Chemoimmune prophylaxis of superficial bladder carcinoma with cyclophosphamide and BCG.
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Biomedical subjects
Publications and source records attributed to H D Adolphs.
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Plasma determinations for TPA and CEA resulted in a sensitivity of 90% and 19-42%, respectively, for urothelial bladder cancer. By immunohistochemical staining TPA was positive in 100% and CEA in about 80% of the cases. The CEA staining in cancer tissue seemed to correlate with the WHO grade. Because TPA resulted in strong positive staining and high sensitivity in the plasma, contrary to CEA, showing less positive staining and a lower sensitivity, there seemed to be a good correlation between staining and plasma sensitivity for both markers.
The possibility of a T classification for bladder carcinoma by intravesical sonography was investigated in a 3-year field study (1982-1985) at the Urological Clinic, Bonn University. In a total of 571 patients with histologically verified bladder cancer, the sonographic classification was compared with the histological T category. There was an agreement of 70.1%. While the infiltration of superficial tumors (above all of large tumors) was frequently overestimated (28.7%), understaging predominated in invasive carcinomas (20.9%). The overall precision of conventional staging techniques was 67%. Ultrasonography showed a marked superiority, above all in infiltrative papillary tumors of low diameter (precision 76% compared to 12% with the conventional T classification). The sensitivity of the method with regard to the detection of tumor infiltration (90%) was also markedly higher than that of earlier techniques (66%). Particularly helpful in the evaluation of more deeply infiltrating tumors, intravesical sonography constitutes a major extension of the diagnostic spectrum for T classification of bladder carcinoma.
We performed chemoimmune prophylaxis in 130 patients with superficial urothelial transitional cell carcinoma of the bladder. Two weeks after complete TUR 700 mg Cyclophosphamide (CTX)/m2 were injected intravenously followed by 6 weekly intravesical instillations of 120 mg BCG/50 ml saline together with BCG skin scarifications two weeks later. After 5 years the calculated frequency of recurrence was 18% in the treated group compared with 54% in the untreated historical control group. In a sub-group of 48 patients with recurrent tumors the CTX/BCG treatment success was well documented by comparison of the tumor recurrences during the appropriate time intervals before and after chemoimmune prophylaxis. The progression rate of the disease was generally more favourable in patients treated by CTX/BCG. No significant side effects of this treatment were noticed.
Urine cytology was evaluated in 8,406 male workers of 8 petrochemical factories in western and northern Germany during the routine medical check-up performed by the department of industrial medicine of the respective factory. All relevant data referring to possible private and occupational risk factors were registered and evaluated. Four percent (n = 358) of the 8,406 workers examined exhibited Pap 3/4 cytology. Urological examination did not reveal any bladder tumor in those workers with either a single Pap 4 or a repeated Pap 3 finding on cytology. Our study showed that deterioration of cell differentiation correlated significantly with age and cigarette smoking. Furthermore, a risk group (males above 40 years of age exposed to occupational chemicals, smokers, and coffee drinkers) differed from a non-risk group. Age and cigarette smoking seemed to be the determinant factors. No correlation could be adduced between any kind of industrial exposure and urine cytology.
Results of cell kinetic analyses on transurethrally obtained material from urinary bladder are compared with parallel immunohistochemical tests on carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA), performed on the same material. Labelling index increases from 1.4% in slight to 20% in marked urothelial atypia. CEA reaction in slight atypia is slight or moderate, slight, moderate or distinct in atypia, and moderate to distinct in carcinoma in situ. TPA always shows moderate to distinct reactions. Cell kinetically, urothelial carcinomas yield similar gradations. They were positive for CEA in 70% and for TPA in 100%. In GO and GI carcinomas, negative and slightly positive reactions predominate, poorly differentiated lesions yield predominantly distinct reactions. In all grades, TPA ranges from slight to distinctly positive. As in cell kinetic analyses, there is a relationship between differentiation grade and stage for CEA expression. This does not apply for TPA. The results permit us to draw conclusions on the different biological and histogenetical behavior of urothelial carcinomas. There are undoubtedly differences in the behavior of papillary-exophytical and solid invasive carcinomas in terms of both cell kinetics and immunohistochemistry.
