BACKGROUND: Incidence of renal dysfunction and risks of progression to end-stage renal disease (ESRD) were reported higher in upper urinary tract urothelial carcinoma (UTUC) than in renal cell carcinoma (RCC) patients after unilateral nephrectomy.
METHODS: Totally 193 renal cancer patients, including 132 UTUC and 61 RCC, were studied to clarify whether the pathological changes of the kidney remnant removed from nephrectomy and the clinical factors might predict the risk of ESRD. Renal tubulointerstitial (TI) score and global glomerulosclerosis (GGS) rate were examined by one pathologist and two nephrologists independently under same histopathological criteria.
RESULTS: The glomerular filtration rates at the time of surgery were lower in UTUC than RCC groups (p < 0.001). Average GGS score and average TI rate were higher in UTUC than in RCC groups (p < 0.001; p < 0.001). Competitive risk factor analysis revealed that abnormal GGS rate not related to age, predominant in UTUC with pre-existing renal function impairment, was a histopathological predictor of poor renal outcomes (creatinine doubling or ESRD) within 5 years in UTUC patients.
CONCLUSION: Pre-existing renal function and pathological change of kidney remnant in both UTUC and RCC have the value for prediction of renal outcomes.

PURPOSE: Upper tract urothelial carcinoma with clinically positive regional lymph nodes is an aggressive disease state with a high propensity for metastasis and death. The current literature is limited regarding national practice patterns and outcomes in this patient population.
MATERIALS AND METHODS: We identified 1,658 patients in the NCDB (National Cancer Database) who had cN+M0 upper tract urothelial carcinoma. Patients were stratified into treatment groups. We compared baseline patient and tumor characteristics between the groups, and completed survival analysis using a multivariate Cox regression model.
RESULTS: There were 1,658 patients in the final study population. Preoperative chemotherapy was the least performed treatment. That group comprised 6.8% of the overall population and was associated with the highest median overall survival of 36 months compared to 21 months for adjuvant chemotherapy, 14 for chemotherapy only, 10 for surgery without perioperative chemotherapy and 5 for no treatment. On multivariate analysis preoperative chemotherapy was associated with improved median overall survival compared to that in the adjuvant chemotherapy group (HR 0.58, 95% CI 0.38-0.87). There was no statistically significant difference in survival between the chemotherapy only and the surgery only groups. Of patients in the preoperative chemotherapy group 34.6% achieved pN0 status compared to 10.3% of those who underwent surgery as initial therapy.
CONCLUSIONS: Preoperative chemotherapy was the least performed treatment strategy in the management of cN+M0 upper tract urothelial carcinoma but it was associated with the highest median overall survival. There was no difference in survival between the chemotherapy only and the surgery only groups. Overall these results suggest that initial chemotherapy is appropriate in this population when feasible.

Enfortumab vedotin is an antibody-drug conjugate targeting nectin-4 and is being studied in the treatment of various epithelial carcinomas including urothelial carcinoma; early data suggests efficacy and tolerability. Rash has been described as an adverse event associated with treatment with enfortumab vedotin, but has not been characterized to date. We report a patient with metastatic urothelial carcinoma treated with enfortumab vedotin who developed erythematous, scaly papules and plaques on his torso and extremities with corresponding histologic features of vacuolar interface dermatitis and maturation disarray of keratinocytes. He was successfully treated with topical corticosteroids. Cutaneous toxicity appears to be a common adverse reaction in this growing class of antibody-drug conjugates.

BACKGROUND: The role of neoadjuvant chemotherapy (NAC) for the management of upper tract urothelial carcinoma (UTUC) remains controversial. The aim of present study was to evaluate the contemporary role of NAC for patients with locally advanced UTUC through systematic review and meta-analysis of the literature.
METHODS: Systematic literature searches were conducted in PubMed/Medline and Embase for all studies that examined the role of chemotherapy for UTUC. We performed this study according to the Preferred Reported Items for Systematic Reviews and Meta-analysis guidelines. Endpoints were overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS).
RESULTS: A total of four trials on 318 patients were included in this study. Each of the included studies was retrospective. Compared to controls, NAC improved OS, CSS, and PFS by 57% (95% confidence interval [CI], 0.25-0.73; p = 0.002), 59% (95% CI, 0.27-0.57; p < 0.00001), and 45% (95% CI, 0.50-0.60; p < 0.00001), respectively. The absolute increases in OS, CSS, and PFS were 11%, 18%, and 13%, respectively, and these increases are equivalent to numbers-needed-to-treat of 9, 5.5, and 7.6, respectively. Pooled odds ratio for the effect of NAC on downstaging was 0.21 (95% CI, 0.09-0.60; p = 0.004), which indicates that NAC group had a 4.76-fold higher probability of having pathologic N stage 0 than control group.
CONCLUSIONS: NAC treatment before radical nephroureterectomy might provide better survival outcomes in patients with locally advanced UTUC. Prospective randomized studies are needed to confirm the benefits of NAC in locally advanced UTUC patients.

