Biomedical subjects

J Trachtenberg

Publications and source records attributed to J Trachtenberg.

At least 19 recordsLinked to original sources

PubMed2005

Risk factors for disease progression in patients with lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH): a systematic analysis of expert opinion.

Disease progression has become an important issue for the management of lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH). Although several risk factors have been identified, no specific patient risk profiles have been established that can be useful in the day-to-day management of LUTS/BPH. In this study, an international panel of urologists developed a risk classification based on the attribution of a risk score to 243 unique patient profiles. From the perspective of clinical decision making, it was concluded that postvoid residual, symptom severity and maximum flow rate are the most relevant determinants of the risk of disease progression.

Disease Progression↗

PubMed2005

Integrating risk profiles for disease progression in the treatment choice for patients with lower urinary tract symptoms/benign prostatic hyperplasia: a combined analysis of external evidence and clinical expertise.

The RAND appropriateness method was used to explore the relevance of risk factors for disease progression in the treatment choice for patients with lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH). A total of, 12 international experts assessed the appropriateness of various treatments for 243 risk profiles. Highest appropriateness rates were found for alpha1-adrenoceptor antagonists (68% of profiles) and combination therapy (46%). A large prostate volume was the dominant argument in favour of 5alpha-reductase inhibitors and combination therapy, but was irrelevant for the choice of surgery. Considerable postvoid residual, severe symptoms and poor maximum flow rate were the most important factors in favour of surgery.

Disease Progression↗

PubMed2005

6-Hydroxydopamine-induced alterations in blood-brain barrier permeability.

Vascular inflammation is well known for its ability to compromise the function of the blood--brain barrier (BBB). Whether inflammation on the parenchymal side of the barrier, such as that associated with Parkinson's-like dopamine (DA) neuron lesions, similarly disrupts BBB function, is unknown. We assessed BBB integrity by examining the leakage of FITC-labeled albumin or horseradish peroxidase from the vasculature into parenchyma in animals exposed to the DA neurotoxin 6-hydroxydopamine (6OHDA). Unilateral injections of 6OHDA into the striatum or the medial forebrain bundle produced increased leakage in the ipsilateral substantia nigra and striatum 10 and 34 days following 6OHDA. Microglia were markedly activated and DA neurons were reduced by the lesions. The areas of BBB leakage were associated with increased expression of P-glycoprotein and beta 3-integrin expression suggesting, respectively, a compensatory response to inflammation and possible angiogenesis. Behavioural studies revealed that domperidone, a DA antagonist that normally does not cross the BBB, attenuated apomorphine-induced stereotypic behaviour in animals with 6OHDA lesions. This suggests that drugs which normally have no effect in brain can enter following Parkinson-like lesions. These data suggest that the events associated with DA neuron loss compromise BBB function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Interstitial microwave thermal therapy and its application to the treatment of recurrent prostate cancer.

Interstitial microwave thermal therapy may be an effective alternative to surgery for the treatment of some solid tumours. Arrays of helical antennae can produce complex heating patterns which when combined with active cooling of normal tissue structures can provide conformal heating for thermal coagulation of tumours. The development of a clinical protocol involving phantom and animal model studies, treatment planning, tissue property measurement and methods for on-line treatment monitoring is reviewed. The technology developed has been applied to the problem of recurrent prostate cancer following failed radiation treatment where available curative options are associated with high normal tissue morbidity. The purpose was to develop a treatment option for this group of patients with a very low side-effect profile that would not preclude further treatment if the disease progressed. Results of a Phase I/II trial demonstrate safety, promising efficacy and a low complication rate. As the technology for delivering this treatment matures, larger multi-institutional trials should be considered.

Humans↗

PubMed2004

Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer.

