Diagnostic evaluation of upper tract urothelial carcinoma: can we safely omit diagnostic ureteroscopy?

OBJECTIVE: To identify clinicopathological or radiological factors that may predict a diagnosis of upper urinary tract urothelial cell carcinoma (UTUC) to inform which patients can proceed directly to radical nephroureterectomy (RNU) without the delay for diagnostic ureteroscopy (URS). PATIENTS AND METHODS: All consecutive patients investigated for suspected UTUC in a high-volume UK centre between 2011 and 2017 were identified through retrospective analysis of surgical logbooks and a prospectively maintained pathology database. Details on clinical presentation, radiological findings, and URS/RNU histopathology results were evaluated. Multivariate regression analysis was performed to evaluate predictors of a final diagnosis of UTUC. RESULTS: In all, 260 patients were investigated, of whom 230 (89.2%) underwent URS. RNU was performed in 131 patients (50.4%), of whom 25 (9.6%) proceeded directly without URS - all of whom had a final histopathological diagnosis of UTUC - and 15 (11.5%) underwent RNU after URS despite no conclusive histopathological confirmation of UTUC. Major surgery was avoided in 77 patients (33.5%) where a benign or alternative diagnosis was made on URS, and 14 patients (6.1%) underwent nephron-sparing surgery. Overall, 178 patients (68.5%) had a final diagnosis of UTUC confirmed on URS/RNU histopathology. On multivariate logistic regression analysis, a presenting complaint of visible haematuria (hazard ratio [HR] 5.17, confidence interval [CI] 1.91-14.0; P = 0.001), a solid lesion reported on imaging (HR 37.8, CI = 11.7-122.1; P < 0.001) and a history of smoking (HR 3.07, CI 1.35-6.97; P = 0.007), were predictive of a final diagnosis of UTUC. From this cohort, 51 (96.2%) of 53 smokers who presented with visible haematuria and who had a solid lesion on computed tomography urogram had UTUC on final histopathology. CONCLUSION: We identified specific factors which may assist clinicians in selecting which patients may reliably proceed to RNU without the delay of diagnostic URS. These findings may inform a prospective multicentre analysis including additional variables such as urinary cytology.

Assessment of association between lower ureteric excision technique and oncological outcomes for upper urinary tract urothelial carcinoma: retrospective analysis from the Scottish Renal Cancer Consortium.

PURPOSE: Nephroureterectomy(NU) remains the gold-standard surgical option for the management of upper urinary tract urothelial carcinoma(UTUC). Controversy exists regarding the optimal excision technique of the lower ureter. We sought to compare post-UTUC bladder tumour recurrence across the Scottish Renal Cancer Consortium(SRCC). METHODS: Patients who underwent NU for UTUC across the SRCC 2012-2019 were identified. The impact of lower-end surgical technique along with T-stage, N-stage, tumour location and focality, positive surgical margin, pre-NU ureteroscopy, upper-end technique and adjuvant mitomycin C administration were assessed by Kaplan-Meier and Cox-regression. The primary outcome was intra-vesical recurrence-free survival (B-RFS). RESULTS: In 402 patients, the median follow-up was 29 months. The lower ureter was managed by open transvesical excision in 90 individuals, transurethral and laparoscopic dissection in 76, laparoscopic or open extra-vesical excision in 31 and 42 respectively, and transurethral dissection and pluck in 163. 114(28.4%) patients had a bladder recurrence during follow-up. There was no difference in B-RFS between lower-end techniques by Kaplan-Meier (p = 0.94). When all factors were taken into account by adjusted Cox-regression, preceding ureteroscopy (HR 2.65, p = 0.001), lower ureteric tumour location (HR 2.16, p = 0.02), previous bladder cancer (HR 1.75, p = 0.01) and male gender (HR 1.61, p = 0.03) were associated with B-RFS. CONCLUSION: These data suggest in appropriately selected patients, lower ureteric management technique does not affect B-RFS. Along with lower ureteric tumour location, male gender and previous bladder cancer, preceding ureteroscopy was associated with a higher recurrence rate following NU, and the indication for this should be carefully considered.

