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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

Chevli, K Kent; Shore, Neal D; Trainer, Andrew; Smith, Angela B; Saltzstein, Daniel; Ehrlich, Yaron; Raman, Jay D; Friedman, Boris; D'Anna, Richard; Morris, David; Hu, Brian; Tyson, Mark; Sankin, Alexander; Kates, Max; Linehan, Jennifer; Scherr, Douglas; Kester, Steven; Verni, Michael; Chamie, Karim; Karsh, Lawrence; Cinman, Arnold; Meads, Andrew; Lahiri, Soumi; Malinowski, Madlen; Gabai, Nimrod; Raju, Sunil; Schoenberg, Mark; Seltzer, Elyse; Huang, William C
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.
PMID: 34433303
ISSN: 1527-3792
CID: 5103672

The role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells

Wang, Hsiang-Tsui; Lee, Hyun-Wook; Weng, Mao-Wen; Liu, Yan; Huang, William C; Lepor, Herbert; Wu, Xue-Ru; Tang, Moon-Shong
It has long been recognized that non-muscle-invasive bladder cancer (NMIBC) has a low propensity (20%) of becoming muscle-invasive (MIBC), and that MIBC carry many more p53 point mutations (p53m) than NMIBC (50% vs 10%). MIBC also has a higher mutation burden than NMIBC. These results suggest that DNA repair capacities, mutational susceptibility and p53m are crucial for MIBC development. We found MIBC cells are hypermutable, deficient in DNA repair and have markedly downregulated DNA repair genes, XPC, hOGG1/2 and Ref1, and the tumor suppressor, TAp63γ. In contrast, NMIBC cells are hyperactive in DNA repair and exhibit upregulated DNA repair genes and TAp63γ. A parallel exists in human tumors, as MIBC tissues have markedly lower DNA repair activity, and lower expression of DNA repair genes and TAp63γ compared to NMIBC tissues. Forced TAp63γ expression in MIBC significantly mitigates DNA repair deficiencies and reduces mutational susceptibility. Knockdown of TAp63γ in NMIBC greatly reduces DNA repair capacity and enhances mutational susceptibility. Manipulated TAp63γ expression or knockdown of p53m reduce the invasion of MIBC by 40-60%. However, the combination of p53m knockdown with forced TAp63γ expression reduce the invasion ability to nil suggesting that p53m contributes to invasion phenotype independent from TAp63γ. These results indicate that in BC, TAp63γ regulates DNA repair capacities, mutational susceptibility and invasion, and that p53m contribute to the invasion phenotype. We conclude that concurrent TAp63γ suppression and acquisition of p53m are a major cause for MIBC development.
PMID: 34747697
ISSN: 2050-084x
CID: 5050232

Primary Robot-assisted Retroperitoneal Lymph Node Dissection for Men with Nonseminomatous Germ Cell Tumor: Experience from a Multi-institutional Cohort

Taylor, Jacob; Becher, Ezequiel; Wysock, James S; Lenis, Andrew T; Litwin, Mark S; Jipp, Jacob; Langenstroer, Peter; Johnson, Scott; Bjurlin, Marc A; Tan, Hung-Jui; Lane, Brian R; Huang, William C
BACKGROUND:Primary robot-assisted retroperitoneal lymph node dissection (RA-RPLND) for men with nonseminomatous germ cell tumor (NSGCT) is an alternative to open RPLND for stage I and select stage II patients. OBJECTIVE:To report the complication rates and oncologic outcomes from a multi-institutional series, and to estimate reduction in chemotherapy by using upfront minimally invasive surgery. DESIGN, SETTING, AND PARTICIPANTS/METHODS:A retrospective chart review of men undergoing primary robot-assisted RPLND between 2014 and 2019 in five institutions by eight urologists experienced in testis cancer and robotic surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/UNASSIGNED:Variables such as demographic and clinicopathologic information, operative parameters and complication rates, oncologic outcomes, sexual recovery, and hospital length of stay were collected. Descriptive statistics are presented. RESULTS AND LIMITATIONS/CONCLUSIONS:Forty-nine patients were analyzed with a median follow-up of 15.0 mo (interquartile range 6.5-29.1 mo). Median operative time was 288 min, estimated blood loss was 100 ml, and lymph node yield was 32. Median length of stay was 1 d. There were nine postoperative complications, 44% (4/9) of which were Clavien grade 1. There were no Clavien grade IV complications. Twenty-one patients had metastatic NSGCT (42.8%), of whom nine (18.4%) received adjuvant chemotherapy. Four patients experienced recurrence (three out-of-field and one in-field recurrence). Limitations include the retrospective study design and various surgical techniques among surgeons. CONCLUSIONS:Primary robot-assisted RPLND for NSGCT can be performed safely, with low complication rates and acceptable oncologic outcomes reducing the need for chemotherapy. For a population in which compliance with surveillance is typically challenging, robot-assisted RPLND may improve quality of care and outcomes for patients with NSGCT. PATIENT SUMMARY/UNASSIGNED:In experienced centers, robot-assisted retroperitoneal lymph node dissection can be performed safely with similar oncologic outcomes to an open approach, while providing an option that may reduce the need for chemotherapy.
PMID: 32682794
ISSN: 2405-4569
CID: 4531802

