Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Detection of PD-L1-Expressing Myeloid Cell Clusters in the Hyaluronan-Enriched Stroma in Tumor Tissue and Tumor-Draining Lymph Nodes.

Expression of the transmembrane protein PD-L1 is frequently upregulated in cancer. Because PD-L1-expressing cells can induce apoptosis or anergy of T lymphocytes through binding to the PD1 receptor, the PD-L1-mediated inhibition of activated PD1+ T cells is considered a major pathway for tumor immune escape. However, the mechanisms that regulate the expression of PD-L1 in the tumor microenvironment are not fully understood. Analysis of organotypic tumor tissue slice cultures, obtained from mice with implanted syngeneic tumors (MBT2 bladder tumors in C3H mice, Renca kidney, and CT26 colon tumors in BALB/c mice), as well as from patients with cancer, revealed that tumor-associated hyaluronan (HA) supports the development of immunosuppressive PD-L1+ macrophages. Using genetically modified tumor cells, we identified epithelial tumor cells and cancer-associated mesenchymal fibroblast-like cells as a major source of HA in the tumor microenvironment. These HA-producing tumor cells, and particularly the vimentin-positive fibroblast-like cells of bone marrow origin, directly interact with tumor-recruited myeloid cells to form large stromal congregates/clusters that are highly enriched for both HA and PD-L1. Furthermore, similar cell clusters composed of HA-producing fibroblast-like cells and PD-L1+ macrophages were detected in tumor-draining, but not in distant, lymph nodes. Collectively, our findings indicate that the formation of multiple large HA-enriched stromal clusters that support the development of PD-L1-expressing APCs in the tumor microenvironment and draining lymph nodes could contribute to the immune escape and resistance to immunotherapy in cancer.

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING: FKD Therapies Oy.

Patient and Procedural Determinants of Postoperative Pain Trajectories.

BACKGROUND: The primary goal of this study was to evaluate patterns in acute postoperative pain in a mixed surgical patient cohort with the hypothesis that there would be heterogeneity in these patterns. METHODS: This study included 360 patients from a mixed surgical cohort whose pain was measured across postoperative days 1 through 7. Pain was characterized using the Brief Pain Inventory. Primary analysis used group-based trajectory modeling to estimate trajectories/patterns of postoperative pain. Secondary analysis examined associations between sociodemographic, clinical, and behavioral patient factors and pain trajectories. RESULTS: Five distinct postoperative pain trajectories were identified. Many patients (167 of 360, 46%) were in the moderate-to-high pain group, followed by the moderate-to-low (88 of 360, 24%), high (58 of 360, 17%), low (25 of 360, 7%), and decreasing (21 of 360, 6%) pain groups. Lower age (odds ratio, 0.94; 95% CI, 0.91 to 0.99), female sex (odds ratio, 6.5; 95% CI, 1.49 to 15.6), higher anxiety (odds ratio, 1.08; 95% CI, 1.01 to 1.14), and more pain behaviors (odds ratio, 1.10; 95% CI, 1.02 to 1.18) were related to increased likelihood of being in the high pain trajectory in multivariable analysis. Preoperative and intraoperative opioids were not associated with postoperative pain trajectories. Pain trajectory group was, however, associated with postoperative opioid use (P < 0.001), with the high pain group (249.5 oral morphine milligram equivalents) requiring four times more opioids than the low pain group (60.0 oral morphine milligram equivalents). CONCLUSIONS: There are multiple distinct acute postoperative pain intensity trajectories, with 63% of patients reporting stable and sustained high or moderate-to-high pain over the first 7 days after surgery. These postoperative pain trajectories were predominantly defined by patient factors and not surgical factors.

Slow Dynamics of Acute Postoperative Pain Intensity Time Series Determined via Wavelet Analysis Are Associated With the Risk of Severe Postoperative Day 30 Pain.

