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Objectives: The optimal palliative treatment in patients with advanced hormone-resistant prostate cancer (AHRPC) is still under investigation. We studied the effect of epirubicin, alone or combined with medroxy progesterone acetate (MPA), in this particular patient group. The aim of the study was to investigate the feasibility of quality of life (QOL) measurement and to ascertain whether MPA added to epirubicin produces a better QOL than epirubicin alone., Methods: Of 28 randomized patients with symptomatic AHRPC, 26 were eligible for the study. Fourteen of them received epirubicin (100 mg/m(2) i.v.) every 3 weeks in combination with an oral dose of 500 mg of MPA twice daily. Twelve patients received epirubicin alone. For the QOL assessment, the Rotterdam Symptom Checkliste was used. Toxic side effects of chemotherapy were assed by the WHO criteria. Subjective responses included performance status and pain score., Results: Compliance in completing QOL questionnaires was high (87.5%). In none of the QOL domains studied did any of the patients, irrespective of their treatment, experience an improvement in their QOL. Moreover, after 12 and 24 weeks, patients in both treatment arms experienced a significant worsening of physical symptom distress when compared to study entry. Toxicity was moderate to severe. A biochemical response (drop in prostate-specific antigen of more than 50%) was observed in 5 out of 26 patients (19.1%) and a subjective response in 7 out of 26 patients (26.9%). The median survival for all patients was 30 weeks. There was no statistically significant difference between the two arms. Performance status and the global QOL as judged by the patients themselves were associated with the duration of survival. No relation was found between the initial observed subjective response and survival., Conclusions: The feasibility of measuring QOL in patients with symptomatic AHRPC is demonstrated in the present study. Subjective and biochemical responses were observed in both treatment arms, but these were not translatable as improved measured QOL domains.

Objective: In intravesical Bacille bilié de Calmette-Guérin (BCG) immunotherapy of superficial bladder cancer, a T cell mediated immunological reaction is associated with the antitumor activity. To gain insight into the approximate number of BCG bacteria retained in the normal, noninjured, urinary bladder after intravesical application responsible for induction of the immune reaction, the utility of a sensitive polymerase chain reaction (PCR) based assay was investigated in a guinea pig model., Methods: After one single or six subsequent weekly instillations with 1x10(7) CFU of BCG, the bladders were resected and processed for BCG determination with PCR. The bladders were resected 24 h after instillation, aiming at (semi)quantifying the number of BCG organisms able to resist the natural voiding washout of the bladder. The PCR was based on amplification of a 249 base pair fragment of the insertion element IS6110 and is specific for bacteria belonging to the Mycobacterium tuberculosis complex which includes Mycobacterium bovis BCG., Results: After one single instillation no detectable BCG retention was found. However, after six weekly instillations, BCG bacteria could be demonstrated in 2 out of 5 guinea pig bladders, indicating that the number of adhering BCG organisms was around the detection limit of the assay (600-1,000 BCG bacteria per bladder)., Conclusions: The data suggest that after six instillations, the retention of BCG in the guinea pig bladder is enhanced as compared with one single instillation. This finding is suggestive of a role of the inflammatory process that is, besides immune system mediated reactions, associated with intravesical BCG instillations. The nature of the molecules involved in enhanced BCG retention after repeated instillations remains to be investigated.

Objective: The therapeutic objectives in the initial treatment of superficial tumors are to remove completely the tumor, to assess the need for further therapy and to plan the follow-up., Methods/results: The EORTC Genitourinary Group assessed the percentage of patients with recurrence at 3 months (3RR) after complete resection of all visible lesions taking into account the institution, the number of tumors at presentation and the year of treatment. The 3RR was considered for 18 institutions. For single tumors, the 3RR varied from 0 to 36% and for multiple tumors from 7 to 75%. The 3RR by number of tumors was 8.7% for single tumors, 21% for 2-5 tumors and 32.2% for >5 tumors. The 3RR by year of entry for single tumors ranged from 21.0 to 43.8% during 1975-1978, from 6.3 to 12.7% during 1984-1986 and from 3 to 5.3% during 1987-1989. For multiple tumors it ranged from 50.0 to 61.5% during 1975-1978, from 20.2 to 27.3% during 1979-1983 and from 14.4 to 24.6% during 1984- 1986. The use of more refined instruments probably led to the decreasing percentage of the 3RR in more recent years, the large variation between institutions remains unexplained. The bladder's unique location renders its mucosa accessible to instillation of chemotherapeutic and immunotherapeutic agents. Cytostatics can be instilled into the bladder hours after surgery without severe complications. A single early instillation within 6 h after transurethral resection (TUR) in patients with a solitary bladder tumor category T(a)/T(1)G(1) to G(3) could reduce the recurrence rate per year by nearly 50%. The superiority of any of the commonly used intravesical drugs has never been demonstrated; the time to initiate therapy is important for treatment outcome. Optimal results can be achieved by initiating treatment early (within 24 h after TUR) and for a duration of 6 months, and maintenance (>6 months) for patients with a delayed first instillation (>7 days after TUR). Bacillus Calmette-Guérin (BCG) immunotherapy has been confirmed to be highly effective in the reduction of tumor recurrence, the treatment of residual papillary transitional cell carcinoma and the treatment of carcinoma in situ (CIS). The response rate in the treatment of the papillary disease averages 55%, and for CIS 73%. In the prevention of tumor recurrence the relative benefit of BCG is 45%. A direct prospective randomized comparison of BCG with intravesical chemotherapy has found it to be significantly superior to thiotepa, to doxorubicin and to mitomycin C when only patients with intermediate and high risk for recurrence were treated. In studies including patients with low recurrence risk, no advantage for BCG was found. Clinical trials showed no superiority of BCG immunotherapy to chemotherapy in preventing progression to > or =T(2)., Conclusions: Investigation of the concept of chemoimmunotherapy up to now lacked evidence of advantages for this approach. Preventive regulatory measures directed to decrease tobacco smoking and some occupational exposures to aromatic amines may contribute to the reduction of bladder cancer. Bladder cancer is a multistep process making this tumor a candidate for chemoprevention. To date, retinoids are the best-studied chemopreventive agents achieving mixed clinical results in superficial bladder tumors. The potent apoptosis-inducing retinoid fenretinide is currently in the phase III trials. The follow-up of patients with all types of superficial tumors must be lifelong; unfortunately cystoscopy cannot be replaced yet by the control of any markers present or not in the urine. There is hope this may change in the near future., (Copyright 2000 S. Karger AG, Basel)

