Evaluation of toxicities for intravesical drugs in phase 1 bladder cancer trials.

BACKGROUND: Improving clinical trial design is important for optimizing approval of safe and effective drugs. Phase 1 clinical trials seek to determine phase 2 doses by investigating predefined dose-limiting toxicities. Traditional definitions of dose-limiting toxicity may not be applicable to intravesical therapies for bladder cancer. This study compared the frequency of dose-limiting toxicities and serious adverse events in bladder cancer trials for intravesical therapies to other routes of administration. METHODS: Studies were abstracted from ClinicalTrials.gov and reconciled with a PubMed search. Primary and secondary end points were predefined before data abstraction, and the primary end point was subject-level dose-limiting toxicity rate. Fisher exact tests were performed with p < .05 designated as significant. RESULTS: Eighteen intravesical studies and 24 studies with other routes of administration (the per os/intravenous/intramuscular [PO/IV/IM] group) were identified. Dose-limiting toxicities were reported in 38.9% of intravesical studies, affecting 3.29% of subjects, compared with 30.0% of PO/IV/IM studies representing 4.19% of subjects (p = .52 for study-level and p = .60 for subject-level comparisons). Serious adverse events occurred in 53.9% of intravesical studies in 10.3% of subjects versus 91.0% of studies reporting serious adverse events affecting 41.4% of subjects in the PO/IV/IM group (p = .03 for subject-level and p < .0001 for study-level comparisons). CONCLUSIONS: There was no difference in subject-level dose-limiting toxicity rate between intravesical and PO/IV/IM bladder cancer trials. The serious adverse event rate was lower in the intravesical group. Heterogeneity of dose-limiting toxicity definition may affect interpretation of toxicity in phase 1 bladder cancer clinical trials studying different routes of administration. LAY SUMMARY: Bladder cancer is a common cancer type that may be treated with therapies that are instilled into the bladder and act locally, called intravesical therapies. This study used publicly available regulatory data from early phase clinical trials to determine whether measures of tolerability used in clinical trials are applicable to intravesical therapies for bladder cancer.

Utilizing head-mounted eye trackers to analyze patterns and decision-making strategies of 3D virtual modelling platform (IRIS™) during preoperative planning for renal cancer surgeries.

PURPOSE: IRIS™ provides interactive, 3D anatomical visualizations of renal anatomy for pre-operative planning that can be manipulated by altering transparency, rotating, zooming, panning, and overlaying the CT scan. Our objective was to analyze how eye tracking metrics and utilization patterns differ between preoperative surgical planning of renal masses using IRIS and CT scans. METHODS: Seven surgeons randomly reviewed IRIS and CT images of 9 patients with renal masses [5 high complexity (RENAL score ≥ 8), 4 low complexity (≤ 7)]. Surgeons answered a series of questions regarding patient anatomy, perceived difficulty (/100), confidence (/100), and surgical plan. Eye tracking metrics (mean pupil diameter, number of fixations, and gaze duration) were collected. RESULTS: Surgeons spent significantly less time interpreting data from IRIS than CT scans (- 67.1 s, p < 0.01) and had higher inter-rater agreement of surgical approach after viewing IRIS (α = 0.16-0.34). After viewing IRIS, surgical plans although not statistically significant demonstrated a greater tendency towards a more selective ischemia approaches which positively correlated with improved identification of vascular anatomy. Planned surgical approach changed in 22/59 of the cases. Compared to viewing the CT scan, left and right mean pupil diameter and number/duration of fixations were significantly lower when using IRIS (p < 0.01, p < 0.01, p = 0.42, p < 0.01, respectively), indicating interpreting information from IRIS required less mental effort despite under-utilizing its interactive features. CONCLUSIONS: Surgeons extrapolated more detailed information in less time with less mental effort using IRIS than CT scans and proposed surgical approaches with potential to enhanced surgical outcomes.

The emerging role of immunotherapy in advanced urothelial cancers.

