[A case of collecting duct carcinoma originating from renal cyst].

In December 2003, a 32-year-old man underwent puncture for right renal cyst at a clinic. Since puncture fluid was dark red color in spite of negative cytology, he was being followed, but after a while he did not show up for further examination. In November 2007, he revisited the clinic due to low-grade fever. Computed tomographic findings showed an enlarged cystic mass with a solid component invading the liver and lymph node swelling. He underwent right radical nephrectomy combined with partial liver resection and lymphadenectomy. Histological findings showed collecting duct carcinoma associated with clear cell carcinoma directly invading the liver with lymph node metastasis (pT4N2M0). Although he underwent 4 cycles of gemcitabine-cisplatin therapy and alfa interferon injection 3 times a week thereafter as adjuvant setting, multiple liver metastasis occurred 15 months after surgery. He died of cancer 31 months after surgery in spite of molecular targeted therapy including sorafenib and sunitinib.

Docetaxel in combination with estramustine and prednisolone for castration-resistant prostate cancer.

BACKGROUND: The aim of this study was to investigate the efficacy and toxicity of docetaxel-based chemotherapy, and to investigate pretreatment factors that can predict overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). METHODS: From June 2005 to July 2010, 70 patients with CRPC underwent docetaxel-based chemotherapy at Wakayama Medical University and related hospitals. Docetaxel was given at a dose of 70 mg/m(2) once every 3 weeks or 35 mg/m(2) twice every 3 weeks. Oral estramustine 560 mg was given concurrently for five consecutive days during weeks 1 and 2 of each cycle, and prednisolone 10 mg was given every day. Dexamethasone 8 mg was premedicated intravenously before docetaxel administration. RESULT: The patients received a median of four cycles of treatment (range 1-31). In the serum prostate-specific antigen response, 13 (18.6%) patients achieved a complete response and 29 (41.4%) achieved a partial response. Median OS and time to progression were 14 months and 6 months, respectively. Median follow-up period was 9.5 months. Two independent pretreatment risk factors that predicted OS were visceral metastasis including lymph node metastasis and anemia. Grade 3/4 neutropenia and anemia occurred in 25.7 and 8.6% of the patients, respectively. Four treatment-related deaths were seen during the observation period. CONCLUSION: The combination of docetaxel, estramustine and prednisolone was effective in Japanese patients with CRPC; however, this combination therapy should be carefully indicated to elderly and/or poor performance status patients due to its toxicity. Visceral metastasis and anemia were identified as independent risk factors which could predict OS.

HSP DNAJB8 controls tumor-initiating ability in renal cancer stem-like cells.

Cancer stem-like cells (CSC) are a small population of cancer cells with superior tumor initiating, self-renewal, and differentiation properties. In this study, we show that the cancer-testis antigen and HSP40 family member DNAJB8 contributes to the CSC phenotype in renal cell carcinoma (RCC). DNAJB8 overexpression increased the percentage of side population (SP) cells representing CSCs in RCC cells, enhancing their tumor-initiating ability. Conversely, attenuation of DNAJB8 decreased SP cells and reduced tumor-initiating ability. The utility of DNAJB8 as an immunologic target was established in DNA vaccination experiments. Compared with immunization with the tumor-associated antigen survivin, which was expressed in both CSCs and non-CSCs in RCC, immunization with Dnajb8 expression plasmids yielded stronger antitumor effects. Together, our findings suggest that DNAJB8 plays a role in CSC maintenance and that it offers a candidate for CSC-targeting immunotherapy in RCC.

Efficiency of G2/M-related tumor-associated antigen-targeting cancer immunotherapy depends on antigen expression in the cancer stem-like population.