Background/aim: This study was designed to determine the characteristic features of upper urinary system urothelial carcinomas (UUSUCs) and to evaluate the clinicopathological parameters associated with prognosis.
Materials and methods: A total of 74 cases of UUSUC were included, from three different centers. Demographic data and histopathological features such as tumor localization, concomitant tumor in the urinary system, distant metastasis with overall survival and disease-free survival obtained from the hospital records were evaluated retrospectively. Histopathologic prognostic features such as grade, perineural invasion, lymphovascular invasion, tumor necrosis, and surgical margin status were also evaluated.
Results: Seventy cases (94.6%) underwent open nephroureterectomy whereas 4 cases (5.4%) had laparoscopic nefroureterectomy. Thirty-eight (51.4%) cases were located in the pelvis, 7 (9.5%) in the ureter, 29 (39.2%) both in the pelvis and ureter. Fifty-six (75.7%) cases were alive; however, 18 (24.3%) patients were found to be dead. pTa, pT1, pT2, pT3, and pT4 tumors were reported in 16 (21.6%), 13 (17.6%), 4 (5.4%), 28 (37.8%), and 13 (17.6%) patients, respectively. Histopathologically, 17 cases (23%) were low-grade, 57 cases (77%) were high-grade. Statistically significant correlation was observed between overall survival and lymph node metastasis, distant metastasis, tumor necrosis, and differentiation by univariate analysis. Only distant metastasis was statistically associated with overall survival by multivariate analysis. We found no significant relationship between disease-free survival and all parameters.
Conclusion: Differentiation and necrosis of tumor, lymph node involvement, and presence of distant metastasis is associated with the overall survival of urothelial carcinoma of the upper urinary system.

BACKGROUND: Cancer is a life-threatening disease that causes every fourth death. It is often hard to determine the time point of progression. Therefore, biomarkers for cancer entities that indicate disease progression or aggressiveness and thereby guide therapeutic decisions are required. Unfortunately, reliable biomarkers are rare. In this study, the potential of serum hepcidin and serum GDF-15 as biomarkers that correlate with patient's survival in the two entities upper urinary tract urothelial carcinomas (UUTUC) and renal cell carcinoma (RCC) were analyzed.
METHODS: In this retrospective study n = 38 patients suffering from UUTUC, n = 94 patients suffering from RCC and n = 21 patients without infections or cancer, all hospitalized at the University Hospital Muenster, were included. Serum samples of patients were retrospectively analyzed. Serum hepcidin and GDF-15 levels were measured and correlated to aggressiveness and progression of the disease as well as patient's outcome.
RESULTS: For both entities, UUTUC and RCC, serum hepcidin levels as well as serum GDF-15 levels were increased compared to sera of controls. High serum hepcidin and GDF-15 levels were associated with metastases and cancer relapse. Also, in both entities, the overall survival was decreased in patients with increased serum hepcidin and GDF-15 levels. Hence, high serum hepcidin and GDF-15 levels correlated with patient's outcome.
CONCLUSION: To conclude, the data of this study show a correlation of high serum hepcidin and GDF-15 levels with aggressiveness and progression of the disease and demonstrate potential prognostic properties of serum hepcidin and GDF-15 levels. The data support the further assessment of serum hepcidin and GDF-15 as prognostic markers in RCC and UUTUC.

Introduction: 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.
Methods: 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.
Results: 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.
Conclusions: A relatively higher number females and high number of ureteric tumours were noted compared to similar studies from Asia.

OBJECTIVE: This study assessed a national healthcare intervention launched in Sweden in 2015 to reduce the time between macroscopic haematuria, diagnosis and treatment of urinary tract cancer.
METHODS: The outcome of the first 11 months was evaluated in 1697 individuals referred to a standardized care pathway for urinary tract cancer compared with 174 patients with conventionally diagnosed urothelial carcinoma.
RESULTS: Among the referred individuals, 317 (19%) were diagnosed with cancer, 1034 (61%) had a benign diagnosis and 345 (20%) had a negative evaluation. Bladder cancer was the most common malignant diagnosis [262/317 (83%)]. Cancers were diagnosed in 23% of males and 13% of females, and showed a strong correlation with age: cancer diagnosis in 2% aged <50 years and in 44% aged ≥90 years. Results were affected by bacteriuria but not by anticoagulant medication, with 12%/22% and 19%/19% cancer detection, respectively. The standardized care pathway shortened the diagnostic delay to a median of 25 days compared to 35 days for regular referral (p = .01). However, median time to treatment was unchanged: 39 days from referral to transurethral resection, 42 days from primary resection to re-resection for stage TaG3/T1 disease and 100 days from referral to curative treatment for muscle-invasive disease.
CONCLUSIONS: Macroscopic haematuria had a cancer capture rate of 19%, with higher predictive values in men and at older age, whereas anticoagulant therapy did not influence the diagnostic yield. The demonstrated lack of effect on time to treatment underscores the need to consider the entire patient process when initiating healthcare reforms to improve outcome.

