Mitochondrial complex I promotes kidney cancer metastasis.

Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.

Mitochondrial metabolism in primary and metastatic human kidney cancers.

Most kidney cancers display evidence of metabolic dysfunction1-4 but how this relates to cancer progression in humans is unknown. We used a multidisciplinary approach to infuse 13C-labeled nutrients during surgical tumour resection in over 70 patients with kidney cancer. Labeling from [U-13C]glucose varies across cancer subtypes, indicating that the kidney environment alone cannot account for all metabolic reprogramming in these tumours. Compared to the adjacent kidney, clear cell renal cell carcinomas (ccRCC) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in organotypic slices cultured ex vivo, indicating that suppressed labeling is tissue intrinsic. Infusions of [1,2-13C]acetate and [U-13C]glutamine in patients, coupled with respiratory flux of mitochondria isolated from kidney and tumour tissue, reveal primary defects in mitochondrial function in human ccRCC. However, ccRCC metastases unexpectedly have enhanced labeling of TCA cycle intermediates compared to primary ccRCCs, indicating a divergent metabolic program during ccRCC metastasis in patients. In mice, stimulating respiration in ccRCC cells is sufficient to promote metastatic colonization. Altogether, these findings indicate that metabolic properties evolve during human kidney cancer progression, and suggest that mitochondrial respiration may be limiting for ccRCC metastasis but not for ccRCC growth at the site of origin.

Validation of testicular germ cell tumor staging in nationwide cancer registries.

INTRODUCTION: Nationwide cancer registries such as the National Cancer Database and Surveillance, Epidemiology, and End Results rely on accurate data from tumor registries to formulate hypotheses and report outcomes and treatment patterns. We evaluated the accuracy of our institutional registry for testicular germ cell tumors by comparing data abstracted by urologists with data abstracted by registry. METHODS: We performed a retrospective review of patients receiving initial diagnosis and treatment for germ cell tumors at our hospital system from 2005 to 2016. We compared coding for American Joint Committee on Cancer TNMS staging, overall composite stage, and first-line treatment between urologists and tumor registry at the time of diagnosis. RESULTS: Paired staging from registry and urologist was available for 80 patients. T, N, M, and S-staging were accurate for 90%, 81%, 94%, and 54% of records, respectively. Composite staging and first-line treatment were concordant for 39% and 90% of patients, respectively. A separate review of 33 Stage IS patients per registry for composite staging revealed 15% concordance. CONCLUSION: Our institutional tumor registry had substantial inconsistencies in accurately staging N stage, S stage, and thus, composite stage for testicular cancer. An educational intervention to improve abstraction by registry led to increased concordance. Assuming similar discrepancies may exist at other institutions and for other cancer types, caution should be used when interpreting staging data in nationwide cancer registries. This sheds light on the need for improved clarification of staging guidelines, dynamic institutional internal auditing, and training reform within cancer registries.

Predictive model for systemic recurrence following cisplatin-based neoadjuvant chemotherapy and radical nephroureterectomy for high risk upper tract urothelial carcinoma.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is increasingly used prior to radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Systemic recurrence (SR) carries a dismal prognosis. We sought to determine risk factors associated with SR in this setting. METHODS: We evaluated a multi-center database of patients with UTUC who received cisplatin-based NAC before RNU. Final pathology at RNU was dichotomized into ypT<2 vs ypT≥2. Univariable and multivariable analyses were performed to identify risk factors associated with SR. Three groups were defined based on the number of significant risk factors (groups 1, 2, 3 for 0-1, 2, 3 risk factors, respectively) and evaluated for recurrence-free survival (RFS) using the Kaplan-Meier method. RESULTS: 106 patients were identified between 2004 and 2018. Median age was 67.0 years [IQR = 61-73.3]; 57 (54%) and 49 (46 %) patients received MVAC and GC, respectively. Final pathological stage was ypT<2 in 57 (54%); 23% (24/106) had SR. On univariable analysis, pathological variables on final specimen including ypT≥2, lymphovascular invasion (ypLVI), and nodal involvement were associated with SR. On multivariable analysis, ypLVI OR = 4.1 (95% CI 1.2-13.6; P = 0.024) and pathological nodal involvement OR = 4.5 (95% CI 1.3-15.7; P = 0.017) were predictive of recurrence. Stratifying by the number of risk factors, the 2-year RFS was 95%, 55%, and 18% for groups 1, 2, and 3 respectively (log-rank <0.001). CONCLUSION: This model evaluates the risk of SR following NAC and RNU to guide counseling and decision-making after surgery. Adverse pathological variable including ypLVI and nodal involvement, in combination with ypT-stage, are strongly associated with SR.

