Malignant neoplasms of the pancreas. A study based on autopsy data from 1953 to 1982 in Bialystok, Poland. II. A survey of 195 cases.

Among 195 malignant neoplasms of the pancreas (MNP) diagnosed at autopsy in 1953--1982 the exocrine carcinomas comprised 85.6% and inmular carcinomas 13.8% of cases. MNP were localized most frequently in the head of the pancreas (54.4%), then in the whole pancreas in 14.9%, in the head and the body or in the body and the tail in 20.5%, in the body or in the tail in 10.3% of MNP. There were no infiltrations and no metastases in other organs only in 16 patients (8.2% of MNP). The biliary tracts and duodenum were the most frequent sites of secondary infiltrations. Metastases were most frequent in the liver, then in the liver hilus and mesentery lymph nodes. The concordance of clinical and post mortem diagnosis of MNP was stated in 40.5% cases.

Biochemical and histochemical characteristics of target antigen detected by monoclonal antibody HBCA-12 against a membrane component of human mammary carcinoma cell line.

Monoclonal antibody HBCA-12 obtained by hybridoma procedure after immunization with human mammary adenocarcinoma cell line MDA-MB-231 immunoprecipitated a cell surface sialoglycoprotein gp80 (apparent molecular weight 80 000) from MDA-MB-231 cells and a glycoprotein gp78 from human myeloma cell line ARH 77. A protein of a similar electrophoretic mobility was immunoprecipitated also from 35S-methionine metabolically radiolabeled human melanoma cell line VUP 1. The expression of the antigen recognized by HBCA-12 monoclonal antibody could be detected neither on PHA-induced nor on EBV-transformed peripheral blood mononuclear cells from healthy donors.

Damages of DNA synthesis in normal and tumor cells with sugar alcohol derivatives.

The rates of incorporation of 2-14C-thymidine into DNA of melanoma B16, bone marrow, gastrointestinal mucosa, spleen and liver at various time after administration of dianhydrogalactitol (DAG), 3,4-diacetyldianhydrogalactitol (DiacDAG) and 3,4-disuccinyldianhydrogalactitol (DisuDAG) at maxima nonlethal single doses to tumor-bearing mice were studied. The sugar alcohol derivatives induced the stable inhibition in DNA synthesis of tumor cells. DNA synthesis in normal dividing cells was shown to recover more rapidly than in melanoma B16 cells after administration of all drugs. DisuDAG is characterized by stronger inhibitory effect on DNA synthesis in melanoma B16 cells at the half of the single maxima nonlethal dose compared with DAG and DiacDAG. Differing from DAG, DiacDAG and DisuDAG did not effect the incorporation of 2-14C-thymidine into DNA of liver cells. In vivo inhibition of DNA synthesis in melanoma B16 cells with DiacDAG was not due to damage of the TCA soluble fraction.

Treatment of childhood neuroblastoma at the Clinic of Pediatric Oncology of the Faculty Hospital in Prague during 1965-1982.

The results of a complex treatment of 93 patients with neuroblastoma treated at the Clinic of Pediatric Oncology in Prague during the period of 1965-1982 are presented. A group of 41 patients treated during 1965-1977 was compared to that of 52 patients treated during 1978-1982. The latter group received a more intense chemotherapy treatment. In Group A there survived 7 patients (16.28%), all of them without symptoms of neuroblastoma. In Group B did so 31 patients (59.61%), 25 of them (48.08%) without symptoms of the disease, however, the results obtained in this group are of rather recent origin. A comparison made by means of the log-rank test and by extrapolating the data from curves of survival rates revealed no statistically significant improvement.

Splenectomy and susceptibility to infection in childhood Hodgkin's disease.

In a ten-year analysis (1970-1979) of lymphogranulomatosis performed at the Clinic of Pediatry of the Wilhelm Pieck University, Rostock, special attention was paid to susceptibility to infection after splenectomy. Of 22 children treated for lymphogranulomatosis, 20 underwent explorative laparotomy and splenectomy. After removal of the spleen the rate of infectious complications (of both viral and bacterial origin) doubled as compared to that seen before splenectomy. The finding of immunological investigations did not sufficiently explain the clinically proven susceptibility to infection.

