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Although not commonly available in Canada, cryosurgery (cryoablation) for prostate cancer has been practiced in many countries. The field of cryoablation has evolved significantly over the past 30 years. Two prostate cryoablation programs were started in Canada in the early 1990s, in London, ON and Calgary, AB, focusing, respectively, on salvage therapy following radiation failure and primary local treatment. This article chronicles the development of the two programs and outlines the scientific and clinical contributions by investigators at the two centers.

Introduction: Treatment decisions in localized prostate cancer are complicated by the available choices. A rapid-access cancer clinic (RAC) has been unique to Calgary, AB, since 2007. This RAC offers multidisciplinary prostate cancer education by a urologist, medical oncologist, and radiation oncologist. It is hypothesized that treatment utilization data from decisions taken at RAC may serve to benchmark the appropriateness of treatment decisions on a population level., Methods: Records of patients with clinically localized prostate cancer in Alberta between October 1, 2007 and September 30, 2009 were reviewed with ethics approval. Records were linked to the Alberta Cancer Registry database. Clinical, treatment, and health services characteristics pertaining to patients attending RAC were compared to the general population. The primary endpoint was utilization rates of each initial treatment., Results: During this two-year period, 2838 patients were diagnosed with localized prostate cancer; 375 attended RAC. The utilization rates among RAC patients vs. the whole Alberta population were: prostatectomy 60.3% (95% confidence interval [CI] 55.3-65.2) vs. 48.0% (95% CI 47.1-50.7; χ 2 p<0.001); active surveillance 16.0% (95% CI 12.3-19.7%) vs. 13.5% (95% CI 12.2-15.8; χ 2 p=0.214); radiotherapy 11.7% (95% CI 8.5-15.0) vs. 18.0% (95% CI 16.9-20.5; χ 2 p=0.002); and hormone therapy 8.0% (95% CI 5.2-10.8) vs. 17.4% (95% CI 16.1-18.9; χ 2 p<0.001)., Conclusions: A specialized clinic for localized prostate cancer may be associated with a higher likelihood of receiving surgery or active surveillance as initial treatment compared to the prostate cancer population in Alberta.

Patients presenting for knee replacement on warfarin for medical reasons often require higher levels of anticoagulation peri-operatively than primary thromboprophylaxis and may require bridging therapy with heparin. We performed a retrospective case control study on 149 consecutive primary knee arthroplasty patients to investigate whether anti-coagulation affected short-term outcomes. Specific outcome measures indicated significant increases in prolonged wound drainage (26.8% of cases vs 7.3% of controls, P<0.001); superficial infection (16.8% vs 3.3%, P<0.001); deep infection (6.0% vs 0%, P<0.001); return-to-theatre for washout (4.7% vs 0.7%, P=0.004); and revision (4.7% vs 0.3%, P=0.001). Management of patients on long-term warfarin therapy following TKR is particularly challenging, as the surgeon must balance risk of thromboembolism against post-operative complications on an individual patient basis in order to optimise outcomes., (Copyright © 2014. Published by Elsevier Inc.)

Background: Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence., Methods: Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization., Results: A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events., Conclusions: Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.).

Purpose: Frequent prostate specific antigen testing for screening and monitoring prostate cancer has led to significant stage migration. We evaluated whether overall survival in hormone naïve patients with metastatic prostate cancer has improved during the era of prostate specific antigen use. We also assessed whether any patient subsets benefited differentially during this period., Materials and Methods: We compared overall survival in 3 sequential phase III trials of 3,096 men with hormone naïve, metastatic prostate cancer who received similar androgen deprivation therapy, including 2 trials performed before the prostate specific antigen era (S8494 and S8894) and the other done during this era (S9346). Overall survival was adjusted for patient and disease risk factors in the latter 2 trials. Subgroups were evaluated by interactions of risk factors with trial., Results: Median overall survival was 30 months in S8494, 33 months in S8894 and 49 months in S9346. Adjusting for risk factors, there was a 22% lower risk of death in S9346 than in S8894 (HR 0.78, 95% CI 0.70, 0.87, p <0.001). The improvement in overall survival was greater in black American men (test of interaction p = 0.008). In S8494 and S8894 median survival for black men was 27 months, and 34 and 35 months for nonblack men, respectively. This racial difference disappeared in S9346 with overall survival of 48 and 49 months in black and nonblack men, respectively., Conclusions: Adjusting for risk factors, overall survival was significantly improved in the post-prostate specific antigen era trial. However, it cannot be concluded that this was attributable only to prostate specific antigen monitoring. Black men now have overall survival comparable to that of white men. Current estimates of survival should be used to design new trials in this population., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Screening for prostate cancer remains a contentious issue. As with other cancer screening programs, a key feature of the debate is verification of cancer-specific mortality reductions. Unfortunately the present evidence, two systematic reviews and six randomized controlled trials, have reported conflicting results. Furthermore, half of the studies are poor quality and the evidence is clouded by key weaknesses, including poor adherence to screening in the intervention arm or high rates of screening in the control arm. In high quality studies of prostate cancer screening (particularly prostate-specific antigen), in which actual compliance was anticipated in the study design, there is good evidence that prostate cancer mortality is reduced. The numbers needed to screen are at least as good as those of mammography for breast cancer and fecal occult blood testing for colorectal cancer. However, the risks associated with prostate cancer screening are considerable and must be weighed against the advantage of reduced cancer-specific mortality. Adverse events include 70% rate of false positives, important risks associated with prostate biopsy, and the serious consequences of prostate cancer treatment. The best evidence demonstrates prostate cancer screening will reduce prostate cancer mortality. It is time for the debate to move beyond this issue, and begin a well-informed discussion on the remaining complex issues associated with prostate cancer screening and appropriate management.