Matched-pair analysis of open versus laparoscopic nephroureterectomy for upper urinary tract urothelial cell carcinoma.

OBJECTIVE: Laparoscopic nephroureterectomy (LNU) offers a superior morbidity profile compared with open nephroureterectomy (ONU) in treating upper urinary tract urothelial cell carcinoma. Evidence of oncological equivalence between LNU and ONU is limited. We compare operative and oncological outcomes for LNU and ONU using matched-pair analysis. METHODS: Of 159 patients who underwent a nephroureterectomy at a single institution between April 1992 and April 2010, 13 pairs of ONU and LNU patients were matched for gender, age, tumour location, tumour grade and stage. Operative details, post-operative characteristics and recurrences were collated and survival rates analysed using the Kaplan-Meier method. RESULTS: There was no significant difference in mean operation time between LNU (191 min) and ONU (194 min, p=0.92). There was no significant difference in the 5-year survival rate between LNU and ONU (overall survival 59.1% vs. 73.5%, p=0.18; progression-free survival 24.0% vs. 56.0%, p=0.14; cancer-specific survival 60.9% vs. 73.5%, p=0.56; bladder cancer recurrence-free survival 8.7% vs. 0.0%, p=0.09). CONCLUSION: Amidst limited RCT and comparative studies, this study presents further evidence of oncological equivalence between LNU and ONU. There was a trend towards poorer outcomes following LNU though, which merits further study.

Endoscopic versus laparoscopic management of noninvasive upper tract urothelial carcinoma: 20-year single center experience.

PURPOSE: We compare the outcomes of endoscopic surgery to laparoscopic nephroureterectomy for the management of specifically noninvasive upper tract urothelial carcinoma. MATERIALS AND METHODS: A retrospective database review identified consecutive patients with clinically noninvasive upper tract urothelial carcinoma who underwent endoscopic surgery (59, via ureteroscopic ablation or percutaneous resection) or laparoscopic nephroureterectomy (70) at a single center during 20 years (1991 to 2011). Overall survival, upper tract urothelial carcinoma specific survival, upper tract recurrence-free survival, intravesical recurrence-free survival, progression-free survival and renal unit survival were estimated using Kaplan-Meier methods, with differences assessed using the log rank test. RESULTS: Median age and followup were 74.8 years and 50 months, respectively. Overall renal preservation in the endoscopic group was high (5-year renal unit survival 82.5%), although this came at a cost of high local recurrence (endoscopic surgery 5-year recurrence-free survival 49.3%, laparoscopic nephroureterectomy 100%, p <0.0001). For G1 upper tract urothelial carcinoma, endoscopic surgery 5-year disease specific survival (100%) was equivalent to that of laparoscopic nephroureterectomy (100%). However, laparoscopic nephroureterectomy demonstrated superior disease specific survival to endoscopic surgery for G2 disease (91.7% vs 62.5%, p = 0.037) and superior progression-free survival for G3 disease (88.9% vs 55.6%, p = 0.033). CONCLUSIONS: For G1 upper tract urothelial carcinoma, endoscopic management can provide effective oncologic control and renal preservation. However, endoscopic management should not be considered for higher grade disease except in compelling imperative cases or in patients with poor life expectancy as oncologic outcomes are inferior to those of laparoscopic nephroureterectomy.

Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review.

