Trepanobiopsy as a tool for the study of the influence of presurgical treatment on the steroid receptor status of advanced breast cancer.

Estrogen, progesterone and glucocorticoid receptors were determined in samples obtained by trepanobiopsy before treatment and in surgical material following chemo- or radiotherapy in 131 Stage III a, b, c breast cancer patients. The levels and distribution of the receptors in bioptates coincided with the data obtained earlier for the surgical material from patients, who didn't receive presurgical therapy. It is concluded that breast tumor trepanobioptates may be used for the determination of tumor receptor status. Radiotherapy affected the level and frequency of occurrence of steroid hormone receptors. The degree of variations depended on the dosage of irradiation and after exposure period. After presurgical chemotherapy the percent of receptor-positive tumors increased.

A variant of a descriptive epidemiological study of cancer with the aid of a minicomputer.

The presented method of descriptive epidemiological study with the aid of a computer was designed using the model of an average district with a data file of carcinoma incidence from the period 1975-1983. The method is based on processing the statistical characteristics of a data file and on their evaluation. Plotting the coordinates of the communities and of the boundaries of the district constitutes the frame for the construction of maps. The population is divided into age groups of 5 years, incidence is standardized with respect to the age standard of the district. The selection of boundaries (isolines) of zones in the maps is based on the evaluation of the distribution of incidences and on the relative number of inhabitants in communities classified according to the standardized values. The application of the study to the work of centers for clinical oncology is discussed.

Spectroscopic study of N-nitroso compounds decomposition in presence of DNA bases.

Decomposition kinetics of N-ethyl-N-nitrosourea (ENU) as well as that of N-methyl-N-nitroso-N'-nitroguanidine (MNNG) in water medium was studied by means of differential UV spectroscopy. Rate constants of the first order reaction were evaluated. The influence of DNA bases on decomposition rate of above-mentioned compounds was also estimated. With the help of NMR spectroscopy there were identified several products of decomposition as well as those of interaction of the studied compounds with DNA bases.

Differential responses of carcinogen-induced fibrosarcoma of mice to altered regimes of cold exposure.

The effect of chronic and intermittent cold exposure was studied in benzo(a)pyrene-induced fibrosarcoma of mice. Chronic exposure to 5 degrees C caused decrease in incidence, increase in latent period, and inhibition of tumor growth. Intermittent exposures to +5 degrees C and -10 degrees C induced significant enhancement of tumor growth which increased with the lowering of temperature. Concomitant with the tumor growth alterations, stress reactions assessed by plasma corticosterone levels, differed in these two regimes. The elevation of plasma corticosterone levels correlates with the tumor growth enhancement which is probably mediated by corticosterone-induced immuno-suppression. Inhibition of tumors appears to be a result of adaptation to chronic stress, or metabolic alterations in cold. Physiological alterations of the host, depending upon the nature and duration and severity of the "stress" exposure, determines in our opinion probably the course of neoplastic development.

Qualitative structure-activity relationships (QSAR) by the 1H NMR spectra of methylbenz[c]acridines.

The 1H NMR spectra of benz[c]acridine and its methyl derivatives (BAc) in CDCl3 have been measured. The total assignment of 1H NMR spectra and spin coupling constants of BAc were discussed. The good relationship between the delta delta (delta 2--delta 1) and epithelioma index (EI) have been gained. It was suggested that the utilization of exact NMR method in the screening of some chemical carcinogens can be adaptable.

An iso-effect table for radiation tolerance of the human thoracic spinal cord. A new approach on the basis of the DFT conception.

Forty-four cases of well documented progressive radiation myelopathy of thoracic spinal cord were analyzed in terms of the new DFT conception (Dose-Fraction-Time). The DFT conception is a new radiobiological cell tissue kinetic model comprising explicitly repopulation. The conception has been previously tested against many animal experimental data. Good agreement could be demonstrated. The comparison with clinical data enabled us to establish human thoracic spinal cord tolerance DFT value of DFT = 70. For all cases of thoracic progressive spinal cord radiation myelopathy where the radiation fields were up to 20 cm of the cord length the value of the DFT has been found above the proposed value. Tolerance irradiation doses of various regular irradiation schemes were calculated from the DFT = 70 for practical use. Our predictions are in agreement with tolerance irradiation regimes recommended by various authors on the basis of their clinical experience. Moreover, such an approach enabled to establish safe tolerance doses in cases where currently used NSD or ED conceptions could lead to dangerous consequences--mainly for shorter irradiation schedules. This is the first attempt to utilize the DFT conception in the clinical practice.

