The efficacy of sequential therapy with docetaxel and cabazitaxel for castration-resistant prostate cancer: A retrospective multi-institutional study in Japan.

OBJECTIVE: This study investigated the efficacy of docetaxel (DOC) and cabazitaxel (CBZ) and examined the factors associated with the prognosis of patients with castration-resistant prostate cancer (CRPC) receiving DOC-CBZ sequential treatment in Japanese real-world data. METHODS: We retrospectively evaluated data for 146 patients who received DOC followed by CBZ. The correlations of prostate specific antigen (PSA) decrease rate and time to progression between DOC and CBZ treatment were examined. Combined progression-free survival (PFS) of DOC-CBZ and overall survival (OS) from the initiation of DOC and the diagnosis of CRPC were evaluated and compared between patients with high and low PSA levels at the start of DOC and CBZ treatment. RESULTS: No correlations of PSA decrease rate and time to progression were observed between DOC and CBZ. The patients for whom DOC was started in higher PSA levels had significantly shorter combined PFS (p = 0.003) and OS from the initiation of DOC (p = 0.002). In patients who started DOC at high PSA levels, those who switched to CBZ at low PSA levels had longer OS than those who switched at high PSA levels (p = 0.048). The OS from CRPC of patients who started DOC at low PSA levels was significantly longer than those that started at high PSA levels (p = 0.030). CONCLUSIONS: For patients for whom DOC was not effective, sequential CBZ might have change to be effective. The PSA levels at the start of DOC and CBZ might be a potential prognostic biomarker.

[A Case of Autoimmune Acquired Factor XIII Deficiency Diagnosed from Recurrent Postoperative Bleeding].

The patient was a 79-year-old man with ureteroileal anastomotic stricture after a Bricker ileal conduit. Endourological treatment of stenosis was performed via percutaneous nephrostomy and ileal conduit. The patient experienced lower abdominal pain on the following day, and computed tomographic (CT) scan showed hematoma retention around the kidney and active bleeding from the renal artery branches. Transarterial embolisation (TAE) was performed and the bleeding was controlled. Two days later, there was a sudden progression of anemia and CT showed an increase in hematoma around the kidney. We subsequently performed nephrectomy for hemostasis. Five days later, the anemia progressed further. There was hematoma retention in the retroperitoneal cavity, and emergency laparotomy hemostasis was performed. Routine coagulation test results were normal. Heavy bleeding was observed several days after TAE and the possibility of coagulation factor XIII deficiency was considered. Factor XIII deficiency was confirmed by a low factor XIII activity level. The patient was given plasma-derived factor XIII. After receiving factor XIII replacement, factor XIII activity remained unchanged and the patient continued to bleed. Thereafter, a cross-mixing test was performed and the patient was diagnosed with autoimmune acquired factor XIII deficiency. Cortical steroids were administered to remove the factor XIII inhibitor. Steroid administration showed a rapid increase in factor XIII activity, and bleeding symptoms were no longer observed. In cases of serious bleeding of unknown cause with a normal coagulation profile, acquired factor XIII deficiency should be suspected and factor XIII activity measured.

[Incidence of Antiresorptive Agent-Related Osteonecrosis of the Jaw in Urologic Cancers].

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a serious adverse event of bone resorption inhibitors (BRIs), such as zoledronic acid and denosumab. Based on the results of phase 3 clinical trials for BRIs, the frequency of ARONJ is 1 to 2%, but the actual frequency is presumed to be higher. We studied 143 patients with urologic cancers with bone metastases who were treated with zoledronic acid or denosumab at our hospital between April 2007 and March 2020. ARONJ occurred in 24 patients (16.8%) ; that is, 14 of the 113 patients (12.4%) who received zoledronic acid alone, 8 of the 24 patients (33.3%) who received denosumab alone, and 2 of the 6 patients (33.3%) who sequentially switched from zoledronic acid to denosumab. ARONJ was cured in 8 patients (33.3%), improved in 3 patients (12.5%), unchanged in 4 patients (16.7%), and worsened in 9 patients (37.5%). The frequency of ARONJ increased as the duration of BRI administration prolonged. Time-to-ARONJ was shorter in patients treated with denosumab than in patients treated with zoledronic acid. The occurrence of ARONJ may be underestimated; therefore, further studies are needed to investigate the actual frequency of ARONJ in Japan.

