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Castleman's disease (CD) is a unique lymphoproliferative disorder. It commonly occurs in the mediastinum, neck, axilla, and abdomen, and retroperitoneal involvement is rare. Here we report a unique case of CD in the pelvis. Laparotomy was performed and surgery was complicated by adhesions and vascularity. Total surgical duration was Five hours and 45 min with 4.5 L of blood loss. Ten pints of blood was transfused. The mass was histopathologically diagnosed as hyaline-vascular CD. The patient was free of recurrence after 10 years of follow-up.

OBJECTIVE: This study aimed to assess the relationship of the prostate cancer and Gleason scores (GSs) or ISUP Grade system with prostate volume (PV) as assessed by magnetic resonance imaging (MRI) cognitive biopsy and standard biopsy. MATERIAL AND METHODS: Data were collected from 659 patients who underwent MRI cognitive biopsy and standard biopsy from January 2014 to January 2018. The biopsies were performed because of increased prostate-specific antigen (PSA) levels (>4 ng/mL) and/or abnormal digital rectal examination findings. Transrectal ultrasound was used to measure PV. RESULTS: Prostate cancer detection rates in patients with increased PVs of ≤40 cc and >40 cc were 68.8% and 51.6% (p40 cc were 68% and 73%, and 22.3% and 37.8%, respectively, for those with ISUP Grade group ≥4 (Gleason score ≥8) (p=0.003). Among the patients with PV>40 cc, univariate logistic regression showed a significant relationship between ISUP Grade group ≥2 and PSA, free/total PSA, PSA density, and MRI (p40 cc. CONCLUSION: Although the detection rates of prostate cancer decreased as PV increased, the detection of prostate cancer aggressiveness increased as PV increased. This increase in high ISUP Grade lesions with the rise in PV is due to the use of MRI during prostate biopsy with standard biopsy.

Background: The AR-V7 splice variant is a cause of castration-resistant prostate cancer (CRPC). However, testing for the presence of AR-V7 by real-time polymerase chain reaction (RT-PCR) shows AR-V7 positivity in healthy individuals. We hypothesized that the positivity reflects contamination by hematopoietic cells. We tried a novel circulating tumor cell (CTC) enrichment instrument, using Celsee, to clear hematopoietic cells. Methods: We tested whole blood or Celsee-enriched samples for AR-V7 by RT-PCR, and included samples from 41 CRPC patients undergoing sequential therapy. We evaluated the associations between AR-V7 status and clinical factors. We evaluated factors affecting AR-V7 positivity. Results: AR-V7 positivity was lower in Celsee-enriched than in whole blood specimens. AR-V7 and clinical factors did not predict the therapy effectiveness. We found no significant differences in the effectiveness of enzalutamide/abiraterone (Enz/Abi) upon AR-V7 evaluation. All AR-V7 positive patients had resistance to Enz/Abi. Docetaxel (DTX), cabazitaxel (CBZ), and Radium223 treatment showed no significant difference in the treatment effectiveness, regardless of AR-V7 presence. AR-V7 was more frequently positive than Extent of disease (EOD) 2 in cases with bone metastases. Conclusion: Celsee CTC enrichment suppresses AR-V7 false positivity. All AR-V7 positive patients presented resistance to Enz/Abi. DTX, CBZ, and Radium223 were effective and remain treatment options. AR-V7 positivity should progressively appear in patients with advanced bone metastases.

Background: The AR-V7 splice variant is a cause of castration-resistant prostate cancer (CRPC). However, testing for the presence of AR-V7 by RT-PCR shows AR-V7 positivity in healthy individuals. We hypothesized that the positivity reflected contamination by hematopoietic cells. We tried a novel CTC enrichment instrument using Celsee® to clear hematopoietic cells. Methods: We tested whole blood or Celsee-enriched samples for AR-V7 by RT-PCR and included samples from 41 CRPC patients undergoing sequential therapy. We evaluated the associations between AR-V7 status and clinical factors. We evaluated factors affecting AR-V7 positivity. Results: AR-V7 positivity was lower in Celsee-enriched than in whole blood specimens. AR-V7 and clinical factors did not predict the therapy effectiveness. We found no significant differences in the effectiveness of Enz/Abi upon AR-V7 evaluation. All AR-V7 positive patients had resistance to Enz/Abi. DTX, CBZ, and Radium223 treatment showed no significant difference in the treatment effectiveness, regardless of AR-V7 presence. AR-V7 was more frequently positive than EOD2 in cases with bone metastases. Conclusion: Celsee® CTC enrichment suppresses the AR-V7 false positivity. All AR-V7 positive patients presented resistance to Enz/Abi. DTX, CBZ, and Radium223 were effective and remained treatment options. AR-V7 positivity should progressively appear in patients with advanced bone metastases.

