Biomedical subjects

S Larry Goldenberg

Publications and source records attributed to S Larry Goldenberg.

14 recordsLinked to original sources

PubMed2007

Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes.

PURPOSE: The American Urological Association Prostate Guideline Update Panel was charged with updating the Guidelines for Clinically Localized Prostate Cancer. In assessing outcomes with treatment, it became apparent that a highly variable number of definitions exist with respect to biochemical recurrence. Herein, we review the variability in published definitions of biochemical recurrence and make recommendations directed toward improving this terminology by recommending a standard definition in patients treated with radical prostatectomy. MATERIALS AND METHODS: Four PubMed literature searches were performed between May 2001 and April, 2004 and covered articles published from 1991 through early 2004. The search terms included the MeSH major headings of prostate cancer and prostatic neoplasm. All potentially relevant articles were retrieved and a more detailed screen for relevance was performed. An article was considered relevant if it reported treatment outcomes of patients with clinical T1 or T2N0M0 prostate cancer. Data extractors recorded the definition of biochemical recurrence and definitions were then collapsed into categories representing the same criteria. The results of biochemical failure were subcategorized by initial treatment. RESULTS: Of 13,800 citations, a total of 436 articles were selected. Among these, a total of 145 articles contained 53 different definitions of biochemical recurrence for those treated with radical prostatectomy. Of these, the most common definition (35) was a prostate specific antigen of >0.2 ng/mL or a slight variation thereof. In addition, a total of 208 articles reported 99 different definitions of biochemical failure among those treated with radiation therapy. Of these, the American Society for Therapeutic Radiology and Oncology definition (70) and/or a variation thereof was the most commonly reported. In total, 166 different definitions of biochemical failure were identified. Following radical prostatectomy, the Panel recommends defining biochemical recurrence as an initial serum prostate specific antigen of > or =0.2 ng/mL, with a second confirmatory level of prostate specific antigen of >0.2 ng/mL. The Panel recommends the use of the American Society for Therapeutic Radiology and Oncology criteria for patients treated with radiation therapy and acknowledges that these criteria will soon be updated although not yet published. CONCLUSIONS: A high degree of variability in the definition of biochemical recurrence exists following treatment for localized prostate cancer. Strict definitions for biochemical recurrence are necessary to identify men at risk for disease progression and to allow meaningful comparisons among patients treated similarly. The Panel acknowledges the American Society for Therapeutic Radiology and Oncology criteria and future modifications thereof for those receiving radiation therapy and recommends the newly developed American Urological Association criteria for those treated with radical prostatectomy. The purpose for the establishment of this standard is for data reporting purposes and for comparison of similarly treated patients. It is not intended to represent a threshold value for which to initiate treatment. The Panel acknowledges that the clinical decision to initiate treatment will be dependent on multiple factors including patient and physician interaction rather than a specific prostate specific antigen threshold value.

Humans↗

PubMed2006

Final results of the Canadian prospective phase II trial of intermittent androgen suppression for men in biochemical recurrence after radiotherapy for locally advanced prostate cancer: clinical parameters.

BACKGROUND: This prospective Phase II study was undertaken to evaluate intermittent androgen suppression as a form of therapy in men with localized prostate cancer who failed after they received external beam irradiation. METHODS: Patients who demonstrated a rising serum prostate-specific antigen (PSA) level after they received radiotherapy and who were without evidence of distant metastasis were accepted into the study. Treatment in each cycle consisted of cyproterone acetate given as lead-in therapy for 4 weeks, followed by a combination of leuprolide acetate and cyproterone acetate, which ended after a total of 36 weeks. RESULTS: Of 109 patients registered, 103 patients were eligible for interruption of treatment, yielding a PSA response rate of 95%. The study continued for 6 years with a mean follow-up of 3.7 years (median follow-up, 4.2 years). The time off treatment averaged 53% of the total cycle time but, in absolute terms, decreased with each succeeding cycle, ranging from 63.7 weeks in Cycle 1 to 25.6 weeks in Cycle 5. Prostate volume was reduced by 40% in Cycle 1 and by 34% in Cycle 2, and there were no decreases in Cycle 3 or Cycle 4. At the end of the trial, 38.5% of patients still were receiving treatment, 23.9% of patients had failed, and 15.6% of patients had died. Only 2% of deaths were cancer-specific. CONCLUSIONS: Biochemical recurrence after irradiation for localized prostate cancer was amenable to cyclic androgen withdrawal therapy and showed a high response rate. Despite progressively shorter treatment cycles, the off-treatment interval remained appreciable, ranging from 65% in Cycle 1 to 46% in Cycle 5.

