G. Klöppel

Tumor Cell Deoxyribonucleic Acid Content and Prognosis in Human Renal Cell Carcinoma

Flow cytometry was used to study tumor tissue from 68 patients with stages I to III renal cell carcinoma who were followed for 1 to 4 years. Results of flow cytometry correlated extremely well with the clinical course of the patients: 21 per cent of those with diploid tumor cells had metastases during the interval of observation, compared to 89 per cent of those with aneuploid tumor cells. We concluded that flow cytometry helps to identify at the time of radical nephrectomy patients who are most likely to suffer recurrent tumor and, therefore, are candidates for early chemotherapy. If nuclear grading is applied in addition to flow cytometry the rates of false positive and false negative results in respect to prediction of prognosis are reduced to 3 and 14 per cent, respectively.

Long-Term Mitomycin C Instillation After Transurethral Resection of Superficial Bladder Carcinoma: Influence on Recurrence, Progression and Survival

In a prospective controlled study the influence of long-term mitomycin C instillation therapy on tumor recurrence, progression and patient survival after transurethral resection of superficial bladder tumors was evaluated. This report is an update of a randomized controlled study that was stopped 1.5 years ago. The results show that long-term mitomycin C instillation therapy improves recurrence rate, progression rate and survival in patients with superficial bladder cancer.

Comparison of Different Schedules of Cytostatic Intravesical Instillations in Patients with Superficial Bladder Carcinoma: Final Evaluation of a Prospective Multicenter Study with 419 Patients

In a prospective multicenter study we compared the value of various protocols of mitomycin C and doxorubicin instillation for the prevention of recurrent tumors in patients whose superficial bladder tumors (stages TA and T1) had been removed by transurethral resection. The 3-year and short-term instillation protocols were compared to each other and to a combination of 2 protocols. Evaluation after a mean followup of 28 months confirmed the value of cytostatic bladder instillation in preventing recurrence and progression of tumor in patients with superficial bladder carcinoma. There was no significant difference between the results of long-term and short-term prophylaxis; their combination achieved the best results. Doxorubicin and mitomycin yielded similar results; mitomycin was better tolerated.

Prognosis of renal cell carcinoma related to nuclear grade, DNA content and Robson stage.

In 135 renal cell carcinomas (RCCs), nuclear grade, Robson stage and DNA content, determined by flow cytometry, were related to the 3-year survival rates of the respective patients. All three parameters showed prognostic value, nuclear grading being most effective. Combined evaluation of the parameters showed that staging and also DNA determination add supplementary prognostic information. As the four nuclear grades clearly uncover the biological potential of RCC, they are regarded as the most significant criteria for the prognostic assessment of RCC.

Transplantation of Human Renal Cell Carcinoma Into NMRI NU/NU Mice. I. Reliability of an Experimental Tumor Model

Human renal cell carcinomas of 20 consecutive patients were obtained by radical nephrectomy and were transplanted into nu/nu mice (NMRI). All tumors that were not pretreated were accepted without selection and were identical with the original tumor in morphology and chromosomal modes and usually in DNA content per cell. The growth rate of these tumors after transplantation correlated well with the clinical course of the corresponding patients and was strongly influenced by pretreatment with radiation therapy. This proves the reliability of such an experimental tumor model to study adjuvant therapy in renal cell carcinoma.

Transplantation of Human Renal Cell Carcinoma Into NMRI NU/NU Mice. II. Evaluation of Response to Vinblastine Sulfate Monotherapy

Four different renal cell carcinomas, successfully transplanted into nude mice, were treated with different dosages of vinblastine sulfate. Decrease of tumor growth was observed in 3 out of 4 of the tumors; the response was dose-dependent. The histologic appearance, cytologic grading, proliferation rate (judged by flow cytometry), and growth characteristics in the nude mouse model were correlated with the response to vinblastine therapy. Good response was seen in tumors with low cellular differentiation, progressive tumor growth, and high proliferation rate.

Transplantation of Human Renal Cell Carcinoma into NMRI NU/NU MICE. III. Effect of Irradiation on Tumor Acceptance and Tumor Growth

Irradiation of human renal cell carcinoma before radical tumor nephrectomy resulted in a significantly lower acceptance rate (1 of 7) in nude mice than for nonirradiated tumors (all of 13). The tumor tissue was transplanted into NMRI nu/nu mice immediately after nephrectomy. In this experimental system we demonstrated the reduced vitality of human tumor cells after irradiation. In a second series of experiments, 3 morphologically different human renal cell carcinomas were irradiated at various doses after establishment in nude mice. The irradiated tumor tissue was transplanted to the next passage. The morphology, proliferation rate and growth of these tumors were compared with those of nonirradiated controls. Radiation effect was dose dependent in the responding tumor types. The characteristics correlated with radiosensitivity were high proliferation rate (measured by flow cytometry), low cytologic grading and fast growth rate in the nude mice.

Cytostatic intravesical instillation in patients with superficial bladder carcinoma for the prevention of recurrent tumors.

The value of various protocols of mitomycin C and adriamycin instillation for the prevention of recurrent tumors in patients whose superficial bladder tumors (TA, T1) had been removed by transurethral resection was compared in a prospective multicenter study. Three-year and short-term instillation protocols were compared with each other and with the combination of the two. Evaluation after a mean follow-up of 20 months confirmed our previous conclusion of the great value of cytostatic bladder instillation to prevent recurrent tumors and tumor progression in patients with superficial bladder carcinoma. There is no significant difference between long-term and short-term prophylaxis, but combination has achieved the best results. Similar results were obtained with adriamycin and mitomycin but adriamycin was less well tolerated.

Xenogenic Transplantation of Human Bladder- and Renal-Cell Carcinoma into NMRI Mice Treated with Cyclosporin A and into NMRI nu/nu Mice

128 tumors from three different human renal-cell carcinomas and from one human transitional bladder cancer were transplanted into NMRI mice treated with cyclosporin A at various dosages. Their acceptance rate, proliferation rate, and morphologic and growth characteristics were studied and compared with those of the same human tumors after transplantation into NMRI nu/nu mice. The acceptance rate was 80% in mice treated with cyclosporin A at 100 mg/kg-1 and 150 mg/kg-1/day. The highest acceptance rate was observed after transplantation into nu/nu (thymus-aplastic) mice (100%). Morphologically, the transplanted tumor was similar in the two animal groups and identical with the primary tumors. Metastases were not seen in either animal model. The NMRI mice treated with cyclosporin A had leukocyte infiltration into the transplanted tumor. The growth rate of the human tumors in normal mice depended on the cyclosporin A dosage, and was highest in the nu/nu mice. The proliferation rates of the transplanted human tumors, as judged by flow cytometry, were rather similar in all groups.