PURPOSE OF REVIEW: Recent Food and Drug Administration (FDA) approval of five new immune checkpoint inhibitors for the treatment of metastatic urothelial cancer represents the first major treatment breakthrough for this disease since the introduction of combination chemotherapy over 30 years ago. This review examines the recent clinical trials leading to FDA approval of these agents, the current challenges facing immunotherapy and areas that require further research. RECENT FINDINGS: The programmed death 1 receptor (PD-1) and its ligand programmed death ligand-1 (PD-L1) are important negative regulators of immune activity, preventing destruction of normal tissues and autoimmunity. Aggressive bladder cancer cells express aberrantly high levels of PD-L1, hijacking the normal immune-regulatory pathway to evade detection and destruction by the immune system. Blockade of the PD-1/PD-L1 axis with immune checkpoint inhibitors augments the immune system's ability to eradicate bladder cancer with impressive safety and tolerability profiles. SUMMARY: Recent clinical trials demonstrate that patients with metastatic urothelial carcinoma are responsive to immune checkpoint inhibitor therapy. Optimal treatment regimens are still under development, but activity has been demonstrated in both the first and second-line setting for metastatic disease.

Current Use and Promise of Urinary Markers for Urothelial Cancer.

PURPOSE OF REVIEW: We summarize the current literature regarding the available urinary biomarkers for the detection and surveillance of bladder cancer. RECENT FINDINGS: Four urinary biomarkers have FDA approval for the detection of bladder cancer; however, they have not supplanted cystoscopy and urine cytology as the gold standard. Recent technological advances in next-generation sequencing have allowed the field of urinary biomarker research to move beyond protein biomarkers and now include genomic, transcriptomic, and epigenetic panels. The search for a noninvasive, inexpensive urinary biomarker for the detection of bladder cancer that can replace cystoscopy and cytology continues. There are several promising genomic, transcriptomic, and epigenetic marker panels in development; however, these new tests require further prospective validation before widespread clinical implementation.

Development of a Combined MR Fingerprinting and Diffusion Examination for Prostate Cancer.

Purpose To develop and evaluate an examination consisting of magnetic resonance (MR) fingerprinting-based T1, T2, and standard apparent diffusion coefficient (ADC) mapping for multiparametric characterization of prostate disease. Materials and Methods This institutional review board-approved, HIPAA-compliant retrospective study of prospectively collected data included 140 patients suspected of having prostate cancer. T1 and T2 mapping was performed with fast imaging with steady-state precession-based MR fingerprinting with ADC mapping. Regions of interest were drawn by two independent readers in peripheral zone lesions and normal-appearing peripheral zone (NPZ) tissue identified on clinical images. T1, T2, and ADC were recorded for each region. Histopathologic correlation was based on systematic transrectal biopsy or cognitively targeted biopsy results, if available. Generalized estimating equations logistic regression was used to assess T1, T2, and ADC in the differentiation of (a) cancer versus NPZ, (b) cancer versus prostatitis, (c) prostatitis versus NPZ, and (d) high- or intermediate-grade tumors versus low-grade tumors. Analysis was performed for all lesions and repeated in a targeted biopsy subset. Discriminating ability was evaluated by using the area under the receiver operating characteristic curve (AUC). Results In this study, 109 lesions were analyzed, including 39 with cognitively targeted sampling. T1, T2, and ADC from cancer (mean, 1628 msec ± 344, 73 msec ± 27, and 0.773 × 10-3 mm2/sec ± 0.331, respectively) were significantly lower than those from NPZ (mean, 2247 msec ± 450, 169 msec ± 61, and 1.711 × 10-3 mm2/sec ± 0.269) (P < .0001 for each) and together produced the best separation between these groups (AUC = 0.99). ADC and T2 together produced the highest AUC of 0.83 for separating high- or intermediate-grade tumors from low-grade cancers. T1, T2, and ADC in prostatitis (mean, 1707 msec ± 377, 79 msec ± 37, and 0.911 × 10-3 mm2/sec ± 0.239) were significantly lower than those in NPZ (P < .0005 for each). Interreader agreement was excellent, with an intraclass correlation coefficient greater than 0.75 for both T1 and T2 measurements. Conclusion This study describes the development of a rapid MR fingerprinting- and diffusion-based examination for quantitative characterization of prostatic tissue. © RSNA, 2017 Online supplemental material is available for this article.