Aged↗

PubMed2006

Combined diffusion-weighted and dynamic contrast-enhanced MRI for prostate cancer diagnosis--correlation with biopsy and histopathology.

PURPOSE: To determine whether the combination of diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI provides higher diagnostic sensitivity for prostate cancer than each technique alone. MATERIALS AND METHODS: Fourteen patients with a clinical suspicion of prostate cancer underwent endorectal MRI on a 1.5T scanner prior to transrectal ultrasound (TRUS)-guided biopsies. The average values of the apparent diffusion coefficient (ADC, calculated from b-values of 0 and 600), K(trans), v(e), maximum gadolinium (Gd) concentration, onset time, mean gradient, and maximum enhancement were determined. Correlation with histology was based on biopsy (six patients) and prostatectomy specimen (eight patients) results. The Tukey-Kramer test was used for statistical analysis. RESULTS: The average values of all MRI parameters, except v(e) and maximum Gd concentration, showed significant differences between tumor and normal prostate. The sensitivity and specificity values were respectively 54% (35-72%) and 100% (95-100%) for the ADC data, and 59% (39-77%) and 74% (63-83%) for the DCE data. When both ADC and DCE results were combined, the sensitivity increased to 87% (68-95%) and specificity decreased to 74% (62-83%). CONCLUSION: All but two DW- and DCE-MRI parameters showed significant differences between tumor and normal prostate. Combining both techniques provides better sensitivity, with a small decrease in specificity.

Aged↗

PubMed2005

A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer.

BACKGROUND: Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance. OGX-011 is a 2'-methoxyethyl modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA and has been reported to inhibit clusterin expression and enhance drug efficacy in xenograft models. The primary objective of this clinical study was to determine a biologically effective dose of OGX-011 that would inhibit clusterin expression in human cancer. METHODS: Subjects (n = 25) with localized prostate cancer with high-risk features who were candidates for prostatectomy were treated with OGX-011 by 2-hour intravenous infusion on days 1, 3, and 5 and then weekly from days 8-29 combined with androgen blockade starting on day 1; prostatectomy was performed on days 30-36. Six different doses were tested, from 40 to 640 mg. OGX-011 plasma and prostate tissue concentrations were measured by an enzyme-linked immunosorbent assay method, and the pharmacokinetics of OGX-011 were determined from these data. Prostate cancer tissue, lymph nodes, and serial samples of peripheral blood mononuclear cells were assessed for clusterin expression using quantitative real-time polymerase chain reaction and immunohistochemistry. All statistical tests were two-sided. RESULTS: Only grade 1 and 2 toxicities were observed. The plasma half-life of OGX-011 was approximately 2-3 hours, and the area under the concentration versus time curve and CMAX (peak plasma concentration) increased proportionally with dose (Ptrend < .001). OGX-011 in prostate tissue increased with dose (Ptrend < .001). Dose-dependent decreases in prostate cancer and lymph node clusterin expression were observed by polymerase chain reaction of greater than 90% (Ptrend = .008 and Ptrend < .001, respectively) and by immunohistochemistry (Ptrend < .001 and Ptrend = .01, respectively). CONCLUSIONS: OGX-011 is well tolerated and reduces clusterin expression in primary prostate tumors. The optimal biologic dose for OGX-011 at the schedule used is 640 mg.

