Impact of Late Dosing on Testosterone Suppression with 2 Different Leuprolide Acetate Formulations: In Situ Gel and Microsphere. An Analysis of United States Clinical Data.

PURPOSE: Nonadherence to dosing schedules for androgen deprivation therapy increases the risk of testosterone escape for patients with prostate cancer. Two approved formulations of leuprolide acetate, the most commonly prescribed androgen deprivation therapy in the United States, use different extended release delivery technologies: an in situ gel and microspheres. We evaluated the prevalence and impact of late dosing on testosterone suppression for gel and microsphere formulations of leuprolide acetate. MATERIALS AND METHODS: We retrospectively analyzed records of patients with prostate cancer treated with gel or microsphere delivery of leuprolide acetate. Analyses used 2 definitions of "month," "28-day" (late dosing after day 28, 84, 112 or 168) and "extended" (late dosing after day 32, 97, 128 and 194). Frequencies of late dosing and associated testosterone values were calculated. RESULTS: A total of 2,038 patients received gel and 8,360 received microsphere formulations of leuprolide acetate. More than 80% and 27% of injections were late for 28-day and extended month, respectively. For 28-day month late injections 10% (gel delivery) and 14% (microsphere delivery) of testosterone values were above 50 ng/dl, and 25% (gel) vs 33% (microsphere) were above 20 ng/dl. For extended month 18% (gel) vs 25% (microsphere) were above 50 ng/dl, and 34% (gel) vs 44% (microsphere) were above 20 ng/dl. Microsphere leuprolide acetate was 1.5 times more likely to have testosterone above 50/20 ng/dl vs gel. Least square mean testosterone was 34 ng/dl (gel) vs 46 ng/dl (microsphere) for 28-day month, and 48 ng/dl (gel) vs 76 ng/dl (microsphere) for extended month. CONCLUSIONS: Leuprolide acetate therapies were frequently administered late. Gel formulation demonstrated higher rates of testosterone 50 ng/dl or less and 20 ng/dl or less than microsphere formulation. Optimal testosterone suppression can impact prostate cancer progression and patient survival, and differences in extended release technology for androgen deprivation therapy appear relevant.

Evolving understanding and categorization of prostate cancer: preventing progression to metastatic castration-resistant prostate cancer: RADAR IV.

INTRODUCTION To interpret data and update the traditional categorization of prostate cancer in order to help treating clinicians make more informed decisions. These updates include guidance regarding how to best use next generation imaging (NGI) with the caveat that the new imaging technologies are still a work in progress. MATERIALS AND METHODS: Literature review. RESULTS: Critical goals in prostate cancer management include preventing or delaying emergence of distant metastases and progression to castration-resistant disease. Pathways for progression to metastatic castration-resistant prostate cancer (mCRPC) involve transitional states: nonmetastatic castration-resistant prostate cancer (nmCRPC), metastatic hormone-sensitive prostate cancer (mHSPC), and oligometastatic disease. Determination of clinical state depends in part on available imaging modalities. Currently, fluciclovine and gallium-68 (68Ga) prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) are the NGI approaches with the most favorable combination of availability, specificity, and sensitivity. PET imaging can be used to help guide treatment selection in most patients. NGI can help determine patients who are candidates for new treatments, most notably (next-generation androgen antagonists, eg, apalutamide, enzalutamide, darolutamide), that can delay progression to advanced disease. CONCLUSIONS: It is important to achieve a consensus on new and more easily understood terminology to clearly and effectively describe prostate cancer and its progression to health care professionals and patients. It is also important that description of disease states make clear the need to initiate appropriate treatment. This may be particularly important for disease in transition to mCRPC.

The Impact of Late Luteinizing Hormone-Releasing Hormone Agonist Dosing on Testosterone Suppression in Patients with Prostate Cancer: An Analysis of United States Clinical Data.

