Phase I/II study of multipeptide cancer vaccine IMA901 after single-dose cyclophosphamide in Japanese patients with advanced renal cell cancer with long-term follow up.

BACKGROUND: IMA901 is the first therapeutic vaccine for renal cell cancer (RCC). It contains multiple tumor-associated peptides (TUMAPs) that are naturally present in human cancers. METHODS: In a phase I/II study, we treated a total of 10 Japanese patients with advanced RCC who were human leukocyte antigen A (HLA-A)*02 +. Vaccination involved i.d. injection of GM-CSF (75 µg), followed within 15-30 min by i.d. injection of IMA901 (containing 413 µg of each peptide). No treatment with either anticancer agents or immunosuppressants was allowed within 4 weeks before entering the trial. Patients were scheduled to receive 7 vaccinations during the first 5 weeks of treatment (induction period), followed by 10 further vaccinations at 3-week intervals for up to 30 weeks (maintenance period). The primary endpoints were safety and tolerability, while the secondary endpoints were PFS, OS, and immunogenicity. RESULTS: There were no treatment-related serious adverse events or deaths during the study period. When the response was assessed after 4 months, 10% of patients showed a partial response, 80% had stable disease, and 10% had progressive disease. Among patients in whom the T-cell response was analyzed, five patients showed a vaccine-induced T-cell response against at least one HLA class I-restricted TUMAP and two patients had T-cell responses to multiple TUMAPs. PFS was 5.5 months and OS was 18 months. CONCLUSIONS: This study demonstrated the safety and tolerability of IMA901 vaccine in Japanese RCC patients, and also showed that vaccination elicited an immune response.

Preliminary study of the safety of acrinol in probe-based confocal laser endomicroscopy during transurethral resection of bladder tumors.

We previously reported that probe-based confocal laser endomicroscopy using acrinol can depict cancerous nuclei. The objective of this study was to confirm the safety of acrinol in patients. For all seven patients, '50 ml' of a 0.1% acrinol and '1 ml' of 10% fluorescein in 99 ml of normal saline were introduced into the bladder. The laser probe adhered to the suspicious lesion from the working channel of the cystoscope. The patients underwent mucosal biopsy and transurethral resection after observation. Adverse events were noted during a valuation using common terminology criteria for adverse events version 4.0. Confocal laser endomicroscopy detected the nuclei of cancer cells in all seven patients. No adverse event was observed in any of the seven patients. Confocal laser endomicroscopy using acrinol as a novel dye can help visualize the cancerous nuclei of bladder urothelial carcinoma during cystoscopy without severe adverse events.

Randomized study of intravesical pirarubicin chemotherapy with low and intermediate-risk nonmuscle-invasive bladder cancer in Japan: Comparison of a single immediate postoperative intravesical instillation with short-term adjuvant intravesical instillations after transurethral resection.

PURPOSE: The objective of this study was to evaluate the efficacy, defined by the 3-year tumor recurrence-free survival rate, of intravesical chemotherapy using pirarubicin (THP) in patients with low or intermediate-risk nonmuscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Between October 2010 and January 2015, 206 patients were enrolled, and finally 113 were randomized to receive either a single immediate postoperative intravesical instillation of THP (30 mg) (Group A), or 8 additional weekly intravesical instillations of THP (30 mg) after a single postoperative instillation (Group B). The patients were examined by performing cystoscopy and urine cytology every 3 months after transurethral resection to determine bladder tumor recurrence. The primary endpoint was 3-year-recurrence-free survival rate. RESULTS: All 113 patients were bacillus Calmette-Guérin (BCG)-naïve. The 3-year recurrence free survival rate was 63.7% for Group A and 85.3% for Group B (log-rank test, P = .0070). In patients with intermediate recurrence risk, the 3-year recurrence-free survival rate was 63.4% in Group A and 86.1% in Group B (log-rank test, P = .0036). Cox regression analysis revealed that only additional instillation of THP was a significant independent factor for recurrence-free rate in patients with intermediate risk. No patient with progression was noted during this period. Frequent adverse effects (AEs) were frequent urination and micturition pain, and no severe AEs (Grade 3 or more) occurred. CONCLUSION: Additional instillation of THP (30 mg) weekly for 8 weeks reduced the risk of tumor recurrence without severe AEs in BCG-naïve NMIBC patients with intermediate risk.

