[Outcome of Low-Dose-Rate Brachytherapy in Patients with Prostate Cancer and the Characteristics of Patients with Recurrence].

In our hospital, 553 patients with clinically localized prostate cancer underwent low-dose-rate (LDR) brachytherapy between March 2007 and December 2019. The patients were stratified based on the following prognosis according to the D'Amico risk classification criteria: low-risk and intermediate-risk groups (PSA ＜10, ≦T2a, GS : 3＋4 (≦30%)) were treated with LDR brachytherapy without supplemental extra beam radiotherapy (EBRT), while some patients in the high- and intermediate-risk groups were treated with LDR and supplemental EBRT. The 5- and 10-year overall survival rates were 94.8 and 85.5%, disease-specific survival rates were 99.8 and 97.7%, and biochemical recurrence-free survival rates were 95.7 and 90.7%. By risk stratification, the 5- and 10-year biochemical recurrence-free survival rates were 98.0 and 98.0% (low risk), 96.1 and 89.6% (intermediate risk), and 90.6 and 77.3% (high risk). The LDR outcome was generally good, but, 32 recurrence cases were observed. In the recurrent group, 9 patients did not undergo the recommended therapeutic strategy and 26 patients did not undergo preoperative magnetic resonance imaging.

Successful Treatment of a Large Superficial Bladder Cancer with Neoadjuvant Arterial Infusion Chemotherapy: A Case Report.

We present a case in which neoadjuvant arterial infusion chemotherapy was effective in treating a large superficial bladder cancer. A 50-year-old male was admitted to the Kanazawa Medical Center with the complaint of dizziness. The patient exhibited severe anemia, and his computer tomography showed a large bladder tumor. Cystoscopy revealed a large papillary tumor. Magnetic resonance imaging showed no muscle invasion and no metastasis. To avoid a prolonged operation time and excessive blood loss, we performed neoadjuvant arterial infusion chemotherapy for tumor volume reduction before transurethral resection of the bladder tumor (TUR-BT). The arterial infusion chemotherapy was performed twice, and the tumor size gradually reduced from 275 to 28 cm3. After neoadjuvant chemotherapy, TUR-BT was safely performed without blood transfusion. The tumor was staged as T1 with G1. This is the first report demonstrating that neoadjuvant arterial infusion chemotherapy is effective in treating large superficial bladder cancer and is a possible strategy for bladder preservation.

Impact of Gleason Pattern 5 on outcomes of patients with prostate cancer and iodine-125 prostate brachytherapy.

BACKGROUND: The Gleason grading system is a powerful predictor of prostate cancer (PCa) prognosis. Gleason scores (GS) of 8-10 are considered as a single high-risk grade category, and Gleason Pattern 5 (GP5) predicts biochemical recurrence. We report the clinical outcomes of patients treated with 125I prostate brachytherapy for clinically localized PCa and prognosis in the presence or absence of GP5. METHODS: We enrolled 316 patients with T1c-T2N0M0 PCa and undergoing prostate brachytherapy treatment. All patients were followed up for ≥ 1 year. The primary endpoint was biochemical recurrence-free survival. Biochemical recurrence was defined by the Phoenix criteria. Survival curves were calculated by the Kaplan-Meier method, and the prognostic impact of biochemical recurrence was analyzed using a Cox proportional hazards model. RESULTS: The 5-year biochemical recurrence-free survival rate for all patients was 95.2%, and according to the D'Amico risk classification criteria, the rates were 98.7% for patients in low-risk, 96.9% in intermediate-risk, and 81.1% in high-risk groups (P < 0.0001). The 5-year biochemical recurrence-free survival rates for patients with GS8 or GS9-10 were 87.7% and 61.5%, respectively (P = 0.0057). Multivariate analysis found that GS and clinical T stage were independent predictors of biochemical recurrence. CONCLUSIONS: The presence of GP5 in GS9-10 prostate cancer has a worse prognosis than GS8 prostate cancer in the absence of GP5 for patients undergoing prostate brachytherapy.