Ph1-positive acute leukemia in a patient with Hodgkin's disease treated by irradiation and chemotherapy.

A case of acute undifferentiated leukemia with a Ph1-chromosome and a typical translocation t(9;22) is reported in a 54-year-old female with Hodgkin's disease. The interval from diagnosis of Hodgkin's disease to the development of acute leukemia was 19 months. Treatment of Hodgkin's disease consisted of combined cytotoxic therapy including irradiation and chemotherapy. Detection of Ph1-chromosome in undifferentiated blasts supports the suggestion of leukemogenic chromosomal aberration within uncommitted hemopoietic cells.

PHA responsiveness and adherent cell-lymphocyte interactions in patients with advanced malignant tumors of the ovary prior to treatment and during chemotherapy.

DNA synthesis in cultures of PHA-stimulated blood mononuclear cells from patients with advanced malignant tumors of the ovary before treatment was significantly reduced and responses of lymphocytes alone were, on an average, 40% lower than in control subjects. Adherent cells were found to suppress the PHA response of autologous lymphocytes from 6/12 patients before treatment, 4/18 patients during chemotherapy and only in 2/19 control subjects. The net effects of adherent cell-lymphocyte interactions in autogeneic vs. allogeneic combinations were frequently discordant, which suggests shifts in lymphocyte subpopulations responsive, respectively, to suppressor- and helper-type mediators released by monocytes in patients. PHA responses of mononuclear blood cells from patients after the 1st and 2nd round of chemotherapy were usually higher than the mean in untreated patients, but declined rapidly after subsequent rounds of cytostatic drug treatment and were deeply impaired in a few cured patients examined many months after therapy. Previous radiotherapy appeared to have little effect on the magnitude and patterns of changes of blood mononuclear response to PHA during subsequent chemotherapy.

Renal excretion of neopterine and biopterine in patients with malignant melanoma and Hodgkin's disease.

In two groups of patients with checked diagnoses of the malignant melanoma and Hodgkin's disease we followed changes of the renal excretion of two major pterines, neopterine and biopterine. In patients with the malignant melanoma, we found a remarkable increase of the excretion of neopterine, which depends on the extent of the involvement and, by contrast to this, in patients with Hodgkin's disease we found a remarkable decrease of the excretion of biopterine, also dependent on the extent of the involvement. In both types of the tumor disease the ratio neopterine: biopterine is remarkably increased as compared to controls.

Cytogenetic effects of Me-CCNU on sister chromatid exchange frequency, cellular kinetics and chromosome aberrations.

1-(2-Chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (Me-CCNU) was tested for its in vitro effects on sister chromatid exchanges (SCE), cellular kinetics and chromosome aberrations in CHO cells. There was a relationship between the inhibitory activity of the drug and the cytogenetic damage, which was dose dependent. Increase in SCE values were highly significant (p less than 0.001) for all the four concentrations used. It also delayed the cell cycle progression. Inhibition of DNA synthesis results in increased frequency of chromosomal aberrations, which was highly significant for the higher concentrations, i.e. 5 micrograms and 10 micrograms Me-CCNU/ml.

Immunogenicity of the Gardner lymphosarcoma for the mice of the strain C3H (H-2k). I. The effect of the 60Co-irradiation of recipients and of the interval between the immunization and transplantation of the tumor on the antitumor resistance of immunized mice.

The C3H (H-2k) mice were immunized by 60Co-irradiation-inactivated Gardner lymphosarcoma (LSG) cells. The degree of resistance of mice with transplanted tumors was determined by difference in survival curves of the immunized and nonimmunized mice. When the tumor was transplanted during 26 weeks after the last of the three immunizing injections the mean survival time of immunized mice was always prolonged over that of nonpretreated controls. The prolongation was not always significant. The slope differences between lines characterizing survival of immunized and nonimmunized groups were statistically significant when the transplantation of the tumor was performed up to the 22nd week following the immunization. A small number of immunized mice which survived 60 days without visible tumors belonged to immunized groups transplanted with the tumor up to 14 weeks after the last immunizing dose. A higher degree of resistance has been achieved in mice given increased number of immunizing injections. Similar effect was observed in mice with impaired antitumor resistance due to immunosuppressive dose of 60Co-irradiation given before the tumor transplantation. Skin grafts taken from resistant mice healed up to unaffected isologous mice as well as it was found in reciprocal transplantation experiments.