Robotic Nephroureterectomy vs Laparoscopic Nephroureterectomy: Increased Utilization, Rates of Lymphadenectomy, Decreased Morbidity Robotically.

Introduction and Objective: Robotic radical nephroureterectomy (RRNU) may offer advantages over laparoscopic radical nephroureterectomy (LRNU). The purpose of this study is to evaluate the overall survival (OS) of patients with upper tract urothelial carcinoma (UTUC) who underwent RRNU vs LRNU and identify factors that account for differences. Methods: The National Cancer Database was queried from 2010 to 2016 for patients with American Joint Committee on Cancer 6th/7th edition Stage I/II/III UTUC. Kaplan-Meier analysis compared LRNU and RRNU OS. Univariate analysis detected differences between the groups. Cox regression determined factors associated with mortality rate. Logistic regression identified predictors of a lymph node dissection (LND) and 90-day mortality rate. Results: A total of 2631 patients met the criteria, 1129 of whom underwent RRNU and 1502 LRNU, with a follow-up of 33 and 35 months, respectively (p = 0.063). RRNU had a median OS of 71.1 vs 62.6 months (p = 0.033). LRNU patients were older (72.7 vs 71.4, p < 0.001) and had no differences in comorbidities, pathologic T stage, or grade. The LRNU cohort was less likely to undergo LND (19% vs 35%, p < 0.001) and had a lower median lymph node yield (3 vs 4, p < 0.001). LRNU patients more likely underwent conversion to an open procedure, had longer hospital stays, and higher 30- and 90-day mortality rates. LRNU was independently associated with mortality rate (p = 0.030). Age, grade, positive margins, pT/pN stage were associated with mortality rate. Younger age, RRNU, surgery at an academic center, and neoadjuvant chemotherapy predicted an LND. Conclusions: RRNU demonstrated increased rates of LND and may offer a short-term morbidity benefit to LRNU. Survival differences may be due to improved characterization of disease through LND.

Prospective performance of clear cell likelihood scores (ccLS) in renal masses evaluated with multiparametric magnetic resonance imaging.

OBJECTIVES: Solid renal masses have unknown malignant potential with commonly utilized imaging. Biopsy can offer a diagnosis of cancer but has a high non-diagnostic rate and complications. Reported use of multiparametric magnetic resonance imaging (mpMRI) to diagnose aggressive histology (i.e., clear cell renal cell carcinoma (ccRCC)) via a clear cell likelihood score (ccLS) was based on retrospective review of cT1a tumors. We aim to retrospectively assess the diagnostic performance of ccLS prospectively assigned to renal masses of all stages evaluated with mpMRI prior to histopathologic evaluation. METHODS: In this retrospective cohort study from June 2016 to November 2019, 434 patients with 454 renal masses from 2 institutions with heterogenous patient populations underwent mpMRI with prospective ccLS assignment and had pathologic diagnosis. ccLS performance was assessed by contingency table analysis. The association between ccLS and ccRCC was assessed with logistic regression. RESULTS: Mean age and tumor size were 60 ± 13 years and 5.4 ± 3.8 cm. Characteristics were similar between institutions except for patient age and race (both p < 0.001) and lesion laterality and histology (both p = 0.04). The PPV of ccLS increased with each increment in ccLS (ccLS1 5% [3/55], ccLS2 6% [3/47], ccLS3 35% [20/57], ccLS4 78% [85/109], ccLS5 93% [173/186]). Pooled analysis for ccRCC diagnosis revealed sensitivity 91% (258/284), PPV 87% (258/295) for ccLS ≥ 4, and specificity 56% (96/170), NPV 94% (96/102) for ccLS ≤ 2. Diagnostic performance was similar between institutions. CONCLUSIONS: We confirm the optimal diagnostic performance of mpMRI to identify ccRCC in all clinical stages. High PPV and NPV of ccLS can help inform clinical management decision-making. KEY POINTS: • The positive predictive value of the clear cell likelihood score (ccLS) for detecting clear cell renal cell carcinoma was 5% (ccLS1), 6% (ccLS2), 35% (ccLS3), 78% (ccLS4), and 93% (ccLS5). Sensitivity of ccLS ≥ 4 and specificity of ccLS ≤ 2 were 91% and 56%, respectively. • When controlling for confounding variables, ccLS is an independent risk factor for identifying clear cell renal cell carcinoma. • Utilization of the ccLS can help guide clinical care, including the decision for renal mass biopsy, reducing the morbidity and risk to patients.