Variation in Surgical Margin Status by Surgical Approach among Patients Undergoing Partial Nephrectomy for Small Renal Masses.

PURPOSE: We assessed the relationship of surgical margins across different surgical approaches to partial nephrectomy in patients with clinical T1a renal cell carcinoma in a population based cohort. MATERIALS AND METHODS: We used NCDB (National Cancer Database) to identify all patients who underwent partial nephrectomy for clinical T1a renal cell carcinoma (tumor size less than 4 cm) from 2010 to 2011. The primary outcome was surgical margin status in patients treated with partial nephrectomy by the open, laparoscopic or robotic approach. Multivariable logistic regression analysis was done to identify patient, hospital and surgical factors associated with positive surgical margins. RESULTS: Partial nephrectomy was done in 11,587 patients, including open, laparoscopic and robotic nephrectomy in 5,094 (44%), 1,681 (14%) and 4,812 (42%), respectively. Mean±SD age was 56±12 years. Overall 806 patients (7%) had positive surgical margins. The positive surgical margin prevalence was 4.9%, 8.1% and 8.7% for the open, laparoscopic and robotic approaches, respectively (p<0.001). Laparoscopic and robotic partial nephrectomy had a higher adjusted OR for positive surgical margins (OR 1.81 and 1.79, respectively, each p<0.001) than open nephrectomy. When stratified by hospital type, differences in positive surgical margin rates remained, such that patients treated at academic medical centers who underwent laparoscopic and robotic partial nephrectomy had a higher adjusted OR (1.38, p=0.074 and 1.73, p<0.001, respectively) than patients treated with open partial nephrectomy. CONCLUSIONS: Laparoscopic and robotic partial nephrectomy is associated with higher positive surgical margin rates compared to open partial nephrectomy for clinical T1a renal cell carcinoma. The effect of margin status on long-term oncologic outcomes in this context remains to be determined.

Can preoperative planning using IRIS™ three-dimensional anatomical virtual models predict operative findings during robot-assisted partial nephrectomy?

Objective: To evaluate the predictive validity of IRIS™ (Intuitive Surgical®, Sunnyvale, CA, USA) as a planning tool for robot-assisted partial nephrectomy (RAPN) by assessing the degree of overlap with intraoperative execution. Methods: Thirty-one patients scheduled for RAPN by four experienced urologists were enrolled in a prospective study. Prior to surgery, urologists reviewed the IRIS™ three-dimensional model on an iphone Operating System (iOS) app and completed a questionnaire outlining their surgical plan including surgical approach, and ischemia technique as well as confidence in executing this plan. Postoperatively, questionnaires assessing the procedural approach, clinical utility, efficiency, and effectiveness of IRIS™ were completed. The degree of overlap between the preoperative and intraoperative questionnaires and between the planned approach and actual execution of the procedure was analyzed. Questionnaires were answered on a 5-point Likert scale and scores of 4 or greater were considered positive. Results: Mean age was 65.1 years with a mean tumor size of 27.7 mm (interquartile range 17.5-44.0 mm). Hilar tumors consisted of 32.3%; 48.4% of patients had R.E.N.A.L. nephrometry scores of 7-9. On preoperative questionnaires, the surgeons reported that in 67.7% cases they were confident that they can perform the procedure successfully, and on intraoperative questionnaires, the surgeons reported that in 96.8% cases IRIS™ helped achieve good spatial sensation of the anatomy. There was a high degree of overlap between preoperative and intraoperative questionnaires for the surgical approach, interpreting anatomical details and clinical utility. When comparing plans for selective or off-clamp, the preoperative plan was executed in 90.0% of cases intraoperatively. Conclusion: A high degree of overlap between the preoperative surgical approach and intraoperative RAPN execution was found using IRIS™. This is the first study to evaluate the predictive accuracy of IRIS™ during RAPN by comparing preoperative plan and intraoperative execution.

Do Skills Naturally Transfer Between Multiport and Single-Port Robotic Platforms? A Comparative Study in a Simulated Environment.