PURPOSE: In the prostate testosterone is converted to dihydrotestosterone (DHT) by the enzymes 5alpha-reductase (5alphaR) types 1 and 2 (5alphaR1 and 5alphaR2). Suppression of DHT formation by 5alphaR inhibition may be beneficial in early treatment or prevention of prostate cancer. Although 5alphaR2 is the dominant enzyme in the prostate, evidence indicates that 5alphaR1 may be up-regulated in some prostate cancers. This suggests that dual inhibition of both isoenzymes may be more effective than suppression of 5alphaR2 alone in prostate cancer treatment or prevention. In this short-term pilot study we examined the effect of the dual 5alphaR inhibitor dutasteride on markers of tumor regression. MATERIALS AND METHODS: A total of 46 men with clinically staged T1 or T2 prostate cancer were randomized to receive 5 mg per day of placebo or dutasteride for 6 to 10 weeks before radical prostatectomy. Resected tissues were analyzed to determine the effect of dutasteride on intraprostatic androgen levels, and indices of apoptosis and microvessel density (MVD) in malignant tissue, as well as degree of atrophy in benign tissue. RESULTS: Treatment with dutasteride caused a 97% decrease in intraprostatic DHT and was associated with a trend toward increased apoptosis. In patients receiving dutasteride for 45 days or more, a significant increase in apoptosis and a trend toward decreased MVD in prostate cancer tissue was observed. Dutasteride treatment was also associated with an 18% decrease in mean benign epithelial cell width compared with placebo (p < 0.0001). CONCLUSIONS: In this pilot study dutasteride treatment resulted in almost complete suppression of intraprostatic DHT, increased apoptosis and a trend toward decreased MVD. These findings suggest that short-term treatment with dutasteride can cause regression in some prostate cancers.

5-alpha Reductase Inhibitors↗

PubMed2002

Ultrasound properties of human prostate tissue during heating.

Changes in the ultrasound (US) properties of tissue during heating affect the delivery of US thermal therapy and may provide a basis for US image monitoring of thermal therapy. The US attenuation coefficient and backscatter power of fresh human prostate tissue were measured as the tissue was heated. Samples of human prostate were obtained directly from autopsies and heated rapidly to final temperatures of 45 degrees C, 50 degrees C, 55 degrees C, 60 degrees C and 65 degrees C. A 5.0-MHz transducer was scanned in a raster pattern over the tissue and radiofrequency (RF) data were collected at 36 uncorrelated positions. Both attenuation and backscatter were measured over the frequency range 3.5 to 7.0 MHz at each min of a 30-min heating. Little change was observed in attenuation or backscatter at 55 degrees C or less. The attenuation coefficient and backscatter power increased by factors of 1.25 and 5, respectively, during the 60 degrees C heating. During the 65 degrees C heating, the same properties showed increases by factors of 2.7 and 9.

Hot Temperature↗

PubMed2001

HPC2 variants and screen-detected prostate cancer.

Two studies have reported significant associations between susceptibility to prostate cancer and two common missense variants of the HPC2/ELAC2 gene, with estimated relative risks in the range of two- to threefold. We investigated whether these polymorphisms could be informative in the prediction of the presence of prostate cancer in men undergoing prostatic biopsy for the evaluation of an elevated serum-PSA level (> or = 4.0 ng/ml). We genotyped 944 men who underwent a prostate biopsy at our institution, as well as a control population of 922 healthy, unselected women from the same population. The prevalence of the HPC2 Ala541Thr allele was similar in men with prostate cancer (6.3%), men with other prostatic conditions (6.8%), and healthy women (6.3%) (P = .83). We conclude that HPC2 genotyping is unlikely to be a useful adjunct to PSA in the prediction of the presence of biopsy-detected prostate cancer in asymptomatic men.

Adenocarcinoma↗

PubMed2001

Interstitial microwave thermal therapy for prostate cancer: method of treatment and results of a phase I/II trial.

