[Results of a prospective study of the treatment of rhabdomyosarcoma in childhood].
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Biomedical subjects
Publications and source records attributed to U Willnow.
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Between 1954 and 1984 41 primary testicular tumours were treated in 40 children at the age of 0 to 9 years as well as 9 secondary testicular tumours in malignant systemic diseases or metastases. The histological reclassification of the number of cases revealed 15 yolk-sac-tumours, 10 differentiated teratomas of immature subtype, 1 intermediary malignant teratoma, 3 undifferentiated malignant teratomas, 2 Sertoli-cell-tumours (1 double-sided) and 5 rhabdomyosarcomas. 2 children each with undifferentiated malignant teratomas and rhabdomyosarcomas died, all before 1970. 5 children with yolk-sac-tumours and 2 with rhabdomyosarcomas who since 1974 have been treated with Ablatio testis and combination chemotherapy live without tumour. Histological classification and division into stages are proved and form the basis of a therapy conception which in all testicular tumours apart from the Ablatio testis contains the chemotherapy of different intensity (HTK-84), taking into consideration form of tumour, stage and age of the children. The retroperitoneal lymphadenectomy is recommended only in the proof of metastases.
Sensitivity of 15 Wilm's tumors in children was tested towards cytostatic agents in vitro by means of an autoradiographic short-term test. Sensitivity was measured as a magnitude of the inhibition of 3H-thymidine, resp. 3H-uridine incorporation. The test was performed with Adriamycin, Actinomycin D. Daunomycin, Bleomycin, Cyclophosphamide, Ifosfamide, Trenimon, and Arabinosylcytosine. None of the tumors is resistant to all substances, they are responsive against 2 or more drugs. The most effective drugs tested are Adriamycin, Actinomycin D and Cyclophosphamide. The tumors show a marked individual sensitivity pattern. This behavior is explained mainly by the usually high proliferative activity of Wilms' tumors. The possibilities and limits of long-term and short-term methods for sensitivity testing are discussed critically. For the evaluation of the results of in vitro testing and in vivo effectiveness the close correlation should be considered between the type of cytostatic agent and proliferation kinetics of the tumor, cytostatic agent and effect on tumor metabolism as well as the effect of the cytostatics and the nucleic acid precursors used for the short-term test. Despite the methodological limitations preclinical testing should be preferred to unselected chemotherapy.
With the aim to develop an improved individual therapy of tumor-affected children, tumor particles were in vitro incubated with radioactively labeled precursors in order to determine the parameters of cell proliferation kinetics. The growth rate of the tumors was derived from the 3H-uridine labelling index. A "cell kinetic therapy index" is calculated from the temporal ratio of the cell cycle phases S, G2, and M, which are sensitive to cytostatic compounds and radiation, and of the mean duration of the cell cycle. When the cell kinetic therapy index (ZTI) is below 0.2 chemotherapy is scarcely promising whereas it is promising at 0.5 and above. The experimental data of Wilms tumors, osteogenic sarcomas and rapidly growing neuroblastomas are in good agreement with the clinical rate of tumor remission.
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Proliferation kinetic parameters of 9 osteogenic sarcomas (6 primary tumours, 3 lung metastases) and 3 Ewing's sarcomas were determined using an autoradiographic in vitro method (single and double labelling with 3H- and 14C-thymidine, and 3H-uridine). Osteogenic sarcomas and Ewing's sarcomas, respectively, showed clearly individual pattern of proliferation. The following values were obtained: The average 3H-thymidine labelling indices of 13.8/8.7%, the DNA synthesis times of 12.2/14.4 hours, mitosis times of 1.1/1.9 hours, and mean cell cycle times of 58.0/78.2 hours. The potential tumour doubling times determined with the inclusion of the growth fraction averaged 4.8/5.0 days. Using 3H-uridine labelling of tumours, autoradiography allowed the determination of the growth fraction fair accuracy. It is between 0.26 and 0.71 for osteogenic sarcomas, the average being 0.49. In vitro results were compared with the volume doubling times of metastases of osteogenic and Ewing's sarcomas, reported in the literature which had been determined from series of lung radiographs. The importance of cell kinetic studies of human tumours therapy is demonstrated by a "cell kinetic therapy index".