Objectives: Ureteropyeloscopy has recently become an essential technique in the diagnosis of upper urinary tract tumors. However, no consensus has been reached regarding its indications. In addition, it is accompanied by several limitations and potential adverse events such as dissemination of malignant cells, adhesion of the ureter to the surrounding tissue, ureteral stricture, and ureteral perforation. In order to determine when and what circumstances dictate the need for ureteropyeloscopy to detect upper urinary tract tumors, we investigated the indications for ureteropyeloscopy based on voided urine cytology and preoperative radiographic findings. Patients and Methods: In this retrospective study, we evaluated 92 patients (62 men and 30 women) with a mean age of 66.4 years (range, 15–87 years) who had undergone diagnostic ureteropyeloscopy at our institution for the past 10 years. All patients were divided into six subgroups based on voided urine cytology and preoperative radiographic findings: subgroups A1 (n = 18) and A2 (n = 2), positive cytology (positive catheter urine cytology/negative catheter urine cytology) and positive images; Subgroup B (n = 19), positive cytology and negative images; Subgroups C1 (n = 30) and C2 (n = 10), negative cytology and positive images (upper urinary tract carcinomas/other abnormal findings); Subgroup D (n = 13), negative cytology and negative images. Ureteropyeloscopic findings including histology were compared with urine cytology and radiographic findings. Results: Voided urine cytology exhibited 60.4% sensitivity and 77.3% specificity, while preoperative radiographic findings exhibited 70.8% sensitivity and 63.6% specificity. Carcinomas were detected in all patients in Subgroups A1 and A2. Carcinomas were also detected in 9 patients (47.4%) in Subgroup B, of whom 5 showed a history of bladder tumors. The remaining 10 patients all had a history of bladder cancer. In Subgroups C1, C2, and D, carcinomas were detected in 14 patients (46.7%), 1 patient (10%), and 4 patients (30.8%), respectively. These results suggested that ureteropyeloscopy should be recommended for patients with negative cytology. Three complications (pyelonephritis, renal failure, and urinary retention) were noted, but none of these was severe and all were cured within a few days. No malignant findings were obtained in any of the patients during follow-up after negative findings in ureteropyeloscopy. Conclusions: Ureteropyeloscopy is essential for detecting upper urinary tract carcinoma in patients with negative voided urine cytology and positive radiographic findings. In addition, ureteropyeloscopy seems to be used commonly among patients with positive urine cytology and negative radiographic findings, or those with bleeding from the ureteral orifice. However, unless conservative nephron-sparing treatment is considered, ureteropyeloscopy may be unnecessary for patients with positive urine cytology and positive radiographic findings.

Objectives: Prostatic abscesses are rare. The incidence of prostatic abscess has declined markedly with the widespread use of antibiotics. Obtaining improvement is difficult in many cases of prostate abscess. Today, there are no guidelines or algorithms for the treatment of prostatic abscess. In this study, the shape and size of the abscess, in addition to patient background characteristics and the clinical course, were evaluated, and the treatment strategy for prostatic abscess was examined. Methods and Material: All patients with a diagnosis of prostatic abscess in Showa University Hospital between 2003 and 2017 were retrospectively reviewed. Regarding the treatment options, the patients were divided into two groups, the conservative therapy group and the drainage group. In each group, background characteristics, culture reports, shape/size of abscess, and the presence of recurrence were evaluated. Results: All 18 patients with a diagnosis of prostatic abscess between 2003 and 2017 were retrospectively reviewed; 13 patients improved with conservative treatment alone, but drainage was performed in five patients with poor response to antibiotic therapy. All five cases requiring transurethral drainage were multifocal abscesses. Conclusions: In making a decision about the approach for drainage, it is important to assess the size and shape of the abscess using transrectal ultrasonography (TRUS), computed tomography (CT) and magnetic resonance imaging (MRI). If the abscess is the multifocal type, drainage should be considered. Based on the present study, whether the abscess is focal type or multifocal type, transurethral drainage should be considered if the abscess size exceeds 30 mm.

Excessive ammonia is harmful to the body. It is mostly hepatic in origin. Hyperammonemia due to urinary tract infection (UTI) is rare. We report a case of hyperammonemia with UTI and urinary retention. A 94-year-old female arrived at our hospital with impaired consciousness that lasted for a day. On arrival, her Glasgow Coma Scale was E1V1M5, blood ammonia was 272 ng/dl, and urinalysis revealed a large number of white and red blood cells. Abdominal computed tomography scan revealed a distended bladder and wall thickness with no hydronephrosis. Urine cultures were positive for urease-producing Corynebacterium, Escherichia coli, and Staphylococcus aureus. The patient was diagnosed with hyperammonemia with UTI and urinary retention. After urinary catheterization, blood ammonia levels normalized, and consciousness improved. We need to consider ammonia toxicity in UTI patients with urine retention presenting with altered consciousness.

Upper urinary tract neuroendocrine carcinoma (UUT-NEC) is extremely rare and has a poor prognosis. Although a few cases of successful treatment have been reported, no treatment has shown established efficacy.We analyzed 70 UUT-NEC patients, including 68 with small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) reported between 1985 and 2017 and 2 treated at our hospital.Median patient age was 66 years, 58.6% were men, and 60% were of Asian descent. Most UUT-NECs were SCNEC (68; 95.7%), whereas LCNEC was very rare (2; 2.9%). More than half of the patients had accompanying other histological components, the most common being urothelial carcinoma (51.5%), whereas 41.4% had NEC alone. Of the 70 patients, 27 underwent additional therapy (e.g., chemotherapy and radiotherapy) along with surgery. Median survival was 15 months. In univariate analysis, stages T1-2 disease showed better prognosis than stages T3-4 (P 0.001). Additional treatment (e.g., chemotherapy and radiotherapy) significantly improved prognosis (P = 0.014). Moreover, platinum-based chemotherapy also was associated with improved prognosis (P = 0.017). For platinum-based chemotherapy, multicollinearity with additional treatments was strong, and, thus, these data were not included in the analysis. Multivariate analysis revealed pathological stage (T1-2 vs. T3-4; P = 0.003) and additional treatment (P = 0.028) to be independent predictors of improved prognosis.Although UUT-NEC has a poor prognosis, additional treatment along with surgery and therapeutic intervention and stage T1-2 disease are independent factors to improve prognosis.