PURPOSE: Interstitial microwave thermal therapy is experimental treatment for prostate cancer with the goal of curing disease, while causing fewer complications than standard treatment options. We present a method for delivering interstitial microwave thermal therapy using microwave radiating helical antennae inserted percutaneously under transrectal ultrasound guidance. We report the results of a trial of this method in 25 patients in whom primary external beam radiation therapy had previously failed. This patient group currently has limited curative options that are associated with a high complication rate. However, these recurrent tumors often remain localized to the prostate, and so they may be amenable to localized therapy. MATERIALS AND METHODS: Patients with proved prostatic adenocarcinoma were candidates for treatment when prostate specific antigen (PSA) was 15 ng./ml. or less and prostate volume was 50 cc. or less. Followup included PSA measurement, digital rectal examination, urinalysis, and documentation of adverse events at 4, 8, 12 and 24 weeks. Sextant biopsy was performed at week 24. The procedure involved the insertion of 5 antennae percutaneously through a modified brachytherapy template. The antenna arrangement was determined based on computer simulated predictions of temperature throughout the prostate. The prostate was dissected away from the rectum by an injection of sterile saline to provide a thermal barrier that protected the rectum from thermal damage. Temperatures were monitored using interstitial mapping thermistor probes that were also inserted through the template. A minimum peripheral target temperature of 55C but less than 70C was maintained for 15 to 20 minutes, while the urethra, rectum and hydrodissection space remained below 42C. The urethra and rectum were actively cooled in addition to hydrodissection. RESULTS: Peripheral target temperatures of 55C were achieved. The urethra and rectum remained at a safe temperature. The procedure, including setup and treatment, required approximately 2.5 hours of operating room time. At 24 weeks the PSA nadir was 0.5 ng./ml. or less in 52% of patients and 0.51 to 4 ng./ml. was achieved in an additional 40%. The negative biopsy rate at 24 weeks was 64%, assuming that 3 patients lost to followup would have had positive results. No major complications were observed and in most cases minor complications resolved within 3 months. CONCLUSIONS: Interstitial microwave thermal therapy for prostate cancer was developed to heat the prostate safely to a cytotoxic temperature. Experience with 25 patients in whom external beam radiation therapy for prostate cancer had failed indicates that the treatment is safe. Although our series indicates that this therapy may be effective, further studies and longer followup are required in larger patient groups to confirm the potential role of this therapy as an option for recurrent and primary prostate cancer.

Aged↗

PubMed2001

V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate cancer presence and progression.

OBJECTIVES: The valine (V) to leucine (L) polymorphism of the SRD5A2 gene is associated with 5-alpha reductase-2 activity; patients with the V allele have high activity and patients with the L allele have low activity. We examined whether this polymorphism predicts the presence of prostate cancer in 320 men without cancer who underwent biopsy and cancer progression in 318 men who underwent radical prostatectomy. METHODS: The effect of the SRD5A2 gene in predicting the presence of prostate cancer was examined using logistic regression analysis, controlling for established risk factors. The effect of the SRD5A2 gene in predicting prostate cancer progression was examined using a nested, matched, case-control design. Most of the participants were white. RESULTS: Of the 320 men, 158 (49.4%) were found on biopsy to have prostate cancer. The overall distribution of the V/V, V/L, and L/L genotypes was 47.5%, 42.5%, and 10.0%, respectively. The adjusted odds ratio for having prostate cancer for patients with at least one V allele was 2.53 compared with patients with the L/L genotype (P = 0.03). Of the 318 patients with cancer, 80 had biochemically detected recurrence and 238 had no evidence of recurrence. The odds ratio for progression for patients with at least one V allele was 3.32 (95% confidence interval 1.67 to 6.62, P = 0.0006) compared with patients with the L/L genotype. CONCLUSIONS: Men who have the V allele of the SRD5A2 gene have a twofold increase in the risk of prostate cancer development and an additional twofold increase in the risk of progression compared with men with the L/L genotype.

Aged↗

PubMed2001

Levels of insulin-like growth factor I (IGF-I) and IGF binding proteins 2 and 3 in serial postoperative serum samples and risk of prostate cancer recurrence.

