Up-regulation of secretory leukocyte protease inhibitor in human samples might have a potential role of predicting prostate cancer recurrence and progression after surgery and hormonal therapy.

Using new castration-resistant prostate cancer (CRPC) cell lines developed from LNCaP cells as a model for CRPC, we searched for novel biomarkers by analyzing the proteins secreted in culture supernatants. The results showed that the levels of secretory leukocyte protease inhibitor (SLPI) in these cell lines were 4.7-6.7 times higher than those secreted in parental LNCaP. Patients with localized prostate cancer (PC) and who expressed SLPI had a significantly lower prostate-specific antigen (PSA) progression-free survival rate than those who did not. Multivariate analysis revealed that SLPI expression was an independent risk factor for PSA recurrence. By contrast, when immunostaining of SLPI was performed on consecutive prostate tissue samples obtained from 11 patients, both in hormone naive (HN) and castration resistant (CR) conditions, only one patient expressed SLPI in the HNPC state; however, four of the 11 patients expressed SLPI in the CRPC state. In addition, two of these four patients were resistant to enzalutamide, and there was a discrepancy between their serum PSA levels and radiographic progression of the disease. These results suggest that SLPI can be a predictor of prognosis in patients with localized PC and disease progression in CRPC patients.

Identification of the α2 chain of interleukin-13 receptor as a potential biomarker for predicting castration resistance of prostate cancer using patient-derived xenograft models.

BACKGROUND: Several treatment strategies use upfront chemotherapy or androgen receptor axis-targeting therapies for metastatic prostate cancer. However, there are no useful biomarkers for selecting appropriate patients who urgently require these treatments. METHODS: Novel patient-derived xenograft (PDX) castration-sensitive and -resistant models were established and gene expression patterns were comprehensively compared. The function of a gene highly expressed in the castration-resistant models was evaluated by its overexpression in LNCaP prostate cancer cells. Protein expression in the tumors and serum of patients was examined by immunohistochemistry and ELISA, and correlations with castration resistance were analyzed. RESULTS: Expression of the α2 chain of interleukin-13 receptor (IL13Rα2) was higher in castration-resistant PDX tumors. LNCaP cells overexpressing IL13Rα2 acquired castration resistance in vitro and in vivo. In tissue samples, IL13Rα2 expression levels were significantly associated with castration-resistant progression (p < 0.05). In serum samples, IL13Rα2 levels could be measured in 5 of 28 (18%) castration-resistant prostate cancer patients. CONCLUSION: IL13Rα2 was highly expressed in castration-resistant prostate cancer PDX models and was associated with the castration resistance of prostate cancer cells. It might be a potential tissue and serum biomarker for predicting castration resistance in prostate cancer patients.

Narrative review of challenges in the management of advanced neuroendocrine prostate cancer.

With wide availability of potent androgen receptor targeted agents (ARTAs), the incidence of treatment-related neuroendocrine prostate cancer (t-NEPC) has been dramatically increasing. However, there is no standard effective treatment for this disease state. Recent advances in genomic and molecular medicine have identified some critical features of NEPC that would help in understanding the biology of the disease. Furthermore, invaluable pre-clinical in vivo and in vitro research models that represent NEPC have been developed. These advances in research have revealed a large heterogeneity of t-NEPC with varying degree of androgen receptor (AR), neuroendocrine (NE) marker, and cell cycle associated gene expressions, which may have clinical implication in terms of prognosis and treatment selection. Based on these studies, some potential drug targets have been identified, and early clinical trials are ongoing. In the future, more precise disease classification and biomarker-driven selection of patients will be critical for optimization of treatment for patients with NEPC. In the present review, we describe up-to-date findings of recent research on this topic and introduce ongoing therapeutic developments that are expected to lead to novel treatment strategies for NEPC in the future.

Establishment and characterization of a novel treatment-related neuroendocrine prostate cancer cell line KUCaP13.