Abdominal non-Hodgkin's lymphoma in children. Results of irradiation and chemotherapy in a series of 50 patients.

Results obtained in 50 children with abdominal non-Hodgkin's lymphoma after a treatment program that comprised entire abdominal irradiation and chemotherapy are presented. Actuarial survival of the series at 3, 5 and 10 years is 65.8%, with 75.2% for patients in Stage II and 58.6% in Stage III. Patients in 5-9-year age group, or in Stage II comported with a better prognosis, with significant differences. Majority of deaths occurred during the first 6 months with stabilization of survival after the second year of treatment.

Chemotherapy-induced fatal pulmonary fibrosis.

The case of a girl with relapsing ependymoma is described, who received BCNU and vincristine treatment. She developed progressive, pulmonary fibrosis as a consequence of chemotherapy, which lead to her death. Predisposing factors, clinical and histological findings are discussed and suggestions are made for the regular and preventive checking of the patients' pulmonary function.

The development of joint scientific cooperation within the framework of CMEA on the problem of "viral carcinogenesis".

Major trends of research carried by Council for Mutual Economic Assistance (CMEA) member countries in the field of "viral carcinogenesis" of the complex problem "malignant neoplasia" are outlined for the past 10 years. Steady extension and elaboration of the types of cooperation is emphasized. Scientific cooperation of CMEA member countries has been carried out since 1974 under the sponsorship of the Cancer Research Institute, Slovak Academy of Sciences (Czechoslovakia) within the framework of CMEA. Leading oncological institutions of Bulgaria, GDR, Hungary, Poland, USSR and Czechoslovakia have been contributing to the research.

The role of central dopaminergic processes in chemical carcinogenesis.

The effect of chemical carcinogen N-nitrosodiethylamine (NDEA) was studied in white noninbred male rats in a series of experiments. The animals treated with dopamine receptor agonist (apomorphine) showed statistically significant inhibition of carcinogenesis. Dopamine receptor antagonist (haloperidol) showed a tendency to stimulate the carcinogenesis. Also, the modifying effect of NDEA on behavior stereotypy and aggressiveness of experimental animals was found following apomorphine injection at various dosages. The data obtained are discussed from the point of view of the leading role of ANS in homeostatic regulation of the organism and in carcinogenesis.

Cinematographic study of the effects of cis-diammine-dichloroplatinum on mouse L cells.

Cells of mouse fibroblasts line L were grown one hour in the presence of cisplatin. Their fate was then followed by time-lapse microcinematography during six days. Up to the concentration 3.2 mumol 1(-1) there was little effect observed. Higher concentrations induced prolongation of mitosis and interphase, finally resulting in non-cycling cells with complete and persistent division arrest at 25 mumol 1(-1). After 72 hours following the treatment the cellular and nuclear volumes in non-cycling cells began to grow progressively. The mobility and the ruffling activity of the cell membrane were unaltered. Thus, energy generation, the function of the cytoskeleton, and synthetic processes seemed unchanged. The effect of cisplatin is cytostatic rather than cytotoxic.

Drug resistance induction and cross-resistance studies with Pt-complexes.

In vitro drug resistance was induced against cis-diamminedichloroplatinum(II) (cis-DDP), 1,2-diaminocyclohexaneplatinum-(II)citrate (PEX) and 1,2-diaminocyclohexaneplatinum(II)glucarate (PTU) in L1210 leukemia cell line. Using the resistant sublines cross-resistance was found between cis-DDP and cis-diamminecyclobutane-1,1-dicarboxylatoplatinum(II) (CBDCA) and between the three 1,2-diaminocyclohexane (DACH) derivatives tested. No (or low degree) cross-resistance was found between cis-DDP and DACH derivatives.

The bio-social elements of risk in the invasive cervical cancer incidence among a stationary and migratory woman population. A case-control study.

