Image analysis in superficial transitional cell carcinoma of the bladder.
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Carcinoma, Transitional Cell↗
Biomedical subjects
F M Debruyne
Publications and source records attributed to F M Debruyne.
Overview of current status of total androgen deprivation in metastasized prostate cancer.
The incidence and methods available for the diagnosis of metastatic prostate cancer, together with the development and efficacy of various treatments, are discussed. In patients with good prognostic characteristics, maximal androgen deprivation, with blockade of both testicular and adrenal androgens, seems to be the favored approach. Surgical castration, although effective, seems inferior to depot luteinizing hormone-releasing hormone therapy with respect to patients' acceptance and preference. Nonsteroidal antiandrogens, such as flutamide, have advantages over steroidal compounds both in efficacy and side effects. Recent studies have demonstrated that combination therapy may be superior in terms of progression-free survival and overall survival in patients with metastatic prostate cancer.
Aged↗
Colocalization of basal and luminal cell-type cytokeratins in human prostate cancer.
In the epithelium of secretory acini of the prostate two different cell types can be discriminated on the basis of localization, morphology, and degree of differentiation, the luminal and basal cells. The possibility of a developmental relationship between basal and luminal cells has been a subject of interest in several studies. According to the stem cell model at least three cell types, i.e., stem, amplifying, and transit cells, can be discriminated in the epithelium of prostate secretory acini. We previously reported that in the process of degeneration and regeneration in normal rat prostate a population of cells could be identified as candidates for the amplifying cells. These cells showed a keratin expression profile intermediate between those of basal and luminal cells. We now show, by using keratin antibodies, that also in normal human prostate at least three subpopulations of cells can be identified, one of them putatively representing amplifying cells as defined in the stem cell model. Furthermore, these antibodies were used to obtain a better insight into the different cell types involved in the etiology and progression of prostatic carcinoma. Both primary and hormone-independent prostatic tumors were investigated. Our results indicated that the candidate stem cell population was absent in prostatic carcinoma. Unlike earlier reports on the unique presence of cells with luminal characteristics in prostatic carcinoma, we identified also a population of cells coexpressing basal and luminal cell-type cytokeratins in primary and hormone-independent prostatic carcinoma. Since amplifying cells are defined in the stem cell model as precursors of transit (luminal) cells in the hierarchical pathway of prostatic epithelium differentiation, we postulate that on the basis of the keratin expression profile this subpopulation is most likely the target for neoplastic transformation.
Antibodies, Monoclonal↗
Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer.
E-cadherin is a Ca(2+)-dependent cell adhesion molecule which plays an important role in normal growth and development via mediation of homotypic, homophilic cell-cell interaction. Recent studies suggest that E-cadherin may be important in neoplastic progression as well, particularly as a suppressor of invasion. We have previously demonstrated that the invasive phenotype of rat prostate cancer cells is associated with the decreased expression of E-cadherin (M. J. G. Bussemakers, R. J. A. Van Moorselaar, L. A. Giroldi, T. Ichikawa, J. T. Isaacs, F. M. J. Debruyne, and J. A. Schalken, Cancer Res., 52:2916-2922, 1992). This is of particular interest, since the locus to which the human E-cadherin gene is mapped is frequently involved in allelic loss in prostate cancer (B. S. Carter, C. M. Ewing, W. S. Ward, B. F. Treiger, T. W. Aalders, J. A. Schalken, J. I. Epstein, and W. B. Isaacs, Proc. Natl. Acad. Sci. USA, 87:8751-8755, 1990; U. S. Bergerheim, K. Kunimi, V. P. Collins, and P. Ekman, Genes, Chromosomes Cancer, 3: 215-220, 1991). Impaired E-cadherin function is likely to be associated with aberrant expression of the protein. We therefore analyzed E-cadherin expression in situ by immunohistochemistry in nonmalignant and malignant specimens of human prostatic tissue. Of 92 tumor samples of either primary or metastatic deposits of prostate cancer, 46 had reduced or absent E-cadherin staining when compared to nomalignant prostate, which uniformly stained strongly positive. There was a statistically significant correlation between the decreased expression of E-cadherin and loss of tumor differentiation. Additionally, certain tumors within a histologically similar group could be distinguished by the presence of mixed populations of E-cadherin-negative and -positive cells. The percentage of tumors with aberrant E-cadherin staining increased when clinically localized tumors were compared to either tumors with extensive local progression or metastatic deposits of prostate cancer, suggesting a correlation between loss of E-cadherin and tumor progression. Taken together, these findings suggest that further exploration of E-cadherin as a candidate invasion suppressor molecule in human prostate cancer is warranted.