Urothelial carcinoma in the upper tract is rare and often discussed separately. Many established risk factors were identified for the disease, including genetic and external risk factors. Radiographic survey, endoscopic examination and urine cytology remained the most important diagnostic modalities. In localized upper tract urothelial carcinomas, radical nephroureterectomy with bladder cuff excision are the gold standard for large, high-grade and suspected invasive tumors of the renal pelvis and proximal ureter, whereas kidney-sparing surgeries should be considered in patients with low-risk disease. Advances in technology have given endoscopic surgery an important role, not only in diagnosis, but also in treatment. Although platinum-based combination chemotherapy is efficacious in advanced or metastatic disease, current established chemotherapy regimens are toxic and lack a sustained response. Immune checkpoint inhibitors have led to a new era of treatment for advanced or metastatic urothelial carcinomas. The remarkable results achieved thus far show that immunotherapy will likely be the future treatment paradigm. The combination of immune checkpoint inhibitors and other agents is another inspiring avenue to explore that could benefit even more patients. With respect to the high incidence rate and different clinical appearance of upper tract urothelial carcinomas in Taiwan, a possible correlation exists between exposure to certain external risk factors, such as arsenic in drinking water and aristolochic acid in Chinese herbal medicine. As more gene sequencing differences between upper tract urothelial carcinomas and various disease causes are detailed, this has warranted the era of individualized screening and treatment for the disease.

OBJECTIVE: To estimate postoperative residual renal function after radical nephroureterectomy for upper tract urothelial carcinoma using the preoperative dynamic computed tomography renal cortex enhancement ratio in comparison with the split kidney glomerular filtration rate measured by
METHODS: A total of 47 patients who received radical nephroureterectomy and underwent both preoperative dynamic computed tomography and renography were the model-development cohort; and 109 patients who underwent dynamic computed tomography alone were the validation cohort. Postoperative renal function of the unremoved kidney was estimated using the following formulas: preoperative estimated glomerular filtration rate × the percentage of total renal cortex radiodensity for the intact kidney in Hounsfield units obtained from corticomedullary phase images in the computed tomography-based model, or the percentage of the total glomerular filtration rate measured by renography in the nuclear model. The correlation between observed and estimated postoperative renal function was determined. The computed tomography-based prediction model derived from linear regression analysis was validated externally.
RESULTS: The correlation of computed tomography-based split renal function with the observed postoperative estimated glomerular filtration rate (r = 0.80) was equivalent to that of nuclear split renal function (r = 0.78). In the validation cohort, the computed tomography-based prediction model showed an equivalently strong correlation (r = 0.78).
CONCLUSIONS: The present study showed that the percentage of total renal cortex radiodensity for the intact kidney is a useful tool for predicting unremoved kidney function in upper tract urothelial carcinoma patients, thereby allowing appropriate patient selection for perioperative cisplatin-based combination chemotherapy.

OBJECTIVE: To evaluate microRNA (miRNA) biomarkers for upper tract urothelial carcinoma (UTUC) to improve risk stratification.
METHODS: miRNA was isolated from 157 radical nephroureterectomy specimens from 2 institutions. The relative expression of miRNA was examined for high grade vs low grade tumors as well as muscle invasive vs nonmuscle invasive tumors. Recurrence free survival (RFS) and overall survival (OS) were also stratified using relative expression of specific miRNA.
RESULTS: The optimized model to identify high grade UTUC included miR-29b-2-5p, miR-18a-5p, miR-223-3p, and miR-199a-5p, generating a sensitivity of 83%, specificity of 85%, and generated a receiver operating characteristic (ROC) curve with area-under-the-curve of 0.86. Similarly, the model classifier for predicting ≥pT2 disease incorporated miR-10b-5p, miR-26a-5p-5p, miR-31-5p, and miR-146b-5p, producing a sensitivity of 64%, specificity of 96%, and area-under-the-curve of 0.90. RFS was best reflected by a combination of miR-10a-5p, miR-30c-5p, and miR-10b-5p, while OS was best predicted by miR-10a-5p, miR-199a-5p, miR-30c-5p, and miR-10b-5p.
CONCLUSION: High-grade vs low-grade as well as muscle invasive vs nonmuscle invasive UTUC can be reliable distinguished with unique miRNA signatures. Furthermore, differential expression of UTUC miRNA produces robust classifiers for predicting RFS and OS that may help identify patients who would most benefit from adjuvant therapies.

