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.

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.

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.

Site of extranodal metastasis impacts survival in patients with testicular germ cell tumors.

BACKGROUND: Using a large, nationally representative, population-based cancer registry, this study systematically evaluated the impact of the location and burden of extranodal testicular germ cell tumor (TGCT) metastases on survival. METHODS: Men with stage III TGCTs captured by the Surveillance, Epidemiology, and End Results registry from 2010 to 2015 with distant extranodal metastases were identified. Clinicopathologic information was collected, and patients were subdivided according to the specific organ site or sites of metastatic involvement (lung, liver, bone, and/or brain). Kaplan-Meier analysis and multivariable Cox regression were used to evaluate cancer-specific survival (CSS), and model performance was assessed with Harrell's C statistic. RESULTS: Nine hundred sixty-nine patients with stage III TGCTs were included with predominantly nonseminomatous histology (84%). Most patients (91%) had pulmonary metastases, whereas 20%, 10%, and 10% had liver, bone, and brain metastases, respectively. Over a median follow-up of 21 months, 19% of these men died of TGCTs. When they were grouped by the primary site of metastasis, patients with more than 1 extrapulmonary metastasis exhibited the worst CSS (hazard ratio [HR] vs isolated pulmonary involvement, 4.27; 95% confidence interval [CI], 2.60-7.00; P < .01). Among patients with isolated extrapulmonary involvement, those with brain metastases had the poorest survival (HR, 3.24; 95% CI, 1.98-5.28; P < .01), and they were followed by patients with liver (HR, 2.29; 95% CI, 1.56-3.35; P < .01) and bone metastases (HR, 1.97; 95% CI, 1.11-3.50; P = .02). Harrell's C statistic (multivariable) was 0.71. CONCLUSIONS: The site of metastatic involvement affects survival outcomes for patients with TGCTs, and this may reflect both the aggressive biology and the challenging treatment of these tumors. Further incorporation of organotropism into current prognostic models for metastatic TGCTs warrants attention.

Sex differences in upper tract urothelial carcinomas.

PURPOSE OF REVIEW: To evaluate contemporary sex-specific differences in upper tract urothelial carcinoma (UTUC) by reviewing diagnostic considerations, clinicopathologic features, oncologic outcomes, environmental exposures, and regional variation in UTUC by sex. RECENT FINDINGS: Although some contemporary studies implicate sex-based differences in UTUC, the literature concerning the effect of sex on clinicopathologic features and oncologic outcomes in UTUC reveals mixed findings. Factors accounting for the time to diagnosis in UTUC seem to differ between men and women. The epidemiology and outcomes of UTUC are largely influenced by geographic variation in the disease, which may be due to differences in exposure to environmental risk factors. Sex-based variations and potential differences in disease biology remain to be elucidated. SUMMARY: A global consensus on the effect of sex on clinicopathologic characteristics and oncologic outcomes in UTUC has not been established definitively. Review of this topic does, however, shed light on important considerations given differences in the time to diagnosis, risk factors, and regional variation by sex. Further studies evaluating genetic, anatomic, physiologic, and socioeconomic differences between men and women with UTUC may provide further insight into understanding the effect of sex in UTUC.

Is cytoreductive nephrectomy relevant in the immunotherapy era?

PURPOSE OF REVIEW: The recent approval of immune checkpoint inhibitors (ICI) revolutionized the treatment paradigm for metastatic renal cell carcinoma (mRCC). However, the role of cytoreductive nephrectomy is not well defined in this setting. Here, we review the contemporary role and timing of cytoreductive nephrectomy for advanced RCC in the era of immunotherapy. RECENT FINDINGS: Evidence concerning combination systemic therapy and cytoreductive nephrectomy in the multimodal management of mRCC is primarily limited to studies conducted in the targeted therapy era. The oncologic role of cytoreductive nephrectomy in the setting of ICI remains largely undefined and is supported primarily by case reports. Nonetheless, patient selection for cytoreductive nephrectomy is paramount, and appropriate candidacy in the ICI era will likely be refined as increasing evidence emerges. Until then, a cautious balance between perceived oncologic benefit and risks of intervention must be exercised. Several trials are ongoing to help shed light on patient selection, technical feasibility, and optimal timing of cytoreductive nephrectomy in the immunotherapy era. SUMMARY: Although the role and timing for cytoreductive nephrectomy remain to be further elucidated in the immunotherapy era, patient selection remains critical for treatment planning. Further studies are urgently needed to better define the role of cytoreductive nephrectomy in this setting.