Cadherins↗
Decreased expression of E-cadherin in the progression of rat prostatic cancer.
Cadherins represent a family of Ca(2+)-dependent cell adhesion molecules involved in homotypic, homophilic cell-cell interactions. Recent studies have shown that the cadherins can play a role in invasive and metastatic behavior. Using the established Dunning R-3327 model system of serially transplantable rat prostate cancers, the expression of E- and P-cadherin in rat prostatic cancer was studied. Analysis within this system demonstrated that whereas E-cadherin was expressed in the normal rat prostate and the well- or moderately differentiated, noninvasive Dunning tumors, no expression, either at the mRNA or at the protein level, could be detected in the invasive sublines. Since not all invasive Dunning tumors studied have metastatic ability, these results suggest that a decreased expression of E-cadherin is correlated with invasive behavior rather than with metastatic ability. Recently, genetic instability occurred in an animal bearing the well differentiated, androgen-responsive, slow growing, nonmetastatic Dunning R-3327-H rat prostate cancer resulting in the progression to an anaplastic, androgen-independent, fast growing, highly metastatic state. This spontaneously arising tumor, termed the AT6 subline, in its original host was heterogeneously composed of both a well differentiated and an anaplastic population of cancer cells in which areas of squamous cell differentiation were occasionally observed. The original animal bearing this heterogeneous AT6 cancer developed multiple metastases, the lung metastases being heterogeneously composed of anaplastic and squamous cell populations. Cytogenetic analysis demonstrated that the lung metastases were derived from a specific subpopulation of cancer cells present in the original AT6 primary tumor. Immunohistochemical studies demonstrated that only the area of lung metastases displaying squamous morphology were positive for E-cadherin. In contrast, the anaplastic areas of the lung metastases and the metastases in other organs were E-cadherin negative. By the first passage of the AT6 tumor only the anaplastic cells were present and no detectable E-cadherin mRNA or protein was found in the primary tumor and metastatic deposits. These results suggest that a decreased expression of E-cadherin is associated with the progression of prostatic cancer.
Animals↗
Differential expression of vimentin in rat prostatic tumors.
Differential hybridization analysis was used to identify molecular differences between a relative benign and a highly aggressive rat prostatic tumor derived from the Dunning R-3327-H adenocarcinoma. From the several differentially expressed mRNAs identified, we here report the characterization of pBUS51 which encodes a transcript highly expressed in all-anaplastic Dunning tumors. Only a very low expression was detectable in normal rat prostate or in the differentiated tumors of the Dunning system. Nucleotide sequence analysis and computer-assisted database comparison revealed that pBUS51 was highly homologous to vimentin and therefore likely the rat homolog of this protein.
Amino Acid Sequence↗
Increased expression of retroviral sequences in progressionally advanced rat prostatic tumors.
Differential hybridization analysis revealed two cDNA clones, pBUS19 and pBUS30, to be overexpressed in progressionally advanced rat prostatic tumors. Northern blot analysis suggested the clones to be related although no homology in nucleotide sequence could be shown. Isolation and characterization of a pBUS19-related clone, pJG116, and computer-assisted database comparison showed that all three clones could be mapped within a rat-specific endogenous retrovirus. The importance of overexpression of retroviral sequences in advanced prostatic cancer remains unclear.
Animals↗
Intravesical therapy with adriamycin and 4-epirubicin for superficial bladder cancer: the experience of the EORTC GU Group.
