Alexander C. Small

The Emerging Role of Circulating Tumor Cell Detection in Genitourinary Cancer

PURPOSE Circulating tumor cells are malignant cells in peripheral blood that originate from primary tumors or metastatic sites. The heterogeneous natural history and propensity for recurrence in prostate, bladder and kidney cancers are well suited for improved individualization of care using circulating tumor cells. The potential clinical applications of circulating tumor cells include early diagnosis, disease prediction and prognosis, and selection of appropriate therapies. MATERIALS AND METHODS The PubMed® and Web of Science® databases were searched using the key words circulating tumor cells, CTC, prostate, kidney, bladder, renal cell carcinoma and transitional cell carcinoma. Relevant articles and references from 1994 to 2011 were reviewed for data on the detection and significance of circulating tumor cells in genitourinary cancer. RESULTS Technical challenges have previously limited the widespread introduction of circulating tumor cell detection in routine clinical care. Recently novel platforms were introduced to detect these cells that offer the promise of overcoming these limitations. We reviewed the current state of circulating tumor cell capture technologies and their clinical applications for genitourinary cancers. CONCLUSIONS In genitourinary cancer circulating tumor cell enumeration has been useful for prognosis in patients with castration resistant prostate cancer. Soon characterizing individual circulating tumor cells in blood will serve as a noninvasive real-time liquid biopsy to monitor molecular changes in cancer, allowing clinicians to custom tailor treatment strategies. Circulating tumor cells will serve as a treatment response biomarker. Finally, circulating tumor cell detection promises to assist in the early detection of clinically localized cancers, facilitating curative therapy.

Transition from laparoscopic to robotic partial nephrectomy: the learning curve for an experienced laparoscopic surgeon.

The transition from laparoscopic partial nephrectomy to robotic partial nephrectomy was found to be too rapid for an experienced laparoscopic surgeon.

Targeting the androgen receptor signalling axis in castration‐resistant prostate cancer (CRPC)

Whats known on the subject? and What does the study add?

Clinical development of novel therapeutics for castration-resistant prostate cancer: historic challenges and recent successes.

There have been more drugs approved by the US Food and Drug Administration for the treatment of castration‐resistant prostate cancer in the past 3 years than in the prior 3 decades, with additional drugs on the verge of approval based on the results of recently reported randomized trials. While an improvement in the understanding of the pathogenesis of castration‐resistant prostate cancer has undeniably accelerated the transition of novel approaches from “bench to bedside,” the recent successes in the treatment of prostate cancer are also a result of the efforts of clinical investigators to redefine the framework in which drugs for castration‐resistant disease are evaluated. This review will explore the shifting paradigm in drug development for castration‐resistant prostate cancer over the past several decades, and highlight how new definitions, trial designs, and endpoints have facilitated the emergence of new therapies for this challenging disease. CA Cancer J Clin 2012;.

Trends in the use of cytoreductive nephrectomy in the United States.

BACKGROUND Two randomized trials published in 2001 established CyNx for patients with metastatic renal carcinoma (mRCC) as a treatment standard in the cytokine era. However, first-line systemic therapy for mRCC changed in 2005 with FDA approval of VEGFR TKIs. We evaluated the patterns of use of CyNx from 2000 to 2008. MATERIALS AND METHODS The National Cancer Database was queried for patients diagnosed with mRCC. Patients who underwent CyNx were identified and were further categorized by pre-VEGFR versus VEGFR TKI era, race, insurance status, and hospital. For these subcategories, prevalence ratios (PRs) were generated using the proportion of patients with mRCC undergoing CyNx versus those not undergoing CyNx. RESULTS Of the 47,417 patients (pts) identified with mRCC, the prevalence of cytoreductive nephrectomy increased 3% each year from 2000 to 2005 (P < .0001), then decreased 3% each year from 2005 to 2008 (P = .0048), with a significant difference between the eras (0.97 vs. 1.025; P < .0001). Black and Hispanic pts were less likely than Caucasian pts to undergo CyNx. Pts with Medicaid, Medicare, and no insurance were less likely than pts with private insurance to undergo CyNx. Pts diagnosed at community hospitals were significantly less likely than pts at teaching hospitals to undergo CyNx. CONCLUSION The use of CyNx has declined in the VEGFR-TKI era. In addition, racial and socioeconomic disparities exist in the use of CyNx. The results of pending randomized trials evaluating the role of CyNx in the VEGFR-TKI era are awaited to optimize use of this modality and address potential disparities.

Overcoming castration resistance in prostate cancer.

Purpose of review Recent advances in our understanding of the androgen axis signaling pathway have led to the development of therapeutic strategies to overcome the state of ‘castration resistance’ in prostate cancer. In this review, we examine the mechanisms of castration resistance, as well as recently reported and ongoing clinical studies, which will further identify therapeutic opportunities for novel therapeutics targeting the androgen-signaling axis in advanced prostate cancer. Recent findings As evidenced by recently reported positive phase III clinical trials, secondary hormonal agents such as abiraterone and MDV3100 may still be very effective in the treatment of castration-resistant prostate cancer, even after the use of docetaxel chemotherapy. Summary Novel agents targeting this pathway have demonstrated a proof of principle that overcoming castration resistance is possible, leading to significant changes in the landscape of treatment in this disease. The optimal combination, sequence, and pattern of use in these novel therapies will be the focus of clinical research in the near future.