[A Case of Rapidly Growing Sarcomatoid Urothelial Carcinoma of the Renal Pelvis and Ureter].

75 year-old man followed up regularly for the treatment of lung cancer came to our hospital with a chief complaint of general malaise. Blood test results showed deterioration in the renal function, and computed tomography (CT) confirmed left hydronephrosis. He was admitted to the hospital with the diagnosis of obstructive pyelonephritis. Despite antibiotic therapy after the left ureteral stent placement, CT on day 19 of hospitalization showed an enlarged soft tissue shadow along the renal pelvis and ureter, which was suspected to be peripelvic urinary extravasation caused by stent occlusion. We decided that conservative treatment would not improve his condition and conducted surgical therapy considering the possibility of malignancy. Intraoperatively, viscous and fragile tumor affected the renal pelvis and ureter. The operation resulted in left nephrectomy because radical resection was impossible. The pathological diagnosis was sarcomatoid urothelial carcinoma of the renal pelvis with ureter origin. He died due to multipleorgan failureon day 20 after theope ration. Were port a caseof sarcomatoid urothelial carcinoma in the upper urinary tract that was difficult to diagnose preoperatively based on imaging studies.

[A Case of Renal Epithelioid Angiomyolipoma with Recurrence in the Abdominal Cavity].

A 37-year-old man with no symptoms or family history of tuberous sclerosis complex presented to our hospital with abdominal pain in 2013. Abdominal computed tomography (CT) revealed a rupture in the right renal angiomyolipoma (AML) having a maximum diameter of 7 cm. He had undergone a transarterial embolization. Follow-up CT showed an increase in the size of the right tumor to 11 cm, and therefore, right nephrectomy was performed in 2016. The diagnosis of epithelioid AML (EAML) was confirmed. In 2019, he was diagnosed with a solitary tumor near right-sided transverse colon, which was resected and showed recurrence of EAML. He was disease-free 6 months after surgery. EAML has malignant potential, with 30-50% of reported EAML cases resulting in local recurrence or distant metastasis. Previous recurrence or metastasis may occur 0.25-12 years postoperatively. Furthermore, multiple and unresectable recurrences or metastases, arising early in the postoperative period may lead to a poor outcome. Therefore, close and long-term follow-up is required.

[The Safety of Laparoscopic Radical Cystectomy during Initial Phases in a Japanese Multicenter Cohort].

We evaluated the safety of laparoscopic radical cystectomy (LRC) during initial phases and its learning curve in a Japanese multicenter cohort by studying 436 patients who underwent LRC with no robot assistance at 10 institutions in Japan. We divided the patients into three groups according to cumulative surgical volume at each institution (first 10 cases, 11-30 cases, after 31 cases in each institution), and compared perioperative and pathologic variables among the three groups. The first, second, and third groups included 100, 166, 170 patients, respectively. The preoperative variables were similar in the three groups except for the rate of neoadjuvant chemotherapy. The methods of LRC procedure, such as urinary diversion, the extent of lymph node dissection, and concomitant urethrectomy or nephroureterectomy, were similar in the three groups. Mean operative time was 629, 562 and 531 minutes, respectively, and mean blood loss was 755, 650 and 435 ml, respectively. Both values decreased over time with the institution's experience. There was no significant difference among the three groups in the rate of positive surgical margin, the number of retrieved lymph nodes, and the rate of intra- and postoperative complications. LRC was safely performed during initial phases with an acceptable complication rate and without compromising oncological results, although operative time was longer and blood loss increased.

A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial.