Immunogenicity of the Gardner lymphosarcoma for the mice of the strain C3H (H-2k). II. Alteration of the growth and dissemination of solid Gardner lymphosarcoma following immunization by an extract of the ascitic tumor.

Aqueous 1-butanol extracts were prepared from the ascites form of Gardner lymphosarcoma (LSG) maintained in C3H (H-2k) mice and from the solid Lewis lung carcinoma (LLCa) transplanted in B6 mice. C3H mice primed at least two times with cell surface antigens extracted from Gardner tumor cells (LSG-extract) lived longer than untreated controls if challenged with the solid Gardner lymphosarcoma cells. Tumors growing in immunized C3H mice differed from those growing in controls by shape, necrotization and inhibition of dissemination. If C3H mice were primed three times with LLCa extract then the survival was in comparison to intact controls prolonged only when the mice were pretreated into the site of tumor challenge. Survival time of B6 and B10 mice with transplanted LLCa was not markedly changed by previous priming injections of LSG-extract. An increase in mortality was recorded when LSG-extract-primed B10 mice were compared to the group of mice of the same line; similar effect has not been found in B6 mice.

The use of protein as a carrier of methotrexate for experimental cancer chemotherapy. II. Chemotherapy of Gardner lymphosarcoma with pea seed lectin-methotrexate derivative.

It was demonstrated that the tumorigenicity of tumor cells preincubated in low concentration of free methotrexate (MTX) has not been changed. On the other hand the preincubation of these cells with pea seed lectin (PL), MTX and PL mixture and especially pea seed lectin-methotrexate derivative (PL-MTX) influenced markedly the tumor cells tumorigenicity. The chemotherapy of Gardner lymphosarcoma (LSG) bearing mice with PL-MTX derivative was performed. After one dose therapy of LSG ascitic form with PL alone no effect on mice survival time was observed. The administration of PL-MTX derivative was efficient at a higher dose only. But free MTX was effective at both examined doses. Four times repeated injection of lectin to mice bearing the ascitic form of LSG shortened the survival time of mice. Repeated application of the higher dose of free MTX was accompanied with a considerable number of toxic deaths, but the life span of most surviving animals was prolonged. The similar but less expressive result has been reached by using PL-MTX derivative. The post mortem examinations suggest that the marked local inflammatory reactions are probably caused by the PL cytotoxicity. Therapy of solid LSG bearing mice with four i.t. injections of PL had no obvious effect on the survival. PL-MTX derivative prolonged distinctly the life span of tumored mice but the administration of sole MTX was the best.

Antimetastatic effect of flurbiprofen and other platelet aggregation inhibitors.

In the present study, we have examined the antimetastatic effect of flurbiprofen, a nonsteroidal antiinflammatory drug, on spontaneous metastases formation in mice bearing Lewis lung carcinoma and these results were compared with effects of other inhibitors of platelet function (mopidamole, dipyridamole, pentoxifylline). Flurbiprofen decreased significantly spontaneous metastases formation in a dose-depending manner. From the results obtained, it appears that the treatment with flurbiprofen, either on days 1-8 or days 1-21, was similarly effective. In mopidamole treated groups the number of animals with lung metastases was significantly decreased. This effect was not observed after treatment with dipyridamole or pentoxifylline.

Immune complexes in the serum of hamsters with transplanted melanomas.

Rosette EA and EAC inhibition test was used to compare levels of immune complexes in the serum of control hamsters and of hamsters with transplanted melanomas of the same origin, but differing in malignancy. The serum of individual animals with transplanted melanomas was found to cause a higher rosette inhibition. Inhibitory rate was more marked in hamsters with amelanotic tumors which grew faster and caused the death of an animal within a shorter time.

Morphological alterations in blood vessel endothelia of rat brain after administration of CCNU (lomustine).