Aged↗

PubMed2005

Serial tumour blood-flow measurements in androgen-dependent and -independent Shionogi tumour models.

OBJECTIVE: To investigate the relationship between blood supply and hormonal status of hormone-dependent and -independent tumours in mice. MATERIALS AND METHODS: Contrast-enhanced dynamic magnetic resonance imaging (MRI) was used to measure tumour blood flow (TBF) in Shionogi tumours implanted subcutaneously in mice. Serial measurements were taken throughout the initial tumour growth period, and during regression and subsequent androgen-independent (AI) relapse of the tumours in male mice, and throughout the growth of AI tumours in female mice. Average TBF values and coefficients of variation were calculated from tumour tissue perfusion maps reconstructed from MRI data. The Tukey-Kramer test was used to identify differences between androgen-dependent (AD), male AI and female AI tumours. RESULTS: The mean TBF strongly depended on tumour size in all three stages of the tumour growth cycle. AI tumours had a significantly higher TBF than AD tumours, with mean (sd) values of 0.8 (0.3) (male AI) and 0.27 (0.1) mL/g/min (AD), (P < 0.001), and 0.61 (0.31) (female AI) and 0.27 (0.1) mL/g/min (AD) (P < 0.01), respectively. Tumour tissue perfusion was more homogenous in AI than in AD tumours, with a coefficient of variation of 0.91 (0.31) in male AI and 1.89 (0.48) in AD tumours (P < 0.001), and 1.47 (0.38) in female AI and 1.89 (0.48) in AD tumours (P < 0.05). CONCLUSIONS: AI Shionogi tumours have a higher TBF than AD tumours; this could have implications in the diagnosis, prognosis, therapy and monitoring of hormone-sensitive tumours.

Animals↗

PubMed2004

A survey of urological manpower, technology, and resources in Canada.

INTRODUCTION: Knowledge of the current status of manpower and resources is important in understanding the state of any medical specialty, and critical in planning for future recruitment, funding and infrastructure development. METHODS: In 2003, the Canadian Urological Association (CUA) conducted two nationwide surveys examining manpower, resources, and the technology available. One survey went only to academic and hospital leaders across the country (the resources survey), while the other was sent to the entire general membership of the CUA. RESULTS: The response rate for the resources survey was 67%, while that for the membership survey was 50.4%. The respondents' ages were evenly distributed, with the modal 5-year range being 51 to 55 years of age. Eighty-eight percent of respondents were Canadian-trained. Two-thirds of respondents spent over 80% of their practice time in direct patient care, and most practiced general urology. The majority of respondents practiced in smaller hospitals: 57.6% in centres with 300 or fewer inpatient beds, and 47.2% of centres reported < 500 procedures/year. Community hospitals (62% of responses to the resources survey) generally had fewer advanced technologies than academic centres. A quarter of the cystoscopy equipment used by respondents was over 15 years old. CONCLUSIONS: The results of these surveys present a snapshot of the current state of urology resources and manpower across Canada, potentially allowing better planning and negotiations with hospitals and governments.

Biomedical Technology↗

PubMed2003

Intermittent androgen suppression in prostate cancer: an update of the Vancouver experience.

