Faculty Bibliography

Purpose Neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care for the management of muscle-invasive bladder cancer (MIBC). Dose-dense cisplatin-based regimens have yielded favorable outcomes compared with standard-dose chemotherapy, yet the optimal neoadjuvant regimen remains undefined. We assessed the efficacy and tolerability of six cycles of neoadjuvant dose-dense gemcitabine and cisplatin (ddGC) in patients with MIBC. Patients and Methods In this prospective, multicenter phase II study, patients received ddGC (gemcitabine 2,500 mg/m² on day 1 and cisplatin 35 mg/m² on days 1 and 2) every 2 weeks for 6 cycles followed by RC. The primary end point was pathologic downstaging to non-muscle-invasive disease (< pT2N0). Patients who did not undergo RC were deemed nonresponders. Pretreatment tumors underwent next-generation sequencing to identify predictors of chemosensitivity. Results Forty-nine patients were enrolled from three institutions. The primary end point was met, with 57% of 46 evaluable patients downstaged to < pT2N0. Pathologic response correlated with improved recurrence-free survival and overall survival. Nineteen patients (39%) required toxicity-related dose modifications. Sixty-seven percent of patients completed all six planned cycles. No patient failed to undergo RC as a result of chemotherapy-associated toxicities. The most frequent treatment-related toxicity was anemia (12%; grade 3). The presence of a presumed deleterious DNA damage response (DDR) gene alteration was associated with chemosensitivity (positive predictive value for < pT2N0 [89%]). No patient with a deleterious DDR gene alteration has experienced recurrence at a median follow-up of 2 years. Conclusion Six cycles of ddGC is an active, well-tolerated neoadjuvant regimen for the treatment of patients with MIBC. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.

BACKGROUND:Radical nephrectomy (RN) with/without (±) thrombus excision (ThE) is the undisputed standard treatment for kidney cancer (KC) with renal or caval thrombus (Th). However, partial nephrectomy (PN) ± ThE may be considered in rare cases due to imperative (I) indications. OBJECTIVE:To evaluate the efficacy of IPN ± ThE and to compare it with RN ± ThE for KC with Th. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Records of 2,549 patients undergoing surgery for KC with Th at 24 institutions between 1971 and 2014 were retrospectively reviewed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/UNASSIGNED:Primary outcomes were overall survival (OS) and cancer specific survival (CSS), renal function variation after surgery and complications. Secondary outcomes were predictors of OS and CSS for IPN cases. To reduce bias IPN group was matched with RN using a propensity score with greedy algorithm on the basis of age, gender, tumor size, TNM, and histology. RESULTS AND LIMITATIONS/CONCLUSIONS:Forty-two patients underwent IPN ± Th. All thrombi were ≥level I; 5 patients experienced Clavien ≥ 3 complications with 2 complications-related deaths. At 27.3 (interquartile range: 7.1-47.7) months OS and CSS were 54.8% and 78.6%, respectively whereas at 9.7 (interquartile range: 1.4-43.7) months eGFR change was -17.3 ± 27.0ml/min. On univariate analysis tumour size, preoperative eGFR, transfusions, hospital stay, high serum creatinine, operating time, complications, lymphadenectomy, and metastases related to an increased risk of death. After matching (n = 38 per arm) no significant differences were present except for tumor necrosis (IPN = 39.5%; 15.8%; P = 0.01), thrombus level (P = 0.02), so as for operating time (P = 0.27), perioperative transfusions (P = 0.74) and complications (P = 0.35). A 5-year OS and CSS for IPN were 57.9% and 73.7%, respectively with no significant differences with RN (OS = 63.2, P = 0.611; CSS = 68.4, P>0.99). After 14.9 months creatinine and eGFR changes were (+0.4 ± 0.6mg/dl and -23.2 ± 37.3ml/min; P = 0.2879). CONCLUSIONS:In selected cases due to imperative indications PN ± ThE is a complex procedure and may be an alternative to RN ± ThE for KC with Th yielding noninferior oncological outcomes, functional outcomes, and complications. Further studies are needed to determine the role of PN ± ThE for KC with Th.