Studies were performed on adult Wistar strain rats which were given four one-week spaced, intragastric doses of 2.5 mg or (the last dose) 5.0 mg CCNU. The animals were sacrificed one week after the last dose of the cytostatic drug. Cell nuclei of blood vessel endothelia in the parietal cerebral cortex and in the frontal-lateral part of the thalamus were examined. Karyo- and cytophotometric measurements were performed on sections subjected to Feulgen's reaction, using an automatic microscope image analyzer Morphoquant (Carl Zeiss, Jena). In CCNU-administered rats, blood vessel endothelia in the brain exhibited morphological alterations in the form of edema, increased DNA content in cell nuclei, modified distribution and density of chromatin lumps (nuclear chromatin lumps shifted towards the center of cell nucleus in the parietal cortex and in the thalamus, increased density of nuclear chromatin in the thalamus). Morphological alterations, changes in DNA content and in the nuclear chromatin status were of a similar type in blood vessel endothelia in the two examined structures but were somewhat more intense in endothelia of the cortex than in thalamus endothelia.

Chromosome aberration and mitotic activity in human peripheral blood lymphocytes following in vitro action of platinum cytostatics cis-DDP and EM-Pt.

Platinum-based preparations, the commercially available Platidiam (Lachema, Brno; cis-diaminodichloroplatinum) and the second generation experimental version--ethylmalonate platinum complex--EM-Pt (Institute of Macromolecular Chemistry, Czechoslovak Academy of Sciences, Prague) were left to act 3, 6 and 24 h on human peripheral blood lymphocytes, cultured in vitro for a short period of time. The utilized concentrations affected cell mitosis, provoking chromosome aberrations. A relationship was found between the effect of the concentration employed and the duration of action of the agent. cis-DDP proved to be a more powerful clastogenic agent than EM-Pt. Under in vitro conditions, neither of the two cytostatics required metabolic activation to trigger its action.

Significance of carcinoembryonic and tissue polypeptide antigen determination in the diagnosis of metastases in breast cancer.

A radioimmunological assay of CEA and TPA levels in breast cancer patients revealed a 93.7% concordance of negative and 93.4% of positive values with the clinical activity of the disease. In 26 out of a group of 38 patients (68.4%) with progressive breast carcinoma, an enhanced CEA and TPA level was the first indicator of the presence of metastases. In view of the results obtained, the authors consider this procedure to be a suitable method for monitoring and early detection of metastases in patients with breast cancer.

Significance of nucleo-cytoplasmic maturation asynchrony in multiple myeloma.

Bone marrow samples of 97 patients with multiple myeloma were examined ultrastructurally over a period of eight years, and the degree of nucleo-cytoplasmic maturation asynchrony (NCA) of myeloma plasmocytes was estimated according to the classification scale of Graham and Bernier. One half of the patients showed first degree, 40 percent second and 10 percent third degree of NCA. Clinical classification of the disease according to the staging system of Durie and Salmon and the quantitative staging system of Salmon and Wampler showed some relation to the degree of NCA. The degree of NCA was found to be related to the density of the bone marrow infiltration with myeloma plasmocytes but not to the response to chemotherapy. Some relation was seen to exist between the degree of NCA in myeloma plasmocytes at diagnosis and the prognosis of the disease. The role of electron microscopical analysis in MM diagnostics and its contribution to management of the disease are discussed.

Distribution of subclasses in a series of 62 sera with IgA paraprotein.

IgA1-2 subclass distribution was determined in a series of 62 sera with diagnosed IgA paraprotein. Throughout the series the participation of IgA1 : IgA2 subclasses showed a ratio 9 : 1 even after division of the series into myeloma and nonmyeloma paraproteinemias. On dividing the series according to the antigenic type of the light chains, IgA2 paraproteins with kappa light chains predominated over the lambda type (6 : 1).

Phagocytic activity of the tumor associated macrophages in relation to tumor growth: modulation with levamisole.

The phagocytic activity of the tumor associate macrophages isolated at different days of the growth of a murine transplantable ascites tumor was assessed by measuring the engulfment of Na2 51CrO4 labeled antibody coated sheep erythrocytes. Binding of the targets by the macrophages was also assessed. It was observed that, excepting the day 3, till day 7 of tumor growth the phagocytic activity of the tumor associated macrophages was very high as compared to that of resident macrophages of normal mice. Augmented target binding by the macrophages was recorded till day 7. Levamisole was observed to augment phagocytosis and target binding by the macrophages but a differential requirement as regard to the dose of Levamisole was noted for modulation of phagocytosis and target binding by the tumor associated macrophages at early and advanced stages of the tumor growth.