Mucosa-associated lymphoid tissue lymphoma involving the kidney: a case report and review of the literature.

Mucosa-associated lymphoid tissue (MALT) lymphomas arise from various anatomic sites, mostly observed in the gastrointestinal tract; however, involvement of the kidney is extremely rare. We report a case of MALT lymphoma involving the kidney in a 70-year-old man. Radical nephrectomy was performed under the diagnosis of renal cell carcinoma preoperatively. However, the renal specimen showed that the diffuse small- to medium-sized lymphocytes were scattered and formed colonies, and the neoplastic lymphoid cells were positive for CD20, CD79α, and Bcl-2, but negative for CD10 and Cyclin D1; therefore, the final histological diagnosis was MALT lymphoma involving the renal pelvis. Although he was referred to the department of hematology, no additional treatment was given postoperatively, and he has survived for 4 months without evidence of a recurrence of lymphoma at the last follow-up. To the best of our knowledge, to date 37 reports of MALT lymphoma involving the kidney have been published in the literature. We report a case of MALT lymphoma involving the kidney, and review the existing literature.

Simple Risk Stratification to Detect Prostate Cancer with High Gleason Score in Repeat Biopsies in a Population Screening Follow-up Study.

BACKGROUND: To investigate the clinical usefulness of percentage free prostate-specific antigen (%fPSA) and PSA velocity (PSAV) for detecting prostate cancer in repeat biopsies in a population-based screening cohort. PATIENTS AND METHODS: In total, 178 men with serum PSA levels within 2.1-10 ng/ml who underwent repeat biopsies after initial negative biopsy results, were enrolled. Prostate cancer detection rates with a Gleason score of 7 or more according to age, serum PSA, %fPSA, and PSAV were investigated. The cumulative probability of detecting cancer according to risk factors was also investigated. RESULTS: Out of 178 men who underwent repeat biopsy, 48 (27.0%) were diagnosed with prostate cancer during the observation period, and pathological examination revealed prostate cancer with a Gleason score of 7 or more in 17 patients (35.4%). In the multivariate logistic regression analysis, %fPSA ≤ 12 at repeat biopsy and PSAV >0.40 ng/ml/year were determined to be independent risk factors for prostate cancer, and %fPSA ≤ 12 at initial biopsy and PSAV >0.40 for cancer of Gleason score 7 or greater. The cumulative probabilities of developing high-grade cancer after 5 years were 55.8% and 4.0% in men with %fPSA ≤ 12 at initial biopsy and PSAV >0.40, and in men without both, respectively. There was a statistically significant difference in probabilities between groups by the log-rank test. CONCLUSION: The present results demonstrated that %fPSA and PSAV were predictors of prostate cancer with a Gleason score of 7 or more in repeat biopsy after a negative initial biopsy on a population follow-up basis.

Age-specific reference range of prostate-specific antigen and prostate cancer detection in population-based screening cohort in Japan: verification of Japanese Urological Association Guideline for prostate cancer.

OBJECTIVES: To investigate the age-specific reference range of prostate-specific antigen and clinical characteristics of screening-detected cancer in prostate-specific antigen-based screening, and to verify the age-specific prostate-specific antigen cut-offs in the Japanese Urological Association Guidelines. METHODS: Prostate-specific antigen distributions were estimated in a total of 69,028 screening tests according to the age of the participants in population screening from 2000 to 2013. The age-specific reference range of prostate-specific antigen for detection of cancer was investigated by analyzing the receiver operating characteristic curves. Furthermore, the clinicopathological features of screening-detected cancer with serum prostate-specific antigen levels below the age-specific prostate-specific antigen cut-off in the Japanese Urological Association Guidelines were also investigated. RESULTS: Of all 69,028 screens, 2053 prostate biopsies (2.97%) were carried out and 549 cases of cancer (0.79%) were diagnosed. The 95th percentiles in all participants aged 54-59, 60-64, 65-69 and 70-75 years old were 2.90, 3.60, 4.10, and 4.70 ng/mL, respectively. The optimal prostate-specific antigen cut-offs for cancer detection determined from the receiver operating characteristic curves were 2.3 and 2.6 for the age ranges 54-69 and 70-75 years, respectively. These values were lower than the age-specific cut-offs in the Japanese Urological Association Guidelines. Of all 137 patients with prostate-specific antigen levels below the age-specific cut-offs in the Japanese Urological Association Guidelines, 80 (58.4%) had unfavorable clinicopathological features as active surveillance criteria. CONCLUSIONS: The age-specific reference range of prostate-specific antigen might be lower than that recommended in the Japanese Urological Association Guidelines. An individualized and natural history-adjusted screening system should be established for screening participants with low prostate-specific antigen level.

