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Surgery is one of the most common curative modalities in prostate cancer. Unfortunately, as with any therapy, patients can suffer recurrence. Postoperative adjuvant therapy has been shown to prevent or delay recurrence. The presence of positive margins puts the patient at a high risk for recurrence. Additional risk factors have been identified that can predict for recurrence, but it is still uncertain as to who warrants immediate treatment. We reviewed the extensive surgical literature for prognostic factors for recurrence in addition to positive margins. We attempted to be exhaustive, first searching PubMed and Medline for all papers for radical prostatectomy and then checking the articles cited in those papers. We sought out papers that reviewed the effect of positive margins and its modifying factors on outcome. With the supposition that patients with >70% risk of failure is enough to consider additional treatment, we were able to identify the factors that appear to consistently place patients at or above that level of recurrence. For patients with positive margins, any one of these factors places the patients at a very high risk of recurrence: positive lymph nodes or seminal vesicles, preoperative PSA > 20 ng/ml, or a Gleason score > 7. Many Gleason 7 patients with positive margins fall into the >70% risk of failure category, especially if they have additional risk factors (i.e., those with extraprostatic extension). While there are no absolutes, all these patients should be strongly considered for adjuvant therapy in addition to radical prostatectomy. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To understand the additional benefits of HAL compared with conventional cystoscopy at the patient level and to explore relationships of urine cytology and CIS. Methods: We reanalyzed pooled data from 3 phase III studies comparing hexaminolevulinate (HAL, Hexvix) fluorescence cystoscopy with white light (WL) cystoscopy for detecting CIS. Results: Of 551 patients, 174 had at least one CIS lesion detected by HAL, WL, or random biopsy. The CIS detection rate of HAL was 0.87 vs. 0.75 for WL (P = 0.006). By multivariate Poisson regression, female patients had fewer CIS lesions (P < 0.0001) while older patients (≥65) had a higher number of CIS lesions detected by HAL (P = 0.04). HAL was less likely to detect CIS in patients previously treated with chemotherapy or BCG (P = 0.01 and 0.03, respectively), after adjusting for age. CIS was unifocal in 44% and multifocal in 56%. Multifocal CIS was associated with positive cytology more frequently than unifocal (65% vs. 45%; P = 0.016) whereas a negative cytology was more frequently associated with unifocal CIS. Patients with positive urine cytology had twice as many CIS lesions detected by HAL as patients with negative urine cytology (P = 0.02). Conclusions: HAL cystoscopy had a higher CIS detection rate than WL cystoscopy. The average number of CIS lesions detected was associated with baseline clinical characteristics. Cytology was positive more frequently in multifocal CIS suggesting that HAL may be particularly useful in this setting to optimize detection of the extent of CIS. [Copyright &y& Elsevier]

Abstract: The Bladder Cancer Think Tank III brought together a multidisciplinary group of clinician scientists, patient advocates, representatives from the National Cancer Institute, and Industry leaders to discuss the current state of the field in urothelial cancer and to develop strategies to move forward. This paper summarizes the session devoted to prevention. Experts sought to define primary, secondary, and tertiary prevention and discussed clinical trials performed to date testing retinoids, difluoromethylornithine, celecoxib, and other oral agents in a tertiary prevention setting following transurethral resection with or without intravesical therapy. Urologists practice tertiary prevention in the form of intravesical therapy, and strategies were discussed to identify biomarkers, including urinary cytokines and pathway single nucleotide polymorphism analysis associated with response to treatment. Optimizing delivery of intravesical chemotherapy to the target tissue with simple pharmacologic manipulations or packaging drugs in nanoparticles may improve treatment outcome. Defining a premalignant lesion should be a focus of future research as a strategy for early detection and secondary prevention. Cigarette smoking is the most prevalent risk factor for urothelial cancer, and emphasis was placed on smoking cessation as a powerful tool to reduce the burden of urothelial cancer, and the central role physicians must play in educating patients and providing resources. There is a strong need for research to develop markers of disease initiation and progression. These markers, combined with histories of environmental exposure to bladder carcinogens, may provide a tool to identify patients who will benefit from primary prevention. [Copyright &y& Elsevier]

