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We report on a 69-year-old man with locally-advanced left maxillary sinus cancer who underwent treatment with intra-arterial chemoradiotherapy. Angiography showed that the main feeding arteries were the left maxillary artery and the ophthalmic artery, arising from the internal carotid artery. Due to acute branching of the ophthalmic artery, conventional microcatheters could not be inserted. Using a steerable microcatheter, we were able to repeatedly administer chemoradiotherapy via the ophthalmic artery. The tumor has mostly disappeared after intra-arterial chemoradiotherapy, and the patient is still alive two years after treatment. A steerable microcatheter is very useful for acute-angled vascular branches.

Although systemic therapy is standard management for patients with metastatic disease, several recent reports have indicated that an addition of local therapies including stereotactic body radiation therapy (SBRT) for patients with oligometastatic disease (OMD) could improve survival. The lung is the most common site of distant metastasis from many solid tumors, and the strategy of SBRT, such as dose-fraction schedules, timing, etc., would be different depending on the type of primary tumor, location, and patterns of OMD. This review describes the role of SBRT with curative-intent for patients with pulmonary OMD for each of these variables. First, differences according to the type of primary tumor, for which many studies suggest that SBRT-mediated local control (LC) for patients with pulmonary OMD from colorectal cancer (CRC) is less successful than for those from non-CRC tumors. In addition, higher dose-fraction schedules seemed to correlate with higher LC; hence, different SBRT treatment strategies may be needed for patients with pulmonary OMD from CRC relative to other tumors. Second, differences according to location, where the safety of SBRT for peripheral pulmonary tumors has been relatively well established, but safety for central pulmonary tumors including pulmonary OMD is still considered controversial. To determine the optimal dose-fraction schedules, further data from prospective studies are still needed. Third, differences according to the patterns of OMD, the number of metastases and the timing of SBRT whereby 1–5 lesions in most patients and patients with synchronous or metachronous OMD are considered good candidates for SBRT. We conclude that there are still several problems in defining suitable indications for local therapy including SBRT, and that further prospective studies are required to resolve these issues.

Objective To explore radiation oncologists’ attitudes and practice patterns of radiotherapy for hormone-naïve prostate cancer with bone metastases in Japan. Methods An internet-based survey was distributed to board-certified radiation oncologists of the Japanese Society of Radiation Oncology. Three hypothetical cases were assumed: hormone-naïve prostate cancer with single, three or multiple non-symptomatic bone metastases. The respondents described their attitude regarding such cases, treatment methods and the radiotherapy dose fractionation that they would recommend. Results Among the 1013 board-certified radiation oncologists in Japan, 373 (36.8%) responded to the questionnaire. Most of the respondents (85.0%) believed that radiotherapy may be applicable as a primary treatment for hormone-naïve prostate cancer with bone metastases in some circumstances. For Case 1 (single bone metastasis), 55.0% of the respondents recommended radiotherapy for the prostate and bone metastasis. For Case 2 (three bone metastases), only 24.4% recommended radiotherapy for all lesions, and 31.4% recommended radiotherapy for the prostate only. For Case 3 (multiple bone metastases), 49.1% of the respondents stated that there was no indication for radiotherapy. However, 34% of the respondents still preferred to administer radiotherapy for the prostate. The radiotherapy techniques and dose fractionations varied widely among the respondents. Conclusion Most of the respondent radiation oncologists believed that radiotherapy may be beneficial for hormone-naïve prostate cancer with bone metastases.

The role of stereotactic body radiotherapy (SBRT), which can deliver high radiation doses to focal tumors, has greatly increased in not only early-stage hepatocellular carcinoma (HCC), but also in portal vein or inferior vena cava thrombi, thus expanding this therapy to pre-transplantation and the treatment of oligometastases from HCC in combination with immune checkpoint inhibitors (ICI). In early-stage HCC, many promising prospective results of SBRT have been reported, although SBRT is not usually indicated as a first treatment potion in localized HCC according to several guidelines. In the treatment of portal vein or inferior vena cava tumor thrombi, several reports using various dose-fraction schedules have shown relatively good response rates with low toxicities and improved survival due to the rapid advancements in systemic therapy. Although SBRT is regarded as a substitute therapy when conventional bridging therapies to transplantation, such as transarterial chemoembolization (TACE) and radiofrequency ablation (RFA), are not applicable or fail in controlling tumors, SBRT may offer advantages in patients with borderline liver function who may not tolerate TACE or RFA, according to several reports. For oligometastases, the combination of SBRT with ICI could potentially induce an abscopal effect in patients with HCC, which is expected to provide the rationale for SBRT in the treatment of oligometastatic disease in the near future.

The aim of the present study was to evaluate the feasibility and preliminary outcomes of high-dose-rate (HDR)-brachytherapy as a monotherapy in two fractions within 1 day for localized prostate cancer, including high-/very high-risk cases. Among the 68 patients treated with HDR monotherapy between July 2011 and December 2014, 65 had a minimal follow-up of 12 months without adjuvant androgen deprivation therapy and were enrolled in the present study [42/65 (64.6%) exhibited high-/very high-risk diseases]. HDR monotherapy was performed in two fractions with a minimal interval of 6 h and the prescribed dose was 13.5 Gy (×2). Adverse events (AEs) were assessed using Common Terminology Criteria for Adverse Events (version 4; http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40), and biochemical failure was assessed by the Phoenix definition. The median follow-up time was 30.1 months. The majority of patients had Grade 0-1 acute AEs. Four patients (6.2%) exhibited urinary retention, requiring a Foley catheter. Grade 3 acute AEs occurred at a frequency of 3.1% and hematuria at 1.5%. The majority of patients also exhibited Grade 0-1 chronic AEs. Grade 3 chronic AEs occurred at a frequency of 1.5% and urethral stricture at 1.5%, for which endoscopic treatment was indicated. Acute and chronic gastrointestinal AEs were uncommon, and no Grade 3 or above AEs developed. Biochemical failure occurred in 4 patients who all exhibited high-/very high-risk diseases. Kaplan-Meier estimated that 3 year biochemical failure-free survival was 91.6% overall and 88.0% in high-/very high-risk cases. The present two-fraction 1 day HDR monotherapy is feasible with minimal AEs and achieved acceptable biochemical control of localized prostate cancer, including high-/very high-risk cases, although long-term follow-up is required.

