F. M. J. Debruyne

Chromosomal analysis of bladder cancer. III. Nonrandom alterations

Chromosome analysis using G- and C-banding was performed on 13 primary transitional cell carcinomas of the bladder. The chromosome preparations were obtained by a direct method. In eight tumors with a (near) diploid modal chromosome number, the most frequently observed chromosome aberrations were: (partial) monosomy 9 in four cases, deletion of 10q in two cases, and partial trisomy 1 in two cases. In five tumors with a modal chromosome number in the triploid or tetraploid range the chromosomes #1, #3, #7, #9, #11, and #17 were numerically and or structurally abnormal in at least four cases. In three out of ten males, the Y chromosome was missing. These findings suggest that the loss of chromosome #9, and possibly also loss of 10q is a primary event in the karyotypic evolution of transitional cell carcinoma of the bladder.

Analysis of prognostic factors in disseminated prostatic cancer. An update

A statistical analysis of prognostic factors in 175 patients with hormonally treated disseminated prostatic cancer was done. The prognostic significance of performance status (PS), hemoglobin (Hb), alkaline phosphatase (Alk P), and testosterone was assessed with a univariate analysis. The authors did not find significant prognostic value in age, tumor size or grade, prostatic acid phosphatase, and prostate‐specific antigen in these patients. In a multivariate logistic model (Cox regression), PS, Hb, and Alk P were found useful for dividing patients into prognostic groups. The prognosis for high‐risk patients on standard hormonal treatment was very poor. The authors concluded that research on prognostic factors is useful and permits a division of patients into risk groups that makes choice of treatment more accurate. The use of new treatment combinations as a start treatment is appropriate for high‐risk patients with disseminated prostatic cancer.

Tissue-specific markers in flow cytometry of urological cancers: cytokeratins in bladder carcinoma

Thirty‐eight transitional‐cell carcinomas (TCC) were analyzed by flow cytometry (FCM) using propidium iodide for DNA analysis and antibodies to cytokeratin by indirect immunofluorescence. By means of two‐dimensional FCM analysis, cytokeratin‐positive tumor cells could be analysed separately from cytokeratin‐negative stromal and inflammatory cells. This resulted in an 18% increase in sensitivity of FCM detection of aneuploidy (10/38 samples with one‐parameter DNA analysis versus 15/38 samples with two‐parameter DNA and cytokeratin analysis). In addition, S‐phase could be determined in the 15 aneuploid samples by means of two‐parameter analysis where this was not possible using only DNA content because of the overlap of diploid and aneuploid populations. FCM analysis allowed quantification of the percentage of tumor cells expressing cytokeratin 18 which has previously been shown to correlate quantitatively with higher grade, higher stage TCC. The quantitative measurement of tumor‐cell expression of cytokeratin 18 by FCM analysis appears to provide additional information of potential prognostic value, independent of tumor‐cell ploidy and proliferative fractions.

A new extra long acting depot preparation of the LHRH analogue Zoladex®. First endocrinological and pharmacokinetic data in patients with advanced prostate cancer

A new depot formulation of the LHRH analogue Zoladex (goserelin acetate) has been developed which releases the drug over a period of at least 3 months as judged by measurement of drug content in depots at intervals after insertion in male rats and by the suppression of oestrogen secretion and oestrus in female rats. This formulation is based on the lactide/glycolide polymer system used for the standard 1-month Zoladex depot, but the dose has been increased to 10.8 mg and the characteristics have been modified to enable a longer release of drug to be achieved. Thirty-eight patients with histologically proven, locally advanced (stage T3 or T4) and/or metastatic prostate cancer were treated with this new longer acting LHRH analogue depot formulation containing 10.8 mg Zoladex. After initial increase of serum testosterone in the first week of therapy, castration levels were reached in all patients after 4 weeks and this was maintained for more than 14 weeks. At the time of depot exhaustion, when escape from castration levels of androgen occurred, all patients received a single injection of a standard 1-month depot containing 3.6 mg Zoladex which restored castration levels of androgen thus showing that the pituitary gland was again suppressed. The tolerance and acceptability of the longer-acting depot is high and comparable to the 1-month depot. Taking into account social and psychological factors, patients with advanced prostate carcinoma will soon be able to be treated with a longer acting LHRH depot formulation every 3 months an alternative of the 1-month depot now widely used clinically.