Using auto-radiographic techniques in vitro studies performed to analyse the growth rate in 13 cases of neuroblastoma, 6 recurrent tumours (assorted) and 7 metastatic tumours. The cell kinetic parameters using 3H thymidine markers, DNS synthesis, mitotic rate and mean cycle rate were investigated. The growth rate can only be calculated approximately. The results show that neuroblastomas grow incredibly fast. The cell-cycle period varies between 13.1 and 266.3 hours and averages 71 hours. Recurrent tumours have a tendency to have the same growth rate as the primary tumour. Primary metastases of Wilm's tumours and osteogenic sarcomas proliferate rapidly with a cell-cycle of 13.0- 87.0 hours (average 37.7 hours). All tumours have a distinctly individual proliferation pattern. Cell division and growth rate of malignant tumours are important in relation to radiotherapy and the use of cytotoxic drugs. These factors are expressed as a "cell-kinetic therapeutic index", which helps to predict the effectiveness of cytotoxic drugs and radiotherapy. Two cases of neuroblastoma were classified as resistant. Most tumours excluding the fibrosarcomas react well against two cytotoxic reagents. The cell-kinetic pattern and the sensitivity results are used in determining the treatment of recurrences and metastases. The relationship of these investigations in clinical practice is discussed.
The mesodermally differentiated and only in newborns and young infants occurring mesoblastic nephroma is regarded as benign. Recidivations with malignant course, inclination to infiltration and richness in mitosis make arise doubts about the benignity despite good prognosis. The results of a proliferation-kinetic examination received by an autoradiographic in vitro method of a mesoblastic nephroma which was observed in a 20-day-old infant are characteristic for a malignant tumour of low degree of malignity: 3H-thymidine marking index 5.8%, DNA synthesis time 18.2 hours, mean generation time 141.1 hours (= 5.9 days). Growth fraction 0.28 and potential doubling time of the tumour 16.4 days. These data decisively deviate from those of the Wilms-tumours, which are cell-kinetically characterized as extraordinarily quickly growing, highly malignant tumours. The position of the mesoblastic nephroma in the system of the dysontogenetic renal tumours is briefly discussed. The ureteronephrectomy performed in time is the only necessary therapeutic measure, since also the mesoblastic nephroma follows the general rule of dysontogenetic tumours that the prognosis is the better the younger the infant is.
The proximal ureter atresia as a cause of a congenital hydronephrosis with functioning normal kidney is to a certain extent unknown. The histological elaboration of an uretero-pelvic resection preparation of a 7-year-old boy after Anderson-Hynes-plasty showed the transition of a stenosis of the ureter passage into a ureter atresia. Cause of the development of a proximal ureter atresia are secondary changes of the structure in the ureteropelvic segment due to the disturbed urodynamics in stenosis of the ureter passage. The possibilities of the genesis of atresia are discussed and it is referred to the clinical picture of the disease.
The incorporation of 3H-uridine into the RNA was studied under normothermia 37 degrees C/120 min, hyperthermia 42.5 degrees/120 min, and both in combination with Actinomycin D by an autoradiographic in vitro method in 19 solid tumors of children: 6 Wilms' tumors, 5 neuroblastomas, 4 osteogenic sarcomas, and 4 different tumors. Hyperthermia invariably reduces the 3H-uridine incorporation into RNA by 11.7--86.4%, with an average of 47.5%. Actinomycin D consistently inhibits the 3H-uridine incorporation between 27.7 and 99.8%, with the average inhibition of 62.0% being far greater than that recorded for hyperthermia. The highest degree of 3H-uridine incorporation inhibition is obtained using hyperthermia in combination with Actinomycin D. The inhibition varies from 45.5--99.8%, with an average of 81.4%. In spite of the general regularity, the effect of hyperthermia and Actinomycin D are characterized by individual patterns. Obviously, they are dependent on proliferative activity rather than upon the particular type of tumor. The use of supranormal temperatures for the treatment of malignant tumors in man, also in combination with radiation or cytostatic drugs, is a possible and promising method of therapy.