Clinical characteristics and prostate-specific antigen kinetics of prostate cancer detected in repeat annual population screening in Japan.

OBJECTIVES: To clarify the present status regarding repeat examination in the annual population screening system in Japan, and to analyze the clinical characteristics and prostate-specific antigen kinetics of prostate cancer detected in this setting. METHODS: We summarized the annual individual data of prostate-specific antigen-based population screening in Kanazawa, Japan, and analyzed the prostate cancer detection rates at first and repeat screening. The clinical characteristics were compared between patients detected at first and repeat screening. The patients were classified according to favorable or unfavorable clinical characteristics of cancer, and prostate-specific antigen kinetics were compared between the two groups. RESULTS: From 2000 to 2011, 19 620 men participated in this screening program, and a total of 59 019 screenings were carried out. The total annual numbers of examinees increased, and the annual rates of first examinees gradually decreased. The annual detection rates of cancer at total screening decreased in the second year. The annual detection rate at first screening was not different from that in the first year. The rate of patients with favorable cancer features was significantly higher among patients detected at repeat screening than at first screening. The rates of patients with high prostate-specific antigen velocity and low prostate-specific antigen doubling time were significantly higher in unfavorable than favorable cancer patients in repeat screening. CONCLUSIONS: Repeat population screening could contribute to early detection of prostate cancer, and it seems that prostate-specific antigen kinetics might predict the cancer characteristics in repeat screening.

Efficacy of androgen deprivation therapy for localized prostate cancer: analysis of pT0 evaluated by radical prostatectomy specimen.

AIM: In order to investigate which types of localized prostate cancer can be treated most effectively by androgen deprivation therapy (ADT), cases of no residual cancer in radical prostatectomy specimens (pT0) after neoadjuvant ADT were analyzed. PATIENTS AND METHODS: Patients with localized prostate cancer who underwent radical prostatectomy after neoadjuvant ADT were investigated retrospectively. RESULTS: Thirty-two patients (24.2%) were diagnosed with pT0 disease by pathological evaluation. The positive-core proportion of prostate biopsy was lower, the duration of neoadjuvant ADT was longer, and prostate-specific antigen (PSA) nadir before radical prostatectomy was lower in pT0 cases compared to non-pT0 cases, and these differences were statistically significant. The percentage of pT0 cases with PSA nadir <0.2 ng/ml and <0.008 ng/ml before radical prostatectomy were 29.2% (21 out of 72 cases) and 83.3% (5 out of 6 cases), respectively. The positive-core proportion of prostate biopsy and PSA nadir before radical prostatectomy had a significant impact on pT0 status after neoadjuvant ADT. CONCLUSION: ADT for localized prostate cancer is thought to be highly effective in cases with low cancer volume. ADT is effective in cases of localized prostate cancer with PSA below the levels of detection by supersensitive PSA assay, and such cases show no cancer recurrence. Treatment options in such cases include intermittent or discontinuation of ADT.

Clinical outcomes of prostate cancer patients detected by prostate-specific antigen-based population screening in Kanazawa City, Japan.