UNLABELLED: What's known on the subject? and What does the study add? Endoscopic management of upper tract urothelial carcinoma (UTUC) using either ureteroscopy and laser ablation, or percutaneous resection, is a management option for treating selected low-grade tumours with favourable characteristics. However, the evidence base for such practice is relatively weak, as the reported experience is mainly limited to small case series (level of evidence 4), or non-randomised comparative studies that are unmatched for tumour stage (level of evidence 3b), with variability of follow-up duration and reported outcome measures. The present systematic review comprehensively reviews the outcomes of all studies of endoscopic management of UTUC, including the role of topical adjuvant therapy. It establishes for the first time a structured reference for endoscopic management of UTUC, and is a foundation for further clinical studies. OBJECTIVE: To systematically review the oncological outcomes of upper tract urothelial carcinoma (UTUC) treated with ureteroscopic and percutaneous management. The standard treatment of UTUC is radical nephroureterectomy (RNU). However, over the last two decades several institutions have treated UTUC endoscopically, either via ureteroscopic ablation or percutaneous nephroscopic resection of tumour (PNRT), for both imperative and elective indications. METHODS: For evidence acquisition the Pubmed database was searched for English language publications in December 2011 using the following terms: upper tract (UT) transitional cell carcinoma (TCC), upper tract TCC, UTTCC, upper tract urothelial cell carcinoma, upper tract urothelial carcinoma, UTUC, endoscopic management, ureteroscopic management, laser ablation, percutaneous management, PNRT, conservative management, ureteroscopic biopsy, biopsy, BCG, mitomycin C, topical therapy. RESULTS: There are no randomised trials comparing endoscopic management with RNU. Most published studies were retrospective case series (and database reviews), or unmatched comparative studies. There was strong selection bias for favourable tumour characteristics in many endoscopically treated groups. There was variation in medical comorbidity and indication for treatment across different study groups. The biopsy verification of underlying UTUC pathology was inconsistent. The follow-up in most studies was limited, typically to a mean 3 years. CONCLUSIONS: There is a high rate of UT recurrence with endoscopically managed UTUC, and a grade-related risk of tumour progression and disease-specific mortality. Overall, renal preservation may be high with ≈20% of patients proceeding eventually to RNU. For highly selected Grade 1 (or low-grade) disease managed in experienced centres, 5-year disease-specific survival (DSS) may be equivalent to RNU, although the small study groups and short follow-ups preclude comments on less favourable Grade 1 (or low-grade) tumour characteristics, or DSS, in the longer-term. For Grade 3 (or high-grade) disease, DSS outcomes are poor and endoscopic management should only be considered for compelling imperative indications in the context of the patient's overall life expectancy and competing comorbidity.

Long-term endoscopic management of upper tract urothelial carcinoma: 20-year single-centre experience.

UNLABELLED: Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Endoscopic management of small, low-grade, non-invasive upper tract urothelial cell carcinoma (UTUC) is a management option for selected groups of patients. However, the long-term survival outcomes of endoscopically-managed UTUC are uncertain because only four institutions have reported outcomes of more than 40 patients beyond 50 months of follow-up. Moreover, there is significant variance in the degree of underlying UTUC pathology verification in some of these reports, which precludes an analysis of disease-specific survival outcomes. The present study represents one of the largest endoscopically managed series of patients with UTUC, with a long-term follow-up. The degree of verification of underlying UTUC pathology is one of the highest, which allows a grade-stratified analysis of different outcomes, including upper-tract recurrence-free survival, intravesical recurrence-free survival, renal unit survival and disease-specific survival. These outcomes provide further evidence suggesting that endoscopic management of highly selected, low-grade UTUC can provide effective oncological control, as well as renal preservation, in experienced centres. OBJECTIVE: • To report the long-term outcomes of patients with upper tract urothelial cell carcinoma (UTUC) who were treated endoscopically (either via ureteroscopic ablation or percutaneous resection) at a single institution over a 20-year period. PATIENTS AND METHODS: • Departmental operation records were reviewed to identify patients who underwent endoscopic management of UTUC as their primary treatment. • Outcomes were obtained via retrospective analysis of notes, electronic records and registry data. • Survival outcomes, including overall survival (OS), UTUC-specific survival (disease-specific survival; DSS), upper-tract recurrence-free survival, intravesical recurrence-free survival, renal unit survival and progression-free survival, were estimated using Kaplan-Meier methods and grade-stratified differences were analyzed using the log-rank test. RESULTS: • Between January 1991 and April 2011, 73 patients underwent endoscopic management of UTUC with a median age at diagnosis of 67.7 years. • All patients underwent ureteroscopy and biopsy-confirmation of pathology was obtained in 81% (n = 59) of the patients. In total, 14% (n = 10) of the patients underwent percutaneous resection. • Median (range; mean) follow-up was 54 (1-223; 62.8) months. • Upper tract recurrence occurred in 68% (n = 50). Eventually, 19% (n = 14) of the patients proceeded to nephroureterectomy. • The estimated OS and DSS were 69.7% and 88.9%, respectively, at 5 years, and 40.3% and 77.4%, respectively, at 10 years. The estimated mean and median OS times were 119 months and 107 months, respectively. The estimated mean DSS time was 190 months. CONCLUSIONS: • The present study represents one of the largest reported series of endoscopically-managed UTUC, with high pathological verification and long-term follow-up. • Upper-tract recurrence is common, which mandates regular ureteroscopic surveillance. • However, in selected patients, this approach has a favourable DSS, with a relatively low nephroureterectomy rate, and therefore provides oncological control and renal preservation in patients more likely to die eventually from other causes.