Oncologic outcomes of radical nephroureterectomy (RNU).

Radical nephroureterectomy is the mainstay of surgical treatment for upper tract urothelial carcinoma (UTUC), a disease which comprises approximately 5% of urothelial malignancies. Minimally-invasive and nephron-sparing interventions have been explored, although thus far have not shown comparable oncologic outcomes except in a relatively narrow set of patients. Due to the relative rarity of the disease, it has taken decades and multi-disciplinary efforts to sufficiently identify prognostic factors of oncologic outcomes. Despite these efforts, however, oncologic outcomes of nephroureterectomy have remained remarkably stable over the past 30 years. New techniques, such as laparoscopic and robotic surgery, have been applied to this procedure. High level evidence regarding equivalent oncologic outcomes is lacking and open surgery remains the standard of care for high-stage disease, although there is a role for laparoscopic and robotic nephroureterectomy. The importance of bladder cuff removal in improving oncologic outcomes has been broadly accepted, although there is no consensus as to the most oncologically appropriate technique. There does appear to be evidence that endoscopic techniques confer worse oncologic control. The role of lymphadenectomy remains controversial, although there is evidence that increased nodal yield could have oncologic benefit. Given disease heterogeneity and varied technical approaches to the procedure, no consensus standardized template has been identified. There is level 1 evidence for the use of intravesical chemotherapy peri-operatively and that this intervention can improve the risk of intravesical recurrence. Advances in systemic neoadjuvant and adjuvant chemotherapy have yielded promising results and are likely to become standard of care for patients without contraindications. Immunotherapy and targeted biologic agents are also likely to improve the surgical efficacy of radical nephroureterectomy as well. Ultimately, more high level evidence is needed to identify successful surgical and medical approaches to UTUC and multi-institutional collaboration is critical to this progress.

Feasibility and Safety of Robotic Excision of Ipsilateral Retroperitoneal Recurrence After Nephrectomy for Renal Cell Carcinoma.

OBJECTIVE: To determine feasibility and safety of robotic excision of local ipsilateral recurrences after nephrectomy for renal cell carcinoma (RCC). Surgical resection is an option for treatment of low burden locally recurrent RCC, potentially delaying the use of systemic therapy. This has historically been performed by open technique, which can impart significant morbidity. We present our experience with robotic excision. METHODS: We reviewed our institutional experience of patients with surgically excised RCC who underwent robotic excision of ipsilateral retroperitoneal recurrence in 2015-2018. Demographics and clinicopathological variables, including operative and postoperative outcomes, were examined. RESULTS: Twelve robotic excisions of ipsilateral local recurrences were performed in our hospital in 2015-2018. Mean age was 65.48 years (± standard deviation, SD: 9.51), 10 patients were male, and mean BMI 34.75 kg/m2 (± 6.71). Nine patients recurred after radical nephrectomy, and 3 after partial nephrectomy. Mean size of recurrence was 2.97 cm (±1.69). Mean anesthesia time, EBL, and LOS were 213 minutes (± 38.92), 152 mL (± 130.75), and 43 hours (± 12.64), respectively. All surgical margins were negative. No surgical complications were reported. Median follow-up was 19.0 months [interquartile range, IQR 12.7-30.0]. Five patients out of 12 recurred following robotic excision, these were treated with either systemic therapy, radiation, or palliative surgeries. Mean time for subsequent recurrence was 26.5 months. CONCLUSION: In this small case series, robotic excision of ipsilateral RCC retroperitoneal recurrence appears safe, technically feasible, and oncologically sound in expert hands and carefully selected patients.