AIM: To describe the findings and behaviour of contrast-enhanced ultrasound in the study of upper tract urothelial tumours and to assess its usefulness for diagnosis.
MATERIAL AND METHODS: We reviewed our hospital's database over a period of 45 months to identify patients diagnosed with upper tract urothelial carcinomas. We reviewed the findings on mode B-ultrasound, contrast-enhanced ultrasound (location and qualitative assessment of intensity and washout of enhancement), and made a comparison with other techniques (computed tomography or magnetic resonance), and with the surgical specimen.
RESULTS: We found 42 patients with a diagnosis of upper tract urothelial carcinoma confirmed with surgery over the period reviewed. Twenty-eight (67%) patients underwent contrast-enhanced ultrasound. Baseline ultrasound showed hydronephrosis with or without ureteral dilatation with echogenic content occupying the renal calyx (6), pelvis (10) or ureter (12). After injection of contrast, enhancement was noticed in 100% of the lesions, with similar intensity to the cortex in 23, and less in 5. Twenty-four lesions showed early washout, before the cortex, between 40 and 55seconds after the injection. The diagnosis was correct in 27 cases. Localisation coincided with the histological specimen in 28 cases, and 3 patients had additional distal carcinoma foci.
CONCLUSION: Contrast-enhanced ultrasound is a useful technique for diagnosing upper tract urothelial tumours that increases confidence in the diagnosis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been increasingly adopted in the management of high-grade upper tract urothelial carcinoma (UTUC), largely extrapolating from level I evidence in urothelial carcinoma of the bladder. Studies examining pathologic outcomes in patients with UTUC receiving NAC are mostly limited to retrospective, single-center studies with limited sample size, with results of a phase II trial recently presented. Hypothesizing that NAC is associated with improved pathologic response (PR), we compared pathologic outcomes in patients with high-grade UTUC who did and did not receive NAC before extirpative surgery.
PATIENTS AND METHODS: A total of 6174 patients with nonmetastatic, high-grade UTUC who underwent extirpative surgery from 2006 to 2014 were identified from the National Cancer Database. Patients were stratified by NAC status. PR was defined as pathologic stage less than clinical stage. Univariate and multivariable logistic regression analysis was employed to identify predictors of PR.
RESULTS: Two hundred sixty (4.2%) patients received NAC. A higher incidence of PR was observed in patients receiving NAC (25.2% vs. 1.8%; P < .001), with complete PR observed in 6.1% of patients receiving NAC and 0.4% of patients undergoing surgery alone. NAC (odds ratio [OR], 19.8; 95% confidence interval [CI], 11.8-33.5), nonwhite race (OR, 3.2; 95% CI, 1.7-6.3), and ureteral tumor location (OR, 1.6; 95% CI, 1.02-2.6) were independently associated with PR.
CONCLUSIONS: Examining a large national cancer registry, we observed a higher incidence of PR in patients with UTUC receiving NAC, validating findings of prior studies. Our findings support consideration of NAC in high grade UTUC. Prospective trials will better define the impact of NAC on pathologic and survival outcomes.

Urothelial carcinoma (UC), originating in the bladder or upper urinary tract, is the most common histological type of cancer. Currently, platinum-based cytotoxic chemotherapy is the standard treatment for metastatic UC (mUC) and the preferred treatment option in the perioperative (neoadjuvant and/or adjuvant) setting of muscle invasive bladder cancer (MIBC). In addition, intravesical bacillus Calmette-Guerin immunotherapy or chemotherapy is applied as the adjuvant therapeutic option in non-muscle invasive bladder cancer (NMIBC) after transurethral resection, to prevent recurrence and progression. In recent years, with an increased understanding of cancer immunobiology, systemic immunotherapies targeting immune checkpoint inhibition has been explored and clinically used in the area of UC. The programmed cell death 1 receptor (PD-1) and its ligand (PD-L1) are important negative regulators of immune activity, preventing the destruction of normal tissues and autoimmunity. To date, five immune checkpoint inhibitors blocking PD-1 (pembrolizumab, nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved by the United States Food and Drug Administration (US-FDA) for first- or second-line use in mUC, based on durable therapeutic response and manageable safety profiles observed in relevant clinical trials. In addition, the clinical use of several immune checkpoint inhibitors is currently being tested for MIBC and NMIBC. In this article, we review the current and ongoing clinical trials, regarding immune checkpoint inhibitors, being conducted in various clinical settings of UC, including mUC, MIBC, and NMIBC.

This paper is to elucidate the correlation between different symptoms of UTUC and the clinicopathological characteristics and prognosis. The clinicopathological data of 700 consecutive patients with UTUC who were treated with radical nephroureterectomy were reviewed, and symptoms were categorized into three groups: S1-no direct symptoms, S2-local symptoms (including hematuria and flank pain) and S3-systemic symptoms. We found that the distributions of patients in the S1, S2 and S3 groups were 96 (13.7%), 601 (85.9%) and 3 (0.4%), respectively, and most patients in S1 were incidentally found to have abnormal findings on ultrasound during regular health examination. Altogether, 534 patients (76.3%) presented with gross hematuria, and 111 (15.9%) presented with flank pain. Patients in S1 had a higher rate of hydronephrosis (p < 0.001), ureteral tumors (p < 0.001), worse pre-operative renal function (p = 0.020) and lower tumor stage (p = 0.038). The presence of hematuria was significantly related with renal pelvic tumors (p < 0.001), higher pre-operative eGFR (p = 0.047), papillary tumor architecture (p = 0.005) and less hydronephrosis (p < 0.001); and the presentation of flank pain was correlated with older age (p = 0.008), ureteral location (p < 0.001), hydronephrosis (p < 0.001), sessile architecture (p < 0.001) and higher tumor grade (p = 0.003). The presence of hematuria or flank pain also failed to reach significance as an independent prognostic factor. In conclusion, asymptomatic UTUC patients are featured for more hydronephrosis and lower tumor stage, while patients who presented with flank pain had a higher risk of sessile architecture and higher tumor grade. Regular health examinations might play a useful role in the early detection of UTUC patients with no symptoms.