An 82-year-old man underwent radiotherapy (brachytherapy, external beam radiotherapy) for prostate cancer, followed approximately five years later by endocrine therapy for biochemical recurrence, which controlled the prostate-specific antigen (PSA) level. His later admission due to severe gross hematuria and dysuria is described. Computed tomography and magnetic resonance imaging findings revealed a cystic tumor continuous with the prostate between the prostate and rectum, and this tumor was thought to be the cause of the hematuria and dysuria. Transrectal biopsy and transurethral resection of the prostate were performed for pathological diagnosis and improvement of dysuria. The pathological diagnosis was remnant prostate cancer, and the cystic tumor was thought to have developed as a result of prostate cancer recurrence. Although chemotherapy using docetaxel was considered postoperatively, the patient refused this treatment. Even though the PSA level was under control, the patient's condition progressed rapidly, with onset of pulmonary and cervical lymph node metastases within a short period of time, and the patient subsequently died.

(Objective) Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with castration-resistant prostate cancer (CRPC). We retrospectively evaluated clinical efficacy and safety of enzalutamide in CRPC. (Patients and methods) We reviewed clinical records of 73 patients who had received enzalutamide for the CRPC at Showa University and affiliated 7 hospitals. Enzalutamide was given at a dose of 160 mg/day, but some patients were treated at lower dose because of there age or poor performance status. Prostrate-specific antigen (PSA) response, prior docetaxel use and the previously administered agents were evaluated retrospectively. (Results) The median patients age was 77 years, the median Gleason score was 9 and the median PSA level at baseline was 26.9 ng/ml. The patients who had prior docetaxel use were 29 (39.7%) and the median of total docetaxel dose was 460 mg/body. The median number of total prior treatments (anti-androgens, Estramustine and steroid) was 3. Twenty seven (61.4%) patients with docetaxel-naive achieved over 50% reduction of PSA level from baseline, but only 7 (24.1%) in patients previously treated with docetaxel. The most common adverse events included fatigue (24.7%), anorexia (24.7%) and the nausea (16.4%). We found a small proportion of responders to enzalutamide experienced a PSA flare. (Conclusion) Our results of the use of Enzaltamide for CRPC were similar with previous reports. PSA flare was found in some patients with CRPC who responded to enzaltamide. It should be noted that this possible PSA flare phenomenon.

Polyorchidism is a rare congenital condition associated with various anomalies; triorchidism is the most common form of this condition. A 21-year-old patient visited our hospital with pain in the right testis. He was diagnosed with right-sided polyorchidism with torsion and underwent manual detorsion followed by orchidopexy. We preserved the extra testis but did not perform histology, as radiological examination revealed no malignant features.

Metastatic renal cell carcinoma (mRCC) treatment consists of molecular targeted agents and cytokines that have fundamentally different mechanisms of action. Clinical responses also differ; complete response is rare with molecular targeted agents but is sometimes achieved with cytokine therapies. Because of the relatively high efficacy of combination therapy with low-dose interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) against mRCC, it is important to reevaluate cytokine therapies in vitro. Here, we show that when IL-2 is administered in combination with IFN-alpha, a stronger cytotoxic effect of PBMCs on RCC cell lines is observed than when IL-2 is administered alone. The upregulation of TNF-related apoptosis-inducing ligand on NK cell by IL-2 and suppression of regulatory T cells (Tregs) by IFN-alpha were recognized at the same time when cytotoxicity of peripheral blood mononuclear cells (PBMCs) was enhanced. IL-2 is known to activate natural killer cell cytotoxicity; however, IL-2 also stimulates Treg expansion, which enhances immunosuppression. On the other hand, IFN-alpha negatively regulates Treg cells, thereby increasing the function of immune effector cells. Our in vitro results may explain, at least in part, the clinical efficacy of combination low-dose IL-2 and IFN-alpha therapy against mRCC.

In recent years, various new drugs such as molecularly targeted drugs and immune checkpoint inhibitors have been developed. Liquid biopsy is becoming increasingly important as a guide for selecting these new drugs and determining their efficacy. In urological cancers, given the lack of serum markers for kidney cancer or urothelial cancers, the development of liquid biopsy is strongly desired. Liquid biopsy is less invasive than conventional tissue biopsy, enabling frequent biopsies, and is therefore considered effective for monitoring of the treatment course. Liquid biopsy is largely divided into three types: circulating tumor cells (CTCs), cell-free DNA, and exosomes, each of which has its own set of advantages and disadvantages with regard to the identification method and utility. In the present article, we focus on CTCs and discuss issues in their identification method as well as recent findings.