Overcoming sociodemographic factors in the care of patients with testicular cancer at a safety net hospital.

BACKGROUND: The objective of this study was to determine whether standardized treatment of germ cell tumors (GCTs) could overcome sociodemographic factors limiting patient care. METHODS: The records of all patients undergoing primary treatment for GCTs at both a public safety net hospital and an academic tertiary care center in the same metropolitan area were analyzed. Both institutions were managed by the same group of physicians in the context of multidisciplinary cancer care. Patients were grouped by care center; clinicopathologic features and outcomes were analyzed. RESULTS: Between 2006 and 2018, 106 and 95 patients underwent initial treatment for GCTs at the safety net hospital and the tertiary care center, respectively. Safety net patients were younger (29 vs 33 years; P = .005) and were more likely to be Hispanic (79% vs 11%), to be uninsured (80% vs 12%; P < .001), to present via the emergency department (76% vs 8%; P < .001), and to have metastatic (stage II/III) disease (42% vs 26%; P = .025). In a multivariable analysis, an absence of lymphovascular invasion (odds ratio [OR], 0.30; P = .008) and an embryonal carcinoma component (OR, 0.36; P = .02) were associated with decreased use of adjuvant treatment for stage I patients; hospital setting was not (OR, 0.67; P = .55). For patients with stage II/III nonseminomatous GCTs, there was no difference in the performance of postchemotherapy retroperitoneal lymph node dissection between the safety net hospital and the tertiary care center (52% vs 64%; P = .53). No difference in recurrence rates was observed between the cohorts (5% vs 6%; P = .76). CONCLUSIONS: Sociodemographic factors are often associated with adverse clinical outcomes in the treatment of GCTs; they may be overcome with integrated, standardized management of testicular cancer.

Intraoperative prophylactic intravesical chemotherapy to reduce bladder recurrence following radical nephroureterectomy.

PURPOSE: Single, postoperative instillation of prophylactic intravesical chemotherapy (pIVC) is effective in reducing bladder cancer recurrences following radical nephroureterectomy (RNU). Despite high level evidence, pIVC is underutilized. Intraoperative pIVC (I-pIVC) may be easier and safer to implement than postoperative pIVC (P-pIVC). We aimed to evaluate the efficacy of I-pIVC during RNU. MATERIALS AND METHODS: Retrospective analysis of patients undergoing RNU and I-pIVC or postoperative pIVC (P-pVC) with 20 to 40 mg mitomycin-C or 1 to 2 g gemcitabine. Recurrence rates were evaluated using the Kaplan-Meier curves and log rank test. Cox regression was used for univariable and multivariable analysis. RESULTS: One hundred and thirty-seven patients were included in the final analysis. 81% (111/137) had I-pIVC and 19% (26/137) had P-pIVC. In the I-pIVC group higher rates of HG, muscle invasive disease and gemcitabine use were observed. Overall, 74% (101/137) and 26% (36/137) had mitomycin-C and gemcitabine instillations, respectively. Within 12 months 14% (19/137) of the patients experienced bladder recurrence. Median time to bladder recurrence was 7 months (range 3-27). Twelve months bladder recurrence-free survival rates were 82% for the I-pIVC group, and 72% for the P-pIVC group ((log rank P = 0.365). CONCLUSIONS: I-pIVC during RNU may reduce bladder recurrence rates. Bladder recurrence rates are comparable to those reported using postoperative instillations. Intraoperative instillations may be easier to implement and may increase usage rates.

Does grossly complete transurethral resection improve response to neoadjuvant chemotherapy?

