John Trachtenberg

Combined T2-Weighted and Diffusion-Weighted MRI for Localization of Prostate Cancer

OBJECTIVE The objective of our study was to compare T2-weighted MRI alone and T2 combined with diffusion-weighted imaging (DWI) for the localization of prostate cancer. SUBJECTS AND METHODS T2-weighted imaging and DWI (b value = 600 s/mm2) were performed in 49 patients before radical prostatectomy using an endorectal coil at 1.5 T in this prospective trial. The peripheral zone of the prostate was divided into sextants and the transition zone into left and right halves. T2 images alone and then T2 images combined with apparent diffusion coefficient (ADC) maps (T2 + DWI) were scored for the likelihood of tumor and were compared with whole-mount histology results. Fixed window and level settings were used to display the ADC maps. Only tumors with an area of more than 0.13 cm2 (> 4 mm diameter) and a Gleason score of > or = 6 were considered significant. The area under the receiver operating characteristic curve (A(z)) was used to assess accuracy. RESULTS In the peripheral zone, the A(z) value was significantly higher (p = 0.004) for T2 plus DWI (A(z) = 0.89) than for T2 imaging alone (A(z) = 0.81). Performance was poorer in the transition zone for both T2 plus DWI (A(z) = 0.78) and T2 (A(z) = 0.79). For the whole prostate, sensitivity was significantly higher (p < 0.001) with T2 plus DWI (81% [120/149]) than with T2 imaging alone (54% [81/149]), with T2 plus DWI showing only a slight loss in specificity compared with T2 imaging alone (84% [204/243] vs 91% [222/243], respectively). CONCLUSION Combined T2 and DWI MRI is better than T2 imaging alone in the detection of significant cancer (Gleason score > or = 6 and diameter > 4 mm) within the peripheral zone of the prostate.

Increasing Hospital Admission Rates for Urological Complications After Transrectal Ultrasound Guided Prostate Biopsy

PURPOSE Transrectal ultrasound guided prostate biopsy is widely used to confirm the diagnosis of prostate cancer. The technique has been associated with significant morbidity in a small proportion of patients. MATERIALS AND METHODS We conducted a population based study of 75,190 men who underwent a transrectal ultrasound guided biopsy in Ontario, Canada, between 1996 and 2005. We used hospital and cancer registry administrative databases to estimate the rates of hospital admission and mortality due to urological complications associated with the procedure. RESULTS Of the 75,190 men who underwent transrectal ultrasound biopsy 33,508 (44.6%) were diagnosed with prostate cancer and 41,682 (55.4%) did not have prostate cancer. The hospital admission rate for urological complications within 30 days of the procedure for men without cancer was 1.9% (781/41,482). The 30-day hospital admission rate increased from 1.0% in 1996 to 4.1% in 2005 (p for trend <0.0001). The majority of hospital admissions (72%) were for infection related reasons. The probability of being admitted to hospital within 30 days of having the procedure increased 4-fold between 1996 and 2005 (OR 3.7, 95% CI 2.0-7.0, p <0.0001). The overall 30-day mortality rate was 0.09% but did not change during the study period. CONCLUSIONS The hospital admission rates for complications following transrectal ultrasound guided prostate biopsy have increased dramatically during the last 10 years primarily due to an increasing rate of infection related complications.

Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer

The prostate-specific gene, TMPRSS2 is fused with the gene for the transcription factor ERG in a large proportion of human prostate cancers. The prognostic significance of the presence of the TMPRSS2:ERG gene fusion product remains controversial. We examined prostate cancer specimens from 165 patients who underwent surgery for clinically localised prostate cancer between 1998 and 2006. We tested for the presence of TMPRSS2:ERG gene fusion product, using RT–PCR and direct sequencing. We conducted a survival analysis to determine the prognostic significance of the presence of the TMPRSS2:ERG fusion gene on the risk of prostate cancer recurrence, adjusting for the established prognostic factors. We discovered that the fusion gene was expressed within the prostate cancer cells in 81 of 165 (49.1%) patients. Of the 165 patients, 43 (26.1%) developed prostate-specific antigen (PSA) relapse after a mean follow-up of 28 months. The subgroup of patients with the fusion protein had a significantly higher risk of recurrence (58.4% at 5 years) than did patients who lacked the fusion protein (8.1%, P<0.0001). In a multivariable analysis, the presence of gene fusion was the single most important prognostic factor; the adjusted hazard ratio for disease recurrence for patients with the fusion protein was 8.6 (95% CI=3.6–20.6, P<0.0001) compared to patients without the fusion protein. Among prostate cancer patients treated with surgery, the expression of TMPRSS2:ERG fusion gene is a strong prognostic factor and is independent of grade, stage and PSA level.

