Results of radiotherapy and combined radiotherapy and chemotherapy of inoperable lung cancer.

In this study there is presented a comparative analysis of immediate results after radiotherapy and combined treatment (radio- and chemotherapy) in 174 patients with highly differentiated inoperable lung cancer. The data were provided by participants of a joint investigation in some CMEA member countries (Hungary, USSR, Czechoslovakia) during the period of 1976 to 1980. In the randomized study radiotherapy (a total dose of 60 Gy) was applied in 98 patients, radiotherapy with chemotherapy (methotrexate and 5-fluorouracil) was applied in 76 patients. The comparative analysis showed that the employment of complementary chemotherapy tend to improve the immediate therapeutic effects. In the case of highly differentiated planocellular carcinoma a pronounced positive effect was seen in 48.6% of patients as compared to the 31.2% of those treated with radiotherapy alone. Nevertheless, with respect to survival rate prolongation, these differences are not manifested in favor of the combined method of treatment. After a conservative treatment (radiotherapy and radiotherapy in combination with chemotherapy) of patients with differentiated types of inoperable lung cancer there was a one-year survival rate of 55.7%, 17.27% of the patients survived for 2 years, and 8.55% for 3 years. In radiotherapy applied alone as in the combined method as well, a direct dependence of survival rate prolongation on immediate therapeutical effects was detected. For more than 1 year survived 49 patients (73.1%) out of 67 exhibiting pronounced immediate effects, and for 3 years survived 8 patients out of 9.

Rectal cancer pathomorphology after preoperative radiation treatment.

Using histological and histochemical investigations and morphometric analysis the tumors and surrounding tissues of 70 rectal cancer patients were studied before and after preoperative radiotherapy with the total dose of 19.5 Gy and 40 Gy. Morphological changes proving the radiation damage of the tumors were determined. The extent of radiation damage depended on histological structure, degree of differentiation and radiation dose. The maximum damage was observed in poorly differentiated adenocarcinomas and the minimum--in colloidal cancer.

Factors associated with prognosis in human breast cancer. III. Estradiol receptors and short term relapse.

Prognosis in breast cancer is one of the most important subjects currently studied because of the heterogeneity of the disease even inside the same clinical stage. Estrogen receptor determination in human breast cancer has been recognized as a prognostic factor since it is related to the long-term survival and disease-free interval. In a series of papers concerning prognosis in breast cancer this the third one which includes estrogen receptor determination in the multivariate analysis, because of the limitations of the clinical factor to conform stratification groups. We have analyzed the short term probability of relapse in a group of 136 patients treated for breast cancer. Multivariate stratification analysis was performed with the aid of Bintree computer program, which produces binary splits of the population according to the criterion of maximal reduction of variance and generates a binary stratification tree. Lymph node involvement is the most important prognostic factor in the probability of relapse. Patients without nodal involvement lacking estradiol receptor had 25% of relapse. It is therefore evident that estradiol receptor is a factor of prognostic value even inside node negative patients.

Factors associated with prognosis in human breast cancer. IV. Progesterone receptors and clinical factors.

We have found no correlation between progesterone receptor PgR content in human breast tumors and clinical factors associated with the presence of estrogen receptor (ER, age, menopausal status, parity, age at first childbirth, menarche), in spite of the positive correlation between both receptors. Moreover, the association between clinical factors and the percentage of ER(-) PgR(-) tumors were identical to those of ER(-) tumors, but the association between clinical factors and the percentage of ER(+) PgR(-) tumors were inverse to those of ER(-) tumors. That implies that clinical factors associated with the presence of estrogen receptor can not distinguish ER(+) PgR(+) and ER(+) PgR(-) tumors. The stage of the disease is the most important clinical feature in breast cancer patients. In our series the pattern of hormone-receptor was different between Stages I/II and Stage III patients, while the percentage of PgR(+) tumors was constant, a decrease in ER(+) tumors occurred in Stage III patients. In addition similar percentages of ER(+) PgR(+) were found in both groups, but an increase in ER(-) PgR(-) tumors and a decrease in ER(+) PgR(-) tumors occurred in the Stage III patients. Altogether these results suggest that primary loss of progesterone receptors and primary loss of estrogen receptors could be related to different pathogenic mechanisms.