OBJECTIVE: To examine the antitumor activity of zoledronic acid (ZA) combined with androgen deprivation therapy (ADT) for men with treatment-naive prostate cancer and bone metastasis. METHODS: We enrolled 227 men with treatment-naive prostate cancer and bone metastasis. Participants were randomly assigned (1:1 ratio) to receive combined androgen blockade alone (CAB group) or ZA with combined androgen blockade (CZ group). Time to treatment failure (TTTF), time to the first skeletal-related event (TTfSRE), and overall survival (OS) rates were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazards model. Median follow-up duration was 41.5 months. RESULTS: Median TTTFs were 12.4 and 9.7 months for the CZ and CAB groups, respectively (HR 0.75; 95 % CI 0.57-1.00; p = 0.051). For men with baseline prostate-specific antigen levels <200 ng/mL, median TTTFs were 23.7 and 9.8 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.35-0.93; p = 0.023). Median TTfSREs were 64.7 and 45.9 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.38-0.88; p = 0.009). OS was similar between the groups. CONCLUSIONS: This study failed to demonstrate that combined use of ZA and ADT significantly prolonged TTTF in men with treatment-naive prostate cancer and bone metastasis. However, it generates a new hypothesis that the combined therapy could delay the development of castration resistance in a subgroup of patients with low baseline prostate-specific antigen values <200 ng/mL. The treatment also significantly prolonged TTfSRE but did not affect OS.

Evaluation of predictors of unfavorable pathological features in men eligible for active surveillance using radical prostatectomy specimens: a multi-institutional study.

OBJECTIVE: Active surveillance has emerged as an alternative to immediate treatment in men with favorable-risk prostate cancer; however, consensus about defining the appropriate candidates is still lacking. To examine the factors predicting unfavorable pathology among active surveillance candidates, we assessed low-risk radical prostatectomy specimens. METHODS: This retrospective study included 1753 men who had undergone radical prostatectomy at six independent institutions in Japan from 2005 to 2011. Patients who met the active surveillance criteria were categorized depending on the pathological features of the radical prostatectomy specimens. 'Reclassification' was defined as upstaging (≥pT3) or upgrading (radical prostatectomy Gleason score ≥7), and 'adverse pathology' was defined as pathological stage ≥pT3 or radical prostatectomy Gleason score ≥4 + 3. Multivariate analysis was used to analyze the preoperative factors for reclassification and adverse pathology. The rates of reclassification and adverse pathology were evaluated by classifying patients according to biopsy core numbers. RESULTS: The active surveillance criteria were met by 284 cases. Reclassification was identified in 154 (54.2%) cases, while adverse pathology in 60 (21.1%) cases. Prostate-specific antigen density and percentage of positive cores were independently associated with reclassification and adverse pathology. The rates of reclassification and adverse pathology were significantly higher among patients with <10 biopsy cores than among others. Thus, focusing on 149 patients with ≥10 biopsy cores, prostate-specific antigen density was the only independent predictor of unfavorable pathological features. The receiver operating characteristic curve analysis determines an optimal cut-off value of prostate-specific antigen density as 0.15 ng/ml2. CONCLUSIONS: Prostate-specific antigen density is the most important predictor of unfavorable pathological features in active surveillance candidates.

[Urinary Diversion Using an Appendicovesicostomy for Idiopathic Urethral Stricture : A Case Report].

A 55-year-old woman was referred to our hospital with dysuria. We were unable to catheterize her using a nelaton catheter because of a urethral stricture, resulting in a large residual urine volume on ultrasonography. The circumference of the periurethral tissue was also thickened and the entire length of the urethra was stenotic, without apparent cause, on magnetic resonance imaging. Biopsy did not reveal malignancy. The pathological diagnosis of the periurethral tissue was simply fibrosis, and there was no definitive diagnosis. We decided to place a guidewire to attempt transurethral dilation, but it was unsuccessful because of the urethral stricture. The patient then underwent Mitrofanoff appendicovesicostomy. Three years later, there was no difficulty with catheterization through the appendix, despite her suffering from a bladder stone during the interim. We consider the Mitrofanoff appendicovesicostomy a good substitute technique for catheterization in patients with very severe urethral stricture.