PURPOSE: We evaluated the timeliness of androgen deprivation therapy dosing, the impact of dosing nonadherence on testosterone, and the frequency of testosterone and prostate specific antigen testing in patients with prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of 22,860 patients with prostate cancer treated with luteinizing hormone-releasing hormone agonists. Analyses were done using 2 definitions of month, including a 28-day month (late dosing after day 28, 84, 112 or 168) and an extended month (late after day 32, 97, 128 or 194) for 1, 3, 4 and 6-month formulations, respectively. The prevalence of late dosing, associated testosterone values, and the frequency of testosterone and prostate specific antigen testing were assessed. Statistical significance was assessed with the unpaired t-test. RESULTS: Of the injections 84% and 27% were late for the 28-day and extended month analyses, respectively. For the 28-day month 60% and 29% of injections were late by more than 1 and more than 2 weeks, respectively. Of testosterone values 4% were greater than 50 ng/dl for early/on time injections using both definitions, and 15% and 27% were greater than 50 ng/dl when late, and for the 28-day month and the extended month, respectively. For early/on time vs late injections 22% vs 31% of testosterone values were greater than 20 ng/dl for the 28-day month and 21% vs 43% for the extended month. Mean testosterone was higher when late (49 ng/dl for 28-day month, 79 ng/dl for extended month) vs early/on time (both 21 ng/dl). Of the injections prostate specific antigen measurements were performed in 83% and testosterone assessment was done in only 13%. CONCLUSIONS: Luteinizing hormone-releasing hormone agonists were frequently (84%) administered later than the schedules used in pivotal trials. Nearly half of the late testosterone values for the extended month were greater than 20 ng/dl and mean testosterone was almost double the castration level. Elevated testosterone remained unidentified with infrequent testing.

A Clinician's Guide to Next Generation Imaging in Patients With Advanced Prostate Cancer (RADAR III).

PURPOSE: The advanced prostate cancer therapeutic landscape has changed dramatically in the last several years, resulting in improved overall survival of patients with castration naïve and castration resistant disease. The evolution and development of novel next generation imaging techniques will affect diagnostic and therapeutic decision making. Clinicians must navigate when and which next generation imaging techniques to use and how to adjust treatment strategies based on the results, often in the absence of correlative therapeutic data. Therefore, guidance is needed based on best available information and current clinical experience. MATERIALS AND METHODS: The RADAR (Radiographic Assessments for Detection of Advanced Recurrence) III Group convened to offer guidance on the use of next generation imaging to stage prostate cancer based on available data and clinical experience. The group also discussed the potential impact of next generation imaging on treatment options based on earlier detection of disease. RESULTS: The group unanimously agreed that progression to metastatic disease is a seminal event for patient treatment. Next generation imaging techniques are able to detect previously undetectable metastases, which could redefine the phases of prostate cancer progression. Thus, earlier systemic or locally directed treatment may positively alter patient outcomes. CONCLUSIONS: The RADAR III Group recommends next generation imaging techniques in select patients in whom disease progression is suspected based on laboratory (biomarker) values, comorbidities and symptoms. Currently 18F-fluciclovine and 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography are the next generation imaging agents with a favorable combination of availability, specificity and sensitivity. There is ongoing research of additional next generation imaging technologies, which may offer improved diagnostic accuracy and therapeutic options. As next generation imaging techniques evolve and presumably result in improved global accessibility, clinician ability to detect micrometastases may be enhanced for decision making and patient outcomes.

Approach to Androgen Deprivation in the Prostate Cancer Patient with Pre-existing Cardiovascular Disease.

PURPOSE OF REVIEW: Androgen deprivation therapy (ADT) is a mainstay of treatment for advanced prostate cancer. Several studies have reported an association between ADT and an increase in cardiovascular events, especially in those receiving gonadotropin-releasing hormone (GnRH) agonists compared to GnRH antagonists. We review the body of literature reporting the association of ADT and cardiovascular morbidity, and discuss the proposed mechanism of cardiovascular disease due to ADT including metabolic changes that may promote atherosclerosis and local hormonal effects that may increase plaque rupture and thrombosis. RECENT FINDINGS: GnRH agonists appear to increase the risk of cardiovascular morbidity by 20-25% in men on these agents compared those who do not receive ADT. GnRH antagonists may appear to have halve this risk while improving PSA progression-free survival. GnRH antagonists may be superior to GnRH agonists for patients with significant cardiovascular disease, significant metastatic disease burden, or severe lower urinary tract symptoms.

The Role of Therapeutic Layering in Optimizing Treatment for Patients With Castration-resistant Prostate Cancer (Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II).

OBJECTIVE: To offer recommendations on identification of disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific castration-resistant prostate cancer (CRPC) treatments. MATERIALS AND METHODS: The Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II Working Group convened to provide guidance on sequencing, combination, or layering of approved treatments for metastatic CRPC based on available data and clinical experience. RESULTS: A consensus was developed to address important questions on management of patients with metastatic CRPC. CONCLUSION: In the absence of large-scale clinical trials, the Working Group recommends that patients may best be managed with a layered approach of approved therapies with unique or complimentary mechanisms of action.