Update on the management of T1 renal cortical tumours.

There are a range of treatment strategies for the management of patients with small incidental renal cortical tumours including active surveillance, radiofrequency ablation, cryotherapy, radical nephrectomy and partial nephrectomy. A large number of such tumours are benign and might therefore be over-treated with radical nephrectomy. There are emergent short-term oncological and clinical outcomes for cryotherapy and radiofrequency ablation, and recent studies have illustrated the benefits of partial nephrectomy for minimizing the risk of progression to chronic kidney disease. The outcomes of these different treatment methods are discussed.

Shockwave Lithotripsy Is an Efficacious Treatment Modality for Obese Patients with Upper Ureteral Calculi: Logistic Regression and Matched-Pair Analyses from a Dedicated Center Comparing Treatment Outcomes by Skin-to-Stone Distance.

Objectives: To assess the association of skin-to-stone distance (SSD) and stone-free rates following extracorporeal shockwave lithotripsy (SWL) using two statistical methods: logistic regression and a matched-pair analysis approach. Patients and Methods: Patients with a solitary radio-opaque upper ureteral calculus diagnosed on noncontrast computed tomography were included. Patients were treated with a Sonolith I-Sys Lithotripter (focal depth 17 cm). Stone treatment success was defined as stone free (fragments ≤3 mm) at 3 months. Failure was defined as persistent fragments beyond 3 months or requirement for intervention with ureteroscopy. The outcome was assessed by a plain kidney, ureter, and bladder radiograph (KUB) at 2 weeks. Logistic regression was used to determine association of patient and stone factors with treatment failure. The patient cohort was divided into tertiles by SSD, and matched-pair analysis was undertaken between individuals from the top and bottom tertiles (SSD ≤12 cm and SSD ≥14 cm). Matching criteria consisted of age, sex, maximum stone diameter (±2 mm), and stone density (±250 HU). Results: From a database of 2849 patients who underwent SWL, 397 patients were identified who had treatment of a single upper ureteral stone. Age (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.01-1.04, p = 0.007), SSD (OR: 1.16, 95% CI: 1.03-1.32, p = 0.02), stone side (OR: 1.65, 95% CI 1.01-2.73, p = 0.05), stone diameter (OR: 1.09, 95% CI: 1.00-1.19, p = 0.05), and multiple sessions (OR: 4.65, 95% CI: 2.61-8.29, p < 0.001) were significantly associated with treatment failure by logistic regression univariable analysis. Multiple sessions was the only factor significantly associated with treatment failure on multivariable analysis (OR: 4.03, 95% CI: 2.18-7.42, p < 0.001). From a cohort of 141 patients with SSD ≥14 cm and 174 patients with a SSD ≤12 cm, 66 matches were identified (132 patients). Forty-nine patients (74.2%) with SSD ≥14 cm were deemed stone free at follow-up vs 51 patients (77.3%) with SSD ≤12 cm (p = 0.85). Conclusion: This study demonstrates by two statistical methods that SWL can provide efficacious treatment of upper ureteral stones in obese patients and that the upper threshold of SSD for SWL with Sonolith I-SYS could be revised to allow these patients the benefits of SWL.