[Laparoscopic Radical Cystectomy in the Elderly Patients].

We compared the perioperative and oncological outcomes of laparoscopic radical cystectomy (LRC) between elderly patients over 75 years old and younger patients. Fifty-three patients underwent LRC between 2003 and 2014 at Tenriyorozu Hospital. Eighteen patients were classified as elderly (over 75) and the other 35 patients were considered young. The median operating time (434 vs 465 min, p＝0.35), estimated bloodloss (534 vs 525 g, p＝0.74), time to recommencing foodintake (7 vs 6 days, p＝1.00), and hospital stay (35 vs 32 days, p＝0.81) were not significantly different between the groups. Perioperative pyelonephritis was significantly more frequent in the elderly group (50% vs 20%, p＝0.02), while other complications were not significantly different between the two groups. The perioperative mortality rate was 0% in both groups. There were no significant differences between the elderly and young groups with respect to 2-year overall survival (74. 4% vs 91. 6%), cancer-specific survival (74. 4% vs 91. 6%), and recurrence-free survival (70.2% vs 81. 8%). LRC is a safe andefficient procedure for selected elderly patients.

[A case of adrenal metastasectomy in renal cell carcinoma after neoadjuvant therapy with sunitinib].

A 58-year-old man had undergone laparoscopic radical nephrectomy for right renal cell carcinoma. The histopathological diagnosis was clear cell carcinoma, grade 2＞3, pT1b. Two years and 10 months postoperatively, computed tomography scans demonstrated an enhanced mass on the right adrenal gland. As we could not detect other metastatic lesions, it was diagnosed as solitary adrenal metastasis of renal cell carcinoma. Albeit metastasectomy was planned with curative intent, right hemihepatectomy was also required for surgical removal because the tumor was adherent to the right lobe of the liver broadly and had indistinct margins. So we started neoadjuvant therapy with sunitinib. Eight courses of treatment shrunk the metastatic tumor enough to allow it to be removed completely without partial hepatectomy. Neoadjuvant therapy with the molecular targeted drugs may provide an effective option for metastasectomy in renal cell carcinoma regarding increased curability and decreased the risk of an operation.

[Case of juxtaglomerular cell tumor (reninoma) treated with laparoscopic partial nephrectomy].

We report a case of a 22-year-old male with juxtaglomerular cell tumor treated with laparoscopic partial nephrectomy. He was referred to our hospital with hypertension, high concentration of plasma renin activity (PRA) and renal mass. Dynamic enhanced computed tomography showed 17-mm weak contrast-enhancing tumor at the upper pole of the left kidney. Renin suppression and stimulation test revealed autonomous renin secretion although renal venous sampling failed to show significant difference in the PRA between the right and left renal vein. We performed laparoscopic left partial nephrectomy. The histological diagnosis was juxtaglomerular cell tumor. After the operation, his blood pressure and PRA were immediately normalized. Juxtaglomerular cell tumor is an important renal tumor as a curable cause of secondary hypertension.

[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.

Secreted CXCL1 is a potential mediator and marker of the tumor invasion of bladder cancer.

PURPOSE: The purpose of this study was to identify proteins that are potentially involved in the tumor invasion of bladder cancer. EXPERIMENTAL DESIGN: We searched for the candidate proteins by comparing the profiles of secreted proteins among the poorly invasive human bladder carcinoma cell line RT112 and the highly invasive cell line T24. The proteins isolated from cell culture supernatants were identified by shotgun proteomics. We found that CXCL1 is related to the tumor invasion of bladder cancer cells. We also evaluated whether the amount of the chemokine CXCL1 in the urine would be a potential marker for predicting the existence of invasive bladder tumors. RESULTS: Higher amount of CXCL1 was secreted from highly invasive bladder carcinoma cell lines and this chemokine modulated the invasive ability of those cells in vitro. It was revealed that CXCL1 regulated the expression of matrix metalloproteinase-13 in vitro and higher expression of CXCL1 was associated with higher pathologic stages in bladder cancer in vivo. We also showed that urinary CXCL1 levels were significantly higher in patients with invasive bladder cancer (pT1-4) than those with noninvasive pTa tumors (P = 0.0028) and normal control (P < 0.0001). Finally, it was shown that CXCL1 was an independent factor for predicting the bladder cancer with invasive phenotype. CONCLUSIONS: Our results suggest that CXCL1 modulates the invasive abilities of bladder cancer cells and this chemokine may be a potential candidate of urinary biomarker for invasive bladder cancer and a possible therapeutic target for preventing tumor invasion.

