Impact of intra-tumoral immunity on predicting response and survival after neoadjuvant cisplatin-based chemotherapy in patients with muscle invasive bladder cancer.

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Pathologic complete response (pCR) is associated with favorable outcomes, but only 30%-40% of patients achieve that response. The aim of this study is to investigate the role played by the Tumor and Immune Microenvironment (TIME) in association with the clinical outcome of patients with MIBC undergoing NAC. METHODS: Nineteen patients received NAC and were classified as pCR (n = 10) or non-pCR (n = 9). Bulk RNA-seq and immune protein evaluations using Digital Spatial Profiling (DSP) were performed on formalin-fixed paraffin-embedded (FFPE) tumor biopsies collected before NAC (baseline). Immunohistochemistry (IHC) evaluation focused on CD3 and CD20 expression was performed on baseline and end-of-treatment (EOT) FFPEs. Baseline peripheral blood was assessed for lymphocyte and neutrophil counts. Kaplan-Meier analyses and Cox PH regression models were used for survival analyses (OS). RESULTS: In the periphery, pCR patients showed lower neutrophil counts, and neutrophil/ lymphocyte ratio (NLR) when compared to non-pCR patients. In the tumor microenvironment (TME), gene expression analysis and protein evaluations highlighted an abundance of B cells and CD3+ T cells in pCR versus non-pCR patients. On the contrary, increased protein expression of ARG1+ cells, and cells expressing immune checkpoints such as LAG3, ICOS, and STING were observed in the TME of patients with non-pCR. CONCLUSIONS: In the current study, we demonstrated that lower NLR levels and increased CD3+ T cells and B cell infiltration are associated with improved response and long-term outcomes in patients with MIBC receiving NAC. These findings suggest that the impact of immune environment should be considered in determining the clinical outcome of MIBC patients treated with NAC.

Cell-free and extracellular vesicle microRNAs with clinical utility for solid tumors.

As cutting-edge technologies applied for the study of body fluid molecular biomarkers are continuously evolving, clinical applications of these biomarkers improve. Diverse forms of circulating molecular biomarkers have been described, including cell-free DNA (cfDNA), circulating tumor cells (CTCs), and cell-free microRNAs (cfmiRs), although unresolved issues remain in their applicability, specificity, sensitivity, and reproducibility. Translational studies demonstrating the clinical utility and importance of cfmiRs in multiple cancers have significantly increased. This review aims to summarize the last 5 years of translational cancer research in the field of cfmiRs and their potential clinical applications to diagnosis, prognosis, and monitoring disease recurrence or treatment responses with a focus on solid tumors. PubMed was utilized for the literature search, following rigorous exclusion criteria for studies based on tumor types, patient sample size, and clinical applications. A total of 136 studies on cfmiRs in different solid tumors were identified and divided based on tumor types, organ sites, number of cfmiRs found, methodology, and types of biofluids analyzed. This comprehensive review emphasizes clinical applications of cfmiRs and summarizes underserved areas where more research and validations are needed.

Diagnostic miRNA Signatures in Paired Tumor, Plasma, and Urine Specimens From Renal Cell Carcinoma Patients.

BACKGROUND: The incidence of patients diagnosed with renal cell carcinoma (RCC) is increasing. There are no approved biofluid biomarkers for routine diagnosis of RCC patients. This retrospective study aims to identify cell-free microRNA (cfmiR) signatures in urine samples that can be utilized as biomarkers for early diagnosis of sporadic RCC patients. METHODS: Tissue, plasma, and urine samples (n = 221) from 56 sporadic RCC patients and respective normal healthy donors were profiled for 2083 microRNAs (miRs) using the next-generation sequencing-based HTG EdgeSeq miR Whole Transcriptome Assay. DESeq2 (FC |1.2|, false discovery rate <0.05) was performed to identify differentially expressed miRs. Data from RCC tissue samples of The Cancer Genome Atlas database were used for miR validation. RESULTS: We found a 10-miR signature that distinguished RCC tissues from remote normal kidney tissue or benign kidney lesion samples. Additionally, we identified subtype-specific miRs (miR-122-5p, miR-210-3p, and miR-21-3p) and miRs specific for all RCC subtypes (miR-106b-3p, miR-629-5p, and miR-885-5p). We observed that miR-155-5p was associated with tumor size. Using The Cancer Genome Atlas data sets, we validated the miRs found in RCC tissue samples. In plasma or urine analysis, we found cfmiRs that were consistently and significantly upregulated in RCC tissue samples. A 15-cfmiR signature was proposed in urine samples of RCC patients, of which miR-1275 was consistently upregulated in tissue, plasma, and urine samples. CONCLUSIONS: This integrative study found diagnostic miRs/cfmiRs for RCC patients, which were validated using The Cancer Genome Atlas data sets. Distinctive cfmiR signatures found in urine may have clinical utility for the diagnosis of RCC.

