Renal cell carcinoma and pathologic nodal disease: Implications for American Joint Committee on Cancer staging.

BACKGROUND: Lymph node (LN) metastases are associated with poor outcomes for patients with renal cell carcinoma (RCC). This study compared the survival outcomes of patients with stage III, node-positive disease (pT123 N1 M0 ) and patients with stage III, node-negative disease (pT3 N0 M0 ). METHODS: A database of 4652 patients with RCC of any histological subtype treated with surgery at The University of Texas MD Anderson Cancer Center from 1993 to 2012 was retrospectively assessed. A total of 115 patients with pT123 N1 M0 disease, 274 patients with pT3 N0 M0 disease, and 523 patients with pT123 N0/x M1 disease were included. Overall survival (OS) and cancer-specific survival (CSS) were estimated and compared between each cohort. RESULTS: Median OS and CSS times were significantly better for pT3 N0 M0 patients than pT123 N1 M0 patients (OS, 10.2 vs 2.4 years, P < .0001; CSS, not reached vs 2.8 years, P < .0001). Similar median OS and CSS times were noted for pT123 N1 M0 and pT123 N0/x M1 patients (OS, 2.4 vs 2.4 years; P = .62; CSS, 2.8 vs 2.4 years; P = .10). In a multivariate analysis, tumor grade (hazard ratio [HR] for OS, 2.47; P < .0001; HR for CSS, 2.99; P < .0001) and pathologic LN involvement (HR for OS, 2.44; P < .0001; HR for CSS, 2.85; P < .0001) were associated with worse OS and CSS. CONCLUSIONS: Among RCC patients classified with stage III disease, those with pT123 N1 M0 disease had significantly worse survival than those with pT3 N0 M0 disease. OS and CSS were similar for patients with pT123 N1 M0 disease and patients with pT123 N0/x M1 disease (stage IV). If validated, these findings suggest that RCC patients with nodal disease should be reclassified as having stage IV disease.

Anti-inflammatory use may not negatively impact oncologic outcomes following intravesical BCG for high-grade non-muscle-invasive bladder cancer.

PURPOSE: To evaluate whether anti-inflammatory agents affect outcomes in patients receiving intravesical BCG therapy for high-grade (HG) non-muscle-invasive bladder cancer (NMIBC). METHODS: We reviewed the records of 203 patients in a prospective database of HG NMIBC from 2006 to 2012 at a single institution. Patients who had muscle-invasive disease (n = 32), low-grade pathology (n = 4), underwent early cystectomy within 3 months (n = 25), had <3 months of follow-up (n = 11), or did not receive an induction course of intravesical BCG (n = 32) were excluded. Clinicopathologic data were tabulated including demographics, comorbidities, pathologic stage and grades, intravesical therapy, and concomitant use of aspirin, NSAIDs, COX inhibitors, and statins. Multivariate Cox regression analysis explored predictive factors for recurrence, progression (stage progression or progression to cystectomy), cancer-specific survival (CSS), and overall survival (OS). RESULTS: Ninety-nine patients with HG NMIBC who received at least one induction course of intravesical BCG were identified, with median follow-up of 31.4 months. There were 20 (20.2 %) deaths, including 6 (6.1 %) patients with bladder cancer-related mortality. 13 % patients experienced tumor progression and 27 % underwent cystectomy following failure of intravesical therapy. Anti-inflammatory use included statins (65 %), aspirin (63 %), or non-aspirin NSAIDs/COX inhibitors (26 %). Anti-inflammatory use was not significantly predictive of recurrence, progression, or mortality outcomes on Cox regression. CIS stage was associated with higher progression, while age, BMI, and Charlson score were independent predictors of overall mortality. CONCLUSION: Despite speculation of inhibitory effects on BCG immunomodulation there was no evidence that anti-inflammatory agents impacted oncologic outcomes in patients receiving BCG for HG NMIBC.

Repeat Excision and Primary Anastomotic Urethroplasty for Salvage of Recurrent Bulbar Urethral Stricture.