Interaction of smoking and urban air pollution in the etiology of lung cancer.

Surveillance of lung cancer incidence based on mortality was carried out over 6 years in Cracow. It appeared that lung cancer death rates among Cracow inhabitants were higher than average rate in the population of Poland but this difference in the large extent could be explained by the greater prevalence of smoking habit in Cracow than in whole Poland. Very intriguing was a substantial excess of lung cancer deaths only in male residents of the city center having the highest level of the air pollution. Since this excess in the lung cancer deaths could not be exclusively explained by smoking or occupational hazards the air pollution should be assumed as a responsible factor. Lack of the similar phenomenon in females living in the city center can be explained by the fact that the air pollution alone is not sufficient cause in the etiology of lung cancer but that in combination with other adverse factors like smoking or occupational hazards it develops its carcinogenic effect.

Surgery and combined treatment of breast cancer. Development and present status of the topic within the framework of joint scientific cooperation of the CMEA member countries.

Nitroblue tetrazolium test in patients with neoplasma during surgical treatment.

In 20 patients with alimentary tract neoplasma, nitroblue tetrazolium test (NBT) with resting and stimulated granulocytes was done using Park's et al. [14] method. NBT test was determined in peripheral blood before surgical intervention, in blood from vessel draining of tumor before its excision and in peripheral blood 2-3 weeks after excision of tumor. In parallel experiments the NBT test was estimated in peripheral blood of 21 healthy individuals. We have shown that NBT dye reduction was evidently diminished in patients with cancer disease especially in blood samples from vein draining of tumor both in resting and stimulated granulocytes. The excision of tumor caused improvement of NBT dye reduction. The importance of determination of NBT test in patients with cancer disease is briefly discussed.

Early effects of medium change in cultured cells: evidences for the existence of negative modulators of cell proliferation.

Serum deprivation of cells in culture leads usually to an arrest of DNA synthesis and cell proliferation but the transfer of cultured cells from serum-containing to serum-free medium results in a transient stimulation of the incorporation of radioactive thymidine to macromolecules. This stimulation effect produced by medium change can be separated into two different phenomena: a stimulation of thymidine incorporation induced by transfer of cells from conditioned serum-containing medium to fresh serum-containing medium and an additional stimulation induced by transfer of cells from serum-containing medium to serum-free medium. Experimental results indicate that the first effect is probably due to the removal of inhibitors released by the cells even in exponentially growing cultures, and that the second effect is probably due to the removal of inhibitory molecules coexisting in serum with stimulatory factors.

Colony growth in soft agar of human melanoma cells from biopsy material, cell lines and xenografts.

Colony growth in soft agar of human melanoma cells from biopsy material, cell lines and xenografts was evaluated. Colony forming potential is constantly very low in all studied types of tumor tissue, however slight increase in clonogenic potential was seen during subsequent xenograft passages, but within the range of less than 1%. Results of presented studies suggest that the number of colonies does necessarily express the degree of colony forming potential and the culture preparation and conditions as well. It appears that there is no reliable correlation between the number of colonies in soft agar and the clinical course of melanoma patients under study.

Dynamic dose-fractionation combined with oxygen breathing at ambient pressure and high-dose metronidazole in head and neck, and uterine cervix cancer.

The paper summarizes the results of dynamic dose-fractionation combined with oxygen breathing at ambient pressure and metronidazole in head and neck, and uterine cervix cancer. The patients were given high oral doses of metronidazole (5-6 g/m2) three hours before dose fractions (4.5 Gy for two days) initiating the radiation treatment series. After successive daily irradiation with 2 X 1 Gy in 8 hours interval (without metronidazole) to the tumor dose 29 Gy, 5-day radiation free interval was inserted and then the identical treatment series was repeated to the total dose 60 Gy. Nausea and vomiting were the principal toxic symptoms which were rather severe in gynecological patients. The benefit of metronidazole combination was studied in comparison with a group of patients given dynamic dose-fractionation with breathing of oxygen only. Preliminary analysis of the data suggests that the combination with radiosensitizer has not produced an increase in the curability of cancer in these particular sites.

Cis-diamminedichloroplatinum in the treatment of disseminated malignant melanoma.

