Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2.

The micropapillary subtype of urothelial carcinoma (MPUC) of the bladder is a very aggressive histological variant of urothelial bladder cancer (UBC). A high frequency of MPUC contains activating mutations in the extracellular domain (ECD) of ERBB2. We sought to further characterize ERBB2 ECD-mutated MPUC to identify additional genomic alterations that have been associated with tumor progression and therapeutic response. In total, 5,485 cases of archived formalin-fixed, paraffin-embedded UBC underwent comprehensive genomic profiling to identify ERBB2 ECD-mutated MPUC and evaluate the frequencies of genomic co-alterations. We identified 219 cases of UBC with ERBB2 ECD mutations (74% S310F and 26% S310Y), of which 63 (28.8%) were MPUC. Genomic analysis revealed that TERT, TP53, and ARID1A were the most common co-altered genes in ERBB2-mutant MPUC (82.5%, 58.7%, and 39.7%, respectively) and did not differ from ERBB2-mutant non-MPUC (86.5%, 51.9%, and 35.3%). The main differences between ERBB2 ECD-mutated MPUC compared with non-MPUC were KMT2D, RB1, and MTAP alterations. KMT2D and RB1 are tumor-suppressor genes. KMT2D frequency was significantly decreased in ERBB2 ECD-mutated MPUC (6.3%) in contrast to non-MPUC (27.6%; P < .001). RB1 mutations were more frequent in ERBB2 ECD-mutated MPUC (33.3%) than in non-MPUC (17.3%; P = .012). Finally, MTAP loss, an emerging biomarker for new synthetic lethality-based anticancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than in non-MPUC (26.9%; P = .018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.

Clinical features of patients with MTAP-deleted bladder cancer.

Advanced urothelial carcinoma continues to have a dismal prognosis despite several new therapies in the last 5 years. FGFR2 and FGFR3 mutations and fusions, PD-L1 expression, tumor mutational burden, and microsatellite instability are established predictive biomarkers in advanced urothelial carcinoma. Novel biomarkers can optimize the sequencing of available treatments and improve outcomes. We describe herein the clinical and pathologic features of patients with an emerging subtype of bladder cancer characterized by deletion of the gene MTAP encoding the enzyme S-Methyl-5'-thioadenosine phosphatase, a potential biomarker of response to pemetrexed. We performed a retrospective analysis of 61 patients with advanced urothelial carcinoma for whom demographics, pathologic specimens, next generation sequencing, and clinical outcomes were available. We compared the frequency of histology variants, upper tract location, pathogenic gene variants, tumor response, progression free survival (PFS) and overall survival (OS) between patients with tumors harboring MTAP deletion (MTAP-del) and wild type tumors (MTAP-WT). A propensity score matching of 5 covariates (age, gender, presence of variant histology, prior surgery, and prior non-muscle invasive bladder cancer) was calculated to compensate for disparity when comparing survival in these subgroups. Non-supervised clustering analysis of differentially expressed genes between MTAP-del and MTAP-WT urothelial carcinomas was performed. MTAP-del occurred in 19 patients (31%). Tumors with MTAP-del were characterized by higher prevalence of squamous differentiation (47.4 vs 11.9%), bone metastases (52.6 vs 23.5%) and lower frequency of upper urinary tract location (5.2% vs 26.1%). Pathway gene set enrichment analysis showed that among the genes upregulated in the MTAP-del cohort, at least 5 were linked to keratinization (FOXN1, KRT33A/B, KRT84, RPTN) possibly contributing to the higher prevalence of squamous differentiation. Alterations in the PIK3 and MAPK pathways were more frequent when MTAP was deleted. There was a trend to inferior response to chemotherapy among MTAP-del tumors, but no difference in the response to immune checkpoint inhibitors or enfortumab. Median progression free survival after first line therapy (PFS1) was 5.5 months for patients with MTAP-WT and 4.5 months for patients with MTAP-del (HR = 1.30; 95% CI, 0.64-2.63; P = 0.471). There was no difference in the time from metastatic diagnosis to death (P = 0.6346). Median OS from diagnosis of localized or de novo metastatic disease was 16 months (range 1.5-60, IQR 8-26) for patients with MTAP-del and 24.5 months (range 3-156, IQR 16-48) for patients with MTAP-WT (P = 0.0218), suggesting that time to progression to metastatic disease is shorter in MTAP-del patients. Covariates did not impact significantly overall survival on propensity score matching. In conclusion, MTAP -del occurs in approximately 30% of patients with advanced urothelial carcinoma and defines a subgroup of patients with aggressive features, such as squamous differentiation, frequent bone metastases, poor response to chemotherapy, and shorter time to progression to metastatic disease.

