Tumor heterogeneity of renal cell carcinoma.
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Biomedical subjects
Publications and source records attributed to U Otto.
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To evaluate whether response to alpha-2- or gamma-interferon in metastatic renal cell carcinoma is associated with a prolonged survival, we studied a total of 65 patients being treated in two phase-II- or phase-III-trials between 1984 and 1986 with one of these interferons. After a median follow-up of 3 years for the alpha-interferon-treated patients and of more than 4 years for gamma-interferon-therapy, respectively, there is a significantly increased duration of survival for patients showing an objective response or stabilisation of the disease due to either therapy compared to those with continuing progression. Therapy with alpha-interferon leading to objective remissions in 26% or with gamma-interferon with an objective response rate of 36% therefore is beneficial for responding patients and can be performed with moderate side effects on an out-patient basis.
Carrier experiments using Echo- and Influenza-viruses on denture basis resins and fragments of orthodontic appliances resulted in good and even very good virucidal effects of disinfectant sprays Desident and Fesia-sept. The application of the disinfectant as spray seem to be advantageous, but is not recommendable. The diverse causes of this conclusion are discussed and an alternative way is proposed.
Three disinfectant sprays (Arugeen, Desident and Fesia-sept) proved to be very efficient against pure cultures of aero bacteria species, Cand. albicans, saliva flora and entero- and influenza viruses. The methods included carrier experiments using denture basis resins, fragments of orthodontic appliances and screws (instead of instruments).
A software package was developed for computerized recording and processing of clinical data in a urological out-patient clinic. In a pilot study this program proved to be useful for the rapid evaluation of all important clinical and laboratory results of patients with renal cell carcinoma, and its use also accelerated the preparation of medical reports. The experience gained in this initial project shows that the application of this newly developed concept of data processing can easily be extended to routine out-patient followup in other special areas within the field of oncology.
The binding of antigen-loaded carrier to mononuclear cells of heart transplant recipients has been investigated by means of an antigen-specific rosette technique. The increase of rosette forming cells and the inhibition of this reaction with monoclonal antibodies against activated T-cells is a sign of a beginning rejection. 3-6 days later infiltrating immunological competent cells are seen in biopsy.
A total of 1226 psychiatric emergencies from three socially different catchment areas in Sweden were analyzed. Data were obtained over 28 consecutive days at the beginning of 1985. Very small differences were found between urban and rural catchment areas, which is probably due to a high degree of equality for both social and medical services throughout Sweden. The largest diagnostic subgroup was patients with an alcohol problem (33%). A measure of the patients network of close relatives, yielded small differences between the diagnostic subgroups.
In a phase-II and a phase-III study patients with histopathologically documented metastatic renal cell carcinoma were treated either with gamma-interferon in two different doses (100 micrograms/m2 3x/week for 4 h i.v. every other week or 500 micrograms/m2 5x/week for 24 h i.v. every other week) or with alpha-2-interferon alone (18 x 10(6) U 3x/week weekly i.m.) or in combination with vinblastine (0.1 mg/kg every third week i.v.). The purpose of these studies was to evaluate the response rate, the duration of response, the survival, the efficacy and the toxicity of the different forms of treatment. The overall response rate to gamma-interferon was 30% in both regimens. The response rate of treatment with alpha-2-interferon was found to be 31%. The duration of response ranged between 2 and 34+ months in patients treated with gamma-interferon and between 2 and 24+ months in those receiving alpha-2-interferon. Patients with objective tumor response showed a significantly longer survival than those not responding (p = 0.0056). Low-dose-gamma-interferon and alpha-2-interferon treatment could be easily done on an outpatient basis. In conclusion, interferon treatment seems to be of value in the therapy of patients with well documented progressive disease in metastatic renal cell cancer.
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.
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A clinical Phase II study was performed to evaluate the efficacy and safety of treatment with interferon gamma in patients with metastatic renal cell carcinoma. Patients received interferon gamma by two different regimens: 1. 100 micrograms/m2 3x/week i.v. over 4 h every other week--low dose. 2. 500 micrograms/m2 5x/week i.v. over 24 h every other week--high dose--for non-responders to regimen 1. The response rate, duration of response, survival and toxicity in the two regimens were evaluated. Treatment with interferon gamma resulted in an overall response rate of 31%, with a duration of response ranging between 2 and 44+ months. Patients responding objectively to interferon gamma or showing stable disease survived significantly longer than non-responders (p = 0.0056).
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Thirty human renal cell carcinomas, subpassaged into NMRI-nu/nu mice, were analyzed during long term serial transplantation (range, 10-50 passages) with regard to their histological differentiation, mitotic activity, and DNA content. A quantitative methodology was applied to determine the mitotic rate. The DNA content was measured by flow cytometry. Only five tumors (four primaries and one metastasis) changed their mitotic rate significantly (P less than 0.01). In each case this change was paralleled by a simultaneous alteration of the DNA content. Histological pattern and nuclear grade remained stable in all but one tumor where the change in histological pattern occurred simultaneously with changes in DNA index and mitotic rate. These results indicate that the majority of renal cell carcinomas remain stable during long term serial transplantation, at least with regard to the parameters examined. This is a basic prerequisite for making the grafting of renal cell carcinomas into nude mice a reliable in vivo model for drug sensitivity testing. However, since a few of the transplanted tumors showed instability, continuous monitoring of phenotypic and genotypic tumor features is necessary during long term xenotransplantation.
In Drosophila as in many organisms beta tubulins are encoded by a gene family. We have determined the complete nucleotide sequences coding for the beta 1 and beta 2 tubulins of Drosophila melanogaster and the beta 2 tubulin of D. hydei, and found these insect beta tubulins to be highly conserved and like beta tubulins of other organisms. This is discussed with reference to the possible functional domains of these proteins. The beta 1 tubulin gene of Drosophila is constitutively expressed, whereas the beta 2 tubulin is expressed specifically in the testes. In D. melanogaster the amino acid sequences of these proteins are 95% homologous, differing at only 25 positions. In the testes the beta 2 tubulin participates in different microtubules as shown by genetic analysis (Kemphues et al. 1982). Interestingly, all of the amino acids characteristic of the testis-specific beta 2 tubulin are also present in the corresponding gene of D. hydei. Of special interest is the high degree of conservation of the carboxy-terminal domain in these functionally equivalent beta tubulins.
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.
Sixteen human bladder carcinomas (BCs) were transplanted into NMRI nu/nu mice with an acceptance rate of 62.5%. Six of the 16 (37.5%) BCs were successfully retransplanted up to 14 passages. Histologic grading and traumatization during surgery influenced the acceptance rate. Grade-I tumors were rarely accepted, unless they were obtained during open surgery, rather than by transurethral resection (TUR). Specimens taken by TUR or by electric cut during open surgery were almost never accepted. Identity of the transplanted tumor tissue with the original human BCs could be demonstrated by flow cytometry and by light microscopy through several passages in all accepted tumors. However, although the tumors retained their major structural features, their proliferative activity increased, particularly that of grade-I tumors. The five tumors that were transitional-cell carcinomas and could be subpassed had three characteristics not seen before in transplanted renal cell carcinomas: tumor growth started after a delay which shortened with each further passage; growth rates of tumors only in their first passage correlated with the prognosis of the corresponding patients, and with each further passage, tumor growth accelerated until a doubling time of about 1 week was observed. From then on, tumor growth was almost identical in all five tumors. In contrast to our experience with transplanted renal cell carcinomas, flow cytometric evaluation of the transplanted and further passaged BCs revealed changes in DNA index and an increase in proliferative rate and it seems that BCs were strongly influenced by host factors.