INTRODUCTION: There is controversy regarding the benefit of a grossly complete transurethral resection of bladder tumor (TURBT) for muscle-invasive bladder cancer (MIBC) in patients prior to neoadjuvant chemotherapy (NAC). Advocates for this approach suggest a higher response rate to NAC, while others suggest this can increase the surgical risk for no clear benefit. METHODS: We retrospectively reviewed our institutional radical cystectomy (RC) database from 2011 to 2018 for patients who received an adequate course of cisplatin-based NAC for nonmetastatic MIBC. Univariable and multivariable logistic regression analyses were performed to identify factors associated with complete response [ypT0] or no residual muscle invasive bladder cancer [ypT < 2] following NAC based on clinicopathologic characteristics and grossly complete or incomplete TURBT. RESULTS: A total of 167 patients received NAC followed by RC for MIBC during the study period and 100 patients were included in the analysis due to known status of the completeness of TURBT-of these 49 patients underwent complete resection while 51 patients underwent incomplete resection prior to NAC. There were no significant differences in baseline clinicopathologic characteristics between patients who had complete vs. incomplete TURBT. At the time of RC, the overall ypT0 rate was 24% (n = 24), while the overall rate of ypT < 2 was 45%. On logistic regression, there was no association between completeness of TURBT and ypT0 or ypT < 2. Age, histology, and organ-confined disease were not significantly associated with response to NAC. Only smoking status (current or prior history) was negatively associated with ypT0 on univariable and multivariable analysis (odds ratio = 0.36, 95% confidence interval: [0.14-0.91], P = 0.031). CONCLUSION: We found no association between response to cisplatin-based NAC and completeness of TURBT in a cohort of MIBC patients. The study is limited by its retrospective nature and lack of ability to predict response to NAC based on TURBT tissue evaluation.

Pathologic stage as a surrogate for oncologic outcomes after receipt of neoadjuvant chemotherapy for high-grade upper tract urothelial carcinoma.

OBJECTIVE: Whether pathologic stage at radical nephroureterectomy (RNU) can serve as an appropriate surrogate for oncologic outcomes in patients with high-grade (HG) upper tract urothelial carcinoma (UTUC) treated with neoadjuvant chemotherapy (NAC) is not defined. We sought to determine whether patients who achieve pathologically non-muscle-invasive (ypT0, ypTa, ypT1, ypTis) HG UTUC after receipt of NAC exhibit oncologic outcomes comparable to those who are inherently low stage without chemotherapy. METHODS: We identified 647 UTUC patients who underwent RNU among 3 institutions from 1993to2016. Patients with low or unknown grade, pathologic muscle invasion, or receipt of adjuvant chemotherapy were excluded. We compared clinicopathologic data and oncologic outcomes between pT0-1 and ypT0-1 patients. Kaplan-Meier analysis was used to assess overall (OS), cancer-specific (CSS), and systemic recurrence-free (RFS) survival. Predictors of these endpoints were identified using Cox regression. RESULTS: 234 (43 ypT0-1, 191 pT0-1) patients with HG UTUC were included. Two patients exhibited pathologic complete response after NAC. OS (P = 0.055), CSS (P = 0.152), and RFS (P = 0.098) were similar between ypT0-1 and pT0-1 patients. Predictors of worse outcomes included African-American race (RFS, CSS, and OS), Charlson score (OS), and systemic recurrence (OS and CSS). CONCLUSIONS: Patients with HG UTUC who achieve ypT0-1 stage after NAC exhibit favorable oncologic outcomes comparable to those inherently non-muscle-invasive who do not receive chemotherapy. Improvements in clinical staging will play an important role in better defining candidacy for NAC in treating HG UTUC while minimizing overtreatment. Furthermore, pathologic stage may serve as an appropriate early surrogate for oncologic endpoints in designing clinical trials.

Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: An analysis of the National Cancer Database.

