Early androgen suppression may reduce disease progression and improve long term survival compared with deferred androgen suppression in locally advanced prostate cancer.
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Comment↗
Biomedical subjects
Hideyuki Akaza
Publications and source records attributed to Hideyuki Akaza.
Antineoplastic activity of honey in an experimental bladder cancer implantation model: in vivo and in vitro studies.
OBJECTIVES: The antitumor effect of bee honey against bladder cancer was examined in vitro and in vivo. METHODS: Three human bladder cancer cell lines (T24, 253J and RT4) and one murine bladder cancer cell line (MBT-2) were used in these experiments. In an in vitro study, the antitumor activity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay, 5-Bromodeoxyuridine (BrdU) labeling index and flowcytometry (FCM). In the in vivo study, cancer cells were implanted subcutaneously in the abdomens of mice, and the effects were assessed by the tumor growth. RESULTS: In vitro studies revealed significant inhibition of the proliferation of T24 and MBT-2 cell lines by 1-25% honey and of RT4 and 253J cell lines by 6-25% honey. BrdU labeling index was significantly lower. FCM showed lower S-phase fraction, as well as absence of aneuploidy compared with control cells. In the in vivo studies, intralesional injection of 6 and 12% honey as well as oral ingestion of honey significantly inhibited tumor growth. CONCLUSION: Bee honey is an effective agent for inhibiting the growth of T24, RT4, 253J and MBT-2 bladder cancer cell lines in vitro. It is also effective when administered intralesionally or orally in the MBT-2 bladder cancer implantation models. Our results are promising, and further research is needed to clarify the mechanisms of the antitumor activity of honey.
Administration, Intravesical↗
Protecting spermatogonia from apoptosis induced by doxorubicin using the luteinizing hormone-releasing hormone analog leuprorelin.
PURPOSE: The present study was performed to investigate the protective effect of leuprorelin (LH-RH analog), on spermatogonia apoptosis induced by doxorubicin (DXR) in the Sprague-Dawley rat model. METHODS: Twenty-four adult male rats were divided into the following four groups: (i) control group; (ii) group given doxorubicin (intravenous injection, 8 mg/kg); (iii) group given leuprorelin (subcutaneous injection, 3 mg/kg); and (iv) group given both doxorubicin (intravenous injection, 8 mg/kg) and leuprorelin (subcutaneous injection, 3 mg/kg). Evaluation for quantification of apoptotic spermatogonia was made by the ratio of TUNEL-labeled spermatogonia versus 100 Sertoli cells in each seminiferous tubule. Two hundred seminiferous tubules of each rat were assessed. RESULTS: The ratio of apoptotic spermatogonia versus 100 Sertoli cells at stages II-IV of the groups given DXR (groups 2 and 4) were significantly higher than those of the other groups. However, the value at stages II-IV of the group given both DXR and leuprorelin (group 4) was significantly lower than that of the group given DXR (group 2). CONCLUSION: The significant prophylactic effect (P < 0.05) of LH-RH analog against doxorubicin-induced spermatogonial apoptosis was observed in a stage specific manner by microscopic evaluation with TUNEL.
Analysis of Variance↗
Paclitaxel, ifosfamide and cisplatin regimen is feasible for Japanese patients with advanced germ cell cancer.
