Total scatter factors and tissue maximum ratios for small radiosurgery fields: comparison of diode detectors, a parallel-plate ion chamber, and radiographic film.

Two p-type diode detectors, a parallel-plate ion chamber, and radiographic film were used to measure total scatter factors and tissue maximum ratios (TMRs) for a stereotactic radiosurgery system with circular fields ranging from 5 to 50 mm in diameter. One diode has a square detection diagonal of 2.3 mm and the other diode has a circular detection diameter of 1 mm. It is found that the two diodes measured essentially the same total scatter factors for all field sizes. Total scatter factors measured by film are within 3% of diode values. Our results also suggest that the parallel-plate ion chamber could underestimate total scatter factors for fields as large as 15 mm in diameter, although it is recommended for field diameters > or = 12.5 mm. The total scatter factors used in our clinic are combined from data measured with the ion chamber and the 2-mm-diam diode. The combined total scatter factors generally agree with published data. While film overestimates TMRs for the smallest fields at large depths because of energy dependence of the film, the measurements with the 1-mm-diam diode agree with published data measured with thermoluminescent dosimeters. It is demonstrated that the accurate measurements of total scatter factors and TMRs for small fields can be obtained by combining results of the commercially available detectors used in this study.

Performance evaluation of a diode array for enhanced dynamic wedge dosimetry.

The performance of a diode array (Profiler) was evaluated by comparing its enhanced dynamic wedge (EDW) profiles measured at various depths with point measurements using a 0.03 cm3 ionization chamber on a commercial linear accelerator. The Profiler, which covers a 22.5 cm width, was used to measure larger field widths by concatenating three data sets into a larger field. An innovative wide-field calibration technique developed by the manufacturer of the device was used to calibrate the individual diode sensitivity, which can vary by more than 10%. Profiles of EDW measured with this device at several depths were used to construct isodose curves using the percentage depth dose curve measured by the ionization chamber. These isodose curves were used to check those generated by a commercial treatment planning system. The profiles measured with the diode array for both 8 and 18 MV photon beams agreed with those of the ionization chamber within a standard deviation of 0.4% in the field (defined as 80% of the field width) and within a maximum shift of less than 2 mm in the penumbra region. The percentage depth dose generally agreed to within 2% except in the buildup region. The Profiler was extremely useful as a quality assurance tool for EDW and as a dosimetry measurement device with tremendous savings in data acquisition time.

Effects of tamoxifen on human breast cancer cells in vitro.

Long-term treatment of the estrogen sensitive human breast cancer cell line EFM-19 with the antiestrogenic compound Tamoxifen resulted in a variant line EFM-19 T, which was stimulated by Tamoxifen. Estrogen receptor analysis by radioligand assay (charcoal method), revealed a 2.5 fold higher receptor concentration in EF-19 T cells than in the parental EFM-19 cell-line. As demonstrated with the immunocytochemical assay (ER-ICA) only 60% of the parental EFM-19 cells were estrogen receptor positive, whereas 98% of the EFM-19 T cells expressed estrogen receptor protein. In addition, receptor content per cell was higher in the Tamoxifen treated subline than in the parental cell line. Analogous with the growth promoting effect of Tamoxifen on EFM-19 T cells, Tamoxifen acted like estrogen leading to a down regulation of cellular estrogen receptor concentration. The partial growth dependency of the EFM-19 T cells on the presence of Tamoxifen demonstrates estrogenic effects of Tamoxifen and explains the withdrawal response obtained in the treatment of breast cancer patients when remission occurs after termination of ineffective treatment with Tamoxifen.

Release of anti-PAF activity from PAF-binding human ovarian cancer cells in culture.

The human ovarian cancer cell line EFO-27 in culture spontaneously produced anti-PAF activity, which eluted from HPLC in the range of synthetic PAF. The activity therefore appears to be due to an antagonistic PAF-analogue. It was detected by a suppressed PAF-induced platelet aggregation in vitro. EFO-27 cells were found to be able to bind synthetic PAF with saturable binding kinetics. This binding led to reduced cell proliferation. The production of anti-PAF activity by EFO-27 cells resembles an autocrine growth regulation in the light of recent findings that other malignant transformed cell lines produce PAF-like activity in vitro if stimulated appropriately.

