Urothelial Cancer Of Upper Urinary Tract Research Articles

Significance of the timing of ureteral ligation on prognosis during radical nephroureterectomy for upper urinary tract urothelial cancer.

To investigate the impact on intravesical recurrence and prognosis according to the ureteral ligation timing during radical nephroureterectomy for upper urinary tract urothelial carcinoma. We carried out a retrospective chart review of 664 patients with non-metastatic upper urinary tract urothelial carcinoma who underwent radical nephroureterectomy with ureteral ligation (supplementary analysis of JCOG1110A). We excluded patients with previous and/or synchronous bladder cancer, clinically node-positive disease, no ureteral ligation data, those without ureteral ligation and those with any missing data. We investigated the cumulative incidence of intravesical recurrence and cancer-specific mortality, and overall survival between patients with ureteral ligation before renovascular ligation (early ureteral ligation), or ureteral ligation after renovascular ligation (late ureteral ligation). Early and late ureteral ligation was carried out in 243 patients (36.6%) and 421 patients (63.4%), respectively. Intravesical recurrence occurred in 218 patients (32.8%) during follow up (median 3.9years). No significant difference in the intravesical recurrence was found between early and late ureteral ligation groups. Meanwhile, survival in the early ureteral ligation group was significantly worse compared with the late ureteral ligation group. Multivariable analysis showed that early ureteral ligation was an independent prognostic factor for overall survival (hazard ratio 1.88, 95% confidence interval 1.24-2.85, P=0.003) and cancer-specific mortality (hazard ratio 1.93, 95% confidence interval 1.14-3.25, P=0.014). Our findings suggest that the incidence of intravesical recurrence is not affected by the timing of ureteral ligation during radical nephroureterectomy. However, early ureteral ligation might have a negative impact on survival outcomes.

1136 - Does double J stenting during transurethral resection of a bladder tumor increase the risk for metachronous upper urinary tract urothelial cancer development?

1136 - Does double J stenting during transurethral resection of a bladder tumor increase the risk for metachronous upper urinary tract urothelial cancer development?

Initial experience of complete laparoscopic radical nephroureterectomy combined with transvesical laparoscopic excision of distal ureter in patients with upper urinary tract cancer

BackgroundSelecting the treatment procedure for cancer patients is a challenging task. We report our initial experience of complete laparoscopic radical nephroureterectomy (RNU) for patients with upper urinary tract urothelial cancer (UTUC).MethodsA total of four patients with UTUC underwent complete laparoscopic RNU combined with transvesical laparoscopic excision of the distal ureter using three 5-mm ports. Transvaginal specimen extraction was applied in female patients to reduce incisional pain and improve cosmesis. Peri-operative complications were evaluated using the Clavien-Dindo classification system. Postoperative pain was evaluated during hospitalization using a numeric pain rating scale (scales of 1 to 10). Patients who underwent retroperitoneal laparoscopic surgery combined with open excision of the distal ureter during the same period were included as a control group (conventional RNU, consisting of laparoscopic nephrectomy combined with open bladder cuff excision) for pain scale evaluation.ResultsThe novel surgery was successfully completed for all four patients (two males and two females). The mean pneumoperitoneum time for retroperitoneoscopic nephroureterectomy and specimen extraction was 174 min, while the mean pneumovesicum time for the ureteral orifice excision was 88 min. One male patient had bladder leakage at the suture site of the bladder wall, which lasted for 2 weeks. No patient experienced recurrent disease during the follow-up period (median, 10 months). Mild to moderate pain lasted for 5 or 6 days after RNU. A couple of days after surgery, the numeric pain rating scale of complete laparoscopic RNU and conventional RNU group reached its peak level at 3.0 ± 1.8 and 5.3 ± 2.8, respectively. There was no statistical difference in the degree of postoperative pain (P = 0.31).ConclusionsWe described our initial experience and outcome of complete laparoscopic RNU for UTUC. Further experience and research are required to determine whether this advanced laparoscopic technique yields better outcomes and has true clinical value.