p53 Expression, Programmed Death Ligand 1, and Risk Factors in Urinary Tract Small Cell Carcinoma.

Introduction: Small cell carcinoma of the urinary tract (SCCUT) is a rare finding with poor clinical course. This study sheds light on the molecular subtype and identifies risk factors in patients diagnosed with SCCUT. Methods: Immunohistochemical expression of immunotherapy target programmed death ligand 1 (PD-L1) and luminal (GATA3), basal (p63), and p53 markers are assessed in patients diagnosed with SCCUT. Univariate analysis identified risk factors. Overall survival (OS) is computed using the Kaplan-Meier method. Results: Tissue was available for 70.2% (33/47). All showed a high PD-L1 expression phenotype. p53 is seen in 93.9% (31/33), mostly as overexpression, GATA3 in 45.5% (15/33), and p63 in 57.6% (19/33). For the entire cohort (n = 47), 1-year survival was 59.6%, and the median OS was 17 months. Univariate analysis shows that chemotherapy [hazard ratio (HR) = 0.29, 95% confidence interval (CI) = 0.14-0.61, p = 0.001], radical surgery (HR = 0.37, 95% CI = 0.18-0.76, p = 0.007), and diagnosis of non-pure SCCUT (HR = 0.44, 95% CI = 0.22-0.86, p = 0.02) are favorable prognostic features. Metastasis had negative associations with survival (HR = 2.1, 95% CI = 1.1-4.2, p = 0.03). Conclusions: In this series, pure and mixed SCCUT are characterized by p53 overexpression and a high PD-L1 phenotype. Histology of non-pure SCCUT is a positive prognosticator, and radical cystectomy or chemotherapy can improve OS. These findings demonstrate that SCCUT may be eligible for PD-L1 immunotherapy.

Effectiveness and safety of computed tomography-guided radiofrequency ablation of renal cancer: a 14-year single institution experience in 203 patients.

OBJECTIVES: To define effectiveness and safety of CT-guided radiofrequency ablation (RFA) of renal tumours and prognostic indicators for treatment success. METHODS: Patients with a single treatment of a solitary, biopsy-proven renal tumour with intent to cure over a 14-year period were included (n = 203). Probability of residual disease over time, complication rates and all-cause mortality were assessed in relation to multiple variables. RESULTS: Mean tumour size was 2.5 cm (range 1.0-6.0). Mean follow-up was 34.1 months (range 1-131). There was an increase in likelihood of residual disease for tumours ≥3.5 cm (P < 0.05), clear cell subtype of renal cell carcinoma (P ≤ 0.005) and maximum treatment temperature ≤70 °C (P < 0.05). There was a decrease in likelihood of residual disease for exophytic tumours (P = 0.01) and no difference based on age, gender, tumour location or type of radio freqency (RF) electrode used. Major complications occurred in 3.9 %. Median post-treatment survival was 7 years for patients with tumours <4 cm, and 5-year overall survival was 80 %. Probability of minor complication increased with tumour size (P = 0.03), as did all-cause mortality (P = 0.005). CONCLUSIONS: CT-guided RFA is safe and effective for early-stage renal cancer, particularly for exophytic tumours measuring <3.5 cm. Overall 5-year survival with tumours <4 cm is comparable to partial nephrectomy. KEY POINTS: • Prognostic indicators for success of CT-guided RFA of renal tumours are reported. • Tumour size ≥3.5 cm confers an increased risk for residual tumour. • Clear cell renal cell carcinoma subtype confers increased risk for residual tumour. • Tmax <70 °C within the ablation zone confers increased risk for residual tumour. • Exophytic tumours have a lower probability of residual disease.