The prevalence of neuroendocrine prostate cancer (NEPC) arising from adenocarcinoma (AC) upon potent androgen receptor (AR) pathway inhibition is increasing. Deeper understanding of NEPC biology and development of novel therapeutic agents are needed. However, research is hindered by the paucity of research models, especially cell lines developed from NEPC patients. We established a novel NEPC cell line, KUCaP13, from tissue of a patient initially diagnosed with AC which later recurred as NEPC. The cell line has been maintained permanently in vitro under regular cell culture conditions and is amenable to gene engineering with lentivirus. KUCaP13 cells lack the expression of AR and overexpress NEPC-associated genes, including SOX2, EZH2, AURKA, PEG10, POU3F2, ENO2, and FOXA2. Importantly, the cell line maintains the homozygous deletion of CHD1, which was confirmed in the primary AC of the index patient. Loss of heterozygosity of TP53 and PTEN, and an allelic loss of RB1 with a transcriptomic signature compatible with Rb pathway aberration were revealed. Knockdown of PEG10 using shRNA significantly suppressed growth in vivo. Introduction of luciferase allowed serial monitoring of cells implanted orthotopically or in the renal subcapsule. Although H3K27me was reduced by EZH2 inhibition, reversion to AC was not observed. KUCaP13 is the first patient-derived, treatment-related NEPC cell line with triple loss of tumor suppressors critical for NEPC development through lineage plasticity. It could be valuable in research to deepen the understanding of NEPC.

Consecutive Prostate Cancer Specimens Revealed Increased Aldo⁻Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer.

Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to understand the role of AKR1C3 in PCa progression. Correlation of AKR1C3 immunohistochemical expression between benign and cancerous epithelia in 134 patient specimens was analyzed. Additionally, correlation between AKR1C3 expression and prostate-specific antigen (PSA) progression-free survival (PFS) after radical prostatectomy was analyzed. Furthermore, we evaluated the consecutive prostate samples derived from 11 patients both in the hormone-naïve and castration-resistant states. AKR1C3 immunostaining of cancer epithelium was significantly stronger than that of the benign epithelia in patients with localized HNPC (p < 0.0001). High AKR1C3 expression was an independent factor of poor PSA PFS (p = 0.032). Moreover, AKR1C3 immunostaining was significantly stronger in CRPC tissues than in HNPC tissues in the same patients (p = 0.0234). Our findings demonstrate that AKR1C3 is crucial in PCa progression.

Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer.

The therapeutic landscape of castration-resistant prostate cancer (CRPC) has rapidly expanded. There is a need to develop noninvasive biomarkers to guide treatment. We established a highly sensitive method for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma circulating cell-free DNA (cfDNA) and evaluated the AR statuses of patients with CRPC. AR amplification was detectable in VCaP cell line (AR amplified) genomic DNA (gDNA) diluted to 1.0% by digital PCR (dPCR). AR mutation were detectable in LNCaP cell line (AR T878A mutated) gDNA diluted to 0.1% and 1.0% by dPCR and target sequencing, respectively. Next, we analyzed AR status in cfDNA from 102 patients. AR amplification and mutations were detected in 47 and 25 patients, respectively. As a biomarker, AR aberrations in pretreatment cfDNA were associated with poor response to abiraterone, but not enzalutamide. In serial cfDNA analysis from 41 patients, most AR aberrations at baseline diminished with effective treatments, whereas in some patients with disease progression, AR amplification or mutations emerged. The analysis of AR in cfDNA is feasible and informative procedure for treating patients with CRPC. cfDNA may become a useful biomarker for precision medicine in CRPC.

[A case of retroperitoneal liposarcoma with inflammatory pseudotumor].

A 54-year-old man presented with pollakiuria and dysuria. Ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) showed a retroperitoneal tumor 10 cm in diameter. Pathological examination of a transrectal biopsy specimen obtained from the patient revealed the presence of an inflammatory myofibroblastic tumor (IMT). The patient underwent surgical resection of the tumor. Histopathologically, the tumor was composed of 3 parts : the largest part was compatible with an inflammatory pseudotumor: the second part, well-differentiated liposarcoma: and the third part, a myxoid liposarcoma. He has been followed up for 14 months ; but there was no evidence of local recurrence of the tumor. We believe that the inflammatory pseudotumor complicated in repairing the inflammation arising from the liposarcoma.