Bevacizumab treatment of prostate cancer

Introduction: Angiogenesis plays an important role in the development and progression of prostate cancer. Vascular endothelial growth factor (VEGF) is a primary mediator of this process and is a target for novel therapies. Bevacizumab is a recombinant anti-VEGF monoclonal antibody that has demonstrated antitumor activity in a variety of cancers. Areas covered: In this review, we present the results of several clinical trials for bevacizumab in prostate cancer. Overall, these trials have shown improvements in progression-free survival but no changes in overall survival. Ongoing clinical trials are testing bevacizumab in combination with novel cytotoxic drugs and targeted therapies in metastatic and localized settings. Expert opinion: Bevacizumab has biological activity in prostate cancer. However, the mixed clinical trial results support the theory that prostate cancers may be driven only in part by angiogenesis. Questions remain about the future role of bevacizumab in the treatment of prostate cancer.

Comparison of 3 Upper Tract Anticarcinogenic Agent Delivery Techniques in an Ex Vivo Porcine Model

OBJECTIVE To evaluate the degree of urothelial exposure using 3 upper tract delivery techniques in an ex vivo porcine model, to determine the optimal modality to locally deliver topical anticarcinogenic agents in patients with upper tract urothelial carcinoma. MATERIALS AND METHODS An indigo carmine solution was infused into en bloc porcine urinary tracts to test the 3 techniques: antegrade infusion via nephrostomy tube, reflux via indwelling double-pigtail stent, and retrograde administration via a 5F open-ended ureteral catheter. Nine renal units (3 per delivery method) were used. After a 1-hour dwell time, the urinary tracts were bivalved and photographed. Each renal unit was evaluated by 3 blinded reviewers who estimated the total percentage of stained urothelial surface area using a computer-based area approximation system. In addition, as a surrogate for exposure adequacy, a validated equation was used to calculate the staining intensity at 6 predetermined locations in the upper tract, with lower values representing more efficient staining. RESULTS Mean percent of surface area stained for the nephrostomy tube, double-pigtail stent, and open-ended ureteral catheter groups was 65.2%, 66.2%, and 83.6%, respectively (P = .002). Mean staining intensities were 40.9, 33.4, and 20.4, respectively (P = .023). CONCLUSION Our results suggest that retrograde infusion via open-ended ureteral catheter is the most efficient method of upper tract therapy delivery. Larger studies using in vivo models should be performed to further validate these findings and potentially confirm this method as optimal for delivery of topical anticarcinogenic agents in upper tract urothelial carcinoma.

Laparoscopic Needle-Retrieval Device for Improving Quality of Care in Minimally Invasive Surgery

BACKGROUND Loss of a needle during laparoscopic surgery is a rare but potentially serious adverse event that can cause prolonged operative time and patient harm. Standard recovery techniques currently include instrument count, standard visual search, and plain abdominal x-rays. We developed a laparoscopic instrument to speed the retrieval of lost needles in the abdomen and pelvis. STUDY DESIGN We performed in vivo testing of a novel articulating laparoscopic magnet in a porcine model. Three experienced surgeons and 3 inexperienced surgeons conducted 116 needle-retrieval trials with the device and 58 trials with a standard visual approach. Surgeons were blind to the locations of randomly placed surgical needles within the abdominal cavity. Time to recovery was measured and capped at 15 minutes. Analysis was performed using univariate and multivariable methods. RESULTS The magnetic device was able to retrieve needles significantly faster than the standard approach (2.9 ± 4.0 minutes vs 8.0 ± 6.0 minutes; p < 0.0001). On multivariable analysis, faster recovery time remained independently significant when controlling for surgeon experience, needle size (small, medium, or large), and needle location (by quadrant) (p < 0.0001). There were 2 (2%) injuries to abdominal organs during the device trials and 4 (7%) injuries during the standard trials (p = 0.182). CONCLUSIONS Recovery of lost surgical needles during porcine laparoscopic surgery is safe and feasible with a simple articulating magnetic device. Our initial in vivo experience suggests that recovery is markedly faster using the magnetic device than the standard approach, even in the hands of experienced laparoscopic surgeons. This device will be particularly useful as minimally invasive robotic and single-site surgical techniques are adopted and, in the future, it should be integrated into the standard protocol for locating lost needles during surgery.

Aortic Distensibility in Type 1 Diabetes

OBJECTIVE To evaluate the relationship between long-term glycemia, traditional cardiovascular disease (CVD) risk factors, and ascending aortic stiffness in type 1 diabetes. RESEARCH DESIGN AND METHODS Eight hundred seventy-nine subjects in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study were evaluated. The stiffness/distensibility of the ascending thoracic aorta (AA) was measured with magnetic resonance imaging. Associations of AA distensibility and CVD risk factors, mean HbA1c, and cardiovascular complications including macroalbuminuria were assessed using multivariate linear regression models. RESULTS The mean age of the subjects was 50 ± 7 years (47% women, mean diabetes duration of 28 years). Over 22 years of follow-up, 27% of participants had cardiovascular complications. After adjusting for gender and cohort, AA distensibility was lower with increasing age, mean systolic blood pressure, LDL, and HbA1c measured over an average of 22 years (−26.3% per 10 years, −11.0% per 10 mmHg SBP, −1.8% per 10 mg/dL of LDL, and −9.3% per unit mean HbA1c [%], respectively). Patients with macroalbuminuria had 25% lower AA distensibility compared with those without (P < 0.0001). Lower AA distensibility also was associated with greater ratio of left ventricular mass to volume (−3.4% per 0.1 g/mL; P < 0.0001). CONCLUSIONS Our findings indicate strong adverse effects of hypertension, chronic hyperglycemia and macroalbuminuria on AA stiffness in type 1 diabetes in the DCCT/EDIC cohort.