Diagnostic potential of SDHB mRNA contained in serum extracellular vesicles among patients with prostate cancer.

BACKGROUND: Androgen receptor signaling inhibitors(ARSIs) have been used to treat patients with metastatic prostate cancer (PC) and castration-resistant prostate cancer (CRPC). In this study, we aimed to identify novel serum extracellular vesicle (EV)-based biomarkers to diagnose ARSI-resistance and therapeutic targets for ARSI-resistant CRPC. METHODS: Total RNA contained in serum EVs from 5 cases of CRPC before ARSI treatment and after acquiring ARSI-resistance was subjected to RNA-sequencing. The expression changes of selected RNAs contained in EVs were confirmed in 48 cases of benign prostatic hyperplasia (BPH) and 107 PC using reverse transcription-quantitative PCR (RT-qPCR) and compared with tissue RNA expression using public datasets. RESULTS: RNA-sequencing revealed that mitochondrial oxidative phosphorylation (OXPHOS)-related genes were increased in EVs after acquiring ARSI-resistance. Among them, RT-qPCR and datasets analysis demonstrated that SDHB mRNA was upregulated after acquiring ARSI-resistance in EVs and ARSI-exposed PC tissue compared to ARSI-naïve EVs and tissue, respectively. SDHB mRNA levels both in EVs and tissue were increased in localized PC compared with BPH and decreased in advanced PC. Tissue expression of SDHB mRNA was significantly correlated with those of other OXPHOS-related genes. SDHB mRNA in EVs (EV-SDHB) was elevated among 3 out of 7 ARSI-treating patients with stable PSA levels who later progressed to ARSI-resistant CRPC. CONCLUSIONS: The levels of OXPHOS-related mRNAs in EVs correlated with those in PC tissue, among which SDHB mRNA was found to be a novel biomarker to diagnose ARSI-resistance. EV-SDHB may be useful for early diagnosis of ARSI-resistance.

[A Renal Leiomyoma --A Case Report-].

A 49-year-old female was incidentally found to have a left renal tumor during a medical check-up. The tumor was too small to be fully diagnosed using computed tomography (CT) or magnetic resonance imaging (MRI). Since it was small and showed a homogenous enhancement pattern on contrast-enhanced CT, which made it difficult for us to distinguish the malignancy of the tumor, we performed regular CT follow-up. On the fifth year of her regular follow-up, the tumor had grown apparently larger and showed a heterogenous enhancement pattern, which suggested a malignant tumor. Since the tumor was exophytic, we decided to perform a laparoscopic partial nephrectomy. The operation was performed without any serious complications, and her renal function remained unchanged. The histopathology of the tumor was leiomyoma. Here, we discuss the characteristics of this tumor and the role of immunohistopathology in the diagnosis.

[Small cell carcinoma of the prostate: a case report--a prognostic analysis of case reports and literature in Japan].

A 62-year-old Japanese man had been suffering from dysuria since January 2011. Since symptoms persisted regardless of antibiotics therapy at a urological clinic, he consulted our clinic in February 2011. Digital rectal examination revealed a large irregular and stony hard prostatic mass, with the serum prostated specific antigen (PSA) of 2.76 ng/ml. T2-weighted magnetic reasonance imaging showed diffuse hypointensity and sharp margin in prostatic peripheral zone. Transperineal biopsy of the prostate was performed in March 2011. Considering histopathological findings of tumor cells in all specimens combined with positive immunoreactivity of neoplastic cells to chromogranin A but negative immunoreactivity to PSA, we diagnosed him with small cell carcinoma. The whole body computed tomography showed no metastatic lesion, he was diagnosed with small cell carcinoma of the prostate at clinical stage T2cN0M0. He received 4 cycles of chemotherapy (cisplatinum and etoposide) and underwent external beam radiotherapy to the pelvis and prostate, up to a total dose of 64 Gy. The urologic and radiologic outcomes including the serum levels of neuron-specific enolase and pro-gastrin releasing peptide have been satisfactory after more than 3 years of follow-up.

[Conservative management of symptomatic or asymptomatic urinoma after grade III blunt renal trauma: a report of three cases].