The potential role of follicle-stimulating hormone in the cardiovascular, metabolic, skeletal, and cognitive effects associated with androgen deprivation therapy.

PURPOSE: To explore how follicle-stimulating hormone (FSH) may contribute to cardiovascular, metabolic, skeletal, and cognitive events in men treated for prostate cancer, with various forms of androgen deprivation therapy (ADT). MATERIALS AND METHODS: A colloquium of prostate cancer experts was convened in May 2015, to discuss the role of FSH in the development of unwanted effects associated with ADT. Subsequently, a literature review (Medline, PubMed, and relevant congress abstract databases) was performed to further explore and evaluate the collected evidence. RESULTS: It has become evident that, in the setting of ADT, FSH can promote the development of atherosclerotic plaque formation, metabolic syndrome, and insulin resistance. Data also suggest that FSH is an important mediator of bone remodeling, particularly bone resorption, and thereby increases the risk for bone fracture. Additional evidence implicates a role for FSH in bone metastasis as well. The influence of FSH on ADT-induced cognitive deficits awaits further elucidation; however, the possibility that FSH may be involved therein cannot be ruled out. CONCLUSIONS: The widespread molecular and physiological consequences of FSH system activation in normal and pathological conditions are becoming better understood. Progress in this area has been achieved by the development of additional investigative and clinical measures to better evaluate specific adverse effects. More research is needed on FSH function in the development of cancer as well as its association with cardiovascular, metabolic, musculoskeletal, and cognitive effects in ADT.

Six Weeks of Fluoroquinolone Antibiotic Therapy for Patients With Elevated Serum Prostate-specific Antigen Is Not Clinically Beneficial: A Randomized Controlled Clinical Trial.

OBJECTIVE: To evaluate asymptomatic men with elevated serum prostate-specific antigen (PSA) to determine whether a 6-week course of fluoroquinolone antibiotics lowers serum PSA and affects recommendations for prostate biopsy. MATERIALS AND METHODS: A randomized, single-center prospective trial of 150 men with an initial elevated PSA was conducted. Patients were randomized to 6 weeks of ciprofloxacin or observation. Those patients with persistently elevated PSA were recommended to proceed with transrectal ultrasound-guided 12-core biopsy. Those with reduced PSA were offered transrectal ultrasound-guided biopsy but could opt to continue serial digital rectal examination/PSA. Patients were followed an average of 4.6 years to assess trends in PSA and biopsy results. RESULTS: Of 136 men who completed the trial, 63 were in the treatment and 73 were in the observation group. The average PSA change from baseline was borderline statistically significant with a change of -0.68 ng/mL in the treatment arm and 0.01 ng/mL in the observation arm (P = .052). Of those who underwent biopsy, prostate cancer was diagnosed in the first biopsy in 24 (63%) of the treatment vs 27 (52%) of the observation group (P = .60) over follow-up. CONCLUSION: In a cohort of asymptomatic men with elevated PSA, there was only a borderline statistically significant change in serum PSA between patients randomized to a 6-week course of fluoroquinolones vs observation, and there was no difference in positive prostate biopsy results. Our clinical recommendation is one should not treat patients with elevated serum PSA with antibiotics in the absence of clinical symptoms of prostatitis.

Avoiding obsolescence in advanced prostate cancer management: a guide for urologists.

Prostate cancer is one of the most common cancers diagnosed in men in the USA and 20­30% of men treated for localised prostate cancer will fail therapy and develop advanced prostate cancer. More drugs have been approved for the treatment of advanced prostate cancer in the past 3 years than in the past three decades, and each drug has its own mechanism of action and, often, unique monitoring requirements. As the treatment landscape for men with advanced prostate cancer is undergoing significant expansion, the roles of both oncologists and urologists are shifting, and the decision for the urologist to treat vs refer requires early assessment to identify which patients are candidates for these novel treatments and the monitoring of patients for tolerability, response, and potential side-effects. Given these rapid changes, the authors of this review met in January 2013 and again in April 2013 to discuss the current challenges facing urologists in adopting these new treatments into their own practices. Here, we provide a brief overview of advanced prostate cancer medical therapies approved in the past decade, the necessary monitoring procedures and early detection methods needed to safely and effectively manage patients receiving these therapies, and our recommendations for applying these new therapies within different models of urology practice, such that urologists can remain an integral component of their patient's care once he has transitioned into advanced prostate cancer

Phase I trial of weekly docetaxel, total androgen blockade, and image-guided intensity-modulated radiotherapy for localized high-risk prostate adenocarcinoma.