Abstract: Purpose: The Southwest Oncology Group conducted a randomized trial of induction bacillus Calmette-Guérin (BCG) with or without maintenance BCG. In these additional retrospective analyses, our goal was to evaluate the association of a complete response (CR) or remaining with no evidence of disease (NED) vs. no CR during induction therapy with subsequent survival after adjusting for other potential confounders. Among all patients randomized to maintenance treatment, we also wanted to identify combinations of baseline covariates in order to define prognostic groups for subsequent worsening-free survival. Methods: Outcome measures of worsening-free and overall survival were assessed using Kaplan Meier estimates and proportional hazards regression models. For the classification and regression tree (CART) analysis, 434 patients randomized to maintenance vs. no therapy with complete covariate information were included. Results: Of the 593 evaluable patients, 341 were not randomized to maintenance BCG. Patients who achieved a prior complete response during induction BCG had a 5-year survival probability of 77% compared with 62% for patients who did not [hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.44, 0.81; P = 0.0008]. Prior CR retained significance when adjusted for age, gender, prior intravesical chemotherapy, and papillary disease versus CIS (HR = 0.63; 95% CI: 0.46, 0.86; P = 0.003). CART analysis identified 4 prognostic groups. Older patients (≥62 years old) previously treated with intravesical chemotherapy who failed to achieve a CR had a 5-fold higher risk of a worsening event relative to those who are younger (<67 years old) and achieve a CR (HR = 5.09; 95% CI: 3.37, 7.68; P < 0.0001). Conclusion: Failure to achieve a complete response after induction BCG is associated with a significant risk of a worsening event and death for patients with CIS or Ta or T1 bladder cancer at increased risk of recurrence. [Copyright &y& Elsevier]

Abstract: The prostate is commonly involved by transitional cell carcinoma (TCC) in patients with bladder cancer. A number of clinicopathologic factors including multifocal carcinoma in situ, tumor location, and tumor stage are associated with prostatic TCC (pTCC). In addition, the manner and extent of pathologic examination also makes a significant difference in the detection rate. Distinct patterns and extent of pTCC have been described and are associated with pathologic stage of the primary bladder tumor as well as prognosis. Preoperative transurethral biopsy of the prostatic urethra is a sensitive and accurate method to detect pTCC and is helpful for surgical planning. Given the high incidence of pTCC and prostatic adenocarcinoma, radical cystoprostatectomy is the treatment of choice for loco-regional control for patients with T4a disease. Further studies are necessary to establish the role of neoadjuvant and adjuvant therapy for patient with prostatic stroma invasion. [Copyright &y& Elsevier]

Abstract: Objective: To review the development of nomograms and consortia efforts applying these tools to model outcome predictions associated with radical cystectomy. Findings: Nomograms have been developed that provide individualized prediction of recurrence and survival following radical cystectomy, which provide significant improvement in predictive accuracy over tradition TNM staging. Conclusions: Nomograms provide individualized risk assessment and outperform expert physician and conventional models used to predict outcome. Addition of biologic markers may improve predictive capability and improve the clinical utility of these valuable tools. [Copyright &y& Elsevier]

Abstract: The urologic oncology community recognizes the importance of bladder cancer as a significant public health problem. As the fourth most common malignancy diagnosed in U.S. men and the ninth most common in women, bladder cancer is a highly prevalent cancer with an estimated 5-year prevalence of 490,000 patients in the U.S. (2001) and over 1,000,000 worldwide (2004). Bladder cancer is the most expensive cancer to diagnose and treat. Important clinical questions abound and there are a growing number of both NIH and industry funded clinical trials attempting to answer these questions. The EORTC has played a critical role in conducting phase II and large phase III randomized trials addressing critical questions in the management of non-muscle invasive and invasive bladder cancer. The present article reviews this important area of clinical trials research. [Copyright &y& Elsevier]

Radical cystectomy with bilateral pelvic lymphadenectomy and trimodality bladder-sparing therapy or TMT, are both curative options for patients with nonmetastatic muscle invasive bladder cancer. Patients should be afforded the opportunity for a multidisciplinary evaluation with equipoise in discussing these options for eligible patients. We discuss the barriers to broader acceptance and utilization of TMT and encourage support of clinical trials of TMT. [ABSTRACT FROM AUTHOR]