The aim of this study was to establish a novel efficient cancer DNA vaccine approach. Many tumor-associated antigens (TAAs) have been reported; however, there is little information of the efficiency of each TAA. Normal cells barely undergo mitosis, whereas cancer cells divide frequently and grow well. Thus, G2/M-related antigens are cancer cell-specific and are regarded to be suitable candidates as targets of cancer immunotherapy. In this study, we compared the efficiencies of G2/M-related antigens including Birc5, Aurka, Nke2 and Plk1 by using a DNA vaccination model. Mice that had been immunized with G2/M-related antigens coding plasmid were challenged with CT26 colon cancer cells. Interestingly, Birc5- and Aurka-immunized mice showed an anti-tumor effect, whereas Nek2- and Plk1-immunized mice did not show any anti-tumor effect. We investigated the expression of G2/M-related antigens in cancer stem-like cell (CSC)/cancer-initiating cell (CIC) population to verify the difference in the anti-tumor effect. CSCs/CICs were isolated as side population (SP) cells using Hoechst 33342 dye from CT 26 cells. It was found that Birc5 and Aurka are expressed in both CSCs/CICs and non-CSCs/CICs (shared antigens), whereas Nek2 and Plk1 are expressed preferentially in non-CSCs/CICs (non-CSC antigens). Therefore, antigen expression in the CSC/CIC population might be related to the anti-tumor efficiency of cancer immunotherapy. Furthermore, we established a heat shock protein (Hsp90)-fused Birc5 plasmid to improve anti-cancer immunity. Birc5 fused to the N-terminal region of Hsp90 showed a stronger anti-tumor effect, whereas Birc5 fused to the C-terminal region of Hsp90 did not show enhancement compared with Birc5. These observations indicate that expression in the CSC/CIC population is essential to achieve tumor regression and that fusing antigens to the N-terminal region of Hsp90 enhances the anti-tumor effect.

IL-23 gene therapy for mouse bladder tumour cell lines.

OBJECTIVES: • To evaluate the antitumour effects of IL-23 gene transfer into mouse bladder carcinoma (MBT2) cells. • To investigate the mechanisms underlying the subsequent constitutive secrection of IL-23 by the MBT2 cells MATERIALS AND METHODS: • An expression vector containing IL-23 gene was introduced into MBT2 cells by liposome-mediated gene transfer, and secretion of IL-23 was confirmed by ELISA. • The in vivo antitumour effect of IL-23-secreting MBT2 cells (MBT2/IL-23) was examined by injecting the cells into syngeneic C3H mice. • A tumour vaccination study using mitomycin C (MMC)-treated IL-23-secreting MBT2 cells was carried out, and the usefulness of in vivo CD25 depletion for an additional vaccine effect was also investigated. • The mechanisms underlying the antitumour effects were investigated by antibody depletion of CD8 or CD4 T cells, or natural killer cells, and cells infiltrating the tumour sites in vivo were assessed using immunohistochemistry. RESULTS: • Stable transformants transduced with MBT2/IL-23 secreted IL-23 into the culture supernatant. • Genetically engineered IL-23-secreting MBT2 cells were rejected in syngeneic mice. • MBT2/IL-23-vaccinated mice inhibited the tumour growth of parental MBT2 cells injected at a distant site and this vaccine effect was enhanced by combination with in vivo CD25 depletion by an antibody. • The main effector cells for the direct antitumour effect of MBT2/IL-23 were CD8 T cells, which was shown by in vivo depletion and immunohistochemical study. CONCLUSIONS: • IL-23-secreting MBT2 cells were rejected in syngeneic mice by the activation of CD8 T cells. • MMC-treated MBT2/IL-23 can have a tumour vaccine effect for parental MBT2 cells, and this effect was enhanced by combination with in vivo CD25 depletion.

[Extra-adrenal pheochromocytoma with the manifestation of catecholamines cardiomyopathy: a case report].

A 22-year old female had an episode of acute heart and respiratory failure requiring mechanical ventilation ducing a trip overseas. Echocardiography demonstrated akinesis of the apical area (left ventricle ejectionfraction(LVEF) =15%). Since computed tomography (CT) with coronary angiography to rule out acute coronary syndrome showed no abnormalities, she was diagnosed with morphological stress cardiomyopathy due to akinesis of the apical area. After returning to Japan, she was admitted to our hospital for further examination. She had an increased level of catecholamines in 24-hour urine. ¹³¹Imetaiodobenzyguanidine scintigraphy, CT scan and fluorodexyglucose positron emission tomography revealed a retroperitoneal mass. From these results, a diagnosis of extra-adrenal pheochromocytoma with catecholamine-induced cardiomyopathy was made. Histological diagnosis of the laparoscopically resected tumor was pheochromocytoma. After the operation, the level of catecholamines in 24-hour urine was normalized.