Probe-Based Confocal Laser Endomicroscopy Using Acrinol as a Novel Dye Can Be Used to Observe Cancer Nuclei of Bladder Carcinoma In Situ.

Background: Cystoscopy using white light is a standard procedure for diagnosing bladder cancer; however, white light can result in missed lesions that are present, but not visible, such as in cases of carcinoma in situ (CIS). In this case report, we describe observing the nuclei of urothelial carcinoma cells in situ that were not visible with cystoscopy under white light using probe-based confocal laser endomicroscopy (pCLE) with acrinol and fluorescein during transurethral resection of a bladder tumor (TURBT). Case Presentation: A 59-year-old male with a medical history of neurogenic bladder dysfunction with multiple bladder diverticula was referred to the urology department for gross hematuria. TURBT was performed with the assistance of pCLE, using acrinol as a novel dye. Standard cystoscopy under white light could not detect any bladder tumor; however, pCLE using acrinol could detect the abnormal nuclei of bladder CIS. Subsequent histopathologic analysis of the specimen confirmed a diagnosis of bladder CIS. To our knowledge, this is the first reported case of bladder CIS diagnosed with the assistance of pCLE using acrinol in a patient undergoing a TURBT. Conclusion: pCLE using acrinol as a novel dye can help observe the cancerous nuclei of bladder CIS that cannot be detected using conventional cystoscopy under white light. Therefore, pCLE using acrinol is one possible modality for performing an optical biopsy during TURBT.

CDK1 and CDK2 activity is a strong predictor of renal cell carcinoma recurrence.

BACKGROUND: In renal cell carcinoma (RCC), the prediction of metastasis via tumor prognostic markers remains a major problem. The objective of our study was to evaluate the efficacy of cyclin-dependent kinase (CDK)1 and CDK2 activity as a prognostic marker in human RCC. METHODS: Surgical specimens were obtained from 125 patients with RCC without metastasis. Protein expression and kinase activity of CDKs were analyzed using a newly developed assay system named C2P (Sysmex, Kobe, Japan). We then examined the specific activities (SAs) of CDK1 and CDK2 and calculated CDK2SA-CDK1SA ratio in RCC. Also, risk score (RS) was examined. RESULTS: A total of 125 cases were tested, though 34 cases were excluded because of low sample quality (25 cases) and assay failure (9 cases). In total, 91 cases were analyzed. They included 68 male and 23 female patients, ranging in age from 19 to 83 years. At a median follow-up of 36 months (1-109M), tumor with low CDK2SA-CDK1SA ratio showed significantly better 5-year recurrence-free survival than those with high CDK2SA-CDK1SA ratio (88.7% vs. 54.7%, P = 0.00141). Also, RS enabled the classification of RCCs into high-risk and low-risk groups, and patients with tumors classified as low RS showed better recurrence-free survival than patients with tumors with high RS (88.7% vs. 54.7%, P = 0.0141). CONCLUSION: CDK1SA of tumors and the CDK2SA are both associated with recurrence and prognosis. IMPACT: CDK-based risk demonstrated is strongly associated with clinical outcome. CDK-based risk should be an accurate system for predicting recurrence and survival for planning follow-up.

Significance of serum tumor necrosis factor-related apoptosis-inducing ligand as a prognostic biomarker for renal cell carcinoma.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is endogenously expressed in immune cells and contributes to immunosurveillance for cancer. TRAIL induces apoptosis preferentially in various cancer cells, including renal cell carcinoma (RCC) cells. In this study, the serum TRAIL level was examined using an enzyme-linked immunosorbent assay in 52 healthy controls and in 84 RCC patients prior to surgery and its significance as a biomarker was evaluated. The median serum TRAIL level was lower in RCC patients compared to the healthy controls (55.9 vs. 103.1 pg/ml; P=0.019). RCC with lymph node metastasis (N1-2), distant metastasis (M1), stage III-IV, or microscopic venous invasion was associated with decreased serum TRAIL levels (P=0.032, 0.067, 0.020 and 0.011). When comparing serum TRAIL levels in the same RCC patients prior and subsequent to surgery (n=11), the levels were significantly higher after surgery (P=0.031). The cause-specific survival rate was significantly higher in RCC patients with high serum TRAIL levels compared to those with low serum TRAIL levels (P=0.0451). TRAIL was estimated to contribute 64 and 13% of the lymphocyte-mediated cytotoxicity against human RCC ACHN and Caki-1 cells, respectively. These data suggest that the serum TRAIL level may be useful as a prognostic biomarker in RCC patients.