For early diagnosis of urinary bladder tumors, autoradiographic, cytological, and impulse cytophotometric examinations were performed on fresh bladder tissue with carcinomas of different grades of malignancy and various depths of infiltration, and also on tissues with concomitant urothelial atypias. Cell kinetic examinations of urothelial atypias of mild, moderate, and severe grade revealed labeling indices comparable to those of urothelial carcinomas grade I, II, and III, respectively. The labeling indices of the carcinomas increased with both the grades of malignancy and the depth of invasion up to factor 5. Cytophotometrically mild atypias showed euploidy, while moderate to severe atypias revealed aneuploidy. By means of cytologic, cytophotometric, and cell kinetic analyses, two subgroups of G I urothelial carcinomas were distinguished. Subgroup I a corresponded to highly differentiated papillary urothelial carcinomas with low labeling indices, pap I-III differentiation, and euploidy. Subgroup I b, on the other hand, revealed pap differentiations of IV-V, aneuploidy, and higher labeling indices. This subgroup seems to be more prone to recurrences and apparently indicates higher grades of malignancy and depths of infiltration. The data presented provide evidence that a combination of these methods is helpful for early recognition of precursors of bladder cancer atypias as well as for exact evaluation of the biological potential of carcinomas.
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Plasma concentrations of tissue polypeptide antigen (TPA) were determined in 104 patients with all stages and grades of urinary bladder cancer. Patients with evidence of bacterial or virus infections were excluded. In addition, follow-up controls after treatment were performed. At a rate of 5% false positive values, the diagnostic sensitivity for the tumour stage pTis/pT1 was 63% and for the stages pT2-4 it was 76%. Patients with proved lymph node or distant metastases showed elevated values in 100% of cases. A positive correlation was found between the 3 grades of malignancy and the TPA concentrations. Except for the tumour diagnosis, TPA is a valuable parameter for follow-up controls. Our results show a very good correlation of the plasma TPA concentration with tumour progression as well as with stabilisation and regression after treatment.
During and after chemoimmune prophylaxis with i.v. cyclophosphamide (CTX) and both intravesical and systemic BCG-treatment, the bladder mucosa is prone to morphological changes which might resemble tumor recurrences. Therefore, morphological parameters which can discriminate between treatment effects and tumor recurrences are of interest. In a prospective study, routine cytology, determination of granulocytes, lymphocytes, and macrophages in the urine sediment as well as flow-cytophotometry (FCM) for DNA analysis were performed before, during, and after chemoimmune prophylaxis. In addition, bladder biopsies and all recurrent tumors were histologically analysed. Our results show that FCM is the best method for monitoring the bladder mucosa for recurrent tumors during treatment. After termination of BCG, it takes at least 4 months for cytological normalization to take place. Urine excretion of granulocytes, lymphocytes, and macrophages does not correlate with this process. Histological alterations during treatment are demonstrated; their normalization requires at least 3 months. In 10% of the patients chronic inflammatory lesions ("pseudotumors") develop.
Since January 1978 we performed chemoimmune prophylaxis in 130 patients with superficial transitional cell carcinoma of the bladder. After complete tumor resection and exclusion of an urinary tract infection as well as an impaired global immune competence treatment consisted of one intravenous application of 700 mg Cyclophosphamide (CTX)/m2 followed by 6 intravesical instillations of 120 mg BCG/50 ml saline together with BCG skin scarifications. In a total of 12.3% of the treated patients tumor recurrences were observed until the 18th month. These results compared favourably with the high recurrence rate in a group of 80 patients without CTX/BCG prophylaxis. In 48 patients with a history of recurrent tumors statistically significant treatment effects were noted after CTX/BCG (p less than 0.01) using the Wilcoxontest. In 10% of the cases, inflammatory tumor-like lesions developed. Side effects of the treatment were generally well tolerable. From the presented data it is concluded that chemoimmune prophylaxis effectively prevents recurrences in superficial bladder cancer.