PURPOSE: We compared the results of initial excision and primary anastomosis urethroplasty to the excision and primary anastomosis outcomes of other challenging reoperative clinical settings, including secondary cases (prior urethroplasty of any technique other than excision and primary anastomosis) and repeat cases (prior excision and primary anastomosis). MATERIALS AND METHODS: We reviewed our database of patients who underwent excision and primary anastomosis urethroplasty for bulbar urethral stricture at our tertiary referral center from 2007 to 2014. Patients without available data and those with a history of lichen sclerosus, radiation, pelvic fracture urethral injuries, distal strictures and/or hypospadias were excluded from analysis. Patient characteristics and outcomes were compared between those undergoing initial, secondary, and repeat excision and primary anastomosis urethroplasty for bulbar urethral stricture. RESULTS: Among 898 urethroplasties performed during the study period we identified 305 men who underwent excision and primary anastomosis urethroplasty of the bulbar urethra, including an initial procedure in 268 of 305 (88%) and reoperation in 37 (12%). Of patients with reoperation 18 of 37 (49%) underwent secondary excision and primary anastomosis following a different type of prior urethroplasty and 19 (51%) underwent repeat excision and primary anastomosis. Repeat excision and primary anastomosis in the bulbar urethra was successful in 18 of 19 patients (95%), which was comparable to the success rate of initial bulbar excision and primary anastomosis (251 of 268 or 94%) as well as secondary bulbar excision and primary anastomosis (17 of 18 or 94%, p = 0.975) with a similar mean stricture length. Mean followup for all patients was 41.5 months (range 6 to 90) and mean followup in each group was greater than 30 months. CONCLUSIONS: Repeat excision and primary anastomosis urethroplasty has excellent results for short bulbar strictures, comparable to those achieved in the initial and secondary setting.

Robotic or open superficial inguinal lymph node dissection as staging procedures for clinically node negative high risk penile cancer.

OBJECTIVE: To evaluate perioperative and oncologic outcomes of a cohort of clinically node negative high-risk penile cancer patients undergoing robotic assisted inguinal lymph node dissection (RAIL) compared to patients undergoing open superficial inguinal lymph node dissection (OSILND). PATIENTS AND METHODS: We retrospectively reviewed the clinical characteristics and outcomes of clinically node negative high-risk penile cancer patients undergoing RAIL at MDACC from 2013-2019. We sought to compare this to a contemporary open cohort of clinically node negative patients treated from 1999 to 2019 at MDACC and Moffit Cancer Center (MCC) with an OSILND. Descriptive statistics were used to characterize the study cohorts. Comparison analysis between operative variables was performed using Fisher's exact test and Wilcoxon's rank-sum test. The Kaplan-Meier method was used to estimate survival endpoints. RESULTS: There were 24 patients in the RAIL cohort, and 35 in the OSILND cohort. Among the surgical variables, operative time (348.5 minutes vs. 239.0 minutes, P < 0.01) and the duration of operative drain (37 vs. 22 days P = 0.017) were both significantly longer in the RAIL cohort. Complication incidences were similar for both cohorts (34.3% for OSILND vs. 33.3% for RAIL), with wound complications making up 33% of all complications for RAIL and 31% of complications for OSILND. No inguinal recurrences were noted in either cohort. The median follow-up was 40 months for RAIL and 33 months for OSILND. CONCLUSIONS: We observed similar complication rates and surgical variable outcomes in our analysis apart from operative time and operative drain duration. Oncological outcomes were similar between the two cohorts. RAIL was a reliable staging and potentially therapeutic procedure among clinically node negative patients with penile squamous cell carcinoma with comparable outcomes to an OSILND cohort.

Performance Characteristics of a Rule-Based Electronic Health Record Algorithm to Identify Patients with Gross and Microscopic Hematuria.