[Age-related Epstein-Barr virus-associated lymphoproliferative disorder presenting as rapidly developing renal mass].

An 83-year-old man visited our department with a slightly enhanced mass of about 2 cm in diameter, detected incidentally in the left kidney on computed tomography (CT) performed for other reasons in a different department. Fluorodeoxyglucose-positron emission tomography was performed under the suspicion of metastatic renal tumor and malignant lymphoma. Accumulation was observed in the mass but not in other regions. The tumor size was about 2 mm on CT 4 months previously, indicating rapid enlargement. Based on these observations, a malignant renal tumor was diagnosed and laparoscopic left nephrectomy was performed. Pathologic examination revealed relatively large cells diffused within a background of many small lymphocytes and histiocytes. The large cells were positive when tested by Epstein-Barr virus (EBV)-encoded RNA in situ hybridization. No clinically apparent immunodeficiency was observed, suggesting age-related EBV-associated lymphoproliferative disorder caused by an underlying age-related reduction in immunocompetence. This is the first report of a kidney-localized case in Japan.

Incidence of upper urinary tract stone during 15 years in Tajima area, Japan: a hospital-based study.

Time trend of incidence of upper urinary tract stone during 15 years was evaluated by hospital-based cohort study in Tajima area, northern part of Hyogo prefecture, Japan, which has only two general hospitals with Department of Urology. Due to isolation in terms of traffic network and geographic circumstances, almost all patients with urinary stone in Tajima area are referred to the two hospitals. During the period 2005-2007, patients of the two hospitals with radiologically proven upper urinary tract stone were included in this study. The survey included the age and gender, location of stones, history of urinary stone, treatment received, and stone composition, if available. Annual incidence of upper urinary tract stone was estimated using the data of population census of Japan 2005 and compared with the data of Tajima during 1991-1993. 1,305 patients were included in this study. Age-adjusted incidence (+/-95% CI) was 157 (+/-22.4) for men, and 57 (+/-12.6) for women, compared with 141 (+/-20.7) for men, and 63 (+/-13.4) for women during 1991-1993. In total, 30.7% of patients received interventional treatment including shock wave lithotripsy, endoscopic lithotripsy and open surgery, whereas 25.3% in 1991-1993. Calcium oxalate/phosphate stone was 89.6%, struvite stone was 4.5%, cystine stone was 1.0%, uric acid stone was 4.0%, and others were 1.0%. In Tajima area, incidence of upper urinary tract stone has not changed during 15 years.

[Multi-institute survey on actual conditions of urologic management for severe bladder dysfunction after hysterectomy].

We conducted a multi-institute survey on the conditions related to urologic management of severe voiding dysfunction after hysterectomy for uterine cancer with or without postoperative irradiation. Our first study population was a group of adult female patients currently managed by urologists, using clean intermittent catheterization (CIC). Of the 287 patients in this group, 99 (34%) had suffered from uterine cancer. Of these patients, 94 underwent hysterectomy for this disease; 44 and 30 were treated with or without postoperative radiation, respectively, while postoperative irradiation status was unknown for 20. Median follow-up after surgery was 21 (0.2-52) years and median interval from operation to the introduction of CIC was 4.0 (0-49) years. CIC tended to be introduced later for patients with postoperative radiation than those without it. Seventy-four patients, who required invasive urologic interventions other than CIC for voiding dysfunction after hysterectomy, are the second study population. Most of these (82%) had received postoperative irradiation. Continuous Foley catheter placement was the most frequent procedure. Long-term follow-up and urologic management for voiding dysfunction is required for patients undergoing hysterectomy.

Adult wilms tumor in the renal pelvis: case report with review of the literature.

An 84-year-old man was referred to our hospital with gross hematuria. Abdominal computed tomography demonstrated a well-circumscribed enhanced mass in the right pelviureteral junction. Retroperitoneoscopic nephroureterectomy was performed because of a clinical diagnosis of renal pelvic carcinoma. Pathologic examination led to a final diagnosis of an adult Wilms tumor arising from the renal pelvis. This is the first report of a Wilms tumor in the renal pelvis of an adult patient.