OBJECTIVES: Despite immune checkpoint inhibitor (ICI) approval for metastatic renal cell carcinoma (mRCC) in 2015, cytoreductive nephrectomy (CN) is guided by extrapolation from earlier classes of therapy. We evaluated survival outcomes, timing, and safety of combining CN with modern immunotherapy (IO) for mRCC. METHODS: From 96,329 renal cancer cases reported to the NCDB between 2015 and 2016, we analyzed 391 surgical candidates diagnosed with clear cell mRCC treated with IO ± CN and no other systemic therapies. Primary outcome was overall survival (OS) stratified by the performance of CN (CN + IO vs. IO alone). Secondary outcomes included OS stratified by the timing of CN, pathologic findings, and perioperative outcomes. RESULTS: Of 391 patients, 221 (56.5%) received CN + IO and 170 (43.5%) received IO only. Across a median follow-up of 14.7 months, patients who underwent CN + IO had superior OS (median NR vs. 11.6 months; hazard ratio 0.23, P < 0.001), which was upheld on multivariable analyses. IO before CN resulted in lower pT stage, grade, tumor size, and lymphovascular invasion rates compared to upfront CN. Two of 20 patients (10%) undergoing CN post-IO achieved complete pathologic response in the primary tumor (pT0). There were no positive surgical margins, 30-day readmissions, or prolonged length of stay in patients undergoing delayed CN. CONCLUSION: Using a large, national, registry-based cohort, we provide the first report of survival outcomes in mRCC patients treated with CN combined with modern IO. Our findings support an oncologic role for CN in the ICI era and provide preliminary evidence regarding the timing and safety of CN relative to IO administration.

Rational Approaches to Treatment Duration with Immunotherapy in Metastatic Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for metastatic renal cell carcinoma. The appropriate duration for ICI treatment is not clear, however. Analyses of landmark trials reveal that some patients exhibit sustained durable responses to ICIs even after treatment discontinuation, resulting in prolonged treatment-free intervals that can mitigate potential toxicities and the considerable financial burden associated with treatment. Adaptive approaches with PD1 monotherapy and combination immunotherapy tailored to tumor response are ongoing. More efforts will be needed to clarify the ideal ICI dosing regimen to maximize oncological benefit while minimizing treatment-related adverse effects and costs. PATIENT SUMMARY: We reviewed considerations surrounding treatment strategies when using immunotherapy to treat patients with kidney cancer. It is clear that some patients can experience prolonged cancer control when discontinuing immunotherapy. However, individualized approaches will be necessary to strike a balance between optimizing patient outcomes and reducing unnecessary side effects and cost.

Nationwide Patterns of Care for Stage II Nonseminomatous Germ Cell Tumor of the Testicle.

BACKGROUND: Management strategies for advanced testicular cancer published from a few, high-volume clinical centers may not be generalizable. OBJECTIVE: To discern treatment patterns for stage II nonseminomatous germ cell tumor (NSGCT) in a nationwide cancer registry. DESIGN, SETTING, AND PARTICIPANTS: The National Cancer Database was queried for patients with a stage II NSGCT from 2004 to 2014. Patients were stratified by clinical nodal status: cN1/stage IIA, cN2/stage IIB, and cN3/stage IIIC. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression was performed to determine factors independently associated with primary retroperitoneal lymph node dissection (RPLND), primary chemotherapy, and postchemotherapy RPLND (PC-RPLND). RESULTS AND LIMITATIONS: A total of 2203 patients (stages IIA, n=1060; IIB, n=869; and IIC, n=274) met the inclusion criteria. Overall, 83% of patients underwent primary chemotherapy, while 17% underwent primary RPLND. Stratified by stage, use of primary chemotherapy was 78%, 88%, and 86% for stages IIA, IIB, and IIC, respectively. Overall, 24% of patients underwent PC-RPLND. Factors independently associated with a lower likelihood of undergoing primary RPLND were a more recent diagnosis and a higher clinical nodal stage. Conversely, patients treated at high-volume facilities were more likely to receive primary RPLND. Factors associated with a higher likelihood of undergoing PC-RPLND included a higher clinical nodal stage, treatment at a high-volume center, and a greater distance of patient travel. Associations based on serum tumor markers could not be assessed. CONCLUSIONS: For clinical stage II NSGCT, nationwide utilization of primary chemotherapy is increasing compared with RPLND and is the preferred therapy for more advanced nodal disease. Primary RPLND may be underutilized in stage IIA disease. Utilization of PC-RPLND is driven by nodal stage as well as accessibility of a high-volume center. PATIENT SUMMARY: The use of primary retroperitoneal lymph node dissection (RPLND) in early nodal disease is declining, while upfront chemotherapy is increasingly utilized. Primary RPLND may identify patients who are actually pN0 and would not benefit from systemic chemotherapy. Primary RPLND and postchemotherapy RPLND are performed more frequently at centers of excellence.