The incidence risk of invasive cervical cancer has been analyzed in two groups of women--autochthones and migrants--and the higher risk-rate has been proved for the latter. The essential interdependence between the incidence risk of invasive cervical cancer and the danger of industrial dusts and gases influence have been proved for both fractions of women. The higher incidence risk of invasive cervical cancer has been observed among those who had suffered from lithiasis, diabetes, arterial hypertension before, among those who while undergoing the cancer treatment might have also been operated on reproductive organs because of myoma or erosion, or had suffered from syphilis (this has been observed only in relation to the autochthones' population).

The growth and dissemination of continuously irradiated LS/B1 lymphosarcoma cells.

Transplantable strain of murine lymphosarcoma growing as a free suspension in the peritoneal cavity of isologous hosts was continuously irradiated by 60Co unit at a low exposure rate of 1.2 Gy/day for 350 weeks. Long-term irradiation did not alter substantially the viability and invasiveness of tumor cells. In the host of irradiated cells the spleen mass was six times higher around the day 8. Histological sections of the spleen revealed areas of edema and hemorrhage and infiltration and proliferation of tumor cells mostly in subcapsular area. Most of the splenomegaly is considered to be due to hyperemia caused by mass of erythrocytes in dilated spleen sinuses. Continuous irradiation is supposed to lead to more pronounced sarcomatous character of LS/B1 tumor.

CAP (cyclophosphamide, adriamycin, cisplatinum) in the treatment of advanced breast cancer.

Fourteen patients with advanced carcinoma of the breast were treated with CAP combination therapy. An objective therapeutic response (partial remissions with a mean duration of 6.3 months) was achieved in 6 of 13 evaluated patients. This response was observed in soft tissue metastases. Nausea and vomiting were found to be the most frequent undesirable side effects in all patients and could not be avoided by administration of antiemetics. In 2 patients mild nephrotoxicity was found without any effects on further therapy. The results of this study were considered as promising; a definitive assessment of the CAP regimen is expected to come from a randomized study which started in the CMEA countries in 1983.

Circulating immune complexes in patients with lymphomas and leukemias.

Immune complexes (IC) were examined in the sera of 100 patients with histologically confirmed non-Hodgkin's lymphoma (NHL) and 80 leukemic patients by the EA-rosette forming cell inhibition assay. Sera from 55 healthy controls were also tested for the presence of IC. Using 9% rosette inhibition as a base-line, IC were observed to be present in 66 out of 100 sera from patients with NHL (66%), 35 out of 80 sera from patients with leukemia (43.7%) and 10 out of 55 control subjects (18%, p less than 0.001). The percentage of positive results was significantly lower in NHL patients with favorable prognosis (45%) than in patients with unfavorable prognosis (80%). IC from the sera of 7 ALL and 6 CML patients were investigated before chemotherapy, in remission and at relapse. The mean inhibitory rate of rosette inhibition was significantly higher in patients during the blastic stage of leukemia than during the complete remission (12.5%), and later it became higher again at the time of relapse. In CML patients, the previously normal serum rosette inhibition activity increased during the blastic crisis. These observations indicate that the follow-up studies of such patients may determine their prognosis accurately.

Masked Philadelphia chromosome due to the translocation (1q-;22q +) and small chromosome 19 in a case of acute leukemia.

The case of a 51-year-old female with acute myelomonocytic leukemia (AMMoL) and masked Philadelphia (Ph1) chromosome is reported. The Ph1 resulted from a translocation involving chromosomes 1 and 22, in which a segment of the long arm of one chromosome 1 (1q12----q25) was translocated to the long arm of one chromosome 22 at band 22q11. Additionally, a marker chromosome of unknown origin and deletion of the long arm of one chromosome 19 at band 19q12 were found. The literature on masked Ph1 chromosomes and changes of chromosomes 1 and 19 is briefly summarized.

Treatment of basal cell carcinoma with 13-cis-retinoic acid.

Patients with basal cell carcinoma were treated locally with 13-cis-retinoic acid. Disappearance of the tumors was observed in two of fifteen patients. Thirteen patients whose tumors diminished after the treatment were finally managed surgically. Biopsy specimens were examined histopathologically and by autoradiography. Treated tumors showed reduction of labeling indices as compared with the nontreated group.