OBJECTIVES: Most common population screening systems for prostate cancer are administered by municipal governments in Japan. These systems suffer from difficulties in adequate follow up of patients at several urology departments in the region. We analyzed the clinical characteristics and outcomes of prostate cancer patients detected in our prostate-specific antigen (PSA)-based population screen, and examined the efficiency of the system. METHODS: Since 2000, we have carried out PSA-based population screening in men aged 55-69 years. For the present study, primary treatments and clinical outcomes of prostate cancer patients diagnosed by this screening program were obtained from each urology department in the region. RESULTS: A total of 32,769 men participated in this screening program from 2000 to 2006. Overall, 249 cases (0.76%) of prostate cancer were diagnosed. The rate of patients within gray zone levels of serum total PSA on primary screening increased and this was significantly higher in 2003 than in the first 2 years of the program. Clinical T stage was defined in 247 patients (99.2%), and 231 (93.5%) were cases of clinically localized cancer. A total of 75% of these patients underwent radical treatment. Eight-year cause-specific and overall survivals were 97.5% and 93.3%, respectively. Four patients, all of them presenting with advanced disease at diagnosis, died from prostate cancer. CONCLUSIONS: The present study showed good clinical outcomes for screening-detected prostate cancer patients and it showed the effectiveness of our screening system.

Establishment and characterization of androgen-independent human prostate cancer cell lines, LN-REC4 and LNCaP-SF, from LNCaP.

AIM: To investigate the mechanisms of androgen-independent growth in prostate cancer (PCa), we established two PCa cell lines, LN-REC4 and LNCaP-SF, from the androgen-dependent PCa cell line, LNCaP. MATERIALS AND METHODS: LN-Pre and LN-REC4 cells were generated from LNCaP tumors grown on intact and castrated severe combined immunodeficient (SCID) mouse, respectively. After we cultured LNCaP cells under a steroid-free conditions for 6 months in vitro, LNCaP-SF cells were established. To show the character of LN-REC4 and LNCaP-SF cells, androgen sensitivity was investigated through examination of growth rate, and prostate-specific antigen (PSA), androgen receptor (AR), p21, p27, and cyclin D1 expression were examined by reverse transcription-polymerase chain reaction (RT-PCR). Angiogenesis assay in vitro was carried out using conditioned medium. To examine the expression level of vascular endothelial growth factor (VEGF), RT-PCR and enzyme-linked immunosorbent assay were also done. RESULTS AND CONCLUSIONS: LN-REC4 cells proliferated better than LNCaP cells in castrated mice and did well irrespective of castration, although responsiveness for androgen of LN-REC4 cells attenuated less than that of LNCaP cells in vitro. LNCaP-SF cells in castrated mice proliferated more rapidly than in normal mice. The PSA expression in LNCaP-SF cells was still induced by androgen. Expression of AR, p21, p27 and cyclin D1 were not changed in LN-REC4 and LNCaP-SF cells. Angiogenesis assay showed that both cells stimulated angiogenesis. LN-REC4 induced VEGF more than LNCaP and LN-Pre cells. However, expression of VEGF per cell in LNCaP-SF was lower than LNCaP cells, suggesting that other factors might be involved in angiogenesis. These cell lines might be a useful tool for researching androgen-independent growth and treatments of recurred PCa.

Novel HER2 selective tyrosine kinase inhibitor, TAK-165, inhibits bladder, kidney and androgen-independent prostate cancer in vitro and in vivo.