Impact of double J stenting or nephrostomy placement during transurethral resection of bladder tumour on the incidence of metachronous upper urinary tract urothelial cancer

BackgroundWhether or not double J (DJ) stenting during transurethral resection of a bladder tumour (TURBT) harms patients with regard to possible metachronous upper urinary tract urothelial cancer (UUTUC) development remains controversial. This study evaluated the impact of DJ compared to nephrostomy placement during TURBT for bladder cancer (BCa) on the incidence of metachronous UUTUCs.MethodsWe retrospectively analysed 637 patients who underwent TURBT in our department between 2008 and 2016. BCa, UUTUC and urinary drainage data (retrograde/anterograde DJ and percutaneous nephrostomy) were assessed, along with the prevalence of hydronephrosis, and mortality. Chi-square and Fisher’s exact test was performed for univariate analyses. Survival analysis was performed by the Kaplan-Meier method and log-rank tests.ResultsUUTUC was noted in 28 out of 637 patients (4.4%), whereas only eight (1.3%) developed it metachronously to BCa. Out of these, four patients received DJ stents, while four patients received no urinary drainage of the upper urinary tract. Placement of urinary drainage significantly correlated with UUTUC (50.0% vs. 17.9%; p = 0.041). DJ stenting significantly correlated with UUTUC (50.0% vs. 11%; p < 0.01), while no patient with a nephrostomy tube developed UUTUC. UUTUC-free survival rates were significantly lower for patients with DJ stents than for all other patients (p = 0.001). Patients with or without DJ stents had similar overall survival (OS) rates (p = 0.73), whereas patients with nephrostomy tubes had significantly lower OS rates than all other patients (p < 0.001).ConclusionsPatients with DJ stenting during TURBT for BCa might have an increased risk of developing metachronous UUTUC. This study indicated advantages in placing nephrostomy tubes rather than DJ stents; however, confirmation requires investigation of a larger cohort. Even so, the increased mortality rate in the nephrostomy group reflected hydronephrosis as an unfavourable prognostic factor.

The role of adjuvant chemotherapy for pT2-4 upper urinary tract urothelial cancer: Exploratory analysis of large multi-institutional study (JCOG1110A).

374 Background: Recently, it was presented that adjuvant chemotherapy (AC) after radical nephroureterectomy (RNU) improved metastasis-free survival in pT2-4 upper urinary tract urothelial cancer (UTUC) with a median follow-up of 17.6 months (POUT study). However, the impact of AC on other outcomes remains unclear, especially for pT2 disease. Methods: The large case-series study, JCOG1110A, included 2,744 patients with non-metastatic UTUC who underwent RNU in 30 institutions in Japan between 1995 and 2009. In this analysis, patients with prior history or synchronous bladder cancer, patients who received neoadjuvant chemotherapy were excluded. Patients who received AC except for GC (gemcitabine, cisplatin) or MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) were also excluded. We extracted pT2-4 patients as study subjects from remaining patients, and identified 950 patients. The impact of AC on overall survival (OS) and extravesical recurrence-free survival (RFS) were examined by the multivariable Cox regression model in all patient and pT2, pT3-4 subgroups. Results: Of 244 pT2 and 706 pT3-4 patients with a median follow-up of 41.1 months, AC were performed in 34 (13.9%) and 183 (25.9%). In AC (+) group, high frequency of pT3-4 disease, high grade tumor, pathological node metastasis, lymphovascular invasion, and younger age were seen compared to AC (-) group. The 5-year survival of the AC (+) and AC (-) were 66.0% and 67.4% for OS, 58.0% and 57.8% for RFS, respectively. Multivariable analysis showed the improved outcome in AC (+) group on both OS and RFS in all patients (OS: HR 0.60, 95% CI 0.41-0.89, RFS: HR 0.71, 95% CI 0.51-1.00). Although AC had a great impact on OS in pT3-4 patients (HR 0.56, 95% CI 0.36-0.87), there was no clear impact on either OS or RFS in pT2 patients (OS: HR 0.81, 95% CI 0.32-2.07, RFS: HR 0.69, 95% CI 0.29-1.62). Conclusions: AC after RNU had the significant impacts on OS and RFS in pT2-4 UTUC patients. This tendency was seen strongly in pT3-4 patients, but not in only pT2 patients. The randomized trial is necessary to determine the utility of AC in UTUC patients, especially in pT2 patients. Clinical trial information: NCT01993979.