The present study investigated whether established fibroproliferative changes in the irradiated rat lung are histopathologically reduced by an adenovirus‑mediated soluble transforming growth factor (TGF)‑β type II receptor. Replication‑defective adenoviral vectors expressing a type II human TGF‑β receptor (AdTβ‑ExR) were prepared. Male Fisher‑344 rats were divided into the C, R and R + T groups. The rats in the C group did not receive irradiation or treatment. The rats in the R and R + T group each received 30 Gy irradiation to the right lung. Eight weeks following irradiation, the rats in the R and R + T group were treated with saline or AdTβ‑ExR, respectively. To analyze the TGF‑β expression, myofibroblast proliferation and macrophage/monocyte infiltration, sections of the lung were immunohistochemically stained at 16 weeks following irradiation. Silver staining was performed for semi‑quantitative evaluation of the fibroproliferative changes. Definitive TGF‑β expression, myofibroblast proliferation and macrophage/monocyte infiltration were observed in the lungs of the R group, but were significantly lower in the lungs of the R + T group. With respect to the fibroproliferative changes, the proportion of red‑stained areas in the R + T group was markedly lower than that in the R group. These data indicate that fibroproliferative changes induced by radiation are reversible and that TGF‑β has a critical role in fibroproliferative changes in the irradiated lung. The present results suggest that gene therapy with an adenoviral vector expressing a soluble TGF‑β receptor may be effective in reducing the established pulmonary fibrosis caused by radiation.

Purpose To report outcomes and risk factors of high-dose-rate (HDR) brachytherapy combined with external beam radiotherapy with or without androgen deprivation therapy (ADT) in prostate cancer patients. Materials and Methods This multi-institutional retrospective analysis comprised 3424 patients with localized prostate cancer at 16 Asian hospitals. One-thirds (27.7%) of patients received only neoadjuvant ADT, whereas almost half (49.5%) of patients received both neoadjuvant and adjuvant ADT. Mean duration of neoadjuvant and adjuvant ADT were 8.6 months and 27.9 months, respectively. Biochemical failure was defined by Phoenix ASTRO consensus. Biochemical control rate, clinical disease-free survival (cDFS), cause-specific survival, and overall survival (OS) were calculated. Results Median followup was 66 months. Ten-year biochemical control, cDFS, cause-specific survival, and OS rate were 81.4%, 81.0%, 97.2%, and 85.6%, respectively. Receiving both neoadjuvant and adjuvant ADT was detected as a favorable factor for biochemical control, cDFS, and OS, but pelvic irradiation was detected as an adverse factor for cause-specific survival, and OS. Ten-year cumulative rates of late Grade ≥2 genitourinary and gastrointestinal toxicities were 26.8% and 4.1%, respectively; receiving both neoadjuvant and adjuvant ADT was detected as a favorable factor for preventing both toxicities. Conclusions HDR combined with external beam radiotherapy was an effective and safe treatment for localized prostate cancer. Combination of long-term ADT was suggested to be necessary, even for HDR brachytherapy, and was useful in suppressing late toxicities. Meanwhile, pelvic irradiation was suggested to have an adverse effect on OS of our study population.

Purpose To present, analyze, and discuss results of a nationwide, multicenter, retrospective study on high-dose-rate brachytherapy (HDR-BT) as monotherapy for low-, intermediate-, and high-risk prostate cancer. Methods and Materials From 1995 through 2013, 524 patients, 73 (14%) with low-risk, 207 (40%) with intermediate-risk, and 244 (47%) with high-risk prostate cancer, were treated with HDR-BT as monotherapy at 5 institutions in Japan. Dose fractionations were 27 Gy/2 fractions for 69 patients (13%), 45.5 Gy/7 fractions for 168 (32%), 49 Gy/7 fractions for 149 (28%), 54 Gy/9 fractions for 130 (25%), and others for 8 (2%). Of these patients, 156 (30%) did not receive androgen deprivation therapy, and 202 patients (39%) did receive androgen deprivation therapy 3 years. Median follow-up time was 5.9 years (range, 0.4-18.1 years), with a minimum of 2 years for surviving patients. Results After 5 years, respective actuarial rates of no biochemical evidence of disease, overall survival, cause-specific survival, and metastasis-free survival for all patients were 92%, 97%, 99%, and 94%. For low/intermediate/high-risk patients, the 5-year no biochemical evidence of disease rates were 95%/94%/89%, the 5-year overall survival rates were 98%/98%/94%, the 5-year cause-specific survival rates were 98%/100%/98%, and the 5-year metastasis-free survival rates were 98%/95%/90%, respectively. The cumulative incidence of late grade 2 to 3 genitourinary toxicity at 5 years was 19%, and that of late grade 3 was 1%. The corresponding incidences of gastrointestinal toxicity were 3% and 0% (0.2%). No grade 4 or 5 of either type of toxicity was detected. Conclusions The findings of this nationwide, multicenter, retrospective study demonstrate that HDR-BT as monotherapy was safe and effective for all patients with low-, intermediate-, and high-risk prostate cancer.

We introduced non-surgical therapy with a novel enzyme-targeting radiosensitization treatment, Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II) into early stages breast cancer treatment. The purpose of this study was to examine changes in tumor shadows and microcalcifications on mammography (MMG) following KORTUC II for elderly patients with breast cancer. We also sought to determine whether MMG was useful in evaluating the therapeutic effect of KORTUC II. In addition to MMG, positron emission tomography-computed tomography (PET-CT) was performed to detect both metastasis and local recurrence. In all 10 patients, tumor shadows on MMG completely disappeared in several months following the KORTUC II treatment. The concomitant microcalcifications also disappeared or markedly decreased in number. Disappearance of the tumors was also confirmed by the profile curve of tumor density on MMG following KORTUC II treatment, density fell and eventually approached that of the peripheral mammary tissue. These 10 patients have so far have also shown neither local recurrence nor distant metastasis on PET-CT with a mean follow-up period of approximately 27 months at the end of September, 2010. We conclude that breast-conservation treatment using KORTUC II, followed by aromatase inhibitor, is a promising therapeutic method for elderly patients with breast cancer, in terms of avoiding any surgical procedure. Moreover, MMG is considered to be useful for evaluating the efficacy of KORTUC II.

Background: We have developed a new radiosensitization treatment called Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II). Using KORTUC II, we performed breast-conserving treatment (BCT) without any surgical procedure for elderly patients with breast cancer in stages I/II or patients refusing surgery. Since surgery was not performed, histological confirmation of the primary tumor region following KORTUC II treatment was not possible. Therefore, to precisely evaluate the response to this new therapy, a detailed diagnostic procedure is needed. The goal of this study was to evaluate the therapeutic response to KORTUC II treatment in patients with stage I/II breast cancer using annual breast contrast-enhanced (CE) magnetic resonance imaging (MRI). Methods: Twenty-one patients with stage I/II breast cancer who were elderly and/or refused surgery were enrolled in this study. All patients underwent MRI prior to and at 3 to 6 months after KORTUC II, and then approximately biannually thereafter. Findings from MRI were compared with those from other diagnostic modalities performed during the same time period. Results: KORTUC II was well tolerated, with minimal adverse effects. All of 21 patients showed a clinically complete response (cCR) on CE MRI. The mean period taken to confirm cCR on the breast CE MRI was approximately 14 months. The mean follow-up period for the patients was 61.9 months at the end of October 2014. Conclusions: The therapeutic effect of BCT using KORTUC II without surgery could be evaluated by biannual CE MRI evaluations. Approximately 14 months were required to achieve cCR in response to this therapy.

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.