Antitumor activity of the pineal gland: effect of unidentified substances versus the effect of melatonin.

There is growing evidence that the pineal gland has antineoplastic properties which, however, can only partially be attributed to its hormone melatonin. While the in vivo tumor-inhibiting activity of melatonin is established, observations on its in vitro effects have been contradictory. The effect of this substance was investigated on six human cancer cell lines and compared to the activity of a partially purified, melatonin-free low molecular weight pineal extract (UMO5R). Melatonin showed hardly any effect but UMO5R was capable of inhibiting the growth of all the six cell lines tested. It is therefore concluded that a direct inhibiting action on tumor cells is not a general physiological role of melatonin as opposed to UMO5R. It will be worthwhile to purify the yet unidentified pineal antitumor activity since it may have a considerable therapeutic potential.

Performance characteristics of a commercial dedicated contamination counter.

The dedicated wipe test counter (DWTC) is a commercial geiger-counter type instrument especially designed for wipe test counting. All samples are counted under the same physical conditions within 0.3 cm from a 2-mg cm-2 mica end-window geiger tube of 1.27 cm in diameter. The counting capabilities of the DWTC were tested for different radioisotopes in common use in the nuclear medicine laboratory. Since most of the imaging agents are 99mTc-based radiopharmaceuticals, an experimental efficiency factor, J = 3 cpm kdpm-1, was determined for this radioisotope by the manufacturer and stored in the counting system for default use. In addition, the formulation for the counting time needed to achieve a measurement with adequate level of significance (two standard deviations) and a background measurement time of 20 min was programmed in the firmware of the DWTC. With these parameters, the counting time for a 99mTc wipe (threshold of 2000 dpm) becomes 1.88 min for a background level of 10 cpm. The counting time increases to 3.25 and 4.80 min for the respective background levels of 20 and 30 cpm while the threshold is kept the same. In practice, we were able to measure activities as low as 0.7 kdpm for 99mTc and 0.09 kdpm for 131I. Linearity was maintained for a wide range of activities for all tested radioisotopes. The DWTC was found to be simple to operate and satisfies all requirements for performing wipe tests in the nuclear medicine laboratory.

[Dysgerminomas. Clinical aspects, therapy and prognosis with reference to the cooperative therapy study MAIKEI 83/86 for non-testicular germ cell tumors of the Society of Pediatric Oncology]. / Dysgerminome. Klinik, Therapie und Prognose unter Berücksichtigung der kooperativen Therapiestudie MAKEI 83/86 für nichttestikuläre Keimzelltumoren der Gesellschaft für Pädiatrische Onkologie (GPO).

In comparison to other malignant germ cell tumors, dysgerminomas of the ovary show a high sensitivity to radiotherapy. According to histology and biological behaviour, dysgerminomas of the ovary are similar to testicular seminomas, which seem to be very sensitive to chemotherapy. Therefore, in the protocol for non-testicular germ cell tumors of the German Society of Pediatric Oncology (GPO) a treatment for dysgerminomas is established, in which the indication for primary tumor resection and a supplementary radiotherapy, or, in selected cases, primary chemotherapy and delayed tumor resection after the spreading, has been graded. After a median follow-up of 26 months, 17 of 18 patients were alive and disease-free, from which 3 patients with tumor progression after initial ovariectomy are in the second remission phase following relapse therapy. One patient died of tumor progression despite combined chemotherapy and irradiation. With a stratified therapy regime, fertility could be preserved with high probability in 13 of 17 patients.

[Comparison of the results of preoperative studies with imaging procedures with the surgical status of ovarian cancer]. / Vergleich der präoperativen Untersuchungsergebnisse der bildgebenden Verfahren mit dem operativen Situs beim Ovarialkarzinom.

Optimal cytoreductive surgery of ovarian cancer is based on the preoperative diagnosis and assessment of tumour spread. Of 147 patients who underwent staging laparotomy at the Department of Gynaecology of the University of Tübingen, intraoperative staging was compared retrospectively with the results of sonography, computed tomography, double-contrast enema and urography. Ultrasound and computed tomography were comparable concerning accuracy of the diagnosis in 86 and 79% of the cases, respectively. Combined application of both methods resulted in an accuracy of 90%. Involvement of colon was diagnosed by double-contrast enema in only 41% of the cases in which enterotomy had to be performed. Involvement of bladder and ureter was observed in 80% of the cases by intravenous urography. According to our results abdominal ultrasound and urography should be performed in patients with palpable pelvic masses. The application of computed tomography as an additional method is indicated in patients with tumour classified as benign by sonographic examination. Double-contrast enema is of limited value in the diagnosis of colon involvement.

