Lyso-thermosensitive liposomal doxorubicin for treatment of bladder cancer.

PURPOSE: To evaluate lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox®) in combination with loco-regional mild hyperthermia (HT) for targeted drug delivery to the bladder wall and potential treatment of bladder cancer. MATERIAL AND METHODS: Porcine in vivo studies were performed with the following groups: (i) intravenous (IV) LTLD with hyperthermia (LTLD + HT); (ii) IV doxorubicin (DOX) with hyperthermia (IV DOX + HT) and (iii) IV LTLD without hyperthermia (LTLD - HT). Drug formulations were delivered via 30 min IV infusion coinciding with 1-h bladder irrigation (45 °C water for HT groups, 37 °C for non-HT group), followed by immediate bladder resection. DOX concentrations were measured in consecutive sections parallel to the bladder lumen by liquid chromatography following drug extraction. Computer models were developed to simulate tissue heating and drug release from LTLD. RESULTS: Comparing mean DOX concentrations at increasing depths from the lumen to outer surface of the bladder wall, the ranges for LTLD + HT, IV DOX + HT and LTLD - HT, respectively, were 20.32-3.52 µg/g, 2.34-0.61 µg/g and 2.18-0.51 µg/g. The average DOX concentrations in the urothelium/lamina and muscularis, respectively, were 9.7 ± 0.67 and 4.09 ± 0.81 µg/g for IV LTLD + HT, 1.2 ± 0.39 and 0.86 ± 0.24 µg/g for IV DOX + HT, and 1.15 ± 0.38 and 0.62 ± 0.15 µg/g for LTLD - HT. Computational model results were similar to measured DOX levels and suggest adequate temperatures were reached within the bladder wall for drug release from LTLD. CONCLUSIONS: Doxorubicin accumulation and distribution within the bladder wall was achieved at concentrations higher than with free IV doxorubicin by mild bladder hyperthermia combined with systemic delivery of LTLD.

Comparison of postural ergonomics between laparoscopic and robotic sacrocolpopexy: a pilot study.

STUDY OBJECTIVE: To compare resident, fellow, and attending urologic and gynecologic surgeons' musculoskeletal and mental strain during laparoscopic and robotic sacrocolpopexy. DESIGN: Prospective cohort study (Canadian Task Force classification II-2). SETTING: Academic medical center. PATIENTS: Patients who underwent robotic or laparoscopic sacrocolpopexy from October 2009 to January 2011. INTERVENTIONS: The Body Part Discomfort (BPD) survey was completed before cases, and the National Aeronautics and Space Administration Task Load Index and BPD survey were completed after cases. Higher scores on BPD and the National Aeronautics and Space Administration Task Load Index indicate greater musculoskeletal discomfort and mental strain. BPD scores were averaged over the following body regions: head/neck, back, hand/wrist, arms, and knees/ankles/feet. Changes in body region-specific discomfort scores were the primary outcomes. MEASUREMENTS AND MAIN RESULTS: Multivariable analysis was performed using mixed-effects linear regression with surgeon as a random effect. Sixteen surgeons participated (53% fellows, 34% residents, and 13% attendings). Thirty-three robotic and 53 laparoscopic cases were analyzed, with a median surgical time of 231 minutes (interquartile range, 204-293 minutes) versus 227 minutes (interquartile range, 203-272 minutes; p = .31), a median estimated blood loss of 100 mL (interquartile range, 50-175 mL) versus 150 mL (interquartile range, 50-200 mL; p = .22), and a mean patient body mass index of 27 ± 4 versus 26 ± 4 kg/m(2) (p = .26), respectively. Robotic surgeries were associated with lower neck/shoulder (-0.19 [interquartile range, -0.32 to -0.01], T = -2.49) and back discomfort scores (-0.35 [interquartile range, -0.58 to 0], T = -2.38) than laparoscopic surgeries. Knee/ankle/foot and arm discomfort increased with case length (0.18 [interquartile range, 0.02-0.3], T = 2.81) and (0.07 [interquartile range, 0.01-0.14], p = .03), respectively. CONCLUSION: Surgeons performing minimally invasive sacrocolpopexy experienced less neck, shoulder, and back discomfort when surgery was performed robotically.

Targeted therapies in urothelial carcinoma.