Introduction: It is believed that men diagnosed with prostate cancer and a low baseline serum testosterone (BST) may have more aggressive disease, and it is frequently recommended they forego testosterone replacement therapy. We used two large Phase III trials involving androgen deprivation therapy and external beam radiation therapy to assess the significance of a BST., Methods and Materials: All patients with a BST and complete data (n = 2,478) were included in this analysis and divided into four categories: "Very Low BST" (VLBST) ≤16.5th percentile of BST (≤248 ng/dL; n = 408); "Low BST" (LBST) >16.5th percentile and ≤33rd percentile (>248 ng/dL but ≤314 ng/dL; n = 415); "Average BST" (ABST) >33rd percentile and ≤67th percentile (314-437 ng/dL; n = 845); and "High BST" (HBST) >67th percentile (>437 ng/dL; n = 810). Outcomes included overall survival, distant metastasis, biochemical failure, and cause-specific survival. All outcomes were adjusted for the following covariates: treatment arm, BST, age (<70 vs. ≥70), prostate-specific antigen (PSA; <10 vs. 10 ≤ PSA <20 vs. 20 ≤), Gleason score (2-6 vs. 7 vs. 8-10); T stage (T1-T2 vs. T3-T4), and Karnofsky Performance Status (60-90 vs. 100)., Results: On multivariable analysis age, Gleason score, and PSA were independently associated with an increased risk of biochemical failure, distant metastasis and a reduced cause-specific and overall survival (p < 0.05), but BST was not., Conclusions: BST does not affect outcomes in men treated with external beam radiation therapy and androgen deprivation therapy for prostate cancer., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Localized prostate cancer can be treated several different ways, but head-to-head comparisons of treatments are infrequent. The authors of this report conducted a randomized, unblinded, noninferiority trial to compare cryoablation with external beam radiotherapy in these patients., Methods: From December 1997 through February 2003, 244 men with newly diagnosed localized prostate cancer were assigned randomly to receive either cryoablation or radiotherapy (122 men in each arm). All received neoadjuvant antiandrogen therapy. The primary endpoint was disease progression at 36 months based on a trifecta definition: 1) radiologic evidence of metastatic disease, or 2) initiation of further antineoplastic therapy, or 3) biochemical failure. Two definitions of biochemical failure were used: 1) 2 consecutive rises in prostate-specific antigen (PSA) with a final value >1.0 ng/mL, and 2) a rise above PSA nadir + 2 ng/mL. Secondary endpoints included overall survival, disease-specific survival, and prostate biopsy at 36 months., Results: The median follow-up was 100 months. Disease progression at 36 months was observed in 23.9% (PSA nadir + 2 ng/mL, 17.1%) of men in the cryoablation arm and in 23.7% (PSA nadir + 2 ng/mL, 13.2%) of men in the radiotherapy arm. No difference in overall or disease-specific survival were observed. At 36 months, more patients in the radiotherapy arm had a cancer-positive biopsy (28.9%) compared with patients in the cryoablation arm (7.7%)., Conclusions: The observed difference in disease progression at 36 months was small, 0.2%; however, because of the wide confidence interval, from -10.8% to 11.2%, it was not possible to rule out inferiority (defined a priori as a 10% difference). With longer term follow-up, the trend favors cryoablation. Significantly fewer positive biopsies were documented after cryoablation than after radiotherapy.

Purpose: We report contemporary outcomes of salvage cryoablation at a large number of centers which have participated in the COLD (Cryo On-Line Data) Registry., Materials and Methods: A secure online database was developed to collect data for patients undergoing prostate cryoablation. Kaplan-Meier analysis was performed with biochemical failure defined using the American Society of Therapeutic Radiology and Oncology, and the Phoenix definitions., Results: Data from 279 patients who had undergone salvage cryoablation were entered. Average patient age was 70.0 +/- 7.1 years. Pretreatment prostate specific antigen was 7.6 +/- 8.2 ng/ml and Gleason score was 7.5 +/- 1.1 (median 7). Patients were followed for 21.6 +/- 24.9 months and 47 were followed longer than 5 years. The 5-year actuarial biochemical disease-free rates were 58.9% +/- 5.7% (American Society of Therapeutic Radiology and Oncology) and 54.5% +/- 4.9% (Phoenix). As predicted based on the preservation of some prostatic tissue, 83% +/- 3.5% of patients had a detectable prostate specific antigen 0.2 ng/ml or greater at 5 years. Positive biopsies were observed in 15 of the 46 patients (32.6%) who underwent prostate biopsy after salvage cryotherapy. The incontinence rate (requiring pad use) was 4.4%. The rectal fistula rate was 1.2% and 3.2% of patients underwent transurethral prostate resection to remove sloughed tissue., Conclusions: Biochemical and local control rates support the use of salvage cryoablation for localized recurrence following failed radiation therapy. Efforts to continue to minimize these complications and to improve disease control in patients with persistent cancer following definitive radiotherapy should continue.