Study of B and T lymphocyte surface markers in breast cancer patients using anti-B and anti-T cell monoclonal antibodies.

The immune status of 34 breast cancer patients was investigated by measuring several parameters of peripheral blood lymphocytes--monoclonal antibodies against T cell (Leu-1) and B cell (HLA-DR) antigens, and against cytotoxic/suppressor (Leu-2a) and helper/inducer T cells (Leu-3a); E rosette formation as a T cell marker and surface Ig as a B cell marker; FcIgG receptor expression; and mitogen responsiveness of the peripheral blood lymphocytes to PHA, Con A, and PWM. Most of the patients had normal percentages of B and T cells and T cell subsets but there was a trend to lower percentages of T cells and their subsets in stage IV patients. Due to lymphopenia in stages I and IV and in patients which had received radio- or chemotherapy, the total number of B and T cells and T cell subsets was less in these groups than in the controls. The percentage of FcIgG positive cells was higher in these groups than in controls and therefore the absolute number remained unchanged. In general, a decrease in T cells seems to be indicative of a poor prognosis. Mitogen responsiveness does not have prognostic significance since a patient in stage III, in good general health, had a low mitogenic response and a terminal stage IV patient had a normal mitogenic response.

Trends of cancer incidence in Bulgaria for the period 1964-1980.

Levels of cancer incidence in Bulgaria have been examined by sex, overall and for ten prevailing lesion sites, as recorded over the period 1964-1980. Using linear regression, steady trends of standardized morbidity have been ascertained. The findings indicate rising frequencies for overall malignant disease, as well as for lung cancer in males, breast cancer, cancer of the uterine body and of the ovary, cancer of the prostate, cancer of the urinary bladder, and malignancies of the lymphatic and blood-forming tissues. Stabilization is noted for incidence of cervical cancer and lung cancer in females, and cancer of the larynx in males; decline is observed for stomach cancer and skin cancer in both sexes, and for lip cancer in males. Defining of the magnitude and the dynamic changes in morbidity level and structure provides for more purposeful orientation in long-term planning and in developing complex programs for cancer control.

Novel cytotoxic and antitumor agents. IV. Withaferin A: relation of its structure to the in vitro cytotoxic effects on P388 cells.

In vitro effects of withaferin A and its 9 new derivatives on P388 cells have been studied. The cytotoxicity was calculated from the utilization of precursors in protein and nucleic acid (NA) synthesis and from capacity to suppress cell proliferation. The most potent agents proved to be 4-dehydrowithaferin A and withaferin A diacetate exhibited an equal inhibitory effect on thymidine, uridine, and L-valine incorporation. They stopped cell proliferation and, at the same time, killed the cells. Cytotoxicity was found to be due to a double bond at position C2-3, by dissociating this bond the cytotoxicity markedly decreased in all derivatives. A dissociation of the double bond at C24-25 or a removal of OH group from C27 did not cause any significant changes in the biological effects of the derivatives. An addition of a carbonyl group at C4 increased the effects of the agent. An addition of OH groups to the molecule of withaferin A resulted chiefly in a qualitative change in the action of derivatives manifested by a significant decrease in L-valine inhibition. As withaferin A promptly reacted with L-cysteine, it was presumed that one of the possible target sites in the cell might be the SH groups of enzymes which react with the lactone and epoxide groups of the agent.

Indirect effect of cyclophosphamide on the lung tumor colony formation and on the conditioned media activity.

Mice pretreated with cyclophosphamide (CY) had more tumor colonies in lungs following i.v. injection than their intact counterparts. CY treated mice restored with spleen cells showed incomplete reduction of the artificial metastasis in lungs. Conditioned media prepared from lungs contain two factors: stimulating and inhibiting cell proliferation in vitro. Conditioned media from CY treated mice were found to have a decreased inhibitory ability.

Erythropoietic alterations in mice bearing a transplantable lymphoma.