INTRODUCTION: Minimally invasive nephroureterectomy (MINU) and open nephroureterectomy (ONU) have similar oncological outcomes for treatment of upper tract urothelial carcinoma (UTUC). We investigated perioperative outcomes and predictors of complications associated with MINU and ONU.
MATERIAL AND METHODS: Using the National Surgical Quality Improvement Program (NSQIP) database, 912 patients were identified that underwent radical nephroureterectomy for UTUC between 2005 and 2013. Logistic regression and contingency table methods used preoperative covariates to predict rates of major (Clavien-Dindo grade ≥ 3) and 16 common perioperative complications. Additional comparisons between treatment groups were performed using unpaired t-tests, Wilcoxon rank-sum tests, or Fisher's Exact tests. P values were adjusted to maintain an experiment-wise p < 0.05.
RESULTS: A total of 625 (69%) and 287 (31%) patients underwent MINU and ONU, respectively. ONU was associated with a higher rate of major complications (OR: 2.5, CI: 1.2-5.1, p < 0.03). The incidence of pulmonary embolism (bias adjusted OR: 24, CI: 1.3-441, p < 0.003), postoperative pneumonia (OR: 4.9, CI: 1.7-16, p < 0.0016), and transfusion (OR: 2.7, CI: 1.8-4.0, p < 0.0001) was higher for ONU compared to MINU. There were no significant differences in the incidence of other complications. MINU took longer on average (median 223 versus 213 mins, p < 0.02). Time to discharge was longer for ONU (median 5 versus 4 days, p < 0.0001). No other covariates were independent predictors of major complications regardless of surgical approach.
CONCLUSIONS: Occurrence of major complications were higher for ONU compared to MINU. These data suggest that MINU is an acceptable surgical option with lower morbidity compared to ONU for the management of UTUC.

OBJECTIVES: To elucidate the effects of the preoperative albumin : globulin ratio on the survival of patients with upper tract urothelial carcinoma after radical nephroureterectomy.
METHODS: We retrospectively reviewed 124 consecutive patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy at Chiba Cancer Center, Chiba, Japan between 2002 and 2015. The albumin : globulin ratio was defined: albumin / (total protein - albumin). Associations between preoperative clinicopathological factors, including the albumin : globulin ratio, and recurrence-free survival, cancer-specific survival and overall survival were assessed. The log-rank test and Cox proportional hazards models were used for univariate and multivariable analyses, respectively. The study cohort was separated into two groups based on the optimal albumin : globulin ratio cut-off value determined using receiver operating characteristic curve analysis.
RESULTS: The median survival time was 55 months (interquartile range 28-76 months), and 31 patients died during follow up. A low preoperative albumin : globulin ratio <1.40 was associated with tumor grade and surgical margin status. Kaplan-Meier analyses showed that a low albumin : globulin ratio was more significantly correlated with worse recurrence-free survival, cancer-specific survival and overall survival. Multivariate analyses showed that a low albumin : globulin ratio was an independent predictive factor associated with poor recurrence-free survival (hazard ratio 3.758; P = 0.0028), cancer-specific survival (hazard ratio 5.687; P = 0.0044) and overall survival (hazard ratio 3.124; P = 0.0030).
CONCLUSIONS: A low albumin : globulin ratio is an independent predictive factor associated with poor prognosis in upper tract urothelial carcinoma patients treated with radical nephroureterectomy.

A 68-year-old man classified as III on the American Society of Anaesthesiologists (ASA) physical status classification system, with a high-grade papillary urothelial cell carcinoma of the left distal ureter, underwent open retroperitoneal distal ureterectomy followed by a ureteroneocystostomy with a vesico-psoas hitch. Postoperatively, the patient complained of left proximal lower limb weakness, severe pain and hypaesthesia of the ventral left thigh suggestive of femoral neuropathy. After excluding common causes for postsurgical pain, a surgical re-exploration was eventually performed during which the sutures used in the vesicopexy were removed, resulting in almost complete resolution of the symptoms. Electromyographic analysis 4 weeks after discharge confirmed the diagnosis of femoral neuropathy, most likely caused by the sutures used in the vesicopexy. This is a rare complication with major consequences for postoperative recovery.