Objective: Many erectile dysfunction (ED) cases are attributed to vascular endothelial dysfunction and impaired blood flow due to arteriosclerotic changes. In this study, we examined the association among the erection hardness score (EHS), pulse wave velocity (PWV), and the presence of carotid artery plaques. Subjects and Methods: The study enrolled 67 patients who visited our hospital with the chief complaint of ED. Based on the history at the first visit, 28 of the 67 patients were categorized into the EHS 3–4 group and the remaining 39 into the EHS 0–2 group. The two groups were retrospectively analyzed. Results: The PWV points were significantly higher in the EHS 0–2 group than in the EHS 3–4 group (P = 0.047). In consideration for error in age, the modified points (PWV at the first visit – reference PWV by age) were significantly higher in the EHS 0–2 group than in the EHS 3–4 group (P = 0.026). This group also showed a higher detection rate of plaques by carotid ultrasound (66.7%). Conclusion: This study showed that patients with lower points of EHS had higher PWV and were more likely to have carotid artery plaques. While ED has occasionally been considered as an early risk marker for the onset of cardiovascular events; this study suggests that the hardness of the penis can be an easier-to-measure and more sensitive index.

The transduction efficacy of adenovirus serotype 5 (Ad5) vector in human renal carcinoma cells is generally low due to the down-regulated expression of Coxsackie and adenovirus receptor (CAR) in target cells. By contrast, the infectivity of adenovirus serotype 35 vectors depends on the binding rate to CD46 receptor, independent of CAR. In this study, we examined whether an adenovirus vector containing chimeric type 5 and type 35 fiber proteins (Ad5/F35) increases transduction efficiency compared to Ad5 vector in human renal carcinoma cells in vitro. The expression of CAR was much lower in the human renal carcinoma cells than in control HEK293 cells. By contrast, the expression of CD46 was similar and perhaps at a higher level in the human renal carcinoma cells than in the HEK293 cells. The transduction efficacy of Ad5/F35 vector was dramatically higher compared to that of Ad5 in human renal carcinoma cells, and was correlated to the expression of CD46. Thus, Ad5/35 vector may be useful for the development of novel gene therapy approaches to renal cell carcinoma.

Androgen deprivation therapy is the mainstay of treatment for prostate cancer. Given its frequent failure, new therapy that reduces prostate cancer progression would be a breakthrough in treating this disease. Bisphosphonates are well-established agents for treating skeletal-related events (SREs) in prostate cancer patients with bone metastases. Exposure to bisphosphonates may not only reduce the incidence of SREs, but also have anticancer effects by modulating a patient's immunity. The purpose of this study was to examine the effect of zoledronate (ZOL) on gamma delta T cells, serum prostate-specific antigen (PSA) levels, and velocities. The effect of ZOL, with and without IL-2, on gamma delta T cell activation was examined in vitro. Furthermore, the activated state and the number of gamma delta T cells and changes in serum PSA levels were examined for patients who received ZOL infusion for the prevention of SREs. We found that ZOL activated gamma delta T cells, and the number of gamma delta T cell was increased when IL-2 was administered with ZOL in vitro. Comparisons before and after the first ZOL infusion revealed that gamma delta T cells in peripheral blood were activated by ZOL. Moreover, after the first ZOL treatment, reduction in serum PSA was observed in 3 of 11 patients, and reduction in PSA velocity was observed in 5 of 10 patients. Our findings indicate that ZOL stimulates gamma delta T cells in vivo and in vitro. This study provides further insight into the ability of gamma delta T cells to induce an antitumor immune response.

Many mechanisms involving TNF-alpha, Th1 responses, and Th17 responses are implicated in chronic inflammatory autoimmune disease. Recently, the clinical impact of anti-TNF therapy on disease progression has resulted in re-evaluation of the central role of this cytokine and engendered novel concept of TNF-dependent immunity. However, the overall relationship of TNF-alpha to pathogenesis is unclear. Here, we demonstrate a TNF-dependent differentiation pathway of dendritic cells (DC) evoking Th1 and Th17 responses. CD14(+) monocytes cultured in the presence of TNF-alpha and GM-CSF converted to CD14(+) CD1a(low) adherent cells with little capacity to stimulate T cells. On stimulation by LPS, however, they produced high levels of TNF-alpha, matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either into mature DC or activated macrophages (M phi). The mature DC (CD83(+) CD70(+) HLA-DR (high) CD14(low)) expressed high levels of mRNA for IL-6, IL-15, and IL-23, induced naive CD4 T cells to produce IFN-gamma and TNF-alpha, and stimulated resting CD4 T cells to secret IL-17. Intriguingly, TNF-alpha added to the monocyte culture medium determined the magnitude of LPS-induced maturation and the functions of the derived DC. In contrast, the M phi (CD14(high)CD70(+)CD83(-)HLA-DR(-)) produced large amounts of MMP-9 and TNF-alpha without exogenous TNF stimulation. These results suggest that the TNF priming of monocytes controls Th1 and Th17 responses induced by mature DC, but not inflammation induced by activated M phi. Therefore, additional stimulation of monocytes with TNF-alpha may facilitate TNF-dependent adaptive immunity together with GM-CSF-stimulated M phi-mediated innate immunity.