Introduction and Objective: With introduction of the da Vinci single-port (SP) system, we evaluated which multiport (MP) robotic skills are naturally transferable to the SP platform. Methods: Three groups of urologists: Group 1 (5 inexperienced in MP and SP), Group 2 (5 experienced in MP without SP experience), and Group 3 (2 experienced in both MP and SP) were recruited to complete a validated urethrovesical anastomosis simulation using MP followed by SP robots. Performance was graded using both GEARS and RACE scales. Subjective cognitive load measurements (Surg-TLX and difficulty ratings [/20] of instrument collisions camera and EndoWrist movement) were collected. Results: GEARS and RACE scores for Groups 1 and 3 were maintained on switching from MP to SP (Group 3 scored significantly higher on both systems). Surg-TLX and difficulty scores were also maintained for both groups on switching from MP and SP except for a significant increase in SP camera movement (+7.2, p = 0.03) in Group 1 compared to Group 3 that maintained low scores on both. Group 2 demonstrated significant lower GEARS (-2.9, p = 0.047) and RACE (-5.1, p = 0.011) scores on SP vs MP. On subanalysis, GEARS subscores for force sensitivity and robotic control (-0.7, p = 0.04; -0.9, p = 0.02) and RACE subscores for needle entry, needle driving, and tissue approximation (-0.9, p = 0.01; -1.0, p = 0.02; -1.0, p < 0.01) significantly decreased. GEARS (depth perception, bimanual dexterity, and efficiency) and RACE subscores (needle positioning and suture placement) were maintained. All participants scored significantly lower in knot tying on the SP robot (-1.0, p = 0.03; -1.2, p = 0.02, respectively). Group 2 reported higher Surg-TLX (+13 pts, p = 0.015) and difficulty ratings on SP vs MP (+11.8, p < 0.01; +13.6, p < 0.01; +14 pts, p < 0.01). Conclusions: The partial skill transference across robots raises the question regarding SP-specific training for urologists proficient in MP. Novices maintained difficulty scores and cognitive load across platforms, suggesting that concurrent SP and MP training may be preferred.

HOXB4-transduced embryonic stem cell-derived Lin-c-kit+ and Lin-Sca-1+ hematopoietic progenitors express H60 and are targeted by NK cells.

Embryonic stem (ES) cells are a novel source of cells, especially hematopoietic progenitor cells that can be used to treat degenerative diseases in humans. However, there is a need to determine how ES cell-derived progenitors are regulated by both the adaptive and innate immune systems post transplantation. In this study, we demonstrate that hematopoietic progenitor cells (HPCs) derived from mouse ES cells ectopically expressing HOXB4 fail to engraft long-term in the presence of NK cells. In particular, the H60-expressing Lin(-)c-kit(+) and Lin(-)Sca-1(+) subpopulations were preferentially deleted in Rag2(-/-), but not in Rag2(-/-)gamma(c)(-/-) mice. Up-regulation of class I expression on HPCs prevented their lysis by NK cells, and Ab-mediated depletion of NK cells restored long-term HPC engraftment. In contrast to the notion that ES-derived cells are immune-privileged, we show in this study that NK cells form a formidable barrier to the long-term engraftment of ES cell-derived hematopoietic progenitors.

Comparison of Multi-Parametric MRI of the Prostate to 3D Prostate Computer Aided Designs and 3D-Printed Prostate Models for Pre-Operative Planning of Radical Prostatectomies: A Pilot Study.

OBJECTIVE: To evaluate the use of 3D computed aided designs and 3D-printed models as pre-operative planning tools for urologists, in addition to radiologist interpreted mp-MRIS, prior to radical prostatectomy procedures. METHODS: Ten patients with biopsy-positive lesions detected on mp-MRI were retrospectively selected. Radiologists identified lesion locations using a Prostate Imaging-Reporting and Data System (PI-RADS) map and segmented the prostate, lesion(s), and surrounding anatomy to create 3D-CADs and 3D-printed models for each patient. 6 uro-oncologists randomly reviewed three modalities (mp-MRI, 3D-CAD, and 3D-printed models) for each patient and identified lesion locations which were graded for accuracy against the radiologists' answers. Questionnaires assessed decision confidence, ease-of-interpretation, and usefulness for preoperative planning for each modality. RESULTS: Using 3D-CADs and 3D-printed models compared to mp-MRI, urologists were 2.4x and 2.8x more accurate at identifying the lesion(s), 2.7x and 3.2x faster, 1.6x and 1.63x more confident, and reported it was 1.6x and 1.7x easier to interpret. 3D-CADs and 3D-printed models were reported significantly more useful for overall pre-operative planning, identifying lesion location(s), determining degree of nerve sparing, obtaining negative margins, and patient counseling. Sub-analysis showed 3D-printed models demonstrated significant improvements in ease-of-interpretation, speed, usefulness for obtaining negative margins, and patient counseling compared to 3D-CADs. CONCLUSION: 3D-CADs and 3D-printed models are useful adjuncts to mp-MRI in providing urologists with more practical, accurate, and efficient pre-operative planning.