BACKGROUND: Paclitaxel, ifosfamide and cisplatin (TIP) has been tested with successful results on metastatic testicular cancer in Western countries. Because paclitaxel, the key drug of this regimen, has not been approved for testicular cancer in Japan, there are no established data concerning TIP. The purpose of this study was to assess the feasibility of a TIP regimen for Japanese patients with advanced germ cell cancer. METHODS: Eight patients with advanced germ cell cancer were treated with TIP that was originally reported by Motzer et al (1). The treatment was used for three refractory cases and two late relapse cases as salvage therapy and for three poor-risk cases with extra-pulmonary visceral metastases as a part of induction chemotherapy. TIP consisted of paclitaxel 175 mg/m(2) by 24 h infusion on day 1, followed by ifosfamide 1.2 g/m(2) infusions over 2 h and cisplatin 20 mg/m(2 )given over 2 h on days 2-6. RESULTS: Five patients (62%) achieved a disease-free status after chemotherapy and surgical resection of residual tumor. Three of five patients have remained continuously free from disease progression at a median follow-up duration of 24 months and one additional patient is currently free of evidence of disease. Most patients developed grade 3 or 4 leukocytopenia and thrombocytopenia; however, they could be managed with routine supportive care. Sensory neuropathy was frequently seen, but no patient experienced over grade 3 neurotoxicity. CONCLUSIONS: TIP regimen as salvage chemotherapy is feasible for Japanese patients with advanced germ cell cancer. TIP as a part of induction chemotherapy for poor-risk patients is also feasible; however, larger and longer-term follow-up studies are needed to define the role of TIP in this setting.
Adult↗
[Globalization of clinical trials].
Based on reviews of the Japanese clinical trial situation in lung cancer, gastric cancer, prostate cancer and breast cancer, it was clear that much progress has been made in short time. There are considerable differences between Japan and the West and also differences between clinical areas in Japan. For regulatory purposes bridging studies have become increasingly important. Use of identical protocols are required for effective bridging. Participations in global phase III trials is the best way of achieving registration in Japan. For successful global trials in Japan it is important to include Japanese investigators in the preparation of the protocol and to recognise the challenges facing such a project. Clinical practice in diagnosis and treatment have many differences, thus it is recommended to have clear and detailed information in the protocol. Hard end points like survival are important since they are not biased by cultural differences. There are clear difficulties with HE or QOL outcomes. The emergence of focus on evidence based medicine is also happening in Japan and will help to harmonize documentation across the world. For large adjuvant or prevention cancer global trials are essential. To facilitate global studies further development of infrastructure is necessary in Japan. Use of electronic data capture web based communication etc. will help overcome communication difficulties. Other improvements that will make Japanese participation in global trials easier and better include establishment of clinical trial centre at each hospital, introduction of trial coordinators or study nurses and an improved collaboration with company staff. A critical issue that also need addressing is agreement of centre target recruitment. We need to introduce a new flexible system in Japan if participation in global trial is to be optimised. If we can address these issues Japanese investigators and collaborative groups should be able to initiate and lead global trials in the future.
Antineoplastic Agents↗
Detection of cadherin-6 mRNA by nested RT-PCR as a potential marker for circulating cancer cells in renal cell carcinoma.
To detect circulating RCC cells, we established a nested RT-PCR system for cadherin-6 mRNA, which is specifically expressed in RCC. A total of 121 samples of peripheral blood (34 healthy volunteers and 87 patients with RCC) were analyzed in this study. Total RNA of the monocyte fraction of the blood was extracted, then nested RT-PCR using specific primers was performed to detect mRNA of N-cadherin or cadherin-6. Nested RT-PCR revealed that expression of cadherin-6 mRNA was not present in the blood of most healthy volunteers (absent in 32/34), but positive expression was observed in the blood at concentrations of 10 cells/ml or greater of the SKRC-33 RCC cell line, which is a strong expresser of cadherin-6. In peripheral blood from patients with metastatic disease, cadherin-6 mRNA was detected in 70.4% (19/27). Messenger RNA of cadherin-6 was detectable in 45.0% (27/60) of patients with localized tumors. The PCR-based detection system for peripheral blood samples from patients with metastatic disease could reveal the presence of circulating RCC cells in the blood. Detection of cadherin-6 mRNA in non-metastatic presurgical RCC patients suggests that careful follow-up study is necessary in these patients.
Adult↗
Identification of a type III secretion system in uropathogenic Escherichia coli.