Background: Intravesical bacillus Calmette-Guérin (BCG) immunotherapy is currently the most effective treatment for superficial transitional cell carcinoma (TCC) of the urinary bladder. In recent years, the substantial number of patients not responding to BCG or experiencing considerable toxicities has stimulated studies addressing either the development of improved BCG treatment schedules or the exploration of the therapeutic value of a series of (novel) biological response modifiers, like interferons (IFNs), interleukin (IL) 2 and keyhole limpet hemocyanin. Although the actual mechanism by which BCG exerts its antitumor effect still needs detailed unraveling, current available knowledge suggests the induction of a T helper 1 (Th1) or Th1-like cytokine profile, represented by IL-2, IL-12 and IFN-gamma, as essential in the development of a cell-mediated antitumor activity., Conclusions: In this review, it is argued that incorporation of urinary cytokine determinations, like IL-2 and possibly IL-12 and IFN-gamma, may represent a valuable approach in the optimization and individualization of the BCG therapy and an early, initial evaluation of the potential efficacy of novel immunomodulating agents in the treatment of superficial TCC., (Copyright 2000 S. Karger AG, Basel)

Objectives: We investigated to what extent biopsies of normal-appearing urothelium taken from patients with Ta,T1 bladder cancer showed malignant disease: carcinoma in situ, or papillary tumor. We also investigated biopsies underlying the papillary tumor, adjacent to the tumor, and from suspicious-appearing mucosa., Methods: In EORTC protocol 30863 (low-risk tumors), 393 patients underwent a biopsy of normal-appearing urothelium. In protocol 30911 (intermediate- and high-risk tumors), multiple biopsies were taken from normal- appearing urothelium in 602 patients., Results: No abnormalities were found in the random biopsies of 376 (95.6%) patients with low-risk tumors and in 532 (88.4%) patients with intermediate- and high-risk tumors. Six (1.5%) patients with low-risk tumors and at least 21 (3.5%) patients with higher-risk tumors showed carcinoma in situ in their random biopsies. None of the patients in the low-risk group and 1 (0.2%) patient in higher-risk group had an invasive tumor (T2)., Conclusions: This analysis indicates that biopsies of normal-appearing urothelium in Ta,T1 bladder cancer patients show no abnormalities in about 90% of the patients. Performing such biopsies does not contribute to the staging or to the choice of adjuvant therapy after transurethral resection.

Ureteric peristalsis transports a urinary bolus from the renal pelvis to the bladder. We developed an intraluminal catheter with a pressure transducer on it to study intraluminal pressure changes and a twin bipolar electrode to record the ureteric EMG and impedance (Z) changes during a peristaltic wave. Five female New Yorkshire pigs (50-60 kg) were studied under light halothane anesthesia (5% at induction/1% for maintenance). A steady state of hydration was maintained using intravenous saline infusion. EMG spike burst activity was studied at a 10-cm interval using low (0-30) Hz filters. Impedance between the same electrodes is measured simultaneously in higher frequencies (1-5 KHz) as a function of ureteric motor activity. Pressure generation in the ureteric lumen was also measured simultaneously by a transducer on the same catheter. A digital signal processing program (Poly 4.9) was used for analysis. Parenteral furosemide was used to induce diuresis. Resting ureteric impedance (Z(R)) decreases to Z(B) (Z bolus) during the passage of the urinary bolus. Passage of a contractile zone during a peristaltic wave increases impedance from Z(B) to its Z(R) level and initiates a pressure rise. Bolus length (the length Z(B)) is not constant and decreases distally. EMG corresponds well in time to impedance. Z(R) disappears after infusion of furosemide because of increased urine load and changes of intraluminal ionic environment. The contractile segment of a ureteric peristaltic wave appears to be represented by an elevated Z segment (Z(C)). Pressure rise is recorded only at the beginning of a contractile zone. A specially adapted intraluminal catheter can be used to study peristalsis in the upper urinary tract. One can study all the three components of ureteric peristalsis (excitation, contraction, and intraluminal pressure rise) using such a catheter.

Purpose: In patients with superficial bladder cancer treated with a first 6-week instillation course of bacillus Calmette-Guerin (BCG) the induction pattern of urinary interleukin (IL)-2 has been described, and the levels of urinary IL-2 were associated with the clinical response to BCG treatment. We evaluated urinary IL-2 kinetics in patients with recurrent superficial bladder tumor receiving a second or third 6-week BCG instillation course. To our knowledge there have been no studies of prolonged BCG treatment and urinary cytokine responses., Materials and Methods: Urinary IL-2 was determined in 12 patients with superficial transitional cell carcinoma of the bladder receiving a complete (6-week) second or third BCG instillation course and in 3 patients receiving 3 BCG instillations during a maintenance schedule at month 3. Urinary IL-2 was determined with an enzyme-linked immunosorbent assay using an oligoclonal system., Results: Of 12 patients 10 had a urinary IL-2 positive response during the subsequent BCG course and at week 1 urinary IL-2 was already increased. Comparing the urinary IL-2 kinetics observed during a second or third with a first course, urinary IL-2 tended to be higher during the first and lower during the last weeks. If the interval between subsequent courses was short (12 months or less) significantly higher urinary IL-2 levels at weeks 1 and 2, and a lower level at week 6 were observed., Conclusions: During a repeat BCG instillation course urinary IL-2 reached a maximum at an earlier week, especially if the interval between the subsequent courses was short. Since an association between urinary IL-2 levels and response to BCG treatment during an induction course has been observed, these immunological data argue in favor of a limited number of instillations during prolonged BCG therapy which could reduce side effects as well as costs.

Objectives: Application of immunocytology directed against antigens of urothelial tumor cells or tumor-associated breakdown products intends to improve the sensitivity of the diagnosis of superficial transitional cell carcinoma (TCC) of the urinary bladder. In this study, the mode of action, sensitivity and specificity of the Bard(R) BTA test, detecting a tumor-associated release of a basement membrane complex, was addressed and compared with voided urine cytology (VUC)., Results: Contrary to grade, a significant (p = 0. 003) relationship between tumor stage and BTA test sensitivity was observed, being 23.8, 33.3 to 100% for Ta (n = 42), T1 (n = 6) to >/=T2 (n = 5), respectively. These data suggest an association between an increase of the BTA test sensitivity with an increase of basement membrane degradation or interruption. With regard to this mechanism, the BTA test may be of special importance for monitoring tumor progression or increase in tumor invasiveness. Detection of low-stage, low-grade tumors by noninvasive techniques remains a challenge. The sensitivity of the BTA test for the presence of TCC was 32.3%, while that of VUC was 17.7%, but in this study the difference was not statistically significant. Furthermore, the BTA test was not more effective in identifying the various tumor grades, stages or stage/grade groupings. However, dividing the patients in two groups of low risk (TaG1/TaG2) and high risk (TaG3 to >/=T2) leads to a significant (p = 0.008) increased sensitivity of the BTA test (27.3%) in detecting patients with low-risk tumors compared to VUC (3.0%). The specificity of the BTA test in patients with a history of TCC was 81.6%, while that of VUC was 98.9%., Conclusion: The sensitivity of the BTA test is at least equivalent to VUC and may be suited to monitor increase in stage in patients suffering from bladder carcinoma, but cannot replace cystoscopy in patients suspected for a bladder tumor.