The efficacy of cis-platinum in the treatment of recurrent advanced malignant melanoma is discussed and also the so far unpublished clinical data have been summed up. On account of the considerable differences among these data the clinical study of Stage II had been started which should contribute to the elucidation of efficacy of cis-platinum in malignant melanoma treatment. Here the first part of the trial is presented in which cis-platinum was administered to 21 patients, and the effects were studied in 17 of them. In 5 patients a partial remission was observed. These results are considered to be satisfactory enough to offer further time on the study of effects of cis-platinum.

Influence of cis-platinum on some platelet functions in vitro.

Cis-platinum added to citrated platelet rich plasma in vitro did not influence the aggregation of the platelets, their adhesion to glass, their release of platelet factor 4 or availability of platelet factor 3 and acid phosphatase. Neither any effect on the uptake of 14C-serotonin, the reptilase clot retraction or the coagulation system has been observed.

Monitoring of effects of cis-diamminedichloroplatinum II. Part I. Cytogenetic analysis in vitro.

The cytogenetic effects of cytostatic drug Platidiam Lachema (cis-diamminedichloroplatinum (II) complex, cis-DDP) have been studied employing short-term in vitro cultivation of human peripheral lymphocytes. Three hours following the administration of cis-DDP at a concentration of 12.5 microM (that is a concentration approximately 10 times lower than that applied clinically at a single dose), chromosome aberrations (predominantly breaks, in 73% those of the chromatid type) were seen at an increased rate. They reached their maximum after 24 h of treatment. A time dependence has been revealed: with decreasing mitotic activity and prolonged time of cis-DDP treatment (3, 6, 18, 24, 48, 72 h, respectively) the number of cells with aberrant chromosomes increased, this elevation being statistically significant from 18 h on.

Effect of combined chemotherapy tested in partially hepatectomized rats bearing Zajdela hepatoma.

Ascitic Zajdela hepatoma growing in partially hepatectomized rats was used for testing cytostatics in single and two-drugs combination chemotherapy. At the optimal dosage the highest selective activity against tumor cells (hepatoma) with low inhibition of normal cells (regenerating liver cells) was seen in the combination cis-platinum + methotrexate. Synergistic effect of this combination was found when suboptimal dose of MTX was combined with low doses of cis-Pt. Dose-dependent DNA synthesis inhibition following i.p. administration of cis-Pt was documented by 3H-thymidine incorporation. Although the content of platinum expressed per DNA amount was four times higher in regenerating hepatocytes when compared with hepatoma cells, the growth inhibiting effect of cis-Pt was selectively expressed against the hepatoma cells.

Factors associated with prognosis in human breast cancer. II. Multivariate stratification analysis.

Prediction of the individual fate of breast cancer patient is one of the most important problems for establishment of therapeutic plans. We have analyzed the relationships of clinical factors to 3-year and 8-year survivals in a series of 400 patients treated for breast carcinoma. Multivariate stratification analysis for obtaining subgroups with different survivals was performed with the aid of Bintree, a computer program which produces binary splits of a population according to the criterion of maximal reduction of variance, and generates a binary stratification tree. Lymph node status was the major predictor for both short and long term prognosis but had no important role in the survival of patients who relapsed. Antecedent abortions were related to less relapses. Age, previous benign breast diseases, nulliparity and lactation conditioned better prognosis without association with relapse probability, indicating an association with the speed of evolution of the disseminated disease. In general clinical data were insufficient for establishment of good and bad prognosis polar groups of patients, especially in patients in which no clinical lymph node involvement was recorded.

Cancer mortality in Yugoslavia.

Inhibition of bovine heart adenosine deaminase activity by some pyrimidine analogues.

Some pyrimidine analogues--especially 6-azauridine and 5-azacytidine at a final concentration of 1 mmol dm-3--significantly depressed adenosine deaminase activity isolated and purified from bovine heart. Both the above mentioned azapyrimidine nucleosides were effective competitive inhibitors of this enzyme. The inhibitory effect of some clinically used pyrimidine analogues may be of importance for explanation of their mechanisms of action on the cell metabolism.

The cytotoxic action of granaticin, a sulfhydryl-reactive antibiotic, on Ehrlich ascites carcinoma cells.

Transplantability of Bomirski melanomas in Syrian hamsters.

Multiple tumors in gynecology.