Analysis of the National Cancer Data Base (NCDB) on impact and trend of neoadjuvant chemotherapy in upper urinary tract urothelial cancer.

408 Background: Five year cancer specific survival rate is between 12- 70% for pT2 and higher UUTUC tumors. Adjuvant platinum based therapies have proven to improve Overall survival (OS) in observational series. Compromised renal function after surgery, delayed recovery from surgery pose challenge for adjuvant chemotherapy (AC). Thus, neoadjuvant chemotherapy (NAC) is an appealing option. However, there is only limited evidence on the role of NAC in UUTUC. Methods: We conducted a retrospective study of UUTUC (stage I- III) who underwent complete or partial nephroureterectomy with peri-operative chemotherapy. We then compared OS outcome among NAC vs AC groups. OS was calculated using Kaplan Meier analysis. Multivariate analysis was performed with Cox proportional hazard regression model to adjust for different variables. Results: Out of 50539 UUTUC patients reported in NCDB (2004-2016), 20121 met our inclusion criteria. 360 patients received NAC, 2617 received AC and 17144 received only surgery. Patients who received NAC were more likely to be younger, treated at academic centers, have Medicare and private insurance, have clinical T3 and higher tumor, have lower Charlson-Deyo Score (CDCC) score and undergo complete nephroureterctomy. One, three and five year OS among NAC and AC is depicted in table 1. With 150 months (m) follow up, median OS was 73.89 m for NAC and 54.14 m for AC group. A log rank test with p value=0.3437 shows no significant difference in survival rates of the two groups. Though consistent upward trend is observed in the use of NAC from 2004 to 2015, significantly higher percentages of patients still undergo only surgery without perioperative chemotherapy. Conclusions: Numerically higher mOS in NAC group was not statistically significant different from AC group. Use of perioperative chemotherapy appears to be much lower in UUTUC. Limitations that exist with this registry based study include lack of randomization, differences in surgical and radiation techniques, duration of chemotherapy, and provider/patient selection bias. Overall survival among two groups. [Table: see text]

734 - Selective cytology in detection of high grade upper urinary tract urothelial cancer: A systematic review and meta-analysis

734 - Selective cytology in detection of high grade upper urinary tract urothelial cancer: A systematic review and meta-analysis

Lymph node dissection could bring survival benefits to patients diagnosed with clinically node-negative upper urinary tract urothelial cancer: a population-based, propensity score-matched study.

To evaluate the survival benefits that lymph node dissection (LND) brought to clinically node-negative upper tract urothelial carcinoma (UTUC) patients. Non-metastatic node-negative UTUC patients were identified from the Surveillance, Epidemiology and End Results database. N0 patients were naturally divided as cN0-pNx group (clinically diagnosed as N0 without LND performed) and cNx-pN0 group (pathologically diagnosed as node-negative no matter what clinical node status they have). Of the 2731 patients included, 2240 and 491 cases were cN0-pNx and cNx-pN0, respectively. The overall survival (OS) of cNx-pN0 patients was significantly better than that of cNx-pN0 patients (p = 0.022). After propensity score matching, the survival of cNx-pN0 patients was still significantly better than cN0-pNx group. Besides, multivariate analyses showed cNx-pN0 (received LND) was an independent favorable prognostic factor for OS and CSS compared with cN0-pNx (no LND). Survival advantages of pN0 group were more significant in ≥ T2 patients and patients with tumor size ≤ 5cm. Even in N0 patients who received adjuvant treatment, LND still brought obvious survival improvement (HRos = 0.565, p = 0.013; HRcss = 0.607, p = 0.046). LND could improve survival outcomes in patients with clinically node-negative UTUC, especially for those with muscle-invasive diseases (T2-4 stages) or smaller tumor size (≤ 5cm). Adjuvant treatment after nephroureterectomy is incapable of replacing the therapeutic role of LND.

