Effect of androgen deprivation on epithelial and mesenchymal tissue components in localized prostate cancer.

OBJECTIVE: To measure the area distribution of epithelial and mesenchymal components in the prostate of patients with localized prostate cancer after temporary androgen deprivation. PATIENTS AND METHODS: Surgical specimens from 38 patients treated with the gonadotrophin-releasing hormone agonist triptorelin for 3 months before radical prostatectomy were examined (group I). Specimens from a second group of 54 patients who underwent the same surgical procedure with no prior therapy were used as controls (group 2). The specimens were serially step-sectioned and whole-mount tissue sections prepared. The epithelial, smooth muscle and connective tissue components were stained separately with immunohistochemical and histochemical techniques, respectively. Using colour-based image analyses, the tissue components were classified into three categories, displayed in different colours. The percentage of tumour areas occupied by cancer epithelial cells, connective tissue and smooth muscle was determined. RESULTS: In specimens from group 1, the cancer epithelium was sparse and scattered throughout the tumour area. A mean (SD) of 21 (11)% of the area was occupied by cancer cells, compared with 40 (11)% in the corresponding material from group 2 (P < 0.001). The connective tissue/smooth muscle ratio in stroma (about 1:1) was similar in both groups. CONCLUSIONS: Neoadjuvant hormone treatment of patients with localized prostate cancer was associated with a marked reduction in tumour density and thus in the total amount of cancer epithelium.

Neo-adjuvant GnRH therapy and radical prostatectomy: effects on tumorous and benign tissue volumes - a morphometric study.

UNLABELLED: The effect on tumour and prostate volumes of a 3-month course of neo-adjuvant hormone therapy was studied using computerised planimetry on serially sectioned specimens obtained by radical prostatectomy. Fifty-four specimens from patients not receiving pre-treatment were compared to 38 specimens from patients given the gonadotropin-releasing hormone (GnRH) analogue triptorelin for 3 months before the operation. Glandular volume and volume of the index tumour was determined. To determine the position of the index tumour within the gland, the centre of mass of the tumour was identified and the distance to the gland margin calculated. This value (M1) represents the sum of the tumour radius and the various amounts of normal tissue. The amount of surrounding tissue could be approximated by correlating M1 to the corresponding tumour volume. RESULTS: The two groups differed significantly in total gland volumes, but not in tumour volumes. M1 was strongly correlated to the tumour volume in the treatment group (r = 0.73), whereas in the control group the correlation was found to be significantly weaker (r = 0.44), indicating that there was less tissue surrounding the tumour in the pre-treated group. In a multiple regression analysis of all 92 patients, index tumour volume was found to be associated with total gland volume, DNA ploidy pattern, tumour grade but not whether or not pre-treatment was given. This study found that the volumes of the single largest tumour focus were not significantly affected by hormonal pre-treatment, and that "the prostate condenses around the tumour rather than that the tumour shrinks back into the prostate". However, the precise relationship between tumour epithelial volume and stroma with or without neo-adjuvant hormonal pre-treatment remains to be clarified.

The analgesic efficacy of clodronate compared with placebo in patients with painful bone metastases from prostatic cancer.

Fifty-five patients with hormone refractory prostate cancer and painful bone metastases were randomised either to placebo or to clodronate 300 mg i.v. for 3 days, followed by oral clodronate 3200 mg for four weeks. Pain intensity was assessed using Visual Analogue Scales (VAS). Mean overall pain as well as mean pain during the best and worst periods were recorded. Forty-six patients were evaluable for efficacy. No significant differences were found between the two treatments. As regards mean worst pain a substantial numerical fall was registered for the treatment group, 21 mm, but the improvement was not significant compared to that of the placebo group. This was probably due to the limited number of patients (the study was prematurely ended due to problems recruiting patients). In conclusion, no significant differences were found between the treatment arm and the controls, in contrast to results from previous studies. Possible explanations are that the doses in this study were generally lower than in previous studies, the mean baseline pain was substantially lower and that the current study was placebocontrolled. Our data indicate that if clodronate is to be used for the alleviation of bone pain in prostate cancer, patients with high baseline should be selected and high intravenous doses should be given at start of the treatment.