Background: Immunotherapy with bacillus Calmette-Guerin (BCG) for bladder cancer is successful, although the precise mechanism is unclear. Natural killer (NK) cells are a candidate for BCG-activated killer cells, but the roles of other T lymphocytes, such as NKT cells and γδT cells, are not fully understood. Mycobacterium tuberculosis is a potent activator of both NKT cells and γδT cells. However, it is known that the patient's prognosis is good if there are increased numbers of dendritic cells (DCs) in the urine after BCG therapy. Therefore, we investigated whether DCs are matured by BCG and whether BCG-pulsed DCs stimulate NKT cells and γδT cells. Methods: Naive Pan T cells were isolated form peripheral blood mononuclear cells (PBMCs) and DCs were obtained by culturing CD14+ monocytes with granulocyte–macrophage colony-stimulating factor and interleukin-4. The DCs were pulsed with BCG and their maturation was measured by fluorescence-activated cell sorter analysis using the CD86 antibody. Naive T lymphocytes were stimulated by coculture with BCG-pulsed DCs in vitro, followed by FACS analysis to estimate the ratio and activation of NKT cells and the ratio of γδT cells. The 51Cr (chromium) release assay was used to estimate the cytotoxic activity of the stimulated T cells. Cytolytic proteins in the patient's PBMCs were measured during BCG therapy using semiquantitative reverse transcriptase-polymerase chain reaction. Results: The DCs were matured by BCG stimulation and the number of NKT cells and γδT cells increased after culturing with BCG-pulsed DCs. The BCG-pulsed DCs also activated the NKT cells and γδT cells. Also, the lymphocytes that were cocultured with the BCG-pulsed DCs showed unspecific cytotoxic activity against a bladder cancer cell line. Conclusion: Sensitization of NKT cells and γδT cells by BCG-pulsed DCs might be one of the mechanisms of BCG immunotherapy.

Objective: Although primary care practitioners (PCP) take an active role in diagnosis of prostate disorders in Western countries, how PCP take part in management of prostate disease still differs worldwide by country. We investigated practice and referral patterns concerning prostate disease among Japanese PCP and compared these with reported patterns in the West. Methods: A 26-question multiple-choice questionnaire was mailed to 935 PCP in Tokyo for anonymous completion. Most items involved prostate cancer screening or management of benign prostatic hyperplasia (BPH). Results: The survey was completed by 281 non-urological practitioners, among whom digital rectal examination was performed by 43%. Prostate-specific antigen (PSA) was determined in serum by 89%. For asymptomatic men older than 50, serum PSA was determined routinely each year by only 17%. When PSA was 4.1–10.0 ng/mL, 70% of respondents immediately referred patients to urologists, while 18% did not make a referral unless PSA exceeded 10.0 ng/mL. Seventy-four percent prescribed medication for benign prostate hypertrophy; among these respondents, 87% reported common use of α-blockers. Although 31% of respondents were aware of the International Prostate Symptom Score (IPSS), only 2% used it. Conclusions: Although Japanese PCP were involved increasingly in diagnosis and management of prostate disease, degree and proficiency of involvement were too limited and less than in Western countries. Continuing medical education appears desirable for PCP in Japan regarding prostate disease.

Purpose: Hot flash (HF) is a common side effect in prostate cancer patient undergoing androgen-deprivation therapy (ADT). In this study, we evaluated the efficacy of paroxetine (selective serotonin reuptake inhibitors (SSRIs)) for HF. Patients and methods: In total, 10 men with prostate cancer under ADH who were suffering with HF entered this study. Self-report questionnaire was used for the evaluation. Results: The average rating for HF frequency decreased (P=0.009) and HF severity decreased (P=0.0332) also, reported QOL score increased (P=0.0218). Conclusion: These preliminary data suggest that low dose (10 mg/day) of antidepressant paroxetine can be helpful in the treatment of HFs in patients under ADT for prostate cancer. Further controlled studies are needed to more fully evaluate the efficacy of the SSRIs.

Objective To investigate the immunology of host-tumour interaction, critical for the development of immunotherapy against cancers, by assessing the major histocompatibility complex (MHC) class I expression in both benign and malignant prostate disease, and the relationship between their expression and degree of tumour-infiltrating lymphocytes. Materials and methods Direct serial analysis of gene expression in tumours is an extremely sensitive and powerful tool for monitoring immunological changes in the immunotherapy of solid tumours. Most previous monitoring protocols rely mainly on the analysis of patient's peripheral blood but in the present study the direct molecular analysis of small tissue samples was used, and its accuracy compared with that of conventional immunohistochemical analysis. Twenty-four formalin-fixed, paraffin-embedded prostate samples (11 benign and 13 carcinoma) were used for the im-munohistochemical analysis of CD8+ T lymphocytes and MHC class I expression. CD8+ T lymphocytes were counted using an ocular grid and MHC class I measured using digital image-analysis software. Twenty-seven frozen prostate tissue samples (12 benign and 15 carcinoma) were used for direct gene measurements of CD8 and interferon-γ using a quantitative real-time polymerase chain reaction. Results There were significantly fewer CD8+ T lymphocytes in prostate carcinoma nests than in benign prostate. There was a significant correlation between the number of CD8+ T lymphocytes and MHC class I expression in the prostate. There was a strong correlation between the immunohistochemical estimates of CD8+ T lymphocytes and CD8 gene by polymerase chain reaction, but no significant difference between benign prostate and prostate carcinoma tissue in gene measurements. Conclusion Down-regulation of MHC class I expression by prostate cancer cells is associated with fewer CD8+ T lymphocytes and hence might be important in cancer growth. In addition, the measurement of gene expression in small tissue samples might be useful for monitoring the efficacy of treatment throughout cancer therapy.