Tumor-induced changes in the pattern of erythropoiesis have been studied in A/RB mice bearing a transplantable ascites tumor, DBA lymphoma. The tumor growth was accompanied by diminished erythropoiesis, and the 51Cr-labeled red cell half-life was also decreased. Plasma iron turnover rate of the tumor bearing hosts, however, was increased and the level of erythropoietic stimulating factor (erythropoietin) in the plasma was not reduced. The existence of an inhibitor(s) to erythropoietic activity was unlikely. Comparative study of the erythropoietic activity revealed suppression in the marrow, but an increment in the spleen. The distribution of pluripotent hematopoietic stem cells (CFUs) also paralleled this alteration. However, the degree of ineffective erythropoiesis, determined by in vitro technique, was significantly elevated in the spleen. Possibly, this has reduced the effectiveness of splenic compensatory erythropoiesis.

Immunohistochemical localization of toxoplasma antigen in reactive and neoplastic lymph nodes.

Sixty-six formalin fixed, paraffin-embedded reactive and neoplastic lymph node biopsies were examined by the immunoperoxidase (PAP) procedure to localize toxoplasma antigen. 13:16 (81.25%) of the histologically suggestive toxoplasmic lymphadenitis and 4:8 (50%) of Hodgkin's lymphoma with histiocytic (epitheloid) cell infiltrates were positive. All other reactive and neoplastic biopsies were negative. Our data prove the usefulness of the PAP procedure as a specific and sensitive test to confirm the diagnosis of histologically suspicious toxoplasmosis. This study, however, is the first of its kind that demonstrates immunohistologically the association of toxoplasmosis with Hodgkin's lymphoma in the same lymph nodes. It also calls in question the nature of the histiocytes in lymphoid neoplasms and suggests the possibility that, at least in some lymphomas especially Hodgkin's, the histiocystic component may be due to the association of other conditions which are worth of further investigation.

Cell electrophoretic characterization of peripheral blood lymphocyte subpopulations enriched by rosette formation, from normal individuals and CLL patients.

Peripheral blood lymphocytes from healthy subjects and patients with chronic lymphatic leukemia (CLL) were isolated and their subpopulations enriched through formation of spontaneous rosettes with sheep or mouse red blood cells, respectively. Electrophoretic measurements were performed in unseparated as well as in fractionated cell populations. Normal blood lymphocytes showed two clearly distinguishable populations of different electrophoretic mobilities. After separation by SRBC rosette formation the rosette-forming cells could be identified as high mobility cells. CLL lymphocytes showed in most cases an unimodally distributed cytopherogram, the mean electrophoretic mobility being intermediate between the low and high mobility cells of control persons. After separation through mouse erythrocytes rosette formation these cells contained two cell fractions differing in their electrophoretic mobility: a fraction of slower mouse rosette-forming cells and a fraction of the non-MRFC which contained mainly cells of higher mobility that could be identified as enriched T cells. These both fractions showed unimodal distributions. This study shows that CLL lymphocyte subpopulations can be further characterized by surface charge density.

Monoclonal antibodies to membrane components of human breast cancer cell line MDA-MB-231. Production and reactivity with various cells in culture.

Hybridoma clones were established by fusing spleen cells from mice hyperimmunized with human breast cancer cells of MDA-MB-231 line with murine myeloma cells P3-X63-Ag8-653. Ten permanent hybridomas were stabilized. The monoclonal antibodies of three of them, i.e. HBCA-6, HBCA-4 and HBCA-12 were tested against 20 various established cell lines. The most restricted binding properties showed HBCA-12 antibody which reacted positively only with two types of target cells. The cross-reactivity of HBCA-12 with human breast cancer cell line MDA-MB-231 and human myeloma derived cells ARH-77 is discussed in view of the pertinent target structure, i.e. differentiation antigens, allospecific antigens, hormone receptors and shared tumor associated antigens. It was shown that the target structure for HBCA-12 is localized on the cell surface.

Three-year follow-up of carcinoembryonal antigen levels in the serum of patients with breast cancer.