Genetics of testicular germ cell tumors.

PURPOSE OF REVIEW: Understanding the molecular basis underlying testicular germ cell tumors (TGCTs) may help improve patient outcomes, particularly for patients with poorer risk or chemoresistant disease. Here, we review the major contemporary advances in elucidating TGCT genetics by discussing patterns of TGCT inheritance, recent genomic and transcriptomic discoveries in TGCT, and the role of genetics in predicting therapeutic resistance and in guiding treatment. RECENT FINDINGS: In the absence of a major high-penetrance TGCT susceptibility gene, inheritance is likely driven by a complex polygenic model with considerable variation. The most common genomic alterations found in TGCTs include gains in chromosome 12p and mutations in KIT, KRAS, and NRAS, particularly in seminomas. Sensitivity to cisplatin-based chemotherapy likely relies on intact TP53, reciprocal loss of heterozygosity, and high mitochondrial priming. Targetable mutations are uncommon in TGCTs, however, posing a challenge for the development of effective personalized therapies. Consistent with the characteristically low tumor mutational burden, immune checkpoint inhibitors do not appear to be effective for most TGCTs. SUMMARY: Refinements in next-generation sequencing techniques over the last few years have enabled considerable advances in elucidating the genomic, transcriptomic, and epigenetic landscape of TGCTs. Future efforts focused on developing novel treatment modalities are needed.

Molecular Predictors of Complete Response Following Neoadjuvant Chemotherapy in Urothelial Carcinoma of the Bladder and Upper Tracts.

Urothelial carcinoma of the bladder (UCB) and upper tracts (UTUC) is often regarded as one entity and is managed generally with similar principles. While neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is an established standard of care in UCB, strong evidence for a similar approach is lacking in UTUC. The longest survival is seen in patients with complete response (pT0) on pathological examination of the RC specimen, but impact of delayed RC in nonresponders may be detrimental. The rate of pT0 following NAC in UTUC is considerably lower than that in UCB due to differences in access and instrumentation. Molecular markers have been evaluated to try to predict response to chemotherapy to reduce unnecessary treatment and expedite different treatment for nonresponders. A variety of potential biomarkers have been evaluated to predict response to cisplatin based chemotherapy including DNA repair genes (ATM, RB1, FANCC, ERCC2, BRCA1, and ERCC1), regulators of apoptosis (survivin, Bcl-xL, and emmprin), receptor tyrosine kinases (EGFR and erbB2), genes involved in cellular efflux (MDR1 and CTR1), in addition to molecular subtypes (Basal, luminal, and p53-like). The current state of the literature on the prediction of response to NAC based on the presence of these biomarkers is discussed in this review.

Active Surveillance is Superior to Radical Nephrectomy and Equivalent to Partial Nephrectomy for Preserving Renal Function in Patients with Small Renal Masses: Results from the DISSRM Registry.