A 3-year follow-up of patients with localized prostate cancer operated on with or without pre-treatment with the GnRH-agonist triptorelin.

OBJECTIVE: To examine the effect of pre-operative androgen deprivation on the progression rate of malignancy in patients operated on for localized prostate cancer. PATIENTS AND METHODS: A total of 53 patients received no hormone therapy (group 1) and a further 38 patients (group 2) received the generic releasing-hormone agonist triptorelin during the 3 months before surgery. The patients in group 1 had T1b-T2 tumours, whereas 12 of those in group 2 had clinical stage T3 tumours. Despite this, the surgical specimens from the patients in group 2 showed a rate of cancer invasion of the surgical margins 20% lower than those from the patients in group 1. After prostatectomy, the patients were followed for 3 years by repeated analyses of prostate-specific antigen (PSA) in serum. RESULTS: During the follow-up, the PSA level exceeded the upper threshold (0.6 ng/mL) in 16% of the patients in group 1 and in 43% of those in group 2 (P < 0.05). This difference was mainly related to the pre-treatment stage of the tumor. Some of the patients in group 1 received post-operative radiotherapy but this was not reflected in their PSA levels. Of the patients in group 1 and 2, 4% and 14% respectively (P > 0.05), developed symptoms from skeletal metastases. CONCLUSION: There was no evidence that pre-operative hormone therapy slowed the progression of prostate cancer.

DNA ploidy patterns in androgen-deprived localized prostate cancer.

Prostatectomy was performed in 48 patients with localized prostate cancer. Before surgery, they had been treated with the GnRH agonist triptorelin for 3 months. Specimens from the largest tumor focus (n = 6.3 + 3.6, mean + SD) were analyzed with regard to the DNA ploidy pattern. The results were compared with those obtained in a previous investigation of 54 patients who were subjected to surgery without hormone pretreatment. In both series, about 50% of the tumors showed a diploid DNA ploidy pattern, the rest being nondiploid. Ploidy heterogeneity, i.e., a mixture of diploid and nondiploid ploidy patterns in the single largest tumor focus, was found in 36% of the cases compared to 48% in the previous report (NS). In 13% of the tumors, all samples revealed a nondiploid DNA ploidy pattern as compared to 6% in the previous report (NS). In both series, needle biopsy examination (1/patient) prior to prostatectomy was associated with a significant and similar underestimate of the chromosomal aberration. In conclusion, despite the marked histopathological changes previously reported, there is no evidence that neoadjuvant triptorelin treatment during 3 months has any effect on the DNA ploidy pattern.

Rectal perforation after retropubic radical prostatectomy: occurrence and management.

OBJECTIVES: A surgical audit of the management of rectal perforations during retropubic radical prostatectomy. Assessment of incidence, risk factors, management and outcome. METHODS: All 10 cases (3.6%) sustaining a rectal injury of a total series of 270, while undergoing retropubic radical prostatectomy at our 2 institutions were reviewed. In all cases, the injury was immediately recognized and treated by primary suture, anal dilatation and antibiotics. In 1 case, a temporary colostomy was performed. RESULTS: Recovery was uneventful in all cases, and the postoperative hospitalization was only slightly longer than usual in the 9 cases without fecal diversion. No fistulae or wound infections occurred, but closure of 1 colostomy was complicated. CONCLUSION: Provided that the injury is promptly recognized and properly sutured, a rectal perforation at radical prostatectomy is not of great significance and should not deter from an adequate preoperative investigation by multiple transrectal core biopsies or neoadjuvant hormonal treatment. The use of preoperative bowel preparation, routine antibiotic prophylaxis, omental interposition or a proximal colostomy does not appear to be necessary in order to achieve immediate safe repair.