The Uncertainty Of Radio Frequency Treatment Of Renal Cell Carcinoma: Findings At Immediate And Delayed Nephrectomy

PURPOSE Radio frequency thermal therapy for the ablation of renal cell carcinoma has been reported. Outcomes are usually measured by imaging alone. We have performed ex vivo and in vivo experiments using radio frequency in porcine models in our laboratory. We now report our early experience in the treatment of renal cell carcinoma in patients who underwent post-radio frequency radical or partial nephrectomy. MATERIALS AND METHODS We treated 10 patients diagnosed with small renal masses with radio frequency. All masses were biopsied before treatment. In 4 patients 5 renal cell carcinomas were treated with radio frequency after surgical exposure of the tumor followed immediately by partial or radical nephrectomy (acute group). Six other patients were treated percutaneously with ultrasound or computerized tomography guided radio frequency under local anesthesia and intravenous sedation 7 days before partial or radical nephrectomy (delayed group). A median of 2 radio frequency cycles was applied. Mean total heating time was 17 minutes 15 seconds. Specimens were analyzed grossly and histologically. Triphasic contrast-enhanced computerized tomography and/or magnetic resonance imaging was performed before and 7 days after radio frequency treatment in the delayed group. RESULTS Mean radiological largest diameter of all 11 masses was 2.4 cm. and mean gross diameter was 2.2 cm. Pathological examination demonstrated residual viable tumor in approximately 5% of the volume in 4 of the 5 tumors in the acute group and in 3 of the 6 masses of the delayed group. In 1 delayed case the viable tumor appeared to be in contact with the renal vein. No significant complications were observed in 9 of the 10 patients. In 1 delayed case, a subcapsular hepatic hematoma, biliary fistula and pneumonia developed and resolved. CONCLUSIONS Based on our experience, we continue to consider percutaneous radio frequency for the treatment of small renal cell carcinomas as a potentially curative therapy. However, complete tumor cell death appears to be difficult to achieve with our current treatment protocol. More phase II testing is indicated to ensure that this technique is an effective and reproducible treatment alternative.

The Role of Focal Therapy in the Management of Localised Prostate Cancer: A Systematic Review

Context The incidence of localised prostate cancer is increasing worldwide. In light of recent evidence, current, radical, whole-gland treatments for organ-confined disease have being questioned with respect to their side effects, cancer control, and cost. Focal therapy may be an effective alternative strategy. Objective To systematically review the existing literature on baseline characteristics of the target population; preoperative evaluation to localise disease; and perioperative, functional, and disease control outcomes following focal therapy. Evidence acquisition Medline (through PubMed), Embase, Web of Science, and Cochrane Review databases were searched from inception to 31 October 2012. In addition, registered but not yet published trials were retrieved. Studies evaluating tissue-preserving therapies in men with biopsy-proven prostate cancer in the primary or salvage setting were included. Evidence synthesis A total of 2350 cases were treated to date across 30 studies. Most studies were retrospective with variable standards of reporting, although there was an increasing number of prospective registered trials. Focal therapy was mainly delivered to men with low and intermediate disease, although some high-risk cases were treated that had known, unilateral, significant cancer. In most of the cases, biopsy findings were correlated to specific preoperative imaging, such as multiparametric magnetic resonance imaging or Doppler ultrasound to determine eligibility. Follow-up varied between 0 and 11.1 yr. In treatment-naïve prostates, pad-free continence ranged from 95% to 100%, erectile function ranged from 54% to 100%, and absence of clinically significant cancer ranged from 83% to 100%. In focal salvage cases for radiotherapy failure, the same outcomes were achieved in 87.2–100%, 29–40%, and 92% of cases, respectively. Biochemical disease-free survival was reported using a number of definitions that were not validated in the focal-therapy setting. Conclusions Our systematic review highlights that, when focal therapy is delivered with intention to treat, the perioperative, functional, and disease control outcomes are encouraging within a short- to medium-term follow-up. Focal therapy is a strategy by which the overtreatment burden of the current prostate cancer pathway could be reduced, but robust comparative effectiveness studies are now required.