Advantage of urological experience with both transperitoneal and retroperitoneal laparoscopy in lymph node biopsy for malignant lymphoma diagnosis.

PURPOSE: Laparoscopic urologists are familiar with both transperitoneal and retroperitoneal approaches. That experience is an advantage when devising a strategy for intra-abdominal lymph node biopsy. We report the feasibility and effectiveness of laparoscopic biopsy using a urological laparoscopic technique for the treatment of patients with clinically suspected intra-abdominal lymphoma. MATERIALS AND METHODS: From October 2010 to April 2015, a total of 22 patients underwent laparoscopic biopsy for suspected intra-abdominal lymphoma. We adopted a retroperitoneal approach for paraaortic or paracaval masses, whereas we used a transperitoneal approach for mesenteric, iliac, or obturator masses. Whenever possible, an entire node was removed; otherwise, the biopsy consisted of wedge resection sized at least 1 cm3. RESULTS: Biopsy specimens were obtained from the following lymph node sites: 10 paraaortic, 5 paracaval, 3 mesenteric, 2 obturator, 1 common iliac, and 1 perinephric fat. Laparoscopic lymph node biopsy was completed in all patients, and there were no conversions to open surgery. The median operating time was 97 minutes (range, 62-167 minutes). The estimated blood loss was <50 mL in all cases. Postoperatively, one patient (4.5%) had symptomatic chylous lymphocele that required surgical intervention. Precise diagnosis was established for all patients: malignant lymphoma in 20 patients and metastatic urothelial carcinoma and squamous cell carcinoma of unknown origin in 1 patient each. All lymphomas could be fully subclassified. CONCLUSIONS: Appropriate use of the transperitoneal or retroperitoneal approach is safe and effective for laparoscopic lymph node biopsy in patients with suspected intra-abdominal lymphoma.

[Superselective endovascular treatment of renal artery aneurysms with detachable microcoils].

Selective transcatheter embolization using an interlocking detachable coil was performed in two cases with renal artery aneurysms. Case 1, a 73-year-old male, was referred to our department complaining of macrohematuria persisting for three days. Case 2, a 52-year-old female, visited our department because calcifications in both renal pedicle areas were found in a health check up. Drip infusion pyelography (DIP) and computerized tomography (CT) revealed in case 1 an aneurysm which was 11 x 10 cm in diameter with nearly circumferential calcification in the right renal pedicle area and in case 2 two aneurysms, one 12 x 10 cm in the right and one 22 x 20 cm in the left with imperfect calcification. Enhanced CT confirmed blood flow in the aneurysms. Because abdominal surgery, was considered to be a highrisks in both cases 1 and 2 the coil embolization was performed. The patients have been followed up after the embolization without any particular complications or changes in the coil location.

Leiomyosarcoma of the spermatic cord: a case report.

A 61-year-old man presented to our hospital with a 1.5-year history of a gradually enlarging mass in the left scrotum. The mass was apart from the testis and fixed to the spermatic cord. The firm consistency and heterogeneous expression on ultrasonography suggested a malignant tumor. Orchiectomy with high ligation of the spermatic cord was performed and a histological examination revealed leiomyosarcoma of the spermatic cord. Distant metastases were not observed. Because the incidence of local recurrence has been reported to be high, we performed irradiation to control the disease. At 32 months post-surgery he was alive with no evidence of disease.