BACKGROUND: Two million patients per year are referred to urologists for hematuria, or blood in the urine. The American Urological Association recently adopted a risk-stratified hematuria evaluation guideline to limit multi-phase computed tomography to individuals at highest risk of occult malignancy. OBJECTIVES: To understand population-level hematuria evaluations, we developed an algorithm to accurately identify hematuria cases from electronic health records (EHRs). METHODS: We used International Classification of Diseases (ICD)-9/ICD-10 diagnosis codes, urine color, and urine microscopy values to identify hematuria cases and to differentiate between gross and microscopic hematuria. Using an iterative process, we refined the ICD-9 algorithm on a gold standard, chart-reviewed cohort of 3,094 hematuria cases, and the ICD-10 algorithm on a 300 patient cohort. We applied the algorithm to Geisinger patients ≥35 years (n = 539,516) and determined performance by conducting chart review (n = 500). RESULTS: After applying the hematuria algorithm, we identified 51,500 hematuria cases and 488,016 clean controls. Of the hematuria cases, 11,435 were categorized as gross, 26,658 as microscopic, 12,562 as indeterminate, and 845 were uncategorized. The positive predictive value (PPV) of identifying hematuria cases using the algorithm was 100% and the negative predictive value (NPV) was 99%. The gross hematuria algorithm had a PPV of 100% and NPV of 99%. The microscopic hematuria algorithm had lower PPV of 78% and NPV of 100%. CONCLUSION: We developed an algorithm utilizing diagnosis codes and urine laboratory values to accurately identify hematuria and categorize as gross or microscopic in EHRs. Applying the algorithm will help researchers to understand patterns of care for this common condition.

Identifying the risk of disease progression after surgery for localized renal cell carcinoma.

OBJECTIVE: To identify factors in a large cohort of patients with pathologically localized renal cell carcinoma (RCC) that predicted disease progression after surgery, as RCC most commonly presents as a localized tumour which is treated with surgical excision. PATIENTS AND METHODS: Using an institutional database, we identified all patients who underwent radical or partial nephrectomy and had pathologically confirmed pT1 or pT2 RCC. Multivariable stepwise logistic regression analysis was used to calculate an odds ratio corresponding to the odds of progression to metastatic disease during surveillance, based on several clinical and pathological variables. We defined those variables that remained significant on multivariable analysis as risk factors and, based on the number of risk factors, we assessed risk of disease progression. RESULTS: In all, 925 patients were eligible for analysis with a median follow-up of 48.2 months. There was progression to metastatic disease in 53 (5.7%) patients; pT1 in 20/774 (2.6%), pT2 in 33/151 (21.9%). Risk factors included pT2 disease, male gender, symptoms at presentation (local or constitutional), presence of sarcomatoid de-differentiation, and macroscopic necrosis on final pathology. In 177 patients with no risk factors, none progressed; 20 of 618 (3.2%) with one or two risk factors had progression at a median of 37.1 months; 33 of 130 (25.4%) with three or more risk factors progressed at a median of 25.2 months. CONCLUSIONS: We identified five risk factors that can help to predict those patients with pT1 or pT2 RCC at highest risk for disease progression after surgery. The potential for disease progression is exceedingly low in patients with no risk factors and surveillance can be minimized in this group.

Metastatic urothelial carcinoma to the liver with unknown primary tumor.

Cancer of unknown primary (CUP), a rare and aggressive clinical entity, accounts for approximately 3% of all malignancies. CUP with urothelial origin is even more unusual, with no other cases reported in the current literature. As imaging and other studies often do not reveal the tumor origin, the approach to CUP involves a focused search for the primary tumor, relying on guidance from immunohistochemical staining of biopsy specimens. Treatment consists of standard therapies directed at the most likely tumor origin.

Perioperative management of cold agglutinin autoimmune hemolytic anemia in an older adult undergoing radical cystectomy for bladder cancer.

Patients diagnosed with bladder cancer are most frequently older adults who have multiple chronic conditions. Frequently, new conditions are unmasked during preoperative evaluation for surgery such as radical cystectomy. We report the case of an 85 year old male with muscle invasive bladder cancer who was concurrently diagnosed with cold agglutinin hemolytic anemia. This case demonstrates the importance of close attention to underlying chronic conditions in older adults considering major cancer surgery and the need for multidisciplinary management in medically complex cases.

Adjuvant therapy for advanced renal cell carcinoma.