Variability in adherence to guidelines based management of nonmuscle invasive bladder cancer among Society of Urologic Oncology (SUO) members.

PURPOSE: The American Urological Association (AUA) introduced evidence-based guidelines for the management of nonmuscle invasive bladder cancer (NMIBC) in 2016. We sought to assess the implementation of these guidelines among members of the Society of Urologic Oncology (SUO) with an aim to identifying addressable gaps. METHODS AND MATERIALS: An SUO approved survey was distributed to 747 members from December 28, 2018 to February 2, 2019. This 14-question online survey (Qualtrics, SAP SE, Germany) consisted of 38 individual items addressing specific statements from the AUA NMIBC guidelines within 3 broad categories - initial diagnosis, surveillance, and imaging/biomarkers. Adherence to guidelines was assessed by dichotomizing responses to each item that was related to recommended action statement within the guidelines. Statistical analysis was applied using Pearson's chi-squared test, where a P-value of <0.05 was considered statistically significant. RESULTS: A total of 121 (16.2%) members completed the survey. Members reported a mean of 71% guidelines adherence; adherence was higher for the intermediate- and high-risk subgroups (82% and 76%, respectively) compared to low-risk (58%). Specifically, adherence to guideline recommended cystoscopic surveillance intervals for low-risk disease differed based on clinical experience (60.9% [<10 years] vs. 36.8% [≥10 years], P = 0.01) and type of fellowship training (55.2% [urologic oncology] vs. 28.0% [none/other], P = 0.02). CONCLUSION: Adherence to guidelines across risk-categories was higher for intermediate- and high-risk patients. Decreased adherence observed for low-risk patients resulted in higher than recommended use of cytology, imaging, and surveillance cystoscopy. These results identify addressable gaps and provide impetus for targeted interventions to support high-value care, especially for low-risk patients.

Prognostic Implication of the United States Food and Drug Administration-defined BCG-unresponsive Disease.

The category "BCG-unresponsive disease", formulated by experts at the request of the United States Food and Drug Administration, denotes a group of patients with recurrent non-muscle-invasive bladder cancer for whom continued BCG treatment is unlikely to provide benefit. Although quickly adopted for trial design, many of the nuances within the definition lack validation. In this study, we evaluated the prognostic value of BCG unresponsive designation (i.e. recurrence after induction plus at least 1 maintenance course of BCG) by comparing the oncologic outcomes of these patients with those recurring after induction BCG alone. We confirm that appropriately defined, BCG-unresponsive patients are more likely to require salvage radical cystectomy (54.5% vs 17.9%, p=0.002). Moreover, those opting for second-line bladder-sparing therapies are less likely to remain free of tumor recurrence (23% vs 69.2%, p=0.003). On multivariate analysis, BCG-unresponsive disease independently predicts inferior high-grade recurrence-free survival (hazard ratio [HR]: 6.25, 95% confidence interval [CI]: 2.27-16.67; p<0.001) and cystectomy-free survival (HR: 3.85, 95% CI: 1.49-10.0; p=0.006). Our data confirm the prognostic implication of the BCG unresponsive definition i.e. recurrence of high grade disease after induction and one course of maintenance BCG, and support its use in counseling and risk stratification of patients with tumor recurrence after BCG. Patient summary: Patients who have BCG-unresponsive disease, that is, high-grade non-muscle-invasive bladder cancer recurring after BCG induction and maintenance, have a low likelihood to respond to further BCG treatment and should consider radical cystectomy or clinical trial enrollment.