Impact of four loci on serum tamsulosin hydrochloride concentration.

Tamsulosin hydrochloride is one of the most potent drugs for treatment of benign prostatic hyperplasia (BPH), however, the efficacy of tamsulosin hydrochloride varies among individuals. In this study, we measured the maximum serum concentration (Cmax) of tamsulosin hydrochloride in 182 of BPH patients and found remarkable individual variability. To investigate the genetic factors that regulate pharmacokinetics of tamsulosin hydrochloride, we conducted a genome-wide association study in these 182 BPH patients. As a result, rs16902947 on chromosome 5p13.2, rs7779057 on 7q22.3, rs35681285 on 7p21.2 and rs2122469 on 8p21.3 indicated possible associations with Cmax of tamsulosin hydrochloride (P=1.29 × 10(-7), 2.15 × 10(-7), 4.35 × 10(-7) and 7.03 × 10(-7), respectively), although these single-nucleotide polymorphisms (SNPs) did not reach the genome-wide significance threshold after Bonferroni correction. As these associated SNPs showed additive effects on serum tamsulosin hydrochloride concentration, we defined the 'Cmax prediction index' based on genotypes of these SNPs. This index clearly associated with Cmax values (P=4.5 × 10(-6)), indicating the possible roles of these four variants in tamsulosin hydrochloride pharmacokinetics. Our findings would partially explain the variability of the response to the tamsulosin hydrochloride treatment.

Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival.

IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02(+) subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3)(+) regulatory T (T(reg)) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T(reg) cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.

Expression and role of HMGA1 in renal cell carcinoma.

PURPOSE: Although molecular targeted therapy has improved the clinical outcome of metastatic renal cell carcinoma, a complete response is rare and there are various side effects. Identifying novel target molecules is necessary to improve the clinical outcome of metastatic renal cell carcinoma. HMGA1 is over expressed in many types of cancer and it is associated with metastatic potential. It is expressed at low levels or not expressed in normal tissue. We examined HMGA1 expression and function in human renal cell carcinoma. MATERIALS AND METHODS: HMGA1 expression in surgical specimen from patients with renal cell carcinoma was examined by immunoblot. HMGA1 expression in 6 human renal cell carcinoma cell lines was examined by immunoblot and immunofluorescence. The molecular effects of siRNA mediated knockdown of HMGA1 were examined in ACHN and Caki-1 cells. RESULTS: Immunoblot using surgical specimen showed that HMGA1 was not expressed in normal kidney tissue but it was expressed in tumor tissue in 1 of 30 nonmetastatic (3%) and 6 of 18 metastatic (33%) cases (p=0.008). Immunoblot and immunofluorescence revealed significant nuclear expression of HMGA1 in ACHN and Caki-1 cells derived from metastatic sites. HMGA1 knockdown remarkably suppressed colony formation and induced significant apoptosis in ACHN and Caki-1 cells. HMGA1 knockdown significantly inhibited invasion and migration in vitro, and induced anoikis associated with P-Akt down-regulation in ACHN cells. CONCLUSIONS: HMGA1 is a potential target for novel therapeutic modalities for metastatic renal cell carcinoma.

Significant induction of apoptosis in renal cell carcinoma cells transfected with cationic multilamellar liposomes containing the human interferon-ß gene through activation of the intracellular type 1 interferon signal pathway.