PSA at postoperative three months can predict biochemical recurrence in patients with pathological T3 prostate cancer following radical prostatectomy.

OBJECTIVES: To identify the prognostic factors and determine which pT3 prostate cancer patients can be safely followed up after surgery without any adjuvant treatment. METHODS: A retrospective review was carried out on 106 patients with pT3 prostate cancer. All preoperative and postoperative parameters, including the postoperative serum prostate-specific antigen (PSA) level at 3 months after surgery, were assessed by univariate and multivariate analyses. RESULTS: Mean follow-up period was 18 months. The overall biochemical recurrence-free rate was 53.7% and 34.1% at 12 and 36 months, respectively. On univariate analysis, all preoperative clinical factors were significantly correlated with biochemical progression. On multivariate analysis, pathological Gleason score, pathological stage and postoperative PSA were significant predictors. Among those with undetectable PSA after surgery, 38 patients (88.4% of 43) did not have disease progression during the follow-up period. On the other hand, of the 27 patients with detectable PSA that was not defined as progressive (range 0.01-0.20), 22 (81.5%) had biochemical disease progression. The progression free probability was significantly different between these two groups (P-value < 0.0001). CONCLUSIONS: pT3 prostate cancer patients showing low pathological Gleason score, without seminal vesicle invasion, and undetectable postoperative PSA values have low probability of PSA progression. Careful follow up including periodic PSA assessment and clinical observation represents an adequate strategy in the management of these patients.

[Primary adrenal leiomyosarcoma: a case report].

A 78-year-old female complained high fever and vomiting. The ultrasonographic examination revealed a giant tumor above the left kidney. She was referred to our hospital for further examinations and treatments. Radiographic examination showed a solid mass of 10 cm in diameter, smooth surface, and sharply-delimited, above the left kidney corresponding to the left adrenal gland. Other organs showed no evidence of disease. Hormonal examination was normal. She was diagnosed as left non-functioning adrenal tumor, and underwent surgery. The resected specimen was 11 x 10 x 7 cm, 460 g with a part of normal adrenal tissue on the surface. Histopathological examination revealed it as leiomyosarcoma. She has no evidence of disease twenty months after the operation. Primary adrenal leiomyosarcoma is extremely rare. To the best of our knowledge, there were only 22 reported cases including ours in the English and Japanese literature.

Dendritic cells with transduced survivin gene induce specific cytotoxic T lymphocytes in human urologic cancer cell lines.

OBJECTIVES: To investigate whether survivin-specific cytotoxic T lymphocytes (CTLs) could be induced by dendritic cells (DCs) transduced with survivin gene by adenoviral vector, and whether these CTLs would display cytotoxic activities against human urologic cancer cell lines. Survivin, a member of the inhibitor of apoptosis protein family, is expressed in most malignancies, but not in normal tissue. METHODS: Adenoviral vector encoding the human survivin gene was generated. Human DCs from healthy donors were transduced with human survivin gene by infection with adenoviral vector encoding the human survivin gene using the centrifugal method. Survivin-specific CTLs were induced from autologous peripheral blood mononuclear cells by DCs transduced with the survivin gene. The ability of CTLs to lyse cancer cell lines was assessed using the (51)Cr-release assay. RESULTS: DCs transduced with survivin gene could induce survivin-specific CTLs against various urologic malignancies such as bladder, kidney, and prostate cancer cells. This cytotoxic activity could be blocked by anti-CD8 and anti-major histocompatibility complex class I antibodies. We also found that this cytotoxic activity was specific for the survivin protein and human leukocyte antigen haplotype. CONCLUSIONS: DCs transduced with the survivin gene induced potent survivin-specific CTL responses in vitro. This suggests that cancer immunotherapy targets for survivin might offer a novel approach to treating various urologic cancers.