The management of urinoma after blunt renal trauma is still controversial, ranging from percutaneous drainage or ureteral stent placement for the symptomatic urinoma and waiting for spontaneous vanishment of the asymptomatic urinoma. We present two cases of symptomatic urinoma and a case of asymptomatic urinoma after renal laceration. All patients underwent selective renal arterial embolization for vascular complications, including active bleeding, pseudoaneurysm and arteriovenous fistula. Urinomas, which had been observed in all cases gradually reduced and vanished 1-24 months later. All cases were successfully managed without catheterization or percutaneous drainage for urinoma.

Impact of Tumor Grade Distribution on Genetic Alterations in Clear Cell Renal Cell Carcinoma and Prostate Cancer.

BACKGROUND/AIM: A genomic analysis based on next-generation sequencing is important for deciding cancer treatment strategies. Cancer tissue sometimes displays intratumor heterogeneity and a pathologic specimen may contain more than two tumor grades. Although tumor grades are very important for the cancer prognosis, the impact of higher tumor grade distribution in a specimen used for a genomic analysis is unknown. PATIENTS AND METHODS: We retrospectively analyzed the data of 61 clear cell carcinoma and 46 prostate cancer patients that were diagnosed between December 2018 and August 2022 using the GeneRead Human Comprehensive Cancer Panel or SureSelect PrePool custom Tier2. Genome annotation and curation were performed using the GenomeJack software. RESULTS: Tumor mutation burden (TMB) was increased in proportion to the higher tumor grade distribution in grade 2 clear cell renal cell carcinoma (ccRCC). In PC, Grade Group 3/4 specimens that included an increased distribution of Gleason pattern 4 had more frequent gene mutations. CONCLUSION: Our results suggest the importance of selecting the maximum distribution of higher tumor grade areas to obtain results on the precise gene alterations for genomics-focused treatments.

CCR1/CCL5 interaction promotes invasion of taxane-resistant PC3 prostate cancer cells by increasing secretion of MMPs 2/9 and by activating ERK and Rac signaling.

Castration-refractory prostate cancer (CRPC) is treated with taxane-based chemotherapy, but eventually becomes drug resistant. It is thus essential to identify novel therapeutic targets for taxane resistance in CRPC patients. We investigated the role of the chemokine (C-C motif) receptor 1 (CCR1) and its ligand, chemokine (C-C motif) ligand 5 (CCL5), in taxane-resistant CRPC using paclitaxel-resistant prostate cancer cells (PC3PR) established from PC3 cells. We found that the expression levels of CCR1 mRNA and protein were up-regulated in PC3PR cells compared to PC3 cells. In order to investigate the role of increased CCR1 in PC3PR cells, we stimulated cells with CCL5, one of the chemokine ligands of CCR1. In CCL5-stimulated PC3PR cells, siRNA-mediated knockdown of CCR1 expression reduced phosphorylation of ERK1/2 and Rac1/cdc42. Furthermore, CCR1 knockdown and MEK1/2 inhibition decreased CCL5-stimulated secretion of MMPs 2 and 9, which play important roles in cancer cell invasion and metastasis. In the Matrigel invasion assay, knockdown of CCR1 and inhibition of the ERK and Rac signaling pathways significantly decreased the number of invading cells. Finally, the serum CCL5 protein level as measured by ELISA was not different among the three groups of patients: those with negative prostate biopsy, those at initial diagnosis of prostate cancer, and those with taxane-resistant prostate cancer. These results demonstrated for the first time that the interaction of CCR1 with CCL5 caused by increased expression of CCR1 promotes invasion of PC3PR cells by increasing secretion of MMPs 2 and 9 and by activating ERK and Rac signaling. Our findings suggest that CCR1 could be a novel therapeutic target for taxane-resistant CRPC.

H19 in Serum Extracellular Vesicles Reflects Resistance to AR Axis-targeted Therapy Among CRPC Patients.

