-
[show abstract]
[hide abstract]
ABSTRACT: PURPOSE OF REVIEW: Treatment of all stages of prostate cancer has changed considerably in recent years, as our understanding of its biochemical pathways has improved. Testosterone, true to Huggin's original observation, remains a key player not only in newly diagnosed prostate cancer but also in castration-resistant prostate cancer, and our understanding of how to combine and sequence drugs that attack these pathways continues to grow. New US Food and Drugs Administration approved pharmaceutical agents further eliminate testosterone ligand or its activity via inhibition of key synthetic enzymes and through strong inhibition of the androgen receptor. RECENT FINDINGS: This review will briefly examine our knowledge of the complex relationship between testosterone, androgen receptor and advanced prostate cancer, discuss the limits of traditional androgen deprivation therapy in the form of gonadotropin-releasing hormone agonists and newer antagonists, examine combination therapies, including combined androgen blockade and newer studies with 5α-reductase inhibitors, and overview two new therapeutics that target hormonal pathways. SUMMARY: This review provides guidance on trials that examine combination therapies in various prostate cancer disease states. Androgens and prostate cancer remain inexorably linked, and this review will shed light on renewed focus on eliminating activity of this trophic ligand.
Current opinion in urology 03/2013; · 2.50 Impact Factor
-
The Journal of urology 04/2012; 187(6):2049; discussion 2050. · 4.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Metastasis to bone represents an all-too-frequent complication of advanced-stage prostate cancer (PCa): 50% to 70% of these patients will ultimately develop this devastating complication. PCa preferentially metastasizes to bone, and the skeletal complications increase mortality and decrease quality of life. The clinical consequences of skeletal metastasis also include pain, skeletal-related events (SREs), and increased costs of therapy. Recent advances in our understanding of the mechanisms of metastasis and the physiologic changes that occur with it, together with the introduction of new treatments, are furthering our ability to combat this problem. In this review, we examine bone-targeted palliative agents, nontargeted systemic cytotoxic therapies, and bone-targeted agents that go beyond palliation to also potentially improve progression-free and overall survival. We specifically focus on post-treatment outcomes--including pain relief, decreased opioid use, improvement in quality of life, freedom from SREs or new bony metastases, and increases in overall survival--in men with symptomatic, metastatic PCa. Treatments discussed include varied drug classes, such as bisphosphonates and human monoclonal antibodies; beta-emitting radiopharmaceuticals; external beam radiotherapy; systemic chemotherapies; Src inhibitors; endothelin-A receptor antagonists; clusterin inhibitors; and alpha-emitting radiopharmaceuticals.
Oncology (Williston Park, N.Y.) 12/2011; 25(14):1362-70, 1375-81, 1387. · 1.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Histone deacetylase inhibitors represent promising cancer treatments since they offer improved access to target DNA/protein complexes by cytotoxic agents. We hypothesized that histone deacetylase inhibitors would be most effective when combined with DNA damaging agents such as mitomycin C. Valproic acid is a safe, affordable histone deacetylase inhibitor. We examined the effect of the combination of valproic acid and mitomycin C on human bladder cancer cells in vitro and compared this to the effect of valproic acid or mitomycin C alone on the cells.
We used HTB5 and HTB9 cells derived from low and high grade bladder tumors, respectively. HTB5 and HTB9 cells were grown in modified Eagle's and RPMI medium, respectively. Cell growth and proliferation were measured by standard methods. Apoptosis was evaluated microscopically after dual staining of cells with annexin V-fluorescein isothiocyanate/propidium iodide. The change in protein expression was analyzed by Western blot.
Treatment of HTB5 and HTB9 bladder cancer cells for 24 to 72 hours with valproic acid and mitomycin C resulted in concentration and time dependent decreases in viability and proliferation. HTB9 cells showed marked sensitivity to mitomycin C with a 48-hour 50% median inhibitory concentration of 1 μg. Cells were less sensitive to valproic acid alone with a 48-hour 50% median inhibitory concentration of 2.5 mM. The chromatin structure relaxation induced by valproic acid pretreatment sensitized the bladder cancer cell lines, augmenting the cytotoxic action of mitomycin C. Valproic acid potentiated the induction of cell death by mitomycin C in each cell line in synergistic fashion. The effect of combining the 2 drugs was greater than the sum effect of each drug alone.
Results indicate that the valproic acid and mitomycin C combination is effective, likely due to synergistic mechanisms. Animal model validation is needed but early results suggest promising intravesical treatments for superficial bladder cancer.
The Journal of urology 12/2011; 186(6):2426-33. · 4.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This article aims to review the merits of the use of prostate-specific antigen (PSA) as a screening tool in the detection of prostate cancer and the evidence presented by the US and European population-based, randomized controlled trials evaluating screening. Many studies have attempted to ascertain whether PSA screening is beneficial with respect to cancer-specific mortality. This report aims to clarify the issues specific to the PSA test, prostate cancer, sources of bias, and the future of screening.