Analysis of a large single-center experience with robot-assisted pyeloplasty.

OBJECTIVES: To report a single-center experience with robot-assisted pyeloplasty. METHODS: Medical records of 100 consecutive robot-assisted pyeloplasty cases carried out between May 2004 and August 2010 were retrospectively reviewed, and major perioperative parameters were recorded. Patients underwent functional (renal scan) and/or anatomical (ultrasound or computerized tomoghraphy) imaging at 6 months. RESULTS: The mean patient age was 39.8 years. A total of 12 patients underwent prior attempts at repair. Ureteral stents were placed in all patients except one, and closed-suction drains were placed in 59 patients. There were two intraoperative complications and two postoperative complications requiring surgical intervention. One patient with a complex prior surgical history developed a urine leak that was managed with prolonged drainage. A total of 42 patients were discharged on postoperative day 1, and 44 were discharged on postoperative day 2. Mean length of follow up was 22.8 months. The operative success rate was 96%. CONCLUSIONS: The majority of patients undergoing robot-assisted pyeloplasty can expect a short hospitalization with minimal morbidity. The operative success rate is high, even in patients with prior attempts at repair. Complication rates including urine leaks are quite low, and routine placement of a closed-suction drain is likely to be unnecessary.

Robot-assisted partial nephrectomy: analysis of the first 100 cases from a single institution.

Robot-assisted partial nephrectomy (RAPN) is an alternative to open and laparoscopic partial nephrectomy for small renal tumors. Our objectives were to report our experience and short-term outcomes from the first 100 cases of robot-assisted partial nephrectomy (RAPN) performed at a single institution, as well as to evaluate the effect of the learning curve and identify any factors associated with adverse perioperative outcomes. Patient records of the first 100 RAPN cases performed by three surgeons between October 2007 and March 2010 were retrospectively reviewed. The cases were divided into two groups to analyze a possible learning curve effect. Group 1 consisted of the first half (chronologically) of the cases performed by each surgeon, and Group 2 consisted of the second half. For the entire series, the median warm ischemia time was 24 min (range 11-49), mean length of follow-up was 13.4 months, and the median postoperative change in glomerular filtration rate (GFR) was -6.6 mL/min/1.73 m(2). Three patients had microscopically positive margins on final pathology, three intraoperative complications occurred, and 13 postoperative complications were recorded (10 Clavien grade IIIa or less). Median operative time was significantly longer in Group 1 (193 min) than in Group 2 (165 min, P = 0.003). Multivariate analysis identified male gender and cases done in Group 1 to be associated with increased operative time, while male gender and higher nephrometry scores were associated with increased blood loss. Tumor characteristics associated with greater reductions in GFR included higher nephrometry scores, endophytic tumors, and hilar tumors. In conclusion, RAPN appears to be safe and the major effect of the learning curve appears to be on operative time. Warm ischemia times are sufficiently low to prevent significant renal impairment, while male gender and higher nephrometry scores may be predictors of longer operative times and more intraoperative blood loss. Overall operative time decreased with increasing case volume, although this was not uniform among the three surgeons in the study. Further longitudinal study is necessary to establish oncologic outcomes.

Androgen deprivation therapy for advanced prostate cancer: why does it fail and can its effects be prolonged?