BACKGROUND: This was a phase I study to find the maximum tolerable dose (MTD) of weekly docetaxel combined with high-dose intensity-modulated radiotherapy (IMRT) and androgen deprivation therapy (ADT). PATIENTS AND METHODS: Men with localized high-risk prostate cancer (HRPC) were treated with weekly docetaxel at 10 to 30 mg/m(2) concurrent with IMRT of 77.4 Gy to the prostate and 45 Gy to the seminal vesicles. ADT consisted of a gonadotropin-releasing hormone agonist (GnRHa) and bicalutamide beginning 2 months before and during chemoradiation. GnRHa was continued for 24 months. RESULTS: Nineteen patients were enrolled. No dose-limiting toxicity (DLT) was seen with docetaxel doses up to 25 mg/m(2). At the 30 mg/m(2) level, 2 of 4 patients experienced DLTs of both grade 3 fatigue and dyspepsia. At 41 months' median follow-up, 2 patients had died--1 from metastatic prostate cancer and the other from heart failure. Two other patients experienced biochemical failure. One patient with bladder invasion at diagnosis experienced late grade 2 urinary hesitancy 9 months after completion of radiotherapy, requiring short-term intermittent catheterization. All patients had erectile dysfunction, but no late toxicities worse than grade 2 were identified. CONCLUSION: Weekly docetaxel may be combined with high-dose IMRT and long-term ADT up to a MTD of 25 mg/m(2). Acute toxicities and long-term side effects of this regimen were acceptable. Future studies evaluating the efficacy of docetaxel, ADT, and IMRT for localized HRPC should use a weekly dose of 25 mg/m(2) when limiting the irradiated volume to the prostate and seminal vesicles.

Challenges and recommendations for early identification of metastatic disease in prostate cancer.

Prostate cancer is often associated with metastases to bone and/or soft tissue. The progression to metastatic castrate-resistant prostate cancer is a seminal event in disease progression affecting treatment decisions. A multidisciplinary group was convened to review the currently available imaging guidelines for metastatic disease in prostate cancer and found no consensus on eligibility criteria, type of imaging modality, and the frequency of scanning for detecting metastatic disease. The aim of this review was to present the recommendations from the group to identify optimal strategies for early identification of metastases in patients with prostate cancer.

Impact of prostate cancer on sexual relationships: a longitudinal perspective on intimate partners' experiences.

INTRODUCTION: In this prospective study of localized prostate cancer patients and their partners, we analyzed how partner issues evolve over time, focusing on satisfaction with care, influence of cancer treatment, and its impact on relationship with patient, cancer worry, and personal activities. AIMS: Our study aims were twofold: (i) to determine whether the impact of treatment on patients and partners moderate over time and (ii) if receiving surgery (i.e., radical prostatectomy) influences partner issues more than other treatments. METHODS: Patients newly diagnosed with localized prostate cancer and their female partners were recruited from three states to complete surveys by mail at three time points over 12 months. MAIN OUTCOME MEASURES: The four primary outcomes assessed in the partner analysis included satisfaction with treatment, cancer worry, and the influence of cancer and its treatment on their relationship (both general relationship and sexual relationship). RESULTS: This analysis included 88 patient-partner pairs. At 6 months, partners reported that cancer had a negative impact on their sexual relationship (39%--somewhat negative and 12%--very negative). At 12 months, this proportion increased substantially (42%--somewhat negative and 29%--very negative). Partners were significantly more likely to report that their sexual relationship was worse when the patient reported having surgery (P = 0.0045, odds ratio = 9.8025, 95% confidence interval 2.076-46.296). A minority of partners reported significant negative impacts in other areas involving their personal activities (16% at 6 months and 25% at 12 months) or work life (6% at 6 months, which increased to 12% at 12 months). CONCLUSION: From partners' perspectives, prostate cancer therapy has negative impact on sexual relationships and appears to worsen over time.

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse.

Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.

Burden among partner caregivers of patients diagnosed with localized prostate cancer within 1 year after diagnosis: an economic perspective.