Purpose To investigate whether an adenoviral-mediated soluble transforming growth factor-beta (TGF-β) type II receptor could ameliorate fibroproliferative change in rat irradiated lung. Methods and materials We used an adenoviral vector expressing a soluble TGF-β receptor (AdTβ-ExR), which adsorbs TGF-β and inhibits the function of the wild-type receptor as a dominant-negative mutant. Rats were i.v. injected with either 0.5 mL of AdTβ-ExR (1.0 × 10 9 plaque-forming units/mL) or AdLacZ (1.0 × 10 9 plaque-forming units/mL), a control adenovirus expressing bacterial β-galactosidase, or saline, then 3 days later they received 4-MV X-ray irradiation of 30 Gy in a single fraction to the right lung. Eight weeks after irradiation, the rats were killed, and their right lungs were examined histopathologically. The respiratory rates of all rats were observed with a charge-coupled device video system before the rats were irradiated and killed. Results A significant increase in breathing rates was observed in the saline- or AdLacZ-infected rats. The respiratory rate of the AdTβ-ExR–treated rats was significantly lower than that in the saline- or AdLacZ-infected rats. Fibroproliferative change in the irradiated lung was markedly reduced in the AdTβ-ExR–treated rats in comparison with the saline- or AdLacZ-infected rats. With respect to active TGF-β1 expression, myofibroblast proliferation, and macrophage/monocyte infiltration, the findings were identical to those for fibroproliferative change. Conclusions Our results indicate that TGF-β plays a critical role in radiation-induced fibroproliferation of the lung and suggest that the adenoviral-mediated soluble TGF-β receptor may have potential for use in the amelioration of this intractable pulmonary damage.

Purpose: The aim of this study was to determine the differences in renal damage particularly associated with the effect of a small dose per fraction with a constant total dose. Methods and Materials: Guinea pigs, 12-week-old English Hartley females, were used. The animals were divided into five groups according to irradiation schedule: No irradiation (control group); 2.0 Gy × 1/day, 5 fraction (f)/week (wk), 40 f, total 80 Gy (Group CF-2.0 [CF = conventional fractionation]); 1.0 Gy × 2/day, 10 f/wk, 80 f, total 80 Gy (Group HF-1.0 [HF = hyperfractionation]); 3.0 Gy × 1/day, 5 f/wk, 27 f, total 81 Gy (Group CF-3.0); and 1.5 Gy × 2/day, 10 f/wk, 54 f, total 81 Gy (Group HF-1.5). Only unilateral irradiation was performed. A histologic analysis was performed before irradiation and at 6 and 12 months after the completion of irradiation. The severity and severity ratios of urinary tubule atrophy, the number of large nuclei per unit area in the renal tubules, the average diameter of the glomeruli, and the number of cells composing the glomerulus were used as parameters for evaluating renal damage. Results: In Groups CF-2.0 and CF-3.0 (the conventional fractionation [CF] groups), all the renal tubules showed severe atrophy 12 months after irradiation. On the other hand, only 20% of the renal tubules showed slight atrophy in Group HF-1.0 at 12 months. In Group HF-1.5, 70% of the renal tubules were atrophic at 12 months. The number of large nuclei markedly increased in Groups HF-1.0 and HF-1.5 (the hyperfractionation [HF] groups) at 12 months, whereas the number was very low in the CF groups at 12 months. Only in Group HF-1.0 had the average diameter of glomeruli not shrunk at 12 months. The number of cells composing the glomerulus in the CF groups markedly decreased at 12 months. The number of cells in the HF groups was also reduced, however the reduction was not as severe as that observed in the CF groups. Conclusion: 1.0 Gy per fraction delivered by HF greatly reduces renal damage even in the 80 Gy–irradiated kidney, which is one of the most radiosensitive organs.

Nitric oxide (NO) released from (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1- ium-1,2-diolate (DETA/NO or NOC-18) induces apoptosis in human leukemia HL-60 cells. In this study, we isolated a HL-60 variant cell line, HL-NR6, that is resistant to DETA/NO toxicity as assessed by DNA fragmentation, morphology, and colony forming ability. The variant cells also showed resistance to reactive oxygen species (ROS) such as superoxide and hydrogen peroxide as well as NO donors, but not to anti-tumor drugs. We found that HL-NR6 cells when compared with HL-60 cells possessed twice the activities of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and catalase, but no change in Mn-SOD nor in glutathione peroxidase. Immunoblotting confirmed the high levels of both enzymes in the variant cell. We also observed that ROS generation following DETA/NO exposure was substantially higher in HL-60 cells than in HL-NR6 cells, using the 2',7'-dichlorofluorescein fluorometric method. Moreover, the SOD mimetic Mn(III) tetrakis(1-methyl-4-pyridyl) porphyrin and exogenous catalase effectively attenuated DETA/NO-elicited DNA fragmentation in HL-60 cells. Taken together, these data suggested that the NO resistance in HL-NR6 cells is associated with the increased Cu,Zn-SOD/catalase and that NO-mediated apoptosis in HL-60 cells is correlated with the generation of ROS and derived molecules like peroxynitrite.

Public concern on the radiation therapy for prostate cancer has increased recently. The leading causes of this phenomenon are thought of as popularization of prostate-specific antigen (PSA) measurement and having been able to tell the curable patients apart by means of the accom‐ plished risk classifications. Massive development of radiation therapy technology also seems to be one of the leading causes. This chapter focuses on the variety of curative radiation therapy for clinically localized prostate cancer.

Diffusion-weighted imaging (DWI) is a magnetic resonance imaging (MRI) method and is considered potentially useful for detecting prostate cancer. We evaluated the clinical value of DWI with apparent diffusion coefficient (ADC) maps in addition to T2-weighted imaging (T2WI) using 3 tesla (3 T) MRI. Thirty-three patients with elevated prostate specific antigen were evaluated by MRI with T2WI and DWI prior to transperineal template-guided mapping biopsy. The MRI findings were compared with the pathology of biopsy specimens in six parts of prostate : both sides of outer peripheral zones, inner peripheral zones, and transition zones. The sensitivities, specificities and accuracies were 42.1, 84.4 and 76.3％ in T2WI, 57.1, 84.7 and 80.8% in T2WI/DWI, and 87.5, 85.2 and 85.4% in DWI/ADC using 0.951×10 -3 mm2/s as cutoff ADC value. The hazard ratio of patients whose ADC values were under the cutoff was 25.86 by multivariate analysis. Mean ADC values were significantly different between cancer positive and negative cores (p＜0.001). The ADC value showed a negative correlation with increasing tumor length (p＝0.0047). Although further study with a large number of patients is necessary, DWI/ADC using 3 T MRI is a useful tool for detecting prostate cancer.

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 radio-resistant neoplasm, it has potential for worldwide and immediate use.

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.