Urine specimens of 24 patients receiving polychemotherapy for malignancies of the gonads were examined by flow cytophotometry (FCM) and routine cytology. The results show abnormal DNA histograms during chemotherapy due to an arrest of the cell cycle at the S- and G2M level. In treatment protocols with ifosfamide leucocyturia develops. No cytological changes of the urothelial cells occur during treatment. All these alterations are completely reversible within 4 weeks. It is concluded that the measurable nuclear changes of urothelial cells may serve as parameters for cellular events during polychemotherapy.
Reactivity of regional lymph node cells was determined in 87 patients with urological cancer by measuring the S-phases of the cell cycle using flow cytophotometry. Compared with a control group of 28 individuals with and without infectious disease regional to the extirpated lymph nodes, analysis of 250 lymph nodes in tumour patients exhibited either normal, reduced, or elevated S-phases. No relation could be established between the reduced or elevated pattern of reactivity of regional lymph node cells and any known tumour parameter, such as organ manifestation, histology, stage, and grade. Whether the determined S-phases correlate with the prognosis remains to be determined.
In 36 patients with renal carcinoma ploidy and cell cycle analysis of the tumour tissues by flow cytophotometry were performed. Considering the tumour stages pT, pN, and M no relationship between stage and DNA distribution could be established. With reference to the histological grading, grade I tumours showed only euploid DNA distributions, whereas grade II and III carcinomas exhibited both euploid and aneuploid DNA patterns. Whether ploidy analysis is correlated with the prognosis of the tumour disease remains to be determined.
Chemoimmune prophylaxis with intravenous cyclophosphamide and intravesical as well as systemic bacillus Calmette-Guerin treatment was begun after complete tumor resection in 90 patients with superficial urothelial bladder cancer. Compared to a historical patient control group treated by tumor resection alone a distinct decrease in the recurrence rate was noted in the immune treated group, which was most marked during the first 12 months postoperatively. The side effects of this treatment were tolerable. Our results are discussed with regard to the reported findings in the literature. Possible immune biological mechanisms of the tumor protection achieved by cyclophosphamide and bacillus Calmette-Guerin are suggested.
Intracavitary sonography proved to be advantageous with regard to the T-classification of urinary bladder tumours in comparison with conventional diagnostic methods. Besides the good practicability, the high degree of correspondence between sonography and histopathological findings is emphasized. In 97 patients with urothelial bladder cancer this method yielded 63% correct results. In 32% overstaging was noticed, possible factors of which were exemplified. Part of the sonographic failures can be avoided by means of technical manipulation (gain-modification) together with increasing experience of the examiner. In particular benign bladder disease, which can be sonographically confused with cancer, has to be considered. These cases indicate the need to correlate particular sonographic findings with histopathology.
Two rare cases of adolescent and adult Wilms' tumors are reported. All pertinent clinical data are presented. Both patients have been treated by radical tumor nephrectomy, irradiation and polychemotherapy. Only 4 patients with such triple treatment have been reported in the literature. The adolescent girl experienced a complete remission, but the 59-year-old patient rapidly deteriorated and died 4 months postoperatively.
Using pulse cytophotometry, almost quantitative separation of the leucocyte fraction from DNA histograms was possible by means of an anticoincidence discrimination device, This modified technique was employed for biparametric DNA/protein measurements of voided urine samples, bladder washings, and tumour tissues. The results show a high degree of correlation between these samples so that, for tumour diagnosis from DNA histograms, voided urine specimens can be used rather than bladder washings. The criteria for the bladder tumour diagnosis are derived from DNA measurements of 32 controls and 35 tumour patients. The diagnostic sensitivity of this method is 0.91 and the specificity 0.75.