Impact of Microvascular Invasion and Tumor Necrosis on the Prognosis of Korean Patients with pT1b Renal Cell Carcinoma.

OBJECTIVES: To evaluate prognostic factors in pT1b renal cell carcinoma (RCC) patients for which no specific studies have been conducted on. METHODS: The data of 270 patients diagnosed with pT1bN0M0 RCC at 2 institutions between January 1998 and June 2010 were retrospectively analyzed. Univariate and multivariate analyses using Cox proportional hazard models were used to identify pathologic and clinical factors that influenced prognosis. Five-year recurrence-free survival and cancer-specific survival were analyzed using the Kaplan-Meier method. RESULTS: The median follow-up period was 55.5 months, and the mean patient age was 55.2 years (range: 26-80). There were 12 cancer-related deaths, and tumor recurrence was noted in 22 patients between 8 and 120 months after surgery. Sites of metastases included the lung in 13 patients, bone in 5 patients, and other sites in 4 patients. Five-year recurrence-free survival and cancer-specific survival rates were 91.2 and 93.5%, respectively. Multivariate analyses revealed that the presence of microvascular invasion and tumor necrosis independently predicted prognosis. CONCLUSIONS: Microvascular invasion and tumor necrosis were found to be independent prognostic factors in pT1b RCC. This result will help urologists to provide patients with more accurate prognoses, and patients with confirmed microvascular invasion and tumor necrosis will require closer follow-up.

Urethroplasty using autologous urethral tissue-embedded acellular porcine bladder submucosa matrix grafts for the management of long-segment urethral stricture in a rabbit model.

We conducted this study to evaluate the combined effect of acellular bladder submucosa matrix (BSM) and autologous urethral tissue for the treatment of long segment urethral stricture in a rabbit model. To prepare the BSM, porcine bladder submucosa was processed, decellularized, configured into a sheet-like shape, and sterilized. Twenty rabbits were randomized to normal control, urethral stricture, urethroplasty using BSM only or BSM/autologous urethral tissue (n=5 per group). Retrograde urethrography was performed at 4, 8, and 12 weeks postoperatively, and the grafted specimens were harvested at week 12 to evaluate urethral reconstruction through histopathologic and immunohistochemical analysis. The mean urethral width of the control, stricture, BSM, and BSM/autologous urethral tissue groups at week 12 was 10.3±0.80, 3.8±1.35, 8.8±0.84, and 9.1±1.14 mm, respectively. The histopathologic study revealed that the BSM/autologous urethral tissue graft had a normal area of urethral lumen, compact muscular layers, complete epithelialization, and progressive infiltration by vessels in the regenerated urethra. In contrast, the BSM grafts revealed keratinized epithelium, abundant collagenized fibrous connective tissue, and were devoid of bundles of circular smooth muscle. Nontransected ventral onlay-augmented urethroplasty using an acellular BSM scaffold combined with an autologous urethral tissue graft represents a feasible procedure for urethral reconstruction.

Combined injection of three different lineages of early-differentiating human amniotic fluid-derived cells restores urethral sphincter function in urinary incontinence.

OBJECTIVE: To investigate whether a triple combination of early-differentiated cells derived from human amniotic fluid stem cells (hAFSCs) would show synergistic effects in urethral sphincter regeneration. MATERIALS AND METHODS: We early-differentiated hAFSCs into muscle, neuron and endothelial progenitor cells and then injected them into the urethral sphincter region of pudendal neurectomized ICR mice, as single-cell, double-cell or triple-cell combinations. Urodynamic studies and histological, immunohistochemical and molecular analyses were performed. RESULTS: Urodynamic study showed significantly improved leak point pressure in the triple-cell-combination group compared with the single-cell- or double-cell-combination groups. These functional results were confirmed by histological and immunohistochemical analyses, as evidenced by the formation of new striated muscle fibres and neuromuscular junctions at the cell injection site. Molecular analysis showed higher target marker expression in the retrieved urethral tissue of the triple-cell-combination group. The injection of early-differentiated hAFSCs suppressed in vivo host CD8 lymphocyte aggregations and did not form teratoma. The nanoparticle-labelled early-differentiated hAFSCs could be tracked in vivo with optical imaging for up to 14 days after injection. CONCLUSION: Our novel concept of triple-combined early-differentiated cell therapy for the damaged sphincter may provide a viable option for incontinence treatment.