PURPOSE: Urothelial carcinoma of the upper urinary tract (UUTUC) is a rare genitourinary tumor. Pre-operative lymphocyte-to-monocyte ratio (LMR) is associated with worse outcome in several malignancies. The aim of this study was to determine the prognostic value of pre-operative LMR in UUTUC.
MATERIALS AND METHODS: A historical cohort of 100 UUTUC patients was recruited from January 1990 to June 2011. The counts of peripheral lymphocyte and monocyte were retrieved, and the LMR was calculated by dividing lymphocyte count by monocyte count. Receiver operating characteristic curve (ROC) analysis, Log-rank test and Cox proportional hazards regression models were used for univariate and multivariate analyses to evaluate theassociations of LMR with overall survival (OS) and disease-free survival (DFS).
RESULT: Univariate analysis revealed that low level of LMR (? 3.0) was significantly associated with worse OS (P = .024) but not DFS (P = .993). Multivariate Cox proportional hazard analysis showed that low level of LMR was a significantly independent predictor for worse OS (hazard ratio = 0.366, 95% confident interval: 0.180-0.744). Based on the results of multivariate analysis, the rates of OS at 5 years developed by the prognostic model were asfollows: low risk, 88.0%, intermediate risk, 44.0%, and high risk, 13.0%, respectively.
CONCLUSION: The pre-operative LMR serves an independent prognostic biomarker in UUTUC. The prognostic model based on the LMR and pathologic factors can be available in selection of high risk patients for further aggressive therapy.

OBJECTIVES: To determine the diagnostic accuracy of urinary cytology to diagnose bladder cancer and upper tract urothelial cancer (UTUC) as well as the outcome of patients with a positive urine cytology and normal haematuria investigations in patients in a multicentre prospective observational study of patients investigated for haematuria.
PATIENT AND METHODS: The DETECT I study (clinicaltrials.gov NCT02676180) recruited patients presenting with haematuria following referral to secondary case at 40 hospitals. All patients had a cystoscopy and upper tract imaging (renal bladder ultrasound [RBUS] and/ or CT urogram [CTU]). Patients, where urine cytology were performed, were sub-analysed. The reference standard for the diagnosis of bladder cancer and UTUC was histological confirmation of cancer. A positive urine cytology was defined as a urine cytology suspicious for neoplastic cells or atypical cells.
RESULTS: Of the 3 556 patients recruited, urine cytology was performed in 567 (15.9%) patients from nine hospitals. Median time between positive urine cytology and endoscopic tumour resection was 27 (IQR: 21.3-33.8) days. Bladder cancer was diagnosed in 39 (6.9%) patients and UTUC in 8 (1.4%) patients. The accuracy of urinary cytology for the diagnosis of bladder cancer and UTUC was: sensitivity 43.5%, specificity 95.7%, positive predictive value (PPV) 47.6% and negative predictive value (NPV) 94.9%. A total of 21 bladder cancers and 5 UTUC were missed. Bladder cancers missed according to grade and stage were as follows: 4 (19%) were ≥ pT2, 2 (9.5%) were G3 pT1, 10 (47.6%) were G3/2 pTa and 5 (23.8%) were G1 pTa. High-risk cancer was confirmed in 8 (38%) patients. There was a marginal improvement in sensitivity (57.7%) for high-risk cancers. When urine cytology was combined with imaging, the diagnostic performance improved with CTU (sensitivity 90.2%, specificity 94.9%) superior to RBUS (sensitivity 66.7%, specificity 96.7%). False positive cytology results were confirmed in 22 patients, of which 12 (54.5%) had further invasive tests and 5 (22.7%) had a repeat cytology. No cancer was identified in these patients during follow-up.
CONCLUSIONS: Urine cytology will miss a significant number of muscle-invasive bladder cancer and high-risk disease. Our results suggest that urine cytology should not be routinely performed as part of haematuria investigations. The role of urine cytology in select cases should be considered in the context of the impact of a false positive result leading to further potentially invasive tests conducted under general anaesthesia.

PURPOSE: To identify the impact of albumin-globulin ratio (AGR) on pathologic and survival outcomes in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU).
PATIENTS AND METHODS: We retrospectively reviewed medical records of 620 patients treated with RNU for UTUC at our institution. Logistic regression analysis was used to evaluate the relation between low AGR (<1.45) and adverse pathologic features. Kaplan-Meier curves were used to estimate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) probabilities between 2 groups. Univariable and multivariable Cox regression models were performed to address prognostic factors related to RFS, CSS, and OS.
RESULTS: Of the 620 patients, 323 (52.1%) had AGR < 1.45. During a median follow-up of 50.0 months (interquartile range, 28-78 months), 277 (44.7%) experienced disease recurrence and 194 (31.3%) died of disease. The results showed that low AGR was significantly associated with adverse pathologic features (all P < .05). Kaplan-Meier analysis showed that compared to those with high AGR (≥1.45), patients with low AGR had poorer RFS, CSS, and OS (P < .001). After adjusting for the confounding clinicopathologic factors, multivariate analyses showed that AGR < 1.45 independently predicted poor RFS (hazard ratio [HR] = 1.321, P = .029), CSS (HR = 1.503, P = .010) and OS (HR = 1.403, P = .015).
CONCLUSION: Low preoperative AGR is an independent predictor of worse pathologic and oncologic outcomes in patients with UTUC after RNU. The application of AGR as an easily assessed blood-based biomarker in predicting the prognosis of patients with UTUC is promising.