PURPOSE: Informal care plays an important role in the overall care for people with cancer. This study estimates lost productivity and informal caregiving and associated costs among partner caregivers of localized prostate cancer patients within 1 year after diagnosis. METHODS: We applied data from the Family and Cancer Therapy Selection study, a three-wave self-administered survey among patients diagnosed with localized prostate cancer and their partner caregivers in multiple clinics in the USA. Time spent was measured by the sum of working hours lost, informal caregiving hours performed, and hours spent on household chores. The national median income for women 55 years or older was used to calculate costs associated with the time spent using the opportunity cost method. Descriptive and bivariate analyses were conducted. RESULTS: The average working hours decreased from 14.0 h/week (SD = 17.6) to 10.9 h/week (SD = 15.9), without a significant change in responsibility/intensity at work. The mean annual time spent on informal caregiving and household chores was 65.9 h/year (SD = 172.4) and 76.2 h/year (SD = 193.3), respectively. The mean annual economic burden among partner caregivers was US$6,063 (range US$571-US$47,105) in 2009 dollars accounted for by a mean of 276.2 h (range 26-2,146) in the study sample. The time spent on informal caregiving and household chores varied by patient and caregiver characteristics. CONCLUSIONS: Pilot estimates on non-medical economic burden among partner caregivers (spouses) during the initial phase of the treatment provide important information for comprehensive estimation of disease burden and can be used in cost-effectiveness analyses of prostate cancer interventions.

Improved performance of SPECT-CT In-111 capromab pendetide by correlation with diffusion-weighted magnetic resonance imaging for identifying metastatic pelvic lymphadenopathy in prostate cancer.

PURPOSE: To preliminarily evaluate the potential for an improvement in diagnostic performance by a combined interpretation of In-111 capromab pendetide single photon emission computed tomography (SPECT) including computed tomography (CT) image fusion with magnetic resonance diffusion-weighted imaging (MR-DWI) for identifying prostate cancer in pelvic lymph nodes thru correlation with histopathology. MATERIALS AND METHODS: This institutional approved, retrospective study identified patients with available histopathology of lymph nodes removed at the time of radical prostatectomy and who had undergone staging with In-111 capromab pendetide SPECT-CT and/or pelvic MRI (including DWI). The performance of In-111 capromab pendetide SPECT for identifying malignant lymph nodes was assessed. Subsequently, a combined reading of In-111 capromab pendetide SPECT and prostate MRI with DWI was performed and the performance assessed. RESULTS: 18 patients underwent In-111 capromab pendetide SPECT-CT. Of these, 12 patients had also undergone imaging with MR-DWI. In-111 capromab pendetide SPECT-CT had a sensitivity of 40.0% and specificity of 96.7% for identification of malignant lymph nodes. However, In-111 capromab pendetide SPECT-CT combined with MRI with DWI had a sensitivity of 88.9% and specificity of 98.5%. CONCLUSIONS: The addition of MR-DWI to the interpretation of In-111 capromab pendetide SPECT-CT may increase the sensitivity for detecting malignant lymph nodes in prostate cancer. Future prospective evaluation of combined In-111 capromab pendetide SPECT-CT and MR-DWI is indicated and may improve clinical evaluation of nodal disease in prostate cancer.

Willingness to pay for prostate cancer treatment among patients and their family members at 1 year after diagnosis.

OBJECTIVES: To explore an alternative approach to quantifying the burden of side effects at 1 year after treatment for prostate cancer among both patients and their partners. METHODS: We analyzed data from 75 couples in the Family and Cancer Therapy Selection study. Paired patients and family members were independently asked about their willingness to pay (WTP) for a hypothetical new treatment that cures prostate cancer without side effects if they could reconsider their treatment decision by indicating the maximum amount they would be willing to pay given 11 separate "bids" ranging from $0 to $1500 per month. Descriptive and regression analyses were conducted for patients and family members controlling for sociodemographic characteristics and health status; Spearman correlations were also examined. RESULTS: Among 75 couples analyzed, the income-adjusted mean WTP estimates per month were $400.8 (standard error [SE] $54.3) for patients and $650.2 (SE 72.2) for family members. The WTP between patients and family members was correlated (Pearson ρ 0.30; P = 0.01). After adjusting for covariates, the adjusted mean WTP per month was $588.1 (SE 65.77) for patients and $819.4 (SE 74.33) for family members. Wanting to avoid side effects at baseline predicted higher WTP for patients (P = 0.010). Experiencing sexual side effects was predictive of higher WTP for family members (P = 0.047). CONCLUSIONS: Fairly high WTP amounts for a hypothetical treatment without side effects suggests that patients and their partners are experiencing important burdens 1 year after treatment. The higher amounts partners are willing to pay and the correlation with sexual side effects suggest that they are perceptive of significant treatment burdens.

Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance.