OBJECTIVES: To determine changes of insulin-like growth factor I (IGF-I), IGF binding protein-2 (IGFBP-2), and IGFBP-3 levels in serial postoperative serum samples from prostate cancer patients with and without relapse and to evaluate the prognostic value of these molecules in the recurrence of prostate cancer. METHODS: From a group of patients with prostate cancer who had been followed for disease recurrence for almost 5 years after radical prostatectomy, we selected 38 patients (cases) who developed recurrent disease and 40 patients (controls) who were in remission. Of these patients, 70 had 4 and 8 had 3 serial postoperative serum samples collected. The median times for serum collection after surgery were 1.5 years for the first serial samples, 2.6 years for the second, 3.5 years for the third, and 4.5 years for the fourth. Serum levels of IGFBP-2, IGFBP-3, and IGF-I were measured, using commercial immunoassay kits. RESULTS: The study showed lower serum levels of IGFBP-2 and IGFBP-3 in the cases than in controls(P <0.05) but no difference in IGF-I levels between the two groups (P = 0.277). In the sequential samples, IGFBP-2 levels increased over time in the controls (P = 0.014) but did not change in the cases (P = 0.528). There were no increasing or decreasing trends for IGF-I and IGFBP-3 in either case or control group(P >0.05). CONCLUSIONS: The study suggests that IGFBP-2 may play a role in the progression of prostate cancer, but serum levels of IGFBP-2 as well as IGF-I and IGFBP-3 have no predictive values in the prognosis of prostate cancer.

Biomarkers, Tumor↗

PubMed2001

Helical antenna arrays for interstitial microwave thermal therapy for prostate cancer: tissue phantom testing and simulations for treatment.

Interstitial microwave therapy is an experimental treatment for prostate cancer. The objective of this work was to measure the power deposition (specific absorption rate, SAR) patterns of helical microwave antennae both individually and in array patterns that would be useful for clinical treatment protocols. Commercial helical antenna 3D SAR patterns were measured in muscle equivalent phantoms using a thermographic technique. Two array patterns were tested: a 'square' and a 'crescent' array, both surrounding the urethra. To assess the feasibility of pre-treatment planning, the measured SAR patterns were input to a treatment planning computer simulation program based on a series of trans-rectal ultrasound images from a prostate cancer patient. The simulation solved the Pennes linear bioheat heat transfer equation in prostate tissue, with the aim of achieving a target of 55 degrees C at the prostate periphery while not allowing normal surrounding tissues (bladder, urethra, rectum) to rise above 42 C. These criteria could not be met with the square array but they could be met with the crescent array, provided that the prostate was first dissected away from the rectum. This can be done with a procedure such as 'hydrodissection', where sterile saline is injected to separate the prostate and rectum. The results of these SAR measurements and heat transfer simulations indicate that arrays of helical antennae could be used for safe and effective thermal therapy for prostate cancer.

Acrylic Resins↗

PubMed2001

Emerging pharmacologic therapies for prostate cancer.

The last decade has seen explosive growth in the therapy of prostate cancer. Three areas of therapeutics are emerging: 1) new compounds with novel uses; 2) available compounds with new applications; and 3) new compounds applied to established indications. The novel compounds target specific receptor sites of cancer pathways and attack cancer cells with less effect on normal tissue. Earlyphase trials with compounds targeting the endothelin-A and EGF receptors have shown encouraging results in hormone-refractory prostate cancer. In addition, the Early Prostate Cancer Trial of over 8000 men is currently underway to determine the benefit of adjuvant androgen ablation with bicalutamide in men with localized prostate cancer. Early results show a significant 42% reduction in the progression of the disease in the bicalutamide treatment arm. Further, in large, phase 3 clinical trials in patients needing androgen ablation, the GnRH antagonist abarelix caused no testosterone surge and demonstrated a significantly more rapid decline in serum testosterone to the castrate level than did an LHRH agonist analogue. Abarelix should thus have application as a monotherapy in patients who need a rapid onset of action or are at high risk of complications from the clinical flare seen with LHRH agonists. Abarelix also uniquely caused a sustained decline in serum FSH levels, which have been shown in vitro to stimulate prostate cancer cell growth. If these favorable effects can be duplicated in patients, abarelix might also offer a survival benefit.