Purpose To study the effect of hydrogen peroxide (H 2 O 2 ) on radiation-induced apoptosis in human prostate cancer PC-3 cells. Methods and Materials At 4h before the irradiation, PC-3 cells were exposed to 10mM ammonium chloride (NH 4 Cl) concentrations. Subsequently, cells were exposed to 0.1mM H 2 O 2 just before the irradiations, which were administered with 10-MV X-rays at doses of 10Gy. Results The percentage of apoptotic cells at 48h after X-irradiation alone, H 2 O 2 alone, and combined X-irradiation and H 2 O 2 was 1.85%, 4.85%, and 28.4%, respectively. With use of combined X-irradiation and H 2 O 2 , production of reactive oxygen species (ROS) occurred 4h after the irradiation. This resulted in lysosomal rupturing, mitochondrial fragmentation, and the release of cytochrome c into the cytoplasm from the mitochondria. In contrast, when cells were exposed to NH 4 Cl before the X-irradiation and H 2 O 2 administration, apoptosis was almost completely suppressed, ROS production did not occur, lysosomal rupture and mitochondrial fragmentation were blocked, and cytochrome c was not released. Conclusions Hydrogen peroxide strongly enhanced lysosome-dependent radiation-induced apoptosis in human prostate cancer PC-3 cells. A combined use of X-rays and H 2 O 2 can also injure the mitochondrial cytoplasmic organelles and lead to the production of ROS that in and of itself might possibly induce apoptosis.

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.

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.

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.

To compare the frequency of "subjective" complications and their severity between conventional and short fractionation and to analyze the differences between the two groups.Data from 350 patients with breast cancer who received breast conservation therapy between 1992 and 2003 were retrospectively analyzed. One hundred and ninety-six patients and 154 patients received 50 Gy in 25 fractions over 35 days (group C) and 44 Gy in 16 fractions over 22 days (group S), respectively. Early sequelae were evaluated at the end of radiation therapy (point A) and 7-10 days after the treatment (point B). Late sequelae were assessed at least 6 months after the end of radiation therapy (point C).The most commonly observed toxicity at point A was erythema, followed by heat sensation, sense of discomfort, and pain. There were no significant differences in these symptoms between the two groups. The frequency of these symptoms hardly changed between points A and B. At point C a sense of hardness more frequently appeared in group S than in group C with a significant difference. Other commonly noted symptoms had no significant difference between the two groups.Short fractionation results in acceptable patient "subjective" sequelae comparable to the sequelae experienced following conventional fractionation.

The purpose of this study is to evaluate the accuracy of mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging for the diagnosis of intraductal spread of breast cancer following preoperative neoadjuvant chemotherapy. We evaluated a total of 168 areas of normal breast tissue outside the mass in 42 consecutive female patients with breast cancer using each imaging modality both before and after neoadjuvant chemotherapy. Neoadjuvant chemotherapy comprised two to four cycles of adriamycin-based CAF regimen. Multivariate analysis indicated that calcification on mammography and size of hypoechoic structures on ultrasonography prior to neoadjuvant chemotherapy shows a correlation with intraductal spread on pathologic study. Our study reveals that mammography and ultrasonography are useful in avoiding residual cancer cells caused by intraductal spread following conservative breast surgery.

Background Reduced hippocampal volume in schizophrenia is a well-replicated finding. New imaging techniques allow delineation of hippocampal subfield volumes. Studies including predominantly chronic patients demonstrate differences between subfields in sensitivity to illness, and in associations with clinical features. We carried out a cross-sectional and longitudinal study of first episode, sub-chronic, and chronic patients, using an imaging strategy that allows for the assessment of multiple hippocampal subfields. Methods Hippocampal subfield volumes were measured in 34 patients with schizophrenia (19 first episode, 6 sub-chronic, 9 chronic) and 15 healthy comparison participants. A subset of 10 first episode and 12 healthy participants were rescanned after six months. Results Total left hippocampal volume was smaller in sub-chronic (p = 0.04, effect size 1.12) and chronic (p = 0.009, effect size 1.42) patients compared with healthy volunteers. The CA2-3 subfield volume of chronic patients was significantly decreased (p = 0.009, effect size 1.42) compared to healthy volunteers. The CA4-DG volume was significantly reduced in all three patient groups compared to healthy group (all p < 0.005). The two affected subfield volumes were inversely correlated with severity of negative symptoms (p < 0.05). There was a small, but statistically significant decline in left CA4-DG volume over the first six months of illness (p = 0.01). Conclusions Imaging strategies defining the subfields of the hippocampus may be informative in linking symptoms and structural abnormalities, and in understanding more about progression during the early phases of illness in schizophrenia.

Hepatic steatosis is a frequent complication, which sometimes develops nonalcoholic steatohepatitis (NASH), in breast cancer patients treated with tamoxifen, a potent antagonist of estrogen. Recently we reported the impairment of fatty acid beta-oxidation and the enhancing fatty infiltration to hepatocytes in aromatase deficiency (ArKO) mice as the estrogen deficiency models. This experimental observation let us speculate strong link between estrogen and hepatic steatosis. In this study, we investigated whether a polymorphism in the cytochrome P450c17alpha gene (CYP17), which is associated with circulating estrogen levels, influences the development of tamoxifen-induced hepatic steatosis. This consecutive study included 180 breast cancer patients undergoing tamoxifen treatment. Genomic DNA extracted from the peripheral blood of each patient was analyzed by restriction fragment length polymorphism (defined as the A1 and A2 alleles). The extent of hepatic steatosis was assessed by computed tomography (CT) as the liver/spleen (L/S) ratio. While receiving adjuvant tamoxifen, 57 of 180 patients developed hepatic steatosis (L/S ratio0.9) without obvious changes in body mass index (BMI). We observed a significant association between the A2/A2 genotype and the development of hepatic steatosis compared with the A1/A1 genotype [odds ratio (OR), 3.60; 95% confidence interval (C.I.)=1.42-9.10]. The A1/A2 genotype was at an intermediately increased risk of hepatic steatosis (OR, 2.24; 95% C.I.=0.99-5.08). The presence of the A2 allele possibly increased the progression of hepatic steatosis with a gene dosage effect (P=0.06). Our results suggest that functional polymorphism in CYP17 may be involved in determining susceptibility of tamoxifen-induced hepatic steatosis.