[Importance of clinically prognostic factors in the treatment of advanced ovarian carcinoma]. / Die Bedeutung klinisch-prognostischer Faktoren für die Behandlung fortgeschrittener Ovarialkarzinome.

25 patients with stage III and IV ovarian carcinoma were treated with radical surgery and postoperative chemotherapy. Analysis of the disease-free intervals and the survival rates indicated significant differences related to the stage of the disease. Furthermore patients with minimal residual disease (tumor mass less than 2 cm in diameter) had a far better prognosis than patients with extensive residual disease (greater than 3 cm). No correlation could be demonstrated between histological grading, in vitro proliferation rates, hormone receptor status, type of postoperative chemotherapy and survival rates.

In vitro modulation of prolactin binding to human mammary carcinoma cells by steroid hormones and prolactin.

This study demonstrates the specific binding of human (h) PRL to mammary carcinoma cells of the newly established line EFM-19. Under saturating conditions, [125I]hPRL bound to these cells with high affinity (Ka = 4.3 X 10(10) M-1) and low capacity (4080 binding sites/cell). In serum-free medium, stimulation of cell proliferation by PRL was found, suggesting a biological role in the growth of human breast cancer. hPRL was more effective in binding to and promoting the growth of EFM-19 cells than ovine PRL or other lactogenic hormones. Up- and down-regulation of [125I]hPRL binding occurred after pretreatment of EFM-19 cell cultures with subphysiological or higher hPRL concentrations, respectively. Physiological concentrations of 17 beta-estradiol or dihydrotestosterone increased the cellular capacity of hPRL binding. Pharmacological concentrations of dihydrotestosterone or physiological concentrations of progesterone reduced the binding of [125I]hPRL. The results provide evidence for complex regulatory mechanisms of PRL binding by human mammary carcinoma cells involving steroid hormones.

Individual chemosensitivity of in vitro proliferating mammary and ovarian carcinoma cells in comparison to clinical results of chemotherapy.

Cell lines established from advanced mammary and ovarian carcinomas were assayed for the inhibition of in vitro proliferation by various antineoplastic drugs. The assays were performed with multiple experimental cultures derived from stock cultures of the tumor cell lines in early passages of the cultivation. As determined by comparison of the 50% inhibition of in vitro growth, differential sensitivity of the individual cell lines was observed. Based on the 2-h plasma level of the drugs as discriminatory threshold between resistance and sensitivity, the in vitro effectiveness of each drug on the individual cell lines was compared with the clinical results of chemotherapy applied to the corresponding patients. In total, positive in vitro/in vivo correlations were observed in 39 of 42 cases. The 17 cell lines evaluated retrospectively were resistant to those drugs which had been tried unsuccessfully during chemotherapy. Among the 25 cases tried prospectively 11 cases showed sensitivity in vitro and in vivo, and furthermore 11 prospective cases were resistant in vitro and in vivo.

Effectiveness of antineoplastic drugs on the proliferation of human mammary and ovarian carcinoma cells in monolayer culture.

Procedures for the in vitro determination of the drug-induced inhibition of mammary and ovarian carcinoma cell growth were established. In monolayer cultures derived from advanced tumors, separation of epithelial carcinoma cells from concomitant cells of fibroblast-like or mesothelial appearance was achieved by differential trypsinization. The carcinoma cell character of the stock cultures was verified by chromosome analyses showing a high degree of aneuploidy for the epitheloid cell lines and euploidy for cells of apparently mesenchymal origin. When cultured carcinoma cells were injected in nu/nu mice, the tissue and cell cultures obtained from the heterotransplantation tumors closely resembled the original tumors and cell cultures in morphology, karyotype, and expression of tumor markers. The action of carcinostatic drugs in the logarithmic phase of the carcinoma cell proliferation was tested by kinetics experiments in multiple experimental cultures. In cell proliferation assays based on cell counts the 50% inhibition dose (ID50) of the drug effects was determined from the dose-response curves. Comparison of the ID50s revealed highly differential effectiveness of the drugs examined. The inhibitory effects were reproducible, rendering the procedures used suitable for testing the chemosensitivity of newly explanted gynecological carcinoma cells by proliferation assays.