Incidence rates of prostate cancer in Bulgaria during the period 1967-1981.

The age- and residence-specific incidence rates of prostate cancer in Bulgaria have been studied for a fifteen-year period (1967-1981). Actual and standardized incidence and the cumulative incidence rates and risk have been determined and the secular trend of the standardized incidence rates has been defined by a linear regressive model. It has been found out that 90 percent of the new cases were over 60 years of age. The urban population was more strongly affected by the disease than the rural one, but the upward of the incidence rates was more pronounced among the latter. The annual increase in the incidence rates was 0.11 +/- 0.06 per 100,000 men. The risk of prostate cancer to the male population (cumulative risk) from 0 to 84 years of age was 2.54 percent, i.e. one out of forty men was at risk. The incidence rates were significantly higher in these districts of the country, where the largest and the most strongly industrialized towns were concentrated. The study gives the possibility to determine some characteristics of the incidence rates of prostate cancer in Bulgaria and hence to assess the efficiency of cancer control and to formulate some of its future trends.

Risk factors in mass screening for breast cancer, multivariate analysis of data from the Cuban diagnosis pilot study.

The evolution of mammography has provided possibilities for mass screening programs. Early diagnosis is considered the most important factor in reducing the breast cancer mortality but the mass screening is very expensive if we include all female population. In this paper we show the results of an early diagnosis pilot study with a multivariate data analysis. Data concerning risk factors (age, age at menarche, menopause, parity, age at first childbirth, lactation, abortions and previous benign breast disease) were recorded in 438 patients with breast carcinoma and 1750 patients with benign breast diseases diagnosed in the Early Diagnosis Pilot Program at the National Institute of Oncology and Radiobiology in Cuba. A group of 449 healthy women living in Havana City was also studied. Age and age at first childbirth were the major factor considered. Multivariate data analysis allowed to build stratification trees identifying subgroups with different breast cancer incidence. The usefulness of these stratifications for screening with optimal coverage, sufficiency and efficacy, is discussed.

Spontaneous lymphoma in an AKR mouse with dominance of 42 chromosomes.

The chromosome content of the lymphoma cells derived from various organ manifestations of an AKR female mouse with spontaneous lymphoma was investigated. It was found that the lymphoma cells were heterogeneous and the dominant subpopulation of the lymphoma cells contained 42 chromosomes. At least 8 subpopulations of the lymphoma were detected at the karyotype analysis, from which the 41XX; +15; 41XX; +18; 42XX; +15, +18 and 44XX; +5, +8, +15, +18 karyotypes were the most frequent aberrations. The frequency of the presence of various subpopulations was different also in the thymus, spleen and lymph nodes. The authors suggest that over the trisomy of chromosomes 15, other trisomies (e.g. gain of chromosome 18) can play a role in the AKR mouse lymphomagenesis.

Stimulation of glycolysis in Ehrlich ascites carcinoma cells with phenylhydrazonopropanedinitrile and others uncouplers of oxidative phosphorylation.

The metabolic consequences of the uncoupling effect of phenylhydrazonopropanedinitrile and others uncouplers of oxidative phosphorylation on Ehrlich ascites carcinoma (EAC) cells were investigated. Upon application of uncouplers in concentrations stimulating the respiration of EAC cells the accelerate glucose uptake and lactate production was observed. The maximal glycolysis stimulation was fourfold in relation to control at the given experimental conditions. Simultaneously the degree of conversion of glucose on lactate was increased. The acceleration of glycolysis was accompanied by stimulation of 14C-labeled adenine and valine incorporation indicating the increased rate of biosynthetic processes. The prolongation of uncoupler action time and application of their higher concentrations cause the inhibition of glycolysis and biosynthetic processes which is evoked with nonspecific effects of the compounds.

Kinetics of some immunological and biochemical changes of immunocompetent cells during tumor growth in rats.