Clinico-pathological characteristics and outcome of upper urinary tract urothelial carcinoma presenting to a tertiary care urology unit in Sri Lanka

Upper urinary tract urothelial cancers account for 5% of urothelial tumours. In the West, the majority affect the pelvicalyceal system, with pyelocalyceal to ureteric ratio of 3:1. This study aims to describe the clinico-pathological features and outcome of upper urinary tract urothelial cancer treated surgically in a tertiary care unit in Sri Lanka. A retrospective analysis of all patients who underwent nephroureterectomy for upper urinary tract urothelial cancer at the Urology Unit at National Hospital of Sri Lanka between January1997 and December 2016 was carried out. There were 43 patients. Male: female=1.87. Median age was 65 years (range:42-83). Macroscopic haematuria was the commonest presentation (n=29; 67.4%). Median duration of symptoms was 3 months (range 0.5-6). In the majority (n=20;46.5%) the tumour was confined to the ureter. Thirty-three (75.6%) were papillary tumours. Twenty-one had non-muscle invasive tumours (pTa: n=6(14%), pT1: n=15(34.9%) and others had invasive cancers (pT2: n=11(25.6%), pT3: n=7(16.3%) and pT4: n=4(9.3%)). Majority were low grade tumours (n=23;53.5%). Twelve (27.9%) had preceding urothelial bladder cancer. Nineteen (44.2%) were lost to follow up after surgery. Median follow up duration of the rest was 40 months (range:4-224months). Of them, 9(20.9%) developed metachronous bladder tumours. Nine had recurrence free survival of ≥5years and 15 had overall survival of ≥5 years. Of them, 4 patients survived ≥10 years. Older age (p=0.015) and presence of necrosis(p=0.05) were the only clinico-pathological parameters predictive of tumour recurrence. A relatively higher number females and high number of ureteric tumours were noted compared to similar studies from Asia.

1018 - Regional distribution of lymph node metastasis in upper urinary tract urothelial cancer, sub-analysis of large multi-institutional study (JCOG1110A)

1018 - Regional distribution of lymph node metastasis in upper urinary tract urothelial cancer, sub-analysis of large multi-institutional study (JCOG1110A)

IJU this issue

In this issue of International Journal of Urology, six Review Articles with three Editorial Comments, four Original Articles and two Urological Notes were published. Husmann (Rochester, USA) reviewed 385 patients that have experienced an enteric bladder augmentation as a result of spina bifida or bladder exstrophy, using either the ileum or colon. Based on the finding of increasing complications with body mass index, the author concluded long-term follow-up evaluations and the nutritional management of patients undergoing an enteric bladder augmentation are necessary to prevent the long-term sequela of this procedure. As the reviewer notes in the Editorial Comment, urologists should bear in mind that complicated surgeries are not a goal, but the start of a new daily care routine of their bladder. Takeuchi et al. (Fukuoka, Japan) reviewed the mechanism of immunological tolerance induced by cyclophosphamide (CY) and other immune factors in kidney transplantation. The authors established their own CY-induced experimental chimera mouse model consisting of intravenous injection of allogeneic bone marrow and spleen cells, followed by intraperitoneal injection of CY. In this model, they showed destruction of allo-reactive T cells by CY. Interestingly, they modified their tolerance system for the experimental treatment of malignancy. Inamoto et al. (Osaka, Japan) compared the oncological and quality of life results of bladder preservation therapy including trimodal therapy with that of radical cystectomy, and concluded that trimodal therapy has emerged as a potential alternative treatment option for muscle-invasive bladder cancer. As muscle-invasive bladder cancer is a systemic disease, trimodal therapy might become an attractive alternative when considering the combination or adjuvant setting of immuno-oncology drugs because of the abscopal effect as a result of radiation therapy. Several interesting Original Articles have been published. Nishioka et al. (Osaka, Japan) reported the utility and safety of high-dose mizoribine combination therapy using cyclosporine and tacrolimus as calcineurin inhibitors in patients undergoing kidney transplant from a Japanese multicenter study that enrolled 156 kidney transplant patients between 2009 and 2013. The authors concluded that two calcineurin inhibitors yielded equivalent efficacy, and high-dose (6 mg/kg at the start) mizoribine in combination with calcineurin inhibitors basiliximab, and corticosteroids can provide effective immunosuppression. This study is worthwhile, not only for showing the utility and safety of this regimen, but also for showing the commitment of Japanese urologists to kidney transplantation worldwide. Urakami et al. (Tokyo, Japan) studied DNA mismatch repair proteins for 143 patients with upper urinary tract urothelial cancer, and found seven (5%) had loss of mismatch repair proteins, so-called microsatellite instability (MSI). Malignant tumors show an inherent genetic instability that can be classified as MSI or chromosomal instability. Although the frequency of MSI was reportedly higher in upper urinary tract urothelial cancer than bladder cancer, the figure and clinical characteristics were almost identical to bladder cancer (9/100; 9%, all with a low grade without tumor progression; Yamamoto T. Clin Cancer Res 2006; 12: 2752). Study of the genetic status of MSI will be more important because of the higher mutational burden than chromosomal instability with a good response to immuno-oncology drugs. Unfortunately, other interesting papers could not be published in this issue due to limited space. None declared.