A workflow to generate patient-specific three-dimensional augmented reality models from medical imaging data and example applications in urologic oncology

Wake, Nicole; Rosenkrantz, Andrew B; Huang, William C; Wysock, James S; Taneja, Samir S; Sodickson, Daniel K; Chandarana, Hersh
Augmented reality (AR) and virtual reality (VR) are burgeoning technologies that have the potential to greatly enhance patient care. Visualizing patient-specific three-dimensional (3D) imaging data in these enhanced virtual environments may improve surgeons' understanding of anatomy and surgical pathology, thereby allowing for improved surgical planning, superior intra-operative guidance, and ultimately improved patient care. It is important that radiologists are familiar with these technologies, especially since the number of institutions utilizing VR and AR is increasing. This article gives an overview of AR and VR and describes the workflow required to create anatomical 3D models for use in AR using the Microsoft HoloLens device. Case examples in urologic oncology (prostate cancer and renal cancer) are provided which depict how AR has been used to guide surgery at our institution.
PMID: 34709482
ISSN: 2365-6271
CID: 5042602

Overall Survival of Biopsy-confirmed T1B and T2A Kidney Cancers Managed With Observation: Prognostic Value of Tumor Histology

Michael, Jamie; Velazquez, Nermarie; Renson, Audrey; Tan, Hung-Jui; Rose, Tracy L; Osterman, Chelsea; Milowsky, Matthew; Raynor, Matt; Kang, Stella K; Huang, William C; Bjurlin, Marc A
INTRODUCTION/BACKGROUND:The natural history of T1b (4-7 cm) or T2a (> 7-10 cm) kidney cancers managed with observation is not well-understood. The aim of our study was to determine if the addition of histologic subtype to a predictive model of overall survival (OS) that includes covariates for competing risks in observed, biopsy-proven, T1b and T2a renal cell carcinomas (RCCs) improves the model's performance. MATERIALS AND METHODS/METHODS:We queried the National Cancer Database for patients with biopsy-proven stage T1b or T2a RCC and managed nonoperatively between 2004 and 2015. OS was estimated by Kaplan-Meier curves based on histologic subtype. The concordance index (c-index) from a Cox proportional hazards model was used to estimate the extent to which histologic subtypes predict survival for each stage when included in a model along with competing risks of age, gender, race/ethnicity, insurance status, area-level socioeconomic indicators, Charlson-Deyo index, and tumor grade. RESULTS:A total of 937 patients (754 with T1b and 185 with T2a) with biopsy-proven RCC were identified. Kaplan-Meier analysis suggested differences in OS by histologic subtype where sarcomatoid, followed by clear cell, papillary, and chromophobe, had the highest mortality risk at 1, 3, and 5 years. However, there was marginal improvement in the multivariable model of OS using competing risks and histology (c-index, 0.64 and 0.697) compared with competing risks alone (c-index, 0.631 and 0.671) for T1b and T2a RCCs, respectively. CONCLUSIONS:In patients with T1b or T2a RCC managed with observation, incorporation of histologic subtype into a risk-stratification model to determine prognostic OS did not improve modeling of OS compared with variables representing competing risks. Histologic subtype of observed T1b and T2a RCC appears to have prognostic OS value when not considering competing risks. These findings may impact the usefulness of renal biopsy to inform decision-making when managing patients with T1b and T2a renal tumors with observation.
PMID: 33582101
ISSN: 1938-0682
CID: 4799832

Application of the PRECISION Trial Biopsy Strategy to a Contemporary MRI-Targeted Biopsy Cohort: How Many Clinically Significant Prostate Cancers are Missed?