BACKGROUND: Evidence suggests that increased early postoperative pain (POP) intensities are associated with increased pain in the weeks following surgery. However, it remains unclear which temporal aspects of this early POP relate to later pain experience. In this prospective cohort study, we used wavelet analysis of clinically captured POP intensity data on postoperative days 1 and 2 to characterize slow/fast dynamics of POP intensities and predict pain outcomes on postoperative day 30. METHODS: The study used clinical POP time series from the first 48 hours following surgery from 218 patients to predict their mean POP on postoperative day 30. We first used wavelet analysis to approximate the POP series and to represent the series at different time scales to characterize the early temporal profile of acute POP in the first 2 postoperative days. We then used the wavelet coefficients alongside demographic parameters as inputs to a neural network to predict the risk of severe pain 30 days after surgery. RESULTS: Slow dynamic approximation components, but not fast dynamic detailed components, were linked to pain intensity on postoperative day 30. Despite imbalanced outcome rates, using wavelet decomposition along with a neural network for classification, the model achieved an F score of 0.79 and area under the receiver operating characteristic curve of 0.74 on test-set data for classifying pain intensities on postoperative day 30. The wavelet-based approach outperformed logistic regression (F score of 0.31) and neural network (F score of 0.22) classifiers that were restricted to sociodemographic variables and linear trajectories of pain intensities. CONCLUSIONS: These findings identify latent mechanistic information within the temporal domain of clinically documented acute POP intensity ratings, which are accessible via wavelet analysis, and demonstrate that such temporal patterns inform pain outcomes at postoperative day 30.

Mechanisms of immune evasion in bladder cancer.

With the introduction of multiple new agents, the role of immunotherapy is rapidly expanding across all malignancies. Bladder cancer is known to be immunogenic and is responsive to immunotherapy including intravesical BCG and immune checkpoint inhibitors. Multiple trials have addressed the role of checkpoint inhibitors in advanced bladder cancer, including atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab (all targeting the PD1/PD-L1 pathway). While these trials have demonstrated promising results and improvements over existing therapies, less than half of patients with advanced disease demonstrate clinical benefit from checkpoint inhibitor therapy. Recent breakthroughs in cancer biology and immunology have led to an improved understanding of the influence of the tumor microenvironment on the host's immune system. It appears that tumors promote the formation of highly immunosuppressive microenvironments preventing generation of effective anti-tumor immune response through multiple mechanisms. Therefore, reconditioning of the tumor microenvironment and restoration of the competent immune response is essential for achieving optimal efficacy of cancer immunotherapy. In this review, we aim to discuss the major mechanisms of immune evasion in bladder cancer and highlight novel pathways and molecular targets that may help to attenuate tumor-induced immune tolerance, overcome resistance to immunotherapy and improve clinical outcomes.

Metabolic bone disease following urinary diversion in adults.

PURPOSE OF REVIEW: Urinary diversions are created following radical cystectomy or for the palliation of recalcitrant lower urinary tract symptoms. Chronic metabolic acidosis, one of the several long-term complications associated with urinary diversion, has been shown to lead to metabolic bone disease if untreated. RECENT FINDINGS: The incidence of chronic acidosis can be influenced by several factors, including type and length of bowel segment utilized, renal function, and type of urinary diversion. The observed rate of acidosis has been noted to be high, particularly in patients undergoing continent ileal neobladders using long bowel segments. Results from the five selected case series evaluating the association between urinary diversion and development of metabolic bone disease are inconsistent, but the majority report a low incidence of bone disease, ranging from 0 to 15%. In order to decrease the risk of developing metabolic bone disease and the other associated disorders, attention to the diagnosis of acidosis postoperatively, along with preventive therapy, is crucial. Treatment of acidosis secondary to urinary diversion may be accomplished in the long term with oral alkalizing agents. SUMMARY: Although there is no clear relationship between urinary diversion and the future development of metabolic bone disease, diagnosis and treatment of postoperative acidosis are recommended.