Perioperative antithrombotic therapy in patients undergoing endoscopic urologic surgery: where do we stand with current literature?

The number of patients on chronic anticoagulant or antiplatelet therapy requiring endoscopic urological surgery is increasing worldwide. Therefore, there is a strong demand to standardize the perioperative treatment of this cohort of patients, both from a surgical and cardiological point of view, balancing the risks of bleeding versus thrombosis, and the important possible clinical and medical legal repercussions therein. Although literature is scarce and the quality of evidence quite low, in line with other surgical specialties, guidelines and recommendations for the management of urological patients have begun to emerge. The aim of this review is to analyze current available literature and evidence on the most common endoscopic procedures performed in this high-risk group of patients, focusing on the perioperative management. In particular, to analyze the most frequently performed endoscopic procedures for the treatment of benign prostate enlargement (transurethral resection of the prostate, Thulium, Holmium and greenlight laser prostatectomy), bladder cancer (transurethral resection of the bladder), upper urinary tract urothelial cancer, and nephrolithiasis. Despite the lack of randomized studies, regardless of individual patient considerations, studies would support continuation of acetylsalicylic acid, which is recommended by cardiologists, in patients with intermediate/high risk of coronary thrombosis. In contrast, multiple studies found that bridging with light weight molecular weight heparin can potentially lead to more bleeding than continuation of the anticoagulant(s) and antiplatelet therapy, and caution with bridging is advised. All urologists should familiarize themselves with emerging guidelines and recommendations, and always be prepared to discuss specific cases or scenarios in a dedicated multidisciplinary team.

Preoperative chronic kidney disease is predictive of oncological outcome of radical cystectomy for bladder cancer.

To evaluate the impact of preoperative chronic kidney disease (CKD) on oncological outcomes after radical cystectomy (RC) for bladder cancer. We reviewed the medical records of patients with urothelial bladder carcinoma who underwent RC with curative intent at seven hospitals between 1990 and 2013. After excluding patients with a history of upper urinary tract urothelial cancer or neoadjuvant chemotherapy, we analyzed 594 cases for the study. Preoperative estimated glomerular filtration rate (eGFR) was calculated using the three-variable Japanese equation for GFR estimation from serum creatinine level and age. Patients were divided into four groups of different CKD stages based on eGFR values (mL/min/1.73m2), i.e.,≥60 (CKD stages G1-2), 45-60 (G3a), 30-45 (G3b), and<30 (G4-5). Survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression analyses addressed survivals after RC. Median age of patients was 67years. Patients were classified into CKD stages: G1-2 (n=388; 65.3%), G3a (n=122; 20.5%), G3b (n=51; 8.6%), and G4-5 (n=33; 5.6%). During a median follow-up of 4.0years, 200 and 164 patients showed cancer progression and died of bladder cancer, with the 5-year progression-free survival (PFS) and cancer-specific survival (CSS) of 64.9 and 70.2%, respectively. On multivariate analyses, CKD stages of G3b or greater, advanced pT stage, lymph node metastasis, and positive lymphovascular invasion were independent poor prognostic factors for PFS and CSS. We demonstrated that the advanced preoperative CKD stage was significantly associated with poor oncological outcomes of the bladder cancer after RC.