OBJECTIVES In this study, we investigated MHC-class I expression on both prostate cancer and normal prostate and compared those data with the number of CD8+ lymphocyte. Secondary, we investigated effect of IFN-gamma to the MHC-class I expression on prostate carcinoma. MATERIALS AND METHODS Twenty cryo-preserved benign prostate samples (Seven normal prostates and five benign prostatic hypertrophy samples.) and fifteen prostate carcinoma samples were used for immunohistochemistry of CD8 and MHC-class I. Eleven fresh single cell suspensions of prostate carcinoma were used for IFN-gamma study. After 24 hours IFN-gamma stimulation, MHC-I expression was measured by FACs analysis. RESULTS Interestingly, significant correlation was observed between MHC-class I expression and the CD8+ lymphocyte infiltrate (r = 0.705, P < 0.0001). After 24 hrs IFN-gamma stimulation, MHC-class I expression was up-regulated in all samples (p < 0.05). CONCLUSION Reduced expression of MHC-class I was thought as one of the factor which is related to the reduced degree of TILs (tumor infiltratig lymphocytes) in prostate cancer. IFN-gamma which is secreted mainly from CTL (cytotoxic T lymphocyte) might increase the degree of TIL through up-regulated MHC-class I.

Developing new treatments that reduce prostate cancer progression is important. Therapeutic efficacy of conventional gene therapy for metastatic prostate cancer is still low. Lower induction rate of naked genes into target cell is due to reduced expression of adenovirus receptor on cancer cell and also due to high seroprevalence of anti-Ad antibodies in adults. Therefore, efficient Ad carrier systems that circumvent these problems should be developed. Gamma-delta T cells have demonstrated high affinity to cancer cells. CD46, which leads to broad tropism in Ad35 vectors, is expressed in hematopoietic cells, including γδ T cells. In this study, we demonstrate the potential of γδ T cells as “vehicles” for transporting Ad5/F35 vectors and genes into cancer cells.

A giant cystic formation was found behind the prostate of a 69-year-old man who presented with urinary retention. Ultrasonography, computed tomography scans and magnetic resonance imaging revealed a large cystic intrapelvic mass and biopsy of the cyst wall diagnosed papillary cyst adenocarcinoma. Immunohistochemically, the tumor originated from the prostate.

症例は65歳, 女性. 咳嗽, 発熱を主訴に約5か月にわたり肺炎, 気管支炎の診断のもとに加療を行っていたが, 腎不全を併発, 血液透析を行ったが2日後に強度の血痰を伴う急性呼吸不全を起こし, 急死した. 死亡直前に行った検査のうち血中抗基底膜抗体が陽性を示したため, 死後Goodpasture症候群と判明した. そこで今回我々は, Goodpasture症候群と症状との解析, また血液透析等との関連について検討してみたところ, 治療として約79%の症例で血液透析を行っており, そのうち約50%で死亡し, 先行症状として微熱を繰り返すような上気道感染が多いことが分かった. また生存例では, パルス療法またはセミパルス療法が有効であると思われた.

The aim of this study wsa to evaluate the additive effect of valproic acid (VPA) to γδ T-cell cytotoxicity against bladder cancer cells.Human bladder cancer cell lines TCCSUP and 253J were treated with VPA and mRNA expression of natural killer group 2D (NKG2D) ligands was determined. The antitumour effect of expanded γδ T-cells against zoledronic acid (ZOL) and VPA pre-treated cancer cells was subsequently determined.VPA increased mRNA expression of NKG2D ligands on both cancer cell types. A blocking study revealed that 253J cells were recognised through NKG2D, while TCCSUP cells were mainly recognised through γδ T-cell receptor. VPA pre-treatment increased sensitivity to cytolysis by γδ T-cells for both cancer cell types, whereas ZOL pre-treatment was only effective against TCCSUP.Induction of NKG2D ligands by VPA increased the susceptibility of cancer cells that are recognised by NKG2D to cytolysis by γδ T-cells.

Androgen deprivation therapy is the mainstay of treatment for prostate cancer. Given its frequent failure, new therapy that reduces prostate cancer progression would be a breakthrough in treating this disease. Bisphosphonates are well-established agents for treating skeletal-related events (SREs) in prostate cancer patients with bone metastases. Exposure to bisphosphonates may not only reduce the incidence of SREs, but also have anticancer effects by modulating a patient's immunity. The purpose of this study was to examine the effect of zoledronate (ZOL) on gamma delta T cells, serum prostate-specific antigen (PSA) levels, and velocities. The effect of ZOL, with and without IL-2, on gamma delta T cell activation was examined in vitro. Furthermore, the activated state and the number of gamma delta T cells and changes in serum PSA levels were examined for patients who received ZOL infusion for the prevention of SREs. We found that ZOL activated gamma delta T cells, and the number of gamma delta T cell was increased when IL-2 was administered with ZOL in vitro. Comparisons before and after the first ZOL infusion revealed that gamma delta T cells in peripheral blood were activated by ZOL. Moreover, after the first ZOL treatment, reduction in serum PSA was observed in 3 of 11 patients, and reduction in PSA velocity was observed in 5 of 10 patients. Our findings indicate that ZOL stimulates gamma delta T cells in vivo and in vitro. This study provides further insight into the ability of gamma delta T cells to induce an antitumor immune response.

