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Although reduction in the serum prostate specific antigen (PSA) correlates with clinical outcome for high dose rate Iridium-192 (HDR Ir-192) brachytherapy, it takes a long latency period. We investigated numerical chromosome changes of prostatic cancer during the pre- and post-treatment periods of HDR Ir-192 brachytherapy (and external beam radiotherapy), using fluorescence in situ hybridization (FISH) to clear the effect of treatment in early phase. Transitional changes in the frequency of aneuploidy for chromosomes 7, 8, 10, 12, 16, X, and Y in prostate cancer during the pre- and post-treatment periods were observed. Gains of chromosomes 7, 8 and 12 were noted in the pre-treatment samples (4 out of 12 cases in chromosomes 7 and 8; 1 out of 12 cases in chromosome 12), while a notable reduction in the number of cells with extra copies of these chromosomes was observed in post-treatment specimens. This change appears earlier than the reduction in the value of prostate specific antigen (PSA) and strongly reflects the effect of HDR brachytherapy with external beam radiotherapy in localized prostate cancer. Decrease in the number of cells with high ploidies of chromosomes 7, 8 and 12 at 12 weeks after treatment may predict clinical effects of radiation therapy, which may explain the radiation dependency of localized prostate cancer cells.

The effectiveness of granulocyte colony-stimulating factor (G-CSF) for granulocytopenia has been widely recognized. However, although granulocyte counts rapidly increase after a few injection of G-CSF, a large proportion of the increased granulocytes disappear from peripheral blood within a few days following G-CSF withdrawal. Where do they go? In this report, the answer can be seen at a glance. Using MitoCapture and a CCD camera-equipped fluorescence microscope, we succeeded in demonstrating that G-CSF withdrawal induced loss of mitochondrial membrane potential, i.e., an early stage of apoptosis, in human peripheral granulocytes increased by G-CSF.

We examined sequential changes in post-irradiated peripheral blood T cells taken from normal volunteers, by using targeted Atlas cDNA Expression Arrays and mitochondrial membrane potential assay. At 1 and 3 hours after 5 Gy irradiation, changes of gene expression were examined by targeted Atlas cDNA Expression Arrays using Apoptosis Array. The Atlas Human Apoptosis Array includes 205 key genes that are known to control apoptosis, including extracellular and cytoplasmic effectors. Concerning Fas, no significant changes of spot intensities were identified between irradiated T cells and non-irradiated ones at both 1 h and 3 h after 5 Gy irradiation. Caspase families, including caspases 9 and 3 also showed no changes between these two groups. An apoptosis regulator bclw showed a remarkable decrease in irradiated T cells. These results suggested that irradiation induced direct apoptosis of T cells by changing the membrane potential of mitochondria. Using a CCD camera-equipped fluorescence microscope and MitoCapture, a mitochondrial membrane potential indicator, we demonstrated 5 Gy radiation induced loss of membrane potential, i.e., an early stage of apoptosis, in human peripheral blood T cells at 10 hours after irradiation.

We have described fatty liver, diagnosed by computed tomography scanning (CT) in more than 30% of patients with breast cancer who received tamoxifen. Therefore, it is urgent to elucidate the frequency and the degree of fatty liver induced by toremifene, an analogue of tamoxifen, which is also used in breast cancer. We enrolled 52 breast cancer patients who were treated with breast-conservation treatment and administered oral toremifene for 3-5 years as adjuvant endocrine therapy. We evaluated the degree of fatty liver by abdominal CT performed annually. CT demonstrated toremifene-induced fatty liver in four (7.7%) of 52 breast cancer patients. Toremifene-induced fatty liver did not correlate with abnormal levels of AST, ALT, GGT or total cholesterol. One patient who demonstrated moderate fatty liver by CT was histologically diagnosed as non-alcoholic steatohepatitis (NASH) by liver biopsy. The incidence of toremifene-induced fatty liver was significantly lower than that induced by tamoxifen. Accordingly, in terms of fatty liver and NASH, toremifene is considered to be more appropriate agent than tamoxifen. Though toremifene is less likely to induce fatty liver, the possibility remains that toremifene-induced steatohepatitis occurs. Because the diagnosis of fatty liver or NASH can be easily missed if only a blood test is performed, it is necessary to screen fatty liver by annual CT examination for patients who receive an antiestrogen agent.