PURPOSE: We compared renal function outcomes among patients in the surveillance and intervention arms of the DISSRM registry. MATERIALS AND METHODS: Patients were grouped into chronic kidney disease stages by estimated glomerular filtration rate range. Cases were considered up staged if a more advanced chronic kidney disease stage was entered during followup. Chronic kidney disease up staging-free survival was compared among groups using Kaplan-Meier analysis and paired comparisons log rank tests. Multivariate Cox regression identified independent predictors of chronic kidney disease up staging-free survival. RESULTS: A total of 162 patients met the study inclusion criteria, with 68 in the surveillance arm, 65 undergoing partial nephrectomy, 15 undergoing radical nephrectomy and 14 undergoing cryoablation. Median tumor size was 2.2 cm. Mean estimated glomerular filtration rate change was significantly larger for radical nephrectomy vs surveillance (-9.2 vs -0.5 ml/minute/1.73 m(2)) and for radical vs partial nephrectomy (-9.2 vs -1.9 ml/minute/1.73 m(2)) (p=0.001). No other groups differed significantly. On Kaplan-Meier analysis patients undergoing radical nephrectomy had significantly worse chronic kidney disease up staging-free survival vs those treated with partial nephrectomy (p=0.029), surveillance (p=0.007) and cryoablation (p=0.019). No other groups differed significantly. On multivariate analysis radical nephrectomy independently predicted poor chronic kidney disease up staging-free survival (odds ratio vs surveillance 30.6, p=0.001). Neither partial nephrectomy (p=0.985) nor cryoablation (p=0.976) predicted poor chronic kidney disease up staging-free survival relative to surveillance. CONCLUSIONS: Patients in the surveillance arm had superior estimated glomerular filtration rate preservation compared to those in the radical nephrectomy but not the partial nephrectomy arm. In certain patients with small renal masses surveillance and partial nephrectomy may offer comparable renal functional outcomes. This could be partly attributable to a modest estimated glomerular filtration rate decrease associated with surveillance itself. A thorough understanding of the renal functional impacts of treatment modalities is critical in the management of small renal masses.

Mixed low- and high-grade non-muscle-invasive bladder cancer: a histological subtype with favorable outcome.

OBJECTIVE: To determine whether heterogeneity of tumor grade affects the response to Bacillus Calmette-Guérin (BCG) treatment for patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: Patients with Ta or T1 NMBIC receiving a 6-week induction course of intravesical BCG therapy after transurethral resection were divided according to the tumor grade. Clinical and pathological variables were compared. Advanced intervention-free survival (AIFS), defined as duration of freedom from advanced intervention (including non-BCG intravesical agents or cystectomy) or metastasis, was plotted using Kaplan-Meier methods. The effect of grade on survival duration was assessed by multivariate Cox proportional hazards modeling. RESULTS: One hundred and fifty-three patients were identified: 17 with mixed low- and high-grade (MG) and 136 with pure high-grade (PHG) NMIBC. Demographic and additional pathologic variables were comparable between groups (p > 0.05). Five-year AIFS was 88.2% for MG patients, compared to 48.5% for PHG patients (p = 0.030 by log-rank test). On multivariate analysis, PHG was an independent risk factor for worse AIFS (HR 4.4, 95% CI 1.1-18.4, p = 0.040). Among patients failing to respond to primary BCG induction, who underwent a secondary induction of BCG with interferon, MG patients had better response than PHG patients (100 vs. 26.3%, p = 0.035). CONCLUSIONS: Mixed low- and high-grade NMIBC exhibits a significantly better response profile to intravesical BCG therapy compared to PHG NMIBC. The implications of these results are that less aggressive treatment strategies for this unique cancer entity may be needed and that there is a benefit to the reporting of tumor heterogeneity in transurethral resection of bladder tumor specimens.

The natural history of clinically complete responders to neoadjuvant chemotherapy for urothelial carcinoma of the bladder.