Purpose: To compare the effectiveness of standard treatment using partial nephrectomy and personalized management strategies for small renal tumors using a simulation model.
Material(s) and Method(s): A decision-analytic model was constructed to compare life expectancy of management strategies for small renal tumors using: (1) uniform treatment with partial nephrectomy; or personalized options incorporating (2) percutaneous ablation; (3) biopsy, with triage of renal cell carcinoma (RCC) to nephron-sparing therapy; (4) watchful waiting for growth; and (5) MRI-based selection of papillary RCC for watchful waiting. The model included patient age, gender, chronic kidney disease (CKD) stage, renal functional decline specific to treatment type, comorbidities, benign and malignant tumors, RCC subtypes, and differential risks of cancer progression. Decisionmaking based on histologic subtype from biopsy was tested in sensitivity analysis.
Result(s): Partial nephrectomy was favored in patients of all ages with normal renal function. Otherwise, personalized strategies improved life expectancy compared with partial nephrectomy. The favorability of personalized therapy depended upon CKD stage, tumor anatomy and comorbidities. For example, patients with CKD stages 2 or 3a and moderate or high tumor anatomic complexity were most effectively treated with MRI-based management when they had no comorbidities (+ 2.57 years for MRI vs. partial nephrectomy in CKD 3a, Nephrometry Score 10), but with Charlson Comorbidity Index >=1, biopsy or watchful waiting for growth were most effective. Biopsy-based management became most effective in multiple patient subcategories when histologic subtype guided treatment selection.
Conclusion(s): Personalized treatment selection for small renal tumors likely improves life expectancy for patients with abnormal renal function

BACKGROUND:Diffusion-weighted imaging (DWI) provides insight into the pathophysiology underlying renal dysfunction. Variants of DWI include intravoxel incoherent motion (IVIM), which differentiates between microstructural diffusion and vascular or tubular flow, and diffusion tensor imaging (DTI), which quantifies diffusion directionality. PURPOSE/OBJECTIVE:To investigate the reproducibility of joint IVIM-DTI and compare controls to presurgical renal mass patients. STUDY TYPE/METHODS:Prospective cross-sectional. SUBJECTS/METHODS:Thirteen healthy controls and ten presurgical renal mass patients were scanned. Ten controls were scanned twice to investigate reproducibility. FIELD STRENGTH/SEQUENCE/UNASSIGNED:Subjects were scanned on a 3T system using 10 b-values and 20 diffusion directions for IVIM-DTI in a study approved by the local Institutional Review Board. ASSESSMENT/RESULTS:Retrospective coregistration and measurement of joint IVIM-DTI parameters were performed. STATISTICAL ANALYSIS/METHODS:Parameter reproducibility was defined as intraclass correlation coefficient (ICC) >0.7 and coefficient of variation (CV) <30%. Patient data were stratified by lesion side (contralateral/ipsilateral) for comparison with controls. Corticomedullary differentiation was evaluated. RESULTS:In controls, the reproducible subset of REnal Flow and Microstructure AnisotroPy (REFMAP) parameters had average ICC = 0.82 and CV = 7.5%. In renal mass patients, medullary fractional anisotropy (FA) was significantly lower than in controls (0.227 ± 0.072 vs. 0.291 ± 0.044, P = 0.016 for the kidney contralateral to the mass and 0.228 ± 0.070 vs. 0.291 ± 0.044, P = 0.018 for the kidney ipsilateral). In the kidney ipsilateral to the mass, cortical Dp,radial was significantly higher than in controls (P = 0.012). Conversely, medullary Dp,axial was significantly lower in contralateral than ipsilateral kidneys (P = 0.027) and normal controls (P = 0.044). DATA CONCLUSION/UNASSIGNED:REFMAP-MRI parameters provide unique information regarding renal dysfunction. In presurgical renal mass patients, directional flow changes were noted that were not identified with IVIM analysis alone. Both contralateral and ipsilateral kidneys in patients show reductions in structural diffusivities and anisotropy, while flow metrics showed opposing changes in contralateral vs. ipsilateral kidneys. LEVEL OF EVIDENCE/METHODS:2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