First analysis of the safety and efficacy of UGN-101 in the treatment of ureteral tumors.

OBJECTIVE: UGN-101 has been approved for the chemoablation of low-grade upper tract urothelial cancer (UTUC) involving the renal pelvis and calyces. Herein is the first reported cohort of patients with ureteral tumors treated with UGN-101. PATIENTS AND METHODS: We performed a retrospective review of patients treated with UGN-101 for UTUC at 15 high-volume academic and community centers focusing on outcomes of patients treated for ureteral disease. Patients received UGN-101 with either adjuvant or chemo-ablative intent. Response rates are reported for patients receiving chemo-ablative intent. Adverse outcomes were characterized with a focus on the rate of ureteral stenosis. RESULTS: In a cohort of 132 patients and 136 renal units, 47 cases had tumor involvement of the ureter, with 12 cases of ureteral tumor only (8.8%) and 35 cases of ureteral plus renal pelvic tumors (25.7%). Of the 23 patients with ureteral involvement who received UGN-101 induction with chemo-ablative intent, the complete response was 47.8%, which did not differ significantly from outcomes in patients without ureteral involvement. Fourteen patients (37.8%) with ureteral tumors had significant ureteral stenosis at first post-treatment evaluation, however, when excluding those with pre-existing hydronephrosis or ureteral stenosis, only 5.4% of patients developed new clinically significant stenosis. CONCLUSIONS: UGN-101 appears to be safe and may have similar efficacy in treating low-grade urothelial carcinoma of the ureter as compared to renal pelvic tumors.

Advances in chemoablation in upper tract urothelial carcinoma: overview of indications and treatment patterns.

Localized upper tract urothelial carcinoma (UTUC) is a difficult disease for clinicians to treat, due to the multitude of oncological and patient factors to consider. Despite the challenges of diagnostic staging, endoscopic management, and disease recurrence, there is still a need for local therapeutic options that do not subject patients to the morbidities of radical nephroureterectomy (RNU). Intraluminal chemotherapies have allowed for improved oncological control in patients with low-grade disease receiving renal-sparing treatment approaches. This narrative review discusses the treatment modalities available for localized low-grade UTUC, with a focus on the current status of chemoablation. The OLYMPUS trial was a pivotal study that lead to the Food and Drug Administration (FDA) approval of UGN-101 (mitomycin-C) in April 2020 for the treatment of low-grade UTUC, and intraluminal chemotherapy is now a widely used modality for managing this disease. The trial reported a complete response (CR) rate of 59%, and an estimated treatment durability of 82% at 1 year. However, a concern was the reported 44% ureteral stricture rate using the retrograde approach. More research is currently underway to determine the ideal instillation method for intraluminal therapies (e.g., retrograde vs. antegrade). Lastly, we discuss upcoming treatment options. Newer novel agents like padeliporfin vascular targeted photodynamic (VTP) therapy (brand name TOOKAD) are currently being studied, which will in hope provide additional treatment options for UTUC patients.

Route of Administration for UGN-101 and Impact on Oncological and Safety Outcomes.