PURPOSE OF REVIEW: Greater understanding of the biology and genetics of urothelial carcinoma is helping to identify and define the role of molecules and pathways appropriate for novel-targeted therapies. Here, we review the targeted therapies that have been reported or are in ongoing urothelial carcinoma clinical trials, and highlight molecular targets characterized in preclinical and clinical studies. RECENT FINDINGS: Trials in nonmuscle-invasive bladder cancer are evaluating the role of immunotherapy and agents targeting vascular endothelial growth factor (VEGF) or fibroblast growth factor receptor-3. In muscle-invasive bladder cancer, neoadjuvant studies have focused on combining VEGF agents with chemotherapy; adjuvant studies are testing vaccines and agents targeting the human epidermal growth factor receptor 2, p53, and Hsp27. In the first-line treatment of metastatic urothelial carcinoma, tubulin, cytotoxic T-lymphocyte antigen 4, Hsp27, and p53 are novel targets in clinical trials. The majority of targeted agents studied in urothelial carcinoma are in the second-line setting; new targets include CD105, polo-like kinase-1, phosphatidylinositide 3-kinases (PI3K), transforming growth factor ß receptor/activin receptor-like kinase ß, estrogen receptor, and the hepatocyte growth factor receptor (HGFR or MET). SUMMARY: Development of targeted therapies for urothelial carcinoma is still in early stages, consequently there have been no major therapeutic advances to date. However, greater understanding of urothelial carcinoma and solid tumor biology has resulted in a proliferation of clinical trials that could lead to significant advances in treatment strategies.

Lymph node dissection during radical cystectomy following prior radiation therapy: results from the SEER database.

PURPOSE: Population studies of patients undergoing radical cystectomy (RC) for bladder cancer (BC) suggest that a more extended lymph node dissection (LND) increases survival. However, information regarding LNDs of patients undergoing RC with a history of radiation therapy for BC is largely unknown. This study aims to define the lymph node yield (LNY) in patients undergoing RC for BC following radiation of the bladder using the surveillance epidemiology and end results (SEER) database. METHODS: Data were collected using SEER 18 registries from 1988 to 2013 to identify patients undergoing RC for BC. Data on extent and yield of LND were obtained. Logistic regression and multivariate Cox proportional hazard regression were done to identify predictors of adequate LND and all-cause mortality, respectively. RESULTS: In total, 27,451 patients were identified, of which, 27,362 (99.7%) were radiation naïve and 89 (0.3%) had prior radiation therapy for BC. The average LNY in radiation naïve patients (15, SD [13.5]) was slightly higher than the LNY in patients with prior radiation (12.3 SD [9.2], p = 0.157). Prior radiation was not an independent predictor of overall mortality (HR = 1.3, 95% CI [0.98-1.7]; p = 0.076). CONCLUSIONS: A lower proportion of patients with a history of radiation underwent a LND. The LNYs of radiation naïve patients, and those with a history of radiation, were not statistically different; however, the proportion of irradiated patients was small. Further investigation will be required to elucidate the patient and provider characteristics that contribute to the similar LNYs.

Financial Relationships between Urologists and Industry: An Analysis of Open Payments Data.

INTRODUCTION: The Open Payments Program was enacted to increase transparency of financial relationships between physicians and the medical device and pharmaceutical industry. We examined nonresearch related financial relationships between urologists and industry in the United States using the latest Open Payments data. METHODS: We performed a descriptive analysis of Open Payments data released by the Centers for Medicare and Medicaid Services for 2014. Total payment amounts associated with various urological drug and device categories were calculated. We then examined for correlations between payments and prescribing at the national level using Medicare Part D prescribing data. RESULTS: There were 232,207 payments totaling $32,418,618 made to 8,618 urologists (73.6% of practicing urologists in the United States) during calendar year 2014. Median payment was $15 (IQR $11 to $24). While the majority of individual payments (68%) were $20 or less, 82% of the urologists in the database received more than $100 from industry during 2014. The frequency of industry payments was positively correlated with Medicare Part D prescribing frequency as well as the sum of claims (r = 0.726, p = 0.005 and r = 0.755, p = 0.003, respectively). CONCLUSIONS: Nearly 75% of urologists in United States received nonresearch payments from industry in 2014. Most individual payments were for less than $20 but the majority of urologists received more than $100 in aggregate during the study year, with most of the money going toward speaker fees. Payments were positively correlated with Part D prescribing, yet confounding variables make it difficult to establish a cause and effect relationship.

Epidermal Growth Factor Receptor (EGFR)-targeted Photoimmunotherapy (PIT) for the Treatment of EGFR-expressing Bladder Cancer.