We previously reported that cationic multilamellar liposome containing the human interferon-ß (huIFN-ß) gene (IAB-1) demonstrated significant cytotoxic effect in the NC65 human renal cell carcinoma (RCC) cell line. In this study, we investigated the molecular mechanisms of IAB-1-induced apoptosis and cytotoxicity in RCC cells. Remarkable in vitro cytotoxic and apoptosis-inducing effects of IAB-1 against NC65 cells were observed by a colorimetric method and TUNEL staining, respectively. In contrast, treatment of NC65 cells with exogenously added huIFN-ß protein induced low-level cytotoxicity without apoptosis. Neutralizing antibodies against huIFN-ß significantly suppressed the cytotoxic effect of huIFN-ß protein, but they were unable to block the effect of IAB-1. Cytotoxicity assays using transwell plates revealed that NC65 cells treated with IAB-1 did not secrete cytotoxic soluble factors other than IFN-ß. Substantial enhancement of interferon-stimulated response element (ISRE) activity of NC65 cells by IAB-1 was demonstrated by promoter reporter assays. In addition, immunofluorescence using confocal microscopy revealed the intracellular expression of IFN-ß and its receptor induced by IAB-1. The induction of c-Myc by IAB-1 was suggested by a cDNA macroarray and was confirmed by western blot analysis. These findings indicate that IAB-1 induces significant cytotoxicity and apoptosis in NC65 cells, possibly through enhanced ISRE activity, that is associated with increased intracellular localization of huIFN-ß and IFN-receptor. Our data support the potential clinical application of IAB-1 gene therapy for RCC resistant to IFN.

High mobility group protein AT-hook 1 (HMGA1) is associated with the development of androgen independence in prostate cancer cells.

BACKGROUND: We previously reported that the level of high mobility group protein AT-hook 1 (HMGA1) is low in androgen-dependent prostate cancer (PCa) cells (LNCaP), but is high in androgen-independent PCa cells (DU145 and PC-3) and that HMGA1 is a strong candidate gene playing a potential role in the progression of PCa. These findings have prompted us to evaluate the effect of HMGA1 on developing androgen independency, which is associated with the progression of PCa. METHODS: Expression of HMGA1 in PCa cells and mouse tissues was examined by Western blot. In order to examine the effect of HMGA1 on cell growth under androgen-deprived condition, we transfected HMGA1 into LNCaP cells, and siRNA into both DU145 and PC-3 cells, respectively. RESULTS: Androgen-deprivation induced an increase in the level of HMGA1 in LNCaP cells in vitro and in vivo, but did not in normal prostate tissue. Overexpression of HMGA1 maintained the cell growth of LNCaP under androgen-deprived condition. Furthermore, knockdown of HMGA1 suppressed the cell growth of DU145 and PC-3. CONCLUSIONS: These data suggest that elevated expression of HMGA1 is associated with the transition of PCa cells from androgen-sensitive to androgen-independent growth and plays a role in the cell growth of androgen-independent PCa cells.

Feasibility of tri-weekly docetaxel-based chemotherapy for elderly patients (age 75 and older) with castration-resistant prostate cancer.

OBJECTIVES: To evaluate the efficacy and safety of docetaxel-based chemotherapy for elderly metastatic castration-resistant prostate cancer (CRPC) patients aged 75 or higher. METHODS: Twenty CRPC patients aged 75 or higher (older group) and 31 CRPC patients younger than 75 years (younger group) were treated by a regimen of docetaxel (70 mg/m(2)) once every 3 weeks. Adjustment for docetaxel dosage and period per cycle was subject to investigator's judgment. RESULTS: The median relative dose intensity of both groups was 0.84, while the median dose intensity and the number of treatment cycles of the younger and older groups were 14.6 versus 12.3 mg/m(2)/week (p = 0.021), and 9 versus 8 cycles (p = 0.15), respectively. In the older group, PSA response rate was 50%, median time to biochemical progression was 7.5 months, and median survival time was 15.5 months, without any significant difference compared to those of the younger group. No significant difference in the incidence of grade 3-4 adverse events was noted between both groups. All these parameters for efficacy are comparable to those reported for tri-weekly docetaxel regimen. CONCLUSIONS: Tri-weekly treatment by docetaxel (70 mg/m(2)) with proper adjustment might contribute to maintaining efficacy and safety of the treatment for elderly CRPC patients.

Optimal duration of androgen deprivation in combination with radiation therapy for Japanese men with high-risk prostate cancer.