Impact of surgical wait time on oncologic outcomes in upper urinary tract urothelial carcinoma.

BACKGROUND AND OBJECTIVES: To assess the effect of surgical wait time on the oncologic outcomes of patients with upper urinary tract urothelial carcinoma (UTUC), particularly in the ureter. METHODS: Using an optimal surgical wait time cutoff value of 30.5 days, we allocated patients to an early group or a late group. Cancer specific survival (CSS) and local/distant recurrence-free survival (RFS) rates were estimated using the Kaplan-Meier method. Factors influencing CSS and RFS after radical surgery were identified using Cox proportional hazards regression models. Subgroup analysis was performed on ureteral urothelial carcinoma using the same methods. RESULTS: Of the 138 UTUC patients, CSS and RFS were not significantly different between the two groups. However, subgroup analysis of the 80 patients with ureteral urothelial carcinoma showed that CSS and RFS were significantly higher in the early subgroup, and multivariate analysis showed that a surgical wait time of >1 month was an independent prognostic factor of CSS and RFS in ureteral urothelial carcinoma (P = 0.04 and P < 0.001). CONCLUSIONS: A surgical wait time of >1 month in ureteral urothelial carcinoma was found to be an independent prognostic factor of disease recurrence and cancer-specific mortality.

Human amniotic fluid stem cell-derived muscle progenitor cell therapy for stress urinary incontinence.

The most promising treatment for stress urinary incontinence can be a cell therapy. We suggest human amniotic fluid stem cells (hAFSCs) as an alternative cell source. We established the optimum in vitro protocol for the differentiation from hAFSCs into muscle progenitors. These progenitors were transplanted into the injured urethral sphincter and their therapeutic effect was analyzed. For the development of an efficient differentiation system in vitro, we examined a commercial medium, co-culture and conditioned medium (CM) systems. After being treated with CM, hAFSCs were effectively developed into a muscle lineage. The progenitors were integrated into the host urethral sphincter and the host cell differentiation was stimulated in vivo. Urodynamic analysis showed significant increase of leak point pressure and closing pressure. Immunohistochemistry revealed the regeneration of circular muscle mass with normal appearance. Molecular analysis observed the expression of a larger number of target markers. In the immunogenicity analysis, the progenitor group had a scant CD8 lymphocyte. In tumorigenicity, the progenitors showed no teratoma formation. These results suggest that hAFSCs can effectively be differentiated into muscle progenitors in CM and that the hAFSC-derived muscle progenitors are an accessible cell source for the regeneration of injured urethral sphincter.

Identification and characterization of bioactive factors in bladder submucosa matrix.

In spite of long term clinical use of decellularized bladder submucosa matrix (BSM), little is known about the active factors within this material. In this paper, we analyzed the biological factors from the decellularized BSM using ELISA, Western blotting, and immunohistochemistry for the purpose of effective utilization of this material in the field of regenerative medicine. At least 10 growth factors, including VEGF, BMP4, PDGF-BB, KGF, TGFbeta1, IGF, bFGF, EGF and TGFalpha were found to be preserved in the decellularized BSM. The existence of collagen (type 1, 2, 3, 4), laminin and elastin within the matrix was also demonstrated. The soluble BSM extracts showed a conspicuous effect on cell proliferation when added as a supplement in vitro. These findings demonstrate that growth factors and extracellular matrix in the BSM maintain valuable biological activity even after the decellularization and extraction processes, thus supporting the wide applicability of BSM in tissue regeneration. The identification and characterization of growth factors and extracellular matrix in the BSM is a prerequisite for understanding tissue regeneration using this scaffold.