BACKGROUND/AIM: We aimed to evaluate the changes of androgen receptor (AR) signaling-related long non-coding RNAs (lncRNAs) in serum extracellular vesicles (EVs) from prostate cancer (PC) patients, in order to identify novel biomarkers for AR axis-targeted therapy (ARAT)-resistance among castration-resistant PC (CRPC) patients. PATIENTS AND METHODS: EVs were isolated from 2 patients before and after acquiring ARAT-resistance. RNA profiling of EVs was performed by RNA-sequencing. The expression levels of selected lncRNAs in EVs were analyzed by digital droplet PCR (ddPCR) in 58 localized and 14 metastatic PC patients at diagnosis, 7 ARAT-naïve and 6 ARAT-resistant CRPC patients. LncRNA H19 expression in PC tissue was examined using published data. In order to analyze the role of H19, the prognosis was analyzed in PC patients and proteomic analysis was performed in 22Rv1 PC cells. RESULTS: RNA-sequencing revealed that AR-regulated RNAs were most enriched in EVs after acquiring ARAT-resistance. Among them, up-regulation of AR signaling-related lncRNAs (PCAT1, H19, HOXA-11AS, ZEB1-AS1, ARLNC1, PART1, CTBP1-AS and PCA3) was confirmed by ddPCR. H19 contained in EVs (EV-H19) was significantly increased among ARAT-resistant patients compared to ARAT-naïve CRPC or metastatic PC patients. In PC tissue, H19 was negatively correlated with AR protein and AR-activity score and up-regulated in neuroendocrine CRPC tissue with low AR expression. Furthermore, EV-H19 expression was significantly associated with worse outcome to androgen-deprivation therapy. Proteomic analysis demonstrated that H19 knockdown enhanced PC-related protein expression. CONCLUSION: EV-H19 may negatively correlate with AR-signaling activity and could be a marker to diagnose ARAT-resistance among CRPC patients.

[A case of urethrovesical foreign body in an adolescent boy].

We report an unusual case of a 14-year old boy who presented with proteinuria and pyuria detected in a medical checkup at school. After denial of kidney disease, computed tomography of the pelvis showed a bladder stone with an internal low density and urethroscopy showed an odd stick at the prostatic urethra. Because of the failure of removal by the transurethral technique, he underwent suprapubic cystostomy against the foreign body stuck into the prostatic urethra. After surgery, he admitted that he had self-introduced a sewing instrument into the bladder for the purpose of masturbation one year three months previously.

[Two cases of prostatic stromal tumor of uncertain malignant potential (STUMP) on pathological diagnosis after surgery for benign prostatic hyperplasia].

Prostatic stromal tumor of uncertain malignant potential (STUMP) is a rare neoplasm characterized by an atypical, unique stromal proliferation of the prostate. Two patients consulted our hospital with the complaint of urinary retardation. We performed holmium laser enucleation of the prostate since by digital rectal examination, magnetic resonance imaging and needle biopsy suggested benign prostatic hyperplasia. The pathologic examination of the surgical specimens revealed prostatic STUMP. Urologic and radiologic examinations have revealed no abnormalities after more than 2 years of follow-up.

[A case of xp11.2 translocation renal cell carcinoma].

Xp11.2/TFE3 translocation renal cell carcinoma (RCC), a recently classified distinct subtype, is a rare tumor that usually affects children and adolescents. The morphology and biological behavior are not widely recognized, Xp11.2 translocation RCC is suggestive of early metastases despite the small tumor size. The definitive diagnosis requires the evidence of several different reciprocal translocations involving the TFE3 gene located on chromosome Xp11.2. Here, we present a case of Xp11.2 translocation RCC in an 18-yearold male. He was referred to our hospital because of a right renal tumor with macroscopic hematuria and right flank colic. The radiographic evaluation including magnetic resonance imaging (MRI) suggested it to be a typical papillary renal cell carcinoma or benign renal tumor. He underwent laparoscopic nephrectomy against the repeat symptom in spite of small tumor (3.5 cm in diameter). The immunohistochemical study revealed nuclear staining for TFE3 protein in the cancer cells. The urologic and radiologic outcomes were satisfactory after more than 1 year of follow-up.

[Clinical analysis of 35 cases of penile cancer].

We retrospectively reviewed the records of 35 patients with penile cancer, who had been treated at Gifu University Hospital and its affiliated hospitals between July 1994 and January 2009. The mean values of follow-up periods, ages, serum squamous cell carcinoma levels and maximum diameters of the tumor were 23.7±28.0 months, 72.3±10.5 year-old, 4.5±4.3 ng/ml, and 4.0±2.6 cm, respectively. Systemic chemotherapy and local radiotherapy were performed in six, and three cases, respectively. Ten patients died of penile cancer. By univariate analyses, maximum tumor diameter (＜- 4.3 cmvs ＞4.3 cm), T factor (＜T3 vs ＞- T3) and N factor (＜N2 vs ＞- N2) were significantly associated with cancer-specific survival. The five-year survival of stage N2 cases (28.6%) were significantly lower than that of stage N0 and N1 cases (68.4%) (p＝0.0003). By multivariate analyses N factor (＜N2 vs ＞- N2) was significantly associated with cancer specific survival (p＝0.020). We concluded that the development of effective systemic chemotherapy might be crucial to improve the prognosis of patients with metastatic diseases.