PURPOSE: TAK-165 is a new potent inhibitor of human epidermal growth factor receptor 2 (HER2) tyrosine kinase. Several reports suggest HER2 expression in bladder cancer, renal cell carcinoma (RCC) and androgen-independent prostate cancer. We therefore investigated the antitumor effect of TAK-165 on these urological cancer cells. MATERIALS AND METHODS: Western blot analysis was performed to confirm HER2 expression in cell lines. To study in vitro efficacy, cells were treated with TAK-165 at various concentrations for 72 h and then counted using a hemocytometer. Then the IC50 value was calculated. In the xenograft model, after the tumor reached 200-300 mm3 in volume, mice were orally administered TAK-165 10 mg/kg per day or 20 mg/kg per day or saline for 14 consecutive days (n=6-8). RESULTS: HER2 expression was observed in HT1376, UMUC3, T24 (bladder), ACHN (kidney), DU145, LNCaP, LN-REC4 (prostate), although the expression level in these cells was weak compared with BT474 (a breast cancer cell line which expresses HER2 strongly). IC50 was varied from 0.09 to greater than 25 micromol/L in the bladder cancer cell line. ACHN cells were less sensitive in vitro. The prostate cancer cell lines studied were all sensitive (IC50 0.053-4.62 micromol/L). In the xenograft model, treatment with TAK-165 significantly inhibited growth of UMUC-3, ACHN, and LN-REC4. The antitumor effect (T/C [%]=growth of TAK-165 treated tumor/average growth of control tumorx100) after 14 days treatment were 22.9%, 26.0%, and 26.5% in UMUC3, ACHN and LN-REC4, respectively. CONCLUSIONS: TAK-165 may be a hopeful new agent for bladder, kidney and androgen-independent prostate cancer.

Bisphosphonate induces apoptosis and inhibits pro-osteoclastic gene expression in prostate cancer cells.

AIM: Bisphosphonates are well established for the management of cancer-induced skeletal complications. Recent studies suggest that bisphosphonates promote apoptosis of cancer cells as well as osteoclasts in bone metastatic sites. To determine the direct effects of bisphosphonate on prostate cancer, we examined the effects of minodronate on prostatic cancer cell growth and the expression of apoptosis-related proteins and osteoclastogenic factors. METHODS: PC-3, DU145 and LNCaP cells were treated with amino-bisphosphonate minodronate. Then proliferation, apoptosis and expression of bcl-2, bax, poly (ADP)-ribose polymerase (PARP), caspase-3, receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinases-2 (MMP-2), and parathyroid hormone related protein (PTHrP) were assessed. RESULTS: The proliferation of prostatic cancer cells was inhibited by minodronate. DNA fragmentation and TUNEL-positive nuclei were observed in minodronate-treated PC-3 cells. Minodronate decreased bcl-2 expression and induced bax expression, caspase-3 activity and degradation of PARP in DU145 and PC-3 cells. Minodronate decreased expression of RANKL, PTHrP and MMP-2 in PC-3 cells. CONCLUSIONS: Our results suggest that bisphosphonate not only promotes apoptosis directly but also decreases pro-osteoclastic gene expression in prostate cancer cells.

Four year clinical statistics of iridium-192 high dose rate brachytherapy.

BACKGROUND: We evaluated the efficacy and complications of high dose rate (HDR) brachytherapy using iridium-192 (192Ir) combined with external beam radiotherapy (EBRT) in patients with prostate cancer. METHODS: Ninety-seven patients underwent 192Ir HDR brachytherapy combined with EBRT at our institution between February 1999 and December 2003. Of these, 84 patients were analysed in the present study. 192Ir was delivered three times over a period of 2 days, 6 Gy per time, for a total dose of 18 Gy. Interstitial application was followed by EBRT at a dose of 44 Gy. Progression was defined as three consecutive prostate-specific antigen (PSA) rises after a nadir according to the American Society for Therapeutic Radiology and Oncology criteria. The results were classified into those for all patients and for patients who did not undergo adjuvant hormone therapy. RESULTS: The 4-year overall survival of all patients, the nonadjuvant hormone therapy group (NAHT) and the adjuvant hormone therapy group (AHT) was 87.2%, 100%, and 70.1%, respectively. The PSA progression-free survival rate of all patients, NAHT, and AHT was 82.6%, 92.0%, and 66.6%, respectively. Of all patients, the 4-year PSA progression-free survival rates of PSA<20 and PSA>or=20 groups were 100%, and 46.8%, respectively. According to the T stage classification, PSA progression-free survival rates of T1c, T2, T3, and T4 were 100%, 82.8%, 100%, and 12.1%, respectively. Prostate-specific antigen progression-free survival rates of groups with Gleason scores (GS)<7 and GS>or=7 were 92.8% and 60.1%, respectively. Of NAHT, PSA progression-free survival of PSA<20 was 100% vs 46.8% for PSA>or=20, that of T1c was 100% vs 75% for T2, and that of GS<7 was 100% vs 75% for GS>or=7. No significant intraoperative or postoperative complications requiring urgent treatment occurred except cerebellum infarction. CONCLUSIONS: 192Ir HDR brachytherapy combined with EBRT was as effective as radical prostatectomy and had few associated complications.