Target molecule expression profiles in metastatic renal cell carcinoma: Development of individual targeted therapy.

The aim of this study is to analyze the level of target molecule expression in metastatic renal cell carcinoma (RCC) to determine whether there is a correlation between molecular marker expression and clinical response. Ten patients with metastatic RCC, who received receptor tyrosine kinase (RTK) targeted therapy after cytoreductive or radical nephrectomy, were included. The expression of target molecules relating to the RTK, mammalian target of rapamycin, hypoxia inducible factor, mitogen activated protein kinase, and adenosine monophosphate-activated protein kinase pathways were analyzed using real-time polymerase chain reaction and immunohistochemistry. We correlated the level of target molecule expression with clinical response, including efficacy and adverse events experience during RTK targeted therapy. All patients showed similar histological subtype and grade on pathological examination; however, the expression of RCC target molecules was very different among the patients. The expression of molecules related to the RTK pathway in RCC tissue as well as relative expression of molecules in RCC tissue compared to normal kidney tissue, were higher in patients who showed a good response to RTK targeted therapy compared to those that showed a poor response. Target molecule expression in normal kidney tissue was higher in patients who experienced high-grade adverse events than in patients who experienced low-grade events. Target molecule expression in metastatic RCC correlates with targeted therapy clinical response including efficacy and adverse events. Personalized target molecule expression profiles could be used to predict clinical response to different targeted therapies, thus helping optimization of targeted therapies for patients with metastatic RCC.

Complications and oncologic outcomes following robot-assisted radical cystectomy: What is the real benefit?

PURPOSE: The aim of this study was to assess the advantages of robotic surgery, comparing perioperative and oncological outcomes between robot-assisted radical cystectomy (RARC) and open radical cystectomy (ORC). MATERIALS AND METHODS: Between August 2008 and May 2014, 112 radical cystectomies (42 RARCs and 70 ORCs) were performed at a single academic institution following Institutional Review Board approval. Patient demographics, perioperative variables (e.g., complications), and oncologic outcomes including metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were reported using the Kaplan-Meier analyses. RESULTS: The median follow-up period was 40 months (range, 0-70 months) vs. 42 months (range, 0-74 months) in RARC and ORC, respectively. Baseline characteristics of both groups were balanced. Blood loss (median, [range]; 300 mL [125-925 mL] vs. 598 mL [150-2,000 mL], p=0.001) and perioperative transfusion rates (23.8% vs. 45.7%, p=0.020) were significantly lower in the RARC group than in the ORC group. The overall complication rates were greater in the ORC group, but this was not statistically significant (65.7% vs. 64.3%, p=0.878). However, there were significantly higher major complication rates in the ORC group (45.7% vs. 26.2%, p=0.040). No significant differences were found with regards to MFS, CSS, and OS. CONCLUSIONS: While histopathological findings, overall complications, and survival rates do not reveal definite differences, RARC has more advantages compared to ORC in terms of estimated blood loss, perioperative transfusion rates and fewer perioperative major complications. We propose that RARC is a safer treatment modality with equivalent oncological outcomes compared to ORC.

Can lymphovascular invasion replace the prognostic value of lymph node involvement in patients with upper tract urothelial carcinoma after radical nephroureterectomy?