We performed an Ovid-Medline literature search for articles pertaining to the introduction of the PSA test, its use for screening for prostate cancer, confounders and biases specific to PSA and prostate cancer's natural history, and reports specific to the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO), and the European Randomized Study of Screening for Prostate Cancer (ERSPC). We reviewed these articles and present relevant data.
PSA emerged as one of the most-used serum tests to screen for cancer, particularly in the US, but in Europe as well. The PLCO trial showed no benefit to screening, and the ERSPC showed a 20% relative risk reduction of cancer-specific mortality. This translated to an absolute reduction of PCa-related deaths of 0.71 per 1,000. Each trial has criticisms that may or may not have affected power and outcome, although the rate ratios comparing screening to not screening are similar.
Definitive evidence for or against screening is still lacking, as interim analyses from the ERSPC and PLCO await further follow-up in the years to come.
World Journal of Urology 11/2011; 30(2):137-42. · 2.41 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We determined the impact of a grid based, transperineal 3-dimensional mapping biopsy on decision making for primary management of early stage prostate cancer.
We prospectively performed 3-dimensional mapping biopsy on 180 consecutive men who presented to our clinic between 2006 and 2009 with early stage, organ confined prostate cancer based on transrectal ultrasound guided 10 to 12-core biopsy, and on 35 with prior negative transrectal ultrasound biopsies.
At presentation median patient age was 60.5 years (range 43 to 77), median prostate specific antigen was 4.8 ng/ml (range 0.5 to 72.4) and median prostate volume was 35 cc (range 9 to 95). The median number of cores acquired by transrectal ultrasound and 3-dimensional mapping biopsy was 12 and 56, and the median number of positive cores was 1 and 2, respectively. We documented Gleason score upgrade in 49 of 180 cases (27.2%) and up-stage in 82 (45.6%). The incidence of urinary retention catheter requirement of greater than 48 hours was 3.2% and the incidence of transient orthostatic hypotension was 5%. No urinary tract infections were documented. A total of 38 men received radical extirpative therapy, 11 radiation and 45 cryotherapy while 60 enrolled in a targeted focal therapy study, 44 entered active surveillance and 5 underwent other focal investigational treatments. Post-mapping data on 12 men were not available for analysis.
Three-dimensional mapping biopsy revealed that a significant portion of men initially diagnosed with apparently low risk disease harbored clinically significant cancers requiring more aggressive therapy. The technique also enabled a number of men with low risk disease to elect surveillance or another less morbid option.
The Journal of urology 07/2011; 186(1):80-5. · 4.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: What's known on the subject? and What does the study add? Large population screening trials like the ERSPC, PCPT and PLCO have noted that men with seemingly low PSA (even as low as 0.5 ng/dL) still can have prostate cancer. Despite these findings, PSA is still predominantly used as a current indicator for possible presence of prostate cancer rather than also serving as a prognostic marker. This study examines a larger number of men in a diverse US population to determine the prognostic value of a man's baseline or first PSA.
• To assess the value of a PSA threshold of 1.5 ng/mL as a predictor of increased prostate cancer risk over a four-year period based on a man's first PSA test, including racial differences. • To review the risk of progression of benign prostatic hyperplasia (BPH) based on a similar PSA threshold.
• A retrospective review involving 21,502 men from a large Midwestern health system was performed. • Men at least 40 years old with baseline PSA values between 0 and 4.0 ng/mL and at least four years of follow-up after initial PSA test were included. • Optimal PSA threshold and predictive value of PSA for development of prostate cancer were calculated.
• Prostate cancer rates were 15-fold higher in patients with PSA ≥1.5 ng/mL vs patients with PSA <1.5 ng/mL (7.85% vs 0.51%). • African American patients with baseline PSA <1.5 ng/mL faced prostate cancer rates similar to the whole study population (0.54% vs 0.51%, respectively), while African American patients with PSA 1.5-4.0 ng/mL faced a 19-fold increase in prostate cancer.
• Both Caucasian and African American men with baseline PSA values between 1.5 and 4.0 ng/mL are at increased risk for future prostate cancer compared with those who have an initial PSA value below the 1.5 ng/mL threshold. • Based on a growing body of literature and this analysis, it is recommended that a first PSA test threshold of 1.5 ng/mL and above, or somewhere between 1.5 and 4.0 ng/mL, represent the Early-Warning PSA Zone (EWP Zone). • This should serve to inform patients and clinicians alike to future clinical activities with respect to prostate cancer and BPH.