Oral administration of tamoxifen, an endocrine therapy for breast cancer, often induces hepatic steatosis (THS, tamoxifen-induced hepatic steatosis) as a complication, which can progress to non-alcoholic steatohepatitis (NASH). The development of this complication is strongly associated with three clinical risk factors; specifically, insulin resistance, central obesity, and hypertriglyceridemia, however a genetic predisposition to THS has yet to be investigated. The aim of this study is to determine whether genetic polymorphism of the P450c17alpha enzyme coded for by the CYP17 gene, responsible for regulating serum estrogen, has an association with THS. After obtaining informed consent from 180 eligible breast cancer patients treated with tamoxifen, DNA was collected and analyzed by restriction fragment length polymorphism assay and classified into alleles defined as A1 and A2. The absence or presence and extent of THS was evaluated by calculating the liver/spleen (L/S) ratio based on Hounsfield units with a CT scanner. Administration of tamoxifen led to THS (L/S ratio

Human peripheral T cells are considered to be easily susceptible to oxidative stress because these cells lack peroxidase activity. Therefore, in a previous study, we investigated the site of ROS formation by utilizing Mito-Capture, H(2)DCFDA (succinimidyl ester of dichlorodihydrofluorescein diacetate), DAPI (4',6-diamidino-2-phenylindole), and LysoSensor. Our results showed that ROS formation was apparently diffusely distributed in T cells oxidatively stressed with 0.1 mM hydrogen peroxide. Moreover, lysosomal swelling and deformity, possibly revealing lysosomal membrane destabilization, were observed in these cells. Based on the above-mentioned results, we concluded that an apoptotic cascade involving early lysosomal membrane destabilization exists in the hydrogen peroxide-induced apoptosis of human peripheral T cells. Therefore, the possible involvement of lysosomal protease leakage caused by hydroxyl radical formation in lysosomes (possibly resulting in mitochondrial membrane dysfunction) is considered to play an important role in hydrogen peroxide-induced T cell apoptosis. Hydrogen peroxide-mediated destabilization of lysosomal membranes with release of hydrolytic enzymes such as many kinds of cathepsins into the cell cytoplasm can lead to a cascade eventuating in cell death. To assess the importance of the intralysosomal pool of redox-active iron, we examined the effect of blockade of lysosomal digestion by exposing T cells to the lysosomotropic alkalinizing agent ammonium chloride (NH(4)Cl). Preincubation of human peripheral T cells with 10 mM NH(4)Cl for 4 h dramatically decreased apoptotic death caused by subsequent exposure to hydrogen peroxide (H(2)O(2)), and lysosomes and mitochondria showed almost normally preserved appearance. Therefore, we concluded here that lysosomal protease leakage caused by hydrogen peroxide in T cells was prevented by preincubation with ammonium chloride (NH(4)Cl).

In our previous study, we examined reactive oxygen species (ROS) formation in T lymphocytes following 5 Gy irradiation. We found that ROS formation occurred immediately after irradiation, continued for several hours, and resulted in oxidative DNA damage. Therefore, the origin of the hyper-radiosensitivity of T lymphocytes seemed to be the high production of ROS in the mitochondrial DNA following irradiation. In the succeeding study, we examined radiation-induced ROS formation, oxidative DNA damage, early apoptotic changes, and mitochondrial membrane dysfunction in the human osteosarcoma cell line HS-Os-1. We found that ROS formation and oxidative DNA damage were actually scarcely seen after irradiation of up to 30 Gy in these cells, that mitochondrial membrane potential was preserved, and that apoptotic changes were not demonstrated despite the relatively high-dose irradiation of 30 Gy. In the present study, we examined the immunocytochemical characteristics of the apoptotic-resistance of the HS-Os-1 cell line against irradiation in order to clarify its possible implications regarding radiosensitivity. The results showed that these cells lack P53 and Bax protein expression, and strong peroxidase activity was confirmed in the nuclei of the cells. Moreover, SODII (manganese superoxide dismutase II) protein expression was gradually increased in spite of irradiation of up to 30 Gy. Therefore, it is concluded that HS-Os-1 cells are originally apoptotic-resistant and that the cells possess a strong ability to scavenge for free radicals. To convert these cells to a state of apoptotic-susceptibility, a powerful oxidant such as hydrogen peroxide might exert such an effect in terms of the production of hydroxyl radicals in lysosomes in the cells as shown in our previous studies. The origin of the radioresistance of the human osteosarcoma cell line HS-Os-1 is considered to to be low degree of ROS formation following irradiation, reflecting the strong scavenging ability of these cells for free radicals including hydroxyl radicals.

In our previous studies, we showed that the apoptotic resistance of the human osteosarcoma cell line HS-Os-1 against irradiation was easily converted to a state of apoptotic-susceptibility by the addition of a relatively low concentration of hydrogen peroxide to the culture medium just prior to irradiation. When we consider the combined use of radiotherapy and hydrogen peroxide in a clinical setting for patients with radioresistant neoplasms, we need to be careful of the possible augmentation of the radiation effect to normal tissues of patients who undergo radiation therapy for their tumor in the presence of a low concentration of hydrogen peroxide in their topical tumor tissue. Therefore, we examined the combined effect of irradiation and hydrogen peroxide compared to that of irradiation alone for human peripheral T cells which were considered to be representative of normal tissue susceptible to apoptosis induced by irradiation. In this study, we compared the morphological changes in human peripheral T cells between both groups by utilizing MitoCapture, H2DCFDA (succinimidyl ester of dichloro-dihydrofluorescein diacetate), DAPI (4',6-diamidino-2-phenylindole), and LysoSensor. Our results showed that ROS formation was apparently augmented in the mitochondria and/or lysosomes instead of in the nuclei of irradiated T cells in the presence of a low concentration of hydrogen peroxide compared to those treated with irradiation alone. Moreover, dysfunction of mitochondrial membrane potential was also more evidently shown in human peripheral T cells irradiated under existence of a low concentration of hydrogen peroxide compared to T cells treated with 5 Gy irradiation alone. Based on these results, we concluded the possible existence of an augmentation effect of irradiation by the existence of a low concentration of hydrogen peroxide for human peripheral T cells. Therefore, we should be alert for the combined effects of radiation therapy and hydrogen peroxide on normal tissues in possible clinical situations when this combination is used for treatment of patients having radioresistant neoplasms such as osteosarcoma, malignant melanoma, and glioblastoma multiforme.

In our previous study, we examined the effect of exogenous hydrogen peroxide, which causes a potent oxidative stress and has been demonstrated to be a potent apoptosis-inducer in many kinds of cells. We found that the addition of 1 or 10 mM hydrogen peroxide induced reactive oxygen species (ROS) formation, oxidative DNA damage, dysfunction of the mitochondrial membrane potential, and early apoptotic changes in the human osteosarcoma cell line HS-Os-1. We therefore concluded that intracellular ROS formation was involved in the hydrogen peroxide-induced apoptosis of HS-Os-1 cells. In contrast to the osteosarcoma cell line HS-Os-1, human peripheral T cells are considered to be easily susceptible to oxidative stress, because these cells lack peroxidase activity. Therefore, in this study, we investigated the site of ROS formation by utilizing MitoCapture, H2DCFDA (succinimidyl ester of dichloro-dihydrofluorescein diacetate), DAPI (4',6-diamidino-2-phenylindole), and LysoSensor. Our results showed that ROS formation was apparently diffusely distributed in T cells oxidatively stressed with 0.1 mM hydrogen peroxide. Moreover, lysosomal swelling and deformity, possibly revealing lysosomal membrane destabilization, were observed in these cells. Based on the above results, there exists an apoptotic cascade involving early lysosomal membrane destabilization in the hydrogen peroxide-induced apoptosis of human peripheral T cells. Therefore, the possible involvement of lysosomal protease leakage caused by hydroxyl radical formation in lysosomes (possibly resulting in mitochondrial membrane dysfunction) is considered to play an important role in hydrogen peroxide-induced T cell apoptosis.

