Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal.

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.

Surgery for high-risk locally advanced (pT3c) renal tumours: oncological outcomes and prognostic significance of a modified International Metastatic Renal Cell Cancer Database Consortium (IMDC) score.

OBJECTIVES: To evaluate contemporary oncological outcomes and long-term survival in patients undergoing surgery for urological tumours involving the peridiaphragmatic inferior vena cava up to the level of the right atrium. To apply prognostic factors developed for metastatic renal cancer to patients with very-high-risk but apparently localized tumours, and develop a scoring system. PATIENTS AND METHODS: A retrospective cohort study of 54 patients referred between December 2007 and April 2018 to a single surgical and oncological team was conducted. Electronic patient records were used to obtain peri-operative data and oncological follow-up. For operated patients lost to follow-up, survival data were obtained from primary care physicians. We used Kaplan-Meier curves to estimate overall survival (OS) and disease-free survival. For the subgroup undergoing curative surgery (n = 32) the prognostic value of a renal cancer score developed at Guy's Hospital using five of the six criteria in the International Metastatic Renal Cell Carcinoma Database Consortium prognostic model (one point for each of anaemia, neutrophilia, thrombophilia, hypercalcaemia and Karnofsky performance status <80), in order to be relevant for M0 disease, was assessed using the log-rank test. RESULTS: The median (interquartile range [IQR]) OS of the whole cohort was 29 (11-57) months. The median (IQR) survival of the curative subgroup (n = 32) was 32 (16-57) months, vs 11 (4-upper limit not reached) months for the cytoreductive subgroup (n = 13; P = 0.14). The median (IQR) follow-up time was 14 (1-65) months for patients alive at analysis. Disease-free survival in the curative subgroup was 10 (6-30) months. The median (IQR) OS by risk category for curative cases, as defined by the Guy's renal cancer score, was not reached in the favourable risk group (score = 0 points) because there were no patient deaths, 43 (30-61) months in the intermediate-risk group (score = 1 point), and 18 months (11-32) months in the poor-risk group (score ≥ 2 points; P = 0.005). CONCLUSION: A median survival of 29 months appears to justify this type of surgery. A prognostic model, the Guy's renal cancer score, using five readily available clinical measures, appears promising in patients with very-high-risk locally advanced tumours.

Impact of the COVID-19 pandemic on urological cancers: The surgical experience of two cancer hubs in London and Milan.

Objective: To report on the outcomes of urological cancer patients undergoing radical surgery between March-September 2020 (compared with 2019) in the European Institute of Oncology (IEO) in Milan and the South East London Cancer Alliance (SELCA). Materials and Methods: Since March 2020, both institutions implemented a COVID-19 minimal 'green' pathway, whereby patients were required to isolate for 14 days prior to admission and report a negative COVID-19 polymerase chain reaction (PCR) test within 3 days of surgery. COVID-19 positive patients had surgery deferred until a negative swab. Surgical outcomes assessed were: American Society of Anaesthesiologists (ASA) grade; surgery time; theatre time; intensive care unit (ICU) stay >24 h; pneumonia; length of stay (LOS); re-admission. Postoperative COVID-19 infection rates and associated mortality were also recorded. Results: At IEO, uro-oncological surgery increased by 4%, as compared with the same period in 2019 (n = 515 vs. 534). The main increase was observed for renal (16%, n = 98 vs. 114), bladder (24%, n = 45 vs. 56) and testicular (27%, n = 26 vs. 33). Patient demographics were all comparable between 2019 and 2020. Only one bladder cancer patient developed COVID-19, reporting mild/moderate disease. There was no COVID-19 associated mortality. In the SELCA cohort, uro-oncological surgery declined by 23% (n = 403 vs. 312) compared with the previous year. The biggest decrease was seen for prostate (-42%, n = 156 vs. 91), penile (-100%, n = 4 vs. 0) and testicular cancers (-46%, n = 35 vs. 24). Various patient demographic characteristics were notably different when comparing 2020 versus 2019. This likely reflects the clinical decision of deferring COVID-19 vulnerable patients. One patient developed COVID-19, with no COVID-19 related mortality. Conclusion: The COVID-19 minimal 'green' pathways that were put in place have shown to be safe for uro-oncological patients requiring radical surgery. There were limited complications, almost no peri-operative COVID-19 infection and no COVID-19-related mortality in either cohort.

Safety of "hot" and "cold" site admissions within a high-volume urology department in the United Kingdom at the peak of the COVID-19 pandemic.

OBJECTIVES: To determine the safety of urological admissions and procedures during the height of the COVID-19 pandemic using "hot" and "cold" sites. The secondary objective is to determine risk factors of contracting COVID-19 within our cohort. PATIENTS AND METHODS: A retrospective cohort study of all consecutive patients admitted from March 1 to May 31, 2020 at a high-volume tertiary urology department in London, United Kingdom. Elective surgery was carried out at a "cold" site requiring a negative COVID-19 swab 72-hours prior to admission and patients were required to self-isolate for 14-days preoperatively, while all acute admissions were admitted to the "hot" site.Complications related to COVID-19 were presented as percentages. Risk factors for developing COVID-19 infection were determined using multivariate logistic regression analysis. RESULTS: A total of 611 patients, 451 (73.8%) male and 160 (26.2%) female, with a median age of 57 (interquartile range 44-70) were admitted under the urology team; 101 (16.5%) on the "cold" site and 510 (83.5%) on the "hot" site. Procedures were performed in 495 patients of which eight (1.6%) contracted COVID-19 postoperatively with one (0.2%) postoperative mortality due to COVID-19. Overall, COVID-19 was detected in 20 (3.3%) patients with two (0.3%) deaths. Length of stay was associated with contracting COVID-19 in our cohort (OR 1.25, 95% CI 1.13-1.39). CONCLUSIONS: Continuation of urological procedures using "hot" and "cold" sites throughout the COVID-19 pandemic was safe practice, although the risk of COVID-19 remained and is underlined by a postoperative mortality.