The anthracycline derivatives Adriamycin and 4-epirubicin are used to prevent recurrent tumors after transurethral resection of superficial bladder tumors. Both drugs are instilled intravesically. The present report describes the results of two multicenter, prospective, randomized phase III studies carried out by the EORTC GU Group. In protocol 30,790, after a mean follow-up period of 26.6 months, the recurrence rate for 165 patients treated with Adriamycin was 0.29 and the tumor rate was 0.74. For 156 patients treated with Epodyl, the recurrence rate was 0.29 and the tumor rate was 0.57. This difference was not statistically significant. For 70 patients who received transurethral resection alone, the recurrence rate was 0.65 and the tumor rate, 2.04. In protocol 30,763, patients with good prognostic factors were treated with one single instillation of 4-epirubicin versus sterile water. After a mean follow-up period of 16 months, in 190 patients treated with 4-epirubicin the recurrence rate was 0.20 and the tumor rate was 0.35; in 196 patients treated with sterile water, the recurrence rate was 0.37 and the tumor rate was 0.65 (P = 0.0001). Adriamycin and 4-epirubicin were efficacious, and severe side effects were not encountered. The superiority of Adriamycin over Epodyl could not be proven.
Administration, Intravesical↗
Karyometry in recurrent superficial transitional cell tumors of the bladder.
Transitional cell carcinoma of the bladder has a high recurrence rate after local treatment. Progression to a higher stage occurs in 10-30% of the recurrent tumors, and early detection of potentially progressive tumors is important. In the current study morphometric, densitometric, and chromatin textural features of nuclei of superficial bladder tumors (pTa-T1) were studied to determine the value of karyometric features in the prediction of tumor progression. Seventy-two histological samples from 36 patients, consisting of both the primary and the first recurrent superficial tumor, were analyzed. Patients were divided into two groups: those with tumor progression, defined as an increase in tumor stage or occurrence of metastatic disease, and those without. Discriminant analysis on four karyometric features resulted in correct prediction of prognosis of 78% and 97% in the primary and recurrent tumors, respectively (P < 0.001). Tumor grade and stage did not offer additional information concerning prognosis. Karyometric analysis of recurrent superficial transitional cell tumors can be useful in selecting patients who need a more aggressive therapy. However, tumor characteristics of recurrent tumors varied and continuous evaluation of the karyometric features is necessary for early detection of an increase in the malignant potential of the tumor.
Carcinoma, Transitional Cell↗
Induction of urinary interleukin-1 (IL-1), IL-2, IL-6, and tumour necrosis factor during intravesical immunotherapy with bacillus Calmette-Guérin in superficial bladder cancer.
To study the local immunological effects of intravesical bacillus Calmette-Guérin (BCG) therapy in superficial bladder cancer patients, the production of interleukin-1 (IL-1), IL-2, IL-6, tumour necrosis factor alpha (TNF alpha), and interferon gamma (IFN gamma) was investigated in the urine. Urine specimens were collected during the six weekly BCG instillations, before instillation, and 2, 4, 6, 8, and 24 h thereafter. Results were standardized to urine creatinine. In general, the concentration of IL-1 increased markedly during the first three BCG instillations, reaching a plateau from instillations 3 to 6. IL-2 was not detected after the first BCG instillation, but from the second instillation onwards the mean IL-2 concentration increased rapidly. With respect to IL-6, patients had relatively high levels in the urine after the first BCG instillation. A relatively moderate increase of the IL-6 concentration was observed during the following weeks. Like IL-2, TNF alpha was only detected after repeated BCG instillations. Generally the highest TNF levels were found after BCG instillation 5. The presence of IFN gamma could not be demonstrated. With respect to the occurrence of the cytokines during the first 24 h after the BCG instillation, TNF, IL-2, and IL-6 were detectable 2 h after the instillation. In contrast, IL-1 seemed to appear later, i.e. from 4 h onwards. TNF decreased most rapidly; it was nearly absent in 6-h samples. Generally IL-2 was not detectable in the 8-h samples, whereas IL-1 and IL-6 were present up to 8 h after instillation of BCG. The presence of TNF was found less frequently than the presence of IL-1, IL-2, and IL-6. Neutralization experiments indicated that most of the IL-1 present in the urine after BCG treatment was IL-1 alpha. In conclusion, activation of BCG-specific T cells was indicated by the detection of IL-2. The presence of IL-1, IL-6, and TNF alpha might suggest activation of macrophages by intravesically administered BCG, although production by other cell types cannot be excluded. It is suggested that these cytokines, in combination with the leucocytes that are known to be recruited to the bladder in reaction to the BCG treatment, may play an important role in the antitumour activity of BCG against bladder cancer. For monitoring purposes, collection of urine might be performed during the first 6 h after BCG instillations 4-6.(ABSTRACT TRUNCATED AT 400 WORDS)
BCG Vaccine↗
Quantitative light microscopy in urological oncology.