BJU International 06/2011; 108(11):1743-9. · 2.84 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In response to ACGME work-hour restrictions, residency programs that require continuous inpatient clinical care for educational objectives will be forced to increase the proportion of junior resident experience involved in shift work. Maintaining the balance of education over service at these levels will be a challenge, where a considerable amount of time must be spent gathering data for morning rounds and signing out patients at shift change. Patient safety is an issue with this new paradigm. We hypothesized that computerized sign-out would improve resident efficiency.
A multidisciplinary clinical team collaborated to design a computerized rounding and sign-out (CSO) program to automate collection of clinical information in addition to a brief narrative describing ongoing care issues. Residents returned a self-administered questionnaire before (n = 168) and after implementation (n = 83) examining: pre-rounding time, missed patients, handoff quality, and duty hours.
Residents reported spending 11 fewer min/d pre-rounding (P = 0.006). After implementation, residents missed fewer patients on rounds (P = 0.01). A majority (70%) of responders stated that the new program helped them with duty hours.
The current study demonstrates the reproducibility of the University of Washington model system for rounding and sign-out at an independent site, using basic infrastructure and leadership common to all residency programs. Developing a CSO was associated with a modest reduction in pre-rounding time and fewer patients missed on rounds. Although automating resident tasks may improve workflow in an increasingly complex hospital environment, structured handoff education and other institutional changes are necessary.
Journal of Surgical Research 05/2011; 172(1):11-7. · 2.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Renal cell carcinoma (RCC) is a disease in which cancer cells form in the tubules of the kidney. RCC, the incidence of which is increasing annually, represents five percent of adult epithelial cancers. Clear cell carcinoma represents the most frequent histological subtype. RCC is characterized by a lack of early warning signs, diverse clinical manifestations. Incidentally detected tumors in asymptomatic individuals have been steadily increasing owing to the increased usage of various imaging technologies. Currently there are no recommendations for screening to detect and make an early diagnosis of renal cancer. But in recent years, the discovery of new molecular and cytogenetic markers has led to the recognition and classification of several novel subtypes of RCC, and the introduction of molecular-targeted therapy for advanced-stage RCC. We performed a literature review using PubMed and discuss current knowledge of epidemiology, pathophysiology, evaluation, treatment, and future research directions of RCC.
American journal of cancer research. 01/2011; 1(2):240-254.
-
[show abstract]
[hide abstract]
ABSTRACT: Prostate cancer will be diagnosed in one of six men during their lifetimes, and a small portion of these will progress after primary and salvage therapies. For many years, there were few treatment options for these patients after routine hormonal maneuvers, and standard of care since the early 2000s has consisted primarily of docetaxel, which improved survival over the previous first-line therapy mitoxantrone. In recent years, however, new therapies have begun to emerge to treat this devastating form of prostate cancer. This review examines the mechanisms behind these therapeutics and the key trials seeking to validate their clinical use.
Oncology (Williston Park, N.Y.) 12/2010; 24(14):1308-13, 1318. · 1.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To the Editor: We have witnessed a new renaissance in the treatment of castration-resistant prostate cancer,(1) but the progression of this disease beyond a form treatable by means of hormone deprivation still begs scientific and clinical inquiry. The adverse events associated with androgen-deprivation therapy are well characterized.(2) Risks of cardiovascular-related side effects, skeletal-related events, loss of libido, and depression - among others - that are associated with androgen-deprivation therapy are major concerns for physicians and patients alike. An adverse event that is frequently overlooked, however, is the failure to lower or maintain levels of testosterone that would be present after . . .
New England Journal of Medicine 11/2010; 363(20):1976. · 53.30 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Prostate cancer (CaP) is the second most common cause of cancer deaths in the United States and the incidence of CaP has remained constant at 165 cases per 100,000 men. Since 1990, the age-adjusted death rate has decreased by 31%. In this article, the authors review the current literature on the experimental therapy for HIFU. The HIFU technique, its mechanism of action, patient selection, current efficacy studies, complications, follow-up after HIFU treatment, and future developments are discussed.
Urologic Clinics of North America 02/2010; 37(1):27-35, Table of Contents. · 1.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Metastasis to the bone represents a frequent complication of visceral cancers, most commonly in patients with advanced breast, prostate, and lung cancer. More than 50% of patients with advanced breast or prostate cancer have identifiable bone metastasis, and 30% to 40% of patients with non-small-cell lung cancer ultimately develop metastases to bone. Most tumors preferentially metastasize to the axial skeleton, targeting the vertebrae, pelvis, proximal ends of long bones, and skull. Skeletal complications as a result of these metastases are widely recognized to increase mortality and decrease quality of life--specifically the loss of mobility, independence, and social functioning of a patient. Advances in understanding the mechanisms of metastasis to bone, the resulting physiologic disturbances that take place, screening, diagnosis, and availability of better treatment options are advancing clinicians' abilities to combat this devastating problem.
Oncology (Williston Park, N.Y.) 12/2009; 23(14 Suppl 5):21-7. · 1.03 Impact Factor