OBJECTIVE:To describe novel 3-dimensional (3D) printing and augmented reality (AR) methods of image data visualization to facilitate anatomic understanding and to assist with surgical planning and decision-making during robotic partial nephrectomy. MATERIALS AND METHODS/METHODS:We created a video of the workflow for creating 3D printed and AR kidney models along with their application to robotic partial nephrectomy. Key steps in their development are (1) radiology examination (magnetic resonance imaging and computed tomography), (2) image segmentation, (3) preparing for 3D printing or AR, and (4) printing the model or deploying the model to the AR device. RESULTS:We demonstrate the workflow and utility of 3D printing and AR kidney models applied to a case of a 70-year-old woman with a 3.4 cm renal mass on her left pelvic kidney. A 3D printed kidney model was created using multicolor PolyJet technology (Stratasys J750), allowing a transparent kidney with coloring of the renal tumor, artery, vein, and ureter. An AR kidney model was created using Unity 3D software and deployed to a Microsoft HoloLens. The 3D printed and AR models were used preoperatively and intraoperatively to assist in robotic partial nephrectomy. To date, we have created 15 3D printed and AR kidney models to use for robotic partial nephrectomy planning and intraoperative guidance. The application of 3D printed and AR models is safe and feasible and can influence surgical decisions. CONCLUSION/CONCLUSIONS:Our video highlights the workflow and novel application of 3D printed and AR kidney models to provide preoperative guidance for robotic partial nephrectomy. The insights gained from advanced visualization can influence surgical planning decisions.

INTRODUCTION/BACKGROUND:We sought to evaluate the discordance between ureteroscopic biopsy and surgical pathology for grading and staging of upper tract urothelial carcinoma (UTUC) and to establish preoperative predictors of aggressive tumors. METHODS:We performed a retrospective review of 314 patients who underwent ureteroscopic biopsy followed by surgical management for UTUC from 2000-2016 at three institutions. Our primary outcomes were muscle-invasive (≥pT2) disease at surgical pathology and upgrading of clinical low-grade (cLG) tumors to pathologic high-grade (pHG). RESULTS:At biopsy, 61% of patients had high-grade (cHG) tumors, and 21% had subepithelial connective tissue invasion (cT1+). On final pathology, 79% had pHG tumors, and 45% had stage ≥pT2. On multivariate analysis, advanced age, cHG, and cT1+ were independently associated with ≥pT2. The combined presence of cHG and cT1+ had a PPV of 86% for muscle invasion, and the combined absence of cHG and cT1+ had a NPV of 80%. The likelihood of missing invasion on biopsy in patients with muscle-invasive disease was increased when biopsy fragments were limited to ≤1mm. Among patients with cLG disease on biopsy, 51% were upgraded at surgery. The presence of positive urine cytology was associated with an increased risk of upgrading; however, this was not statistically significant. CONCLUSIONS:cHG, cT1+ on biopsy, and advanced patient age are independent risk factors for muscle-invasive UTUC. There is a significant risk of upgrading among patients with cLG tumors on biopsy, especially when urine cytology is positive. The predictive value of biopsy can likely be improved by more extensive ureteroscopic sampling.

PURPOSE/OBJECTIVE:We compared blue light flexible cystoscopy with white light flexible cystoscopy for the detection of bladder cancer during surveillance. MATERIALS AND METHODS/METHODS:Patients at high risk for recurrence received hexaminolevulinate intravesically before white light flexible cystoscopy and randomization to blue light flexible cystoscopy. All suspicious lesions were documented. Patients with suspicious lesions were referred to the operating room for repeat white and blue light cystoscopy. All suspected lesions were biopsied or resected and specimens were examined by an independent pathology consensus panel. The primary study end point was the proportion of patients with histologically confirmed malignancy detected only with blue light flexible cystoscopy. Additional end points were the false-positive rate, carcinoma in situ detection and additional tumors detected only with blue light cystoscopy. RESULTS:Following surveillance 103 of the 304 patients were referred, including 63 with confirmed malignancy, of whom 26 had carcinoma in situ. In 13 of the 63 patients (20.6%, 95% CI 11.5-32.7) recurrence was seen only with blue light flexible cystoscopy (p <0.0001). Five of these cases were confirmed as carcinoma in situ. Operating room examination confirmed carcinoma in situ in 26 of 63 patients (41%), which was detected only with blue light cystoscopy in 9 of the 26 (34.6%, 95% CI 17.2-55.7, p <0.0001). Blue light cystoscopy identified additional malignant lesions in 29 of the 63 patients (46%). The false-positive rate was 9.1% for white and blue light cystoscopy. None of the 12 adverse events during surveillance were serious. CONCLUSIONS:Office based blue light flexible cystoscopy significantly improves the detection of patients with recurrent bladder cancer and it is safe when used for surveillance. Blue light cystoscopy in the operating room significantly improves the detection of carcinoma in situ and detects lesions that are missed with white light cystoscopy.