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Adenocarcinoma↗
Penile pharmacological duplex ultrasonography: a dose-effect study comparing papaverine, papaverine/phentolamine and prostaglandin E1.
Alternations of penile blood flow are believed to be the most frequent organic cause of erectile dysfunction. Penile duplex ultrasonography following intracavernous injection of a vasoactive agent is an accepted method for diagnosis of penile vascular dysfunction. To determine the diagnostic efficacy of commonly used vasoactive drugs we studied the hemodynamic effects of different dosages of papaverine, the combination of papaverine and phentolamine, and prostaglandin E1 in men with erectile dysfunction and men with normal erectile potency using color duplex ultrasonography. We concluded that 12.5 mg. papaverine and 10 micrograms. prostaglandin E1 are the drugs of choice to be used in conjunction with penile duplex ultrasonography because of optimal effects on cavernous arterial dilatation and low risk of prolonged erection. However, low dose papaverine or prostaglandin E1 has a limited value in evaluating veno-occlusive function.
Aged↗
Inhibition of rat bladder tumor (RBT323) growth by tumor necrosis factor alpha and interferon-gamma in vivo.
The antiproliferative activities of recombinant rat gamma-interferon and recombinant human tumor necrosis factor alpha were evaluated in a new rat bladder tumor model, RBT323. The RBT323 is a spontaneously arisen, serially transplantable, bladder tumor in ACI rats. Histologically and ultrastructurally this tumor is a grade 2-3 transitional tumor without squamous cells. The RBT323 appears to be non-immunogenic in tumor excision and rechallenge experiments. The tumor was transplanted subcutaneously and the drugs were administered peritumorally. Gamma-interferon and tumor necrosis factor monotherapy starting two days after tumor implantation showed dose-dependent growth inhibiting effects in the dose range tested. Combination treatment with gamma-interferon and the highest dose of tumor necrosis factor resulted in synergistic antiproliferative effects. After cessation of the combination treatment all tumors resumed growth, initially with a low doubling time, but finally with their original growth rate. Gamma-interferon treatment initiated at a tumor volume of 0.2 to 0.5 cm.3 had no antitumor effects, whereas treatment with 100 micrograms. tumor necrosis factor per rat inhibited tumor growth significantly. Different combinations of the cytokines had synergistic effects against established tumors. These studies demonstrate antitumor effects of gamma-interferon and tumor necrosis factor in a rat bladder tumor model system. Combination therapy has synergistic effects and prolongs the time to tumor recurrence.
Animals↗
Impaired immune response by isoniazid treatment during intravesical BCG administration in the guinea pig.
At present, isoniazid (INH) is being used prophylactically to reduce the side effects of intravesical BCG therapy for superficial bladder cancer, although it is not clear whether or not this reduces the antitumor efficacy of BCG. In this study the impact of INH treatment on the immune response after repeated intravesical BCG administration was investigated in guinea pigs. INH was given on the 3 days around each BCG instillation. We found that the administration of INH severely impaired the immunological effects of BCG. The induction of mononuclear cell infiltration in the bladder wall was reduced. Enlargement of the regional lymph nodes (weight and number of cells), and increase of MHC Class II expression on the lymph node cells, normally observed after intravesical BCG administration, were inhibited by INH. Systemic immunity, measured by the DTH reaction in the skin to PPD, was also diminished due to the combined treatment of BCG with INH. When INH was administered during the last 4 of 6 BCG instillations, the immune response to BCG was still impaired. A five-fold increase of the dose of BCG did not overcome the effect of INH. INH probably did not exert a direct suppression of the immune system of the guinea pig as the DNCB skin reactivity was not influenced. Although INH concentrations in the urine were high at the onset of the instillation, in vitro experiments indicated that the effect of INH may not be caused by killing of the BCG organisms shortly after application in the bladder. In conclusion, our data in guinea pigs suggest that the use of INH may impair the immune response to intravesical BCG. As this response may be important for the antitumor effect of BCG, urologists should be cautious with the prophylactic use of INH. The influence on the antitumor efficacy is now investigated in man.