OBJECTIVES: To evaluate the efficacy and toxicity of external beam radiation therapy (EBRT) combined with androgen deprivation therapy (ADT) for Japanese high-risk prostate cancer (PCa) patients in a single institution. METHODS: Seventy-five high-risk PCa patients were treated by three-dimensional conformal radiotherapy of 70 Gy combined with neoadjuvant, concurrent and adjuvant ADT. RESULTS: Median age was 72 (59-82) years. Median initial serum prostate-specific antigen (PSA) was 19.0 (4.7-200) ng/ml. Median duration of the entire ADT was 27 (8-63) months. Median follow-up after initiating ADT and after completing EBRT was 66 (41-105) and 59 (36-94) months, respectively. Five-year overall, clinical progression-free, and biochemical progression-free survival rates were 98.3, 97.2, and 87.4%; 2 (2.7%) cancer deaths, 3 (4.0%) clinical progressions, and 11 (14.7%) biochemical progressions. Multivariate analysis suggested a total duration of ADT shorter than 24 months as an independent risk factor of biochemical progression (p = 0.01). Grade 3 toxicities related to EBRT were observed: 1 patient with proctitis and rectal bleeding and 1 patient with rectal bleeding. CONCLUSIONS: It is suggested that 70 Gy EBRT combined with ADT confers disease-free survival benefit with tolerable adverse events for Japanese high-risk PCa patients. ADT of 24 months or longer might be recommended to minimize biochemical progression.

[Radio-frequency ablation (RFA) for post-chemotherapeutic metastatic germ cell tumors as minimally invasive salvage therapy].

Radio-frequency ablation (RFA) has been successfully applied for local control of metastatic tumor. The aim of this study was to assess the effectiveness and safety of RFA to post-chemotherapeutic metastatic germ cell tumors (GCTs). As combined modality therapy, RFA was performed to 42 tumors in 19 patients of GCTs at our institution between November 2000 and December 2008. RFA was performed for 10 liver metastatic tumors (in 6 cases), 32 lung metastatic tumors (in 13 cases), and median age was 36 years old (range 20-53) and the median tumor size was 12 mm (range 2-40). We used Cool-tip RF system (straight electrode needle of the internal cooling type, Radionics, Palm Coast, USA) for RFA with ultrasound or CT fluorosent guidance under intravenous or local anesthesia. The therapeutic effect was assessed by the contrast-enhanced CT or MRI. When contrast enhancement was remained in the tumor, the treatment was repeated. The 28 evaluable lesions followed were with median 25 months in the term of the surveillance, and 9 tumors were treated by an additional session of RFA repeatedly. complete response (CR) was achieved in 12 out of 12 tumors (100%) with tumor maker normalization. On the other hand, 12 out of 16 tumors (75%) without marker normalization showed CR. All of the 24 tumors with tumor diameter of 30 mm or less achieved CR, and the tumor greater than 30 mm achieved no CR. Major complications included pneumothorax (n=9) and hemato-thoraxes (n=2), but no complications in surrounding organs. The chest drainage tube was required in 4 cases (36%). RFA might be an alternative therapeutic option of combined modality therapy as salvage therapy for post-chemotherapeutic metastatic germ cell tumors.

Salvage chemotherapy with paclitaxel and gemcitabine plus nedaplatin (TGN) as part of multidisciplinary therapy in patients with heavily pretreated cisplatin-refractory germ cell tumors.

BACKGROUND: We investigated the efficacy and toxicity of a regimen consisting of paclitaxel and gemcitabine plus nedaplatin, a derivative of cisplatin (TGN) in patients with heavily pretreated cisplatin-refractory germ cell tumors (GCTs). METHODS: Fifteen patients with advanced GCTs were treated with the TGN regimen. The combination chemotherapy consisted of paclitaxel (210 mg/m(2)) on day 1 and gemcitabine (1000 mg/m(2)) on days 1 and 8 in combination with nedaplatin (100 mg/m(2)) on day 2 every 3 weeks. RESULTS: Patients enrolled in this study had been heavily pretreated with a median of 12 platinum-containing cycles (range, 7 to 26 cycles). Most of the regimens had included paclitaxel and ifosfamide plus cisplatin or nedaplatin (TIP/TIN) chemotherapy. The median follow-up period of the present study was 15 months. Patients received 2-11 cycles of the TGN combination chemotherapy. Six patients received the treatment combined with other therapeutic modalities; 2 patients received radiation therapy for retroperitoneal lymph node metastasis, 1 patient had cyber-knife radiosurgery for brain metastasis and 3 patients had radiofrequency ablation for liver and lung metastasis. Seven (46.7%) of the 15 patients achieved an objective response; 6 had marker-negative partial responses (PRs) and 1 had a marker-positive PR. Two (13%) of the 7 patients with PRs achieved a disease-free status after chemotherapy combined with RT and followed by surgical resection. However, 10 patients died of the disease and 3 patients are still alive with the disease. CONCLUSION: The TGN regimen alone had limited efficacy in this patient population, with severe but manageable toxicities. However, TGN chemotherapy may offer a chance of cure for some heavily pretreated cisplatin-refractory (TIP/TIN-refractory) patients as part of multidisciplinary therapy.

Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis.

X-linked inhibitor of apoptosis protein (XIAP) is the most potent caspase-inhibitory IAP family member and a negative regulator of various apoptotic stimuli. Thus, XIAP overexpression in cancer cells may select for tumor cell survival following various cytotoxic therapeutic modalities. The anatomical staging system in renal cell carcinoma (RCC) currently provides good prognostic information, albeit insufficient. We hypothesize that overexpression of XIAP in RCC may serve as a molecular prognostic marker in RCC and improve the staging of RCC. This study examined the protein level of XIAP in lysates from surgical specimens of 109 patients with RCC and 109 normal kidney specimens from the same patients. The level of XIAP expression was quantified by Western blot analysis using non-fixed fresh frozen tissues of RCCs and normal kidneys. Results indicated that the mean level of XIAP expression was higher in RCC compared to autologous normal kidney, and the XIAP expression level in 38/109 (35%) of RCC was more than 2-fold greater than that in normal kidney tissue. In Stage I/II RCC, the mean XIAP expression level was almost identical to that detected in normal kidney, whereas XIAP expression in Stage III/IV was 2.5-fold higher than that in Stage I/II RCC. Levels of XIAP expression also correlated with the grade of RCC. Patients with RCC with low XIAP expression had a longer postoperative disease-specific survival as compared to those with high expression in the 5-year follow-up. The suggested role of XIAP in the regulation of resistance in apoptosis was examined in vitro following treatment of RCC cell lines with XIAP antisense oligonucleotide and the cells were sensitized to both Fas-mediated and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The present study demonstrates at the protein level that XIAP is overexpressed in RCC, and that high XIAP expression in RCC predicted a worse prognosis. In addition, XIAP antisense oligonucleotide sensitized RCC to Fas/TRAIL-induced apoptosis. These results suggest that XIAP expression in RCC may be used as a prognostic parameter, and that downregulation or inhibition of XIAP expression in RCC may reverse immune resistance.

The significance of the expression of dihydropyrimidine dehydrogenase in prostate cancer.

OBJECTIVE: To measure dihydropyrimidine dehydrogenase (DPD), an enzyme involved in the metabolism of 5-fluorouracil (5-FU), expression in prostate cancer and determine whether 5-chloro-2,4-dihydroxypyridine (CDHP), a potent inhibitor of DPD, enhances the antitumoral activity of 5-FU against prostate cancer. PATIENTS, MATERIALS AND METHODS: In all, 44 prostate tissue specimens were obtained from men who had a radical prostatectomy alone for prostate cancer, and 38 specimens from men who had had neoadjuvant hormonal therapy. We analysed the cancerous tissue and normal prostate tissue for DPD expression using immunohistochemistry, and determined its prognostic significance. In cultured human prostate cancer lines (DU145 and LNCaP), we compared the cytotoxicity of 5-FU/CDHP with that of 5-FU alone. Finally, in experiments on immunodeficient mice, we studied the effect of oral administration of tegafur, a pro-drug for 5-FU, with or without CDHP on the growth of tumours introduced by injection of DU145 cells. RESULTS: The expression of DPD was significantly higher in cancerous than normal prostate tissue; 36 of 44 (82%) specimens of prostate cancer expressed DPD, whereas only 25 of 44 (57%) specimens of normal prostate tissue expressed DPD. For men with prostate cancer who had radical prostatectomy alone, men with negative DPD expression tended to have a longer recurrence-free survival than those with positive expression; there were no recurrences in men with prostate cancer and negative DPD expression in the 5-year follow-up. DPD expression was significantly lower in men with prostate cancer who received neoadjuvant hormonal therapy. In vitro treatment of human prostate cancer cell lines with 5-FU/CDHP showed more cytotoxicity than with 5-FU treatment alone. Finally, DU145 tumours in mice treated with tegafur and CDHP were significantly smaller than in mice given tegafur alone. CONCLUSION: The present study showed that DPD expression is elevated in prostate cancer, and indicate that DPD inhibitors might enhance the antitumour activity of 5-FU against prostate cancer.

