Keishiro Fukumoto

Tumor budding, a novel prognostic indicator for predicting stage progression in T1 bladder cancers

Tumor budding has been defined as an isolated single cancer cell or a cluster composed of fewer than five cancer cells scattered in the stroma. It is a strong predictor for lymph node metastasis in T1 colorectal cancer. We introduced this concept to T1 non‐muscle invasive bladder cancer and evaluated whether tumor budding could have a prognostic impact on the clinical outcome. We identified 121 consecutive patients with newly diagnosed T1 bladder cancer between 1994 and 2014 at Keio University Hospital. All slides were re‐reviewed by a dedicated uropathologist. Budding foci were counted under ×200 magnification. When the number of budding foci was 10 or more, tumor budding was defined as positive. The relationship between tumor budding and clinical outcomes was assessed using a multivariate analysis. The median follow‐up was 52 months. Tumor budding was positive in 21 patients (17.4%). Tumor budding was significantly associated with T1 substaging, tumor architecture and lymphovascular invasion. The 5‐year progression‐free survival rate in T1 bladder cancer patients with tumor budding was 53.8%, which was significantly lower than that in patients without tumor budding (88.4%, P = 0.001). A multivariate Cox regression analysis revealed that tumor budding was independently associated with stage progression (P = 0.002, hazard ratio = 4.90). In a subgroup of patients treated with bacillus Calmette‐Guérin instillation (n = 88), tumor budding was also independently associated with stage progression (P = 0.003, hazard ratio = 5.65). Tumor budding may be a novel indicator for predicting stage progression in T1 bladder cancer, and would likely be easily introduced in clinical practice.

Lymphovascular invasion status at transurethral resection of bladder tumors may predict subsequent poor response of T1 tumors to bacillus Calmette-Guérin

BackgroundLymphovascular invasion (LVI) is an important step in the process of tumor dissemination and metastasis outside the primary organ, but the relationship between LVI and the prognosis of T1 non-muscle invasive bladder cancer (NMIBC) has not been fully evaluated. Accordingly, the present study was performed to evaluate whether LVI had an impact on the clinical outcome in patients with T1 NMIBC.MethodsA total of 116 consecutive patients were diagnosed with T1 NMIBC from 1994 to 2013 at Keio University Hospital. All cases were reviewed by a single uro-pathologist. The prognostic significance of LVI was assessed in relation to recurrence and stage progression.ResultsThe median follow-up period was 53 months. LVI was histologically confirmed in 30 patients (25.9%). There were no significant differences of clinical features between the patients with and without LVI. In T1 patients, univariate analysis demonstrated that LVI positivity was associated with stage progression (p = 0.003), but not with tumor recurrence (p = 0.192). Multivariate analysis confirmed that LVI was independently associated with stage progression (p = 0.006, hazard ratio = 4.00). In 85 patients who received BCG instillation, LVI was independently associated with both tumor recurrence and stage progression (p = 0.036 and 0.024, hazard ratio = 2.19 and 3.76).ConclusionsLVI is a strong indicator of an increased risk of recurrence and progression in BCG-treated patients with T1 NMIBC. This information might assist clinicians to develop appropriate management and counseling strategies for these patients.

Retrocaval Ureter Manifested after Ureteral Reimplantation for Ipsilateral Vesicoureteral Reflux: A Case Report

We report a female patient diagnosed with retrocaval ureter (RCU) after ureteral reimplantation for vesicoureteral reflux (VUR). She was diagnosed as right grade IV VUR with breakthrough urinary tract infections, and underwent ureteral reimplantation with Cohen cross-trigonal technique. Thereafter, she developed severe right hydronephrosis associated with RCU, which was presumably due to caudal traction of right ureter at ureteral reimplantation. Sheunderwent uretero-ureterostomy anterior to the inferior vena cava, and recovered well. Detailed evaluation for upper urinary tract is mandatory for high grade VUR, and Cohen technique should be avoided for VUR associated with RCU.

History of Non–Muscle-Invasive Bladder Cancer May Have a Worse Prognostic Impact in cT2-4aN0M0 Bladder Cancer Patients Treated With Radical Cystectomy