Two large groups of patients, i.e. 1893 patients treated at the Institute for carcinoma cervicis uteri and 1184 patients with Ca corporis uteri were selected and evaluated for a follow-up study and statistical processing of tumor duplicity of gynecological origin. Double tumor in the group with Ca cervicis uteri was found in 88 women, i.e. 4.6%, and in that treated for Ca corporis uteri in 85, i.e. 7.2% of the patients. The most frequent combination in the two groups of carcinoma is breast cancer amounting to 28.4% in Ca cervicis uteri and to 35.3% in Ca corporis uteri. The second most frequent primary carcinoma in Ca cervicis uteri is dermal carcinoma--23.9%, and in Ca corporis uteri that of the digestive tract--21.1%. A statistical follow-up over 40 years indicates a rise in tumor duplicity in both groups of gynecological carcinoma--cervical and endometrial, with the number in the former having increased more than twofold.

Localization of carcinoembryonic antigen in mesenteric lymph nodes of patients with gastrointestinal cancer.

Mesenteric lymph nodes obtained at surgery from 36 patients with gastrointestinal tract cancer were studied by immunofluorescence for the presence of carcinoembryonic antigen (CEA). Granular deposits of CEA in a homogenous mixture with immunoglobulins and complement were detected in the activated germinal centers in 12 lymph nodes from 8 investigated cases. Identification of CEA in germinal centers was confirmed by blocking and absorbtion procedures. Successful elution of immunoglobulins and part of CEA content with a buffer known to dissociate antigen-antibody bonds suggested that these deposits represent CEA immune complexes.

Mutagenic effects of nitrofurylacrylic acid on V79 cells under hypoxic conditions.

Induction of 6-thioguanine-resistant mutations was studied in Chinese hamster V79 cells treated with nitrofurylacrylic acid under aerobic and hypoxic conditions. The results obtained demonstrated that the mutagenic activity of this substance, less significant in aerobic conditions, was very high under hypoxic conditions. A gradual increase in mutation frequencies according to the applied concentrations of nitrofurylacrylic acid was observed, the maximal values being at 0.8 mg of the substance per 1 ml of growth medium. The mutagenic effects of nitrofurylacrylic acid were independent of its cytostatic effect that was higher in aerobic than hypoxic conditions. Mutagenic capacity of this substance found in vitro in mammalian V79 cells suggests its possible carcinogenic potential in vivo under conditions favorable for metabolic activation of this nitrofuran-derived compound.

Circulating immune complexes in Hodgkin's disease.

Levels of circulating immune complexes (CIC) were estimated in the sera of 110 patients with Hodgkin's disease (HD) and of 103 normal subjects by polyethylene glycol precipitation method. Levels of CIC were significantly elevated in HD patients compared to normal subjects with 63% of the patients showing levels above 95th percentile of the normal. Patients with symptoms showed significantly elevated levels of CIC compared to patients without symptoms. There was a good correlation between the levels of CIC and the clinical stages, the former increasing from stage I to IV. However, no such correlation was noticed with respect to the histological type of the disease. On polyacrylamide gel electrophoresis CIC of normal subjects as well as of HD patients showed a number of protein bands. But CIC of HD patients had one additional band with approximate molecular weight of 130 000 which was absent in CIC of normal subjects.

Geographic patterns and trends of liver, biliary tract and pancreas cancer mortality in Slovakia.

The age-adjusted mortality rates and trends of primary liver cancer in Slovakia showed during the investigated decade 1968-1977 small reduction in males, accompanied with statistically significant decline in females. The slightly increasing trends of mortality from the cancer of gallbladder and extrahepatic bile ducts were not significant while the growing rates and upward trends of mortality from pancreatic malignant neoplasms were statistically significant for both sexes. Geographic distribution of standardized mortality rates from these cancer sites displayed various differences within the districts of Slovakia during the whole investigated period. The need for further descriptive and analytical studies of these less common cancer sites of the alimentary system using more detailed and classified data on incidence and mortality is stressed.

Natural cell-mediated cytotoxicity in Ehrlich ascites tumor-bearing mice.