Intravesical bacillus Calmette-Guerin (BCG) is a successful therapy for superficial bladder cancer. However, the working mechanism of BCG after intravesical instillation is not completely understood. A functional role of urothelial (tumor) cells in the initiation of the BCG-induced immune reaction should be considered. Here, the possibility of a causal relationship between BCG-induced interleukin-6 (IL-6) synthesis and BCG internalization by urothelial tumor cells was examined in a series of human transitional bladder cancer (TCC) cell lines with different degrees of differentiation. The results showed that the well differentiated TCC cell lines, RT4, SBC-2, and SBC-7, did not possess the capacity to internalize BCG, which was associated with an inability to upregulate IL-6 synthesis when stimulated with BCG. Moreover, these cell lines expressed a low level of constitutive IL-6 synthesis. In contrast, the poorly differentiated TCC cells, T-24, TCC-SUP and J-82, were able to internalize BCG. In T24 and J82, but not in TCC-SUP cells, BCG internalization appeared to result in an upregulation of IL-6 synthesis. Constitutive IL-6 synthesis of the high grade cell lines was found to be cell line-dependent: both TCC-SUP and J82 cells exhibited a high level of constitutive IL-6 synthesis, whereas T24 cells exhibited a low level. The possible relationship between BCG internalization and IL-6 upregulation was studied in detail with the T24 cell line, which exhibited a low constitutive and high BCG-inducible IL-6 synthesis, using anti-BCG antibodies (alphaBCG) and Cytochalasin B as internalization inhibitors. Upregulation of IL-6 synthesis was significantly inhibited by alphaBCG or Cytochalasin B, indicating that internalization is a prerequisite for BCG-induced upregulation of IL-6 synthesis. In conclusion, upregulation of IL-6 production due to BCG internalization by poorly differentiated bladder carcinoma cells may be part of the mode of action of intravesical BCG therapy.

Retroperitoneal endoscopic nephrectomy with the patient in the prone position was performed in 12 patients. Indications for this procedure were end-stage kidneys with ureteropelvic junction stenosis or distal ureteric obstruction, nonfunctional kidneys with drug resistant renin-mediated hypertension, and distal ureter malignancy. The retroperitoneal area was exposed using an open surgical technique in combination with the use of a liquid-filled dissection balloon. Removal of kidney tissue was performed with a morcellator through one of the ports. On average, the operating time was 210 min (range 160-480 min) to complete a one-sided nephrectomy. No major complications occurred. Mean hospital stay in this series was 6.6 days, and the follow-up period was uncomplicated in all cases. Retroperitoneal endoscopic nephrectomy with the patient in the prone position is an acceptable alternative to open nephrectomy in selected indications.

A growing number of data support the importance of urinary cytokines in the BCG immunotherapy of superficial bladder tumours. To investigate kinetics and stability, urinary levels of IL-8, IL-2 and IL-6 cytokines after BCG treatment, were determined. Significant elevation in the level of IL-8 was established immediately following the first BCG instillation and it reached its highest value 4-6 hours after the treatment. During the first three weeks of the treatment and follow-up period IL-8 peaked significantly earlier than IL-2 or IL-6. Its early appearance associated with high stability makes IL-8 a good candidate for being considered as an effective agent with high predictive value in BCG immunotherapy.

Multichannel Urethral Pressure Profilometry (MCUPP) is a method used to get more information on the pressure distribution within the female urethra. This information may be of value in the diagnostic work up of women with urinary incontinence. Different systems are used for this technique. The pump is an important part of such a system. The catheter is perfused with water pumped through the side hole of the catheter. Air bubbles inside one or more of the eight channels alter the elastic properties of the catheter making the results unreliable. In daily urodynamic practice it is important that the system is patient and user-friendly, is quick to set up, and the performance of measurements is easy. For this reason a new type of pump was developed that is able to produce a pressure stable continuous flow through the eight channels of the catheter. The problem of air bubbles has been solved and different measurements can be performed serially in a short time. The system currently used by us is described.

Purpose: We compared the efficacy of transurethral resection alone or transurethral resection followed by bladder instillations of doxorubicin or ethoglucid for 1 year in patients with superficial bladder carcinoma, and followed them long term for the incidence of progression to muscle invasion., Materials and Methods: A total of 443 patients with superficial transitional cell carcinoma of the bladder was randomized. After randomization of 206 patients the control arm was closed to patient entry based on the results of an interim analysis showing a significant difference in favor of those receiving adjuvant chemotherapy., Results: Final analysis of treatment results for recurrence included 432 patients at a median followup of 3.4 years for time to first recurrence, 5 years for analysis of time to invasion (Category T2 disease or worse) and 10.7 years for duration of survival. Time to first recurrence was significantly prolonged by both drugs compared to transurethral resection alone (doxorubicin versus transurethral resection alone p < 0.001 and ethoglucid versus control p < 0.001). Recurrence rate per year was 0.30 for both adjuvant treatment arms and 0.68 for the resection only group. Progression to muscle invasion was rare (15.1% of cases) and not apparently different in the 3 treatment arms. Of the 423 patients death from any cause in 199 and from malignant disease in 59 was not correlated with treatment. However, there was a strong correlation between death from malignant disease, and T category and tumor grade., Conclusions: In regard to time to first recurrence and recurrence rate per year this study indicates that adjuvant chemotherapy with doxorubicin and ethoglucid using the indicated schedule is superior to transurethral resection alone. However, progression in stage or survival was not influenced by the treatment regimen.

Urethral pressure profilometry (UPP) is used to investigate the pressure distribution in the urethra. Single UPP is dependent on the orientation of the catheter during the study. To circumvent this problem, we developed a system for multichannel profilometry (MCUPP) that can be used in daily clinical practice. In the study reported in this article, 29 healthy female volunteers (mean age 34.6 years) underwent MCUPP. The mean time needed to make five pressure profiles ranged from 4 to 12 minutes (mean 7.6). The system is patient- and user-friendly. The volunteers scored the discomfort on a 1 to 10 scale, with 10 meaning no discomfort at all, rendering a mean score of 7.6. The Symmetry Index (SI) is a calculated variable expressing the asymmetry in the pressure profiles. An SI of 1 means a completely symmetrical pattern of pressure distribution. The mean SI for the whole group was 0.7 (range 0.407-0.930). The standard deviation was 0.109. Within-subject SI was highly reproducible (Greenhouse-Geisser epsilon = 0.98292).