OBJECTIVE: To evaluate the effectiveness of ureteroscopy (URS) with laser ablation as an alternative treatment for upper tract urothelial carcinoma (UTUC) lesions larger than 2 cm. Traditionally, patients with large UTUC are treated with radical nephroureterectomy (RNU). However, in patients with pre-existing renal disease, a solitary kidney, or those who decline RNU, management of UTUC may prove challenging METHODS: An institutional database review identified 80 patients with biopsy proven low-grade UTUC who had at least one lesion larger than 2 cm. We collected clinical data including demographics, operative parameters, and pathologic features. Follow-up for all patients was standardized and included cystoscopy and URS every 3 months until clear, every 6 months through the fifth year, and yearly thereafter. We calculated rates of recurrence, progression, and overall survival.
RESULTS: In total, 86 unique lesions ≥2cm were identified in the 80 qualifying patients; mean tumor size was 3.04 cm. Median follow-up was 43.6 months. During follow-up of patients treated curatively, 90.5% of tumors had ipsilateral recurrence and 31.7% progressed in grade at a median of 26.3 months. RNU was performed in 16 patients (20%); mean time to surgery was 23.2 months. Overall survival was 75%, and cancer specific survival was 84% at 5-year follow-up.
CONCLUSION: Under strict surveillance, ureteroscopic management of large (≥ 2cm) UTUC lesions is a viable treatment alternative to RNU. While recurrence is common, URS can potentially preserve renal units in patients with large lesions.

BACKGROUND: We performed a comparative survival analysis of patients undergoing robotic-assisted versus laparoscopic or open surgery for upper tract urothelial carcinoma (UTUC).
MATERIALS AND METHODS: Patients diagnosed with non-metastatic UTUC undergoing removal of the kidney and/or ureter were identified using Medicare-linked Surveillance, Epidemiology, and End Results Program data (2004-2013). Patients aged 65-85 years were categorized based on surgical approach (open, laparoscopic, or robotic-assisted). Kaplan-Meier methods were used to determine survival (overall and cancer-specific) and intravesical recurrence rates, the former using a propensity score-weighted model. Independent predictors of survival were determined using multivariable Cox proportional hazards regression analysis.
RESULTS: We identified a total of 3801 patients meeting the final inclusion criteria: open (n = 1862), laparoscopic (n = 1624), and robotic (n = 315). Robotic surgery was associated with the shortest length of hospital stay (p < 0.001) but highest in-hospital charges (p < 0.001), with no difference in readmission rates (p = 0.964). No difference was found in overall or cancer-specific survival in the robotic cohort when compared with open or laparoscopic surgery. In addition, no difference in the rate of intravesical recurrence was noted in robotic-assisted laparoscopy compared with the other groups. The sole predictor of improved survival was extent of lymphadenectomy, which was highest in the robotic cohort.
CONCLUSIONS: Using a large, population-based cancer database, there was no survival difference when a robotic-assisted approach was utilized in patients undergoing surgery for UTUC. These findings are important with the increased use of robotic surgery in the management of UTUC.

BACKGROUND: We evaluated the prognostic impact of the preoperative neutrophil-to-lymphocyte ratio (NLR) in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy treatment.
METHODS: A total of 717 patients were identified between 2003 and 2016. The cutoff value of NLR was set as 2.5. Kaplan-Meier method and Cox's proportional hazards regression models were utilized to analyze the association between NLR and oncological outcomes.
RESULTS: The median follow-up was 42 months. The results suggested that preoperative elevated NLR was associated with worse pathological features. Also, patients with NLR ≥ 2.5 had worse survival outcomes than those with NLR <2.5 (all P < .001). Multivariate cox analysis revealed that NLR ≥ 2.5 was an independent predictor of worse cancer-specific survival, disease recurrence-free survival, metastasis-free survival and overall survival (HR 1.95, 95%CI: 1.42-2.69, P < .001; HR 1.70, 95%CI: 1.31-2.20, P < .001; HR 1.67, 95%CI: 1.22-2.31, P = .002; and HR 1.88, 95%CI: 1.42-2.50, P < .001; respectively). Notably, NLR was ascertained to be a useful prognostic predictor in patients with high-grade disease, but not in those with low-grade UTUC.
CONCLUSIONS: Preoperative elevated NLR was associated with worse outcomes in patients with UTUC. Subgroup analysis affirmed that NLR was a useful predictor in patients with high-grade disease, but not in those with low-grade UTUC.