INTRODUCTION: This report will review the long-term follow-up of a prospective Phase II evaluation of intermittent androgen suppression in the treatment of prostate cancer. Specifically, this analysis will address completed cycle characteristics, the concept of prolonged off-treatment cycles, the time to cancer progression, cancer-specific survival and the association between PSA and bone scan changes. METHODS: A total of 102 patients have been entered into this protocol. Treatment was initiated with combined androgen blockade and continued for 6 months or longer to reach a serum PSA nadir. Medication was then withheld until the serum PSA increased to predetermined trigger points based on initial parameters. Each cycle of treatment and no-treatment was repeated until the regulation of PSA became biochemically androgen independent. RESULTS: One hundred two patients have been commenced on IAS with an average follow-up time of 219 weeks (range: 14.5 to 588). Ninety-one patients have completed at least one therapeutic cycle with a total of 188 completed cycles available for analysis. The average time off therapy (percentage time off therapy) for cycles 1, 2, 3 and 4 was 13 months (53%), 11 months (51%), 10 months (47%) and 8 months (45%), respectively. A prolonged off-treatment time of greater than 72 weeks was observed in 33 (18%) of all completed cycles, and was most common in the men being treated for radiation failure stage C. Progression and survival data was calculated for the entire trial cohort (n=102). The average time to androgen independent progression in the 29 (28%) patients who progressed was 194 weeks. Death from prostate cancer occurred in 19 (18%) patients at an average of 258 weeks following treatment initiation. A review of bone scans revealed 22 events of newly detected lesions, all but 2 of which were preceded by a rise in serum PSA. CONCLUSIONS: Longer duration follow-up of a single cohort continues to support IAS as a viable treatment option for men with prostate cancer. This approach affords an improved quality of life when the patient is off therapy, with reduced toxicity and costs. There is a trend toward extended times to progression and death compared to contemporary studies of continuous androgen suppression. Randomized, prospective protocols are currently underway to determine whether survival is affected in a beneficial or adverse way in men with locally recurrent or metastatic cancer.

Adult↗

PubMed2003

Implementation of a PDA based program to quantify urology resident in-training experience.

INTRODUCTION: There currently is no simple and reliable mechanism for Residency program directors to assess how well their trainees are being exposed to all spheres of their specialty. We report on the use of hand-held personal digital assistants (PDA's) to document all clinical and academic activities of urology residents at one academic institution. MATERIALS AND METHODS: Software was developed to create customized pick lists allowing residents to record all activities on their individual PDA's. Categories included Adult Ambulatory, Pediatric Ambulatory, Adult operative, Pediatric operative, and Academic. Activities were subcategorized into detailed pick lists and time-tracking fields. Residents synchronized with a central database on a standalone hotsync server. RESULTS: In the first 8 months, 21 178 resident-hours and 5333 activities were recorded. Preliminary observations can be made regarding how residents spend the majority of their time: 28% operative, 20% self-study, 19% ward work, 10% Academics, 6% ER consultations, 5% clinic, and 4% inpatient consultations. The most common adult diagnoses encountered while attending to clinic, ward, or ER consultations were lower urinary tract symptoms, urolithiasis and hematuria. Similarly for Pediatrics: neurogenic bladder, antenatal hydronephrosis, infection, and hypospadias were most often reported. Residents reported 5,333 activities, relating to the following spheres of Urology: academics (23%), endourology (18%), oncology (15%), lower urinary tract symptoms (10%), congenital anomalies (5%), urolithiasis (5%), reconstruction (5%), and infection (3%). CONCLUSIONS: This tool provides an objective assessment of resident experience as it relates to selection of rotations, and for addressing curriculum weaknesses. It is applicable at a national level for the study of regional differences in training experience, and trends in graduate Urological education. With minimal effort it could be modified for application to other specialty training programs.

Adult↗

PubMed2002

Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy.

INTRODUCTION AND OBJECTIVES: Progression of prostate cancer to androgen independence (AI) results in part from the upregulation of anti-apoptotic genes following androgen withdrawal, and androgen-independent disease remains the primary obstacle to improved survival. Testosterone-repressed prostate message-2 (TRPM-2) encodes the anti-apoptotic protein clusterin, which is upregulated in response to cellular compromise as observed in normal and malignant tissues undergoing apoptosis. Systemic administration of antisense clusterin oligonucleotides in prostate cancer xenograft models delays progression to AI and enhances chemosensitivity. The objective of this study was to define changes in clusterin expression following neoadjuvant hormone therapy (NHT) in prostate cancer patients. MATERIALS AND METHODS: Archival radical prostatectomy (RP) specimens were obtained for 128 patients who received either no NHT or treatment for 2-8 weeks, 3 months, or 8 months. Paired needle biopsy specimens were acquired for 30 patients and all tissues were subjected to clusterin immunohistochemistry. Western blot analysis was performed on frozen tissue from 5 untreated and 5 treated patients. RESULTS: Clusterin expression in malignant prostatic tissue was significantly greater in patients who underwent preoperative NHT (P < 0.001). Needle biopsies obtained prior to NHT consistently demonstrated lower staining intensity than corresponding RP specimens (P < 0.001). Western blot analysis confirmed clusterin levels increased 17-fold beginning within 4 weeks after androgen withdrawal. CONCLUSIONS: Upregulation of clusterin levels following androgen ablation therapy may represent an adaptive cell survival response following apoptotic signals like androgen withdrawal. These findings support clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced prostate cancer.