Among patients with breast cancer who consulted the Department of Radiology, Kochi Medical School to undergo breast-conservation treatment, toremifene (TOR) alone was administered to 7 postmenopausal women as initial treatment for reasons such as the patient's desire, advanced age, and concomitant disease. In 6 patients, breast-conserving surgery was performed 1-12 months after the start of the administration of TOR alone. A 90-year-old patient has been treated with TOR alone for 56 months, and is being followed up. Six of 7 patients showed 50% or greater reduction of tumors, including 1 in whom the administration of TOR alone for 5 months reduced the tumor from a clinical diagnosis of skin invasion (T4b) to T1c, allowing lumpectomy under local anesthesia. In one patient, there were no changes (reduction ratio: 14%). No progressive disease was detected in any patient. In this study, the administration of TOR alone markedly reduced tumors in patients with estrogen receptor (ER)-positive breast cancer, facilitating down-staging. Treatment with TOR alone may be a useful neoadjuvant therapy or single therapy in elderly patients.

In our previous studies, we showed that the apoptotic resistance of the human osteosarcoma cell line HS-Os-1 against irradiation was easily converted to a state of apoptotic-susceptibility by the addition of a relatively low concentration of hydrogen peroxide to the culture medium just prior to irradiation. When we consider the combined use of radiotherapy and hydrogen peroxide in a clinical setting for patients with radioresistant neoplasms, we need to be careful of the possible augmentation of the radiation effect to normal tissues of patients who undergo radiation therapy for their tumor in the presence of a low concentration of hydrogen peroxide in their topical tumor tissue. Therefore, we examined the combined effect of irradiation and hydrogen peroxide compared to that of irradiation alone for human peripheral T cells which were considered to be representative of normal tissue susceptible to apoptosis induced by irradiation. In this study, we compared the morphological changes in human peripheral T cells between both groups by utilizing MitoCapture, H2DCFDA (succinimidyl ester of dichloro-dihydrofluorescein diacetate), DAPI (4',6-diamidino-2-phenylindole), and LysoSensor. Our results showed that ROS formation was apparently augmented in the mitochondria and/or lysosomes instead of in the nuclei of irradiated T cells in the presence of a low concentration of hydrogen peroxide compared to those treated with irradiation alone. Moreover, dysfunction of mitochondrial membrane potential was also more evidently shown in human peripheral T cells irradiated under existence of a low concentration of hydrogen peroxide compared to T cells treated with 5 Gy irradiation alone. Based on these results, we concluded the possible existence of an augmentation effect of irradiation by the existence of a low concentration of hydrogen peroxide for human peripheral T cells. Therefore, we should be alert for the combined effects of radiation therapy and hydrogen peroxide on normal tissues in possible clinical situations when this combination is used for treatment of patients having radioresistant neoplasms such as osteosarcoma, malignant melanoma, and glioblastoma multiforme.

In our previous study, we demonstrated that the radioresistance of the human osteosarcoma cell line HS-Os-1, was considered to arise, at least in part, from the low level of ROS formation following irradiation, which in turn may have resulted from the strong scavenging ability of the cells for free radicals, including hydroxyl radicals. Following the study, we found that addition of 1 or 10 mM hydrogen peroxide induced ROS formation, oxidative DNA damage, dysfunction of the mitochondrial membrane potential, and early apoptotic changes in the human osteosarcoma cell line HS-Os-1. We therefore speculated that combined use of irradiation and hydrogen peroxide might exert an additive effect for apoptotic-resistant tumors such as the human osteosarcoma cell line HS-Os-1, in terms of preservation of the radiation-induced hydroxyl radical production supported by the intracellular ROS formation that is induced by exogenous hydrogen peroxide addition. Therefore, in this study, we examined the effect of various doses of irradiation on the existence of 0.1 mM hydrogen peroxide in the culture medium. We found that irradiation with 10 or 20 Gy, under the condition of the presence of 0.1 mM hydrogen peroxide, induced ROS formation, oxidative DNA damage, dysfunction of the mitochondrial membrane potential, and early apoptotic changes in the human osteosarcoma cell line HS-Os-1, though ROS formation and oxidative DNA damage were scarcely seen in response to irradiation of up to 30 Gy, as was shown in our previous study. We therefore concluded that the combined modality of irradiation and such a low concentration of hydrogen peroxide (0.1 mM) is potentially applicable in clinical radiotherapy for many kinds of apoptotic-resistant neoplasms in terms of achieving both local control and improving survival benefit of patients.

We describe a 61-year-old woman with diabetes insipidus caused by a pituitary stalk metastasis from breast cancer. She had a medical history of breast conservation therapy for early breast cancer 5 years previously. Pituitary, lung, liver, bone and neck lymphnode metastases was revealed at the same time. She received systemic chemotherapy consisiting of docetaxel and cisplatin. After chemotherapy MRI finding in pituitary gland was improved, lung and liver metastases also improved, however, symptoms of diabetes insipidus did not improve. She is alive, receiving endocrine treatment for 2 years, since onset of diabetes insipidus.

In our previous study, we examined radiation-induced ROS formation, oxidative DNA damage, early apoptotic changes, and mitochondrial membrane dysfunction in the human osteosarcoma cell line HS-Os-1, which was established from an osteoblastic tumor that arose in the left humerus of an 11-year-old girl and was already morphologically characterized in vitro and in vivo. We found that ROS formation and oxidative DNA damage were scarcely seen after irradiation of up to 30 Gy in these cells; that mitochondrial membrane potential was preserved; and that apoptotic changes were not demonstrated despite the relatively high-dose irradiation of 30 Gy. Based on these results, the radioresistance of the human osteosarcoma cell line HS-Os-1, was considered to arise, at least in part, from the low level of ROS formation following irradiation, which in turn may have resulted from the strong scavenging ability of the cells for free radicals, including hydroxyl radicals. Therefore, in this study, we examined the effect of exogenous hydrogen peroxide, which causes a potent oxidative stress and has been demonstrated to be a potent apoptosis-inducer in many kinds of cells. We found that addition of 1 or 10 mM hydrogen peroxide induced ROS formation, oxidative DNA damage, dysfunction of the mitochondrial membrane potential, and early apoptotic changes in the human osteosarcoma cell line HS-Os-1. We therefore concluded that intracellular ROS formation is involved in the hydrogen peroxide-induced apoptosis of HS-Os-1 cells.

