Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03.

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.

Role of transrectal ultrasound guided salvage cryosurgery for recurrent prostate carcinoma after radiotherapy.

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%.

Iridium-192 brachytherapy in the treatment of cancer of the prostate.

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.

A model for the time dependent three-dimensional thermal distribution within iceballs surrounding multiple cryoprobes.

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.

A semi-empirical treatment planning model for optimization of multiprobe cryosurgery.

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.

Suppression of high-density artefacts in x-ray CT images using temporal digital subtraction with application to cryotherapy.

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.

X-ray CT monitoring of iceball growth and thermal distribution during cryosurgery.

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.

A model for the time-dependent thermal distribution within an iceball surrounding a cryoprobe.

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.

Histological findings in the prostate two years following cryosurgical ablation.

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.

Genetic parameters for milk production of Australian beef cows and weaning weight of their calves.

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.

Genetic parameters for growth traits of Australian beef cattle from a multibreed selection experiment.

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.

Complaints management--in-depth review.

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.

Baseline serum testosterone in men treated with androgen deprivation therapy and radiotherapy for localized prostate cancer.

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.

Carcinoma of the Prostate: Screening and investigative techniques and treatments.

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.

Malignant smooth muscle tumors of the epididymis.

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.

Is a policy of cervical screening for all women attending a genito-urinary medicine clinic justified?

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.

Evidence for a transmissible factor in Crohn's disease.

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.

Androgen binding sites on nuclear matrix of normal and hyperplastic human prostate.

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.

Estrogen receptor in human benign prostatic hyperplasia.

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.

Correlation between thermosensor temperature and transrectal ultrasonography during prostate cryoablation.

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.