The levels of carcinoembryonal antigen (CEA) were followed up for three years in 66 patients with breast cancer. In the group of patients treated surgically (N = 36, T1-2, NO-2, MO) the values of CEA were in agreement with the clinical course in 97% of the patients (35 out of 36 patients). Recurrence and/or dissemination of the disease were signalled by a rise in the serum CEA level to more than 15 micrograms/1 out four out of five patients more than 3-10 months before clinical manifestation. In the group of patients without surgery, who were treated by radiation and/or chemotherapy (N = 30, T2-4, NO-3, MO) the serum CEA values were in agreement with the clinical course in 71% of the patients (20/28). Within three years recurrence and/or dissemination were detected in 57% patients (16/28), ten patients died (10/30--two of them were not evaluated). The recurrence or dissemination were signalled in seven out of 16 patients (44%) more than 4-14 months before clinical detection, in three patients (19%) the rise was detected simultaneously with the clinical finding (examinations at 3-4 months intervals), and in 6 patients (38%) the CEA level was at variance with the clinical finding.

No difference in delayed hypersensitivity between breast and cervical carcinomas.

DNCB and PPD skin testing was performed in 130 breast and 110 cervical cancer patients. BATES' instruction with a plea for uniformity was used [1]. Patients were tested while being diagnosed and prior to the treatment. No significant differences either in the frequency of a reactivity or grade of response in corresponding stages of breast and cervical cancer were found.

Comparison of folylderivative biosynthesis in Ehrlich ascites carcinoma cells and in some organs of healthy and tumor-bearing mice.

Biosynthesis of folylderivatives derived from subcutaneously injected 2-[14C]folate was studied in Ehrlich ascites carcinoma (EAC) cells and in liver and kidneys of healthy and tumor-bearing mice. Retention of exogenous folate was followed by measurements of the total radioactivity of folylderivatives present in the EAC cells and organs examined. Identification of unconjugated and conjugated folylderivatives was done by means of column chromatography on Sephadex G-25, G-15 and cellulose sheets. The level of retained radioactivity in folyderivatives, being 5% in the liver and 1% in the kidneys of the radioactivity administered to mice, was similar in healthy and tumor-bearing animals. Moreover, no quantitative and qualitative differences were found in folylmono-and polyglutamates originated from the organs of healthy or tumor-bearing mice, although the content of folylpolyglutamates arose faster in liver and kidneys of EAC cells-bearing mice as well as in the tumor cells than in the organs of healthy mice.

Alkylphosphonium salts as a new class of antitumor agents.

A series of twenty-four alkylphosphonium salts were prepared and evaluated as potential antitumor agents in vivo against Ehrlich ascites carcinoma (EAC). Eleven compounds were screened in vivo against lymphoid leukemia L1210 and one against lymphocytic leukemia P388. Out of these, three compounds exhibited mild antitumor activity against EAC. Twenty compounds were tested for their cytotoxic activity against the growth of tissue culture cells originated from human epidermoid carcinoma of the nasopharynx (KB). All compounds but one exhibited significant cytotoxicity in this cell line. 2-Bromoethyltriphenylphosphonium bromide, chosen as a standard compound, was earlier reported [4] to have borderline activity against P388, but it failed to show any activity against EAC though it has exhibited significant in vitro cytotoxicity in KB cell culture. In the course of this study, seven new alkylphosphonium salts were synthesized.

Kinetics of growth inhibition in a neoplastic population after repeated cytostatic treatment.

The analysis of growth kinetics of a neoplastic population after cytostatic treatment (radiation, chemotherapy) has been modeled by means of the cell cycle transition probabilities mu and transition intensities lambda. The transition between phases of the cell cycle and quiescent G0 cells during repeated cytostatic treatment has been exposed by the probabilistic model on the basis of the experimental data. The cytostatic treatment (the most effective time, dose and therapeutic combination) can be scheduled using established size and volume of the tumor and an estimate of cell proportion in various compartments of the neoplastic population. The probabilistic model has been worked out with the object of repeated cytostatic treatments in the optimum time with respect to the reduction of resistant quiescent G0 population. By repeating treatment in these times, the G0 population may be effectively reduced, the tumor is loosing its proliferation (recovery) potential and the further tumor growth may be for a long time delayed or even ceased.