Adult↗

PubMed2002

Preoperative neoadjuvant androgen withdrawal therapy in prostate cancer: the Canadian experience.

The goal of radical prostatectomy is the complete removal of all cancer cells--no more, no less. Unfortunately, this is not always possible, especially in men with higher risk pathologic features. It is recognized that preoperative staging underestimates the extent of disease in < or =66% of cases, and that positive margin rates may be as high as 30% to 60%. Over the past 7 years in Canada, researchers have been investigating therapies that optimize the complete extirpation of all cancer cells with a minimum of morbidity and mortality. An example of this therapy is the combined modality approach of shrinking the prostate and tumor with androgen withdrawal therapy before surgical removal. The availability of potent, reversible, and well-tolerated forms of medical castration, and the sensitivity of serum prostate-specific antigen as a marker of response to therapy, makes neoadjuvant hormone therapy before localized therapy possible and appealing. In this article, we will review the Canadian experience, from the laboratory to the clinic.

Androgen Antagonists↗

PubMed2002

Intermittent androgen suppression in prostate cancer: the Canadian experience.

The role of androgen withdrawal is well established in the treatment of advanced prostate cancer. In metastatic cancer the response rate is 70% to 80%, with a median duration of progression-free survival of 12 to 33 months and a median duration of overall survival of 23 to 37 months. There are limitations to the continuous use of androgen withdrawal therapy, including significant adverse effects with long-term use. More significantly, the cell death process induced by androgen ablation fails to eliminate the entire malignant cell population; recurrent tumors are characterized by androgen-independent growth. The concept of intermittent androgen suppression proposes that the maintenance of apoptotic potential by successive rounds of androgen withdrawal and replacement might forestall tumor progression. Intermittent therapy offers quality-of-life benefits during the off-therapy period, as well as reduced cost of treatment. This article will review the >15 years of Canadian experience with intermittent androgen suppression.

Androgen Antagonists↗

PubMed2002

Pathologic effects of neoadjuvant cyproterone acetate on nonneoplastic prostate, prostatic intraepithelial neoplasia, and adenocarcinoma: a detailed analysis of radical prostatectomy specimens from a randomized trial.