Advancements in the clinical management of upper tract urothelial carcinoma.

Introduction: Upper tract urothelial carcinoma (UTUC) remains a complex disease to manage given challenges in staging, surgical resection, use of perioperative therapy, and prevention of bladder recurrences. High-level evidence is limited to guide management; however, recent data have shifted treatment paradigms. We intend to review recent evidence on advancements in the clinical management for UTUC.Areas covered: This review summarizes advancements in pre-operative work-up, surgical technique, and the use of intravesical and systemic therapy in both the neoadjuvant and adjuvant settings. Special comment is made on progress in the genomics of UTUC and how that can inform clinical practice.Expert opinion: Advancements in the clinical management of UTUC are most prominently being made in the neoadjuvant chemotherapy setting. Although level I evidence is sparse, data from both single and multi-institutional retrospective studies strongly encourage the use of neoadjuvant chemotherapy especially in high-risk or advanced-stage patients.

Pathologic response and surgical outcomes in patients undergoing nephrectomy following receipt of immune checkpoint inhibitors for renal cell carcinoma.

OBJECTIVE: To evaluate the pathologic response, safety, and feasibility of nephrectomy following receipt of immune checkpoint inhibition (ICI) for renal cell carcinoma (RCC). METHODS: Patients who underwent nephrectomy for RCC after exposure to nivolumab monotherapy or combination ipilimumab/nivolumab were reviewed. Primary surgical outcomes included operative time (OT), estimated blood loss (EBL), length of stay (LOS), readmission rates, and complication rates. Pathologic response in the primary and metastatic sites constituted secondary outcomes. RESULTS: Eleven nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 180 days. Six patients received 1 to 4 cycles of ipilimumab/nivolumab, while 5 received 2 to 12 infusions of nivolumab preoperatively. Five surgeries were performed laparoscopically, and 4 patients underwent concomitant thrombectomy. One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no detectable malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 ml, and 4 days, respectively. Four patients experienced a complication, including 3 that were addressed with interventional radiology procedures. One patient died of progressive disease >3 months after surgery, and 1 patient succumbed to pulmonary embolism complicated by sepsis. No complications or readmissions were noted in 6 patients. CONCLUSION: Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. Timing of the nephrectomy relative to checkpoint dosing did not seem to impact outcome. Biopsies of lesions responding radiographically to ICI may warrant attention prior to surgical excision.

Current advances in BCG-unresponsive non-muscle invasive bladder cancer.

Introduction: The current first line therapy for high grade (HG) non-muscle invasive bladder cancer (NMIBC) is intravesical Bacillus Calmette-Guerin (BCG). Patients who recur or progress despite BCG are recommended to undergo radical cystectomy or participate in clinical trials. There is an urgent need for alternative therapies in the BCG-unresponsive NMIBC realm. Areas covered: We queried clinicaltrials.gov and pubmed.gov for current and recently completed early clinical trials pertaining to investigational agents used for the treatment of BCG-unresponsive NMIBC. These included intravesical chemotherapy, immunotherapy, vaccines, gene therapy, viruses, and agents used with novel drug delivery methods. In this article, we discuss the treatment guidelines for non-muscle invasive bladder cancer and therapeutic approaches under investigation in clinical trials. Expert opinion: The FDA is currently allowing single-arm studies as a pathway for approval in BCG-refractory patients with CIS. Although many agents are currently undergoing testing, none have been approved since Valrubicin. Hopefully, we will identify therapies sufficiently effective and durable to achieve FDA approval. Other considerations in this realm include the use of biomarkers in NMIBC to identify patients who will most likely respond to specific interventions. In addition, as systemic agents such as checkpoint inhibitors, are studied further, a multidisciplinary approach may be needed to treat this subset of patients.