Primary SWL Is an Efficient and Cost-Effective Treatment for Lower Pole Renal Stones Between 10 and 20 mm in Size: A Large Single Center Study.

INTRODUCTION: To assess the clinical features, outcomes, complications, and cost-effectiveness of shockwave lithotripsy (SWL), flexible ureterorenoscopy (FURS), and percutaneous nephrolithotomy (PCNL) in the treatment of lower pole (LP) stones (10-20 mm) in a large tertiary referral center. PATIENTS AND METHODS: Consecutive patients treated for solitary LP stones (10-20 mm) between 2008 and 2013 were identified from a prospective database. SWL was used as primary treatment in all cases (following a stone multidisciplinary team assessment), with FURS and PCNL reserved for SWL contraindications, failure, or patient choice. "Success" was defined as stone free and/or clinically insignificant stone fragments (≤3 mm) at 1 and 3 months follow-up. Effect of anatomy on SWL success was determined from using CT images and regression analysis. Average cost per treatment modality (including additional second-line treatments) was calculated for each group using the National Health Service England 2014/15 National Tariff Healthcare Resource Group codes. RESULTS: Two hundred twenty-five patients were included (mean age 54.9; median stone size 12 mm). One hundred ninety-eight (88%), 21 (9.3%), and 6 (2.7%) patients underwent SWL, FURS, and PCNL as primary treatments, respectively, for median stone sizes of 12, 12, and 20 mm. Overall success rates were 82.8%, 76.1%, and 66.7%, respectively (p < 0.05). Sixty-three percent of patients undergoing primary SWL were effectively treated after one session. Anatomical analysis determined infundibulopelvic angle and infundibular length to be significantly different in patients effectively treated with SWL (p = 0.04). The average cost per treatment modality was also significantly lower for SWL (£750) than for FURS (£1261) or PCNL (£2658) (p < 0.01). CONCLUSION: SWL is both an efficacious and cost-effective primary treatment for patients with solitary LP stones (10-20 mm). The majority of patients can be effectively treated with primary SWL in a dedicated stone center, with the benefits of a short length of stay, low complication, and auxiliary treatment rates. The referral of such patients to high-volume lithotripsy centers with demonstrable outcomes should be given due consideration.

A generation of laparoscopic nephrectomy: stage-specific surgical and oncologic outcomes for laparoscopic nephrectomy in a single center.

PURPOSE: To determine the stage-specific operative, postoperative and oncologic outcomes, for patients undergoing a laparoscopic radical nephrectomy (LRN) for renal cell carcinoma (RCC) in a single center and assess changes over a generation of practice. PATIENTS AND METHODS: From December 1992 to July 2011, data were collected prospectively for 854 consecutive simple laparoscopic necphrectomies (LNs) and LRNs, 397 of which were LRNs for RCC. The first LRN was performed in December 1997. Stage-specific surgical and oncologic outcomes were assessed across the study period. Patients were then grouped into three equal consecutive cohorts. Case mix and surgical outcomes were compared to assess changes with departmental experience. RESULTS: There were 206, 71, 118, and 2 patients across stages pT1, pT2, pT3, and pT4, respectively. Median operative time was significantly shorter for pT1 tumors (125, 150 and 150 min for pT1-3, P<0.021), while median estimated blood loss (EBL) was greater for pT3 tumors (50, 50, 100 mL, for pT1-3, P<0.001). Median follow-up time was 31, 30, and 18 months, respectively, across pT1-pT3. There was a significant difference in 5-year overall survival (82.4%, 68.4%, 58.9%), cancer-specific survival (99.5%, 83.6%, 66.5%) and progression free survival (86.5%, 66.3%, 47.5%) across these stage-specific subgroups. Over the three cohorts, there was an increase in LRN performed for locally advanced disease and cytoreduction. With greater surgical experience, there was improvement in median operative time and median EBL in localized disease over the three periods, but no significant changes for locally advanced disease. CONCLUSION: This is the largest reported series of LRN in the United Kingdom. Departmental experience has resulted in improved surgical outcomes for localized RCC, with expansion of practice in more complex advanced disease. Laparoscopic nephrectomy is both operatively and oncologically safe in T1 and T2 disease, and although technically more demanding, it is also safe in selected T3 disease.