PURPOSE: Topical therapy (TT) for upper tract urothelial carcinoma (UTUC) has been explored as a kidney sparing approach to treat carcinoma in situ (CIS) and as adjuvant for endoscopically treated Ta/T1 tumors. In bladder cancer, data support use of salvage TT for repeat induction. We investigate the outcomes of salvage TT for UTUC in patients ineligible for or refusing nephroureterectomy.
METHODS: A single-center retrospective review on patients receiving salvage TT via percutaneous nephrostomy tube or cystoscopically placed ureteral catheters was performed. Primary outcome was response to therapy based on International Bladder Cancer Group criteria.
RESULTS: 51 patients with 58 renal units (RUs) received TT. Of these, 17 patients with 18 RUs received the second-line TT, with a median follow-up of 36.5 months (IQR 24.5-67 months). 44% (8/18) received salvage TT for refractory disease and 56% (10/18) as reinduction. 5 RUs with CIS were unresponsive to initial TT and went on to receive salvage TT, of which 20% (1/5) responded. 13 RUs recurred or relapsed following initial TT and received salvage TT for papillary tumors, with 62% (8/13) responding.
CONCLUSION: Our data provide preliminary clinical rationale for the second-line TT for refractory and recurrent, endoscopically managed papillary UTUC in patients ineligible for or refusing nephroureterectomy. However, refractory upper tract CIS appears to have poor response to salvage TT.

The present paper described a rare case of ureteral IgG4-related disease (IgG4-RD) that mimicked urothelial carcinoma. An otherwise healthy patient presented with computed tomography, ureteroscopic, and biopsy findings that were suspicious of urothelial carcinoma. The patient received a right nephroureterectomy. Histopathology showed ureteral IgG4-RD, without evidence of urothelial carcinoma. Accurate diagnosis of this rare entity should be based on clinical, biochemical, and histopathological findings.

PURPOSE: There is a lack of reporting of the bladder cuff pathology in the literature and ongoing debate regarding the role of bladder cuff excision (BCE) in the prognosis in patients with upper tract urothelial carcinoma (UTUC). We aimed to know the risk factors, the survival, and the clinical course of such pathology.
MATERIALS AND METHODS: The study was retrospective, from 1983-2013 on 305 patients who had diagnosed with UTUC. Patients were managed by radical open/ laparoscopic nephroureterectomy with bladder cuff excision. The tumor was staged using 1997 TNM classification and the 3-tiered WHO grading system was used for grading. Patients who found to have a malignant bladder cuff on the final pathology were further analyzed for the risk factors for such disease and its effect on survivaltheir outcomes.
RESULTS: 13/ 281 (4.6%) cases were found to have malignant bladder cuff. Regarding tumor stage; one case was diagnosed with Tis, eight had T1 and four cases had T2 malignant bladder cuff. All cases were with pure ureteric or multifocalcentric tumors, and none had pure pelvicalyceal tumors (p = .001).Local recurrence at the surgical site and distant metastasis were significantly higher among patients with malignant bladder cuff (p = .001 and .002 respectively), and the last sustained its significance in multivariate analysis. Those patients had a poor prognosis when compared to non-malignant bladder cuff cases (Log Rank test, p = .001)Conclusion: Ureteric tumor is the only independent risk factor for malignant bladder cuff at the final pathology and is associated with increased risks for invasive bladder tumor, distant metastasis and poor survival in comparison with non-malignant bladder cuff. In a clinical implementation, BCE is considered as a mandatory step in management of ureteric tumors, while it could be omitted in pure and low grade renal pelvis tumors.

Neoadjuvant chemotherapy improves survival in patients with muscle-invasive bladder cancer. However, a significant proportion of patients are ineligible for cisplatin owing to renal impairment or other medical comorbidities. The introduction of anti-programmed cell death protein 1/programmed death-ligand 1(PD1/PD-L1) checkpoint inhibitors has redefined the therapeutic landscape for platinum-resistant urothelial cancers; their clinical efficacy and favorable toxicity render these agents attractive therapeutic options either as monotherapy or in combination with other agents in earlier disease states, including muscle-invasive disease. We review potential perioperative immunotherapy strategies, ongoing clinical trials and areas of unmet needs, including upper tract disease and non-urothelial cancers.

A select group of patients with upper tract urothelial carcinoma (UTUC) may meet indications for endoscopic management. Strategies for disease management are provided, based on a comprehensive review of the data using PubMed and Medline databases and marrying this with our experience with endoscopic management of UTUC. Endoscopic management of UTUC via retrograde or antegrade approaches is a viable treatment option for appropriately selected patients with low-risk UTUC, including those with low-grade, low-volume, and solitary tumors. However, recurrence risk limits these procedures to compliant patients under a vigilant surveillance program. Efficacious adjuvant therapies are needed to reduce local recurrences.

This article summarizes the role of adjuvant chemotherapy in muscle-invasive and transitional cell carcinoma of the bladder and upper urinary tract.