The level of NCMC (natural cell-mediated cytotoxicity) in the spleen of Ehrlich ascites tumor-bearing mice at every 5 days after i. p. tumor transplantation, and the effect of cell-free ascitic fluid or serum of tumor bearers on natural cytotoxicity in vitro, were assessed. Spleen lymphocytes were used as effectors and 51Cr-labeled YAC1 cells as targets at the effector: target ratio of 200 : 1. In tumor bearers, the NCMC increased in the first days after i. p. inoculation of 1 X 10(6) Ehrlich cells with a maximum peak on day 5. Thereafter, the activity decreased continuously, on day 20 representing about half of normal value. Ascitic fluid and serum of tumor bearing mice significantly depressed the NCMC activity exerted in vitro by spleen lymphocytes of normal mice.

Evaluation of the LAI test in patients with benign and malignant breast diseases.

Tumor "specific" immune recognition was assayed in 125 patients with various breast diseases including breast cancer of clinical stage I and II, 22 patients with other malignancies and 64 healthy persons employing leukocyte adherence inhibition test (LAI). In the group of breast cancer patients (BC) there were 81% of positive responders (52/65) with a mean nonadherence index (NAI) value 67.4. Sensitization to extract derived from breast cancer was detected in 38.3% (23/60) of patients with benign breast diseases (BBD). The mean NAI value was significantly lower comparing to NAI value of BC patients (34.8 vs. 67.4) but exceeded the upper limit of normal values. The most frequent positive responders of BBD group were found in patients with proliferative mastopathy (11/17). Our study brought further evidence that BC patients and in a lesser degree BBD patients are sensitized to some antigen(s) contained in selected breast tumor extracts. However, high proportion of false positive results in healthy persons (14.1%) and mainly considerable number of positive responders in BBD patients represent a major limitation for clinical diagnostic usefulness of the LAI assay.

Haptoglobin types in ovarian tumors.

Haptoglobin types were determined in 132 patients with cancer of ovaries and 114 patients with nonmalignant tumors of the ovaries, respectively. In comparison with a normal population significant increase in the frequency of Hp1 gene in the both pathological groups was observed. It was mostly reflected in a lower occurrence of haptoglobin type 2-2.

Large granular lymphocytes in blood of healthy donors and patients with tumors.

The percentage of large granular lymphocytes (LGL) in the peripheral blood of patients with less advanced tumors (T1 and T2) averaged 2.15 +/- 1.3 as compared with 3.8 +/- 1.5 in patients with more progressive tumors (T3 and T4) and with metastases. The values of LGL remained constant as long as 6 weeks both in the diseased and healthy subjects and were not age- nor sex-related. This observation confirms the usefulness and reliability of the test as one of the markers of the immunologic state since LGL are considered to represent NK cells responsible for resistance to malignant growth.

Transforming activities of methotrexate, hydroxyurea and 5-fluorouracil in different cell systems.

The transforming ability of methotrexate, hydroxyurea and 5-fluorouracil was studied in mass cultures of embryo cells from BN/a, DBA/2 and Swiss mice. As estimated by virological methods the cells from BN/a mice were infected persistently with ectromelia virus. In parallel a quantitative transformation assay with a cloned BALB/3T3 cell line was employed. Oncogenic transformation could be induced repeatedly in mass cultures from BN/a mice after treatment with every of chemotherapeutic agents studied. Neither of the drugs induced transformation in the cultures deriving from two other strains of mice. In the cloned BALB/3T3 cell line from the three drugs tested only methotrexate induced the appearance of transformed foci, however, the yield of transformants was very low. It has been concluded that under the employed experimental conditions the transforming ability of hydroxyurea and 5-fluorouracil could be expressed exclusively in the cells infected with ectromelia virus. The transforming ability of methotrexate seems to depend either on the presence of viral infection or on the properties of cells enabling additional events necessary for transformation.

Comparison of lipids between tumor and normal hamster melanosomes.

A study of lipid components of melanosomes isolated from eye pigment tissues and pigmented melanoma type Bomirski line Ma of Syrian hamster by thin-layer chromatography is described. Tumor melanosomes contained 8-10% of total lipids, approximately one half of which were phospholipids. Eye melanosomes contained only 3-4% of total lipids, among which no phospholipids could be detected. Cholesterol, cholesteryl esters, free fatty acids and triacylglycerols were found in the fraction of neutral lipids. Phosphatidylcholine, phosphatidylethanolamine and sphingomyelin constituted 70-80% of the phospholipid fraction.