The dynamics of lymphocyte response in peripheral blood, the tumor draining lymph node, spleen and thymus, was followed in a model system of syngeneically transplanted rat MC-1 tumor. Electrophoretic mobility (EPM) of lymphoid cells was determined by the automatic mode of measurement. The results revealed a two-phase pattern of EPM changes during the course of cancer growth. The first phase (day 3 to 6 following intramuscular injection of tumor cells) was characterized by a prevalence of high-mobility cells, while in the second phase (day 14 to 20), depletion of high-mobility cells was compensated for by an increased number of low-mobility cells. The mean EPM value was found to be increased only in the thymus at that time. Changes in the adenosine deaminase activity proved to be most expressive in the tumor draining lymph node and in the second phase also in splenic and thymic lymphocytes. An increased percentage of active lymphocytes with compact nucleoli with nucleolonemas became evident already on the 3rd day in all the lymphoid organs followed. The response was two-phasic only in the lymphocyte population of the peripheral blood, while their percentage in the other organs remained higher even on day 20. Changes in the proportion of high- and low-mobility cells in the lymphoid organs followed here, in correlation with the adenosine deaminase activity and the percentage of active lymphocytes, were interpreted as a response of immunocompetent cells in animals with a growing tumor.

Relation between high-frequency electrical impedance and malignity of two L cell sublines.

Two L cell sublines (L-As and LC3), differing in the ability to induce sarcomas in irradiated C3H mice, were grown on special gold electrodes interrupted in the middle by a 50 micron wide slot. Electrical impedance of the two sublines was compared at 100 kHz in a special measuring device connected with an apparatus used for impedance measurement in clinics. Significantly lower values of impedance characterized the LC3 cells, which induced more sarcomas in susceptibility hosts than the L-As cells. This result agrees with the findings in human tumors compared with corresponding normal tissue or benign growth, and stresses the importance of the cell population as such in impedance measurements.

Cytogenetic monitoring of a 24-hour effect of ethylmalonate platinum complex on human peripheral blood lymphocytes.

Analyses of mitotic activities and chromosome aberrations in lymphocytes of human peripheral blood have been utilized to evaluate 24-hour cytotoxic and genetic effect of various concentrations (0, 12, 60, 120, 240, 360 mumol l-1) of ethylmalonate platinum (EM-Pt) in vitro. EM-Pt was found to exert a mutagenic action, to have the character of a clastogenic agent and to affect primarily the G1-phase of the cellular cycle. Its activity may be affected by the concentration of the agent: a direct dependence was observed as regards occurrence of chromosome aberrations and an indirect one with regard to values of mitotic activity and cytotoxicity.

Study of risk factors in invasive cancer of the corpus uteri.

With the application of the case-control method, 173 patients suffering from invasive cancer of the corpus uteri (plus 346 women not suffering from this type of cancer and any type of neoplastic disease who formed control group) were analyzed. High incidence risk was ascertained for women who suffered previously from various diseases of reproductive organs, circulatory system, thyroid, diabetes, certain diseases of alimentary, urinary and also respiratory tract. Tobacco smoking together with the immediate exposure to dusts and gases in the microenvironment of work does not influence the increase of incidence risk of this organ, but certain type of diet which can be characterized by the high consumption of meat, animal fat and sugar with the lack of raw vegetables in diet influences the incidence risk of invasive cancer of the corpus uteri.

Serum lactate dehydrogenase level in various malignancies.

Total serum lactate dehydrogenase (SLD) values were measured and statistically analyzed with a view to testing the hypothesis that there is some association between enzymatic activity and cancer. Serum samples were collected from 205 normal persons, 201 patients with different malignant tumors and 202 patients with nonmalignant diseases. The age of patients and controls ranged from 19 to 71 years. There is a significant rise in preoperative serum lactate dehydrogenase level in cancer patients (314.56 U/l) than normal healthy individuals (105.50 U/l) and nonmalignant patients (105.87 U/l) irrespective of the site of tumor. The patient and control series did not show any significant bisexual differences. The postoperative follow-up study (breast cancer only) of SLD level indicated decreased enzymatic activity in almost all the cases. The observations of elevation of SLD in patient series than controls suggest release of LD to the surrounding medium by neoplastic cells, thereby indicating relationship between the enzymatic activity and neoplastic conditions. The results of preoperative and postoperative follow-up study of SLD activity in breast cancer prove of value in judging the effectiveness of therapy, diagnosis and prognosis of the cancer patients.