Efficacy of BCG for non-muscle invasive bladder cancer following nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate the efficacy of intravesical (IVe) Bacillus Calmette-Guerin (BCG) to treat non-muscle invasive bladder cancer (NMIBC) recurrences in patients who have previously undergone nephroureterectomy for upper tract urothelial carcinoma (UTUC). METHODS: We performed a single institution retrospective review of patients who underwent nephroureterectomy for UTUC from 2009 to 2021. Patients who subsequently developed NMIBC treated with transurethral resection followed by IVe BCG were included in the study group. A control cohort was formed by retrospective review of patents with primary NMIBC treated with BCG during the same period. Patients in the control cohort were matched by stage of bladder cancer at a 2:1 ratio of control to study subjects. Demographic data, pathology of bladder tumors prior to and following BCG, use of maintenance BCG (mBCG), time to recurrence, time to progression, progression to cystectomy, and progression to metastatic disease were collected on all patients. Descriptive statistics were utilized to compare the 2 groups. The primary outcome was progression to muscle invasive disease. Secondary outcomes included intravesical recurrence free survival, disease free survival, and progression to metastatic disease. Univariable and multivariable logistic regression analysis was performed to elucidate independent variables associated with bladder tumor recurrence. Multivariable Cox regression analysis was used to assess the impact of prior UTUC on time to bladder tumor recurrence. RESULTS: One-hundred and ninety-one patients underwent nephroureterectomy at our institution from 2009 to 2021 for UTUC. Twenty-five patients were identified to have subsequently developed NMIBC recurrences treated with inductions BCG. The control group was comprised of 50 patients with primary NMIBC matched by stage of bladder cancer for which BCG was indicated in the study group. Median (interquartile range [IQR]) follow-up was significantly longer in the control group relative to the study group (64.8 [50.1-85.6] vs 25 months [17-35]; P = 0.001). There were no significant differences in demographics between the study and control groups. The rate of progression to muscle invasive disease was 17% vs 0% in the study group and control group respectively (P = 0.0521). History of UTUC was associated with increased risk of intravesical bladder tumor recurrence post BCG on multivariable analysis (HR 2.5; P = 0.017) and Kaplan Meier survival analysis (P = 0.039). The mean time to bladder tumor recurrence after treatment with BCG was significantly worse in the study group at (7.9 vs. 23.9 months; P = 0.0322). Similarly, the rate of progression to metastatic disease was worse in the study group (24% vs 2%; P = 0.0047). Overall disease-free survival was also noted to be significantly worse on Kaplan Meier survival analysis in the study group (P = 0.0074). No statistically significant differences in the stage grade of bladder tumor recurrence, grade of bladder tumor recurrence, or rate of progression to cystectomy were identified. CONCLUSIONS: Our study suggests reduced efficacy of BCG for NMIBC in patients with a history of UTUC. Patients in this population should be counseled accordingly. Research into alternative treatments for bladder tumor recurrence and more aggressive prophylactic regimens after nephroureterectomy for prevention of bladder tumor recurrence in this population is encouraged.

Case report: A novel somatic SDHB variant in a patient with bladder paraganglioma.

Background: Paragangliomas (PGL) are rare neuroendocrine tumors derived from the autonomic nervous system paraganglia. Urinary bladder paragangliomas (UBPGL) originate from the sympathetic neurons of the urinary bladder wall and represent 0.7% of all paragangliomas and <0.05% of all bladder tumors. PGL and UBPGL can be associated with SDHB, SDHD, NF1, and VHL gene variants, with the most common germline alterations found in SDHB and VHL. Case report: We report a case of a 42-year-old woman who presented with menorrhagia/hematuria, uterine leiomyomas, as well as cardiac and bladder masses. The cardiac mass was favored to be a myxoma based on clinical findings, while the bladder mass was diagnosed as UBPGL. A novel SDHB mutation (c.642G>A, p Q214Q), detected in the UBPGL, was proven to be somatic. Although this variant was seemingly synonymous, it was predicted to have a loss of function due to the splice site effect, which was further supported by the immunohistochemical loss of SDHB. Conclusion: This case highlights the challenges of diagnosing an extremely rare entity, bladder paraganglioma, with an emphasis on the multidisciplinary approach to navigate various clinical and imaging findings that may initially be misleading. In addition, a novel loss of function SDHB variant that could have been overlooked as a synonymous variant is herein reported, while also illustrating the importance of both germline and somatic mutation testing.