[Pelvic lymph node metastasis from bladder cancer markedly responsive to methotrexate vinblastine doxorubicin and cisplatin (M-VAC) therapy followed by radiotherapy: a case report].

We report a case of bladder cancer with pelvic lymph node metastasis effectively treated by chemotherapy followed by radiotherapy. The patient was a 65-year-old man who had undergone radical cystectomy. Histological findings showed urothelial carcinoma, G3 > G2, pT1b. After 31 months, computerized tomography (CT) revealed a bulky tumor (7.0 x 5.6 cm) along the left pelvic wall, indicating pelvic lymph node metastasis. Five courses of chemotherapy consisting of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) was performed. The size of the tumor was reduced to 1.5 x 1.0 cm. Then, external beam radiotherapy (50 Gy) was added to the residual tumor. He has been alive with no evidence of disease progression for 31 months since the radiotherapy.

Significance of electrostimulation in detecting neurovascular bundle during radical prostatectomy.

OBJECTIVE: The reported rate of erectile dysfunction after nerve-sparing prostatectomy varies according to physicians. Because exact preservation of the neurovascular bundle (NVB) solely depends on the judgment of the physician, he or she should try to correctly identify the NVB and also avoid neurophysiologic injury of the NVB during the procedure. The purpose of the present study is to assess the status of the NVB preservation by physician's judgment at the operation, the changes in intracavernous pressure related to intraoperative electrical stimulation and postoperative histopathological examination. PATIENTS AND METHODS: Thirty-eight patients who underwent nerve-sparing radical prostatectomy judged by intraoperative electrical stimulation of the NVB were included in this study. Bilateral, unilateral and non-nerve-sparing procedures were performed in 18, 17, and 3 cases, respectively. The NVB preservation evaluated by intraoperative physician's judgment was compared to that evaluated by postoperative histopathological examination. Furthermore, the NVB preservation evaluated by intraoperative electrical stimulation was compared to that by physician's judgment and postoperative histopathological examination. RESULTS: For 68 of 76 NVB (89.5%), intraoperative subjective judgment and histopathological assessment were identical. For 66 of 76 NVB (86.8%), electrical stimulation findings and the physician's judgments were identical, and for 70 of 76 NVB (92.1%), electrical stimulation findings and histopathological findings were identical. CONCLUSION: Even if physicians are convinced of a successful nerve-sparing procedure, there are some cases in which the NVB is not preserved accurately or neurophysiological damage is suffered. Therefore, intraoperative electrical stimulation of the NVB as well as the cavernosal nerve is very useful in evaluation of NVB preservation.

Prostate cancer mediates osteoclastogenesis through two different pathways.

The present study was undertaken to test the effects of prostate cancer cell lines (LNCaP, DU145, PC3, and MDA PCa 2b) on osteoclastogenesis. Crude conditioned medium (CM) from all four prostate cancer cell lines enhanced expression of the mRNA for receptor activator of NF-kappaB ligand (RANKL) in a mouse osteoblast cell line, MC3T3-E1; however, CM had no effect on expression of osteoprotegerin (OPG) mRNA. Coculture of MC3T3-E1 with prostate cancer cells yielded similar results. The number of mature osteoclasts induced by soluble RANKL increased significantly when osteoclast precursor cells were cultured with CM from LNCaP and DU145 cells. CM from LNCaP and DU145 cells also induced maturation from precursor in the absence of soluble RANKL, and this effect was not blocked by OPG. Addition of CM from DU145 cells increased expression of MMP-9 mRNA by osteoclast precursors. Our findings indicate that prostate cancer mediates osteoclastogenesis through induction of RANKL expression by osteoblasts and through direct actions on osteoclast precursors mediated by some factors other than RANKL.