Clinicopathological characteristics of patients with upper urinary tract urothelial cancer with loss of immunohistochemical expression of the DNA mismatch repair proteins in universal screening.

To assess the detection rate of putative Lynch syndrome-associated upper urinary tract urothelial cancer among all upper urinary tract urothelial cancers and to examine its clinicopathological characteristics. A total of 143 patients with upper urinary tract urothelial cancer who had received total nephroureterectomy were immunohistochemically stained for the expression of mismatch repair proteins MLH1, PMS2, MSH2 and MSH6. For all suspected mismatch repair-deficient cases, MMR genetic testing was recommended and clinicopathological features were examined. Loss of mismatch repair proteins was found in seven patients (5%) who were thus categorized as putative Lynch syndrome-associated upper urinary tract urothelial cancer. Five of these patients showed dual loss of MSH2/MSH6. Two patients were confirmed to be MSH2 germline mutation carriers. Histologically, all seven tumors were low-grade atypical urothelial carcinoma and showed its unique histological features, such as an inverted papilloma-like growth pattern and a villous to papillary structure with mild stratification of tumor cells. Six tumors had no invasion of the muscularis propria. No recurrence or cancer-related deaths were reported in these seven patients. Just three patients met the revised Amsterdam criteria. This is the first report that universally examined mismatch repair immunohistochemical screening for upper urinary tract urothelial cancers. The prevalence (5%) of putative Lynch syndrome-associated upper urinary tract urothelial cancers is much higher than we had expected. We ascertained that putative Lynch syndrome-associated upper urinary tract urothelial cancers were clinically in the early stage and histologically classified into low-grade malignancy with its characteristic pathological features. The clinicopathological characteristics that we found in the present study could become additional possible markers in the diagnosis of Lynch syndrome-associated upper urinary tract urothelial cancers.

Molecular diagnosis of lymph node metastasis in patients with upper urinary tract cancer who underwent lymphadenectomy.

To determine the significance of molecular diagnosis of lymph node metastasis using quantitative reverse transcription polymerase chain reaction in patients with upper urinary tract urothelial cancer. A total of 51 patients with upper urinary tract urothelial cancer who underwent extended lymphadenectomy were included in the present study. Retrieved lymph nodes from each patient were divided into two parts. One part was assessed by quantitative reverse transcription polymerase chain reaction assay for molecular staging, whereas the other one was assessed by routine histopathological examination. Four kinds of molecules (FXYD3, KRT19, KRT20 and UPK2) were selected as markers to detect urothelial cancer cells. The average number of retrieved lymph nodes was 18.3. As UPK2 showed the best discrimination ability among four markers, the patients were classified in three categories according to UPK2 expression: N(+)PCR(+) for patients who had lymph node metastasis by routine pathological diagnosis as well as quantitative reverse transcription polymerase chain reaction (n = 4); N(-)PCR(+) for patients who had lymph node metastasis by polymerase chain reaction but not by routine pathological diagnosis (n = 7); and N(-)PCR(-) for patients who showed no lymph node metastasis not only by routine pathological diagnosis but also by polymerase chain reaction (n = 40). The prognosis of the N(-)PCR(+) group was better than that of the N(+)PCR(+) group, and similar to that of the N(-)PCR(-) group. Quantitative reverse transcription polymerase chain reaction could detect micrometastasis in patients with upper urinary tract urothelial cancer. However, the prognosis of patients with micrometastasis is better than patients with pathologically metastasized lymph nodes, and similar to patients without micrometastasis.

Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma

BackgroundUpper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer. ObjectiveTo characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses. Design, setting, and participantsWe collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis. Outcome measurements and statistical analysisAdjusting for batch effects, consensus mutation calls from independent pipelines identified DNA mutations, gene expression clusters using unsupervised consensus hierarchical clustering (UCHC), and protein expression levels that were correlated with relevant clinical variables, The Cancer Genome Atlas, and other published data. Results and limitationsWES identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were the most common mutational signatures. UCHC of RNAseq data segregated samples into four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA mutations, nonsmokers, high-grade <pT2 tumors, high recurrences. Cluster 2: 100% FGFR3 mutations, low-grade tumors, tobacco use, noninvasive disease, no bladder recurrences. Cluster 3: 100% FGFR3 mutations, 71% PIK3CA, no TP53 mutations, five bladder recurrences, tobacco use, tumors all <pT2. Cluster 4: KMT2D (62.5%), FGFR3 (50%), TP53 (50%) mutations, no PIK3CA mutations, high-grade pT2+ disease, tobacco use, carcinoma in situ, shorter survival. We identified a novel SH3KBP1-CNTNAP5 fusion. ConclusionsMutations in UTUC occur at differing frequencies from bladder cancer, with four unique molecular and clinical subtypes. A novel SH3KBP1 fusion regulates RTK signaling. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation. Patient summaryWe conducted a comprehensive study of the genetics of upper urinary tract urothelial cancer by evaluating DNA, RNA and protein expression in 31 tumors. We identified four molecular subtypes with distinct behaviors. Future studies will determine if these subtypes appear to have different responses to treatments.

Role of lymph node dissection during radical nephroureterectomy for upper urinary tract urothelial cancer: multi-institutional large retrospective study JCOG1110A.

To evaluate the impact of lymph node dissection (LND) on clinical outcome during radical nephroureterectomy (RNU) for patients with upper urinary tract urothelial cancer (UTUC). We, the Urologic Oncology Study Group of the Japan Clinical Oncology Group (JCOG), retrospectively collected data from patients with non-metastatic UTUC who underwent RNU in 30 centers in 1995-2009. Ineligible patients and patients with previous and/or synchronous bladder cancer were excluded, and the remaining 2037 patients were analyzed. We compared overall and cancer-specific mortality between patients who underwent LND (LND group) and those without LND (no-LND group). Among 2037 patients, LND was performed in 1046 (51.4%) patients, and 223 (10.9%) patients had pathological node-positive (pN+) disease. All-cause mortality was observed in 503 patients (24.7%) during follow-up (median 45.8months), including 363 patients (17.8%) who died of UTUC. Patients with pN+ disease showed significantly shorter overall survival (OS) compared with pN0 patients, and the estimated 5-year OS for pN+ patients was 30%. Older age, ≥cT3, and clinical node-positive disease were found as preoperative predictors for pN+ disease by multivariate analysis. In the comparison of OS and cancer-specific mortality between LND and no-LND groups, there was no significant improvement by LND in multivariate analysis. The median number of lymph nodes removed was six (IQR 3-11). There was no significant association between the number of lymph nodes removed and OS. The present study indicates that there is no therapeutic benefit of LND during RNU for UTUC, although pathologically positive LN status can predict poor prognosis.

Impact of lymph node dissection on clinical outcomes during nephroureterectomy in patients with clinically node-negative upper urinary tract urothelial cancer: subanalysis of a multi-institutional nationwide case series of the Japanese Urological Association.

To evaluate the impact of lymph node dissection (LND) on the clinical outcomes during radical nephroureterectomy (RNU) in patients with clinically node-negative upper urinary tract urothelial cancer (UTUC). Within the nationwide case series of the Japanese Urological Association, which comprises 1509 patients with UTUC diagnosed in 2005, we identified 823 patients with clinically node-negative UTUC who underwent RNU. The extent of limited LND was defined as the renal hilar region only for renal pelvic cancer and as either the pelvic region or para-aortic/paracaval region only for ureteral cancer, while the extent of wider LND was defined as at least one perilesional LND region in addition to limited LND. Multivariate analysis with a Cox regression hazard model was used to evaluate the survival benefit. Among the 823 patients, LND was performed in 197 (23.9%) patients, and 26 (13.2%) of them had pathologically node-positive disease. Of 197 patients who underwent LND, limited and wider LND was performed in 119 (60.4%) and 78 (39.6%) patients, respectively. Patients with node-positive disease showed significantly shorter overall survival than those with node-negative disease. No LND-associated survival improvement was observed in a direct comparison between patients with and without LND. In addition, limited or wider LND was not associated with overall survival or cancer-specific survival. The therapeutic benefit obtained by LND remains unclear regardless of the extent of LND, although LND has diagnostic value with respect to the prediction of a poor prognosis especially in patients with clinically muscle-invasive disease.