Purpose: We report the largest data set to date to our knowledge regarding outcomes for primary whole gland prostate cryoablation., Materials and Methods: The COLD (Cryo On-Line Data) Registry consists of case report forms obtaining pretreatment and posttreatment information for patients undergoing whole gland prostate cryoablation. A total of 1,198 patients were stratified into low, intermediate and high risk groups. Biochemical success was defined according to the traditional American Society for Therapeutic Radiology and Oncology definition (3 increases) and the newer (Phoenix) definition (nadir +2). Biopsy was performed at physician discretion but most commonly for cause if a patient had an increasing or suspicious prostate specific antigen., Results: Average patient age was 69.8 +/- 7.5 years. Pretreatment prostate specific antigen was 9.6 +/- 8.6 ng/ml and median Gleason sum was 7 (range 4 to 10). Patients were followed for 24.4 +/- 25.9 months with 136 having minimum 5-year data. The 5-year biochemical disease-free status for the entire population was 77.1% +/- 2.1% (American Society for Therapeutic Radiology and Oncology) and 72.9% +/- 2.1% (Phoenix). Five-year American Society for Therapeutic Radiology and Oncology biochemical disease-free status was 84.7% +/- 4.5%, 73.4% +/- 4.3% and 75.3% +/- 3.7% for the low, moderate and high risk groups, respectively. Using the Phoenix definition the biochemical disease-free status was 91.1% +/- 2.9%, 78.5% +/- 3.6% and 62.2% +/- 4.9%, respectively. As predicted based on intentional preservation of some prostatic tissue, 72.5 +/- 1.8% had a detectable prostate specific antigen 0.2 ng/ml or greater at 5 years. Biopsy after cryotherapy was positive during empiric without cause biopsy in 30 of 207 patients (14.5%), and the highly selected group biopsied based on suspicion of treatment failure due to abnormal or increasing prostate specific antigen had positive results in 38.0% (49 of 129). The rectal fistula rate was 0.4% and incontinence was 4.8% with 2.9% of patients using pads. Intercourse was reported by 25.2% but only 8.8% without pharmaceutical or device assistance., Conclusions: Whole gland cryoablation, practiced in a spectrum of academic and community users, maintains efficacy and morbidity similar to that of single center reports.

Purpose: Previous research has raised concerns that although salvage cryosurgery may be an effective treatment to prevent the progression of prostate cancer after radiotherapy failure, the quality of life cost many be so severe as to prevent its acceptance as a viable treatment. The present study's purpose was to further the understanding of the quality of life outcomes of salvage cryosurgery., Materials and Methods: A total of 46 men with locally recurrent prostate cancer after radiotherapy were recruited to participate in a prospective Phase II clinical trial using salvage cryosurgery. There were 2 questionnaires (i.e., the European Organization of Research and Treatment of Cancer QLQ C30 and the Prostate Cancer Index) administered before cryosurgery, and at 1.5, 3, 6, 12, 18, and 24 months after treatment., Results: Quality of life returned to preoperative levels by 24 months after cryosurgery in all domains, with the exception of urinary and sexual functioning. At 24 months, 29% of men reported urinary bother as a moderate-to-big problem, and 56% reported sexual bother as a moderate-to-big problem., Conclusions: To our knowledge, this is the first study to evaluate prospectively men's quality of life for 2 years after salvage cryosurgery for locally recurrent prostate cancer after radiotherapy. Long-term impairments in quality of life appear to be limited to the sexual and urinary function domains. Overall quality of life appears to be high. These results support salvage cryosurgery as a viable treatment option.

Despite improvements in treatment of localized prostate cancer, local recurrence remains a significant problem. A total of 46 patients with proven local cancer recurrence following external beam radiotherapy entered a prospective clinical trial using ultrasound-guided cryosurgery to ablate the residual prostate gland. Persistent complications included one urethra-rectal fistula, incontinence (2), retention (3), and treatment induced erectile dysfunction (7). Using the PSA definitions for biochemical failure as PSA>or=0.3 ng/ml, the Kaplan-Meier plots showed the incidence of patients to be free of biochemical recurrence at 51 and 44% at 1 and 2 y, respectively. For a PSA>or=1.0, the values at 1 and 2 y were 72 and 58%.

Purpose: To determine if nonenhancing tissue on gadolinium-enhanced magnetic resonance (MR) images obtained 3 weeks after cryoablation of the prostate helps reliably and accurately predict nonviable cryoablated tissue at 6-month biopsy., Materials and Methods: Fifty-four consecutive patients with prostate cancer who underwent cryoablation were followed up prospectively. Fifty-one underwent gadolinium-enhanced MR imaging at 3 weeks (three had gadolinium allergy); 49, biopsy at 6 months (three refused and two had other primary malignancies); and all, prostate-specific antigen (PSA) tests at 6 weeks, 3 months, and every 3 months thereafter. MR images were evaluated and scored according to the degree of signal void and were correlated with the 6-month biopsy reports and, to a lesser degree, PSA levels. The biopsy reports were examined for the presence or absence of cancerous tissue, viable tissue, and nonviable tissue. A one-way analysis of variance was used for statistical and regression analyses., Results: The correlation of MR imaging scores with PSA levels and MR imaging scores with biopsy findings resulted in P values of.337 and.780, respectively. A slight statistically significant trend existed for the relation of biopsy results with PSA levels, with a P value of.041, which was expected., Conclusion: Findings of postoperative gadolinium-enhanced MR imaging are not predictive of 6-month biopsy results or follow-up PSA levels., (Copyright RSNA, 2004)

Objectives: To determine in a prospective pilot study the safety and efficacy of cryosurgical ablation for localized prostate carcinoma., Methods: A total of 87 cryosurgical procedures were performed on 76 consecutive patients between December 1994 and February 1998. All patients had histologically proved adenocarcinoma of the prostate, with prostate-specific antigen (PSA) readings of less than 30 ng/mL. Clinical evaluations, PSA determinations, and patient self-reported quality-of-life questionnaires (functional assessment of cancer treatment-prostate; FACT-P) were used to determine biochemical and clinical disease-free status and complications. Patients had a mean follow-up of 50 months (minimum 36)., Results: Follow-up biopsies were performed in 73 patients, and 72 were negative for malignancy after one or more treatments. Ten patients required two treatments and 1 patient required three treatments. The 5-year overall and cancer-specific survival rate was 89% (95% confidence interval, 83% to 97%) and 98.6% (95% confidence interval, 96% to 100%), respectively. The undetectable PSA rate (less than 0.3 ng/mL) for low-risk patients (n = 13) was 60% at 5 years; for moderate-risk patients (n = 23), it was 77%, and for high-risk patients (n = 40), 48%. The corresponding percentage of patients with a PSA level less than 1.0 ng/mL at 5 years was 75%, 89%, and 76%. Sloughing occurred in 3 patients (3.9%), incontinence in 1 (1.3%), and testicular abscess in 1 (1.3%). At 3 years, 18 (47%) of 38 patients capable of unassisted intercourse at the time of cryosurgery had resumed sexual intercourse, 5 spontaneously and 13 with sildenafil or prostaglandin., Conclusions: The results of this prospective evaluation show cryosurgery to be both a safe and an effective option in the treatment of localized prostate cancer.