A pretreatment nomogram predicting recurrence- and progression-free survival for nonmuscle invasive bladder cancer in Japanese patients.

PURPOSE: Our aim was to provide nomograms that allow urologists to easily calculate a nonmuscle invasive bladder cancer patient's risk of recurrence and progression. MATERIALS AND METHODS: We retrospectively analyzed 800 nonmuscle invasive bladder cancer patients newly diagnosed between 1991 and 2001 from the Gifu urothelial cancer registry program. We developed the nomogram using the original 500 patients and validated it using the remaining 300 patients. The prognostic factors of recurrence and progression were identified by multivariate analysis in 500 patients. RESULTS: In the multivariate analysis, tumor number, shape, grade, and intravesical instillation were associated with recurrence-free survival. Tumor shape and grade were associated with progression-free survival. Six factors for recurrence and three factors for progression were used to make the nomogram. Using the original 500 patients who were modeled for the nomogram, the areas under the receiver operating characteristic curves (AUCs) were calculated to be 0.61 for recurrence and 0.71 for progression. To validate nomogram performance, we applied an additional 300 patients to the nomograms. The AUCs were 0.57 for recurrence and 0.67 for progression. CONCLUSIONS: The nomograms that have been developed can be used to predict the probability of recurrence and progression of nonmuscle invasive bladder cancer.

CD44v8-10 mRNA contained in serum exosomes as a diagnostic marker for docetaxel resistance in prostate cancer patients.

BACKGROUND: Docetaxel is first-line chemotherapy for castration-resistant prostate cancer (CRPC), but most patients acquire docetaxel resistance. CD44 has been shown to be involved in drug resistance of cancers including prostate cancer. We hypothesized that CD44 in serum exosomes could be a diagnostic marker for docetaxel resistance in CRPC patients. In this study, we examined CD44 protein and mRNA expression in cell lysates and exosomes isolated from prostate cancer cells, evaluated the effect of CD44v8-10 knockdown on docetaxel sensitivity and measured CD44 mRNA copy numbers contained in serum exosomes in prostate cancer patients. MATERIALS AND METHODS: Docetaxel-sensitive PC-3 prostate cancer cells and docetaxel-resistant PC-3R cells established previously from parental PC-3 cells were used. CD44v8-10 knockdown was performed by siRNA transfection. Blood was collected from 50 docetaxel-naïve and 10 docetaxel-resistant patients and 15 control males. CD44 protein expression was evaluated by Western blotting. CD44 mRNA expression was measured by RT-digital PCR. RESULTS: The levels of CD44v8-10 protein and mRNA in cell lysates and exosomes were higher in PC-3R cells than in PC-3 cells. CD44v8-10 knockdown significantly increased docetaxel sensitivity of PC-3R cells. The CD44v8-10 mRNA copy numbers in serum exosomes were higher in docetaxel-resistant patients than in docetaxel-naïve patients and control males (median 46, 12 and 17 copies/mL serum, respectively, P = 0.032). In contrast, the serum exosomal mRNA copy numbers of CD44 standard isoform (CD44s) were not different among 3 groups (median 25, 14 and 13 copies/mL serum, respectively, P = 0.150). CONCLUSIONS: CD44v8-10 may be involved in docetaxel resistance in prostate cancer and serum exosomal CD44v8-10 mRNA could be a diagnostic marker for docetaxel-resistant CRPC.

[A case of primary retroperitoneal mucinous cystadenocarcinoma].