In our previous study, we examined reactive oxygen species (ROS) formation in T lymphocytes following 5 Gy of irradiation. Using a CCD camera system, we monitored fluorescence in T lymphocytes loaded with the succinimidyl ester of Dichlorodihydrofluorescein diacetate (H2DCFDA), which is non-fluorescent until oxidized by ROS. We found that ROS formation occurred immediately after irradiation, continued for several hours, and resulted in oxidative DNA damage. Therefore, the origin of the hyper-radiosensitivity of T lymphocytes seemed to be the high production of ROS in the mitochondrial DNA following irradiation. In this study, we examined radiation-induced ROS formation, oxidative DNA damage, early apoptotic changes, and mitochondrial membrane dysfunction in the human osteosarcoma cell line HS-Os-1, which was established from an osteoblastic tumor that arose in the left humerus of an 11-year-old girl and was already morphologically characterized in vitro and in vivo. We found that ROS formation and oxidative DNA damage were actually scarcely seen after irradiation of up to 30 Gy in these cells; that mitochondrial membrane potential was preserved; and that apoptotic changes were not demonstrated despite the relatively high-dose irradiation of 30 Gy. Therefore, the origin of the close similarity of radiosensitivity between adult articular chondrocytes and the human osteosarcoma cell line HS-Os-1, is considered to involve the low degree of ROS formation following irradiation; the similarity possibly results from the strong scavenging ability of these two kinds of cells for free radicals including hydroxyl radicals.

In breast cancer patients, several regimens of neoadjuvant chemotherapy have been developed in order to achieve prognostic advantages for individual patients. Though some percentages of breast cancer patients show clinically complete response to neoadjuvant chemotherapy, the histopathological specimens of these patients demonstrate a considerably high frequency of the existence of residual disease. In this study, we aimed to evaluate the therapeutic effect of neoadjuvant chemotherapy for breast cancer patients showing clinically complete response (cCR) to neoadjuvant chemotherapy, using thin-section (5 mm) helical CT (prone position) with bolus injection of contrast agent. Between April 1994 and March 2002, 9 patients with breast cancer showing cCR to the neoadjuvant chemotherapy, who had undergone thin-section CT study both before and following neoadjuvant chemotherapy, enrolled in the study. The mean age of the patients was 46.2 years and all of them were female. The clinical stages were, 8 patients in stage II, and one in stage IIIA. In the CT evaluation, residual disease was visualized in 5 out of the 9 patients. Histopathological examination disclosed the existence of residual cancers in 6 out of the 9 patients, but only non-invasive cancer was revealed in 1 out of the 6. As patients having residual disease composed only of non-invasive cancer are classified into the pathologically complete response group according to the WHO classification, 4 out of these 9 patients showing clinically complete response to the neoadjuvant chemotherapy were classified into pCR (pathologically complete response) group, and another 5 were classified into the pPR (pathologically partial response) group. As a result, the diagnostic accuracy of the second CT study performed after neoadjuvant chemotherapy was evaluated as 77.8%, with a sensitivity of 80.0%, a specificity of 75.0%, a positive predictive value (PPV) of 80.0%, and a negative predictive value (NPV) of 75.0%. Therefore, for precise evaluation of the neoadjuvant chemotherapeutic effect for breast cancer, thin-section CT studies are considered to be essential.

One-third of the breast cancer patients who underwent tamoxifen intake showed less than 0.9 of their liver/spleen CT (computed tomography) ratio on their annual CT study, and were diagnosed as having fatty liver (hepatic steatosis). Among them, patients who showed a lower liver/spleen CT ratio of less than 0.5 were recommended to undergo needle biopsy of the liver in order to obtain histopathological confirmation of non-alcoholic steatohepatitis (NASH), with 15 patients undergoing needle biopsy of the liver. As a result, 14 out of the 15 patients were diagnosed as having NASH, and these patients were additionally administered bezafibrate in order to prevent possible progressive changes of NASH into liver cirrhosis. In this study, we show the changes of follow-up CT findings of 6 patients with histopathologically-proven NASH who continued to undergo bezafibrate intake after the diagnosis of NASH. Two patients showed almost complete improvement as indicated by the liver/spleen CT ratio several months after completion of a tamoxifen intake of 5 years, and another 3 showed partial improvement on their liver/spleen CT ratio by bezafibrate intake in spite of continuing tamoxifen intake. Another patient with diabetes mellitus (type II) showed a continually decreasing liver/spleen CT ratio during adjuvant tamoxifen in spite of bezafibrate intake. Therefore, we concluded that the progression of NASH could be prevented by bezafibrate without any interruption of adjuvant tamoxifen treatment. For patients with diabetes mellitus, critical follow-up using CT study and laboratory tests is considered essential.

In breast cancer patients, several regimens of neoadjuvant chemotherapy have been developed in order to achieve prognostic advantages for individual patients. Though some percentages of breast cancer patients show clinically complete response to neoadjuvant chemotherapy, the histopathological specimens of these patients demonstrate a considerably high frequency of the existence of residual disease. In this study, we aimed to evaluate the therapeutic effect of neoadjuvant chemotherapy for breast cancer patients showing clinically complete response (cCR) to neoadjuvant chemotherapy, using thin-section (5 mm) helical CT (prone position) with bolus injection of contrast agent. Between April 1994 and March 2002, 9 patients with breast cancer showing cCR to the neoadjuvant chemotherapy, who had undergone thin-section CT study both before and following neoadjuvant chemotherapy, enrolled in the study. The mean age of the patients was 46.2 years and all of them were female. The clinical stages were, 8 patients in stage II, and one in stage IIIA. In the CT evaluation, residual disease was visualized in 5 out of the 9 patients. Histopathological examination disclosed the existence of residual cancers in 6 out of the 9 patients, but only non-invasive cancer was revealed in 1 out of the 6. As patients having residual disease composed only of non-invasive cancer are classified into the pathologically complete response group according to the WHO classification, 4 out of these 9 patients showing clinically complete response to the neoadjuvant chemotherapy were classified into pCR (pathologically complete response) group, and another 5 were classified into the pPR (pathologically partial response) group. As a result, the diagnostic accuracy of the second CT study performed after neoadjuvant chemotherapy was evaluated as 77.8%, with a sensitivity of 80.0%, a specificity of 75.0%, a positive predictive value (PPV) of 80.0%, and a negative predictive value (NPV) of 75.0%. Therefore, for precise evaluation of the neoadjuvant chemotherapeutic effect for breast cancer, thin-section CT studies are considered to be essential.