Hypercalcemia is a well known complication of renal cell carcinoma (RCC). As RCCs can produce IL-6, and IL-6 may stimulate bone resorption and cause mild hypercalcemia, we examined whether IL-6 is involved in renal cancer-associated hypercalcemia in vivo. Three human renal cell carcinoma tumor lines (RC-8, RC-9, and NC-65) growing in nude mice were studied. Tumors were implanted s.c., and parameters of bone metabolism and serum human IL-6 levels were determined in relation to tumor volume (TV). All three tumor lines secreted human IL-6, although in different quantities. The maximum level of IL-6 in RC-8 was 434 pg/ml (TV, 200 mm3), that in RC-9 was 81 pg/ml (TV, 1800 mm3), and that in NC-65 was 2368 pg/ml (TV, 1800 mm3). Hypercalcemia developed in RC-8 and RC-9 tumor-bearing animals, but not in NC-65-bearing animals. The hypercalcemia in both RC-8 and RC-9 tumor lines was associated with elevated levels of PTH-related peptide (PTHrP) and loss of trabecular bone volume. Serum calcium and phosphate concentrations showed an almost linear relationship with plasma PTHrP independently of the tumor line and serum IL-6 levels. No hypercalcemia occurred in the NC-65 animals, which had the highest levels of IL-6, but no detectable plasma PTHrP and PTHrP messenger RNA expression in the tumor. Administration of neutralizing antibodies to IL-6 to RC-8 animals normalized serum calcium concentrations and PTHrP values and induced a significant inhibition of tumor growth. No such effect on tumor growth of anti-IL-6 was seen in the other two tumor lines. The normalization of serum calcium in RC-8 mice is most likely attributed to the growth-inhibiting effect of anti-IL-6 on RC-8 tumor. We conclude that IL-6 secreted by RCC does not contribute directly to hypercalcemia, but may enhance hypercalcemia by stimulating the tumor growth of a subpopulation of PTHrP-secreting carcinomas.

Objective: To evaluate the prevalence of urological morbidity in patients with prostate cancer and its influence on global quality of life (QL)., Methods: 379 patients with prostate cancer completed several questionnaires (EORTC QLQ-C33, I-PSS, PAIS [sexuality]) and were grouped according to the type of treatment they had undergone: observation only (n = 57), androgen deprivation (n = 112), radiotherapy (n = 114) and radical prostatectomy (n = 96). A group of 86 urologists also completed the questionnaires, imagining that they had stable prostate cancer and had been undergoing androgen deprivation for at least 1 year. Their responses were compared with those from patients who had undergone androgen deprivation., Results: In all patient groups urinary symptoms were mostly mild to moderate but 12% of patients who had undergone radiotherapy and 11% of hormonally treated patients described severe symptoms. Severe urinary leakage occurred in 16% of patients who had undergone radical prostatectomy. 22% of all patients were impotent before treatment; after treatment sexual life was considerably disturbed in all patients except those who had undergone observation only. Fatigue was a general problem in all patients. In the logistic regression analysis fatigue and lower urinary tract symptoms (LUTS), but not disturbance of sexual life or urinary leakage, were correlated with global QL. In the doctor-patient comparison, doctors underestimated the disturbance of sexual life in patients who had undergone androgen deprivation therapy but overestimated the impairment of QL and psychological distress experienced by these patients., Conclusions: LUTS and fatigue are independent predictive factors for global QL after initial treatment in patients with prostate cancer. Radiotherapy of the prostate leads to more significant morbidity than was generally anticipated by doctors. The disagreement between doctors' and patients' assessments of QL following treatment indicates the necessity for further systematic QL evaluation in these patients.

In intravesical therapy for superficial bladder carcinoma urothelial cells may, through the production of cytokines, contribute to the bacillus Calmette-Guerin (BCG)-induced local immunological reaction and associated antitumor efficacy. The aim of this study was to investigate such a role for the neutrophil-attracting cytokine interleukin-8 (IL-8). The appearance of IL-8 in patients urine after BCG therapy was compared with BCG-induced IL-6 and IL-2 and the stability of IL-8 in urine was tested. Compared to IL-6 and IL-2, a rapid induction of IL-8 was observed, occurring after the first BCG instillation. Urinary IL-8 was highly stable, even after 24 h incubation at 37 degrees C. The IL-8 concentration after the first instillation seemed to be associated with subsequent development of an immune response. Consequently, IL-8 seems an attractive candidate for investigation of its prognostic value for a clinical response to BCG therapy.

Development and progression of prostate cancer is a multistep process of cumulative genetic damage, acquired during a life-time. However, the altered genotype acts against an appropriate background of epigenetic control mechanisms. Several mechanisms of mitotically heritable, epigenetic control of differential gene transcription have been noted, such as stromal-epithelial and cell-cell interactions. In prostate cancer, an important, supporting and/or inhibiting role of stromal-epithelial interaction has been implicated in tumor growth, angiogenesis and metastasis, which includes cell proliferation, adhesion and motility. Within these processes, data mainly obtained in systems other than the prostate have shown a crucial (regulatory) role of proteoglycans (PGs) acting at the level of cell-cell and cell-pericellular matrix interactions. Although little information has been recorded from normal, benign hyperplastic and malignant prostate tissue, PGs are components of both the cell surface and the extracellular matrix (ECM) that form associations with other molecules, such as fibronectin and laminin. On the basis of cell-ECM adhesion/interaction as a prerequisite for both cell proliferation and motility, and the involvement of PGs, the purpose of this study was to investigate the possible biological relevance of (free) glycosaminoglycans (GAGs), as major functional substructures of PGs, on cell adhesion of a series of human prostatic cell lines cultured in vitro. The effects of a series of exogenously applied GAGs on cell adhesion and proliferation were studied in the human cell lines LNCaP, DU 145 and PC-3, cultured on tissue culture plastic as substratum. The applied GAGs were the natural GAGs heparin, heparan, dermatan, chondroitin-4 and chondroitin-6 sulfate, and the semisynthetic, GAG-like pentosan polysulfate (PPS). Addition of GAGs (1-300 micrograms/ml) to cultures that were allowed to adhere for 24 h prior to GAG addition did not affect cell proliferation. In contrast, whereas the natural GAG added during cell adhesion had no effect. PPS strongly inhibited proliferation of LNCaP and DU145, but not the less anchorage-dependent PC-3 cells. Under the latter conditions, after 6 days of culturing the IC50 of proliferation were determined to be < 1 and 50 micrograms PPS/ml for LNCaP and DU145, respectively, corresponding with a profound effect on cell morphology. Direct measurements of cell adhesion confirmed that, in contrast to the natural GAGs, PPS inhibited cell adhesion. In conclusion, the interference of a nonnatural, GAG-like structure with cell adhesion may be interpreted as the involvement of PGs of the cell surface in cell adhesion, possibly affecting the various processes (proliferation, angiogenesis and metastasis) of prostate tumor progression. Although similar interferences of nonnatural GAGs with cell-adhesion-associated proliferation of anchorage-dependent cells remain to be established under in vivo conditions, this type of compounds deserves further attention as a tool with which to study the role of cell adhesion in the progression of prostate cancer and as a potential candidate for the development of a stromal-epithelial targeted therapy.