Using Grade of Recurrent Tumor to Guide Further Therapy While on Bacillus Calmette-Guerin: Low-grade Recurrences Are not Benign.

BACKGROUND: Tumors that recur after bacillus Calmette-Guerin (BCG) therapy are considered to be of very high risk, and patients are often recommended to undergo radical cystectomy (RC). However, the nuances associated with the grade of tumor recurrence after BCG treatment are not well understood. OBJECTIVE: To characterize the pattern of bladder cancer progression and cancer-specific survival (CSS) in patients with recurrences dichotomized by low grade (LG) versus high grade (HG) after intravesical BCG treatment, and to assess the safety of continued bladder-sparing therapy in these patients. DESIGN, SETTING, AND PARTICIPANTS: We performed an Institutional Review Board-approved review of our bladder cancer database. Overall, 146 non-muscle-invasive bladder cancer (NMIBC) patients were found to have NMIBC recurrence while on BCG therapy; this recurrence was LG in 38 and HG in 108. Baseline clinicopathologic characteristics including age, gender, primary tumor grade, stage, size, multiplicity, and concurrent carcinoma in situ were also evaluated. The primary endpoint was progression-free survival (PFS), with progression defined as the development of muscle-invasive bladder cancer (MIBC)/distant metastasis. In addition, recurrence-free survival (RFS), HG RFS, cystectomy-free survival (CFS), and CSS were also compared. Multivariable analysis was performed using the Cox regression model. All tests were two sided, and p<0.05 was considered statistically significant. INTERVENTION: Further intravesical therapy versus salvage RC. RESULTS AND LIMITATIONS: Overall, estimated 5-yr PFS was 72.4% (95% confidence interval [CI] 60.4-81.3%). As dichotomized by grade of recurrent tumor, PFS was greater for patients with LG recurrences (85.6%, 95% CI 60.8-95.2%) than for those with HG recurrence (67.9%, 95% CI 54.1-78.4%; p=0.010). Furthermore, patients whose initial recurrence on BCG therapy was LG had improved subsequent RFS (median 62 vs 34mo, p=0.007), HG RFS (median 112 vs 36mo, p<0.001), and CFS (estimated 5-yr CFS 80.8% vs 49.8%, p<0.001) compared with those who had HG initial recurrence. On univariate and multivariate analyses, grade of tumor recurrence after BCG was an independent predictor of time to progression to MIBC/distant metastasis (hazard ratio 3.60, 95% CI 1.18-10.94, p=0.024). CONCLUSIONS: Grade of tumor recurrence after intravesical BCG is an important predictor of bladder cancer progression to MIBC/metastatic urothelial carcinoma. While, patients with LG recurrences have less than half the progression events compared with those with HG recurrences, their estimated 5-yr progression rate is still 14.4%. Hence all patients should be carefully counseled on bladder-sparing therapy. This also has implications for clinical trial design. PATIENT SUMMARY: If bladder cancer recurs after bacillus Calmette-Guerin treatment, there are many factors that determine the further clinical outcome. Although low-grade recurrent tumors confer a less aggressive course, disease progression can still occur, and hence continued vigilance is important.

Optimal Timing of Chemotherapy and Surgery in Patients with Muscle-Invasive Bladder Cancer and Upper Urinary Tract Urothelial Carcinoma.

Radical cystectomy with bilateral pelvic lymph node dissection is the standard of care for patients with clinically localized muscle-invasive bladder cancer. Survival after radical cystectomy is associated with final pathologic staging. Survival decreases with increasing pT stage because of the presence of occult micrometastases, indicating the need for systemic chemotherapy. Systemic chemotherapy is delivered as either neoadjuvant therapy preoperatively, or as adjuvant therapy postoperatively. This article reviews the evidence for neoadjuvant and adjuvant chemotherapy for the treatment of muscle-invasive bladder and upper tract urothelial cancer and offers recommendations based on these data and recently updated clinical guidelines.

Evaluating the impact of the genitourinary multidisciplinary tumour board: Should every cancer patient be discussed as standard of care?