INTRODUCTION: Locally advanced, non-metastatic renal cell carcinoma (RCC) is conventionally managed with surgery. However, patients are at a high risk of RCC recurrence and have poor survival outcomes. An effective adjuvant systemic treatment is needed to improve on these outcomes. Targeted molecular and immune-based therapies have been investigated, or are under investigation, but their role in this setting remains unclear. Areas covered: A comprehensive search of PubMed and ClinicalTrials.gov was performed for relevant literature. The following topics pertinent to adjuvant therapy in RCC were evaluated: strategies for patient selection, cytokine-based immunotherapy, vaccine therapy, VEGF and non-VEGF targeted molecular agents, and immune checkpoint inhibitors. Expert commentary: Strong evidence for the incorporation of adjuvant therapy in high-risk RCC is lacking. Multiple targeted molecular therapies have been examined with only one approved for use. Genetic and molecular-based prognostic models are needed to determine who may benefit from adjuvant therapy. Developing adjuvant therapy strategies in the future depends on the results of important ongoing trials with immunotherapy and targeted agents.

The Adverse Survival Implications of Bland Thrombus in Renal Cell Carcinoma With Venous Tumor Thrombus.

OBJECTIVE: To characterize the presence of bland (nontumor) thrombus in advanced renal cell carcinoma and assess the impact of this finding on cancer-specific survival. METHODS: A multi-institutional database of patients treated with nephrectomy with caval thrombectomy for locally-advanced renal tumors was assembled from 5 tertiary care medical centers. Using clinicopathologic variables including patient age, body mass index, Eastern Cooperative Oncology Group performance status, tumor stage, grade, nodal status and histology, and nearest-neighbor and multiple-matching propensity score matched cohorts of bland thrombus vs nonbland thrombus patients were assessed. Multivariable analysis for predictors of cancer-specific survival was performed. RESULTS: From an initial cohort of 579 patients, 446 met inclusion criteria (174 with bland thrombus, 272 without). At baseline, patients with bland thrombus had significantly worse performance status, higher tumor stage, higher prevalence of regional nodal metastases and higher nuclear grade (P < .01 for all). In both nearest-neighbor and multiple-matching propensity score matched cohorts, the presence of bland thrombus presence was associated with inferior median cancer-specific survival (28.1 months vs 156.8 months, and 28.1 months vs 76.7 months, P < .001 for both). The presence of bland thrombus remained independently associated with an increased risk of cancer-specific mortality on multivariable analysis (hazard ratio 4.33, 95% confidence interval 2.79-6.73, P < .001). CONCLUSION: Presence of bland thrombus is associated with adverse survival outcomes in patients treated surgically for renal tumors with venous tumor thrombus. These findings may have important implications in patient counseling, selection for surgery and inclusion in clinical trials.

Surgical Complications of Presurgical Systemic Therapy for Renal Cell Carcinoma: A Systematic Review.

BACKGROUND: Locally advanced and metastatic renal cell carcinoma (RCC) is associated with poor survival outcomes. The integration of presurgical systemic therapy with targeted molecular agents prior to surgical resection of RCC tumors has been utilized to improve on these outcomes. These agents may be associated with an increased risk of perioperative complications due to their action on angiogenesis and cell proliferation. OBJECTIVE: To examine the evidence for the incidence and severity of perioperative complications following presurgical targeted therapy for locally advanced or metastatic RCC. METHODS: We performed a systematic review of retrospective studies, prospective clinical trials, and meta-analyses using key search terms in PubMed and Medline. Studies were screened for eligibility and data were extracted by the authors. A qualitative analysis was performed and the complications for available targeted agents was reported. RESULTS: Retrospective analyses and small prospective trials indicate varying complication rates and types based on presurgical therapies. While some studies indicate a possible increase in wound-related complications, other studies did not show similar results. Additional unique complications reported include an increase in surgical adhesions. There was not any significant difference in overall or bleeding complications. CONCLUSIONS: Overall, these studies demonstrate an acceptable level of surgical complications that should not discourage the clinician considering presurgical therapy. The results of pending trials looking at presurgical therapies will provide further information.

Prognostic serum markers in patients with high-grade upper tract urothelial carcinoma.