To determine virulence-related genes in uropathogenic Escherichia coli (UPEC) showing invasiveness to T-24 bladder cancer cells, genomic subtractive hybridization was performed between a highly invasive and a less invasive strain. Forty-nine DNA fragments were isolated from the invasive strain. One of them showed homology with Salmonella invA gene. By chromosomal walking of the strain, a type III secretion system that has been described in E. coli O157:H7 was identified on the genome of the invasive strains. Three strains out of 100 UPEC isolates had a type III secretion system inserted at 64 min of the chromosome, corresponding to E. coli K-12 MG1655. This finding suggested that the type III secretion system could play a part in uropathogenicity of UPEC.
Bacterial Chromatophores↗
Type 1, P and S fimbriae, and afimbrial adhesin I are not essential for uropathogenic Escherichia coli to adhere to and invade bladder epithelial cells.
Fimbrial (type 1, P, and S) and afimbrial adhesins, the unique virulence traits of uropathogenic Escherichia coli (UPEC), are well recognized for their role in the initial step of uropathogenesis. In this study, we investigated whether these adhesins are dispensable for UPEC in adherence and invasion of uroepithelial cells by using E. coli isolates (n=40) from cystitis patients and T-24 cells, the bladder carcinoma cell line. We found all isolates adherent to T-24 cells within 15 min of infection. In invasion assay, all isolates could invade T-24 cells to a variable degree; 22.5% of them were found highly invasive. About 33% of isolates that do not have any recognized adhesins were as invasive as other isolates. The amplitude of invasiveness was also independent of the adhesins. In conclusion, this study demonstrates that type 1 fimbriae, P fimbriae, S fimbriae, and afimbrial adhesin I are not required for UPEC to adhere to and invade uroepithelial cells.
Adhesins, Escherichia coli↗
Surface antigen expression on bladder tumor cells induced by bacillus Calmette-Guérin (BCG): A role of BCG internalization into tumor cells.
BACKGROUND: The antitumor mechanisms of bacillus Calmette-Guérin (BCG) against bladder cancer is still unclear. We previously reported that BCG was internalized by and survived within murine bladder tumor cells (MBT-2) for at least 40 days. In the present study, we investigated the effect of BCG on the surface antigen expression of bladder tumor cells and the characteristics of these cells as antigen-presenting cells in vitro. METHODS: Surface antigen (major histocompatibility complex (MHC) Class II, CD1, CD80 and intercellular adhesion molecule-1 (ICAM-1)) expression on BCG-treated murine (MBT-2) and human (T-24, J82) bladder tumor cells were analyzed using flow cytometry. The production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) from murine lymphocytes sensitized with BCG or BCG-treated tumor cells were also investigated. RESULTS: The expressions of MHC Class II, CD1, CD80 and ICAM-1 were augmented in all of the bladder tumor cell lines used; however, they were augmented to varying degrees among the cell lines that were treated with live BCG. Heat-killed BCG had little or no effect. When murine lymph node cells sensitized with BCG or BCG-treated MBT-2 cells were cocultured with BCG-treated MBT-2 cells, significant amounts of IL-2 and IFN-gamma were produced in the culture medium. CONCLUSIONS: BCG induced the augmented expression of surface antigens, such as MHC Class II, CD1, CD80 and ICAM-1, of bladder tumor cells. Furthermore, BCG-treated MBT-2 cells could stimulate BCG-sensitized lymphocytes to produce IL-2 and IFN-gamma. These results strongly suggest that bladder tumor cells gained the characteristics and functions of antigen-presenting cells (APC).
Adjuvants, Immunologic↗
Testicular cancers occurring in brothers with cryptorchism.