Androgen deprivation therapy (ADT) has been the cornerstone of treatment for advanced prostate cancer for over 65 years. Although there can be worrisome side effects, data will be presented that for men with metastatic prostate cancer, immediate ADT can reduce the likelihood of developing the rare but catastrophic sequellae of metastatic disease, although it is unlikely to prolong survival compared with waiting for symptoms before initiating ADT. Additionally, for patients with extremely high risk prostate cancer that is not distantly metastatic (e.g. have a life expectancy from prostate cancer less than 10 years with all other available treatments except immediate ADT) and, whose life expectancy from non-prostate cancer diseases is excellent during this period, early ADT both alone and in conjunction with definitive local treatment prolongs survival. Moreover, ADT seems to be most effective when the cancer volume is low. However, eventually most men receiving ADT experience disease progression. The biological mechanisms explaining how prostate cancer escapes from ADT's control include: 1) Alterations in the androgen receptor (AR) and in the AR co-factors (which modify the responsiveness of the AR to androgens) allow molecules and medications which are not normally AR agonists to act as agonists. 2) The human prostate gland, and particularly prostate cancer, may be able to synthesize androgens from both cholesterol and adrenal androgens. This may occur because prostate cancer tissue has higher concentrations of androgens than does the serum in patients receiving ADT. Thus, castrated men may not be starving their prostate cancers of androgens. 3) The AR in prostatic stroma far more strongly stimulates both malignant and benign prostatic epithelial growth than the epithelial AR does. Indeed, the epithelial AR, particularly in advanced prostate cancer, may have anti-proliferative and anti-tumor progression properties. That is, the AR in the prostatic epithelial cells, particularly malignant ones, may act as a tumor suppressor. Thus, by inhibiting the epithelial AR, its protective effects may be abrogated. The controversial nature of these concepts, as well as the clinical and experimental data which support and question them, will be presented. Additionally, strategies for addressing each of these escape mechanisms, which may be able to prolong responsiveness to ADT, will be discussed.

Sensitivity and specificity of 24-hour urine chemistry levels for detecting elevated calcium oxalate and calcium phosphate supersaturation.

OBJECTIVES: The gold standard for determining likelihood of calcium oxalate (CaOx) and calcium phosphate (CaPhos) stone formation in urine is supersaturation of CaOx and CaPhos. Our objective was to investigate whether traditional measurement of total calcium, oxalate and phosphate in a 24-hour urine collection is sufficiently sensitive and specific for detecting elevated supersaturation to preclude the more expensive supersaturation test. METHODS: We performed a retrospective review of 150 consecutive patients with nephrolithiasis who underwent measurement of CaOx supersaturation (CaOxSS) and CaPhos supersaturation (CaPhosSS), as well as total calcium, oxalate and phosphate in a 24-hour urine collection. We used various cut-off values to determine sensitivity and specificity of 24-hour urine measurements for detecting elevated CaOxSS and CaPhosSS. RESULTS: In men and women, the sensitivity of 24-hour calcium for detecting elevated CaOxSS was 71% and 79%, respectively; for oxalate, sensitivity was 59% and 36%, respectively. In men and women, the sensitivity of 24-hour calcium for detecting elevated CaPhosSS was 74% and 88%, respectively; for phosphate, sensitivity was 57% and 8%, respectively. In men and women, the specificity of 24-hour calcium for detecting elevated CaOxSS was 55% and 48%, respectively; it was 60% for detecting elevated CaPhosSS in both men and women. CONCLUSION: Traditional 24-hour urine analysis is sensitive, but not specific, for detecting elevated CaOxSS and CaPhosSS. Most patients with abnormal 24-hour urine analysis have normal supersaturation, and treatment decisions based on traditional urine analysis would lead to overtreatment in these patients.

Androgen deprivation therapy for prostate cancer.

Androgen deprivation continues to play a crucial role in the treatment of advanced and metastatic prostate cancer. In the 65 years since its use was first described, urologists and medical oncologists have developed new and innovative ways to manipulate the hypothalamic-pituitary-gonadal axis with the goal of alleviating symptoms and prolonging the life of men with prostate cancer. Despite the successes that androgen deprivation therapy has brought, each method and regimen possesses unique benefits and burdens, of which the clinician and patient must be cognizant. This review discusses the first-line androgen deprivation methods and regimens presently in use with special attention paid to their side effects and the management of them, as well as the question of when to initiate androgen deprivation therapy.

What's new in urologic ultrasound?

Ultrasonography allows providers to noninvasively image an area of interest in real time without the risks of ionizing radiation or nephrotoxic contrast agents. This article present basic concepts of ultrasound along with new advances in ultrasound technology and their applications in small parts evaluation.