Susumu Tanji

Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase.

Resveratrol is a natural polyphenolic compound and has been shown to exhibit cardio-protective as well as anti-neoplastic effects on various types of cancers. However, the exact mechanism of its anti-tumor effect is not clearly defined. Resveratrol has been shown to have strong hypolipidemic effect on normal adipocytes and as hyper-lipogenesis is a hallmark of cancer cell physiology, the effect of resveratrol on lipid synthesis in cancer stem-like cells (CD24−/CD44+/ESA+) that were isolated from both ER+ and ER− breast cancer cell lines was examined. The authors found that resveratrol significantly reduced the cell viability and mammosphere formation followed by inducing apoptosis in cancer stem-like cells. This inhibitory effect of resveratrol is accompanied by a significant reduction in lipid synthesis which is caused by the down-regulation of the fatty acid synthase (FAS) gene followed by up-regulation of pro-apoptotic genes, DAPK2 and BNIP3. The activation of apoptotic pathway in the cancer stem-like cells was suppressed by TOFA and by Fumonisin B1, suggesting that resveratrol-induced apoptosis is indeed through the modulation of FAS-mediated cell survival signaling. Importantly, resveratrol was able to significantly suppress the growth of cancer stem-like cells in an animal model of xenograft without showing apparental toxicity. Taken together, the results of this study indicate that resveratrol is capable of inducing apoptosis in the cancer stem-like cells through suppression of lipogenesis by modulating FAS expression, which highlights a novel mechanism of anti-tumor effect of resveratrol.

INHIBITION OF TUMOR GROWTH AND ANGIOGENESIS BY VITAMIN D3 AGENTS IN MURINE RENAL CELL CARCINOMA

PURPOSE To investigate the effect of active vitamin D3(VD) agents on tumor growth and metastasis. MATERIALS AND METHODS BALB/c mice were inoculated with murine renal cancer Renca and graded doses of 1,25-dehydrovitamin D3 or 1- hydrovitamin D3 were given intraperitoneally every other day beginning on day 1, 3, or 7 and ending on day 9, 11, or 15. Direct cytocidal activity and angiogenic activity were evaluated by 48-hour MTT assay and by the colorimetric method, respectively. RESULTS Both VD agents inhibited tumor growth and prolonged the life span of Renca-bearing mice in a dose-dependent manner and both suppressed tumor growth in athymic mice and euthymic mice with eliminated NK activity. Marginal body-weight loss without appreciable hypercalcemia was observed in mice given VD agents. When treatment was delayed on day 7, the VD agents failed to inhibit tumor growth. The MTT assay showed no direct cytotoxicity of VD agents on Renca. Tumor angiogenesis was inhibited to 46 to 30% of the control level by VD agents. Furthermore, VD agents reduced pulmonary and hepatic foci in the metastatic models. CONCLUSIONS These results suggest that VD agents may be effective as a treatment for renal cell carcinoma, especially when micrometastases are involved.

Vitamin D receptor gene polymorphisms are associated with increased risk and progression of renal cell carcinoma in a Japanese population.

Aim:  Biological and epidemiologic data suggest that 1 alpha, 25 dihydroxyvitamin D3 (1,25(OH)2D3) levels may influence development of renal cell carcinoma. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of 1,25(OH)2D3 and additionally interacts with other cell signaling pathways that influence cancer progression. VDR gene polymorphisms may play an important role in risk of incidence for various malignant tumors. This study investigated whether VDR gene polymorphisms were associated with increased risk and prognosis of renal cell carcinoma (RCC) in a Japanese population.

Detection of the presence of catalytic subunit mRNA associated with telomerase gene in exfoliated urothelial cells from patients with bladder cancer

PURPOSE Telomerase has an important role in the immortalization and oncogenesis of human cancer cells, and it appears to be a promising new marker for carcinogenesis. We investigated whether expression of the catalytic subunit of telomerase using reverse transcriptase-polymerase chain reaction (RT-PCR) can be detected in exfoliated cells in bladder washing from patients with bladder cancer. MATERIALS AND METHODS Exfoliated cells in bladder washing and voided urine samples from patients with and without bladder cancer were analyzed. To determine the number of cells required for successful detection of the subunit using RT-PCR bladder tumor cell lines were used. RESULTS At least 1 x 10(4) cells were needed in the cell line study for RT-PCR of the subunit. The number of cells in bladder washing fluid and voided urine specimens was more than 5 x 10(4). Human telomerase RT (hTERT) mRNA was expressed in 62 of the 82 bladder washing fluid specimens from patients with bladder cancer but in only 2 of the 86 with benign urological disorders. Overall sensitivity for hTERT was 75.6%, that is 52.4%, 80% and 93.8% for grades 1 to 3 tumors, respectively. In contrast, human telomerase associated protein 1 mRNA was expressed in 17 of the 18 patients with and in 12 of the 23 without cancer. Overall sensitivity for human telomerase associated protein 1 was 94.4%. In 4 (57.1%) of 7 spontaneously voided urine specimens from patients with bladder cancer hTERT mRNA expression was detected. CONCLUSIONS Detecting hTERT mRNA expression in exfoliated cells in bladder washing samples is more useful for the diagnosis, screening and followup of patients with bladder cancer.