INTRODUCTION: We sought to prospectively evaluate the effectiveness of the multidisciplinary tumour board (MTB) on altering treatment plans for genitourinary (GU) cancer patients. METHODS: All GU cancer patients seen at our tertiary care hospital are discussed at MTB. We prospectively collected data on adult patients discussed over a continuous, 20-month period. Physicians completed a survey prior to MTB to document their opinion on the likelihood of change in their patient's treatment plan. Logistic regression was used to asses for factors associated with a change by the MTB, including patient age or sex, malignancy type, the predicted treatment plan, and the provider's years of experience or fellowship training. RESULTS: A total of 321 cancer patients were included. Patients were primarily male (84.4%) with a median age of 67 (range 20-92) years old. Prostate (38.9%), bladder (31.8%), and kidney cancer (19.6%) were the most common malignancies discussed. A change in management plan following MTB was observed in 57 (17.8%) patients. The physician predicted a likely change in six (10.5%) of these patients. Multivariate logistic regression did not determine physician prediction to be associated with treatment plan change, and the only significant variable identified was a plan to discuss multiple treatment options with a patient (odds ratio 2.46; 95% confidence interval 1.09-9.54). CONCLUSIONS: Routine discussion of all urologic oncology cases at MTB led to a change in treatment plan in 17.8% of patients. Physicians cannot reliably predict which patients have their treatment plan altered. Selectively choosing patients to be presented likely undervalues the impact of a multidisciplinary approach to care.

Systematic Review on the Utilization of Maintenance Intravesical Chemotherapy in the Management of Non-muscle-invasive Bladder Cancer.

CONTEXT: Current guidelines remain ill-defined regarding the optimal intravesical chemotherapy type and regimen for the treatment of non-muscle-invasive bladder cancer (NMIBC). Although maintenance therapy is a standard part of bacillus Calmette-Guerin (BCG) therapy, its role in the context of chemotherapy remains debatable. OBJECTIVE: We reviewed the literature regarding the utilization of intravesical maintenance chemotherapy in the treatment of NMIBC to determine its impact on recurrence, progression, and survival. EVIDENCE ACQUISITION: A systematic search was conducted using Ovid and Medline according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify studies between 1970 and 2018 reporting on the utilization of maintenance intravesical chemotherapy. Only randomized controlled trials (RCTs) that included a comparison between an induction regimen and an induction plus maintenance regimen were included. EVIDENCE SYNTHESIS: Sixteen RCTs were included in the final analysis. The most commonly studied intravesical chemotherapy agents used in maintenance regimens were epirubicin, doxorubicin, and mitomycin C. Several maintenance schedules were utilized, some as short as 3mo and others as long as 3 yr, while the most common maintenance regimen utilized was monthly instillation for 1 yr. Of the 16 trials, 13 reported no significant improvement in recurrence for patients receiving maintenance compared with no maintenance, and none of the trials demonstrated a significant impact on progression or survival. CONCLUSIONS: Intermediate length maintenance regimens lasting 7-12mo were the most common maintenance regimens utilized. There was considerable heterogeneity between trial design and duration of follow-up, making direct comparisons for recurrence, progression, and survival outcomes between trials challenging. Although maintenance intravesical chemotherapy is suggested as a treatment option for patients with NMIBC by some guidelines, the majority of evidence suggested that it provided no significant advantage over induction therapy alone with respect to recurrence, progression, or survival. PATIENT SUMMARY: In this review, we reviewed prior clinical trials to determine whether prolonged intravesical chemotherapy ("maintenance therapy") improved the rates of recurrence, progression, and survival. Where differences were found in favor of maintenance therapy, there was no statistical significance demonstrated, possibly due to the underpowered nature of the study design. While there was no consensus on an optimal agent or maintenance schedule, we found no evidence to suggest that maintenance therapy would improve recurrence, progression, or survival.

Soluble HLA revisited.

The goal of this editorial is to revisit soluble human leukocyte antigens (sHLA) and to highlight the findings reported by Albitar et al. in this issue on the relation between sHLA levels in Non-Hodgkin's Lymphoma (NHL) and Hodgkin's Disease (HD). We will review key aspects of sHLA including soluble HLA-G, which has received a lot of attention in recent publications. We will then address the role of sHLA in lymphoproliferative diseases and in solid organ tumors. Lastly, we will comment on the results of Albitar et al. and their relevance to clinical application in NHL.