Neoadjuvant hormonal therapy (NHT; androgen ablation) is used prior to radical prostatectomy (RP) in an attempt to pathologically "downstage" prostatic adenocarcinoma and ultimately to improve disease-free survival. This study describes the pathologic effects of NHT with the antiandrogen cyproterone acetate, 300 mg/day for 12 weeks, on the RP specimens from men with clinically localized (stage T1 or T2) prostatic adenocarcinoma. There were 101 men in the pretreatment group (CPA) and 91 men in a control group who were treated with surgery alone. The prevalence and extent of morphologic effects were recorded for the nonneoplastic prostate, high-grade prostatic intraepithelial neoplasia, and invasive adenocarcinoma. The commonest effects on the nonneoplastic prostate were atrophy and basal cell hyperplasia and prominence. High-grade prostatic intraepithelial neoplasia was more commonly identified in the surgery alone group than the CPA group (p <0.01). In the CPA group, flat and low tufted patterns of high-grade prostatic intraepithelial neoplasia predominated. Following NHT, the adenocarcinoma showed characteristic morphologic alterations, including reduction in cytoplasmic quantity, cytoplasmic vacuolation, nuclear pyknosis, reduced gland diameter, and mucinous breakdown. In many cases there was prominence of collagenous stroma, obscuring malignant glands. Compared with the surgery alone group, the CPA group RP specimens had a significantly lower mean specimen weight (40.3 g vs 46.5 g, p = 0.025) and less tumor extent by several measures. Organ-confined tumor (stage pT2, margin negative) was found in 41.6% of the CPA group compared with 19.8% of the surgery alone group (p = 0.0017). The overall rate of margin positivity was lower in the CPA group (27.7% vs 64.8%, p = 0.001). We consider that the difference in margin positivity is the result of tumor shrinkage with a decreased likelihood of sampling in routine sections. There was no significant difference in the rate of extraprostatic extension between the two groups. There was elevation of the Gleason score in the RP specimens versus baseline biopsy in 60% of the CPA group compared with 33% of the surgery alone group (p = 0.02). The higher rate of elevation in the CPA group largely resulted from an increase in primary or secondary Gleason score 5 tumor, a morphologic artifact introduced by NHT. Because of this, we recommend not giving a Gleason grade to RP specimens following NHT. Monotherapy with CPA has similar pathologic effects on benign and malignant prostate tissue as does dual agent androgen blockade. Prolonged follow-up of these patients is required to determine if NHT with CPA leads to improved disease-free survival.

Adenocarcinoma↗

PubMed2002

Assessing information and decision preferences of men with prostate cancer and their partners.

The purpose of this study was to identify and compare information and decision preferences of men with prostate cancer and their partners at the time of diagnosis. A convenience sample of 80 couples was recruited from The Prostate Centre in Vancouver, Canada. Participants used a computerized version of two previously used measures with this population: Control Preferences Scale and Information Survey Questionnaire. Results showed that men had a preference to play either an active or a collaborative role in decision making with their physician (92.5%) and partners (100%). The majority (55%) of partners wanted to play a collaborative role in treatment decision making. Couples identified prognosis, stage of disease, treatment options, and side effects as the top 4 information preferences. Men ranked information on sexuality more important than partners, and partners ranked information on home self-care higher than men. Men who had sons, a positive family history, and lower levels of education ranked heredity risk significantly higher. Profiles of information categories did not differ according to role preferences of either men or partners. The computer program has been shown to be a reliable and acceptable method of assessing information and decision preferences of these couples. An individualized approach is suggested, given the high reliability of individual's profiles.

Adult↗

PubMedDate not supplied

Provision of individualized information to men and their partners to facilitate treatment decision making in prostate cancer.

PURPOSE/OBJECTIVES: To determine if providing individualized information to men who are newly diagnosed with prostate cancer and their partners would lower their levels of psychological distress and enable them to become more active participants in treatment decision making. DESIGN: Quasiexperimental, one group, pretest/post-test. SETTING: The Prostate Centre at Vancouver General Hospital in British Columbia, Canada. SAMPLE: Convenience sample of 74 couples. 73 men had early-stage prostate cancer. Mean age of the men was 62.2 years, and mean age of the partners was 58.1 years. The majority (> 50%) had received their high school diplomas. METHODS: Respondents completed measures of decision preferences and psychological distress at the time of diagnosis and four months later. All participants used a computer to identify their information and decision preferences. Computer-generated, graphic printouts were used to guide the information counseling session. FINDINGS: Patients reported assuming a more active role in medical decision making than originally intended, partners assumed a more passive role in decision making than originally intended, and all participants had lower levels of psychological distress at four months. CONCLUSIONS: Evidence supports the need to provide informational support to couples at the prostate cancer diagnosis to facilitate treatment decision making and lower levels of psychological distress. Future research is needed to evaluate this type of approach in the context of a randomized clinical trial design. IMPLICATIONS FOR NURSING: The personalized, computer-graphic printouts can provide clinicians with an innovative method of guiding information counseling and providing decisional support to men with prostate cancer and their partners.

Adaptation, Psychological↗