Introduction & Objectives: Radical nephrectomy (RN) +/- thrombectomy is the standard treatment for kidney cancer (KC) with venous thrombus (VT). Whilst in case of localised KC without VT minimally invasive (MI) techniques are largely used, little evidence exists on the laparoscopic approach for the treatment of KC with VT. Materials & Methods: In a multicentre series including 2552 patients from the International Renal Cell Carcinoma-Venous Thrombus Consortium database receiving surgery for KC + VT (T stage >=3a), 120 had a MI approach. Primary outcomes were post-operative renal function, evaluated through serum creatinine levels (sCr) and eGFR, cancer specific survival (CSS) and overall survival (OS). Complications and comorbidities were graded using the Clavien-dindo and ASA classification respectively. Thrombus level was recorded according to the Mayo Clinic Classification. Results: One hundred and ten procedures were laparoscopic whilst 10 were robotic. Mean age and BMI were 66.48 +/-11.24 years and 27.9 +/-5.27 respectively. Approximately half had an ASA score <=2 (50.98%). Mean Pre-operative eGFR was 77.93 +/-30.6mL/min. Mean tumour size was 6.8 +/-2.57cm; 7.89% and 13.33% were N+ or M+ respectively. Thrombus level was confined to the renal vein or to its segmental branches (level<=I) in 94.53%. Mean operating time was 197.05 +/-88.35min with a mean blood loss of 682.37 +/-2156.61mL. Overall 14.42%, 1.11% and 6.73% underwent lymphadenectomy, cardiopulmonary bypass and cavotomy respectively. Major complications (Clavien >=3) occurred in almost 1 on 4 patients (24.8%) with no intraoperative deaths. Mean hospital stay was 7.97 +/-8.50days. After a mean follow up of 935.33 +/-862.14days, mean eGFR variation was -2.04 +/-47.26 mL/min; CSS and OS were 75.85% and 72.65% respectively with 80.26% of the patients being free of recurrence, 7.89% having disease progression and 11.84% stable disease. Conclusions: In KC + VT MI surgery may be feasible yielding acceptable oncological and functional outcomes. However, blood loss, hospital stay and high grade complications remain relatively high. Further large prospective studies are needed to evaluate the role of MI surgery for KC + VT

E-cigarette smoke delivers stimulant nicotine as aerosol without tobacco or the burning process. It contains neither carcinogenic incomplete combustion byproducts nor tobacco nitrosamines, the nicotine nitrosation products. E-cigarettes are promoted as safe and have gained significant popularity. In this study, instead of detecting nitrosamines, we directly measured DNA damage induced by nitrosamines in different organs of E-cigarette smoke-exposed mice. We found mutagenic O6-methyldeoxyguanosines and γ-hydroxy-1,N2 -propano-deoxyguanosines in the lung, bladder, and heart. DNA-repair activity and repair proteins XPC and OGG1/2 are significantly reduced in the lung. We found that nicotine and its metabolite, nicotine-derived nitrosamine ketone, can induce the same effects and enhance mutational susceptibility and tumorigenic transformation of cultured human bronchial epithelial and urothelial cells. These results indicate that nicotine nitrosation occurs in vivo in mice and that E-cigarette smoke is carcinogenic to the murine lung and bladder and harmful to the murine heart. It is therefore possible that E-cigarette smoke may contribute to lung and bladder cancer, as well as heart disease, in humans.

OBJECTIVES: To study the effect of lymph node dissection (LND) at the time of nephrectomy and tumor thrombectomy on oncological outcomes in patients with renal cell carcinoma (RCC) and tumor thrombus. PATIENTS AND METHODS: The records of 1,978 patients with RCC and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1985 to 2014 at 24 centers were analyzed. None of the patients had distant metastases. Extent and pathologic results of LND were compared with respect to cancer-specific survival (CSS). Multivariable Cox regression models were used to quantify the effect of multiple covariates. RESULTS: LND was performed in 1,026 patients. In multivariable analysis, the presence of LN metastasis, the number of positive LNs, and LN density were independently associated with cancer-specific mortality (CSM). Clinical node-negative (cN-) disease was documented in 573 patients, 447 of them underwent LND with 43 cN- patients (9.6%) revealing positive LNs at pathology. LN positive cN- patients showed significantly better CSS when compared to LN positive cN+ patients. In multivariable analysis, positive cN status in LN positive patients was a significant predictor of CSM (HR, 2.923; P = 0.015). CONCLUSIONS: The number of positive nodes harvested during LND and LN density was strong prognostic indicators of CSS, while number of removed LNs did not have a significant effect on CSS. The rate of pN1 patients among clinically node-negative patients was relatively high, and LND in these patients suggested a survival benefit. However, only a randomized trial can determine the absolute benefit of LND in this setting.