Objectives: Twelve patients with superficial papillary transitional cell carcinoma of the bladder (pTa, pT1) were treated with six consecutive weekly intravesical instillations of Rubratin (in a dose of 1.5, 3.0, or 4.5 mg), a cell wall skeleton preparation of Nocardia rubra (NCW). The main objective of this study was to look for local immunomodulating effects of NCW and in the first four patients the effect on a marker lesion was also investigated., Methods: Local immunostimulation in all 12 patients was determined by (1) measurement of cytokine induction [interleukin 1 beta (IL1 beta), IL2, IL6, and tumor necrosis factor alpha (TNF alpha)], (2) leukocyte influx into the urine, and (3) phenotypic analysis of the lymphocyte fraction of these leukocytes., Results: Significantly elevated levels of Rubratin-induced IL1 beta (P < 0.001), IL2 (P < 0.001), IL6 (P < 0.01), and TNF alpha (P < 0.001) were found compared to control pretherapy levels. Rubratin also induced leukocyte influx into the urine. Fluorescence-activated cell sorter (FACS) analysis of the urinary leukocytes indicated T-cell activation (IL2 receptor and HLA-DR expression), while in two out of five patients the CD4/CD8 ratios were increased. Urinary cytokine induction by Rubratin was comparable with cytokine induction observed in nonresponding bacillus Calmette-Guérin (BCG) patients (recurrent tumor within 6 months), but less compared with responding BCG patients (no recurrent tumor within 6 months). Clinical results showed no response on the marker lesion and in five out of eight patients early recurrence was found after complete transurethral resection (TUR) of the bladder tumors. This biological response modifier caused no local or systemic side effects at the doses used., Conclusion: Although local immunostimulation by intravesical Rubratin administration can be induced, the amount of immunocompetent cells attracted to the bladder is not as high as observed in BCG-responding patients, resulting in lower amounts of cytokines produced. This could also explain the lack of clinical efficacy.

Clinical evaluation in oncology has typically focused on outcome indicators, while less attention has been paid to how treatment affects quality of life (QOL) of the patient. In this article some general aspects of quality of life are discussed, a short review of published data on QOL in patients with prostate cancer is given and results of a QOL study executed by the authors on patients with lymph node positive prostatic cancer are presented. The purpose of the study was to examine the impact of immediate or delayed treatment (after objective progression) in patients with prostatic carcinoma (T1-3 N1-3 M0) on quality of life parameters. To this end an extended questionnaire was constructed. Fifty-five patients participated. Assessment was performed twice, in 1994 and 1995. The comparison between patients with and patients without treatment showed in 1994 as well as in 1995 significant differences for hormonal treatment side effects such as sexual functioning and hot flushes, all of which were experienced more frequently by treated patients. In 1994 the treated patients experienced more psychological distress while in 1995 they showed worse physical function, less energy and more fatigue when compared to patients under surveillance. The premise that active treatment would improve the psychological quality of life was not sustained. In addition global health status and quality of life were identified as independent factors for progression in untreated patients with lymph node positive prostate cancer. Finally, an increase in prostate-specific antigen (PSA) in hormonally treated patients not only indicated hormonal escape but also a decrease in QOL.

The detection of potentially highly curable low-grade bladder cancers by noninvasive techniques remains an unsolved problem. Conventional cytology detects such tumors with 50% sensitivity, the addition of DNA image analysis cytometry in patients with previous transitional cell superficial bladder carcinoma increases the chance to detect low-grade tumors. The specificity and sensitivity of detection of low-grade bladder tumors can be further improved by quantitative fluorescence image analysis using antibodies directed against tumor-associated antigens. The chance of subsequent tumor following initial complete resection is significantly lowered compared to resection alone by either intravesical adjuvant chemotherapy or immunotherapy. BCG is superior to chemotherapy in patients with high risk for recurrence, adjuvant intravesical chemotherapy does not prevent progression to > T1 when compared with resection alone, BCG may delay progression and the need for cystectomy in high-risk patients (T1, Cis or Cis associated with papillary Ta/T1, > 3 recurrences/year, grade 3 tumors). Oral medication with bropirimine (an interferon inducer) induced complete response in patients with carcinoma in situ, oral Lactobacillus casei prolonged the recurrence-free interval to 1.8 times that in the control group. New compounds for adjuvant treatment of superficial bladder tumors are best first tested on their ablative effects (marker lesion, Cis) prior to be used for prophylaxis.

This study describes a new flow cytometric method for assessment of phagocytosis of specific bacteria (bacillus Calmette-Guérin (BCG) and Escherichia coli) by bladder epithelial cells. The internalization assay consisted of labeling bacteria chemically with fluorescein isothiocyanate (FITC). Subsequent to incubation of fluoresceinated bacteria with internalizing cells, adherent nonphagocytosed bacteria were marked by two-step labeling using specific antibodies and phycoerythrin (PE)-conjugated antibodies. Double fluorescent FACS analysis differentiated between bacterial phagocytosis and adherence. The validity of the method was shown by inhibition of BCG phagocytosis at 4 degrees C by cytochalasin B, by removal of excess free bacteria, and by anti-BCG antibodies. BCG-phagocytizing and -nonphagocytizing cell lines were discriminated by applying this technique to a series of bladder carcinoma cell lines. There seemed to be a relationship between phagocytic capacity and grade of differentiation in these cell lines, which may have implications for topical BCG immunotherapy in superficial bladder cancer. In conclusion, a new, reliable, rapid, and relatively simple double fluorescent method is described for quantification of specific bacterial internalization by large numbers of (bladder) epithelial cells. This method should be generally applicable to the study of in vitro interaction between bacteria and different types of host cells.

Purpose: The use of prophylactic agents after primary resection can decrease the incidence of tumor recurrence in patients with stage TaT1 bladder cancer. However, the long-term impact on progression to muscle invasive disease as well as on duration of survival is unknown. A combined analysis of individual patient data from previously performed European Organization for Research and Treatment of Cancer (EORTC) and Medical Research Council (MRC) randomized clinical trials was done in an attempt to answer these crucial questions. We compared immediate versus no adjuvant prophylactic treatment after transurethral resection with respect to disease-free interval, time to progression to muscle invasive disease, time to appearance of distant metastases, duration of survival and progression-free survival., Materials and Methods: All EORTC and MRC prophylactic, randomized phase III trials with primary or recurrent, stage TaT1 transitional cell bladder cancer that compared transurethral resection alone or with adjuvant prophylactic treatment were included in the study. Four EORTC and 2 MRC trials using intravesical chemotherapy or oral agents and including a total of 2,535 patients were studied., Results: A statistically significant effect of adjuvant treatment over no adjuvant treatment was found in terms of the duration of the disease-free interval (p < 0.01). No clear advantage of adjuvant treatment was shown with respect to progression to invasive disease, time to appearance of distant metastases or duration of survival and progression-free survival. Median survival followup was 7.8 years., Conclusions: Despite prologation of the disease-free-interval adjuvant treatment has no apparent long-term impact on the evolution of stage TaTi bladder cancer.