Pre- and postoperative DNA ploidy patterns correlated to pT-stage, histological grade and tumour volume in total prostatectomy specimens.

Fifty-four consecutive patients with a preoperative diagnosis of localized prostatic cancer underwent total retropubic prostatectomy. The specimens were step-sectioned at 5 mm intervals. Volumes of invasive cancer (IC) and prostatic intraepithelial neoplasia (PIN) were calculated by computerized planimetry. From preoperative core and fine needle aspiration biopsies and from each prostatectomy specimen, multiple samples were taken from IC and PIN areas for DNA ploidy analysis. The study aimed to evaluate current biopsy sampling techniques as regards their suitability for DNA analysis and to assess the heterogeneity of DNA-ploidy and correlate the latter to postoperative pT-stage and tumour volume. When compared with the prostatectomy specimens, the preoperative assessment of non-diploid DNA patterns in biopsies had a sensitivity of 62% and a specificity of 86%. Samples from 24 surgical specimens contained non-diploid DNA in the main tumour and in one or several of the satellites. However, all these cases also contained diploid cell lines, both in the main tumour and in one or several of the satellites. Tumours with a volume exceeding 12 cc:s were non-diploid in 87.5% of cases (7/8). Tumours with volumes between 8 and 12 cc:s contained non-diploid foci in 50% of cases (2/4). Tumours smaller than 2 cc:s were non-diploid in 18% of cases (2/11). All non-diploid tumours were moderately or poorly differentiated. Of the non-diploid tumours, 96% (23/24) displayed capsular penetration versus 57% (17/30) of the diploid tumours (p < 0.0001). All PIN samples were made up of diploid cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of 3 months' neoadjuvant hormonal treatment with a GnRH analogue (triptorelin) prior to radical retropubic prostatectomy on prostate-specific antigen and tumour volume in prostate cancer.

In this retrospective study the relationship between serum prostate-specific antigen (PSA) and tumour volume (assessed by the planimetric method on whole mount section) was analysed in 56 patients subjected to radical prostatectomy, of whom 28 received 3 months of neoadjuvant GnRH analogue (triptorelin) treatment. Serum PSA in the control group was strongly correlated to the tumour volume while no such correlation was found after hormonal pretreatment (r = 0.84 vs. 0.18), indicating that serum PSA is unreliable as a tumour marker after hormonal deprivation. When the pretreatment PSA (before hormonal deprivation) per tumour volume ratio was calculated, a group of 10 patients (36%) showed considerably higher values, suggesting true tumour volume reduction in those patients as a result of the neoadjuvant hormonal treatment.

Prostatic intraepithelial neoplasia and invasive carcinoma in total prostatectomy specimens: distribution, volumes and DNA ploidy.

Prostatic intraepithelial neoplasia (PIN) has been postulated to be the main precursor of invasive carcinoma of the prostate (IC). The occurrence, distribution and volumes of PIN and IC in addition to grade were studied in 54 patients who underwent total prostatectomy because of localised IC (T0d-T2 NO MO). PIN always occurred multifocally, localised generally in the peripheral zone (PZ) and was found in all cases. PIN 1 was the most common grade, PIN 3 the least. PIN 3 occurred exclusively in the PZ, in the vicinity of or intermingled with high grade IC. PIN and IC grades were usually concordant. The relative volumes of IC and PIN showed an inverse relationship, i.e. at small IC + PIN volumes PIN dominated, whereas at large IC + PIN volumes both relative and absolute PIN volumes were lower. Furthermore, with increasing PIN grade a tendency towards an increase in tumour volume, Gleason score and frequency of disruption of the basal cell layer was observed. These findings indicate progression from PIN to IC. DNA ploidy of PIN areas was determined by means of flow cytometry. Areas containing PIN 1, 2 or 3 were sampled (1 plug/ml of PIN). All foci displayed only diploid DNA profiles regardless of PIN volume and grade, even with coexistent IC displaying heterogeneous DNA patterns. Our results support the claim that low and medium grade prostatic carcinoma arises from near-diploid PIN stemlines and may progress into heterogeneous tumours containing non-diploid stemlines.