Journal Article↗

PubMed2000

The clinical burden of prostate cancer in Canada: forecasts from the Montreal Prostate Cancer Model.

OBJECTIVES: The incidence of prostate cancer is increasing, as is the number of diagnostic and therapeutic interventions to manage this disease. We developed a Markov state-transition model--the Montreal Prostate Cancer Model--for improved forecasting of the health care requirements and outcomes associated with prostate cancer. We then validated the model by comparing its forecasted outcomes with published observations for various cohorts of men. METHODS: We combined aggregate data on the age-specific incidence of prostate cancer, the distribution of diagnosed tumours according to patient age, clinical stage and tumour grade, initial treatment, treatment complications, and progression rates to metastatic disease and death. Five treatments were considered: prostatectomy, radiation therapy, hormonal therapies, combination therapies and watchful waiting. The resulting model was used to calculate age-, stage-, grade- and treatment-specific clinical outcomes such as expected age at prostate cancer diagnosis and death, and metastasis-free, disease-specific and overall survival. RESULTS: We compared the model's forecasts with available cohort data from the Surveillance, Epidemiology and End Results (SEER) Program, based on over 59,000 cases of localized prostate cancer. Among the SEER cases, the 10-year disease-specific survival rates following prostatectomy for tumour grades 1, 2 and 3 were 98%, 91% and 76% respectively, as compared with the model's estimates of 96%, 92% and 84%. We also compared the model's forecasts with the grade-specific survival among patients from the Connecticut Tumor Registry (CTR). The 10-year disease-specific survival among the CTR cases for grades 1, 2 and 3 were 91%, 76% and 54%, as compared with the model's estimates of 91%, 73% and 37%. INTERPRETATION: The Montreal Prostate Cancer Model can be used to support health policy decision-making for the management of prostate cancer. The model can also be used to forecast clinical outcomes for individual men who have prostate cancer or are at risk of the disease.

Adult↗

PubMed2000

The economic burden of prostate cancer in Canada: forecasts from the Montreal Prostate Cancer Model.

BACKGROUND: We developed an economic model of prostate cancer management from diagnosis until death. We have used the Montreal Prostate Cancer Model to estimate the total economic burden of the disease in a cohort of Canadian men. METHODS: Using this Markov state-transition simulation model, we estimated the probability of prostate cancer, annual prostate cancer progression rates and associated direct medical costs according to patient age, tumour stage and grade, and treatment modalities in a 1997 cohort of Canadian men. The estimated lifetime costs of prostate cancer included the costs of clinical staging, initial treatments and complications, follow-up cancer therapies, routine outpatient care, and palliative care following metastatic disease. RESULTS: The clinical burden of prostate cancer forecasted using the model was similar to the projections of the National Cancer Institute. In the 1997 cohort of 5.8 million Canadian men between 40 and 80 years old, prostate cancer would be diagnosed in an estimated 701,491 men (12.1%) over their lifetime. Direct medical costs would total $9.76 billion, or $3.89 billion when discounted 5% annually. INTERPRETATION: The Montreal Prostate Cancer Model indicates that the economic burden of prostate cancer to Canada's health care system will be substantial. Further analyses are needed to identify the most efficient means of treating this disease.

Adult↗

PubMed2000

Magnetic resonance thermometry for predicting thermal damage: an application of interstitial laser coagulation in an in vivo canine prostate model.

