors including advanced breast cancer, soft tissue sarcoma and cervical lymph node metastasis. Moreover, we have developed KORTUC III for locally advanced hepatocellular carcinoma and KORTUC IV for locally advanced pancreas cancer (stage IVa).

Diffusion-weighted magnetic resonance imaging for assessment after neoadjuvant chemotherapy in breast cancer, based on morphological concepts.

The study aimed to evaluate the utility of diffusion-weighted imaging (DWI) and to assess the response of breast cancer patients to neoadjuvant chemotherapy (NAC), based on morphological concepts. This retrospective study included 35 breast cancer patients (36 lesions) who had conventional magnetic resonance imaging (MRI), with DWI acquired before and after NAC. The morphological pattern of delayed enhancement on MRI before NAC was classified into two types: focal mass (FM), and multiple masses and/or non-mass like (MM/NM), based on Breast Imaging Reporting and Data System (BI-RADS). Of the 36 tumors, 26 were classified as FM and 10 as MM/NM. Tumors were clearly visualized on the initial DWI although one case of suspected MM/NM was not observed on DWI following NAC. A correlation was found between changes in the apparent diffusion coefficient and response rates to NAC in FM tumors (r=0.608, p<0.001), but not in MM/NM tumors (r=0.141, p=0.717). There was agreement between MRI findings after NAC and pathological findings in 30 of the 36 tumors (83.3%). Thus, we concluded that DWI is potentially useful in assessing the response to NAC for breast cancer for tumors diagnosed as FM on the initial conventional MRI.

Phase I study of a new radiosensitizer containing hydrogen peroxide and sodium hyaluronate for topical tumor injection: a new enzyme-targeting radiosensitization treatment, Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II).

Using a currently employed linear accelerator, our intent was to inactivate peroxidase/catalase in tumor tissue by the application of hydrogen peroxide, which is degraded to produce oxygen, thus re-oxygenizing the tumor tissue. In this way, we can convert radioresistant tumors into radiosensitive ones. On the basis of this strategy, we previously developed a new enzyme-targeting radiosensitization treatment named KORTUC I, which remarkably enhances the radiotherapeutic effect on various types of superficially exposed and locally advanced malignant neoplasms. Based on our clinical experience using KORTUC I, we also developed a new radiosensitizer containing hydrogen peroxide and sodium hyaluronate for injection into various types of tumors that are not superficially exposed (KORTUC II; described herein). KORTUC II was approved by our local ethics committee for advanced skin cancer, including malignant melanoma, bone/soft tissue malignant neoplasms, breast cancer, and metastatic lymph nodes. A maximum of 6 ml of the agent was injected into tumor tissue one to two times per week under ultrasonographic guidance, just prior to each administration of radiation therapy. Eleven patients, including seven with breast cancer, were enrolled in the KORTUC II trial upon fully informed consent. KORTUC II was well tolerated, with a minimum of adverse effects. Nine of the 11 patients showed a complete response (CR), and no severe complications occurred in any of the 11 patients. This new enzyme-targeting radiosensitization treatment may be indicated for various types of locally advanced neoplasms, including soft tissue neoplasms and breast cancers.

Choline by magnetic spectroscopy and dynamic contrast enhancement curve by magnetic resonance imaging in neoadjuvant chemotherapy for invasive breast cancer.

This study investigated the relationship between choline by magnetic resonance spectroscopy (MRS) and late enhancement curves by dynamic magnetic resonance imaging (DMRI) in determining therapeutic response to neoadjuvant chemotherapy (NAC) among invasive breast cancer patients. Subjects comprised 21 women (22 breasts) with biopsy-confirmed invasive breast cancer (mean age 54 years) who underwent MRS with choline and gadolinium-enhanced DMRI at 1.5 T before and after NAC. Choline signals on MRS were classified into 2 patterns: choline-positive or choline-negative, while late enhancement curves were classified as 'plateau' or 'washout' (type A), or 'persistent' (type B) according to the consensus of 2 radiologists. Maximum tumor diameters and clinical tumor reduction rates were assessed by MRI. Before NAC, choline-positive results were found in all 22 tumors, 21 of which were type A and 1 of which was type B. After NAC, a change from choline-positive to choline-negative was observed with MRS in 11 tumors, while another 11 remained choline-positive. According to DMRI, enhancement curves changed from type A to type B in 14 tumors, remained type A in 7 tumors, and remained type B in 1 tumor. Tumor reduction rates were significantly greater for choline-negative tumors than for choline-positive tumors after NAC (p=0.0115). Following NAC, no significant correlation was noted between enhancement curves and reduction rates (p=0.1210), although a significant correlation was noted between enhancement curves and choline signals (p=0.0014). Changes in choline signals as noted using MRS might offer advantages over changes in enhancement curves by DMRI when evaluating response to NAC in terms of the tumor reduction rate in invasive breast cancer.