The present report describes a 31-year-old Japanese woman with a retroperitoneal cystic mass adjoining below the left kidney. No disseminated tumors were observed, and resection of the tumor only was performed laparoscopically. The surgical specimen showed a well-differentiated papillary mucinous cystadenocarcinoma of the ovarian type. Additional gynecological examination, including positron emission tomography-computed tomography, showed no malignancy at other sites. Recurrence or metastasis has not been observed after more than 1 year of follow-up. Primary retroperitoneal mucinous cystadenocarcinoma is a very rare tumor. Thirty-six and 55 cases have been reported previously in the English and Japanese literature, respectively. The pathogenesis of the disease remains unclear and controversial. A standard treatment has not been established in the literature, and a consistent prognosis has not been reported. Therefore, close post-operative follow-up is strongly recommended.

[Clinical usefulness of chlormadinone acetate as an alternative antiandrogen therapy for prostate cancer relapse after combined androgen blockade therapy].

We prospectively studied the usefulness of chlormadinone acetate (CMA) as an alternative therapy for prostate cancer relapse after combined androgen blockade (CAB) therapy. Sixteen patients with relapsed prostate cancer after treatment with CAB, including surgical or medical castration and nonsteroidal antiandrogens, 80 mg bicalutamide daily or 375 mg flutamide daily, were enrolled. After discontinuing the antiandrogen for evaluating the patient for the antiandrogen withdrawal syndrome, we administered 100 mg CMA daily as alternative antiandrogen and estimated its effect. Four patients showed a > or = 50% decline in prostate-specific antigen (PSA) levels and another 4 patients showed a < 50% decline in PSA levels but residual 8 patients showed no decline in PSA levels. In 8 patients with a decline in PSA levels, the median duration of alternative CMA therapy was 11.4 months. Patients with a PSA level of < 1 ng/ml at the start of CMA therapy showed the tendency of decline in PSA levels. In contrast, patients with a nadir PSA level of > or = 0.2 ng/ml during pretreatment showed no effectiveness of the alternative CMA therapy. The alternative CMA therapy may be useful in a part of patients with prostate cancer relapse after CAB therapy.

Prognostic value of the co-expression of carbonic anhydrase IX and vascular endothelial growth factor in patients with clear cell renal cell carcinoma.

This study aimed to investigate whether the expression of carbonic anhydrase IX (CAIX) is associated with the expression of vascular endothelial growth factor (VEGF) and whether the co-expression of the two correlates with survival outcome in clear cell renal cell carcinoma (ccRCC). The expression of CAIX and VEGF was evaluated immunohistochemically in 122 paraffin-embedded ccRCC specimens. The clinical significance of these markers in relation to disease-specific survival (DSS) was analyzed. Patients with a low expression of CAIX had a significantly worse prognoses than those with a high expression (p=0.0005). Inversely, patients with a high expression of VEGF had a significantly worse prognoses than the patients with a low expression (p=0.0030). Furthermore, CAIX expression significantly stratified the DSS of patients with high-stage (p=0.0001), high-grade (p=0.0392), low-grade (p=0.0273), metastasis (p=0.0034), no metastasis (p=0.0303) and ECOG-PS=0 (p=0.0003). VEGF expression significantly predicted the survival of patients with low-grade (p=0.0003), high-stage (p=0.0401) and ECOG-PS=0 (p=0.0063). A multivariate Cox regression analysis showed that tumor stage (p=0.0054), metastasis (p=0.0193), ECOG-PS (p=0.0065) and CAIX expression (p=0.0001) were independent prognostic factors of DSS. Since CAIX and VEGF expression correlated inversely (p=0.0032), the prognostic value of the co-expression of CAIX-VEGF was evaluated. Multivariate analysis revealed that the co-expression was an independent prognostic factor of DSS (p=0.0002). In addition, the co-expression was able to stratify DSS into three risk groups: high-risk, intermediate-risk and low-risk (p<0.0001). In patients with ccRCC, CAIX and VEGF expression correlated inversely. Independent expression of CAIX and a co-expression of CAIX-VEGF were found to be independent predictors of DSS. Furthermore, the co-expression data for CAIX-VEGF provide more accurate prognostic information than the individual data. This information may be useful for survival prediction and risk stratification of patients with ccRCC.

The potential role of prebiopsy magnetic resonance imaging combined with prostate-specific antigen density in the detection of prostate cancer.