5-Fluorouracil (5-FU) and its prodrugs are used to treat various cancers. Response to 5-FU-based chemotherapy and expression of 5-FU-related enzymes differ among cancers. The objective of the present study was to investigate the relationship between the expression of 5-FU-related enzymes and clinicopathologic factors in bladder cancer. Formalin-fixed, paraffin-embedded sections of 44 bladder cancers and 27 normal bladders were included in this study. After laser capture microdissection, "Danenberg tumor profile," was performed for the measurement of 5-FU-related enzymes. There was no significant difference between dihydropyrimidine hydrogenase (DPD) mRNA expression in bladder cancer and in normal bladder. On the contrary, mRNA expressions of orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), and thymidine phosphorylase (TP) in bladder cancer were higher than those in normal bladder. Compared with previously reported DPD mRNA expressions in other types of cancer, DPD mRNA expression in bladder cancer was relatively low. The 5-FU-related enzymatic condition of bladder cancer is favorable for 5-FU.

The transduction efficacy of adenovirus serotype 5 (Ad5) vector in human renal carcinoma cells is generally extremely low due to the non-expression of Coxsackie and adenoviral receptor (CAR). We investigated whether fiber-modified Ad vector containing an RGD motif in the HI loop of the Ad fiber knob could increase the transduction efficiency of Ad5 in human renal carcinoma cells in vitro.We examined both expressions of CAR, and alpha(v), beta(3) and beta(5) integrins, and the transduction efficacy of fiber-modified adenovirus vector in all cell lines.The expression of CAR was lower and those of alpha(v) and beta(3) integrins were higher in all cell lines compared with control cell line, KK47. The transduction efficacy of fiber-modified Ad vector increased by 125- to 1,800-fold compared with Ad5.The fiber-modified Ad vector may be useful to establish effective new gene therapy strategies for the treatment of renal cell carcinoma.

The effects on quality of life (QOL) after a Phase I/II clinical trial of a combination of osteocalcin promoter-driven herpes simplex virus thymidine kinase (Ad-OC-TK) gene therapy and valacyclovir (VAL) were investigated for patients with hormone-refractory prostate cancer (HRPC).The QOL of six patients was prospectively assessed after gene therapy on days 0, 14, and 28. A modified questionnaire was created based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire's prostate cancer-specific module (EORTC QLQ-PR25).The scores of all items significantly improved along with the total score. Further, bodily pain was significantly reduced on day 28. Moreover, the rate of change in the serum prostate-specific antigen levels from day 0 to day 28 was significantly correlated with the rate of change in bodily pain.In this clinical trial, Ad-OC-TK plus VAL treatment significantly improved the short-term QOL and bodily pain of patients with localized recurrence or bone metastases of HRPC.

Until now, there have been no reliable serum markers for monitoring urothelial cancers. However, it has been reported that it is possible to detect circulating urothelial cancer cells using the CellSearch™ Circulating Tumor Cell (CCTC™) Test (Immunicon, Huntingdon Valley, PA). (1) This case report is a representative example of the good correlation between the change of the number of circulating tumor cells in the blood and the state of an urothelial cancer after therapies. Detection of circulating tumor cells might be a valuable serum marker for urothelial cancer patients with distant metastasis.

Immunotherapy with bacillus Calmette-Guérin (BCG) for bladder cancer is successful, although the precise mechanism is unclear. Natural killer (NK) cells are a candidate for BCG-activated killer cells, but the roles of other T lymphocytes, such as NKT cells and gammadeltaT cells, are not fully understood. Mycobacterium tuberculosis is a potent activator of both NKT cells and gammadeltaT cells. However, it is known that the patient's prognosis is good if there are increased numbers of dendritic cells (DCs) in the urine after BCG therapy. Therefore, we investigated whether DCs are matured by BCG and whether BCG-pulsed DCs stimulate NKT cells and gammadeltaT cells.Naïve Pan T cells were isolated form peripheral blood mononuclear cells (PBMCs) and DCs were obtained by culturing CD14(+) monocytes with granulocyte-macrophage colony-stimulating factor and interleukin-4. The DCs were pulsed with BCG and their maturation was measured by fluorescence-activated cell sorter analysis using the CD86 antibody. Naïve T lymphocytes were stimulated by coculture with BCG-pulsed DCs in vitro, followed by FACS analysis to estimate the ratio and activation of NKT cells and the ratio of gammadeltaT cells. The (51)Cr (chromium) release assay was used to estimate the cytotoxic activity of the stimulated T cells. Cytolytic proteins in the patient's PBMCs were measured during BCG therapy using semiquantitative reverse transcriptase-polymerase chain reaction.The DCs were matured by BCG stimulation and the number of NKT cells and gammadeltaT cells increased after culturing with BCG-pulsed DCs. The BCG-pulsed DCs also activated the NKT cells and gammadeltaT cells. Also, the lymphocytes that were cocultured with the BCG-pulsed DCs showed unspecific cytotoxic activity against a bladder cancer cell line.Sensitization of NKT cells and gammadeltaT cells by BCG-pulsed DCs might be one of the mechanisms of BCG immunotherapy.

Although primary care practitioners (PCP) take an active role in diagnosis of prostate disorders in Western countries, how PCP take part in management of prostate disease still differs worldwide by country. We investigated practice and referral patterns concerning prostate disease among Japanese PCP and compared these with reported patterns in the West.A 26-question multiple-choice questionnaire was mailed to 935 PCP in Tokyo for anonymous completion. Most items involved prostate cancer screening or management of benign prostatic hyperplasia (BPH).The survey was completed by 281 non-urological practitioners, among whom digital rectal examination was performed by 43%. Prostate-specific antigen (PSA) was determined in serum by 89%. For asymptomatic men older than 50, serum PSA was determined routinely each year by only 17%. When PSA was 4.1-10.0 ng/mL, 70% of respondents immediately referred patients to urologists, while 18% did not make a referral unless PSA exceeded 10.0 ng/mL. Seventy-four percent prescribed medication for benign prostate hypertrophy; among these respondents, 87% reported common use of alpha-blockers. Although 31% of respondents were aware of the International Prostate Symptom Score (IPSS), only 2% used it.Although Japanese PCP were involved increasingly in diagnosis and management of prostate disease, degree and proficiency of involvement were too limited and less than in Western countries. Continuing medical education appears desirable for PCP in Japan regarding prostate disease.