We report a case of familial testicular cancer associated with undescended testes in two brothers. The older brother (49 years) presented with a testicular tumor located in the right inguinal canal. The pathologic diagnosis was pure seminoma. Computerized tomography revealed iliac and retroperitoneal lymph node metastases. Four years later, the younger brother (44 years) developed bilateral testicular tumors, one located in the inguinal canal, the other located in the pelvic cavity. The pathologic diagnosis of both tumors was pure seminoma. Radiological examination revealed retroperitoneal lymph node metastases. Both patients received cisplatin-based combination chemotherapy as the initial treatment. The older brother suffered from repeated recurrences with lymph node metastases in the iliac and inguinal regions, but he was successfully treated with high-dose chemotherapy. The younger brother achieved long-term remission after retroperitoneal lymph node dissection following initial chemotherapy. We briefly review the reported cases of familial testicular cancer and discuss the association of the maldescent of the testes and familial testicular cancer cases.
Adult↗
Immunological protection induced by bacillus Calmette-Guérin treatment in a murine bladder tumor model.
BACKGROUND: It has been previously reported that MBT-2 tumor growth is completely inhibited when mice are inoculated with bacillus Calmette-Guérin (BCG). In this study it was examined whether or not vaccination with a mixture of BCG and MBT-2 cells also induces immunological protection against murine bladder tumors. METHODS: Seven hundred thousand MBT-2 cells and 1 mg of BCG (Tokyo 172 strain) per mouse were injected subcutaneously into female C3H/HeN mice. Four and eight weeks after vaccination with this mixture, animals were reinoculated with MBT-2 cells alone or MBT-2 cells cocultured with BCG. RESULTS: Animals vaccinated with a mixture of BCG and MBT-2 cells showed MBT-2 tumor growth but completely rejected the MBT-2 cells cocultured with BCG. MBT-2 cells cocultured with BCG developed into tumors when they were inoculated into the control animals. Splenocytes prepared from vaccinated animals showed specific cytocidal activity against MBT-2 cells precultured with BCG. CONCLUSIONS: The results suggest that a mixture of BCG and MBT-2 cells induces antitumor immunological protection against BCG- or MBT-2-associated antigens presented on MBT-2 cells precultured with BCG.
Animals↗
Advanced renal cell carcinoma treated with granulocyte-macrophage colony-stimulating factor gene therapy: a clinical course of the first Japanese experience.
A phase I study of granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor vaccine for patients with metastatic renal cell carcinoma (RCC) was initiated in 1998, as the first cancer gene therapy in Japan. The study is still ongoing, but the first patient is presented here as a case report. The patient was a 60-year-old man with Stage IV CRC with multiple lung metastases. After surgical resection of the tumor, autologous tumor cells were transduced and cultured to produce GM-CSF. The patient received a total of 2.2 x 108 gene-transduced autologous vaccine cells by subcutaneous injection. During the course of vaccination, growth of the largest metastatic mass slowed to some extent; however, multiple new lesions developed. About 1 month after the start of low-dose IL-2 therapy, rapid and remarkable regression in a large lung hilar metastatic mass was noticed. The patient died of progressive disease 7 months after the start of GM-CSF gene therapy. Careful histological examination by autopsy revealed that the responding mass was infiltrated by CD8 positive dominant T lymphocytes, and did not exhibit vasculitis or any other changes associated with active autoimmune disease.
Carcinoma, Renal Cell↗
Clinical study of varicocele: statistical analysis and the results of long-term follow-up.
BACKGROUND: The results of clinical examinations of varicocele and the clinical outcome of varicocelectomy conducted at Tsukuba University Hospital, Tsukuba City, Japan were analyzed. METHODS: The subjects of the present study were sixty-four infertile male patients with varicocele who visited our hospital from 1991 to 1999. A physical examination, semen analysis and hormonal evaluation were performed for each patient. Patients selected their preferred type of treatment (varicocelectomy or conservative treatment) after providing their informed consent. RESULTS: The age of the patients was 34.1 +/- 5.1(mean +/- standard deviation [s.d.]) years, and the infertile duration was 4.2 +/- 3.0 (mean +/- s.d.) years. Fifty-one cases were left-sided; 13 were bilateral. Mean sperm density ( yen 106/mL) was 37.2 for Grade I, 21.3 for Grade II and 9.4 for Grade III. Sperm density was significantly lower in the higher-graded patients (P = 0.008). Varicocelectomy was performed in 31 cases; the postoperative/preoperative ratio of sperm density was significantly higher in the higher-graded varicocele (P = 0.04), and the peak/base ratio of follicle-stimulating hormone (FSH) after luteinizing hormone-releasing hormone (LH-RH) stimulation was significantly decreased after varicocelectomy (P = 0.007). The pregnancy rate in the partners of the varicocelectomized group (60%) was significantly higher than in the conservatively treated group (28%) P = 0.04; the mean follow-up duration was 76.2 months. CONCLUSION: These results show that varicocele should influence spermatogenesis, therefore altered spermatogenesis could be effectively treated by varicocelectomy, and varicocelectomy should induce a higher probability of pregnancy.