Telomerase activity in human renal cell carcinoma

Purpose : Telomerase activity has been detected in a wide variety of human tumors. The present study evaluated telomerase activity in association with the acquisition of renal cell carcinoma (RCC).

Differences between intraoperative ultrasound-based dosimetry and postoperative computed tomography-based dosimetry for permanent interstitial prostate brachytherapy

PURPOSE To compare the results of intraoperative ultrasound (US)-based dosimetry with those of postimplant computed tomography (CT)-based dosimetry after (125)I prostate brachytherapy. METHODS AND MATERIALS Subjects comprised 160 patients who underwent prostate brachytherapy using (125)I seed implants. Prescribed dose was set as 145 Gy to the periphery of the prostate. Implantation was performed using an intraoperative interactive technique. Postimplant dosimetry was performed on Days 1 and 30 after implantation using CT. Dosimetric results for the prostate, urethra, and rectum were compared among intraoperative US and CT on Day 1 (CT(1)) and Day 30 (CT(30)). RESULTS Mean minimal dose received by 90% of prostate volume was 133.7%, 115.6%, and 125.8% of the prescribed dose on US, CT(1), and CT(30), respectively: This value temporarily decreased on Day 1 and increased on Day 30. Other parameters for the prostate and urethra showed similar trends. Conversely, mean rectal volume receiving 100% of the prescribed dose was 0.69, 0.46, and 1.02 mL on US, CT(1), and CT(30), respectively. Rectal parameters tended to be underestimated on US relative to CT(30)-based dosimetry. A positive linear relationship was identified between US and CT observations for every prostate parameter and the dose covering 30% of the urethra. CONCLUSIONS Our results demonstrate significant differences between dosimetric parameters obtained by US, CT(1), and CT(30). However, significant correlations also exist between US and CT, at least in prostate and urethral parameters. Clarification of the degrees of difference might make US planning more feasible.

Neoadjuvant Gemcitabine Plus Carboplatin for Locally Advanced Bladder Cancer

OBJECTIVE Although cisplatin-based neoadjuvant chemotherapy followed by cystectomy was demonstrated to improve the survival among patients with locally advanced bladder cancer, its severe adverse events, including nephrotoxicity, are critical issues. We investigated the safety and activity of carboplatin, a mild nephrotoxic agent, combined with gemcitabine as a neoadjuvant chemotherapy compared with methotrexate, vinblastine, doxorubicin and cisplatin for patients with locally advanced bladder cancer. METHODS We retrospectively evaluated 68 patients with locally advanced bladder cancer who received neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (n = 34) or gemcitabine and carboplatin (n = 34) followed by cystectomy at our institute. The adverse events, chemotherapy delivery profile, rate of down-stage and recurrence-free survival were assessed for methotrexate, vinblastine, doxorubicin and cisplatin compared with gemcitabine and carboplatin. RESULTS The mean cycles of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, were 2.5 and 2.7, respectively. The hematologic adverse events of Grade 3 or 4 neutropenia, anemia and thrombocytopenia for methotrexate, vinblastine, doxorubicin and cisplatin were 15, 18 and 0%, respectively. The occurrences for gemcitabine and carboplatin were 53, 21 and 50%, respectively. Grade 3 or 4 non-hematologic toxicities for methotrexate, vinblastine, doxorubicin and cisplatin were nausea and vomiting in 24%, and were not observed for gemcitabine and carboplatin. The lowest median estimated glomerular filtration rate during methotrexate, vinblastine, doxorubicin, and cisplatin and gemcitabine and carboplatin was 55.8 and 70.6 ml/min/1.73 m(2), respectively (P = 0.002). The rate of down-stage to pT1 or less was 59% for methotrexate, vinblastine, doxorubicin and cisplatin, and 53% for gemcitabine and carboplatin (P = 0.624). The recurrence-free survival of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, at 36 months from the diagnosis was 79 and 75%, respectively (P = 0.85). CONCLUSIONS Neoadjuvant gemcitabine and carboplatin showed less non-hematologic toxicity than methotrexate, vinblastine, doxorubicin and cisplatin, and especially less nephrotoxicity was demonstrated for gemcitabine and carboplatin. Although observed during the short term, the recurrence-free survival for gemcitabine and carboplatin was comparable to that for methotrexate, vinblastine, doxorubicin and cisplatin.