Magnetic resonance image-guidance for interstitial thermal therapy has proven to be a valuable tool in its traditional role in device localization and, more recently, in monitoring heat deposition within tissue. However, a quantitative understanding of how temperature-time exposure relates to thermal damage is crucial if the predictive value of real-time MR thermal-monitoring is to be fully realized. Results are presented on interstitial laser coagulation of two canine prostate models which are shown to provide an opportunity to evaluate three models of thermal damage based on a threshold maximum temperature, an Arrhenius damage integral, and a temperature-time product. These models were compared to the resultant lesion margin as derived from post-treatment T(1)- and T(2)-weighted MR images, as well as from direct histological evaluation of the excised canine prostate. Histological evaluation shows that the thermal-injury boundary can be predicted from a threshold-maximum temperature of approximately 51 degrees C or an equivalent Arrhenius t(43) period of 200 minutes, but it is not reliably predicted using the temperature-time product. The methods described in this study are expected to have implications for the treatment of benign prostatic hyperplasia and prostate cancer with interstitial laser coagulation, which will be the focus of future human studies.

Animals↗

PubMed2000

Relapse and cure rates of prostate cancer patients after radical prostatectomy and 5 years of follow-up.

OBJECTIVES: We have compared the ability of an ultrasensitive prostate specific antigen assay and a regular PSA assay to identify relapse and cure rates of prostate cancer patients after radical prostatectomy, during a 5-year follow-up period. DESIGN AND METHODS: We measured PSA by an ultrasensitive assay (detection limit 0.001 ng/mL) and a conventional PSA assay (detection limit 0.1 ng/mL) in serial serum samples obtained from 197 patients who have undergone radical prostatectomy. RESULTS: Based on ultrasensitive PSA analysis, we have identified three groups of patients: 62% of patients did not show any significant changes in serum PSA; 15% of patients demonstrated slow PSA increases over time but none of the measurements exceeded 0.1 ng/mL within 4 years; and 23% of the patients had relatively significant increases of serum PSA and were classified as having 'fast relapse'. The vast majority of these patients were subsequently identified to have relapse by the regular PSA assay. The ultrasensitive PSA assay detected relapse by an average of eighteen months earlier than the conventional PSA method. Fast relapsing patients were associated with other prognostic indicators of the disease including pre-operative PSA, tumor volume, Gleason score, clinical stage, surgical margin positivity, periprostatic tissue involvement, capsular invasion and seminal vesicle invasion. The group with slowly rising PSA had prognosis which was between the patients in remission and fast relapsing patients. CONCLUSIONS: The use of ultrasensitive PSA analysis for monitoring patients after radical prostatectomy provides earlier detection of relapse (by 18 months) and identifies three distinct groups of patients. Fast relapsing patients should be good candidates for early therapeutic interventions.

Aged↗

PubMed2000

Construction of the Patient-Oriented Prostate Utility Scale (PORPUS): a multiattribute health state classification system for prostate cancer.

Health status indexes, such as the EuroQol, consist of a health state classification system and a set of utility weights. Indexes measure quality of life using a 0-1 utility score. Utilities for outcomes in prostate cancer (PC) are of unique importance, but generic indexes do not represent PC outcomes (e.g., sexual, urinary, bowel dysfunction) well, and may not capture their full impact. As a step toward improved utility measurement, we constructed a classification system for PC. We generated items for each of six health domains and rated their importance using interviews with 10 clinical experts and 80 patients. Key concepts were selected for each domain using item importance weightings, and a set of predetermined criteria. Text was developed to express levels of severity within each domain. Experts and two additional groups of patients (n = 40, n = 96) evaluated textual clarity and endorsed the content validity of the instrument. The final system consists of 10 domains with 4-6 levels each. The content validity of the system was endorsed by patients and experts. In conjunction with a set of utility weights, it may be used to develop a health status index, to improve utility measurement in patients, and to serve as a short psychometric (nonutility) instrument.

Health Status Indicators↗

PubMed2000

Prostate cancer: MR imaging and thermometry during microwave thermal ablation-initial experience.

Percutaneous interstitial microwave thermoablation of locally recurrent prostate carcinoma was continually guided with magnetic resonance (MR) imaging. Phase images and data were obtained with a rapid gradient-echo technique and were used to derive tissue temperature change on the basis of proton-resonance shift. Thermally devitalized regions correlated well with the phase image findings. MR imaging-derived temperatures were linearly related to the fluoroptic tissue temperatures. MR imaging can be used to guide thermoablation.

Aged↗