Image Guided Photothermal Focal Therapy for Localized Prostate Cancer: Phase I Trial

PURPOSE We ascertained the feasibility and safety of image guided targeted photothermal focal therapy for localized prostate cancer. MATERIALS AND METHODS Twelve patients with biopsy proven low risk prostate cancer underwent interstitial photothermal ablation of the cancer. The area of interest was confirmed and targeted using magnetic resonance imaging. Three-dimensional ultrasound was used to guide a laser to the magnetic resonance to ultrasound fused area of interest. Target ablation was monitored using thermal sensors and real-time Definity contrast enhanced ultrasound. Followup was performed with a combination of magnetic resonance imaging and prostate biopsy. Validated quality of life questionnaires were used to assess the effect on voiding symptoms and erectile function, and adverse events were solicited and recorded. RESULTS Interstitial photothermal focal therapy was technically feasible to perform. Of the patients 75% were discharged home free from catheter the same day with the remainder discharged home the following day. The treatment created an identifiable hypovascular defect which coincided with the targeted prostatic lesion. There were no perioperative complications and minimal morbidity. All patients who were potent before the procedure maintained potency after the procedure. Continence levels were not compromised. Based on multicore total prostate biopsy at 6 months 67% of patients were free of tumor in the targeted area and 50% were free of disease. CONCLUSIONS Image guided focal photothermal ablation of low risk and low volume prostate cancer is feasible. Early clinical, histological and magnetic resonance imaging responses suggest that the targeted region can be ablated with minimal adverse effects. It may represent an alternate treatment approach to observation or delayed standard therapy in carefully selected patients. Further trials are required to demonstrate the effectiveness of this treatment concept.

Androgen-dependent cell cycle arrest and apoptotic death in PC-3 prostatic cell cultures expressing a full-length human androgen receptor

To assess the function of androgen receptor in androgen-independent prostate cancer cells, human PC-3 prostate carcinoma cells, which lack androgen receptor (AR) expression, were transfected with a full length human AR cDNA sequence inserted into an episomal expression vector system. Several clonal lines of transfected cells expressing varying levels of a 110 kDa AR, as determined by immunoblotting and ligand binding assay, were isolated. The expressed ectopic receptors displayed nuclear binding following androgen treatment and mediated androgen inducibility of a mouse mammary tumor virus (MMTV)-luciferase reporter gene construct in a dose-dependent manner. 5 alpha-dihydrotestosterone (DHT) activation of luciferase activity was blocked by the AR antagonist hydroxyflutamide, and was promoter-specific based on the inability of the hormone-insensitive RSV promoter to respond to DHT. Treatment of AR-expressing PC-3 cells with physiological levels of DHT for 3 days resulted in paradoxical inhibition of cell growth. The growth-inhibitory effect was observed in clonal lines expressing low, moderate and high levels of AR, indicating that it was not the result of AR overexpression. To determine whether AR-expressing PC-3 cells had become androgen dependent, albeit with slowed growth, the effect of 1.0 nM DHT on the growth of two clonal lines expressing low and moderate receptor levels (PC-3(AR)13 and PC-3(AR)2, respectively) was examined on over an 18 day period. DHT removed after 3, 6, or 9 days and replaced with steroid-free medium. Surprisingly, after 6 days of DHT treatment, the number of PC-3(AR)2 cells began to decrease such that all cells were dead by 15 days after initiation of DHT treatment. A similar effect was observed in PC-3(AR)13 cells, but required a longer initial period of DHT exposure. PC-3(AR)2 cells were rescued from cell death if DHT was withdrawn 3 days but not 6 or 9 days after initiation of DHT treatment. As determined by DNA cell cycle analysis, the proportion of cells in the G1 phase was enhanced by DHT treatment, accompanied by a decrease in cells in the S and G2M phase of the cell cycle. After 6 days of DHT treatment, the proportion of cells in G1 decreased which was accompanied by an increase in cells in a subG1 population consistent with apoptosis. DNA fragmentation in PC-3(AR)2 cells after 3 or 6 days of DHT treatment was demonstrated by agarose gel electrophoresis, further indicating the cell death was apoptotic. Removal of DHT from PC-3(AR)2 cultures after 3 days, but not after 6 or 9 days, was followed by a large shift in cells from G1 to S and G2M. These data suggest that DHT blocks the progression of AR transfected PC-3 cells through the cell cycle, resulting in growth inhibition and apoptosis.

Prostate Tissue Composition and MR Measurements: Investigating the Relationships between ADC, T2, Ktrans, ve, and Corresponding Histologic Features