PURPOSE: We describe the clinical course of patients who achieved cT0 status after neoadjuvant chemotherapy for muscle invasive bladder cancer. There is no established treatment paradigm for these patients. MATERIALS AND METHODS: We retrospectively reviewed the records of 109 patients with muscle invasive bladder cancer (T2 or greater urothelial carcinoma of the bladder) who underwent platinum based neoadjuvant chemotherapy at our institution from 1988 to 2012. Post-chemotherapy assessment of the response included cytology, cystoscopy with biopsy and cross-sectional imaging. RESULTS: Of 109 patients 32 (29.4%) achieved cT0 status after neoadjuvant chemotherapy. Mean ± SD age of the cohort was 68.3 ± 9.6 years. Of the patients 21 received MVAC, 8 received gemcitabine and cisplatin, and 3 received another regimen. Seven complete responders elected immediate radical cystectomy after the completion of neoadjuvant chemotherapy. Of 25 patients who refused radical cystectomy after achieving cT0 status 7 experienced relapse after the completion of neoadjuvant chemotherapy and proceeded to radical cystectomy. The remaining 18 patients (72%) retained the bladder, including 6 (18.8% of the cohort) in whom nonmuscle invasive relapses were managed conservatively and 12 (37.5%) with no recurrence. In the 25 patients who elected bladder preservation after achieving cT0 status following neoadjuvant chemotherapy 5-year cancer specific survival was 88%. CONCLUSIONS: With proper counseling and identification of treatment goals patients with cT0 after neoadjuvant chemotherapy for muscle invasive bladder cancer may have the option to retain the bladder with durable survival. Larger studies are needed to identify possible predictors of response on the clinical, pathological and molecular levels.

Phase II trial of intravesical nanoparticle albumin bound paclitaxel for the treatment of nonmuscle invasive urothelial carcinoma of the bladder after bacillus Calmette-Guérin treatment failure.

PURPOSE: Response rates to current second line intravesical therapies for recurrent nonmuscle invasive bladder cancer range between 10% and 30%. Nanoparticle albumin bound (nab-)paclitaxel has increased solubility and lower toxicity compared to other taxanes. Results of the phase I intravesical trial of this compound demonstrated minimal toxicity during dose escalation. We now report the results of a phase II trial to assess efficacy. MATERIALS AND METHODS: This study was an investigator initiated, single center, single arm, phase II trial investigating the use of nab-paclitaxel in patients with recurrent Tis, T1 and Ta urothelial carcinoma in whom at least 1 prior regimen of intravesical bacillus Calmette-Guérin failed. Patients received 500 mg/100 ml nab-paclitaxel administered in 6 weekly intravesical instillations. Efficacy was evaluated with cystoscopy, biopsy, cytology and imaging. If complete response was achieved, patients were treated with full dose monthly maintenance treatments for 6 months. RESULTS: A total of 28 patients were enrolled in the study. Of these patients 10 (35.7%) exhibited a complete response after initial treatment. At 1 year all of these responses remained durable after maintenance therapy. At a mean followup of 21 months (range 5 to 47) 19 of 28 (67.8%) patients retained their bladders without progression or distant metastases. A single patient had progression to muscle invasive disease at radical cystectomy. Treatment related adverse events were noted in 9 of 28 (32.1%) patients and were limited to grade 1 or 2. CONCLUSIONS: Intravesical nab-paclitaxel has minimal toxicity and a 35.7% response rate in patients with nonmuscle invasive bladder cancer and previous bacillus Calmette-Guérin failure. Complete response remained durable at 1 year followup in this heavily pretreated patient population.

New agents for bacillus Calmette-Guérin-refractory nonmuscle invasive bladder cancer.

PURPOSE OF REVIEW: Radical cystectomy is the standard of care for patients who fail intravesical bacillus Calmette-Guérin (BCG) for nonmuscle invasive bladder cancer (NMIBC). For patients unwilling or unable to undergo cystectomy, numerous local therapies exist, although few are approved by the Food and Drug Administration. This review describes available therapies for this challenging clinical entity. RECENT FINDINGS: Combination intravesical chemotherapy, targeted therapy, and drug delivery enhancement have all been under recent investigation and are promising, although none has proven superior as of yet. SUMMARY: While BCG is standard treatment for intermediate and high-risk NMIBC, many patients fail therapy with recurrence or progression. Early cystectomy is the standard of care for BCG failure; however, many patients are unwilling or unable to undergo cystectomy. Multiple intravesical therapies have been used in this BCG failure population with moderate success, and, recently, technologies to improve drug delivery or create novel drugs have also been applied. Comparing efficacy of these therapies remain challenging as study cohorts are heterogeneous and study designs are variable. However, there are an increasing number of novel treatment options that can be offered to patients faced with recurrent NMIBC after BCG who seek bladder-sparing therapy.

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.

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.

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.

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.

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.