The use of light as a means of therapy for bladder cancer has a long history but has been hampered by a lack of tumor specificity and therefore, damage to the normal bladder mucosa. Here, we describe a targeted form of phototherapy called photoimmunotherapy (PIT), which targets EGFR-expressing bladder cancer. Anti-EGFR antibody panitumumab was labeled with the photoabsorber (PA), IRDye 700Dx (IR700), to create a panitumumab-IR700 antibody-PA conjugate that is activated by near-infrared radiation (NIR). Bladder cancer tissue microarray (TMA) and bladder cancer cell lines were analyzed for expression of EGFR. Mechanism of PIT-induced cell death was studied using proliferation assays, transmission electron microscopy (TEM), and production of reactive oxygen species. Finally, the in vivo effect was studied in xenografts. EGFR staining of TMAs showed that while most bladder cancers have expression of EGFR to a varying degree, squamous cell carcinomas (SCC) have the highest expression of EGFR. Panitumumab-IR700 activated by NIR light rapidly killed UMUC-5 cells, a bladder SCC line. Panitumumab alone, panitumumab-IR700 without NIR, or NIR alone had no effect on cells. TEM demonstrated that cell death is due to necrosis. Singlet oxygen species contributed toward cell death. NIR-PIT with panitumumab-IR700 reduced growth compared with only panitumumab-IR700-treated UMUC-5 xenograft tumors. PIT is a new targeted treatment for bladder cancer. Panitumumab-IR700-induced PIT selectively kills EGFR-expressing bladder cancer cells in vitro and in vivo and therefore warrants further therapeutic studies in orthotopic xenografts of bladder cancer and ultimately in patients. Mol Cancer Ther; 16(10); 2201-14. ©2017 AACR.

Nonmuscle invasive bladder cancer: a primer on immunotherapy.

Intravesical Bacillus Calmette-Guérin (BCG) has long been the gold standard treatment of nonmuscle invasive bladder cancer. Recently, there has been an emergence of novel immunotherapeutic agents, which have shown promise in the treatment of urothelial cell carcinoma. These agents aim to augment, modify, or enhance the immune response. Such strategies include recombinant BCG, monoclonal antibodies, vaccines, gene therapy, and adoptive T-cell therapy. Here, we review the emerging immunotherapeutics in the treatment of nonmuscle invasive bladder cancer.

Novel immunotherapeutic approaches to the treatment of urothelial carcinoma.

Immunotherapy has long played a role in urothelial cancers with the use of bacille Calmette Guérin (BCG) being a mainstay in the treatment of nonmuscle invasive bladder cancer. Novel therapeutic approaches have not significantly impacted mortality in this population and so a renaissance in immunotherapy has resulted. This includes recombinant BCG, oncolytic viruses, monoclonal antibodies, vaccines, and adoptive T-cell therapy. Herein, we provide a review of the current state of the art and future therapies regarding immunotherapeutic strategies for urothelial carcinoma.

Evolving immunotherapy strategies in urothelial cancer.

The treatment of nonmuscle-invasive urothelial carcinoma with bacillus Calmette-Guérin (BCG) represents the importance of immunotherapy in the treatment of cancer. Despite its clinical efficacy, up to 30% of patients will ultimately experience progression to muscle-invasive disease. This, along with an improved understanding of the biologic pathways involved, has led to efforts to improve, enhance, or alter the immune response in the treatment of urothelial carcinoma. A number of novel therapeutic approaches currently are being pursued, including recombinant BCG to induce T helper type 1 (Th1) immune responses, nonlive Mycobacterium agents, targeted agents toward cancer-associated antigens, immune-modulating vaccines, and adoptive T-cell therapies. Here, we review the current and future immunotherapy treatment options for patients with urothelial cancer.

Continuous monitoring of enzyme reactions on a microchip: application to catalytic RNA self-cleavage.

Kinetic analysis of RNA enzymes, or ribozymes, typically involves the tedious process of collecting and quenching reaction time points and then fractionating by polyacrylamide gel electrophoresis (PAGE). As a way to automate and simplify this process, continuous analysis of a ribozyme reaction is demonstrated here using completely automated capillary sample introduction onto a microfabricated device with laser-induced fluorescence detection. The method of injection is extremely reproducible thereby standardizing data analysis. A 30-nucleotide ribozyme model, the self-cleaving lead-dependent ribozyme, or "leadzyme", which cleaves into a 24-mer and a 6-mer in the presence of Pb(2+), was end-labeled with fluorescein (FAM) and used to demonstrate the potential of this technique. After manually initiating the cleavage reaction by Pb(2+) addition, reaction samples were automatically injected directly into the parallel separation lanes of the chip via a capillary at predetermined time intervals, thus eliminating the need for additional sample-handling steps. The FAM-labeled leadzyme starting material and products were monitored for 60 min in order to ascertain kinetic information. The effect of lead acetate concentration on cleavage rates was also studied, and the results are in agreement with rates determined by conventional hand-mixing/PAGE analysis. This work demonstrates, through the use of a simple ribozyme model, the potential of this method to provide valuable kinetic information for other, more complex, biologically relevant RNA and protein enzymes.