Muscle-invasive bladder cancer (MIBC) is a heterogenous disease that can be broadly categorized into five molecular subtypes associated with varying response to chemotherapy and immunotherapy and clinical outcomes. While significant advances have been made in comprehensive genomic profiling of MIBC, there is an unmet need for high throughput clinical grade assays to classify MIBC using formalin-fixed paraffin-embedded (FFPE) patient biopsy tissue. We hypothesized that MIBC subtypes can be accurately predicted with a custom NanoString codeset based on the TCGA single patient classifier. We designed a custom NanoString codeset based on the reduced gene set used for the TCGA RNA-based single patient classifier for MIBC subtyping (Kim et al. 2019). We ran the codeset aligned to 359 genes (TCGA359) on 48 RNA samples extracted from FFPE tissue from the SWOG S-1011 cohort (NCT 01224665). Whole transcriptome RNA-sequencing was performed to determine the "true" tumor subtype based on the TCGA single patient RNA-based classifier. We revised the codeset to target 399 genes (TCGA399) to optimize the assay's fidelity to the RNA-seq subtype calls and ran the revised assay on these same 48 samples. We then processed the raw data using nCounter software and assigned the TCGA subtype using the published TCGA-classification script in R. To assess the agreement between the predicted subtypes from NanoString codeset and RNA-sequencing, classification error and accuracy were determined, resulting in a measure of concordance between the two profiling methods. RNA sequencing and subtyping based on the TCGA patient classifier demonstrated the following "true" tumor classifications in the 48 samples: 21 (44%) basal/squamous, 3 (6%) luminal, 12 (25%) luminal infiltrated, 11 (23%) luminal papillary, and 1 (2%) neuronal. The subtype classification for the TCGA359 codeset included 19 (40%) basal/squamous, 4 (8%) luminal, 8 (17%) luminal infiltrated, 16 (33%) luminal papillary, and 1 (2%) neuronal.;The subtype classification for the TCGA399 codeset included 20 (43%) basal/squamous, 1 (2%) luminal, 8 (17%) luminal infiltrated, 16 (34%) luminal papillary, and 2 (4%) neuronal (Table 1). TCGA359 achieved 83% accuracy with a classification error of 17% when compared to the RNAseq subtype calls. TCGA399, with an additional 40 genes, showed an accuracy of 74%, and classification error of 26%. Luminal vs basal subtype prediction accuracy was 95.7% for TCGA 359 and 91.3% for TCGA399, respectively. Our custom NanoString codeset demonstrated accurate subtype calls based on the TCGA single patient classifier for patients with MIBC. TCGA399 did not improve accuracy of tumor subtype classification compared to TCGA359 despite the additional probes designed to increase precision of subtype calls. Nonetheless, this NanoString based classifier may provide faster throughput and reduced cost for subtyping and can be incorporated into clinical trials testing utility of molecular subtypes. Validation of this platform for tumor subtyping in MIBC in the full SWOG S-1011 cohort with comparison to RNA seq subtype calls is in progress. [ABSTRACT FROM AUTHOR]