Practice-setting and surgeon characteristics heavily influence the decision to perform partial nephrectomy among American Urologic Association surgeons.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is great variability in the utilization of partial nephrectomy, but the causes of these variations are not well understood. The present study underscores the already observed phenomenon of surgical volume influencing surgical planning and outcomes, but it gets at why this might be so. We observe that high-volume renal surgeons have different thresholds of 'technical feasibility'. OBJECTIVE: To investigate why there continues to be wide variability in the application of partial nephrectomy (PN) for treating small renal masses despite guidelines in the US and Europe stating that a PN is a standard of care for a patient with a T1 renal mass. PATIENTS AND METHODS: In June 2009, 764 surgeon-members of the American Urologic Association (AUA) participated in a survey evaluating the management of renal masses. Renal mass complexity was graded by nephrometry score (NS). Multivariable logistic regression models with generalized estimating equations were constructed to evaluate how tumour, surgeon and practice-setting characteristics influence the use of PN. RESULTS: The survey response rate was 19%. Each urological surgeon responded to eight scenarios, providing 6112 evaluable cases. Tumour NS ranged from 4 to 10, and each unit increase in NS was associated with 59% increased likelihood of a surgeon offering RN on multivariable analysis (odds ratio [OR] = 1.59; 95% CI: 1.52-1.64). When holding patient and tumour characteristics constant, the following surgeon and practice-setting characteristics significantly increased the odds of offering a PN: increasing renal case volume (OR = 1.57; 95% CI: 1.27-1.95), academic practice (OR = 1.80; 95% CI: 1.42-2.29), increasing PN % volume (OR = 3.7; 95% CI: 2.46-5.55) and younger surgeon age (≤ 40 vs >50 years) (OR = 1.64; 95% CI: 1.35-1.96). CONCLUSION: The characteristics of a surgeon and the setting in which he or she practices influence the utilization of PN, the adherence to professional guidelines, and the threshold of tumour complexity at which a surgeon stops offering PN.

Tissue Slice Culture and Analysis of Tumor-Associated Hyaluronan in Urothelial Carcinoma.

Hyaluronan is a major component of the extracellular matrix in both normal and tumor tissue. Many solid cancers, including bladder cancer, are characterized by deregulated hyaluronan metabolism. It is postulated that the deregulated metabolism in cancer tissue is characterized by elevated hyaluronan synthesis and degradation. This results in the accumulation of small hyaluronan fragments in the tumor microenvironment which promotes cancer-related inflammation, stimulates tumor cell proliferation and angiogenesis, and contributes to immune-associated immune suppression. For a better understanding of the complex mechanisms of hyaluronan metabolism in cancer, it has been proposed to use precision-cut tissue slice cultures prepared using freshly excised cancer tissue. Here we describe the protocol for establishing tissue slice cultures and analysis of tumor-associated hyaluronan in human urothelial carcinoma.

Assessment of the pathologic inclusion criteria from contemporary adjuvant clinical trials for predicting disease progression after nephrectomy for renal cell carcinoma.

BACKGROUND: The objective of this study was to evaluate the accuracy of the pathologic inclusion criteria from all contemporary adjuvant trials in predicting disease progression (DP) for renal cell carcinoma (RCC). METHODS: A retrospective review was conducted on 1363 patients treated surgically for M0 RCC at the Mayo Clinic (Rochester, MN), from 1990 to 2001. Clinicopathologic features were reviewed to determine eligibility for the following trials: ARISER, ASSURE, EVEREST, PROTECT, SORCE, and S-TRAC. DP was defined as local recurrence or distant metastasis after surgery. The ability of each trial's inclusion criteria to accurately predict DP was evaluated by the c (concordance) index. RESULTS: From the Mayo Clinic cohort, we determined that 41%, 45%, 45%, 33%, 47%, and 23% of the patients would have been eligible for the ARISER, ASSURE, EVEREST, PROTECT, SORCE, and S-TRAC clinical trials, respectively. Overall, 23% of all patients experienced DP (n = 317). Among eligible patients, 53%, 44%, 44%, 57%, 43%, and 59% developed DP during follow-up and 10%, 6%, 6%, 13%, 6%, and 18% went onto DP while not being eligible for the ARISER, ASSURE, EVEREST, PROTECT, SORCE, and S-TRAC trials, respectively. The c index of each trial to accurately predict DP from the pathologic inclusion criteria of ARISER, ASSURE, EVEREST, PROTECT, SORCE, and S-TRAC were 0.751, 0.751, 0.751, 0.742, 0.745, and 0.691, respectively. CONCLUSIONS: Although the pathologic inclusion criteria of contemporary adjuvant trials have notable differences, all 6 adjuvant trials demonstrated high predictive accuracy of DP. Overall, 43% to 59% of patients included for the adjuvant trials would develop DP, whereas 6% to 18% of patients excluded from the trials would develop DP during follow-up.