Cryosurgery is the in situ ablation of a target tissue by application of extreme cold temperature. The ability of cryosurgery to ablate tissue is unquestioned. It is the controlled application of a cryoinjury in a manner to minimize morbidity that is problematic. Prostate cryosurgery is complicated by the proximity of the prostate to adjacent structures that are sensitive to a freeze injury, namely the urethra, rectal wall, and neurovascular bundles. Several recent technological advances have led to the development of an effective treatment protocol with acceptable morbidity. These include the advent of real-time transrectal ultrasound, cryomachines with almost instant freeze-thaw control through the use of the Joule-Thompson effect, and warming catheters to effectively preserve the integrity of the urethra and external sphincter. Further, temperature monitoring at the posterior margin of the prostate sometimes combined with an injection of saline solution into Denonvilliers fascia has reduced the occurrence of urethrorectal fistula formation to 0% to 0.5% in modern series. We review the key innovations of prostate cryosurgery that differentiate this state-of-the-art procedure from that used by early investigators to even that of the early 1990s. Potential future innovations, specifically related to image guidance of the procedure, are also addressed.

The current study was designed to describe the long-term life quality and sexuality of men enrolled in a phase 2 clinical trial of cryosurgery for the treatment of localized prostate cancer. A total of 75 men were administered the Functional Assessment of Cancer Treatment-Prostate (FACT-P) before treatment and after treatment at 6 weeks, and at 3, 6, 12, 24, and 36 months. Additionally, these men completed a Sexuality Follow-Up Questionnaire (SFQ) 3 years after cryosurgery. By 12 months after cryosurgery, most FACT-P subscales had returned to pretreatment levels. Quality of life remained stable over the subsequent 2 years. The only exception to this general trend was persistent impairment in measures of social/family well-being. At 36 months, 13% (5 of 38) of patients had regained erectile functioning, and an additional 34% (13 of 38) of patients were sexually active with the help of aids. The 3-year quality-of-life outcomes support the renewed interest in cryosurgery. No late complications were observed. Whereas improvements in erectile function were observed between years 1 and 3 for some patients, most continue to experience erectile dysfunction. For these patients, aids are an important adjunct to the treatment of their erectile dysfunction.

Prostate cryosurgery has advanced over the last decade, and is now recognized as a treatment option for patients who have failed radiotherapy. Appropriate patient selection is imperative for successful salvage. Because the treatment is a local therapy, the recurrent cancer must be confined to the prostate and its immediate area, and up to half of patients who undergo salvage cryotherapy may eventually fail treatment because of occult synchronous metastases. Yet some patients with poor prognosticators may still benefit from salvage treatment.

A time dependent three-dimensional finite difference model of iceball formation about multiple cryoprobes has been developed and compared to experimental data. Realistic three-dimensional probe geometry is specified and the number of cryoprobes, the cryoprobe cooling rates, and the locations of the probes are arbitrary inputs by the user. The simulation accounts for observed longitudinal thermal gradients along the cryoprobe tips. Thermal histories for several points around commercially available cryoprobes have been predicted within experimental error for one, three, and five probe configurations. The simulation can be used to generate isotherms within the iceball at arbitrary times. Volumes enclosed by the iceball and any isotherms may also be computed to give the ablative ratio, a measure of the iceball's killing efficiency. This ratio was calculated as the volume enclosed by a critical isotherm divided by the total volume of the iceball for assumed critical temperatures of -20 and -40 degrees C. The ablative ratio for a single probe is a continuously decreasing function of time but when multiple probe configurations are used the ablative ratio increases to a maximum and then essentially plateaus. Maximum values of 0.44 and 0.55 were observed for three and five probe configurations, respectively, with an assumed critical temperature of -20 degrees C. Assuming a critical temperature of -40 degrees C, maximum ablative ratios of 0.21 and 0.3 for three and five probe configurations, respectively, were observed.

Type I antifreeze protein (AFP) from the winter flounder (Pseudopleuronectes americanus) was used as an adjuvant to cryosurgery of subcutaneous tumors of Dunning AT-1 rat prostate cells grown in Copenhagen rats. The cryosurgical procedure was performed with a commercially available cryosurgery device (CRYO-HIT, Galil Medical) with clinically relevant single- and double-freeze protocols. Injury was assessed with the alamar blue indicator of metabolic activity. The assay gave anomalous results when used to assess the extent of injury immediately following the procedure, underestimating the extent of injury. However, a double-freeze procedure with antifreeze protein present was found to give significantly better ablation than a double-freeze without AFP or a single-freeze with or without AFP., (Copyright 2001 Academic Press.)

We examined the pathological findings from prostatic whole mounts obtained at post-mortem, 2 years following cryosurgical ablation of the prostate (CSAP), to evaluate the presence or absence of residual benign or malignant tissue. Whole prostates were obtained from two patients at post-mortem, in which the cause of death was not related to prostate cancer. The patients had received CSAP 24 and 30 months earlier, as the primary treatment for prostate cancer. Complete ablation of the gland was demonstrated in one case, with some residual viable benign glands in the transitional zone in the second case. These results suggest that localized prostate cancer can be successfully eradicated by CSAP.