PURPOSE To investigate relationships between magnetic resonance (MR) imaging measurements and the underlying composition of normal and malignant prostate tissue. MATERIALS AND METHODS Twenty-four patients (median age, 63 years; age range, 44-72 years) gave informed consent to be examined for this research ethics board-approved study. Before undergoing prostatectomy, patients were examined with T2-weighted, diffusion-weighted, T2 mapping, and dynamic contrast material-enhanced MR imaging at 1.5 T. Maps of apparent diffusion coefficient (ADC), T2, volume transfer constant (K(trans)), and extravascular extracellular space (v(e)) were calculated. Whole-mount hematoxylin-eosin-stained sections were generated and digitized at histologic resolution. Percentage areas of tissue components (nuclei, cytoplasm, stroma, luminal space) were measured by using image segmentation. Corresponding regions on MR images and histologic specimens were defined by using anatomically defined segments in peripheral zone (PZ) and central gland tissue. Cancer and normal PZ regions were identified at histopathologic analysis. Each MR parameter-histologic tissue component pair was assessed by using linear mixed-effects models, and cancer versus normal PZ values were compared by using nonparametric tests. RESULTS ADC and T2 were inversely related to percentage area of nuclei and percentage area of cytoplasm and positively related to percentage area of luminal space (P < or = .01). These trends were reversed for K(trans) (P < .001). K(trans) had a significantly negative (P = .01) slope versus percentage area of stroma, and v(e) had a positive (P = .008) slope versus percentage area of stroma. The v(e) was inversely proportional to the percentage area of nuclei (P = .05). All MR imaging parameters (P < or = .05) and the percentage areas of all tissue components (P < or = .001) except stroma (P > .48) were significantly different between cancer and normal PZ tissue. CONCLUSION MR imaging-derived parameters measured in the prostate were significantly related to the proportion of specific histologic components that differ between normal and malignant PZ tissue. These relationships may help define imaging-related histologic prognostic parameters for prostate cancer.

Do Older Men Benefit From Curative Therapy of Localized Prostate Cancer

PURPOSE Prior decision-analytic models are based on outdated or suboptimal efficacy, patient preference, and comorbidity data. We estimated life expectancy (LE) and quality-adjusted life expectancy (QALE) associated with available treatments for localized prostate cancer in men aged >/= 65 years, adjusting for Gleason score, patient preferences, and comorbidity. METHODS We evaluated three treatments, using a decision-analytic Markov model: radical prostatectomy (RP), external beam radiotherapy (EBRT), and watchful waiting (WW). Rates of treatment complications and pretreatment incontinence and impotence were derived from published studies. We estimated treatment efficacy using three data sources: cancer registry cohort data, pooled case series, and modern radiotherapy studies. Utilities were obtained from 141 prostate cancer patients and from published studies. RESULTS For men with well-differentiated tumors and few comorbidities, potentially curative therapy (RP or EBRT) prolonged LE up to age 75 years but did not improve QALE at any age. For moderately differentiated cancers, potentially curative therapy resulted in LE and QALE gains up to age 75 years. For poorly differentiated disease, potentially curative therapy resulted in LE and QALE gains up to age 80 years. Benefits of potentially curative therapy were restricted to men with no worse than mild comorbidity. When cohort and pooled case series data were used, RP was preferred over EBRT in all groups but was comparable to modern radiotherapy. CONCLUSION Potentially curative therapy results in significantly improved LE and QALE for older men with few comorbidities and moderately or poorly differentiated localized prostate cancer. Age should not be a barrier to treatment in this group.

Assessing individual risk for prostate cancer.

PURPOSE To construct a clinical nomogram instrument to estimate individual risk for having prostate cancer (PC) for patients undergoing prostate specific antigen (PSA) screening, using all risk factors known for PC. PATIENTS AND METHODS We conducted a cross-sectional study of 3,108 men who underwent a prostate biopsy, including a subset of 408 volunteers with normal PSA levels. Factors including age, family history of PC (FHPC), ethnicity, urinary symptoms, PSA, free:total PSA ratio, and digital rectal examination (DRE) were incorporated in the model. A nomogram was constructed to assess risk for any and high-grade PC (Gleason score >or= 7). RESULTS Of the 3,108 men, 1,304 (42.0%) were found to have PC. Among the 408 men with a normal PSA (< 4.0 ng/mL), 99 (24.3%) had PC. All risk factors were important predictors for PC by multivariate analysis (P, .01 to .0001). The area under the curve (AUC) for the nomogram in predicting cancer, which included age, ethnicity, FHPC, urinary symptoms, free:total PSA ratio, PSA, and DRE, was 0.74 (95% CI, 0.71 to 0.81) and 0.77 (95% CI, 0.74 to 0.81) for high-grade cancer. This was significantly greater than the AUC that considered using the conventional screening method of PSA and DRE only (0.62; 95% CI, 0.58 to 0.66 for any cancer; 0.69; 95% CI, 0.65 to 0.73 for high-grade cancer). From receiver operating characteristic analysis, risk factors including age, ethnicity, FHPC, symptoms, and free:total PSA ratio contributed significantly more predictive information than PSA and DRE. CONCLUSION In a PC screening program, it is important to consider age, family history of PC, ethnicity, urinary voiding symptoms, and free:total PSA ratio, in addition to PSA and DRE.