Fourteen cases with symptomatic ductal carcinoma in situ (DCIS) were treated with breast-conservation treatment intensified with endocrine therapy. Nine of 14 patients with palpable mass had tumor detected on mammography. CT, ultrasonography, and MRI were able to detect linear and/or spotty lesion or enhancement suggesting DCIS. Whereas these findings were not particular to DCIS, the combination of these modalities would be useful in deciding the extent of resection for DCIS. There was no patient selection for breast-conservation treatment in our department. All patients received tangential and boost radiation, and were treated with endocrine therapy using anti-estrogen drugs. The reason that nine cases had close margins (

In order to improve both cosmetic results and survival rates, we performed breast-conservation treatment (BCT) intensified with tamoxifen and CAF chemotherapy to 218 out of 224 patients who visited our department with the desire of breast-conservation between August 1989 to December 1998. Of these patients, 68 presented with tumors of stage I, and another 122 stage II. All patients were administered tamoxifen (for pre-menopausal women) or tremifene (for post-menopausal women) orally: tamoxifen and tremifene administration was started just after confirmation of the breast cancer based on the findings of fine-needle aspiration cytology. All patients underwent lumpectomy with or without axillary dissection (level I and II). For patients with T2 tumors, the lumpectomy was performed following two to four times of CAF chemotherapy. Following conservative surgery, patients were treated with radiation therapy to the intact breast and ipsilateral axilla to a total dose of 4400 cGy with a conedown to a total median dose of 5300 cGy. At the end of March 1999, the mean follow-up time was 49.0 months. In spite of high-positivity (approximately 30%) of microscopically surgical margin, local recurrence rate is considerably low, and only 2 patients experienced local recurrence. Cause-specific survival rate for patients of stage I is 100%, and that of stage II is 91.7% at 5 years. The cosmetic results of therapy were also considered good.

Most of malignant lymphomas have been shown to be relatively radiosensitive clinically, but some, especially recurrent ones, are frequently highly radioresistant. To clarify the origin of the difference, we examined ionizing radiation (IR)-induced apoptosis in three closely related human lymphoma cell lines (DL-40, DL-95, and DL-110) that differ in p53 status. DL-95 and DL-110 cells have a wild-type p53, whereas DL-40 cells carry a T to G transition in exon 5 of the p53 gene, resulting in a change of Cys to Phe at codon 176. Irradiation of DL-40 cells (mutant-type p53) with 5 Gy gamma-rays resulted in delayed apoptosis with membrane changes (annexin-V expression) 13 h after IR, and caspase-3 activation 23 h after IR, whereas apoptotic response was not identified in DL-95 cells until 48 h after IR in spite of their normal p53 status. Concerning DL-110 cells, delayed and reduced apoptotic response was revealed both microscopically and by DNA fragmentation assay. These results suggested that IR-induced apoptosis in DL-40 cells is mediated by a mechanism involving the caspase-3 cascade of the p53-independent pathway, and that some unknown mechanism inhibited IR-induced apoptosis in existence of wild-type p53, especially for DL-95 cells.

KIN-806 is one of the 2-nitroimidazole derivative hypoxic cell radiosensitizers. Its radiosensitizing effects and the degree of lung metastasis detected were evaluated and compared with its analogs KIN-804 and KIN-844. The immune reactions induced by these radiosensitizers were also analyzed. Female C3H/He mice and SCCVII tumor cells were used. Seventeen days after inoculation of SCCVII tumor cells into the animals, 0.4 g/kg of KIN-806, KIN-804, and KIN-844 was administered to each radiosensitizer group 30 min before 40 Gy was delivered as local irradiation. In each group, KIN-806, KIN-804, and KIN-844 markedly suppressed tumor regrowth in comparison with animals that received irradiation alone. There was no significant difference in the radiosensitizing effects among these three radiosensitizers. A marked suppression of lung metastasis and macrophage/T-lymphocyte infiltration into the tumor were observed only in the KIN-806-administered groups, regardless of the presence or absence of radiation therapy. It therefore appears likely that the lung metastasis suppression was caused by the immune reaction elicited by KIN-806, which is an excellent immunopotentiator as well as an effective radiosensitizer.