Bacillus Calmette-Guérin cell-wall skeleton enhances the killing activity of cytotoxic lymphocyte-activated human dendritic cells transduced with the prostate-specific antigen gene.

UNLABELLED: To determine whether dendritic cells (DC) transduced with the prostate-specific antigen (PSA) gene can induce PSA-specific cytotoxic lymphocytes (CTL) against prostate cancer cells, and whether bacillus Calmette-Guérin (BCG) cell-wall skeleton (CWS) can enhance the maturation of DC-PSA and the killing activity of subsequently induced PSA-specific CTL. MATERIALS AND METHODS; We generated an adenovirus encoding the PSA gene (AxCA-PSA) using the cosmid-terminal protein complex method. DC were infected with AxCA-PSA using the centrifugal method. The ability of CTL to lyse target cells expressing PSA, i.e the PSA-positive prostate cancer cell line, LNCap, and PSA-transduced autologous phytohaemagglutinin (PHA) blasts expressing PSA, was assessed using the 51Cr-release assay. The maturation of DC-PSA stimulated by BCG-CWS was assayed by flow cytometry. The cytotoxic activity enhanced by BCG-CWS was assessed by the 51Cr-release assay. RESULTS: DC-PSA induced PSA-specific CTL with 85% cytotoxic activity against LNCaP (effector: target ratio, E:T, of 50:1). However, the cytotoxic activity against PSA-negative cells was very low. Anti-CD8 and anti-major histocompatibility (MHC) class I antibodies blocked PSA-specific cytotoxicity. The PSA-specific killing was reproducible against autologous PHA blast cells expressing PSA, independently of human leukocyte antigen haplotype. Furthermore, the combination of DC-PSA with BCG-CWS remarkably enhanced the PSA-specific cytotoxicity against PHA blasts expressing PSA (15-30% at an E:T ratio of 50:1). CONCLUSION: These findings suggest that DC-PSA can induce MHC class I-restricted PSA-specific CD8+ CTL responses and that DC-PSA matured by BCG-CWS enhance PSA-specific cytotoxicity. The combination of DC-PSA with BCG-CWS might be a useful approach for treating advanced prostate cancer.

[A case of neonatal testicular torsion].

An infant normally delivered at the 38th week of gestation was referred to our department one day after birth for a firm and painless right hemiscrotal mass with bluish coloration. Since contralateral scrotum showed swelling, we performed emergency surgery on that day. The right spermatic cord was constricted due to extravaginal torsion, and degree and direction of torsion was unclear since the spermatic cord was already organized. Right testis showed irreversible necrotic change, requiring orchiectomy. We confirmed that left testis was intact and performed orchidopexy. Since high incidence of contralateral asymptomatic torsion has been reported in patients with prenatal testicular torsion, emergency surgery should be considered when contralateral scrotum shows abnormal findings.

[Carcinoma in situ of the bladder involving the prostate with an unusual invasive pattern following BCG therapy: a case report].

We report a case of carcinoma in situ (CIS) of the bladder involving the prostate with an unusual invasive pattern following Bacillus Calmette Guerin (BCG) therapy. A 41-year-old man achieved complete response after a course of intravesical instillation of BCG for diffuse CIS of the bladder. Two years later, urine cytology became positive. We performed random biopsy of the bladder and urethra three times and examined the bilateral upper urinary tract with retrograde pyelography and split urine cytology. However, none of these examinations revealed any malignant features, leading to a suspicion that the prostate was the recurrent site. Transrectal needle biopsy of the prostate revealed urothelial carcinoma (UC) at the transition between bladder and prostate. Transurethral biopsy of the prostatic urethra also detected UC in a core of the bladder neck only. Under a diagnosis of UC involving the prostate, we performed total cystectomy with ileal conduit diversion. Histopathological findings of the surgical specimen showed prostatic stromal invasion of the tumor. In this case, CIS at the bladder neck might directly and silently invade the prostatic stroma, thus transurethral biopsy contributed little to the diganosis. We recommend transrectal needle biopsy of the prostate as well as TUR biopsy in such rare cases.