KETOCONAZOLE HIGH DOSE IN MANAGEMENT OF HORMONALLY PRETREATED PATIENTS WITH PROGRESSIVE METASTATIC PROSTATE CANCER

Ketoconazole high dose (H.D.) effectively reduces the testosterone production in both adrenals and testes. Its use in the management of (metastatic) prostate cancer has been advocated. Even in relapsing patients, after previous hormonal therapy, ketoconazole H.D. could be of value. Twenty-eight relapsing patients, of whom 15 were evaluable at three months, have been treated with ketoconazole H.D. As could be expected, objective response was seen in only a small number of patients followed up till nine months. Subjective improvement, however, was noticed in the majority of symptomatic patients. The side effects and toxicity of the therapy remain a major limitation for the use of ketoconazole, be it as first line treatment or as therapy for relapsing patients.

Liarozole (R75251) in hormone-resistant prostate cancer patients

Liarozole is an imidazole derivative that has been identified as an inhibitor of the cytochrome P450‐dependent all‐trans retinoid acid (RA) breakdown. RA is one of the principal endogenous compounds that controls growth and differentiation of epithelial tissues in mammals.

Blood Group Isoantigen Deletion and Chromosomal Abnormalities in Bladder Cancer

The presence or absence of blood group isoantigens in 78 patients with transitional cell carcinoma of the bladder was correlated with tumor stage and grade, and results of chromosomal analysis. For blood group isoantigen detection the indirect immunoperoxidase method with monoclonal antibodies to A, B and H antigen was used. In 51 per cent of the 59 superficial tumors blood group isoantigens were demonstrable, whereas all deeper infiltrating and higher grade tumors were negative. However in superficial tumors the mode of blood group isoantigen expression did not correlate significantly with tumor recurrence and progression. A consistent correlation was demonstrated among chromosomal numbers, tumor grade and clinical course. The chromosomal abnormalities found and mode of blood group isoantigen expression, even in combination, had no prognostic value additional to the grading criteria used.

The effects of intravesical and intradermal application of a new B.C.G. on the dog bladder

SummaryIntravesical and intradermal application of B.C.G. (Bacillus Calmette Guérin) has proven to be effective in the prophylaxis of recurrence of superficial bladder carcinoma after transurethral resection and in the treatment of carcinoma in situ (C.I.S.) in man. Different strains of B.C.G. have been used for this purpose. In this article a new strain of B.C.G. (B.C.G.-R.I.V.M.) has been tested to assess its toxicity. The effects of intravesical and intradermal application of B.C.G.-R.I.V.M. were studied on normal and on coagulated canine urothelium. In this study no general side effects of B.C.G.-R.I.V.M. were seen. Only minor local changes occurred in the bladder wall. Small granulomas were found in the suburothelial tissue. No granulomas or signs of active inflammation were observed in the pelvic lymphnodes, spleen and liver. Because B.C.G.-R.I.V.M. seemed to be a safe agent in the dog we have started to use it for prophylaxis in superficial bladder cancer in man.

Hydronephrosis caused by cystocele Treatment by colpopexy to sacral promontory

A case of marked bilateral hydroureteronephrosis due to extreme prolapse of the bladder is reported. This latter condition led also to obstructive urinary tract symptoms and residual urine. After repair of the cystocele in an unusual way by fixation of the vaginal vault to the sacral promontory, the caliber of the upper urinary tracts became almost normal and postvoiding residual urine disappeared.

Can combined des and lhrh depot therapy (ICI 118630) prevent endocrinologic and clinical flare-up in metastatic prostate cancer?

Medical castration obtained with luteinizing hormone releasing hormone (LHRH) analogues in patients with prostate cancer is now well established. To block the initial stimulation of testosterone production and prevent the risk of the so-called flare-up with this medication, we investigated short-term combination therapy with 1 mg of diethylstilbestrol (DES). Fourteen previously untreated patients with histologically proved metastatic prostatic carcinoma were treated with 1 mg DES po daily one week prior to the initiation of therapy with LHRH analogues depot injection of Zoladex (ICI 116630) and continued during four weeks after the first depot injection. LHRH depot form was maintained as long as patients experienced clinical benefit. Endocrinologic results show that in spite of 1 mg of DES a significant increase of testosterone is still observed in the first week after injection of the LHRH depot form. Hence, this combination is not useful to prevent endocrinologic and clinical flare-up in patients with prostate cancer treated with LHRH analogues.