Trimodal therapy (TMT) for muscle invasive bladder cancer has become an accepted alternative to radical cystectomy and has become integrated into national guidelines as standard a treatment option. The urologist plays a critical role in proper patient selection, thorough transurethral resection, ongoing cystoscopic surveillance and management of local recurrences. There exists multiple patient related and tumor related factors, which contribute to the selection of TMT vs. radical cystectomy for a patient with muscle invasive bladder cancer. Although the ideal patient for TMT has a tumor which can undergo a visibly complete resection, has no associated hydronephrosis, does not invade the prostatic urethra and is not associated with diffuse carcinoma in situ throughout the bladder, select patients who do not meet all these criteria can still be successfully treated with this approach. A multidisciplinary approach including urology, radiation oncology and medical oncology is paramount with clear communication of tumor location, timing of chemoradiation and repeat cystoscopic resection followed by surveillance. Nonmuscle invasive bladder cancer recurrences can occur in up to 26% of patients after completion of TMT, with many being treated by routine and standard therapy for non-muscle invasive bladder cancer. However, in this population after TMT, early salvage cystectomy should be considered in those with adverse features, including T1 disease, tumor greater than 3 cm, CIS, or lymphovascular invasion. Salvage cystectomy can be performed for local recurrences with acceptable oncologic control and no clear evidence of any greater risk of early complications; however, there may be a slightly increased risk for late complications, namely small bowel obstruction, ureteral stricture, and parastomal hernia. An understanding of these surgical considerations is of utmost importance to the treating urologist in selecting and managing a patient through TMT. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Given the frequent inability to administer a conventional 3-weekly schedule of cisplatin to human subjects with urothelial carcinoma, we evaluated a frequent bolus metronomic schedule in a preclinical system of transitional cell carcinoma (TCC) of the urothelium. We hypothesized that the anti-angiogenic and anti-cell-migratory activity of lower concentrations of cisplatin may confer similar anti-tumor activity and demonstrate less nephrotoxicity than conventional cytotoxic concentrations. Materials and methods: We evaluated the activity of cisplatin in vitro against human urothelial carcinoma (5637) and endothelial cells (human umbilical vein endothelial cells, HUVECs). The MTT assay was employed to assess viability, and flow cytometry with Annexin-FITC labeling was employed to assess apoptosis. Cell migration in monolayer culture was assessed by scratch assay. Murine xenografts (n = 12 per group) bearing measurable subcutaneous tumors of 5637 cells were administered either no therapy, cisplatin 2 mg/kg/3 days a week (metronomic) or 6 mg/kg/ once a week (standard) intraperitoneal (i.p.) for 4 weeks. Blood was collected from 5 mice per group at baseline and at the end of therapy to measure changes in serum creatinine. Results: Significant antiproliferative activity, but poor pro-apoptotic activity, was observed against 5637 urothelial carcinoma cells in vitro by MTT assay with cisplatin at concentrations lower than those attainable in vivo. Anti-proliferative activity against HUVECs required higher concentrations than attainable in vivo. Anti-migratory activity was observed against 5637 and HUVECs at earlier time points and with concentrations lower than anti-proliferative concentrations. In murine 5637 xenografts, standard cisplatin was significantly better at inhibiting tumor growth than the no treatment control (P = 0.005), while metronomic therapy was not better than control (P = 0.22). Standard cisplatin was also significantly nephrotoxic (P = 0.016), while metronomic cisplatin (P = 0.374) or no therapy (P = 0.178) did not demonstrate significant nephrotoxicity compared with baseline. Conclusions: Cisplatin exhibited anti-cell-migratory activity against urothelial carcinoma and endothelial cells at lower than cytotoxic concentrations. However, a standard preclinical schedule was better than control in vivo for inhibiting tumor growth, while a metronomic schedule was not better. Despite the lower nephrotoxicity of the metronomic schedule, its lower anti-tumor activity suggests that a standard clinical schedule of cisplatin should not be routinely substituted by a split schedule without definitive clinical data. [Copyright &y& Elsevier]

Purpose: To assess the oncologic impact of adjuvant endocavitary instillation after kidney-sparing surgery (KSS) in the treatment of upper tract urothelial carcinoma (UTUC).Methods: A meta-analysis of the available literature was performed using PUBMED and MEDLINE on June 2018. No time or language restrictions were applied. All included participants were substratified into 2 groups: Ta/T1 UTUC and upper tract (UT) carcinoma in situ. Subjects with higher stage disease, involvement of the bladder, or urethra were excluded. Predefined endpoints of interest were rates of cytology response, UT recurrence, UT progression, cancer-specific survival, and overall survival.Results: Overall, 27 eligible reports for a total of 438 patients were identified and 18 studies included for quantitative analyses. All included reports were nonrandomized observational case series. Among studies that reported on UT recurrence, 154 (35%) patients developed UT recurrence during a median follow-up of 30 months. The overall pooled estimates for adjuvant instillations in Ta-T1 patients were 40% for UT recurrence, 94% for cancer-specific survival, and 71% for OS. Subanalyses stratified by regimen used and instillation approach did not show any significant differences. In patients with UT carcinoma in situ treated with BCG, the pooled estimates for cytology response, UT recurrence, and progression were 84%, 34%, and 16%, respectively. Similarly, comparison between instillation approaches did not show any significant differences.Conclusions: In this meta-analysis of presumed nonmuscle invasive patients treated with kidney-sparing surgery, endocavitary instillations for noninvasive UTUC, did not reveal any differences between the regimens and instillations approaches. Patients with Ta-T1 UTUC had an UT recurrence rate comparable to that reported in the literature for nontreated patients. To date, the efficacy of endocavitary instillations in UTUC remains to be demonstrated. Upcoming novel drugs promise to change this paradigm. [ABSTRACT FROM AUTHOR]