Endoluminal ultrasound (ELUS) with high-frequency transducers is a new technique for imaging tubular structures. In combination with a rotating mirror, 360 degrees cross-sectional images of the wall can be obtained. Because of the high frequency, the axial resolution is much higher and thus more detail can be seen. In the study reported in this article, ELUS was performed to image the wall of the female pig urethra to see whether cross-sectional images obtained by ELUS could be correlated with anatomic cross sections of the urethra. Commercially available transducers with a frequency of 30 and 20 MHz were used, the latter having the best suitable frequency for this procedure. The images were of high quality and the different anatomic layers could be clearly visualized. The mucosa/submucosa, the external sphincter, and the surrounding serosa were all identifiable. The correct interpretation was also confirmed by histological cross-section study. We believe that endoluminal ultrasound is a very promising technique for imaging the urethra. Further studies need to be conducted to improve the catheters for urological use and to develop the clinical usefulness of this technique.

Superficial bladder cancer is the presenting feature in 75% to 80% of patients with newly diagnosed bladder carcinoma. Treatment goals are (1) to eradicate existing disease, (2) to provide prophylaxis against recurrence, and (3) to prohibit muscular invasion and metastases to lymph nodes. First-line treatment for stages Ta and T1 disease is transurethral resection (TUR). Recurrence rates with surgery alone, however, range from 40% to 80%. Study results show a statistically significant benefit in treatment results over those observed with TUR alone when adjuvant intravesical instillation of cytotoxic agents or immunomodulators is added. Patient characteristics are important factors in determining which patients might benefit from adjuvant treatment. Based on several trials reported by the European Organization for the Research and Treatment of Cancer Genitourinary Group, the following conclusions can be drawn: (1) patients with < 1 recurrence/year or with a primary solitary bladder tumor category Ta G2-3 or T1 G1-3 may benefit from a single, early instillation of a cytotoxic agent, (2) solitary Ta G1 lesions may be treated with TUR alone, (3) adjuvant therapy with cytotoxic agents should be instituted as soon as possible after TUR (this is not feasible with immunotherapy), (4) for patients treated within 6 hours after or on the day of TUR, a 6-month course of therapy is sufficient, whereas a 12-month course provides better results for patients in whom such early intravesical instillation is not feasible.

Purpose: An accurate prognostic indicator to identify nonresponding patients with superficial transitional cell carcinoma of the bladder at an early stage of intravesical bacillus Calmette-Guerin (BCG) therapy is urgently needed., Materials and Methods: The processing conditions and stability of several BCG induced urinary cytokines were analyzed, as was the possible correlation between these cytokines (indicating immune responsiveness to BCG) and bladder tumor recurrence. We studied 23 patients with superficial transitional cell carcinoma of the bladder. Monitoring was performed by serial collection of urine during the first 24 hours after each of the 6 consecutive weekly intravesical BCG instillations. Baseline pre-therapy cytokine levels were 3.9 +/- 4.7 pg./mumol creatinine for interleukin-6 and 0.1 +/- 0.2 pg./mumol creatinine for tumor necrosis factor-alpha (all measured by enzyme-linked immunosorbent assay). To investigate the correlation between interleukin-2 and bladder tumor recurrence, patients were stratified into 2 groups based on an early (6 months or less) or late (greater than 6 months) recurrent tumor. For each patient the highest cytokine value measured during the 6-week BCG treatment course was evaluated., Results: The results were positive if the level in urine exceeded 0.34 units interleukin-2 per mumol. creatinine. A significant correlation between urinary interleukin-2 and tumor recurrence was found (p = 0.003, 23 patients). Of the studied cytokines obtained from BCG treated patients, interleukin-1 beta, 2 and 6 but not tumor necrosis factor-alpha were stable in urine at 4C and 20C. At 37C all cytokines were unstable. Interferon-gamma could only be detected in immediately dialyzed urine and its occurrence correlated most with that of interleukin-2. Processing of urine by centrifugation to remove leukocytes immediately after collection was not required for reliable measurements of interleukins-2 and 6. Based on these results interleukins-2 and 6 were preferred for extensive monitoring of the BCG induced immune reaction., Conclusions: Our study provides significant evidence for a correlation between urinary cytokine induction and clinical response following intravesical BCG therapy. Particularly, monitoring of interleukin-2 may have the potential for prognostic value provided that strict precautions regarding urine collection, such as maximal 2-hour sampling and immediate cooling, are taken.

Objective: The ability of prostate-specific antigen density (PSAD) to predict prostate cancer in biopsy specimens is evaluated in patients with benign digital rectal examination (DRE) and prostate-specific antigen (PSA) between 4.0 and 10.0 ng/ml., Material and Methods: 144 referred patients with a benign DRE and PSA > 4.0 ng/ml were additionally evaluated by transrectal ultrasonography and transrectal biopsies. PSAD values were calculated and statistical analysis was performed., Results: The mean PSAD value was able to distinguish significantly between benign prostate conditions and prostate cancer in patients with PSA > 4.0 ng/ml. However, in 73 patients with 4.0 < PSA < or = 10.0 ng/ml no significant stratification was obtained. At a PSAD value of 0.15 the pretest probability of 18% for positive biopsy was lowered to a posttest probability of 8.1% and PSAD appeared to be of limited value regarding sensitivity and specificity at different cutoff values (ROC curve). Applying age-specific reference ranges would have reduced diagnostic procedures for men between 60 and 79 years old with 7.0% without missing prostate cancer., Conclusions: In this study PSAD was shown to have only a moderate additive value in decision making to omit biopsy for the individual patient with benign DRE and PSA between 4.0 and 10.0 ng/ml. Age-specific reference ranges of PSA can prevent unnecessary diagnostic procedures.

Purpose: We attempt to contribute to the understanding of the natural history of prostate cancer metastatic to lymph nodes., Materials and Methods: A total of 61 patients with node-positive prostate cancer was prospectively followed without adjuvant treatment for an average of 41 months. The impact of T and P categories, grade, tumor volume and prostate specific antigen change on interval to progression was studied in a univariate and multivariate analysis., Results: Median interval to progression was 18 months, and correlated with grade and prostate specific antigen doubling time. Changes in prostatic volume with time were not predictive., Conclusions: Our study provides insight into the natural history of node-positive disease and identifies relevant prognostic factors that may be used for treatment decisions.

Prognostic factors in superficial bladder tumours are highly correlated with each other. In this study, their relative importance is examined and grouping of patients in three different prognostic groups suggested. 576 patients (from EORTC protocols 30790 and 30782) were analysed. They have been followed from 3 months to 8.6 years with a median of 4 years. 76 patients developed an invasive tumour (> or = T2); the shortest time to invasion was 12 weeks, the longest was 6.6 years. Time from invasion to death ranged from 3 weeks to 4.4 years with a median of 2 years. Prognostic factors contributing to recurrence, invasion and survival were investigated: age, sex, size of largest tumour, number of tumours, T-category, G-grade, time from diagnosis (years), prior recurrence rate/year, site of involvement. The relative importance of these factors was measured by performing a multivariate analysis based on Cox's proportional hazards regression model. Based on the most important prognostic factors and their association with invasion and death, an index was computed reflecting the risk of both invasion and death due to malignant disease, respectively. The index was used to assign patients to one of three prognostic groups. Three main factors determined patient's prognosis: tumour size, G-grade and prior recurrence rate/year. The model coefficients for invasion were 0.51 (recurrence rate < 1/year, 1-3/year, > 3/year), 84 (grade 1, 2, 3), 0.48 (size < 1.5, 1.5-3, > 3 cm) and for death due to malignant disease 0.89 (recurrence rate), 0.73 (grade) and 0.44 (size), respectively. Risk groups are suggested based on the index. Additional treatment in patients with superficial transitional cell carcinoma of the bladder may be decided depending on the risk group to which the patient belongs.