A model is presented for treatment planning of multiprobe cryosurgery. In this model a thermal simulation algorithm is used to generate temperature distribution from cryoprobes, visualize isotherms in the anatomical region of interest (ROI) and provide tools to assist estimation of the amount of freezing damage to the target and surrounding normal structures. Calculations may be performed for any given freezing time for the selected set of operation parameters. The thermal simulation is based on solving the transient heat conduction equation using finite element methods for a multiprobe geometry. As an example, a semi-empirical optimization of 2D placement of six cryoprobes and their thermal protocol for the first freeze cycle is presented. The effectiveness of the optimized treatment protocol was estimated by generating temperature-volume histograms and calculating the objective function for the anatomy of interest. Two phantom experiments were performed to verify isotherm locations predicted by calculations. A comparison of the predicted 0 degrees C isotherm with the actual iceball boundary imaged by x-ray CT demonstrated a spatial agreement within +/-2 mm.

Image guidance in cryotherapy is usually performed using ultrasound. Although not currently in routine clinical use, x-ray CT imaging is an alternative means of guidance that can display the full 3D structure of the iceball, including frozen and unfrozen regions. However, the quality of x-ray CT images is compromised by the presence of high-density streak artefacts. To suppress these artefacts we applied temporal digital subtraction (TDS). This TDS method has the added advantage of improving the grey scale contrast between frozen and unfrozen tissue in the CT images. Two sets of CT images were taken of a phantom material, cryoprobes and a urethral warmer (UW) before and during the cryoprobe freeze cycle. The high density artefacts persisted in both image sets. TDS was performed on these two image sets using the corresponding mask image of unfrozen material and the same geometrical configuration of the cryoprobes and the UW. The resultant difference image had a significantly reduced artefact content. Thus TDS can be used to significantly suppress or eliminate high-density CT streak artefacts without reducing the metallic content of the cryoprobes. In vivo study needs to be conducted to establish the utility of this TDS procedure for CT assisted prostate or liver cryotherapy. Applying TDS in x-ray CT guided cryotherapy will facilitate estimation of the number and location of all frozen and unfrozen regions, potentially making cryotherapy safer and less operator dependent.

Objective: To evaluate the role and safety of biopsy of the seminal vesicles and neurovascular bundles in determining the pathologic stage of prostatic carcinoma., Methods: Eighty-one consecutive patients were enrolled in a comprehensive cryosurgical biopsy protocol that included sextant intraprostatic plus extraprostatic biopsy. The pathologic stage, determined after biopsy, was compared with the clinical stage, determined by digital rectal examination (DRE) and transrectal ultrasonographic (TRUS) evaluation. As well, complication rates for these patients were compared with rates for a separate group that underwent sextant intraprostatic biopsy alone., Results: Of the 81 patients, 61 (75%) were confirmed to have cancer by biopsy. None of these patients was considered to have extraprostatic extension by clinical evaluation (DRE and TRUS), but 16 of 61 (26%) were identified to have extraprostatic cancer in the seminal vesicles (8 of 61, 13%) or in the neurovascular bundles (8 of 61, 13%) by extraprostatic biopsy. There was no significant difference in the complication rates between sextant intraprostatic biopsy and sextant intraprostatic plus extraprostatic biopsy (p>0.97)., Conclusions: Extraprostatic biopsy identifies extension of carcinoma in a large proportion of patients in whom clinical evaluation by DRE and TRUS indicates organ-confined disease. Extraprostatic biopsy is therefore warranted as routine evaluation before surgery in order to correctly stage prostatic carcinoma and select appropriate therapy.

Background: Cryosurgery was introduced as an alternative to radiotherapy or radical prostatectomy in the mid-1960s. Although it met the primary objective of achieving local control, it was largely abandoned due to a high incidence of complications. Technologic advances in the areas of imaging and urethral warming have renewed interest in this treatment methodology. The aim of the current study was to determine the quality of life of men enrolled in a Phase II clinical trial of cryosurgery for the treatment of localized prostate carcinoma., Methods: Men were administered the Functional Assessment of Cancer Treatment-Prostate (FACT-P) prior to their treatment and at 6 weeks and 3, 6, and 12 months posttreatment., Results: By 12 months after cryosurgery, most of the FACT-P subscales had returned to pretreatment levels, following a decline in well-being immediately after cryosurgery. There were two exceptions to this general trend: At 12 months, impairments in social/family well-being and sexual function still remained. The average time to return to work after therapy was 3 weeks. Stay in hospital after treatment was limited to 1 day for 94% of the participants. Compared with men who received the standard treatments of radical prostatectomy and radical radiotherapy, men treated with cryosurgery appeared to have a similar quality of life, with perhaps the exception of decreased sexual function., Conclusions: The quality-of-life outcomes of this study support the current renewed interest in cryosurgery. The severe impairments reported in other studies were not seen in this sample. In fact, it appeared that all aspects of the participants' well-being had returned to pretreatment levels by 12 months, with the exception of sexual function., (Copyright 1999 American Cancer Society.)

Background and Objectives: Advances in the technology of cryomachines in the last 10 years have led to the development of both liquid nitrogen and argon-based Joule-Thompson cryomachines. Theoretical and practical evaluation of the CMS Accuprobe and the ENDOcare CRYOcare was performed as respective examples of these technologies., Methods: Thermal gradients were calculated about both probes for the best case scenario of probe surface temperature equaling that of the cryogen used. Also, experimental evaluation in gelatin phantoms was performed with five probe arrays., Results: Theoretically, a liquid nitrogen-cooled probe provides only a slight advantage over one cooled with liquid argon. However, the experimental performance evaluation demonstrated that the CRYOcare system creates an iceball faster with steeper internal temperature gradients than the Accuprobe. Further, temperature outputs from the Accuprobe were shown to be in error, likely due to the position of the thermocouple within the probe., Conclusions: Cryomachine performance is determined more by technological innovations than by cryogen temperature. Thermocouple monitoring is urged for users of the Accuprobe.