Long-term comparative outcomes of open versus laparoscopic nephroureterectomy for upper urinary tract urothelial-cell carcinoma after a median follow-up of 13 years*.

BACKGROUND AND PURPOSE: Open nephroureterectomy (ONU) rather than laparoscopic nephroureterectomy (LNU) is still regarded as the standard of care for extirpative surgical management of upper urinary tract urothelial-cell carcinoma (UUT-UCC). The longest published follow-up of LNU is 7 years. We report outcomes for patients having surgery ≥10 years ago. PATIENTS AND METHODS: Consecutive patients with UUT-UCC who were treated with ONU (n=39) or LNU (n=23) between April 1992 to September 2000 were included. Preoperative, tumor, operative and postoperative characteristics, recurrence, and outcomes were collated. Survival was estimated using the Kaplan-Meier method. RESULTS: Median follow-up of censored patients was 163 months (13.6 y). Estimated mean overall survival (OS) was 111 months for ONU and 103 months for LNU. Mean progression free survival (PFS) was 175 months for ONU and 143 months for LNU. Probability of PFS at 10 years was 79% for ONU and 76% for LNU and was unchanged at 15 years. There was no significant difference between ONU and LNU in terms of OS (P=0.51, log-rank test), PFS (P=0.70) or cancer-specific survival (CSS; P=0.43). There were no prognostic differences between ONU and LNU after correcting for confounding variables. There was no increase in the probability of a bladder cancer recurrence from 10 to 15 years postoperation. CONCLUSION: Long-term follow-up of patients who were operated on more than 10 years ago suggests that LNU has oncologic equivalence to ONU because there were no significant differences in OS, PFS, or CSS between ONU and LNU patients followed for a median of 13 years.

Structural basis for the nuclear import of the human androgen receptor.

Ligand-dependent nuclear import is crucial for the function of the androgen receptor (AR) in both health and disease. The unliganded AR is retained in the cytoplasm but, on binding 5alpha-dihydrotestosterone, it translocates into the nucleus and alters transcription of its target genes. Nuclear import of AR is mediated by the nuclear import factor importin-alpha, which functions as a receptor that recognises and binds to specific nuclear localisation signal (NLS) motifs on cargo proteins. We show here that the AR binds to importin-alpha directly, albeit more weakly than the NLS of SV40 or nucleoplasmin. We describe the 2.6-angstroms-resolution crystal structure of the importin-alpha-AR-NLS complex, and show that the AR binds to the major NLS-binding site on importin-alpha in a manner different from most other NLSs. Finally, we have shown that pathological mutations within the NLS of AR that are associated with prostate cancer and androgen-insensitivity syndrome reduce the binding affinity to importin-alpha and, subsequently, retard nuclear import; surprisingly, however, the transcriptional activity of these mutants varies widely. Thus, in addition to its function in the nuclear import of AR, the NLS in the hinge region of AR has a separate, quite distinct role on transactivation, which becomes apparent once nuclear import has been achieved.