In breast cancer patients, the number of surgically resected metastatic axillary lymph nodes has been considered to correlate closely with patient prognosis. Therefore, if metastatic lymph nodes could be controlled by neoadjuvant chemotherapy pre-operatively, we would be able to select a more appropriate regimen of post-operative chemotherapy for the individual patient and expect prognostic advantages of each patient with node-positive breast cancer. In this study, we aimed to evaluate the therapeutic effect of neoadjuvant chemotherapy for metastatic lymph nodes of node-positive breast cancer patients, using thin-section (5 mm) helical CT (prone-position) with bolus injection of contrast agent. Between April 1994 and March 2002, 49 patients with node-positive breast cancer who had undergone thin-section CT study both before and following neoadjuvant chemotherapy enrolled in the study. The mean age of the patients was 48.9 years and all were female. Concerning metastatic lymph nodes status, 45 patients were classified as N1, 2 patients as N2, and another 2 as N3. In the evaluation, if at least one lymph node of >5 mm in the short diameter was detected on the CT study, the case was classified as node-positive. For lymph nodes of >1 cm in short diameter, fine-needle aspiration biopsy guided by ultrasonography was performed in order to obtain pathological confirmation of the existence of cancer metastasis. The diagnostic results of the CT study were compared with the pathologic findings of the resected specimen operatively. The neoadjuvant chemotherapy consisted of 3 to 4 times of CAF chemotherapy and an anti-estrogen agent, and intra-arterial infusion chemotherapy was also performed in patients with lymph node status of N2 or N3. The axillary status of 15 (30.6%) out of the 49 patients was evaluated as N0 after neoadjuvant chemotherapy, and 14 out of the 15 patients were confirmed as node-negative based on the pathological results. Therefore, the diagnostic accuracy of the second CT study performed following the neoadjuvant chemotherapy was 85.7%, with a sensitivity of 96.6%, a specificity of 70.0%, a positive predictive value of 82.4%, and a negative predictive value of 93.3%. The results described above demonstrate that such a sophisticated and precise CT study performed following neoadjuvant chemotherapy and evaluating the therapeutic effect on metastatic lymph nodes following the neoadjuvant chemotherapy can help to determine an appropriate regimen of post-operative chemotherapy and be of prognostic advantage in patients with node-positive breast cancer.

Previously, we examined the formation of reactive oxygen species (ROS) in T lymphocytes following 5 Gy of irradiation. Using a CCD camera system, we monitored fluorescence in T lymphocytes loaded with the succinimidyl ester of dichlorodihydrofluorescein diacetate (H2DCFDA), which is non-fluorescent until oxidized by ROS. We found that ROS formation occurred immediately after irradiation, continued for several hours, and resulted in oxidative DNA damage. Therefore, the origin of the hyper-radiosensitivity of T lymphocytes seemed to be the high production of ROS in the mitochondrial DNA following irradiation. In this study, we examined radiation-induced ROS formation in adult articular chondrocytes, which were demonstrated to be highly resistant to apoptosis in our previous study. We found that ROS formation was actually scarcely seen after irradiation of up to 20 Gy in these cells. Therefore, the origin of the great difference of radiosensitivity between T lymphocytes and adult articular chondrocytes is considered to lie in the degree of ROS formation following irradiation, with this difference possibly resulting from the scavenging acuity of these two kinds of normal tissue cells for free radicals including hydroxyl radicals.

The mechanism leading to the high level of radiosensitivity of T lymphocytes has not yet been fully described. In our previous study, we demonstrated that human peripheral T lymphocytes revealed early apoptotic changes (annexin V-positive) and late apoptotic changes (propidium iodide-positive), at 13 and 24 h after irradiation of 5 Gy, respectively. Changes in mitochondrial membrane potential were observed at 10 h after irradiation of 5 Gy. Subsequently, mitochondrial cytochrome c release was confirmed. In order to elucidate the mechanism which occurs prior to the mitochondrial membrane potential changes, we examined in the present study the radiation dose and the timing of oxidative DNA damage induced in human peripheral T lymphocytes following 10 MV X-ray irradiation. As a result, the production of 8-oxoguanine, i.e., the product of oxidative DNA damage, was clearly identified starting at 10, 6, and 3 h, after 2, 5, and 20 Gy of irradiation, respectively. Therefore, we concluded that it remains necessary to evaluate the extent of radiation-induced oxidative DNA damage. Furthermore, it is important to analyze superoxide radical production and scavenging in terms of the variety of radiosensitivities found among various types of normal tissue cells and neoplastic cells.

We have evaluated the distribution of fatty infiltration in the liver for determination of a suitable biopsy site for diagnosis of tamoxifen-induced non-alcoholic steatohepatitis (NASH) in patients with breast cancer. Thirty-eight consecutive breast cancer patients undergoing tamoxifen treatment were analyzed by CT to identify hepatic steatosis (HS) via calculation of the liver/spleen CT ratio in Couinaud's 8 areas. We defined hepatic fatty infiltration as a liver/spleen ratio of less than 0.9. The extent and distribution of the fatty infiltration was assessed using the liver/spleen ratio of the patients who had the lowest CT ratio below 0.9 in the 8 areas. Thirteen (34.2%) of the 38 patients had hepatic fatty infiltration. The liver/spleen ratios of each area differed significantly in all patients (p

We examined sequential changes in post-irradiated peripheral blood T cells taken from normal volunteers, using a microscopy-video system, mitochondrial membrane potential assay, annexin V, propidium iodide, and cytochrome c ELISA kit. After 5 Gy irradiation with 10 MV X-ray from a linear accelerator, the percentages of apoptotic T cells were estimated as approximately 5, 10, 20, 35, and 70%, at 0, 3, 6, 10, and 20 h after irradiation, respectively, as observed with the microscopy-video system. Using a CCD camera-equipped fluorescence microscope and MitoCapture, a mitochondrial membrane potential indicator, approximately half of the T cells showed dysfunction of mitochondrial membrane potential at 10 h after 5 Gy irradiation. With regard to annexin V and propidium iodide, approximately 40 and 5% of the human peripheral T cells showed positivity against annexin V and propidium iodide at that time, respectively. Mitochondrial cytochrome c release from the mitochondria to the cytosol was confirmed to start at 10 h and to reach a maximum at 20 h after 5 Gy of irradiation. These results demonstrated that mitochondrial cytochrome c release occurred following dysfunction of mitochondrial membrane potential in radiation-induced T cell apoptosis.

An elderly patient with breast cancer received toremifene monotherapy for one year, and about 60% tumor remission rate was obtained. Since viability of the residual tumor was suspected on ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI), lumpectomy was performed under local anesthesia. The histopathological diagnosis was ductal carcinoma in situ (DCIS). The patient did not undergo axillary lymph node dissection or systemic chemotherapy. The patient is alive without disease under postoperative radiotherapy and toremifene treatment. Toremifene monotherapy and/or preoperative adjuvant therapy with toremifene alone may be useful methods for elderly patients with breast cancer considering the patients' quality of life.

Between August 1989 and September 1999, breast-conservation treatment (BCT) was performed in 250 of 256 breast cancer patients. Five of the 250 patients had bilateral breast cancer, and 4 with synchronous bilateral breast cancer of the 5 were concomitantly treated by chemo-endocrine therapy before simultaneous breast-conservation surgery for bilateral breast cancer. Chemotherapy was performed using cyclophosphamide, pirarubicin, and 5-fluorouracil, while endocrine therapy was performed using an antiestrogen agent (tamoxifen or toremifene). All patients were also treated by radiotherapy. Since no severe side effects or complications were induced by these therapeutic approaches, bilateral breast cancer may be successfully treated by BCT as in unilateral breast cancer. However, of the 5 patients with bilateral breast cancer, cancer recurrence in the axillary lymph nodes was detected only in 1 patient with T2N1 cancer 78 months after simultaneous breast-conservation surgery for bilateral breast cancer.