The recommendation of an optimal time for operation of cryptorchidism is based on 70 testis biopsies and 40 measurements of testis volume. Orchidopexy should be performed during the 3rd to the 4th year of age, because impairment of the testes is not to be expected until the beginning of the 3rd year of life. Orchidopexy within the first two years of life may cause additional traumatization of the tissue.
3H-thymidine and 3H-uridine labelling indices (LIth and LIur) were determined simultaneously using an autoradiographic method in 19 solid tumours: 6 Wilms' tumours, 5 neuroblastomas, 4 osteogenic sarcomas, and 4 various tumours. At a LIth of 2.7 to 47.0% (average 22.3%) all LIur were significantly higher with values of 11.6 to 76.3% (average 47.4%). The difference between both indices varies by the factor 1.26 to 7.45 (average 2.83). The magnitude of 3H-uridine incorporation into the RNA is correlated to the proliferation rate as well as that of 3H-thymidine incorporation into the DNA. Rapidly growing tumours show high 3H-thymidine and -uridine labelling indices with a decrease from Wilms' tumours to osteogenic sarcomas and neuroblastomas. 3H-thymidine and -uridine incorporation into nucleic acids are discussed with reference to the cell kinetic system of a solid tumour and the course of the cell cycle. Perhaps, the 3H-uridine labelling index in the autoradiograms represents the growth fraction of a tumour. The significance of the relation of DNA to RNA synthesis for the testing of tumour sensitivity towards cytostatic agents in the short-term test is discussed.
Supranormal temperatures between 40 and 43 degrees C are not necessarily lethal to tumor cells, but lead to characteristic changes of the cell cycle. The parameters of the proliferation kinetics were studied in 35 solid tumors of children at a temperature of 42.5 degrees C with an autoradiographic in vitro method, in comparison to normothermia: 9 Wilms' tumors, 10 neuroblastomas, 8 osteogenic and soft tissue sarcomas, 6 non-Hodgkin-lymphomas, and 3 other tumors. 28 tumors showed significant prolongation of DNA synthesis times by an average factor of 1.27 (1.10--3.12). Mitosis times undergo an average prolongation by the factor 2.75 (1.07--8.87). Together with significant decrease of the 3H-thymidine labeling index the prolongation of the cell cycle time amounts to an average of 2.67 (1.05--8.30). The cause of the changes of the cell cycle are discussed. Probably, the heat sensitivity of tumors is correlated with the proliferation rate and with the degree of histological differentiation; but this cannot be confirmed statistically due to the small number of cases. 2 cases responded with a decrease of the duration of the cell cycle; in one case this was probably due to an exogenic thermotolerance. The changes of the cell cycle are of a particular importance for the therapeutic combination with radio- or chemotherapy. These relations are discussed.
Because of recurrent paronychia of the right thumb "granulation" tissue was removed from the nail-bed of a ten-year-old girl. Histological examination revealed a cornified squamous-cell carcinoma. About five months later a lymph-node metastasis was found in the right axilla. After radical dissection of the axillary region further lymph-node metastases were found, as well as a lymphangitic carcinosis with tumour infiltration in the veins. Despite telecobalt radiation there were recurrent retastases which could no longer be removed by operation. Two years after the diagnosis the girl died. Necrospy revealed diffuse tumour infiltration of the soft tissue of the axilla, upper arm, shoulder, neck and thoracic wall on the right, including the breast tissue, with thoracic para-aortic-abdominal and left-sided axillary lymph-node metastases, and lung and pleural metastases bilaterally.