Objective: To determine the relation between ASA ingestion and the incidence of bleeding complications after transrectal ultrasound (TRUS)-guided biopsy of the prostate., Methods: Overall, 1810 patients with suspected prostate disease were followed after biopsy. ASA use was determined before the procedure. A TRUS-guided sextant biopsy was performed and patients were contacted immediately and by follow-up telephone call to determine whether there were any immediate or delayed bleeding complications., Results: Overall, 46 subjects (2.5%) had bleeding complications. Of the 54 subjects reporting current use of ASA, 2 (3.7%) had such complications. This difference was not significant., Conclusion: There was no evidence of an association between the use of ASA and postbiopsy bleeding complications.

Objectives: To assess the effectiveness and safety of ultrasound (US)-guided cryotherapy as a primary treatment for localized prostate cancer., Materials and Methods: A prospective study of percutaneous transrectal US (TRUS)-guided cryotherapy was performed on 71 patients with T1-T3, N0, M0 prostatic cancer: 10 patients underwent two or more procedures. All cases were newly diagnosed and patients had no previous treatment for cancer. For all patients, TRUS biopsies were performed at 5-6 months. Patients were monitored at 6 weeks; 3, 6, 9, and 12 months; and twice yearly thereafter for prostate specific antigen (PSA) levels, complications, and clinical evidence of residual disease., Results: Follow-up from 10 to 36 months was available for 70 of 71 patients; one patient died of unrelated disease. Initially, 10 of 69 patients had positive postcryotherapy biopsy results. After repeated treatment, nine of these 10 patients had negative biopsy results and one patient had no follow-up. Overall, 68 of 69 patients had negative biopsy results. At 1 year, 43 of 64 (67%) had an undetectable PSA level. Two patients had proven metastases. Complications include three cases with urethral sloughing requiring transurethral resection of the prostate (TURP). One patient had orchitis. Two patients had persistent incontinence, one as the result of a TURP. There was no death, acute serious morbidity, or fistula formation. Impotence was universal at 6 months, but many patients demonstrated late recovery., Conclusion: Cryoablation is an imaging-guided percutaneous intervention for prostate cancer that can safely yield disease-free status in a high percentage of patients with localized disease.

The optimal cooling parameters to maximize cell necrosis in different types of tissue have yet to be determined. However, a critical isotherm is commonly adopted by cryosurgeons as a boundary of lethality for tissue. Locating this isotherm within an iceball is problematic due to the limitations of MRI, ultrasound and CT imaging modalities. This paper describes a time-dependent two-dimensional axisymmetric model of iceball formation about a single cryoprobe and extensively compares it with experimental data. Thermal histories for several points around a CRYOprobe are predicted to high accuracy (5 degrees C maximum discrepancy). A realistic three-dimensional probe geometry is specified and cryoprobe temperature may be arbitrarily set as a function of time in the model. Three-dimensional temperature distributions within the iceball, predicted by the model at different times, are presented. Isotherm locations, as calculated with the infinite cylinder approximation, are compared with those of the model in the most appropriate region of the iceball. Infinite cylinder approximations are shown to be inaccurate when applied to this commercial probe. Adopting the infinite cylinder approximation to locate the critical isotherm is shown to lead the user to an overestimate of the volume of target tissue enclosed by this isotherm which may lead to incomplete tumour ablation.

X-ray CT is able to image the internal architecture of frozen tissue. Phantoms of distilled water, a saline-gelatin mixture, lard and a calf liver-gelatin suspension cooled by a plastic tube acting as a long liquid nitrogen cryoprobe were used to study the relationship between Hounsfield unit (HU) values and temperature. There is a signature change in HU value from unfrozen to completely frozen tissue. No discernible relation exists between temperature in a completely frozen tissue and its HU value for the temperature range achieved with commercial cryoprobes. However, such a relation does exist in the typically narrow region of phase change and it is this change in HU value that is the parameter of concern for quantitative monitoring of the freezing process. Calibration of temperature against change in HU value allows a limited set of isotherms to be generated in the phase change region for direct monitoring of iceball growth. The phase change temperature range, mid-phase change temperature and the absolute value of HU change from completely frozen to unfrozen tissue are shown to be sensitive to the medium. Modelling of the temperature distribution within the region of completely frozen phantom using the infinite cylinder solution to the Fourier heat equation allows the temperature history of the phantom to be predicted. A set of isotherms, generated using a combination of thermal modelling and calibrated HU values demonstrates the feasibility of routine x-ray CT assisted cryotherapy. Isotherm overlay will be a major aid to the cryosurgeon who adopts a fixed target temperature as the temperature below which there is a certainty of ablation of the diseased tissue.

Purpose: To assess the efficacy of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy in patients with muscle-invading bladder cancer treated with selective bladder preservation., Patients and Methods: One hundred twenty-three eligible patients with tumor, node, metastasis system clinical stage T2 to T4aNXMO bladder cancer were randomized to receive (arm 1, n=61 ) two cycles of MCV before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart. Patients assigned to arm 2 (n=62) did not receive MCV before concurrent cisplatin and radiation therapy. Tumor response was scored as a clinical complete response (CR) when the cystoscopic tumor-site biopsy and urine cytology results were negative. The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and one additional dose of cisplatin. Those with less than a CR underwent cystectomy. The median follow-up of all patients who survived is 60 months., Results: Seventy-four percent of the patients completed the protocol with, at most, minor deviations; 67% on arm 1 and 81% on arm 2. The actuarial 5-year overall survival rate was 49%; 48% in arm 1 and 49% in arm 2. Thirty-five percent of the patients had evidence of distant metastases at 5 years; 33% in arm 1 and 39% in arm 2. The 5-year survival rate with a functioning bladder was 38%, 36% in arm 1 and 40% in arm 2. None of these differences are statistically significant., Conclusion: Two cycles of MCV neoadjuvant chemotherapy were not shown to increase the rate of CR over that achieved with our standard induction therapy or to increase freedom from metastatic disease. There was no impact on 5-year overall survival.