Feuer, Zachary; Meng, Xiaosong; Rosenkrantz, Andrew B; Kasivisvanathan, Veeru; Moore, Caroline M; Huang, Richard; Deng, Fang-Ming; Lepor, Herbert; Wysock, James S; Huang, William C; Taneja, Samir S
PURPOSE/OBJECTIVE:To demonstrate the generalizability of PRECISION findings and apply the PRECISION biopsy strategy to a contemporary cohort to characterize cancers missed by employing this strategy. MATERIALS AND METHODS/METHODS:629 men biopsied between 2/2015-9/2018 met PRECISION inclusion criteria. Men with PI-RADS 1-2 MRI were only biopsied if high clinical suspicion for cancer. Missed cancers were defined as prostate cancer (PCa) identified uniquely on systematic biopsy (SB) in men with PI-RADS 3-5 MRI, or on either SB or MRI-targeted prostate biopsy (MRI-TB) in men with PI-RADS 1-2 MRI. Outcomes included 1) clinically-significant PCa (csPCa), ≥Gleason grade group (GG) 2, detection rate (CDR), 2) missed csPCa rate upon application of PRECISION biopsy strategy, 3) GG distribution, core size, spatial orientation, and oncologic risk among missed cancers. RESULTS:Application of the PRECISION biopsy strategy to the study cohort resulted in avoidance of biopsy in 28%, similar MRI-TB CDR to PRECISION, reduction of GG1 CDR by 60%, and reduction of csPCa CDR by 19%. Missed csPCa were often <6 mm (54.5%), GG2 (67.3%), and low-risk by clinical nomogram (74.6%). GG1 cancers identified uniquely on SB were often contralateral to MRI target (46.4%), while missed csPCa was predominantly ipsilateral (81%). Limitations include biopsy of only men with high-risk clinical features among PIRADS 1-2 MRI, potentially overestimating the csPCa CDR. CONCLUSIONS:The study cohort demonstrated generalizability of PRECISION findings. Applying the PRECISION biopsy strategy greatly reduces GG1 CDR, while missing a small number of csPCa, typically small volume, low-risk, and GG2. Missed csPCa are predominantly ipsilateral to MRI target, possibly representing targeting error.
PMID: 33026927
ISSN: 1527-3792
CID: 4626952

Minimally Invasive Surgery for Patients with Locally Advanced and/or Metastatic Renal Cell Carcinoma

Becher, Ezequiel; Jericevic, Dora; Huang, William C
Despite advances in systemic therapy and immunotherapy, surgery continues to have a role in management of advanced renal cell carcinoma (aRCC). Minimally invasive surgery (MIS) is considered standard of care for smaller, localized tumors due to faster recovery without compromising oncologic outcomes. There are concerns about MIS for aRCC due to a potential risk of inferior oncologic outcomes and unusual patterns of disease recurrence. Recent studies, however, suggest that in properly selected patients with aRCC, MIS can provide improved peri-operative outcomes without compromising oncologic control.
PMID: 32600540
ISSN: 1558-318x
CID: 4502762

Current Landscape of Advanced and Metastatic Renal Cell Carcinoma Management [Editorial]

Huang, William C; Becher, Ezequiel
PMID: 32600542
ISSN: 1558-318x
CID: 4510892

Best practices in near-infrared fluorescence imaging with indocyanine green (NIRF/ICG)-guided robotic urologic surgery: a systematic review-based expert consensus

Cacciamani, Giovanni E; Shakir, A; Tafuri, A; Gill, K; Han, J; Ahmadi, N; Hueber, P A; Gallucci, M; Simone, G; Campi, R; Vignolini, G; Huang, W C; Taylor, J; Becher, E; Van Leeuwen, F W B; Van Der Poel, H G; Velet, L P; Hemal, A K; Breda, A; Autorino, R; Sotelo, R; Aron, M; Desai, M M; De Castro Abreu, A L
PURPOSE/OBJECTIVE:The aim of the present study is to investigate the impact of the near-infrared (NIRF) technology with indocyanine green (ICG) in robotic urologic surgery by performing a systematic literature review and to provide evidence-based expert recommendations on best practices in this field. METHODS:and Web of Science™ databases (up to April 2019). Experts in the field provided detailed pictures and intraoperative video-clips of different NIRF/ICG-guided robotic surgeries with recommendations for each procedure. A unique QRcode was generated and linked to each underlying video-clip. This new exclusive feature makes the present the first "dynamic paper" that merges text and figure description with their own video providing readers an innovative, immersive, high-quality and user-friendly experience. RESULTS:Our electronic search identified a total of 576 papers. Of these, 36 studies included in the present systematic review reporting the use of NIRF/ICG in robotic partial nephrectomy (n = 13), robotic radical prostatectomy and lymphadenectomy (n = 7), robotic ureteral re-implantation and reconstruction (n = 5), robotic adrenalectomy (n = 4), robotic radical cystectomy (n = 3), penectomy and robotic inguinal lymphadenectomy (n = 2), robotic simple prostatectomy (n = 1), robotic kidney transplantation (n = 1) and robotic sacrocolpopexy (n = 1). CONCLUSION/CONCLUSIONS:NIRF/ICG technology has now emerged as a safe, feasible and useful tool that may facilitate urologic robotic surgery. It has been shown to improve the identification of key anatomical landmarks and pathological structures for oncological and non-oncological procedures. Level of evidence is predominantly low. Larger series with longer follow-up are needed, especially in assessing the quality of the nodal dissection and the feasibility of the identification of sentinel nodes and the impact of these novel technologies on long-term oncological and functional outcomes.
PMID: 31286194
ISSN: 1433-8726
CID: 3976462

Impact of Surgical Approach on Conversion from Minimally Invasive Operation to Open Operation in 5 Procedures of Different Specialties [Meeting Abstract]

Oh, Daniel S.; de Groot, Alexander; Song, Chao; Kreaden, Usha; Huang, William
ISSN: 1072-7515
CID: 4686582