Histopathological changes in androgen-deprived localized prostatic cancer. A study in total prostatectomy specimens.

Androgen deprivation with triptorelin treatment prior to total prostatectomy gave the opportunity of studying consequent morphological changes in the surgical specimens from 38 men with localized prostatic cancer. Multiple core-needle biopsies were taken prior to treatment and compared to the step-sectioned surgical specimens. The histological changes in the prostate following androgen deprivation include glandular atrophy, nuclear pyknosis, cytoplasmic vacuolation, squamous metaplasia and an increase in the relative amount of stroma. None of these changes could be correlated to pretreatment tumour grade, nor to the volume of the residual tumour. A positive correlation was found between tumour grade prior to therapy and volume of residual tumour after treatment. The treatment was not associated with downgrading of the malignancy. On the contrary, in 16% of the cases, foci of a higher grade were found in the surgical specimens compared to the pretreatment core-needle biopsies.

Lack of influence on collagen accumulation in granulation tissue with 'delayed' defibrinogenation. A study in the rabbit.

Systemic defibrinogenation using Arvin delays wound strength development and collagen accumulation in sponge-induced granulation tissue. Whether this effect is due to interference with the initial fibrin deposition or to any inhibiting action on fibroblast function has not been decided. In the present study the administration of Arvin is started after the initial formation of a fibrin framework. No effect on collagen accumulation in granulation tissue was demonstrated, suggesting that the action of Arvin on wound healing is limited to the first phase of wound healing and that a normal fibrin deposition is necessary for a normal healing process.

Cell composition of granulation tissue in defibrinogenated rabbits.

The influence of systemic defibrinogenation on cell composition and capillary formation in sponge-induced early granulation tissue was studied in rabbits. The tissue was studied histologically and the content of RNA, DNA and Hb was determined. Inflammatory cells were identified and quantified using histochemical and biochemical techniques. An accumulation of PMN-leucocytes was found after defibrinogenation whereas the amount of fibroblasts and capillaries was reduced.

Effect of defibrinogenation on wound strength and collagen formation. A study in the rabbit.

Wound healing was studied in Arvin-defibrinogenated rabbits by determinations of skin wound strength and by analysis of collagen content in sponge induced granulation tissue. Strength development was found to be delayed in skin wounds as was the accumulation of collagen in granulation tissue. These results indicate that the initial fibrin formation in a wound is of significance for repair.

Effect of defibrinogenation on collagen synthesis in granulation tissue. A study in the rabbit.

Collagen synthesis was studied in sponge-induced early granulation tissue from rabbits defibrinogenated by Arvin. Tissue slices were incubated in vitro with 14C-proline. The formation of 14C-hydroxyproline and the incorporation of 14C-proline into proteins was determined. The incorporation of proline into collagen and proteins was equally reduced after defibrinogenation. A possible explanation for this is a reduced number of active fibroblasts in granulation tissue formed during defibrinogenation.

Wound healing and formation of granulation tissue in normal and defibrinogenated rabbits. An experimental model and histological study.

The aim of this investigation was to develop an experimental model for studies on the significance of fibrin deposition for wound healing. Systemic defirbinogenation with Arvin was used to achieve abnormal fibrin deposition in subcutaneously implanted cellulose sponges. The formation of granulation tissue in the sponges was studied histologically. Arvin injections resulted in a rapid decrease in plasma fibrinogen concentration with a concomittant rise in fibrin-degradation products. No change in FXIIIa activity was seen. During defibrinogenation an abnormal fibrin deposition was found in the sponges. The fibrin strands appeared irregular and disrupted. The number of fibroblasts and collagen fibrils was reduced in granulation tissue formed during defibrinogenation. The model used seems to allow controlled studies on the significance of fibrin deposition for wound healing. Defibrinogenation was found to influence granulation tissue formation.