[Non-myeloablative allogenic peripheral blood stem cell transplantation for treatment of advanced renal cell carcinoma].

Non-myeloablative allogenic peripheral blood stem cell transplantation (mini-transplant) is becoming a preferred treatment for those recipients in whom the potential toxicity risk of standard ablative allogeneic therapy may be acceptable. Graft-versus-tumor effect may be generated against epithelial malignancies that are similar to the graft-versus-leukemia activity documented in human hematological malignancies. Renal cell carcinoma has been shown to be responsive to immunotherapy with recombinant human cytokines and may be an ideal model for exploring this novel therapy. Clinical investigations have demonstrated regression of advanced renal cell carcinoma occurs in some patients following non-myeloablative allogenic peripheral blood stem cell transplantation. However, graft-versus-host disease remains a significant toxicity of nonablative transplantation, and directions for further study include the identification of the definitive tumor antigens involved in the graft-versus-tumor effect and means of selecting those patients who will benefit the most from this promising approach with due regard to improve its safety.

Involvement of ABC transporters in chemosensitivity of human renal cell carcinoma, and regulation of MRP2 expression by conjugated bilirubin.

In this study, the involvement of ATP-binding cassette (ABC) transporters in in vitro chemosensitivity of surgically removed human renal cell carcinomas was investigated. The relative expression levels of transporter mRNAs in the renal tumors from 13 patients were similar to those in the surrounding normal kidney tissues. Five renal cell carcinomas cultured successfully in vitro for 14 days showed significantly decreased expression of multi-drug resistance-associated proteins 2 and 6 (MRP2 and MRP6) mRNAs. In vitro chemosensitivity testing of the same specimens using the collagen-gel matrix assay indicated that some anticancer drugs were effective, especially cisplatin, which is an MRP2 substrate. MRP2 mRNA expression in renal carcinoma was significantly increased when cells were cultured in the presence of conjugated bilirubin. In an established renal proximal tubule epithelial cell line (RPTEC), conjugated bilirubin increased MRP2 expression at the mRNA and protein levels, and decreased the cisplatin sensitivity of the cells. These results indicate that MRP2 expression in renal cell carcinoma may be regulated by conjugated bilirubin in the body and decreased during in vitro culture. Thus, the effectiveness of anticancer drugs selected on the basis of in vitro chemosensitivity testing of clinical cancers may be overestimated.

In vitro chemosensitivity test for human genito-urinary tumors using collagen gel matrix.

BACKGROUND: Although the aim of chemosensitivity tests is to predict the efficacy of anticancer agents for individual patients, no generally accepted assay has been established. METHODS: A chemosensitivity test was conducted for solid tumors with an organ culture system using collagen gel matrix (CGM). Seventy-five samples of transitional cell carcinoma (TCC), 20 of germ cell tumor (GCT) and 13 of renal cell carcinoma (RCC) were used for the chemosensitivity test, and 20 patients were treated with anticancer drugs on the basis of the test results. RESULTS: Positive rates of anticancer drugs for the 75 TCC samples were 64.9% for carboplatin, 63.4% for cisplatin, 32.1% for etoposide, 19.7% for THP-adriamycin, 16.7% for vinblastine, and 12.3% for methotrexate, indicating that positive rates of the latter three agents consisting of an MVAC regimen were unexpectedly low. The GCT had higher positive rates than the other cancers while RCC had the lowest. In 20 eligible patients (seven patients with bladder tumors and 13 with GCT), the true positive and true negative rates were 42% (5/12) and 75% (6/8), respectively, and the sensitivity and specificity were 71% (5/7) and 46% (6/13), resulting in a 55% (11/20) accurate predictive value. CONCLUSION: Although predictive accuracy was moderate when combination chemotherapy was used, information about chemosensitivity may have some beneficial effect on the treatment of patients with invasive bladder cancer or advanced GCT, because insensitive drugs detected by the test could be deleted or replaced with more sensitive ones.