BACKGROUND: UGN-101 can be used for chemoablation of low-grade upper tract urothelial carcinoma (UTUC). The gel can be administered via a retrograde route through a ureteral catheter or an antegrade route via a nephrostomy tube. OBJECTIVE: To report outcomes of UGN-101 by route of administration. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective review of 132 patients from 15 institutions who were treated with UGN-101 for low-grade UTUC via retrograde versus antegrade administration. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Survival outcomes are reported per patient. Treatment, complications, and recurrence outcomes are reported per renal unit. Statistical analysis was performed for primary endpoints of oncological response and ureteral stricture occurrence. RESULTS AND LIMITATIONS: A total of 136 renal units were evaluated, comprising 78 retrograde and 58 antegrade instillations. Median follow-up was 7.4 mo. There were 120 cases (91%) of biopsy-proven low-grade UTUC. Tumors were in the renal pelvis alone in 89 cases (65%), in the ureter alone in 12 cases (9%), and in both in 35 cases (26%). Seventy-six patients (56%) had residual disease before UGN-101 treatment. Chemoablation with UGN-101 was used in 50/78 (64%) retrograde cases and 26/58 (45%) antegrade cases. A complete response according to inspection and cytology was achieved in 31 (48%) retrograde and 30 (60%) antegrade renal units (p = 0.1). Clavien grade 3 ureteral stricture occurred in 21 retrograde cases (32%) and only six (12%) antegrade cases (p < 0.01). Limitations include treatment bias, as patients in the antegrade group were more likely to undergo endoscopic mechanical ablation before UGN-101 instillation. CONCLUSIONS: These preliminary results show a significantly lower rate of stricture occurrence with antegrade administration of UGN-101, with no apparent impact on oncological efficacy. PATIENT SUMMARY: We compared results for two different delivery routes for the drug UGN-101 for treatment of cancer in the upper urinary tract. For the antegrade route, a tube is inserted through the skin into the kidney. For the retrograde route, a catheter is inserted past the bladder into the upper urinary tract. Our results show a lower rate of narrowing of the ureter (the tube draining urine from the kidney into the bladder) using the antegrade route, with no difference in cancer control.

The ablative effect of mitomycin reverse thermal gel: Expanding the role for nephron preservation therapy in low grade upper tract urothelial carcinoma.

PURPOSE: Assess the real-world ablative effect of mitomycin reverse thermal gel for low-grade upper tract urothelial carcinoma (UTUC) in patients who undergo biopsy only or partial ablation and evaluate utility of complete ablation prior to UGN-101. MATERIAL AND METHODS: We retrospectively reviewed low-grade UTUC patients treated with UGN-101 from 15 high-volume centers. Patients were categorized based on initial endoscopic ablation (biopsy only, partial ablation, or complete ablation) and by size of remaining tumor (complete ablation, <1cm, 1-3cm, or >3cm) prior to UGN-101. The primary outcome was rendered disease free (RDF) rate at first post-UGN-101 ureteroscopy (URS), defined as complete response or partial response with minimal mechanical ablation to endoscopically clear the upper tract of visible disease. RESULTS: One hundred and sixteen patients were included for analysis after excluding those with high-grade disease. At first post-UGN-101 URS, there were no differences in RDF rates between those who at initial URS (pre-UGN-101) had complete ablation (RDF 77.0%), partial ablation (RDF 55.9%) or biopsy only (RDF 66.7%) (P = 0.14). Similarly, a complimentary analysis focusing on tumor size (completely ablated, <1cm, 1-3cm or >3cm) prior to UGN-101 induction did not demonstrate significant differences in RDF rates (P = 0.17). CONCLUSION: The results of the early real-world experience suggest that UGN-101 may play a role in initial chemo-ablative cytoreduction of larger volume low-grade tumors that may not initially appear to be amenable to renal preservation. Further studies will help to better quantify the chemo-ablative effect and to identify clinical factors for patient selection.

Mitomycin Gel (UGN-101) as a Kidney-sparing Treatment for Upper Tract Urothelial Carcinoma in Patients with Imperative Indications and High-grade Disease.