Patients with Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) are at significant risk for recurrence and progression and there is an unmet need for local, effective, bladder-preserving treatment options. Nadofaragene firadenovec, a non-replicating recombinant adenovirus vector-based gene therapy that delivers a copy of the human interferon alfa-2b gene into the bladder epithelium, is approved by the FDA for treatment of adult patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with/without papillary tumors (±Ta/T1). The Phase 3 study of nadofaragene firadenovec met its primary endpoint;;53.4% of patients with CIS±Ta/T1 achieved;complete response (CR) at three months. The 24-month follow-up results showed that nadofaragene firadenovec was well tolerated, and 36.4% of the patients with CIS±Ta/T1 who achieved a CR remained high-grade recurrence free (HGRF) at 24 months. Herein, we report 36-month follow-up results from the Phase 3 study for the CIS±Ta/T1 cohort. The open-label Phase 3 study enrolled 107 patients with BCG-unresponsive NMIBC with CIS±Ta/T1 (NCT02773849). The efficacy analysis for this cohort included 103 patients who met the protocol definition of BCG-unresponsive NMIBC. Patients received 75 mL of nadofaragene firadenovec (3×1011 viral particles/mL) once every 3 months for up to 4 doses. The protocol mandated a 5-site biopsy (dome, trigone, right and left lateral walls, posterior wall) at 12 months and patients who were HGRF were offered continued treatment once every 3 months at the investigator's discretion. Assessments beyond 24 months were performed in accordance with usual clinical practice. The study is ongoing, with a planned 5-year treatment and monitoring phase; the follow-up results reported here are based on the 36-month interim data for the CIS±Ta/T1 cohort. Mean (standard deviation) duration of follow-up for the entire cohort was 42.1 (12.6) months*, with a total of 13/107 (12.1%) patients having received 36 months of treatment.At 36 months, 14/55 (25.5%) patients who had achieved a CR at 3 months remained HGRF. For these patients, the Kaplan–Meier (KM)-estimated probability of duration of CR for at least 12, 24 and 36 months was 46.5%, 36.6% and 34.2%, respectively (Figure).In the overall CIS±Ta/T1 cohort (N=103), the KM-estimated median (95% confidence interval [CI]) duration of HGRF survival was 6.0 (3.4, 8.3) months, and probability;(95% CI) of HGRF survival for at least 12 months was 30.1% (21.5, 39.2). Two patients (1.9%) discontinued due to adverse events, while four (3.9%) experienced progression to muscle-invasive disease. The KM-estimated cystectomy-free survival (95% CI) at 36 months was 53.8% (43.3, 63.1), and the three-year overall survival was 90.4% (82.3, 94.9). Intravesical nadofaragene firadenovec, administered once every three months, demonstrated a sustained durability of response in patients with BCG-unresponsive CIS±Ta/T1 papillary disease. Nadofaragene firadenovec represents a novel treatment option for BCG-unresponsive NMIBC with a favorable benefit-to-risk ratio.*All patients had passed 36 months at data cutoff on 09 September 2021.Figure. Kaplan–Meier estimated durability of complete response in patients with CIS±Ta/T1 papillary disease. [ABSTRACT FROM AUTHOR]