Radiation-induced severe haemorrhagic cystitis is difficult to treat. Conventional treatments may decrease haematuria but do not affect the radiocystitis itself. Hyperbaric oxygen treatment has been reported to do both. We report the results of a prospective study of hyperbaric oxygen (20 sessions of 100% oxygen inhalation at 3 bar for 90 min in a multiplace hyperbaric chamber) to 40 patients with biopsy-proven radiation cystitis and severe haematuria. Haematuria disappeared completely or improved in 37 patients after treatment. Mean follow-up was 23.1 months (range 1-74); and the recurrence rate was 0.12/year. There were no adverse effects. Hyperbaric oxygen treatment should be considered for patients with severe radiation-induced haematuria.

Purpose: We tested the theoretical concept that a selective decrease in estrogens has a beneficial therapeutic effect on established benign prostatic hyperplasia., Materials and Methods: In a double-blind study 160 patients from 14 centers were randomized between 2 groups to receive either placebo or the aromatase inhibitor atamestane (1-methyl-androsin-1,4 diene-3 17-dione, 400 mg. daily for 48 weeks)., Results: The aromatase inhibitor decreased the mean estradiol level by approximately 40% and estrone by 60%. The testosterone concentration increased by more than 40% and dihydrotestosterone increased to 30%. Analysis of clinical parameters showed no difference between placebo and atamestane., Conclusions: The counter regulatory increase in androgens may counterbalance any positive effect of the decrease in estrogens to preserve intraprostatic homeostasis.

Humoral hypercalcemia of malignancy is a paraneoplastic syndrome believed to be due to production by the tumor of substances that stimulate osteoclastic bone resorption primarily. The human renal cell carcinoma cell line RC-8, grown in nude mice, was investigated for factors involved in renal cancer-induced hypercalcemia. At a tumor load of 200 to 400 mm.3 the mice developed hypercalcemia and hypophosphatemia associated with a rise in serum 1,25-dihydroxyvitamin D concentration and cachexia. The tumor released 1) significant amounts of human interleukin-6 (IL-6) and 2) parathyroid hormone-related peptide (PTHrP) into the circulation. Cancer cells further expressed mRNA for both human IL-6 and PTHrP. No secretion of human tumor necrosis factor-alpha or interleukin-1 beta could be demonstrated in the circulation of the host. Antibodies to IL-6 caused a significant (p = 0.043) inhibition of tumor growth and decreased serum calcium concentrations compared with control animals. Our data suggest that IL-6 is involved, either directly or indirectly, in the development of hypercalcemia in renal cell carcinoma.

The European Organization for Research and Treatment of Cancer genitourinary group has completed 2 parallel prospective randomized studies, one with 30 mg. mitomycin C and the other with 50 mg. doxorubicin as adjuvant intravesical treatment after transurethral resection of superficial transitional cell bladder carcinoma. These studies were designed to compare early (the day of resection) versus delayed (between 7 and 15 days after resection) instillations and short-term (6 months) versus long-term (12 months) treatment. The results indicate that in regard to recurrence rate patients having a delayed and short-term treatment do worse than those having early instillations (for 6 or 12 months) or those having prolonged treatment (either immediate or delayed). With an average followup of 4 years survival, progression beyond T1 disease, development of distant metastases and appearance of a second primary were not influenced by the therapeutic regimen. A multivariate analysis of prognostic factors is presented, which indicates that after adjustment for these factors, patients in the delay, no maintenance arm have a significantly higher recurrence rate than the other patients.

Since its formation in the 1976, the European Organization for Research and Treatment of Cancer Genitourinary group has completed six phase III trails and six phase II trials in prostate cancer. Although these studies did not have a very strong influence on the management of prostate cancer worldwide or even in Europe, they did help investigators to design better studies and to gain some insight into the natural disease of the tumor.

Transrectal ultrasonography (TRUS), digital rectal examination (DRE), and quantification of serum prostate-specific antigen (PSA) are accepted and evaluated methods for detecting prostate cancer. Positive predictive values (PPV) of DRE and TRUS are low, and only slightly enhanced when used in combination with PSA. PSA lacks sufficient sensitivity and specificity to be used alone as a screening test for prostate cancer. The parameters PSA-density and PSA-velocity make PSA a better tumor marker, but they are not reliable on an individual basis. Age-specific reference ranges have the potential to make PSA a more sensitive tumor marker for men less than 60 years of age and a more specific one for men beyond 60 years. With currently available diagnostic methods approximately 10% of patients undergoing transurethral or open resection of the prostate for presumed benign prostatic hyperplasia will have carcinoma detected in the histologic material. In 392 patients successively treated in our clinic for presumed BPH and thoroughly investigated to exclude prostatic carcinoma (DRE, TRUS, biopsy when PSA > 4 ng/ml or PSA-D > 0.15), the tumor was found incidentally in 4%. Another finding in this study was the detection of prostatic carcinoma by random biopsy in patients without a palpable or visible tumor by imaging and without PSA increase (> 4 ng/ml). Biopsies were performed because of a hypoechoic zone in the opposite lobe which turned out to be negative. Such tumors cannot be properly classified in the current TNM system. Treatment options for patients with incidental prostatic carcinoma are age- and stage-dependent. Patients less than 60 years old may be treated with a curative approach, irrespective of the T category (T1a or T1b); patients with a life expectancy longer than 10 years and a pT1b incidental carcinoma likewise should be offered a curative therapy.

Kinetics of prostate-specific antigen (PSA) were investigated after manipulation of the prostate in two groups of patients: those treated with digital rectal examination (DRE), and those with needle biopsy. 8 patients had serial PSA measurements to study the effect of DRE (group 1). 7 of 8 patients had PSA baseline values < 10 ng/ml. Blood samples were taken at 1 min, 30 min, 1, 3, 6, 12 and 24 h after DRE. Some patients were further monitored for 5 days with one blood sample taken at the same time each day. Statistically significant increased PSA levels were found after DRE (P < 0.001). Maximal increase was 70%. In most patients, peak levels were found between 30 and 60 min after DRE. Based on the results, it is concluded that after DRE it is prudent to wait 3 days before PSA is determined. 7 patients had serial PSA measurements after transrectal prostate needle biopsy (group 2). PSA sampling was similar as in the previous group. All patients had increased PSA levels after biopsy (range 1.3-9.5-fold). After 5 days, only 2 of 7 patients had returned to baseline levels. We conclude that biopsies of the prostate induce an important and long-lasting PSA elevation.