Three-dimensional summation of rectal doses in brachytherapy combined with external beam radiotherapy for prostate cancer

BACKGROUND AND PURPOSE To determine the dose constraints for rectal bleeding in brachytherapy (BRT) combined with external beam radiotherapy (EBRT). MATERIALS AND METHODS Post-BRT, pelvic computed tomography images were used for subsequent EBRT planning and BRT postplans in 37 patients. The physical doses for each plan were converted to biologically effective doses, and corresponding voxel doses were integrated to plot the summed dose-volume histogram (sum-DVH). Between 5 patients with (bled-pts) and 32 without (spared-pts) grade 2 or 3 rectal bleeding, the differences in the mean minimal dose (rDn) covering the rectal volume of 0.5-10.0 cc and the rectal volume (rVn) receiving the calculated dose of 20-150Gy were compared. RESULTS The differences in the summed-rDn were determined by BRT exposure, while those of the summed-rVn were determined in the low-dose range and superimposed in the high-dose range by EBRT exposure. Of the 13 patients with rV150 of >1.2 cc, 4 were bled-pts (30.8%). Of the 24 patients with rV150 of ≤ 1.2cc, 1 was a bled-pts (4.2%) (p=0.024; odds ratio, 10.2; CI (95%), 1.0-104.3). CONCLUSIONS The mono-scale DVH analysis is a promising method for exploring the threshold for rectal bleeding in combined radiotherapy.

Narrow safety range of intraoperative rectal irradiation exposure volume for avoiding bleeding after seed implant brachytherapy

Background & PurposeRectal toxicity is less common after 125I seed implant brachytherapy for prostate cancer, and intraoperative rectal dose-volume constraints (the constraint) is still undetermined in pioneering studies. As our constraint failed to prevent grade 2 or 3 rectal bleeding (bled-pts) in 5.1% of patients, we retrospectively explored another constraint for the prevention of rectal bleeding.Materials and methodsThe study population consisted of 197 patients treated with the brachytherapy as monotherapy using real-time intraoperative transrectal ultrasound (US)-guided treatment at a prescribed dose of 145 Gy. Post-implant dosimetry was performed on Day 1 and Day 30 after implantation using computed tomography (CT) imaging. Rectal bleeding toxicity was classified by CTC-AE ver. 3.0 during a mean 29-month (range, 12-48 months) period after implantation. The differences in rV100s were compared among intraoperative, Day 1 and Day 30 dosimetry, and between that of patients with grade 2 or 3 rectal bleeding (the bled-pts) and of the others (the spared-pts). All patients were divided into groups based on provisional rV100s that were increased stepwise in 0.1-cc increments from 0 to 1.0 cc. The difference in the ratios of the bled-pts to the spared-pts was tested by chi-square tests, and their odds ratios were calculated (bled-OR). All statistical analyses were performed by t-tests.ResultsThe mean values of rV100us, rV100CT_1, and rV100CT_30 were 0.31 ± 0.43, 0.22 ± 0.36, and 0.59 ± 0.68 cc, respectively. These values temporarily decreased (p = 0.020) on Day 1 and increased (p = 0.000) on Day 30. There was no significant difference in rV100s between the bled-pts and spared-pts at any time of dosimetry. The maximum bled-OR was identified among patients with an rV100us value above 0.1 cc (p = 0.025; OR = 7.8; 95% CI, 1.4-145.8); an rV100CT_1 value above 0.3 cc (p = 0.014; OR = 16.2; 95% CI, 3.9-110.7), and an rV100CT_30 value above 0.5 cc (p = 0.019; OR = 6.3; 95% CI, 1.5-42.3).ConclusionBy retrospective analysis exploring rV100 as intraoperative rectal dose-volume thresholds in 125I seed implant brachytherapy for prostate cancer, it is proved that rV100 should be less than 0.1 cc for preventing rectal bleeding.

Perinephric angiomyolipoma: A unique development pattern surrounding the kidney

Abstract  We report a case of a 31‐year‐old man with extrarenal angiomyolipoma of the perinephric space. He presented with asymptomatic macrohematuria. Computed tomography of the abdomen revealed a large perinephric mass which was separated from the right kidney and its unique growth appeared to have surrounded the kidney. Extrarenal angiomyolipomas of the perinephric fat are rare and they should be considered in the differential diagnosis of a retroperitoneal mass where asymptomatic macrohematuria was presented at the onset.