INTRODUCTION: This study aimed to evaluate whether lymphovascular invasion (LVI) can replace lymph node (LN) involvement as a prognostic marker in patients who do not undergo lymph node dissection (LND) during surgery in patients with upper tract urothelial carcinoma (UTUC). METHODS: A total of 505 patients who underwent radical nephroureterectomy (RNU) were recruited from four academic centres and divided into four groups: node negative (N0, Group 1); node positive (N+, Group 2); no LND without LVI (NxLVI-, Group 3); and no LND with LVI (NxLVI+, Group 4). RESULTS: Patients in Group 2 had larger tumours, a higher incidence of left-sided involvement, more aggressive T stage and grade, and a higher positive surgical margin rate than patients in other groups. Pathological features (T stage and grade) were poorer in Group 4 than in Groups 1 and 3. Compared to other groups, Group 2 had the worst prognostic outcomes regarding locoregional/distant metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). LVI and LN status in Group 4 was not associated with MFS in multivariate analysis. Among Nx diseases, LVI was not an independent predictor of MFS or CCS. The small number of cases in Groups 2 and 4 is a major limitation of this study. CONCLUSIONS: Clinical outcomes according to LVI did not correlate with those outcomes predicted by LN involvement in patients with UTUC. Therefore, LVI may not be used as a substitute for nodal status in patients who do not undergo LND at the time of surgery.

Effects of Previous or Synchronous Non-Muscle Invasive Bladder Cancer on Clinical Results after Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Multi-Institutional Study.

PURPOSE: To evaluate the effects of the presence of previous or synchronous non-muscle invasive bladder cancer (NMIBC) on the oncologic outcomes of radical nephroureterectomy in patients with upper tract urothelial carci­noma (UTUC). MATERIALS AND METHODS: In total, 505 patients with UTUC were enrolled from four different institutions. The clinicopathologic parameters of patients with and without previous or synchronous NMIBC were compared, and Kaplan-Meier estimates and multivariate Cox regression analyses were performed. RESULTS: The median follow-up period was 38.4 months. In all, 408 patients had primary UTUC, 45 (8.9%) had a history of NMIBC, 59 (11.7%) had concomitant bladder cancer, and seven (1.4%) had experienced both. Tumors in patients with associated NMIBC were more commonly multifocal (P = .001) and associ­ated with surgical margin positivity (P = .001). Kaplan-Meier estimates revealed that previous or synchro­nous NMIBC was significantly associated with bladder recurrence (P < .001) and locoregional recurrence/distant metastasis (P = .008). A multivariate Cox regression model identified previous or synchronous NMIBC as an independent predictor of bladder recurrence (P < .001). However, the presence of previ­ous or synchronous NMIBC was not a prognostic indicator of locoregional recurrence/distant metastasis. CONCLUSION: In patients with UTUC, previous or synchronous NMIBC was significantly associated with an increased risk of cancer recurrences in the bladder after radical nephroureterectomy. The present find­ings suggest that a close monitoring should be required for the patients with previous or concomitant NMIBC.

Two different surgical approaches for prostatic stromal sarcoma: robot-assisted laparoscopic radical prostatectomy and open radical cysto-prostatectomy with ileal conduit.

Stromal sarcoma of the prostate is very rare and shows rapid growth, which consequently is related to poor prognosis. Recently, we treated two cases of prostatic stromal sarcoma: one with robot-assisted laparoscopic radical prostatectomy and the other with open radical cysto-prostatectomy with an ileal conduit. To the best of our knowledge, this is the first case report of a prostatic stromal sarcoma managed by use of a robotic procedure. Here, we report of our experiences in the treatment of prostatic stromal sarcoma by use of two different methods.

Endopelvic fascia preservation during robot-assisted laparoscopic radical prostatectomy: does it affect urinary incontinence?

OBJECTIVE: Urinary incontinence has a significant impact on the quality of life after radical prostatectomy. This study aimed to determine whether preserving the endopelvic fascia influences subsequent urinary incontinence. MATERIAL AND METHODS: Consecutive patients (n = 138) who underwent robot-assisted laparoscopic radical prostatectomy (RALP) for prostate cancer between October 2010 and June 2012 with a minimum of 1 year follow-up were retrospectively analysed. The subjects were divided into two groups: the non-preserved endopelvic fascia group (nPE group) and the preserved endopelvic fascia group (PE group). Continence was defined as not using any pads and having no urine leakages. Continence rates at set time-points after RALP were compared using the chi-squared test. Continence recovery rates were analysed with the Kaplan-Meier method and the log-rank test. Prognostic factors of incontinence were identified using the Cox proportional hazards model. RESULTS: The age, body mass index, preoperative prostate-specific antigen levels, prostate volume, estimated blood loss, mean operative time, Gleason score and pathological stage were not significantly different between the two study groups. The continence rate of the nPE group and PE group was 88.4% and 97.1%, respectively, at 12 months after surgery (p = 0.049), which was also significant according to the Kaplan-Meier analysis (p < 0.001). Preservation of endopelvic fascia was the only significant prognostic factor for urinary incontinence (p = 0.002, hazard ratio = 1.867) according to the multivariate analysis. CONCLUSIONS: Endopelvic fascia preservation during RALP significantly enhances postoperative continence and is related to the speed of recovery of continence.