CONTEXT: We wanted to investigate vitamin D in low-risk prostate cancer. OBJECTIVES: The objective of the study was to determine whether vitamin D(3) supplementation at 4000 IU/d for 1 yr is safe and would result in a decrease in serum levels of prostate-specific antigen (PSA) or in the rate of progression. DESIGN: In this open-label clinical trial (Investigational New Drug 77,839), subjects were followed up until repeat biopsy. SETTING: All subjects were enrolled through the Medical University of South Carolina and the Ralph H. Johnson Veterans Affairs Medical Center, both in Charleston, SC. PATIENTS AND OTHER PARTICIPANTS: All subjects had a diagnosis of low-risk prostate cancer. Fifty-two subjects were enrolled in the study, 48 completed 1 yr of supplementation, and 44 could be analyzed for both safety and efficacy objectives. INTERVENTION: The intervention included vitamin D(3) soft gels (4000 IU). MAIN OUTCOME MEASURES: Adverse events were monitored throughout the study. PSA serum levels were measured at entry and every 2 months for 1 yr. Biopsy procedures were performed before enrollment (for eligibility) and after 1 yr of supplementation. RESULTS: No adverse events associated with vitamin D(3) supplementation were observed. No significant changes in PSA levels were observed. However, 24 of 44 subjects (55%) showed a decrease in the number of positive cores or decrease in Gleason score; five subjects (11%) showed no change; 15 subjects (34%) showed an increase in the number of positive cores or Gleason score. CONCLUSION: Patients with low-risk prostate cancer under active surveillance may benefit from vitamin D(3) supplementation at 4000 IU/d.

The multi-disciplinary management of high-risk prostate cancer.

Prostate cancer is the most frequently diagnosed cancer and the second most common cause of cancer death in men in the United States. Such men can experience a continuum of disease presentations from indolent to highly aggressive. For physicians who care for these men, a significant challenge has been and continues to be identifying and treating those men with localized cancer who are at a higher risk of dying from their disease. We discuss the risk stratification of patients in order to better identify those patients at higher risk of progression. A comprehensive review of the literature was then performed reviewing the roles of surgery, radiotherapy, hormone therapy, and chemotherapy, as well as combinations of these modalities, in treating these challenging patients. An integrated approach combining local and systemic therapies can be beneficial in the management of high-risk localized prostate cancer. The choice of therapy or combination of therapies is dependant upon many considerations, including patient preference and quality of life aspects. It is becoming clearer that the addition of hormonal therapies or chemotherapies to established therapies, such as radiotherapy or surgery, will have significant benefits. As evidence accumulates regarding the efficacy of these new regimens, our hope is that the challenge of optimizing the management of high-risk prostate cancer will be delivered. However, many important questions remain unresolved regarding the optimal type, combination, timing of therapy, and duration of therapy. Such questions will only be answered with large, well-designed prospective clinical trials.

Detection of mitochondrial deoxyribonucleic acid alterations in urine from urothelial cell carcinoma patients.

Our study aims at understanding the timing and nature of mitochondrial deoxyribonucleic acid (mtDNA) alterations in urothelial cell carcinoma (UCC) and their detection in urine sediments. The entire 16.5 kb mitochondrial genome was sequenced in matched normal lymphocytes, tumor and urine sediments from 31 UCC patients and compared to different clinical stages and histological grades. The mtDNA content index was examined in all the specimens. Sixty-five percent (20/31) of the patients harbored at least 1 somatic mtDNA mutation. A total of 25 somatic mtDNA mutations were detected, which were more frequent in the respiratory complex coding regions (Complex I, III, IV and V) of the mtDNA and significantly affected respiratory Complex III compared to the other complexes (p = 0.021-0.039). Compared to Stage Ta, mtDNA mutation was higher in Stage T1 and significantly higher in Stage T2 (p = 0.01) patients. MtDNA mutation was also significantly higher (p = 0.04) in Stage T2 compared to Stage T1 patients. Ninety percent (18/20) of the patients harboring mtDNA mutation in the tumor also had mutation in their urine sediments. Eighty percent (20/25) of the tumor-associated mtDNA mutations was detectable in the urine sediments. Compared to the normal lymphocytes, the mtDNA content increased significantly in the tumor (p = 0.0013) and corresponding urine sediments (p = 0.0025) in 19/25 (76%) patients analyzed. Our results indicate that mtDNA alterations occur frequently in progressive stages of UCC patients and are readily detectable in the urine sediments. MtDNA mutations appear to provide a promising tool for developing early detection and monitoring strategies for UCC patients.