Micro‐Abstract We performed a retrospective study comparing clinical outcomes between patients with initially diagnosed muscle‐invasive bladder cancer (MIBC) without a history of non‐MIBC (NMIBC) and those with MIBC that progressed from NMIBC. A history of NMIBC was independently associated with cancer death in cT2‐T4a MIBC patients treated with radical cystectomy and without lymph node involvement. MIBC that progresses from NMIBC may not respond to neoadjuvant chemotherapy. Purpose To investigate whether a history of non–muscle‐invasive bladder cancer (NMIBC) plays a prognostic role in patients with muscle‐invasive bladder cancer (MIBC) treated with radical cystectomy in the era when neoadjuvant chemotherapy was established as standard therapy for MIBC. Patients and Methods A total of 282 patients who were diagnosed with cT2‐T4aN0M0 bladder cancer treated with open radical cystectomy at our institutions were included. Initially diagnosed MIBC without a history of NMIBC was defined as primary MIBC group (n = 231), and MIBC that progressed from NMIBC was defined as progressive MIBC (n = 51). Results The rate of cT3/4a tumors was significantly higher in the primary MIBC group than in the progressive MIBC group (P = .004). Five‐year recurrence‐free survival and cancer‐specific survival (CSS) rates for the primary MIBC group versus progressive MIBC group were 68.2% versus 55.9% (P = .039) and 76.1% versus 61.6% (P = .005), respectively. Progressive MIBC (hazard ratio, 2.170; P = .008) was independently associated with cancer death. In the primary MIBC group, the 5‐year CSS rate in patients treated with neoadjuvant chemotherapy was 85.4%, which was significantly higher than that in patients without (71.5%, P = .023). In the progressive MIBC group, no significant differences were observed in CSS between patients treated with and without neoadjuvant chemotherapy. Conclusion MIBC that progressed from NMIBC had a significantly worse clinical outcome than MIBC without a history of NMIBC and may not respond as well to neoadjuvant chemotherapy. These results are informative, even for NMIBC patients treated with conservative intravesical therapy.

ASO Author Reflections: PD-1 Expression in Bacillus Calmette–Guérin-Relapsing Bladder Cancer

Programmed cell death (PD)-1 is attracting attention as an important pathway for carcinomas to escape the host immune system. Several studies including urothelial carcinoma have revealed that PD-1 and its ligand, PD-L1 are correlated with poor outcomes. However, although Bacillus Calmette–Guérin (BCG) is an important immune therapy for bladder cancers, there is little information about the impact of BCG on PD-1 expression. We focused on bladder cancers with BCG relapsing, defined as recurrence after achieving disease-free status by initial BCG instillations for 6 months, and evaluated the change of PD-1 expression between before and after BCG therapy and its clinical significance.

MP98-01 PROGRAMMED CELL DEATH-1 EXPRESSION IN BCG RELAPSING TUMORS IS SIGNIFICANTLY ASSOCIATED WITH STAGE PROGRESSION IN NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS

calculated by number of RPs reported from the treatment facility with high volume centers considered to be ones in the top third of reported RPs. Multivariable logistic regression was conducted to determine factors independently associated with quality surgical outcomes using the SOAP score. RESULTS: We identified 72,864 patients with high risk disease, of whom 42.5% (n1⁄431,008) were treated with RP. Overall, 34.1% of patients had a quality surgical outcome with a SOAP score 6. On multivariable logistical regression, factors associated with a quality surgical outcome included surgery at a high volumecenter (OR1.8: CI 1.6-1.9; p1⁄4 <0.01), surgery at an academic hospital (OR 1.8: CI 1.7-1.9: p1⁄4 <0.01), cN1 stage (OR 1.6: CI 1.2-2.0; p1⁄4 <0.01), and omission of neoadjuvent hormonal therapy (OR1.4:CI 1.3-1.5; p1⁄4<0.01). Factorsassociatedwith a poor surgical outcome include robotic approach (OR0.81: CI 0.76-0.87; p1⁄4 <0.01), PSA > 30 (OR 0.59: CI 0.55-0.64; p1⁄4 <0.01), and African American ethnicity (OR 0.89: CI 0.82-0.96; p1⁄4 <0.01). CONCLUSIONS: For patients with high risk prostate cancer, treatment at high volume centers and at academic centers appear to be associated with a high quality surgical outcomes. Given the increased use of this management strategy, optimizing surgical quality is needed in order to achieve the best outcomes for this aggressive malignancy.

MP71-13 EFFICACY OF CHEMOTHERAPY ADMINISTRATION IN ELDERLY PATIENTS WITH METASTATIC UPPER TRACT UROTHELIAL CARCINOMA AFTER RADICAL NEPHROURETERECTOMY.

INTRODUCTION AND OBJECTIVES: The benefit of neoadjuvant chemotherapy (NAC) for patients with locally advanced upper tract urothelial carcinoma (UTUC) remain unclear. The purpose of this study was to access safety and effectiveness of platinum-based NAC for locally advanced UTUC. METHODS: From Feb 1995 to Sep 2016, we underwent radical nephroureterectomy for consecutive 229 patients with UTUC at a single institute. Of these, we identified 50 patients who received NAC and 179 patients without NAC. We selected pair-matched patients from with and without NAC using propensity score by logistic analysis. We retrospectively evaluated the tumor response, post-therapy pathological down staging and toxicity between pair-matched patients. Variables for propensity score matching included age, sex, clinical TNM stage, diabetes, tumor location. Disease free and overall survivals were evaluated using Kaplan e Meier methods with log e lank test between two groups: those with and without NAC. Multivariate Cox regression analysis was performed for independent factor for overall survival. RESULTS: We statistically selected pair-matched 45 patients in each group. The regimens in the NAC group were gemcitabine and carboplatin for 31 cases, gemcitabine and cisplatin for 13 cases, or docetaxel, ifosfamide and nedaplatin for 1 cases. There were no significant differences in patient characteristics between the groups. Median follow up periods in NAC and control group were 21 and 39 months. No severe adverse event associated with NAC was observed. The median response rate in NAC group was 39%. Pathological down staging in primary tumor was achieved in 29 (64%) patients, and it was significantly higher compared with control group (n 1⁄4 11, 24%). Platinum-based NAC for locally advanced UTUC significantly prolonged progression free survival (P1⁄4 0.015) and overall survival (P1⁄4 0.025). In multivariate Cox regression analysis, NAC was selected as an independent predictor for prolonged overall survival (P 1⁄4 0.008, HR: 0.25, 95%CI: 0.90-0.70) CONCLUSIONS: Although present data are preliminary, the platinum-based NAC for advanced UTUC seems to have a potential to improve outcomes. Further prospective randomized studies are needed to confirm the benefit of NAC in patients with locally advanced UTUC. Source of Funding: none