Administration, Intravesical↗
Assessment of penile blood flow by duplex ultrasonography in 44 men with normal erectile potency in different phases of erection.
Duplex ultrasonography is important in the diagnosis of vasculogenic erectile dysfunction. We measured the ultrasonographic parameters of cavernous blood flow in different phases of penile erection. We examined 44 volunteers with normal erectile potency. Doppler spectra of the cavernous artery were obtained in a time-dependent manner after intracavernous administration of papaverine. Following intracavernous pharmacological stimulation, the Doppler spectrum alters according to a specific pattern indicating the different hemodynamic phases of erection. Peak flow velocity and acceleration time, measured in the early post-injection phase, may be used to grade arterial inflow. The difference between resistance index in the pre-injection and late post-injection phases may be used to estimate veno-occlusive function. References values are defined.
Blood Flow Velocity↗
Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer.
Intravesical therapy with bacillus Calmette-Guerin (BCG) has proved to be more effective in the prophylaxis and treatment of superficial bladder tumors and carcinoma in situ than most chemotherapeutic agents. Compared to intravesical chemotherapy, instillations with BCG provoke more local and systemic reactions. In addition to the commonly induced granulomatous inflammatory changes in the bladder, which produce irritative symptoms, this therapy may cause systemic side effects varying from mild malaise and fever to, in rare instances, life-threatening or fatal sepsis. We report the incidence and varieties of toxicities in 2,602 patients treated with intravesical BCG. Side effects are classified according to local and systemic toxicity. Treatment options vary according to the severity of toxicity from delaying or withholding instillations to treatment with antituberculous drugs for up to 6 months. In general, 95% of the patients have no serious side effects. Recognition of risk factors, particularly traumatic catheterization or concurrent cystitis, that result in systemic BCG absorption, as well as the prompt and appropriate treatment of early side effects should significantly decrease the incidence of severe toxicity.
Administration, Intravesical↗
Motor evoked potentials from the bladder on magnetic stimulation of the cauda equina: a new technique for investigation of autonomic bladder innervation.
Although neurophysiological techniques have become widely accepted in the diagnostic evaluation of urogenital tract dysfunction, arguments have been forwarded to question their validity. Current techniques merely deal with somatosensory nerves, whereas micturition and sexual functions depend on autonomic motor nerve function as well. This study presents a new technique of motor evoked potentials obtained after magnetic stimulation of the cauda equina. Bladder and pelvic floor motor evoked potentials could be measured with concentric needle electrodes. Mean latency was 35.6 msec. for bladder motor evoked potentials and 10.6 msec. for pelvic floor motor evoked potentials. The technique was easy to perform, and provided consistent and objective data. No harmful side effects were noted.
Adult↗
The effects of treatment of urinary incontinence in general practice.
A total of 110 women who had reported urinary incontinence to their general practitioners were randomly assigned to a treatment or control group. Treatment consisted of pelvic floor exercises in the case of stress incontinence and bladder training in the case of urge incontinence. The results were measured after 3 and 12 months by a research assistant on the basis of a constructed severity scale, an incontinence diary, and a comparison by the patients themselves of their previous and current conditions. After 3 months the control group were given the same treatment. After a further 3 and 12 months, they were assessed in exactly the same way as the treatment group. After 3 months about 60% of the patients were either dry or only mildly incontinent; the mean number of wet episodes had gone down from 20 to 7, and 74% of the women felt improved or cured. These results were later corroborated by the control group. After 12 months this successful outcome was improved slightly further. It may be concluded that the majority of women with incontinence can be successfully treated by the general practitioner. The effect of this treatment continues after one year.
Adult↗