BACKGROUND: Intracavitary UGN-101 is approved for the treatment of low-grade noninvasive upper tract urothelial carcinoma (UTUC). Post-commercialization studies underscore the benefit of UGN-101 administration for patients with imperative indications for whom radical nephroureterectomy (RNU) is not a viable option. OBJECTIVE: To describe the use, efficacy, and safety of UGN-101 in patients with UTUC with imperative indications for renal preservation, including high-grade disease. DESIGN, SETTING, AND PARTICIPANTS: Patients receiving UGN-101 with imperative indications were retrospectively analyzed using a multicenter centralized registry from 15 high-volume academic and community centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We defined imperative indications as patients with a solitary kidney, the presence of chronic kidney disease (CKD) with a glomerular filtration rate <30 ml/min, bilateral UTUC, and patients unfit for or unwilling to undergo surgical extirpation. Tumor characteristics, disease progression/recurrence, and adverse events were recorded on a per-renal-unit basis. RESULTS AND LIMITATIONS: UGN-101 was instilled into 52 renal units (38%) in 48 patients for imperative indications, including 29 patients (56%) with a solitary kidney, 11 kidneys (21%) in the setting of bilateral UTUC, six patients (12%) with CKD, and six patients (12%) who were unfit for or unwilling to undergo RNU. Twelve renal units had biopsy-proven high-grade papillary disease. Tumors were completely ablated before induction therapy in 34% of cases, while 66% had tumor present. Following induction therapy, 17 patients (40%) had no evidence of disease (NED) on ureteroscopy, 88% of whom maintained this status at median follow-up of 10.8 mo. In the cohort with high-grade disease, five patients (45%) had NED at initial post-induction primary disease evaluation. Adverse events included pyelonephritis (8%), ureteral stenosis (8%), anemia (6%), and acute renal failure (4%). Limitations include the retrospective study design, the lack of long-term follow up, and patient selection bias. CONCLUSIONS: Intracavitary therapy with UGN-101 in patients with UTUC and imperative indications shows promise as a kidney-sparing treatment modality. While long-term follow-up is needed, this intracavitary treatment may help in prolonging time to RNU and delaying the morbidity of hemodialysis in this comorbid population. PATIENT SUMMARY: We reviewed results for patients with cancer in the upper urinary tract and an additional condition that would not allow kidney removal who received treatment with a gel called UGN-101. Our results suggest that UGN-101 shows promise as a kidney-sparing treatment. It may delay the time until kidney removal is needed in these patients and avoid the negative effects associated with dialysis.

Efficacy and Safety of Mitomycin Gel (UGN-101) as an Adjuvant Therapy After Complete Endoscopic Management of Upper Tract Urothelial Carcinoma.

PURPOSE: We describe a novel application of the reverse thermal polymer gel of mitomycin C (UGN-101) as adjuvant therapy after complete endoscopic ablation of upper tract urothelial carcinoma. MATERIALS AND METHODS: We retrospectively reviewed patients treated with UGN-101 from 15 high-volume centers. Adjuvant therapy was defined as treatment administered following visually complete endoscopic ablation. Response at primary endoscopic evaluation was defined as no visual tumor or negative biopsy. Ipsilateral disease-free and progression-free survival were estimated by the Kaplan-Meier method. Ureteral stenosis and other adverse events were abstracted from the medical records. Ureteral stenosis was defined as a condition requiring ureteral stent or nephrostomy, or that would typically warrant stent or nephrostomy. RESULTS: Adjuvant UGN-101 after complete endoscopic ablation was used in 52 of 115 (45%) renal units in the oncologic analysis. At first endoscopic evaluation, 36/52 (69%) were without visible disease. At 6.8 months' median follow-up, the ipsilateral disease-free rate was 63%. Recurrence after adjuvant UGN-101 therapy was more likely in multifocal tumors compared to unifocal (HR 3.3, 95% CI 1.07-9.91). Compared with UGN-101 treatment for chemoablation of measurable disease, there were significantly fewer disease detections with adjuvant therapy (P < .001). Ureteral stenosis after UGN-101 was diagnosed in 10 patients (19%) undergoing adjuvant therapy compared to 17 (29%) undergoing chemoablative therapy (P = .28). CONCLUSIONS: In patients being considered for UGN-101, maximal endoscopic ablation prior to UGN-101 treatment may result in fewer patients with disease at first endoscopy and possibly fewer adverse events than primary chemoablative therapy. Longer follow-up is needed to determine if UGN-101 after complete endoscopic ablation will lead to durable disease-free interval.

Early experience with UGN-101 for the treatment of upper tract urothelial cancer - A multicenter evaluation of practice patterns and outcomes.