INTRODUCTION: The role of preoperative serum-based markers in predicting survival outcomes of patients has been reported for several cancer types; however, their association with upper tract urothelial carcinoma (UTUC) prognosis is unclear. We evaluated the role of systemic serum-based markers in predicting adverse pathological features and survival outcomes in patients surgically treated for high-grade (HG) UTUC. METHODS: We retrospectively reviewed all patients undergoing surgery for HG UTUC between June 2006 and July 2013 at our institution. Comprehensive clinicopathologic data and preoperative serum-based markers including hemoglobin, white blood cell count, platelet count, serum albumin, calcium, and liver function tests were recorded. Associations of serum markers with pathologic features and recurrence-free survival (RFS) were determined by logistic and Cox regression analyses, respectively. The concordance index for the oncologic outcomes model was determined. RESULTS: In total, 101 patients were identified with a median follow-up of 18.5 months (range: 1-74mo). In all, 60% of patients had pT2 or less and 11% had nodal metastases. Preoperative elevated alkaline phosphatase (ALP) (≥116IU/l) was associated with multiple adverse pathologic features including advanced T stage, lymphovascular invasion, and histologic necrosis. On univariate analysis, serum markers independently associated with RFS included hemoglobin≤12.9 (hazards ratio [HR] = 2.51; 95% CI: 1.17-5.36, P = 0.018), albumin≤4g/dl (HR = 4.4; 95% CI: 2.04-9.30; P<0.0001), ALP≥116U/l (HR = 13.3; 95% CI: 5.3-33.52, P<0.0001), alanine transaminase≥27 (HR = 2.63, 95% CI: 1.11-6.21, P = 0.028), serum aspartate transaminase≥20 (HR = 2.21, 95% CI: 1.04-4.69, P = 0.038), and corrected calcium≥9.3 (HR = 2.45, 95% CI: 1.01-5.93, P = 0.047). The 2 strongest predictors, albumin and ALP, were combined to form an AA score (range: 0-2), which improved the baseline preoperative clinical model concordance index for prediction of RFS from 0.626 to 0.799. CONCLUSION: In HG UTUC, elevated preoperative ALP was associated with adverse pathologic features. Additionally, elevated ALP and low albumin were independently associated with worse RFS and overall survival. These serum-based markers are often measured in the preoperative workup of UTUC, and thus they can be included in future prognostic models to risk stratify patients.

Feasibility of obtaining biomarker profiles from endoscopic biopsy specimens in upper tract urothelial carcinoma: preliminary results.

OBJECTIVE: To prospectively evaluate the feasibility of obtaining a reliable histochemical assessment of cell cycle biomarkers from endoscopic biopsy specimens of patients with upper tract urothelial cancer. METHODS: Overall, 17 patients were identified who had an available biopsy as well as those who underwent subsequent radical nephroureterectomy (RNU) or segmental ureterectomy (SU) for clinically localized high-grade upper tract urothelial cancer of the renal pelvis or ureter. Of those 17 patients, 15 (88%) had sufficient tissue to undergo immunohistochemical staining. Biopsies were obtained using various endoscopic techniques. Tumor characteristics were recorded and prospectively evaluated for immunohistochemical expression of 5 biomarkers: p21, p27, p53, cyclin E, and Ki67/pRb. Unfavorable prognostic score (PS) was defined as>2 altered markers. RESULTS: The median age of the patients was 68 years (range: 53-82y) with 87% being males. Of the 15 specimens, 9 (60%) tumors were organ confined (T≤2 and N0), and all were high grade. Of the 15 patients, 4 (27%), 7 (46.6%), 3 (20%), and 1 (6.7%) individuals had 1, 2, 3, and 5 markers altered on biopsy marker profiling, respectively, with Ki67 being the most frequent alteration (13/15; 87.7%). An overall concordance rate of 60% (9/15) was seen between biopsy and RNU/SU PS. Those patients with favorable biopsy biomarker PS were less likely to display adverse pathological features, with organ-confined disease in 7/11 (63.6%) patients and 9/11 (81.8%) being free of carcinoma in situ in the final specimen. Additionally, 10/11 (91%) had no evidence of necrosis and 7/11 (64%) had no evidence of lymphovascular invasion on final pathologic evaluation. CONCLUSIONS: Preliminary results suggest that obtaining interpretable biomarker profile of ureteroscopic biopsy specimens is feasible. Tumor heterogeneity and limited biopsy material may account for the discordance between biopsy and RNU/SU specimens. Meaningful biopsy biomarker profiling could serve as a powerful tool for individualizing treatment regimens and augmenting current predictive variables. Further studies are needed to evaluate clinical applicability.