Adult↗
The Influence of handling censored data on estimating progression-free survival in cancer clinical trials (JCOG9913-A).
BACKGROUND: Progression-free survival (PFS) is a common endpoint in cancer clinical trials. This study was undertaken to assess the impact of data errors and data handling on the statistical estimation of PFS. METHODS: Data from four trials conducted by the Japan Clinical Oncology Group were examined. Three types of data handling methods were defined: (1) data handling method A (METHOD-A), the collected event data are used as much as possible, (2) METHOD-C, only reliable data with firm evidence are used, and (3) METHOD-B is intermediate between METHOD-A and METHOD-C. To assess the impact of each of the three methods, Kaplan-Meier survival curves, median PFS, proportion of PFS, log-rank p values and hazard ratios were estimated. RESULTS: In three trials that collected PFS data periodically, no remarkable differences in median PFS and the proportion of PFS were observed. In one trial with non-periodic data cleaning, however, the ratio of median PFS by METHOD-C to that by METHOD-B was 0.85, the maximum difference of proportion of PFS between METHOD-C and METHOD-B was 12.0% and the largest spread in PFS curves amongst the three methods was observed in this trial. In all trials, log-rank p values and hazard ratios for between arm comparisons did not differ between the three methods. CONCLUSIONS: Periodic data management can reduce errors in comparisons of PFS and is a critical requirement when using PFS as a major endpoint. Furthermore, proper data handling is essential in the estimation of patient benefit and caution is needed when making clinical decisions based on PFS.
Clinical Trials as Topic↗
Is daidzein non-metabolizer a high risk for prostate cancer? A case-controlled study of serum soybean isoflavone concentration.
BACKGROUND: It has been postulated that soybean isoflavones act as inhibitory factors in prostate cancer. However, to date there have been no case-controlled clinical studies carried out to compare the circulating concentrations of isoflavones in prostate cancer patients and control subjects. METHODS: The serum levels of genistein, daidzein and equol were determined and compared in 253 experimental subjects (141 prostate cancer patients and 112 cancer-free controls). RESULTS: The serum concentrations of isoflavones were compared in hospitalized and non-hospitalized subjects and for both the prostate cancer patients and the controls the concentrations were lower in the hospitalized subjects. The serum concentrations of genistein and daidzein were compared in subjects <70 years of age and subjects >/=70 years old and the levels were significantly lower in the younger group. Contrary to our expectation, comparison of the patient group and the control group revealed the serum concentrations of isoflavones to be higher in the patient group. Daidzein non-metabolizers were compared in the hospitalized experimental subjects of the patient group and the control group and they were significantly more common in the patient group. The poorly differentiated cancer patient group included a significantly lower percentage of daidzein metabolizers. CONCLUSIONS: The above findings revealed that equol itself or some unknown factor regulating the metabolism of daidzein is deeply involved in the biology of prostate cancer. Future studies are urgently needed to compare the incidence of daidzein metabolizers among various countries.
Aged↗
Telomerase is upregulated in irreversible preneoplastic lesions during bladder carcinogenesis in rats.