BACKGROUND: UGN-101 is a novel delivery system for intracavitary treatment of upper tract urothelial cancer (UTUC). UGN-101 was approved based on a pivotal trial for small volume residual low-grade UTUC. Our aim was to report our experience with UGN-101 in a more heterogenous and real-world setting. METHODS: We performed a retrospective review of all UGN-101 cases from 15 institutions with a focus on practice patterns, efficacy, and adverse effects. We include UGN-101 utilization in both the chemoablative and adjuvant setting. RESULTS: There were a total 136 renal units treated from 132 patients. The majority of cases were biopsy proven low-grade UTUC. Practice patterns varied considerably - the most common administration technique was antegrade instillation via a percutaneous nephrostomy. When utilized in the adjuvant setting, 69% of patients were disease free at the time of their first endoscopic evaluation, while in the chemoablative setting, 37% were endoscopically clear on the first evaluation (P < 0.001). Complete response was higher in patients with smaller tumor size prior to UGN-101 induction; low volume (<1 cm) residual disease was associated with a 70% complete response, similar to disease free rate at first endoscopic evaluation when UGN-101 was used in the adjuvant setting. The use of maintenance doses of UGN-101 was reported in 27% of cases. The overall incidence of new onset, clinically significant ureteral stenosis was 23%. CONCLUSIONS: This study represents the largest review of patients treated with UGN-101 and can serve as a basis of ongoing hypotheses regarding treatment with UGN-101 for UTUC.

Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial.

PURPOSE: Low-grade intermediate-risk nonmuscle-invasive bladder cancer (LG IR NMIBC) is a recurrent disease, thus requiring repeated transurethral resection of bladder tumor under general anesthesia. We evaluated the efficacy and safety of UGN-102, a mitomycin-containing reverse thermal gel, as a primary chemoablative therapeutic alternative to transurethral resection of bladder tumor for patients with LG IR NMIBC. MATERIALS AND METHODS: This prospective, phase 2b, open-label, single-arm trial recruited patients with biopsy-proven LG IR NMIBC to receive 6 once-weekly instillations of UGN-102. The primary end point was complete response (CR) rate, defined as the proportion of patients with negative endoscopic examination, negative cytology and negative for-cause biopsy 3 months after treatment initiation. Patients with CR were followed quarterly up to 12 months to assess durability of treatment effect. Safety and adverse events were monitored throughout the trial. RESULTS: A total of 63 patients (38 males and 25 females 33-96 years old) enrolled and received ≥1 instillation of UGN-102. Among the patients 41 (65%) achieved CR at 3 months, of whom 39 (95%), 30 (73%) and 25 (61%) remained disease-free at 6, 9 and 12 months after treatment initiation, respectively. A total of 13 patients had documented recurrences. The probability of durable response 9 months after CR (12 months after treatment initiation) was estimated to be 73% by Kaplan-Meier analysis. Common adverse events (incidence ≥10%) included dysuria, urinary frequency, hematuria, micturition urgency, urinary tract infection and fatigue. CONCLUSIONS: Nonsurgical primary chemoablation of LG IR NMIBC using UGN-102 resulted in significant treatment response with sustained durability. UGN-102 may provide an alternative to repetitive surgery for patients with LG IR NMIBC.

Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel: OLYMPUS Trial Final Report.

PURPOSE: Our goal was to evaluate long-term safety and durability of response to UGN-101, a mitomycin-containing reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma. MATERIALS AND METHODS: In this open-label, single-arm, multicenter, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology and negative for-cause biopsy) 4-6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS: Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term followup; 23/41 patients (56%) remained in complete response after 12 months (95% CI 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs. CONCLUSIONS: Durability of response to UGN-101 with or without maintenance treatment is clinically meaningful, offering a kidney-sparing therapeutic alternative for patients with low-grade disease.

Complications Associated With Ureteroscopic Management of Upper Tract Urothelial Carcinoma.

OBJECTIVES: To compile and examine safety data from clinical studies of endoscopic management of patients with low-grade upper tract urothelial carcinoma (UTUC) to identify rates and factors associated with reported complications. METHODS: Ovid Medline and Ovid Medline Daily (with Embase as secondary search) including citations from 1946-2018 were queried using the following terms: ureteroscopy, ureter, catheter, endoscopy, complication, adverse events, morbidity, ablation, laser, upper tract urothelial carcinoma, ureteral stricture, ureteral stenosis, and ureteral injury. Abstracts were reviewed for relevance; diagnostic studies, case studies, and reviews were excluded. RESULTS: Thirty-eight publications (7 prospective, 31 retrospective) representing >1100 patients were identified. Ureteral stricture was the most frequently reported complication (studies; rates) (26/38; 0-27%), with incidence associated with number of procedures and treatment method. Bleeding, infection, and fever were most common with adjuvant treatment (BCG or mitomycin). Serious and fatal complications were rare. CONCLUSIONS: Ureteral stricture is the most frequent complication of endoscopic UTUC management but can be managed successfully in most cases. Most complications were minor. Although additional prospective studies are needed, these results support the safety of ureteroscopic management of UTUC in appropriately selected patients.

Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial.

BACKGROUND: Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel. METHODS: In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5-15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient's renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4-6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128. FINDINGS: Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47-71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1-12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment. INTERPRETATION: Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients. FUNDING: UroGen Pharma.

Effect of 3-Dimensional Virtual Reality Models for Surgical Planning of Robotic-Assisted Partial Nephrectomy on Surgical Outcomes: A Randomized Clinical Trial.

Importance: Planning complex operations such as robotic-assisted partial nephrectomy requires surgeons to review 2-dimensional computed tomography or magnetic resonance images to understand 3-dimensional (3-D), patient-specific anatomy. Objective: To determine surgical outcomes for robotic-assisted partial nephrectomy when surgeons reviewed 3-D virtual reality (VR) models during operative planning. Design, Setting, and Participants: A single-blind randomized clinical trial was performed. Ninety-two patients undergoing robotic-assisted partial nephrectomy performed by 1 of 11 surgeons at 6 large teaching hospitals were prospectively enrolled and randomized. Enrollment and data collection occurred from October 2017 through December 2018, and data analysis was performed from December 2018 through March 2019. Interventions: Patients were assigned to either a control group undergoing usual preoperative planning with computed tomography and/or magnetic resonance imaging only or an intervention group where imaging was supplemented with a 3-D VR model. This model was viewed on the surgeon's smartphone in regular 3-D format and in VR using a VR headset. Main Outcomes and Measures: The primary outcome measure was operative time. It was hypothesized that the operations performed using the 3-D VR models would have shorter operative time than those performed without the models. Secondary outcomes included clamp time, estimated blood loss, and length of hospital stay. Results: Ninety-two patients (58 men [63%]) with a mean (SD) age of 60.9 (11.6) years were analyzed. The analysis included 48 patients randomized to the control group and 44 randomized to the intervention group. When controlling for case complexity and other covariates, patients whose surgical planning involved 3-D VR models showed differences in operative time (odds ratio [OR], 1.00; 95% CI, 0.37-2.70; estimated OR, 2.47), estimated blood loss (OR, 1.98; 95% CI, 1.04-3.78; estimated OR, 4.56), clamp time (OR, 1.60; 95% CI, 0.79-3.23; estimated OR, 11.22), and length of hospital stay (OR, 2.86; 95% CI, 1.59-5.14; estimated OR, 5.43). Estimated ORs were calculated using the parameter estimates from the generalized estimating equation model. Referent group values for each covariate and the corresponding nephrometry score were summed across the covariates and nephrometry score, and the sum was exponentiated to obtain the OR. A mean of the estimated OR weighted by sample size for each nephrometry score strata was then calculated. Conclusions and Relevance: This large, randomized clinical trial demonstrated that patients whose surgical planning involved 3-D VR models had reduced operative time, estimated blood loss, clamp time, and length of hospital stay. Trial Registration: ClinicalTrials.gov identifiers (1 registration per site): NCT03334344, NCT03421418, NCT03534206, NCT03542565, NCT03556943, and NCT03666104.

Hypothermic Cooling Measured by Thermal Magnetic Resonance Imaging; Feasibility and Implications for Virtual Imaging in the Urogenital Pelvis.

OBJECTIVE: To study the combination of thermal magnetic resonance imaging (MRI) and novel hypothermic cooling, via an endorectal cooling balloon (ECB), to assess the effective dispersion and temperature drop in pelvic tissue to potentially reduce inflammatory cascade in surgical applications. METHODS: Three male subjects, before undergoing robot-assisted radical prostatectomy, were cooled via an ECB, rendered MRI compatible for patient safety before ECB hypothermia. MRI studies were performed using a 3T scanner and included T2-weighted anatomic scan for the pelvic structures, followed by a temperature mapping scan. The sequence was performed repeatedly during the cooling experiment, whereas the phase data were collected using an integrated MR-high-intensity focused ultrasound workstation in real time. Pelvic cooling was instituted with a cooling console located outside the MRI magnet room. RESULTS: The feasibility of pelvic cooling measured a temperature drop of the ECB of 20-25 degrees in real time was achieved after an initial time delay of 10-15 seconds for the ECB to cool. The thermal MRI anatomic images of the prostate and neurovascular bundle demonstrate cooling at this interface to be 10-15 degrees, and also that cooling extends into the prostate itself ~5 degrees, and disperses into the pelvic region as well. CONCLUSION: An MRI-compatible ECB coupled with thermal MRI is a feasible method to assess effective hypothermic diffusion and saturation to pelvic structures. By inference, hypothermia-induced rectal cooling could potentially reduce inflammation, scarring, and fistula in radical prostatectomy, as well as other urologic tissue procedures of high-intensity focused ultrasound, external beam radiation therapy, radioactive seed implants, transurethral microwave therapy, and transurethral resection of the prostate.