AIM: Two-thirds of patients with a gray-zone prostate-specific antigen (PSA) level undergo unnecessary biopsy. Sensitivity is not yet sufficient to permit the use of modified PSA parameters or magnetic resonance (MR) imaging alone for prostate cancer screening. Thus, we evaluated the combination of MR imaging and PSA density (PSAD) for specificity and sensitivity. METHODS: During the period April 2004 through March 2006, 185 patients with a PSA level of 4.0-10.0 ng/mL underwent MR imaging and transrectal ultrasonography-guided 8-core biopsy (systemic sextant biopsy of the peripheral zone plus two cores of transition zone). All MR images were interpreted prospectively by two radiologists. An image was considered positive for prostate cancer if any feature indicated a cancerous lesion. Receiver operating characteristic (ROC) curves were used to compare the usefulness of the PSA level, PSAD and PSA transitional zone density (PSATZ) for the detection of prostate cancer. RESULTS: Of the 185 patients, 62 had prostate cancer. Sensitivity and specificity of the axial T2-weighted MR imaging findings for cancer detection were 79.0% and 59.4%, respectively. The area under the ROC curve was 0.590 for the PSA level, 0.718 for PSAD and 0.695 for PSATZ. MR imaging findings and PSAD were shown by multivariate analysis to be statistically significant independent predictors of prostate cancer (P < 0.001). With a PSAD cut-off value of 0.111, sensitivity was 96.8%, but specificity was 19.5%. Combining MR imaging findings with PSAD increased the specificity to 40% and retained 95% sensitivity. CONCLUSION: MR imaging findings combined with PSAD provide high sensitivity and improve the specificity for the early detection of prostate cancer.

Anterior urethral valve in the fossa navicularis presenting as a split urinary stream in a child.

An anterior urethral valve is uncommon compared to a posterior urethral valve as a cause of lower obstructive uropathy. Furthermore, an anterior urethral valve in the fossa navicularis is extremely rare. We describe the case in a 6-year-old boy who presented with a split urinary stream. Endoscopy revealed an anterior urethral valve in the fossa navicularis, and we successfully incised the valve with a hook knife. We should consider the possibility of an anterior urethral valve in any child with an abnormal urinary stream.

[Discrepancy between Gleason score of needle biopsies and radical prostatectomy specimens--current situation of general pathologists].

We retrospectively reviewed the discrepancy in Gleason score between needle biopsy and radical prostatectomy specimens. Specimens from 153 patients who underwent radical retropubic prostatectomy at Gifu University Hospital and 9 community-based institutions between January 2001 and December 2005, were studied. Gleason score was determined by the general pathologist at each institution. The coincidence rate of Gleason score between biopsy and prostatectomy specimens was 49.7%. In contrast, 37.4% of biopsy specimens were undergraded. In biopsy specimens given a Gleason score of 5 or less, the Gleason score was coincident or undergraded compared with prostatectomy specimens. In biopsy specimens given a Gleason score of 6, the coincidence rate was 39.6%. In 56% in biopsy specimens of cancers with a Gleason score of 6 the Gleason score was undergraded compared with the prostatectomy specimen. In this group, extra-prostatic extention was found significantly more often than in other groups (p = 0.04). In patients, who underwent extended biopsy, or had a more positive biopsy core (> or = 25%), the coincidence rate was significantly greater (p = 0.03). We should be aware of the limitations of Gleason scores based on biopsy specimens, and give treatment opinions careful consideration.

[Case of urachal cancer treated by neoadjuvant chemotherapy with FOLFOX4 (oxaliplatin, 5-FU and leukovolin)].

A 52-year-old woman was referred to our hospital for treatment of urachal cancer. She complained of supurapubic dull pain and gross hematuria. Computed tomography and magnetic resonance imaging showed a non-papillary sessile tumor, which was located on the dome of the bladder and invaded the small intestine. The tumor was diagnosed as Sheldon's stage IIIC urachal cancer. After three courses of neoadjuvant chemotherapy with FOLFOX4 (oxaliplatin, 5-FU and leukovolin), the tumor was reduced from 7 x 6 cm to 5.5 x 5 cm in size. Consequently, the patient underwent an en-bloc resection of the urachal tumor with the dome of the bladder and the parts of the ileum invaded by the tumor. One course of adjuvant chemotherapy (FOLFOX4) was performed. Surgical specimen revealed histologically well differentiated squamous carcinoma and invasion to the propria of the ileum. The surgical margins were negative for the cancer. For 1.5 years after the surgery, no local recurrence or distant metastasis has been observed.