P21-activated kinase 1: a new molecular marker for intravesical recurrence after transurethral resection of bladder cancer.

PURPOSE: It is clinically important to identify bladder cancers with a high risk of intravesical recurrence after transurethral bladder tumor resection. We developed molecular markers for predicting intravesical recurrence of superficial bladder transitional cell carcinoma using oligo-microarray analysis. MATERIALS AND METHODS: Gene expression profiles associated with intravesical recurrence were analyzed by oligo-microarray in 27 superficial bladder transitional cell carcinoma samples from cases treated with transurethral resection between 2000 and 2004 at Kyoto University Hospital. Of candidate genes the expression of P21-activated kinase (Pak1) was validated by semiquantitative real-time polymerase chain reaction using another set of samples and immunohistochemistry. Furthermore, Pak1 functions in bladder cancer cells were analyzed by the transfection of constitutively active (T423E) or kinase dead (K299R) Pak1. RESULTS: Microarray identified 25 genes whose expression was associated with recurrence, including Pak1. Pak1 mRNA expression was statistically associated with grade and the risk of recurrence but not with stage in 86 bladder cancers. Immunohistochemistry and multivariate analysis demonstrated that high Pak1 protein expression was an independent factor associated with recurrence (relative risk 2.27, p = 0.008). High Pak1 expression was significantly associated with a high risk of recurrence even in low stage/grade cancers. Transfection with T423E Pak1 into 253J cells progressed cell motility on wound healing assay, whereas transfection with K299R Pak1 decreased EJ cell motility. CONCLUSIONS: These results suggest that Pak1 expression is associated with recurrence and it might be a useful prognostic marker for superficial bladder transitional cell carcinoma.

Association of the PIG3 promoter polymorphism with invasive bladder cancer in a Japanese population.

PIG3 (p53-induced gene 3) is one of the targets of TP53 and is involved in apoptosis. The promoter of PIG3 contains a variable number of tandem repeats (VNTRs) of pentanucleotides (TGYCC)n (Y = C or T) and the number of VNTRs was reported to be correlated with the activation by TP53. In this study, the clinical significance of the PIG3 promoter VNTRs was analyzed in the bladder cancer patients using the genome DNAs from 338 controls and 273 bladder cancer patients. There was no significant difference in the allele frequency of the PIG3 promoter VNTRs between them. However, the presence of 14 or less repeats allele was associated with higher cancer grade (P = 0.038) and higher stage in relative risk (adjusted odds ratio = 2.31, 95% confidence interval = 1.05-5.90). These data suggested that the PIG3 promoter VNTRs was associated with generation of invasive bladder cancer.

High throughput comparative genomic hybridization array analysis of multifocal urothelial cancers.

The purpose of this study was to examine genetic alterations occur during synchronous or metachronous multifocal development of urothelial cancers on the whole genome using a comparative genomic hybridization (CGH) array. We used 10 tumor pairs (2 tumors for each patient), in which we had previously defined a clonal relationship by microsatellite analysis. For CGH array analysis, Vysis GenoSensor Array 300 kit was used. An unsupervised hierarchical cluster analysis revealed that the tumors from one patient were clustered together independent of the tumors of all other patients. On the other hand, many genetic divergences among multifocal urothelial cancers were newly found by a CGH array analysis. The concordant genetic alteration patterns of the chromosomal arm in tumor pairs were most frequently observed in 9p, 9q, 8p, 7p, 7q and 11q, while discordant patterns were most frequently found in 15q, 20q, 2q, 10p and 11q. Investigation using a CGH array showed that genetically stable multifocal tumors were less frequent, and that a large percentage of urothelial cancers accumulate genetic alterations during multifocal development by clonal evolution. We might have to consider these genetic accumulations during multifocal development when designing strategies for prevention and detection of recurrent multifocal urothelial cancers. CGH array can be a powerful tool for genetic analysis of multifocal urothelial cancer.