Enhancing renal tumors in patients with prior normal abdominal imaging: further insight into the natural history of renal cell carcinoma.

PURPOSE: Patients undergoing serial cross-sectional abdominal imaging to evaluate abdominal symptomatology may have a renal tumor develop during followup of an unrelated disease process. Evaluation of such patients provides an opportunity to further define the radiographic inception, natural history and growth patterns of renal tumors. MATERIALS AND METHODS: Renal tumor databases from 2 institutions were reviewed for patients in whom an enhancing renal tumor developed despite a prior normal cross-sectional radiographic examination of the kidneys. Variables evaluated included age, gender, tumor size at presentation, calculated tumor growth rate from negative scan to radiographic presentation and pathology in patients undergoing definitive treatment. RESULTS: We identified 36 patients with an average age of 65 years (range 44 to 82). Mean tumor size on presentation was 2.3 cm (range 1.0 to 5.0). The presumed absolute growth rate based on the timing of the initial negative imaging study and tumor diameter at presentation was significantly greater than the observed absolute growth rate after tumor detection (0.71 vs 0.039 cm per year, p = 0.028). No difference was noted between presumed and observed tumor growth based on absolute change in tumor volume (1.44 vs 5.37 cm(3) per year, p = 0.203). Presumed relative growth rates based on tumor diameter (665% vs 23% per year) and volume (1,397% vs 169% per year) were significantly greater than observed relative growth rates (p = 0.005 and p = 0.013, respectively). CONCLUSIONS: The presumed growth rate of the tumors was significantly greater than the observed growth rate, suggesting that tumor growth rates do not follow a linear pattern throughout their development and progression.

Association of tumor size, location, R.E.N.A.L., PADUA and centrality index score with perioperative outcomes and postoperative renal function.

PURPOSE: Multiple scoring systems have been proposed to standardize the description of anatomical features of renal tumors. However, it remains unclear which of these systems, if any, is most useful, or whether any performs better than simply reporting tumor size or location in patients undergoing partial nephrectomy. To clarify these issues we evaluated the association of tumor size, location, R.E.N.A.L. (Radius/Exophytic/Nearness to collecting system/Anterior/Location), PADUA (Preoperative Aspects and Dimensions Used for an Anatomical classification) and centrality index scores with perioperative outcomes. MATERIALS AND METHODS: Patients undergoing partial nephrectomy with available preoperative imaging were identified from 2005 to 2011. R.E.N.A.L., PADUA and centrality index scores were assigned according to the described protocols for those systems. Associations between each variable and ischemia time, estimated blood loss, total operative time and change in estimated glomerular filtration rate were examined. RESULTS: A total of 162 patients were identified with a median tumor size of 3.1 cm (IQR 2.2 to 4.6). Median estimated blood loss, ischemia time and total operative time were 200 ml (IQR 100 to 300), 24 minutes (IQR 20 to 30) and 211 minutes (IQR 179 to 249), respectively. Each scoring system was found to have a statistically significant (p <0.001) correlation with ischemia time, with the centrality index system showing the strongest correlation. Furthermore, each of the scoring systems showed a stronger correlation with ischemia time than tumor size or tumor location. CONCLUSIONS: Each scoring system outperformed tumor size and location, and may be useful when describing the surgical complexity of renal tumors treated with partial nephrectomy.

Role of cytoreductive nephrectomy in the era of targeted therapy for renal cell carcinoma.

With the advent of targeted therapy for the treatment of metastatic renal cancer, the routine use of cytoreductive nephrectomy has been questioned. However, available data suggest that cytoreductive nephrectomy remains an integral part of treatment in properly selected patients. This review details the rationale for the continued use of cytoreductive nephrectomy in acceptable surgical candidates in the era of targeted therapy.

NMP-22, urinary cytology, and cystoscopy: a 1 year comparison study.