KIN-806 is one of the newly developed 2-nitroimidazole derivative hypoxic cell radiosensitizers. The tumor growth control and the suppression of lung metastasis induced by KIN-806 were evaluated. Female C3H/He mice and SCCVII tumor cells were used. 30 Gy or 40 Gy was delivered as local irradiation. 0.2 g/kg or 0.4 g/kg KIN-806 was administered 30 min before this treatment to the KIN-806 administered groups. The enhancement ratio of KIN-806 evaluated using the growth delay method was 1.8. KIN-806 showed an excellent effect as a radiosensitizer. Furthermore, KIN-806 suppressed lung metastasis regardless of radiation, and the control of the metastatic lung nodules did not depend on the irradiation dose but rather on the KIN-806 dose (0.2 g/kg < 0.4 g/kg). KIN-806 is a promising bifunctional radiosensitizer which promotes anti-tumor activity in addition to having a radiosensitizing effect.

Owing to recent advances in imaging technology and radiologic intervention, survival rates in patients with hepatocellular carcinoma have improved markedly. However, such prolonged survival has resulted in an increase in extrahepatic metastases. Tc-99m (Sn)-N-pyridoxyl-5-methyltryptophan (Tc-99m PMT), developed for hepatobiliary scintigraphy, has been used to visualize extrahepatic metastases, with most related reports limited to osseous metastases. The authors report two cases of hepatocellular cancer presenting as a hypopharyngeal metastasis and intraperitoneal dissemination along the tract of a fine-needle biopsy. Lesions undetectable on planar imaging could be visualized by Tc-99m PMT SPECT.

Although p53 has been shown to directly activate transcriptional bax gene and to inhibit expression of bcl-2 gene during radiation-induced apoptosis, it is poorly understood how the Bcl-2 family changes in p53-deficient cells during radiation-induced apoptosis. The present work describes the effect of X-irradiation on the apoptosis of p53-deficient HL-60 cells as assessed by means of several methods. Apoptosis of HL-60 cells was induced by X-irradiation in a dose- and time-dependent manner. 18 h after 5 Gy irradiation, G2 cells underwent apoptosis, while 15 Gy X-irradiation induced the death of G1/S cells by 6 h. After X-irradiation, expression of Bcl-2 was elevated, while Bax expression was unchanged. We have isolated a clonal HL-60 variant following twice 5 Gy irradiation of HL-XR3 cells. These cells highly expressed Bcl-2 (about 2-fold), showed a reduced activation of caspase-3, and were not only more resistant to X-irradiation-induced apoptosis but also more radioresistant. These results suggest that HL-60 cells may resist apoptosis and radiation by increasing Bcl-2 expression, and that this elevated Bcl-2 expression might be one of the causes of the phenomenon, often seen clinically, that tumor cells gradually acquire radioresistance during fractionated radiation therapy.

4785 Background: In recent years, high-dose-rate (HDR) brachytherapy combined with external beam radiotherapy (EBRT) has come to perform for localized prostate cancer (PC) in Japan. The aim of this study is to report the clinical control rate of patients with HDR brachytherapy combined with EBRT for localized PC. Methods: We enrolled 33 PC patients treated with HDR brachytherapy combined with EBRT between July 1999 and June 2002. Patient age ranged from 55 to 81 years (mean 73). Of the 33 patients, 9, 10, and 14 belong to low risk (stage≤T2, PSA≤10 ng/mL, and Gleason score 10 ng/mL, or Gleason score≥7 (1 intermediate risk factor), and high risk group (2 or more intermediate risk factor), respectively. Nine patients had received neoadjuvant hormonal therapy, which was stopped at the beginning of RT in all cases. Patients in this series were treated on two protocols. In the initial protocol, patients in high risk group were treated with whole pelvis EBRT to 45 Gy in 25 f...