Objective: To determine if the adequacy of freezing in the neurovascular bundle region of the prostate during prostate cryotherapy can be monitored by transrectal ultrasonography (TRUS)., Patients and Methods: The study group consisted of 11 patients undergoing TRUS-guided prostate cryotherapy. The actual temperature in the gland was monitored with thermosensors placed in each prostatic neurovascular bundle. The 2 cryo-operators, working together and blinded to the actual temperature, used sonographic observations to estimate the temperature at the neurovascular bundles every 2 minutes until they believed that the gland was adequately frozen. The congruity between the estimated and measured temperatures was analyzed to determine if the operators could accurately monitor the progress of cryoablation by ultrasonography., Results: There were a total of 85 data points for which the operators thought tumoricidal cryo-injury had been achieved at the neurovascular bundles (temperature -20 degrees C or below). For these points the measured temperature was on average 6.0 degrees C warmer than the estimated temperature (standard deviation, 22). For operator estimates of -20 degrees C or below, the measured temperature was -20 degrees C or below for 37 (44%) data points, between -19 degrees C and 0 degree C for 32 (38%) and greater than 0 degree C for 16 (19%)., Conclusions: The operators were not able to accurately predict subzero temperatures at the neurovascular bundle region by TRUS evaluation. Moreover, the bias and magnitude of the error were significant and might lead to inadequate freezing of the prostate during attempted cryoablation.

OBJECTIVE: To assess the effectiveness of cryoablation in localized prostate cancer in our hands. Early end points are biopsy at 5 months and PSA at 12 months follow-up. METHODS: Percutaneous transperineal cryoablation was performed on 30 patients. A urethral warming catheter was used. All cases were newly diagnosed with no prior radiotherapy, or neoadjuvant hormones. A single freeze cycle was used in the first 10 cases and two cycles in the next 20 cases. RESULTS: Twenty-nine of 30 cases are eligible for follow-up. Six of the first 10 patients had negative biopsies, the 4 positive patients have had repeat cryoablation and only 1 patient remains biopsy positive. In cases 11-30, there were two patients with positive biopsies – both retreated. At this time, 27/29 patients (93%) have a negative biopsy after one (23 patients) or two (6 patients) treatments. At 6 months, 20/29 patients (69%) have undetectable PSA; 25/29 have PSA less than 1 ng/ml. At 12 months, 17/23 cases have an undetectable PSA (74%). Complications were minimal; 3 cases (10%) suffered urethral sloughing requiring TURP. CONCLUSION: Early results are very encouraging, showing 93% negative biopsy rate after one (23 patients) or two (6 patients) treatments; PSA is undetectable in 74% (17/23 patients) at 1 year. Early results of cryoablation for prostate cancer are encouraging.

Background: The study took place at the Genito-Urinary Medicine Department at the University Hospital of South Manchester and the Cytology Department at Christie NHS Trust Hospital. There were two main objectives, as follows: (1) to determine if patients attending a Genito-Urinary Medicine (GUM) Clinic are less likely to have had a cervical smear in the preceding five years than a control group drawn from the general population; (2) to compare the prevalence of cytological abnormalitity in cases and controls., Methods: Cases comprised all women attending the Withington GUM Clinic, between 1991 and 1993, who had had a cervical smear taken at this clinic. Controls were selected from residents of the North West Regional Health Authority who had a cervical smear taken either by a general practitioner (GP) or in an NHS Community Clinic during the same period. The design was a matched case-control study. The main outcome measures considered the proportion of women who had had a cervical smear taken by a GP or in an NHS Community Clinic during the five years preceding the index smear, and the prevalence of abnormal smears in cases and controls., Results: There was no significant difference in the screening history of cases and controls; 363 (50.2 per cent) cases had had a cervical smear taken in the preceding five years as compared with 380 (52.6 per cent) controls [chi 2 (1df) = 0.95; p > 0.05; 95 per cent confidence interval (CI) on difference in proportions, -7.1 per cent to 2.4 per cent]. There was a small case-control difference of borderline significance in the prevalence of all grades of cytological abnormality: 22.7 per cent of cases had abnormal cytology as compared with 18.5 per cent of controls [chi 2 (1df) = 3.98; 0.01 < p < 0.05; 95 per cent CI on difference in proportions, 1 per cent to 8.2 per cent). This excess was largely attributable to differences in the prevalence of minor cytological abnormality. There was no significant difference in the prevalence of cytological abnormality in those case-control pairs who had had a smear in the preceding five years., Conclusion: A policy of cervical screening of all GUM patients can no longer be sustained. We would recommend cervical cytology only for those women who have not been screened in the previous three to five years.

Introduces the Complaints Manager program from Health-TEC to address the problems involved in complaints management and control in the health service. Shows the main screens available for data input. Demonstrates the wide range of reports which can be generated. Suggests that the Complaints Manager program provides an efficient and low-cost means of keeping complaints under control.