INTRODUCTION: Bladder cancer diagnosis and surveillance is costly and frequent. Urinary cytology is used with cystoscopy in the diagnosis and surveillance of bladder cancer with little evidence to support this practice. Nuclear Matrix Protein-22 (NMP-22) is a marker of urothelial cell death and is elevated in the urine of patients with bladder cancer. Our study compares the performance of NMP-22, urinary cytology and office cystoscopy when utilized in a Veteran Affairs urology practice for 1 year. MATERIALS AND METHODS: A total of 391 consecutive office cystoscopy procedures performed over 1 year were included in the study. NMP-22 and cytology were performed on the urine specimens of patients presenting for cystoscopy. Tumor resection/bladder biopsy was performed when cystoscopy, NMP-22 or urinary cytology were abnormal. RESULTS: Cystoscopy, NMP-22, and urinary cytology data were available in 351 encounters and 69 tumor resections were performed. Urothelial carcinoma bladder (UCB) was identified in 37 bladder specimens. NMP-22, urinary cytology and cystoscopy demonstrated sensitivity and specificity of (51%/96%), (35%/97%), and (92%/88%), respectively. NMP-22 cost $8,750 in the study group and urinary cytology cost $52,500 in the same group. CONCLUSIONS: This study demonstrates cystoscopy was the most sensitive test in the diagnosis of UCB. NMP-22 had a higher sensitivity than urinary cytology and similar specificity to cytology. Additional urinary marker testing has a limited role in the management of bladder cancer in the office setting. When adjunct testing is desired in the diagnosis and surveillance of bladder cancer, NMP-22 is a cost effective alternative to urinary cytology.

High Levels of PD-L1+ and Hyal2+ Myeloid-derived Suppressor Cells in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) patients frequently have increased number of immunosuppressive myeloid cells in circulation. High number of myeloid-derived suppressor cells (MDSCs) in the blood are associated with immune suppression as well as with cancer-related inflammation which drives the mobilization of myeloid cells to tumor tissue. Here, we show that peripheral blood from a previously untreated RCC patient has increased the number of monocytic CD33+CD11b+ MDSCs, which also co-expressed PD-L1 and membrane-bound enzyme hyaluronidase 2 (Hyal2). PD-L1 expression is associated with immune suppression, whereas expression of Hyal2 is associated with inflammation, because Hyal2+ myeloid cells can degrade the extracellular hyaluronan (HA), leading to the accumulation of pro-inflammatory HA fragments with low molecular weight. These findings implicate the potential involvement of monocytic MDSCs in both tumor-associated immune suppression and cancer-related inflammation. Analysis of organotypic tumor-tissue slice cultures prepared from cancer tissue of the same patient revealed the significant presence of PD-L1+ HLA-DR+ macrophage-like or dendritic cell-like antigen-presenting cells in tumor stroma. Interestingly, stroma-associated PD-L1+ cells frequently have intracellular hyaluronan. Collectively, data presented in this study suggest that the interplay between tumor-recruited myeloid cells and stromal HA may contribute to the inflammation and immune tolerance in kidney cancer.

Predicting Complete Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer.

Muscle-invasive bladder cancer is a life-threatening disease best managed with multimodal therapy. Neoadjuvant chemotherapy prior to cystectomy significantly improves survival with the greatest benefit noted in patients with a complete pathologic response noted at cystectomy. While radical cystectomy is currently an important part of the treatment plan, surgical morbidity remains high. Accurate prediction of complete responses to chemotherapy would enable avoiding the morbidity of radical cystectomy. Multiple clinical, pathologic, molecular, and radiographic predictors have been evaluated. Clinical and standard pathologic findings have not been found to be accurate predictors of complete response. To date, tumor genomic findings have been the most promising and have led to multiple clinical trials to evaluate if bladder preservation is possible in select patients. Radiomics has shown initial promise with larger validation series needed. These predictors can be further characterized as treatment specific and non-treatment specific. With the potential changing landscape of neoadjuvant therapy prior to radical cystectomy and the limitations of individual predictors of a complete response, a panel of several biomarkers may enhance patient selection for bladder preservation. The aim of this review is to summarize predictors of complete response to neoadjuvant chemotherapy.

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.