Emerging Utility of Urinary Cell-free Nucleic Acid Biomarkers for Prostate, Bladder, and Renal Cancers.

CONTEXT: By 2020 the estimated incidence of genitourinary (GU) cancers (prostate, bladder, and kidney) will be over 2 million worldwide and responsible for ∼800 000 deaths. Current diagnosis and monitoring methods of GU cancer patients are often invasive and/or lack sensitivity and specificity. Given the utility of blood-based cell-free nucleic acid (cfNA) biomarkers, the development of urinary cfNA biomarkers may improve the sensitivity of urine assays utilizing urine sediment for GU cancers. This review of urinary cfNA in GU cancers identifies the current stage of research, potential clinical utility, and the next steps needed to enter clinical use. OBJECTIVE: To critically evaluate the literature of urinary cfNA in GU cancers for clinical utility in diagnosis, screening, and precision medicine. Furthermore, the strategy for future efforts to discover potential new urinary cfNA biomarkers will be described. EVIDENCE ACQUISITION: A PubMed database (2006 to current) search was performed according to Preferred Reporting Items for Systemic Review and Meta-analysis using key Medical Subject Headings terms. Additional studies were obtained by cross-referencing from the literature. EVIDENCE SYNTHESIS: The collective research publications in urinary cfNA of GU cancers present a promising alternative liquid biopsy approach compared with blood biopsies and urine sediment, particularly for early-stage GU diseases. CONCLUSIONS: Urinary cfNA as a liquid biopsy holds potential for a more sensitive alternative to blood biopsies and urine sediment-based tests for clinical use in GU cancers. Not only does urinary cfNA offer advantages including the potential for more frequent testing, monitoring, and home use, but also has applications in early-stage GU cancers. PATIENT SUMMARY: In this review, we evaluated the current status of urinary cell-free nucleic acid in genitourinary cancers. We identified the potential advantages of urinary cell-free nucleic acid over blood and urine sediment and its clinical use in genitourinary cancer.

Intermediate-term oncologic outcomes of robot-assisted radical cystectomy for urothelial carcinoma.

PURPOSE: To evaluate intermediate-term oncologic outcomes in a large series of patients who were treated with robot-assisted radical cystectomy (RARC) for urothelial carcinoma of the bladder (UCB). PATIENTS AND METHODS: Between 2004 and 2010, 162 patients underwent RARC at City of Hope Cancer Center for UCB and were analyzed with respect to overall (OS), disease-specific (DSS), and disease-free survival (DFS). Descriptive statistics were used to summarize demographics and perioperative variables. The Kaplan-Meier method was used to estimate survival and recurrence. Univariable and multivariable Cox proportional hazards regression models were used to determine predictors of survival. RESULTS: Median follow-up was 52 months. Thirty-eight (23.4%) patients received neoadjuvant chemotherapy before RARC; 28% of patients were pT2 and 33% had final pathology status of pT3 or pT4. Median lymph node count was 28, and positive surgical margin rate was 4.3%. Local recurrence occurred in 11 (6.8%) patients. OS, DFS, and DSS at 3 years were 61%, 76%, and 83%, respectively. OS, DFS, and DSS at 5 years were 54%, 74%, and 80%, respectively. Predictors of OS and DFS on multivariable analysis were lymph node density, pathologic stage, and age-adjusted Charlson Comorbidity Index, while receipt of transfusion was also a negative predictor of OS. CONCLUSIONS: RARC provides an effective means of treatment of UCB in a minimally invasive fashion with comparable oncologic outcomes to that reported in the literature of open procedures.