New radiosensitization treatment (KORTUC I) using hydrogen peroxide solution-soaked gauze bolus for unresectable and superficially exposed neoplasms.

We developed a new radiosensitization treatment using a hydrogen peroxide solution (Oxydol)-soaked gauze named KORTUC I (Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas) for superficially exposed and unresectable neoplasms, such as malignant melanoma and malignant fibrous histiocytoma (MFH), based on our experimental results which demonstrated hydrogen peroxide as a strong radiosensitizer for the highly radioresistant osteosarcoma cell line, HS-Os-1. Five patients entered our clinical trial, one of whom had unresectable malignant melanoma; one, unresectable MFH; one, unresectable extramammary Paget's disease; one, locally advanced breast cancer and one with locally recurrent skin cancer. These patients were treated with radiation therapy using a high-energy electron beam from a linear accelerator. The total dose was 48 Gy, and each fraction size was 4 Gy. Radiation therapy for these patients was performed three times per week. Each time the radiation therapy was carried out, the superficially exposed tumors of these patients were covered with hydrogen peroxide solution (Oxydol)-soaked gauze, and the lesion was gently massaged for several minutes so as to allow the hydrogen peroxide solution to soak deeply into the tumor. In the treatment results, two of these five patients showed a clinically complete response (cCR) two to three months following the end of the KORTUC I radiosensitization treatment. The other three patients showed a clinically partial response (cCR) showing a decrement of more than half of the pretreatment volume. KORTUC I was completed without any severe complications, excluding mild radiation-induced dermatitis/mucositis (Grade I). In conclusion, this newly developed radiosensitization treatment using hydrogen peroxide solution (Oxydol)-soaked gauze for superficially exposed unresectable/radioresistant neoplasms appears to be an effective and valuable method of radiosensitization in terms of the blockade of anti-oxidative enzymes such as peroxidases, resulting in local oxygen production. Moreover, the KORTUC I radiosensitization treatment is relatively inexpensive and the method can therefore be utilized worldwide for many patients suffering from superficially exposed and locally advanced radioresistant neoplasms such as malignant melanoma, malignant fibrous histiocytoma (MFH) and various types of sarcomas.

Sentinel lymph node detection using computed tomography lymphography is accurate after neoadjuvant chemotherapy for breast cancer.

For breast cancer patients who have undergone neoadjuvant chemotherapy (NAC), a sentinel lymph node biopsy (SLNB) has not been recommended until recently. This is due to the possible lymph-flow interruption caused by fibrotic changes following chemotherapy and possible increases in false-negative cases. We investigated the changes in the lymph-flow and the detection of sentinel lymph nodes (SLNs) using computed tomography (CT) lymphography before and after NAC. We enrolled 53 patients with breast cancer who had undergone CT lymphography between May 2004 and April 2006. In total, 75 examinations were performed; 44 before NAC and 31 just after NAC. The CT lymphography procedures were approved by the medical ethics committee of our university. After a comprehensive explanation, written informed consent was obtained from all the patients, prior to enrollment in the study. Differences in changes in the lymph-flow, detection of SLNs, and changes in the number of detected SLNs were examined before and after NAC. Differences in the categoric variables were analyzed using the Chi-square test or Fisher's exact test. The identification rate (90.5%) of the SLNs following NAC was higher than the one before NAC (79.5%). However, no statistically significant difference was noted. No interruptions to the lymph-flow prevented the detection of SLNs by NAC. By performing CT lymphography before and after NAC, the interruption to the lymph-flow can be checked and the site of SLNs can be identified prior to surgery. We found that SLNB is recommended for breast cancer patients with or without NAC.