Circulating tumor cells (CTCs) have been shown to aid in the therapeutic management of patients. But, only a few attempts have been made at the detection of urothelial cancer cells in the blood. The purpose of this study was to test the hypothesis that CTCs are detected in patients with urothelial cancers using newly developed CellSearch Assay.Firstly, the bladder cancer cell lines were used to evaluate the reagents for immunocytochemical detection. After, mixed with peripheral blood mononuclear cells (PBMCs) of healthy volunteers, bladder cancer cells were stained with antibodies then multiparameter flow cytometric analysis was performed for the identification of bladder cancer cells in the PBMCs. Secondary, recovery of known numbers of spiked bladder cancer cells from whole blood was examined using CellSearch Assay. Finally, blood samples from nonmetastatic and metastatic urothelial cancer patients were investigated for CTC detection using CellSearch Assay.1: Flow cytometric analysis revealed that it is possible to identify bladder cancer cells in PBMCs. 2: Sensitivity examination for detection of urothelial cancer cells with CellSearch Assay: Single regression analysis of the spiked number of cells vs. the recovered number of cells yielded a good correlation in this experiment. 3: Urothelial cancer cells were detected in 8 of fourteen patients (57.1%) with distant metastasis. Despite, no patient with nonmetastatic urothelial cancers showed positive result for this assay.This is the first report of attempt to detect circulating urothelial cancer cells in the peripheral blood of the patients with metastatic and nonmetastatic urothelial cancers by CellSearch Assay.

A giant cystic formation was found behind the prostate of a 69-year-old man who presented with urinary retention. Ultrasonography, computed tomography scans and magnetic resonance imaging revealed a large cystic intrapelvic mass and biopsy of the cyst wall diagnosed papillary cyst adenocarcinoma. Immunohistochemically, the tumor originated from the prostate.

A 43-year-old infertile man with oligozoospermia and normal serum gonadotropin and cytogenetic findings was treated with follicle-stimulating hormone for 1 year at our institution. Two years later, the patient presented with bilateral palpable testicular tumors. His beta-human chorionic gonadotropin and lactate dehydrogenase levels were elevated. Pathologic examination disclosed a pure seminoma in each testis (pT1N0M0). Adjuvant radiotherapy was administered. The tumors might have been induced by follicle-stimulating hormone treatment. Careful follow-up examination of the testis is necessary in men who have received hormonal treatment for infertility.

OBJECTIVES In order to evaluate the immunological milieu in renal cell carcinoma (RCC), we investigated infiltration by mature dendritic cells (CD83 positive cells), cytotoxic-T cells (CD8 positive cells) and helper-T cells (CD4 positive cells) in RCCs, as well as in surrounding normal tissues and correlations between the cell types. MATERIALS AND METHODS Specimens from 33 surgically resected RCCs were embedded in paraffin and then stained for CD4, CD8, CD83. Each section contained three areas, tumor tissue, tumor margin and normal renal parenchyma. Cells positive for CD4, CD8 and CD83 were counted each area. RESULT Cells positive for CD4, CD8 and CD83 were observed predominantly in the tumor margins, rather than tumor tissue and normal renal parenchyma. The differences were significant in the number of immune positive cells between tumor margin and tumor tissue, and between tumor margin and normal renal parenchyma. A significant correlations was found between CD4 and CD83 positive cells (r = 0.805, p < 0.0001), and also between CD8 and CD83 positive cells (r = 0.505, p < 0.0001). CONCLUSION It has been reported that mature dendritic cells induces cytotoxic-T cell and helper-T cell responses. Infiltrating mature dendritic cells, cytotoxic-T cells and helper-T cells were present only in the tumor margin. This may reflect significant immune reaction around the tumor margin.

The polypeptide component of telomerase (TERT) is an attractive candidate for a broadly expressed tumor rejection antigen because telomerase is silent in normal tissues but is reactivated in more than 85% of cancers. Here we show that immunization against TERT induces immunity against tumors of unrelated origin. Immunization of mice with TERT RNA-transfected dendritic cells (DC) stimulated cytotoxic T lymphocytes (CTL), which lysed melanoma and thymoma tumor cells and inhibited the growth of three unrelated tumors in mice of distinct genetic backgrounds. TERT RNA-transfected human DC stimulated TERT-specific CTL in vitro that lysed human tumor cells, including Epstein Barr virus (EBV)-transformed B cells as well as autologous tumor targets from patients with renal and prostate cancer. Tumor RNA-transfected DC were used as surrogate targets in the CTL assays, obviating the difficulties in obtaining tumor cells from cancer patients. In one instance, where a tumor cell line was successfully established in culture from a patient with renal cancer, the patient's tumor cells were efficiently lysed by the CTL. Immunization with tumor RNA was generally more effective than immunization with TERT RNA, suggesting that an optimal immunization protocol may have to include TERT as well as additional tumor antigens.