In vitro growth promotion of human mammary carcinoma cells by steroid hormones, tamoxifen, and prolactin.

Individually different growth responses of 10 cell lines newly derived from metastasizing mammary carcinomas were determined by cell counts in experimental incubations with the steroid hormones 17 beta-estradiol, progesterone, testosterone, hydrocortisone (cortisol), the antiestrogenic compound tamoxifen, or prolactin. Of 7 cell lines derived from ductal carcinomas, 5 were stimulated by prolactin. The growth of 4 of 7 cell lines established from the tumors of postmenopausal or ovariectomized patients was enhanced by doses of testosterone, which are in the range of the physiologic serum level. The proliferation of 5 cell lines was promoted by hydrocortisone in the physiologic concentration of 100 nM, supporting the notion that concentrations of testosterone or hydrocortisone normally present in body fluids may facilitate the in vivo growth of breast cancer. The in vitro growth of cells derived from tumors after relapse under treatment with medroxyprogesterone acetate or tamoxifen was markedly enhanced by progesterone or tamoxifen (CAS: 10540-29-1) in concentrations corresponding to therapeutical serum levels and in accordance with in vivo resistance to the endocrine therapy applied before cell sampling. The results of this suggest the occurrence of positive endocrine selection mechanisms operating in vivo on human mammary tumor cell populations.

Alteration of steroid hormone sensitivity during the cultivation of human mammary carcinoma cells.

During early cultivation steps of the newly derived and karyotyped human mammary carcinoma line EFM-19, the cells developed faster growth rates and became increasingly less responsive to the presence of serum in the culture medium. No drastic alterations of the morphology and of the karyotype were observed, and carcinoembryogenic antigen remained expressed during the course of the cultivation. In experimental incubations at various time intervals after the explantation, the cell proliferation was analyzed for dose-dependent effects of estradiol, cortisol, progesterone, and testosterone. After 16 wk of cultivation of the stock culture in the presence of estradiol, the cells had acquired a distinct sensitivity to estradiol resulting in permanent growth enhancement. The withdrawal of cortisol from the medium of the stock culture subsequently provoked the loss of the initially noted stimulation of the proliferation by cortisol. The stimulatory effect of progesterone on the proliferation was reversed to inhibition when the stock culture was deprived of cortisol in the growth medium. The results indicate that the choice of steroid hormones in the stock culture medium was determining the quality of the cellular growth responses.

Cell lines derived from human ovarian carcinomas: growth stimulation by gonadotropic and steroid hormones.

Carcinoma cell lines established from 5 patients with advanced tumors of ovarian location were characterized by karyotypes and growth properties in serum-free medium. In early passages of the cultivation, the growth of cell lines derived from tumors of fairly differentiated histology was stimulated by human follicle-stimulating hormone or human chorionic gonadotropin-human luteinizing hormone. Cells obtained from poorly differentiated carcinomas were unresponsive to gonadotropins. The proliferation of cell lines derived from a malignant clear cell carcinoma and from the ovarian metastasis of an advanced mammary carcinoma was enhanced by cortisol. The results imply that hormonal factors in concentrations physiologically occurring in human serum may support the in vivo growth of ovarian tumors.

Hormone sensitivity of gynecological tumor cells in tissue culture.

Proliferating tumor cells obtained from ovarian, mammary, and endometrial tumors in tissue culture were tested for the influence of proteohormones and steroid hormones on cellular DNA synthesis and cell growth. The gonadotropic hormones stimulated DNA synthesis of ovarian tumor cells by single administration, or in combination with cortisol, up to the 11-fold of the comparable controls. The hormone sensitivity of the cell lines was variable, resulting in individual reaction patterns. There was no correlation to the histological diagnosis of the primary tumors with respect to the grade of differentiation. The results suggest that ovarian tumor cells in tissue culture can maintain sensitivity to organotropic hormones. Compared to the ovarian carcinoma lines, mammary or endometrial tumor cells did not respond to a similar extent. Progesterone decreased DNA synthesis of endometrial carcinoma cells.