Kidney cancer presenting with synchronous primary tumor and metastases has demonstrated shorter survival outcome, as compared to the patients relapsing later with metastases after nephrectomy. CARMENA trial demonstrated no overall survival (OS) benefit with addition of nephrectomy to sunitinib therapy. Immune checkpoint based combination therapy has now become the standard of care in frontline setting for RCC. The role of nephrectomy has not been evaluated in the setting of immune checkpoint based systemic therapy. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in advanced RCC within the context of immune checkpoint based combination regimens. The underlying mechanism is that the broader antigen spread and higher neoantigen load enabled by the primary tumor would enhance the efficacy of the immune therapy. CN after initial systemic therapy will potentially enable eradication of the immune resistant clones within the primary tumor. Eligible patients with primary tumor and metastases are treated with one of the 5 FDA approved ICI based combinations: ipililumab and nivolumab, axitinib and pembrolizumab/avelumab, cabozantinib + nivolumab or Lenvatinib + pembrolizumab. Urology evaluation prior to randomization to decide whether patient is surgical candidate is required. Randomization occurs between 10-14 weeks of therapy; 1:1 to receive CN followed by systemic therapy or to continue on systemic therapy Results: Conclusions: [ABSTRACT FROM AUTHOR]

Abstract: Objective: To validate the prognostic relevance of lymph node density (LND) and identify its optimal cut-points in a large international multicenter series of patients treated with radical cystectomy (RC) for invasive bladder cancer. Methods: From 1993 to 2005, 4,430 bladder cancer patients who underwent RC without neoadjuvant chemotherapy were reviewed; of these, 1,038 were pN+M0 disease and form the basis of this report. Results: Median age of patients was 67 years with median follow-up in survivors of 33 months. Overall, 5-year DSS estimate was 36%. Median number of lymph nodes removed was 18 (IQR, 11–32), median number of positive lymph nodes was 2 (IQR, 1–5), and median LND was 14.3% (IQR, 6.67–33.3%). LND as continuous variable was a stronger prognostic factor for DSS in patients that underwent a more extensive PLND (P < 0.001). HR for inverse association of LND with DSS increased incrementally with increasing LND cut-points. Categorizing LND into quintiles revealed strong tertiary distribution of risk based on LND <6%, 6%–41%, or >41% with cumulative 5-year DSS of 47%, 36%, and 21%, respectively (P < 0.001). When patients were stratified by adjuvant chemotherapy, LND remains independently prognostic in patients who received adjuvant chemotherapy as well as those who did not. Conclusion: Lymph node density is prognostic in bladder cancer patients who undergo a more extensive PLND and remains prognostic even when adjuvant chemotherapy is used. Prognostic value of LND is best represented as a continuum of risk and LND <6% represents the best possible outcome in patients with nodal disease. [Copyright &y& Elsevier]

Abstract: Purpose: Sunitinib malate (Pfizer, Inc.) is a multitargeted kinase inhibitor that inhibits vascular endothelial growth factor (VEGF) receptor (R)-1, 2 and 3, platelet-derived growth factor receptors (PDGFR)-α and β, Flt3, RET, and Kit. Angiogenesis and VEGF expression correlate with poor outcomes in human urothelial carcinoma. We designed a preclinical study to examine the efficacy of sunitinib alone and in combination with cisplatin against human urothelial carcinoma. Design: The in vitro activities of sunitinib and cisplatin alone and in combination were determined against human urothelial carcinoma cell lines, TCC-SUP and 5637. Antitumor activities were also determined in vivo against murine subcutaneous 5637 xenografts. Immunohistochemistry (IHC) was performed to detect VEGFR2 and Kit, and modulation of proliferation, apoptosis, and angiogenesis. Results: Both cell lines expressed VEGFR2, but did not express Kit. Sunitinib displayed activity against both cell lines in vitro at low micromolar concentrations, which are not attainable in vivo, and was synergistic with cisplatin. Activity was observed for sunitinib at 20 and 40 mg/kg orally once daily for 4 weeks, which attains low nanomolar concentrations in vivo against murine 5637 xenografts. Sunitinib 20 mg/kg/d in combination with cisplatin 4 mg/kg/wk intraperitoneally induced tumor regression compared to no therapy (P < 0.0001) or cisplatin alone (P = 0.06). Cisplatin, sunitinib, and combination treated tumors displayed significantly reduced ki-67 expression compared with control untreated tumors, and the difference was also statistically significant for the combination compared with cisplatin. Cleaved caspase-3 expression was significantly higher for sunitinib single agent and combination therapy compared with untreated controls, and for combination therapy compared with cisplatin alone. CD31 expression was diminished for both single agents and combination therapy compared with untreated tumors. Conclusions: Sunitinib is preclinically active against urothelial carcinoma, and enhances the activity of cisplatin probably by targeting the stroma. [Copyright &y& Elsevier]