Cytoreductive nephrectomy in the modern era: Predictors of use, morbidity, and survival.

INTRODUCTION: To determine tumour, patient, and provider factors associated with cytoreductive nephrectomy (CN) use and to identify those factors that predicted short-term and long-term surgical outcomes. METHODS: We performed a retrospective review (1998-2011) of the National Cancer Database, a U.S. population-based oncology outcomes database. The review included 36 549 patients with metastatic renal cell carcinoma (mRCC). We assessed predictors of CN use, length of stay (LOS), 30-day readmission, and 30-day mortality using multivariable logistic regression. The Cox proportional hazards model assessed predictors of overall survival (OS). RESULTS: Overall, 10 809 (29.6%) patients received CN, increasing from 15.2% to 36.1% over time. Private insurance (odds ratio [OR] 1.26; 95% confidence interval [CI] 1.16-1.37) and academic facilities (OR 1.83; 95% CI 1.68-1.99) were associated with receiving CN (p<0.0001). Charlson score ≥2 and older age group were less likely to undergo surgery (p<0.0001). Median LOS was five days (inter-quartile range [IQR] 3-7), while 30-day readmission and 30-day mortality were 5.3% and 3.3%, respectively. Undergoing CN (hazard ratio [HR] 0.48; 95% CI 0.44-0.52; p<0.0001) and treatment at academic centres (HR 0.88; 95% CI 0.81-0.95; p=0.001) were independently associated with improved OS. Limitation includes retrospective design with possible selection bias. CONCLUSIONS: Increased CN use continues in the modern era, with relatively low surgical morbidity. Further study is required to determine if the finding of lower all-cause mortality in patients treated at academic centres is due to improved care or unmeasured confounders.

Suppression of tumor metastasis by blockade of transforming growth factor beta signaling in bone marrow cells through a retroviral-mediated gene therapy in mice.

Transforming growth factor B (TGF-beta) is a potent immunosuppressive cytokine that is frequently associated with mechanisms of tumor escape from immunosurveillance. We report that transplantation of murine bone marrow (BM) expressing a dominant-negative TGF-beta type II receptor (TbetaRIIDN) leads to the generation of mature leukocytes capable of a potent antitumor response in vivo. Hematopoietic precursors in murine BM from donor mice were rendered insensitive to TGF-beta via retroviral expression of the TbetaRIIDN construct and were transplanted in C57BL/6 mice before tumor challenge. After i.v. administration of 5 x 10(5) B16-F10 murine melanoma cells into TbetaRIIDN-BM transplanted recipients, survival of challenged mice at 45 days was 70% (7 of 10) versus 0% (0 of 10) for vector-control treated mice, and surviving TbetaRIIDN-BM mice showed a virtual absence of metastatic lesions in the lung. We also investigated the utility of the TGF-beta-targeted approach in a mouse metastatic model of prostate cancer, TRAMP-C2. Treatment of male C57BL/6 mice with TbetaRIIDN-BM resulted in the survival of 80% (4 of 5) of recipients versus 0% (0 of 5) in green fluorescent protein-BM recipients or wild-type controls. Cytolytic T-cell assays indicate that a specific T-cell response against B16-F10 cells was generated in the TbetaRIIDN-BM-treated mice, suggesting that a gene therapy approach to inducing TGF-beta insensitivity in transplanted BM cells may be a potent anticancer therapy.

Prostate Cancer Screening and the Associated Controversy.

Prostate cancer is the most common malignancy diagnosed in men and the second leading cause of cancer death for men in the United States. Widespread use of prostate-specific antigen (PSA) screening led to a decrease in mortality; however, PSA screening may have led to overdiagnosis and overtreatment of clinically insignificant cancers. The US Preventive Services Task Force (USPSTF) released a statement recommending against the use of PSA, which was met with concern from professional organizations. This article reviews the epidemiology of prostate cancer, data from the largest screening trials, USPSTF recommendation statement, and current strategies used to improve overdiagnosis and overtreatment.