Immunotherapy with intravesical instillation of bacillus Calmette-Guérin (BCG) is an effective treatment for superficial bladder carcinoma. In the present study the BCG-induced immunological reaction in the guinea pig (PPD skin test, bladder wall infiltrates and number of cells in the iliac lymph nodes) was investigated after intravesical pretreatment with pentosan polysulphate (PPS), which modulated BCG attachment to the bladder wall. Pentosan polysulfate is a molecule comparable to the naturally occurring glycosaminoglycans (GAGs) of the bladder mucosa. The data obtained after six weekly instillations of BCG-RIVM (5 x 10(6) - 5 x 10(7) cfu) with or without preinstillation with PPS (10 mg. in 1 ml. for 0.5 hour) suggested an elevation of the immunological reaction to intravesical BCG. A strong binding capacity of PPS to the mammalian bladder wall was observed. In addition, and in contrast to bacteria commonly causing cystitis, a significant binding of PPS to mycobacteria was found: 3.5, 3.6 and 3.1 micrograms./ml. dry weight of BCG Connaught, RIVM and Pasteur, compared with 0.2, 0.3, 0.7 and 0.0 microgram./mg. dry weight of Escherichia coli, Streptococcus faecalis, Klebsiella pneumoniae and Proteus. The results suggest that PPS enhances the attachment of BCG to the bladder wall, resulting in an increased BCG-induced immunological reaction in the guinea pig. It may be speculated that pretreatment with PPS may increase the efficacy of BCG therapy in man, especially in those patients not exhibiting an immunological reaction.

Proteoglycans (PGs), macromolecules that contain bound glycosaminoglycans (GAGs), are an abundant and ubiquitously distributed group of proteins with a large variety of heterogeneous structures. In recent years a whole range of functions, varying from structural/mechanical support to involvement in the regulation of cell proliferation and cell mobility, cell-cell interactions, and angiogenesis and modulation of the extracellular matrix, have been attributed to these compounds. In this communication an overview is presented dealing with the available knowledge of the (regulatory) properties of PGs and GAGs as participants in tumor growth and metastasis. Acquaintance with the biochemical, biophysical, and biological characteristics of PGs and GAGs may provide a rational basis of the therapeutic use of GAGs in the prevention of tumor growth and invasion. The scarcely available information related to the role of PGs and GAGs in uro-oncology and the potential application of GAGs in the treatment of urological tumors are discussed.

An attempt was made to interpret bacterial adsorption to the lumenal surface of the urinary bladder wall under normal and pathological conditions according to the DLVO theory of lyophobic colloid stability, which describes the interaction between a bacterium and the bladder-wall surfaces as a balance of attraction and repulsion forces. Computer modeling suggested that a decrease in the surface potential of the bladder wall may well explain an increased bacterial adsorption, possibly associated with bacterial cystitis. With the intent of preventing bacterial adsorption, treatment of bacterial cystitis by intravesical instillation of pentosan polysulfate (PPS) was evaluated. PPS is a polysaccharide with high affinity (4 +/- 2 mg/bladder) to the bladder. The attachment of PPS strongly depends on the intrinsic properties of the bacterial surface. Theoretical considerations indicate that either complete coverage of the bacterium with PPS or an absence of PPS affinity is a prerequisite for obtaining steric interaction or prevention of bacterial sorption. Experimentally, an absence of PPS affinity (0-0.7 microgram/mg bacteria) was found for bacteria commonly found during cystitis. Immunological treatment of superficial bladder cancer by bacillus Calmette-Guérin (BCG) depends on the interaction of BCG with the bladder wall. Improvement of the treatment may be obtained by increasing BCG adsorption. In this respect, the phenomenon of bridging in which PPS binds simultaneously to both BCG and the bladder-wall surface was investigated. Theoretical considerations and experimental results appeared to be in good agreement. It was found that BCG binds a considerable amount of PPS (3.4 +/- 0.3 microgram/mg BCG). In a guinea pig model the theoretical considerations, indicating the occurrence of bridging at a low and narrow range of PPS concentrations, seemed to be confirmed. In contrast to a high PPS concentration of 10 mg/ml, at a low (0.1 mg/ml) PPS concentration a significant stimulation of the BCG-associated immune reaction(s) was observed. The results suggest that to obtain PPS-induced bridging between BCG and the bladder wall and to prevent steric interaction, PPS should be instilled prior to BCG, separated by extensive washout of free PPS.

A total of 171 patients with progressive metastatic prostate cancer following hormonal therapy was randomized to receive either 560 to 700 mg. estramustine orally per day or 15 mg./m.2 mitomycin C by intravenous infusion every 6 weeks. The patients were recruited during a 2.5-year period, and 70% had undergone more than 1 previous therapy for prostate cancer, with some having received as many as 5 different previous treatments. The overall results were disappointing. The median time to progression was 5 months and 50% of the patients died within 10 months. There was no difference in efficacy between the 2 treatment arms. Toxicity was severe in both arms but appeared earlier in those patients receiving estramustine, leading to a tendency for earlier deterioration in performance status. In this group of heavily pretreated patients there appears to be no justification for the use of either of these agents at the present time.

We studied 98 patients with locally confined but lymph node positive prostatic cancer (1 stage T1, 29 stage T2, 55 stage T3 and 2 stage T4) who were not treated by radical prostatectomy. A retrospective analysis was done of deoxyribonucleic acid (DNA) ploidy of pretreatment core biopsies of the primary tumor and lymph node metastases. While DNA ploidy has been shown to be an important prognostic factor if applied to radical prostatectomy specimens, core biopsy specimens and nodal metastases have rarely been studied. Of the 98 patients 87 were evaluable for DNA ploidy: 45 (52%) had diploid, 13 (15%) had tetraploid and 29 (33%) had aneuploid tumors. The ploidy of the primary tumor and of the lymph node metastases correlated significantly with the rate of progression and interval to progression. Also, significant correlations were noted between the percentages of cells in the S phase or S plus G2 phases of the cell cycle and interval to progression. Most patients in this study are part of the European Organization for Research and Treatment of Cancer protocol 30846, a prospective randomized study of early versus delayed treatment in lymph node positive, otherwise locally confined prostate cancer. This study is ongoing. Early endocrine treatment was associated with a significantly longer interval to progression. In a Cox regression analysis of the prognostic factors involved in this study, early endocrine treatment was more important than ploidy or proliferation patterns. Stage (T category) and histopathological grade did not show a correlation with progression. Followup is still too short and the numbers of patients are too small for relevant subgroup analysis. DNA ploidy measurement by flow cytometry on archival (paraffin embedded) core biopsy and lymph node material is possible, and produces meaningful results in predicting the prognosis of prostatic cancer. Since this information can be made available before treatment decisions, its exact value in the management of locally confined prostate cancer can be determined.