Characterization of urine-derived cells from upper urinary tract in patients with bladder cancer.

OBJECTIVE: To investigate whether cells isolated from the upper urinary tract (UTCs) possess stem cell characteristics and could be an alternative cell source for patients with bladder cancer. Current tissue engineering approaches for urologic tissue regeneration require invasive tissue biopsies to obtain autologous cells, and these procedures are associated with potential complications, such as donor site morbidity. Recently, cells isolated from voided urine (VUCs) have been proposed as an alternative cell source for urologic tissue engineering. However, VUCs should not be used in patients with bladder cancer, because the voided urine sample could contain malignant cells. METHODS: Urine samples were collected from the upper urinary tract of 4 male patients with bladder cancer using a ureteral catheter. The samples were centrifuged and the pellets plated for primary culture. The cells were analyzed for colony-forming unit, proliferation rate, cytogenetics, stem cell characterization, and tumorigenicity. The results were compared with those of VUCs collected from 3 healthy men. RESULTS: The UTCs were able to form colonies, had a greater proliferation rate than the VUCs, and had a normal karyotype without any chromosomal aberrations. The UTCs possessed stem cell characteristics (expression of CD44+, CD73+, CD90+, CD105+, SSEA4+) and expressed several markers for urothelial, smooth muscle, and endothelial cell lineages. The UTCs did not form teratoma when implanted into the subcapsular space of a mouse kidney. CONCLUSION: The UTCs possessed stem cell characteristics and can potentially be an alternative cell source for urologic tissue regeneration in patients with bladder cancer.

Differences in tumor characteristics and prognosis in newly diagnosed Ta, T1 urothelial carcinoma of bladder according to patient age.

OBJECTIVES: To evaluate the differences in tumor characteristics and prognosis according to age at presentation in patients with newly diagnosed Stage Ta, T1 urothelial carcinoma of the bladder. METHODS: From 1998 to 2002, 1587 patients with newly diagnosed nonmuscle-invasive bladder cancer treated with transurethral resection were enrolled in this study. The median age was 63 years (range 21-98), and the median follow-up duration was 44 months (range 12-97). The study cohort was subdivided into 3 age groups: age < 60 years (group 1, n = 614), age > or = 60 but < 70 years (group 2, n = 566), and age > or = 70 years (group 3, n = 398). RESULTS: Comparing the clinical and pathologic characteristics, the tumor size (chi(2)(trend) = 4.01, P = .045), multiplicity (chi(2)(trend) = 14.50, P < .001), T category (chi(2)(trend) = 17.11, P < .001), and tumor grade (chi(2)(trend) = 31.36, P < .001) tended to increase in the older age groups. The presence of carcinoma in situ and squamous differentiation, however, did not differ among the age groups (P > .05). The 5-year recurrence-free probability was 63.6%, 52.1%, and 43.9% for groups 1, 2, and 3, respectively (P < .001). The 5-year progression-free probability was 95.7%, 91.1%, and 84.2% for groups 1, 2, and 3, respectively (P < .001). CONCLUSIONS: Stage Ta, T1 bladder urothelial carcinoma in the younger patients tended to be smaller, have fewer lesions, be less invasive, and have a more favorable tumor grade at the initial presentation. Furthermore, younger patients appeared to have a more favorable prognosis than older patients.