Estimates of covariance components were obtained for milk production of beef cows, measured by the weigh-suckle-weigh method, and weaning weight and preweaning growth of their calves for a herd of Polled Herefords and a herd of a multibreed synthetics, so-called Wokalups. Analyses were carried out by restricted maximum likelihood fitting an animal model incorporating both direct and maternal genetic and permanent environmental effects and allowing for the direct-maternal covariances. Average 14-h milk yield was 3.6 kg for Herefords and 4.9 kg for Wokalups and heritabilities were .12 and .08, respectively. Treating preweaning gain of the calf as a trait of the cow, estimates of the additive genetic and permanent environmental correlations between preweaning gain and milk yield were higher for Herefords (.73 and 1.00, respectively) than for Wokalups (.53 and .77). Bivariate analyses of milk production (treated as a trait of the cow) and weaning weight (treated as a trait of the calf) showed virtually no direct additive genetic, direct permanent environmental, or phenotypic association between the two traits but identified strong correlations between direct effects for milk yield and maternal effects for weaning weight. The estimate of the direct-maternal genetic correlation between milk yield and weaning weight was .80 for both breeds, and the estimated correlation between direct, permanent environmental effects for milk yield and maternal, permanent environmental effects on weaning weight was unity for Herefords and .89 for Wokalups. Results indicate that milk production is the main determinant of maternal effects on the growth of beef calves with breed differences in the importance of maternal effects largely attributable to differences in milk production.

Estimates of covariance components and genetic parameters were obtained for birth, weaning, 200-d, and 400-d weight for a herd of Polled Herefords and a herd of a multibreed synthetics, the so-called Wokalups. Data originated from an experiment in Western Australia selecting for preweaning growth rate. Analyses were carried out by REML fitting an animal model including genetic and permanent environmental maternal effects. Wokalups showed consistently more phenotypic variation, partly due to a scale effect, and higher direct and lower maternal heritabilities than Herefords. Maternal environmental effects were more than twice as important in Herefords than in Wokalups. Estimates of both genetic and environmental correlations among weaning and subsequent weights were essentially unity, identifying maternal effects found for postweaning weights as a "carry over" of those on weaning weight.

Aggressive radiotherapy was used in 170 patients with advanced localized carcinoma of the prostate. After pelvic lymphadenectomy, 192Ir brachytherapy was used to deliver 3500 cGy to the prostate within 2 days. External-beam therapy (4500 cGy) was then given to a total of 8000 cGy. Random biopsies 18 months afterward were negative for residual cancer in 62 of 83 patients (75%), and 37 of 45 patients (82%) with pathologically proved localized disease remain without evidence of disease. Morbidity was significantly reduced in the most recent 70 patients by improvements in technique. The authors believe such therapy should be considered for patients with advanced stage B2 or C disease in particular.

Carcinoma of the prostate is a common cancer, and its incidence is rising. A digital rectal examination should be routine to allow early diagnosis. Several screening and investigative techniques are available. Choice of treatment depends on the age and health of the patient and whether the cancer has spread. Treatments include observation, prostatectomy, radiation, and surgical or medical castration.

Estrogens have been proposed as a major etiological factor in the pathogenesis of benign prostatic hyperplasia in man. The presence of estrogen receptor in benign prostatic hyperplasia would support this concept. Using the receptor stabilizer, sodium molybdate, and a hydroxylapatite assay we assayed human benign prostatic hyperplasia for the presence of cytosolic estrogen receptor. For comparison, we assayed estrogen receptor in cytosols of prostatic cancer and normal tissue, and we also measured androgen receptor and progesterone receptor concentrations in the 3 tissue types. Estrogen receptor was present in 8 of 15 benign prostatic hyperplasia specimens at a mean concentration of 9.2 fmol./mg. protein for the estrogen-receptor-positive samples. Sucrose gradient analysis of the estrogen receptor of benign prostatic hyperplasia revealed that it sedimented in the region of 8S, and steroid specificity studies confirmed that the binding to estrogen receptor was estrogen-specific. Estrogen receptor was also found in normal (3 of 3) and malignant (4 of 6) tissues, and all tissues were positive for androgen receptor. The presence of estrogen receptor in human benign prostatic hyperplasia supports the proposal that circulating estrogens may have a role in the pathogenesis of this disorder.

To further characterize human prostatic androgen receptor, nuclei were isolated from normal prostate (no. = 3) and benign prostatic hyperplasia specimens (no. = 10). High ionic strength (0.6 M KCl) treatment of nuclei released nuclear extractable androgen receptor and DNase I digestion then yielded nuclear matrices. Androgen receptor was quantified in the nuclear extract and nuclear matrix preparations by Scatchard analysis of specific R1881 binding. Only 1 of the 3 normal tissues had extractable androgen receptor (113 fmol. per gm. of tissue) while the mean concentration of extractable androgen receptor for BPH was 189 fmol. per gm. of tissue. The mean concentrations of matrix-bound androgen receptor were 325 fmol. per gm. of tissue and 548 fmol. per gm. of tissue for normal and hyperplastic prostate, respectively. The androgen binding sites on nuclear matrix may represent the functional intranuclear androgen receptor and a characterization of these sites may provide an understanding of the etiology of BPH.

The injection of rabbits' ileum with homogenates of both normal and Crohn's affected human bowel tissue gave Crohn's-like changes in 11 of 27 animals after six months, but 12 months after injection the rabbit bowel had reverted to normal. The addition of ampicillin to the homogenates prevented the appearance of these Crohn's-like changes in 12 out of 12 rabbits. These results are interpreted as providing evidence for a transmissible factor present in both normal and Crohn's affected bowel in the aetiology of Crohn's disease.

We report 2 cases of primary leiomyosarcoma of the epididymis. There is no evidence of tumor recurrence in 1 patient 21 years postoperatively and prophylactic chemotherapy has been started in 1 patient because of a high mitotic rate in the tumor. The 9 cases reported previously are reviewed briefly.