Inverse correlation of microvessel density with metastasis and prognosis in renal cell carcinoma.

BACKGROUND: Although a correlation between microvessel density (MVD) and tumor aggressiveness has been established for several malignancies, the data for renal cell carcinoma (RCC) is conflicting. In order to clarify the significance of MVD, we investigated the relationships between MVD and tumor stage, grade, size, occurrence of metastasis and patient survival. METHODS: Tumor specimens from 70 patients with primary renal cell carcinoma were examined by immunohistochemical staining for CD34. RESULTS: There was a tendency for MVD to decrease from G1 to G3 tumors or from stage T1 to T3 tumors, although this was not statistically significant. However, the MVD for 56 non-metastatic and 14 metastatic tumors were significantly different (P = 0.005) at 109 +/- 67 and 58 +/- 35 per x400 field (mean +/- SD), respectively. Microvessel density for 36 large and 34 small tumors was also significantly different (P < 0.0001) at 48 +/- 22 and 142 +/- 54 per x400 field, respectively. The survival rate of patients with small, low grade and hypervascular tumors was significantly higher than that of patients with large (P = 0.0015), high grade (P = 0.05) or low MVD (P = 0.039) tumors. Cox proportional hazards regression analysis showed that tumor grade and size emerged as independent prognostic factors. CONCLUSION: High MVD in RCC was inversely associated with tumor aggressiveness, but MVD was not the independent prognostic factor.

Improved survival of mice bearing liver metastases of colon cancer cells treated with a combination of radioimmunotherapy and antiangiogenic therapy.

We attempted to determine whether the combined regimen of radioimmunotherapy (RIT) and antiangiogenic therapy would favorably affect the survival of animals bearing liver metastases of colon cancer cells. Daily antiangiogenic therapy with 2-methoxyestradiol (2-ME), 75 mg/kg, was initiated at 3 days following intrasplenic cell inoculation of LS180 colon cancer cells. RIT with 7 MBq of (131)I-A7, an IgG1 anti-colorectal monoclonal antibody, or (131)I-HPMS-1, an irrelevant IgG1, was conducted at 7 days. Production of vascular endothelial growth factor (VEGF) by LS180 cells was assessed in vitro. All nontreated mice died by 31 days following cell inoculation ( n=5). Monotherapy comprising 2-ME treatment resulted in slightly better survival of mice ( n=8) ( P<0.05). (131)I-A7 RIT displayed a marked therapeutic effect ( n=8) ( P<0.001); however, all animals eventually died due to metastases by 99 days. The combined regimen of (131)I-A7 RIT and antiangiogenic therapy demonstrated a superior therapeutic effect in comparison to monotherapy consisting of either RIT or antiangiogenic therapy ( n=10) ( P<0.05); three mice survived the entire 160-day observation period. The combination of antiangiogenic therapy and (131)I-HPMS-1 RIT failed to provide an appreciable benefit ( n=5). Treatment with 2-ME decreased VEGF production by LS180 cells in a dose-dependent fashion. In conclusion, a combination regimen comprising RIT and antiangiogenic therapy initiated at the early stage of metastasis would be of great benefit in terms of improvement of the therapeutic efficacy with respect to liver metastases.

Reduced-intensity allogeneic stem cell transplantation for renal cell carcinoma: in vivo evidence of a graft-versus-tumor effect.

We report the cases of 3 patients with advanced renal cell carcinoma who underwent reduced-intensity allogeneic stem cell transplantation. In 2 partial responders, histologic analyses of metastases revealed prominent accumulation of CD8+ T cells and degenerative changes of clear cell carcinoma, suggestive of induction of tumor-specific cytotoxic T lymphocytes.

The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor.

Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse is antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is a stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. These effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR's association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.