Characterization of Small Renal Tumors With Magnetic Resonance Elastography: A Feasibility Study.

OBJECTIVES: The aim of this study was to explore the feasibility of magnetic resonance elastography (MRE) for characterizing indeterminate small renal tumors (SRTs) as part of a multiparametric magnetic resonance (MR) imaging protocol. MATERIALS AND METHODS: After institutional review board approval and informed consent were obtained, 21 prospective adults (15 men; median age, 55 years; age range, 25-72 years) with SRT were enrolled. Tumors (2-5 cm Ø) were imaged using 3-directional, gradient echo MRE. Viscoelastic parametric maps (shear wave velocity [c] and attenuation [α]) were analyzed by 2 independent radiologists. Interobserver agreement (Bland-Altman statistics and intraclass correlation coefficients) was assessed. Anatomical T2-weighted, dynamic contrast-enhanced (DCE) and diffusion sequences completed the acquisition protocol. Imaging parameters were compared between groups (Mann-Whitney U test). RESULTS: Quality of MRE was good in 18 cases (mean nonlinearity <50%), including 1 papillary renal cell carcinoma and 1 metanephric adenoma. A cohort of 5 oncocytomas and 11 clear-cell renal cell carcinomas (ccRCCs) was analyzed for statistical differences. The MRE viscoelastic parameters were the strongest imaging discriminators: oncocytomas displayed significantly lower shear velocity c (median, 0.77 m/s; interquartile range [IQR], 0.76-0.79) (P = 0.007) and higher shear attenuation α (median, 0.087 mm; IQR, 0.082-0.087) (P = 0.008) than ccRCC (medians, 0.92 m/s and 0.066 mm; IQR, 0.84-0.97 and 0.054-0.074, respectively). T2 signal intensity ratio (tumor/renal cortex) was lower in oncocytomas (P = 0.02). The DCE and diffusion MR parameters overlapped substantially (P ≥ 0.1). Oncocytomas displayed a consistent MRE viscoelastic profile, corresponding to data point clustering in a bidimensional scatter plot. Values for MRE intraclass correlation coefficient were 0.982 for c and 0.984 for α, indicating excellent interobserver agreement. CONCLUSIONS: Magnetic resonance elastography is feasible for SRT characterization; MRE viscoelastic parameters were stronger discriminators between oncocytoma and ccRCC than anatomical, DCE and diffusion MR imaging parameters.

Open partial nephrectomy in renal cell cancer - Essential or obsolete?

Since the first partial nephrectomy was first conducted 131 years ago, the procedure has evolved into the gold standard treatment for small renal masses. Over the past decade, with the introduction of minimally invasive surgery, open partial nephrectomy still retains a valuable role in the treatment of complex tumours in challenging clinical situations (e.g. hereditary renal cancer or single kidneys), and enables surgeons to push the boundaries of nephron-sparing surgery. In this article, we consider the origin of the procedure and how it has evolved over the past century, the surgical techniques involved, and the oncological and functional outcomes.

Is routine postoperative diuresis renography indicated in all adult patients after pyeloplasty for ureteropelvic junction obstruction?

OBJECTIVE: To determine if routine follow-up diuresis renography is indicated in all adult patients after pyeloplasty for ureteropelvic junction obstruction (UPJO). METHODS: A multicenter retrospective analysis was conducted in adults who underwent pyeloplasty for symptomatic UPJO between January 2002 and August 2012. Patients with unilateral UPJO demonstrated on diuresis renography, treated with pyeloplasty, and aged >18 years at time of surgery were included in the study. Patients with contralateral renal abnormalities, genitourinary anomalies, and those who declined renography during follow-up were excluded. All eligible patients underwent diuresis renography approximately 3 months postoperatively. Minimal follow-up was 12 months. Patients were divided into 2 groups: patients with persistent pain at 3 months after pyeloplasty and patients who became asymptomatic. Treatment failures in each cohort were identified. Comparisons were performed using the Fisher exact test. RESULTS: A total of 100 pyeloplasties were performed. Of them, 90 were eligible for the study. Mean age was 40 years. Mean follow-up was 21 months. Seventy-three patients (81.1%) became pain free after pyeloplasty. One patient (1.4%) had worsening of differential renal function despite unobstructed drainage on diuresis renogram. None of the patients in the asymptomatic cohort was identified to have unequivocal drainage obstruction on postoperative renogram. Seventeen patients (18.9%) remained symptomatic with pain at 3 months after pyeloplasty; 3 (17.6%) of those patients with loin pain after pyeloplasty were confirmed to have persistent obstructed drainage postoperatively on diuresis renogram (P <.001). All 3 patients required insertion of ureteric stents and/or revision surgery (P <.007). CONCLUSION: In our series, adult patients who became pain free after unilateral pyeloplasty for UPJO did not have persistent obstruction of renal drainage on renography. Routine diuresis renogram to assess drainage and differential renal function in patients who become pain free after pyeloplasty for UPJO may not be necessary. If objective evidence of postoperative outcome is required, then a single renogram at 3 months is recommended.

Penile granuloma following intravesical bacillus Calmette-Guerin (BCG) therapy.

We present a case of penile granuloma following intravesical bacillus Calmette-Guerin (BCG) therapy that is unique in its presentation and management. The patient presented with a subcutaneous cystic lump with no overlying skin changes, inguinal lymphadenopathy or systemic upset. The treatment was excision alone.