Multiple occurrence or recurrence after transurethral resection is an important characteristic of superficial bladder tumors. To study bladder carcinogenesis, we focused on detection of telomerase activation, which was investigated in several human cancers, including bladder tumors. We experimentally examined the telomerase activity during bladder carcinogenesis, especially in precancerous lesions, induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in rats. Male Wistar rats were given 0.05% BBN in water from the age of 8 weeks to 24 weeks. Subgroups were euthanized at 4, 8, 10, 12, 18, and 24 weeks after BBN administration. Using the stretch PCR method, telomerase activity was semiquantified in exfoliated bladder epithelial cells. In addition, telomere length in each subgroup was measured by southern hybridization for the terminal restriction fragment using a (TTAGGG)(4) probe. Statistical analyses were performed using analysis of variance and Fisher's PLSD test. Epithelial cells of normal bladder in the control groups and those of diffuse hyperplasia, which was a reversible change at 4 weeks, expressed no telomerase activity. In contrast, telomerase activity significantly increased in the stage after nodular hyperplasia, an irreversible change at 8 weeks, then elevated with carcinogenesis. However, telomere length was still preserved by the 12th week, and was shortened at 18 and 24 weeks. These results suggest that telomerase activation is probably induced independent of telomere shortening during bladder carcinogenesis in the rat, and might be a biological tumor marker of irreversible preneoplastic lesions, which evolve into bladder tumors in the rat.
Animals↗
Habitual intake of lactic acid bacteria and risk reduction of bladder cancer.
INTRODUCTION: A kind of lactic acid bacteria, Lactobacillus casei strain Shirota, shows antitumor activity in experimental animals. One clinical trial using L. casei showed a significant decrease in the recurrence of superficial bladder cancer. So, to assess the preventive effect of the intake of L. casei, widely taken as fermented milk products in Japan, against bladder cancer, we conducted a case-control study. METHODS: A total of 180 cases (mean age: 67 years, SD 10) were selected from 7 hospitals, and 445 population-based controls matched by gender and age were also selected. Interviewers asked them 81 items. The conditional logistic regression was used to estimate adjusted odds ratios (OR). RESULTS: The OR of smoking was 1.61 (95% confidence interval: 1.10-2.36). Those of previous (10-15 years ago) intake of fermented milk products were 0.46 (0.27-0.79) for 1-2 times/week and 0.61 (0.38-0.99) for 3-4 or more times/week, respectively. CONCLUSION: It was strongly suggested that the habitual intake of lactic acid bacteria reduces the risk of bladder cancer.
Aged↗
Developing therapies for advanced bladder cancer.
Chemotherapy is an indispensable measure in the treatment of invasive or metastatic bladder cancer as even if metastases are not clinically apparent, the majority of cases of invasive bladder cancer are accompanied by micrometastases. At present, MVAC (methotrexate, vinblastine, adriamycin, cisplatin) is the gold standard for bladder cancer chemotherapy. There have consequently been many attempts at MVAC dose-intensification as well as many studies of the feasibility of neoadjuvant chemotherapy using MVAC. Unfortunately, the majority of results from these studies have been negative or contradictory. However, a recent large-scale randomised, controlled study yielded more promising results. Evidence has recently emerged which indicates that a useful chemotherapeutic strategy could possibly be devised by adjusting the dose and timing of MVAC. Increasing effort is also being put into the development of new gold standards for bladder cancer chemotherapy based on the use of newly developed antitumour drugs, and a number of candidates have emerged. It is hoped that the future we will see successful establishment of a number of useful regimens as a result of Phase III clinical studies using MVAC as their control regimen. For example, both gemcitabine and the taxanes, in combination with other drugs, are strong candidates for this purpose. The ultimate therapeutic strategy for bladder cancer will be a therapeutic approach which permits conservation of the bladder even when the malignancy is invasive and steady progress is already being made toward this goal, in limited cases, by means of multidisciplinary treatment.
Antineoplastic Combined Chemotherapy Protocols↗