Factors influencing the operating time for single-port laparoscopic radical nephrectomy: focus on the anatomy and distribution of the renal artery and vein

Objective It is considered that laparoscopic single-site surgery should be performed by specially trained surgeons because of the technical difficulty in using special instruments through limited access. We investigated suitable patients for single-port laparoscopic radical nephrectomy, focusing on the anatomy and distribution of the renal artery and vein. Methods This retrospective study was conducted in 52 consecutive patients who underwent single-port radical nephrectomy by the transperitoneal approach. In patients undergoing right nephrectomy, a 2-mm port was added for liver retraction. We retrospectively re-evaluated all of the recorded surgical videos and preoperative computed tomography images. The pneumoperitoneum time (PT) was used as an objective index of surgical difficulty. Results The PT was significantly shorter for right nephrectomy than left nephrectomy (94 vs. 123 min, P = 0.004). With left nephrectomy, dissection of the spleno-renal ligament to mobilize the spleen medially required additional time. Also, the left renal vein could only be divided after securing the adrenal, gonadal and lumbar veins. In patients whose renal artery was located cranial to the renal vein, PT tended to be longer than in the other patients (131 vs. 108 min, P = 0.070). In patients with a superior renal artery, the inferior renal vein invariably covered the artery and made it difficult to ligate the renal artery via the umbilical approach at the first procedure. Conclusions These findings indicate that patients undergoing right nephrectomy in whom the renal artery is not located cranial to the renal vein are suitable for single-port laparoscopic radical nephrectomy.

Preoperative sarcopenia status is associated with lymphovascular invasion in upper tract urothelial carcinoma patients treated with radical nephroureterectomy

INTRODUCTION Sarcopenia is a novel concept representing skeletal muscle wasting and has been identified as a prognostic factor for several cancers. The aims of this study were to evaluate the prognostic significance of sarcopenia and the relationship between sarcopenia and poor pathological findings in upper tract urothelial carcinoma (UTUC) patients who underwent radical nephroureterectomy (RNU). METHODS We identified 123 UTUC patients who underwent RNU between 2003 and 2014. We assessed sarcopenia by measuring the area of skeletal muscle at the third lumber vertebra on preoperative computed tomography scans. Sarcopenia was classified based on a sex-specific consensus definition. We investigated whether sarcopenia predicts clinical outcomes, such as cancer death and poor pathological findings at RNU. RESULTS A total of 50 (40.7%) patients had sarcopenia. In a multivariate Cox regression analysis, sarcopenia was not associated with cancer-specific survival (CSS), and lymphovascular invasion (LVI) (hazard ratio 5.88; p=0.002) was the only independent risk factor for CSS. A multivariate logistic regression analysis showed that sarcopenia independently correlated with the LVI status (odds ratio 2.36; p=0.025). LVI was positive in 27 of 50 (54%) and 25 of 73 (34%) patients with and without sarcopenia, respectively (p=0.029). CONCLUSIONS Preoperative sarcopenia predicted the LVI status, which was a strong prognostic factor for UTUC patients after RNU.

Prognostic role of programmed cell death protein 1 expression in surgically treated patients with upper tract urothelial carcinoma.

402 Background: Programmed cell death protein (PD-1) expressed on active T cells, and its ligand PD-L1 expressed on the surface of cancer cells, complementarily down-regulate T cell activation and are related to immune tolerance. A close association between PD-1 expression and poor prognosis has been reported in several cancers, however, in upper tract urothelial carcinoma (UTUC) the role of PD-1 expression on clinical outcome has not been investigated. Methods: The protein expression of PD-1 was evaluated by immunohistochemistry and the relationship with clinicopathological features was investigated in surgical specimens obtained from 100 patients who had been surgically treated for UTUC. At a magnification of 200x, PD-1 protein expression was estimated and the positive cells were graded as no (negative), moderate (1-10 cells), and strong ( > 10 cells). Results: Twenty-four patients (24.0%) had strong PD-1 staining, 32 patients (32.0%) had moderate PD-1 staining, and 44 patients (44.0%) had no PD-1 stain...