We evaluated efficacy, toxicity and potential synergism of adenoviral-mediated thymidine kinase (tk)- ganciclovir (GCV) gene therapy in combination with 4 cytotoxic chemotherapeutic agents (doxorubicin, cisplatin, mitomycin C, and methotrexate) in 3 human bladder cancer cell lines. Cell lines were exposed to (1) 10 different concentrations of adenovirus expressing tk plus GCV; (2) 8 different concentrations of either doxorubicin, methotrexate, mitomycin C or cisplatin; or (3) combination treatment consisting of either low-, medium- or high-dose tk-GCV gene therapy plus 8 different concentrations of a single chemotherapeutic agent. Cell survival was determined using a MTT-based cell proliferation-assay. For most combinations, adding chemotherapy to tk-GCV gene therapy did not result in any therapeutic benefit. In some scenarios, we observed modest improvement with combinations of high-dose tk-GCV gene therapy and high-dose standard chemotherapy over tk-GCV monotherapy. Low concentrations of methotrexate enhanced the antitumor effects of low- and medium-dose tk-GCV gene therapy. Low level negative interference between tk-GCV gene therapy and chemotherapy occurred in some combinations but was overall negligible. In general, adding chemotherapy to tk-GCV gene therapy did not demonstrate significant therapeutic benefit in vitro. High doses of chemotherapeutic agents should be used in combination with tk-GCV gene therapy in order to take advantage of the occasional instance where modest improvement occurred with combination therapy. Additional studies exploring the role of methotrexate in enhancing the tk-GCV system are required. Investigation of other, potentially more synergistic chemotherapeutic agents in combination with tk-GCV is warranted. [ABSTRACT FROM AUTHOR]

Background: Optical coherence tomography (OCT) is a novel imaging modality that provides microstructural information of different tissue layers using near-infrared light. This prospective, multicenter phase II trial aimed to assess the accuracy of OCT-assisted cystoscopy for bladder tumor staging.Methods: Patients with primary or recurrent bladder tumors (Ta,T1) identified by outpatient cystoscopy were included. The primary objective was to assess the accuracy and positive predictive value of for determining tumor stage ≥T1 correlated by histopathology. 72 suspicious lesions from 63 patients were eligible to analyze in the study. All suspected lesions were evaluated with conventional cystoscopy, interpreted in real-time using OCT, and then resected. All results were compared to pathology. A total of 363 OCT images of tumor and normal mucosa in 25 patients were obtained to evaluate diagnostic efficacy of the computer-aided texture analysis algorithm.Results: Sensitivity and specificity for predicting invasive tumors (≥ T1, n = 17) were 58.8% and 92.7% for cystoscopy, 64.7% and 100% for OCT-assisted cystoscopy, respectively. Accuracy of cystoscopy and OCT-assisted cystoscopy for predicting invasive tumor was 84.7% and 91.7% (P = 0.063), respectively. Cystoscopy and OCT-assisted cystoscopy correctly predicted T stage in 52/72 and 59/72 cases, respectively (P = 0.016). Cystoscopy missed 2 more invasive tumors than OCT-assisted cystoscopy. Cystoscopy (14.3%, 1/7) and OCT-assisted cystoscopy (28.6%, 2/7) showed relatively low sensitivity in detecting muscle invasion. Computer aided texture analysis demonstrated 75.1% sensitivity, 64.0% specificity, and 74.4% accuracy for differentiating tumor and normal urothelium.Conclusion: OCT-assisted cystoscopy is a real time noninvasive and simple procedure that enhanced the accuracy of staging bladder tumors and prediction of any tumor invasion. Though the study did not meet the prespecified primary endpoint, OCT imaging is a promising adjunct to cystoscopy that may supplement intraoperative decision-making during transurethral resection of bladder tumors and additional prospective studies are warranted. [ABSTRACT FROM AUTHOR]

Objectives: Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC)., Materials and Methods: A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test., Results: The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) had