Upper Urinary Tract Urothelial Cancer in Croatian and Bosnian Endemic Nephropathy Regions.

ObjectivesEndemic nephropathy (EN) is a chronic tubulointerstitial renal disease associated with increased incidence of upper urinary tract urothelial cancer (UTUC) occurring predominantly in geographically limited areas in villages along big Danube river. Based on results obtained by the research it is confirmed that aristolochic acid is causative agent of endemic nephropathy (EN).AimThe aim of this study was to determine characteristics of UTUC in two endemic areas and analyze trends in 5-year period.MethodsThis study included all patients with UTUC with or without synchronous/metachronous urothelial cancer in urinary bladder, from Croatian and Bosnian EN and non-EN regions. We analyzed archival data bases from all patients with UTUC who were admitted and operated in Department for surgery and urology, General Hospital Josip Bencevic Slavonski Brod in the time period between 2005 and 2010. Analyzed groups of patients were divided and compared as EN group (that includes patients from Croatian and Bosnian EN region) and non-EN group (that includes patients from Croatian and Bosnian non-EN region). All surgical specimens were processed according to standardized pathological procedures.ResultsComparing patients basic characteristics from Croatian and Bosnian EN region there was no significant difference in gender (females were more frequently affected in both EN regions, p=0.99) or age (p=0.43) of patients. We found higher blood levels of urea and creatinine in group of patients from Croatian EN region when compared with group of patients from Bosnian EN region but the difference was not statistically significant (p=0.79 and p=0.44, respectively). In patients from Croatian EN group Hemoglobin levels were significantly lower than levels from Bosnian EN region patients, p=0.0049. In group of patients from Bosnian EN region ureteral tumors were more frequently observed than in Croatian group of patients, when compared with renal pelvis tumors but the difference was not statistically significant (p=0.258).ConclusionOur data showed some differences in tumor localization between to investigated, relatively nearly situated, EN regions in Croatia and Bosnia. Statistically significant difference in hemoglobin levels between Croatian and Bosnian EN regions that should be further analyzed to give some reasonable explanation.

Risk Stratification Model to Predict High-Risk Patients for Adjuvant Chemotherapy in Upper Urinary Tract Urothelial Cancer

Objective: Optimal patient selection for adjuvant chemotherapy has not been clarified in upper urinary tract urothelial cancer (UTUC). We aimed to develop a risk model to select candidates for adjuvant chemotherapy after radical nephroureterectomy (RNU). Methods: A retrospective review of 936 patients with UTUC between 1995 and 2015 who received ≥ 2 cycles of platinum-based adjuvant chemotherapy after RNU (n=213) or surgery alone (n=723) was conducted in collaborative institutions. Risk factors for cancer-specific mortality were extracted using the proportional hazard model. The survival benefit in high-risk patients was compared between the groups. Results: At a median follow-up of 1006 days (34 months), disease recurrence, cancer-specific mortality, and allcause mortality were noted in 253 (27.5%), 206 (22.0%), and 285 (30.4%) patients, respectively. On multivariate analysis, baseline serum C-reactive protein (CRP) ≥ 0.32 mg/dL (HR: 1.74, 95% CI: 1.09–2.75, p=0.0201), pathologic T stage ≥ 3 (pT>3) (HR: 2.17, 95% CI: 1.28–3.76, (p=0.0033), cN+ (HR: 2.84, 95% CI: 1.50–5.01, p=0.0021), and lymphovascular invasion (LVI) (HR: 3.94, 95% CI: 2.23–7.17, p<0.0001) were independent predictors of cancer-specific mortality (CSM) in the training set. When they were used to categorize patients into low (0-1 factor) and high-risk groups (2-4 factors), high-risk patients had significantly worse CSM than those with low-risk. In the high-risk patients, 42.3% who received adjuvant chemotherapy had significantly better CSM and all-cause mortality than those who underwent surgery alone. In high-risk patients, multivariate analysis showed adjuvant chemotherapy as an independent prognostic factor for CSM (HR: 0.52) and all-cause mortality (HR: 0.57). Conclusion: CRP, pT>3, cN+, and LVI was useful for identifying high-risk patients.