Search PubMed⌕ Search

Biomedical subjects

V M Kosma

Publications and source records attributed to V M Kosma.

At least 109 records · Page 6Linked to original sources
PubMed1996

The important prognostic value of Ki-67 expression as determined by image analysis in breast cancer.

A series of 191 female breast carcinomas (with long-term follow-up) were analysed immunohistochemically (with a monoclonal MIB1 antibody) for Ki-67 (a proliferation marker) expression with special reference to well-established prognostic factors and patient survival. Expression of Ki-67 was directly related to the S-phase fraction (P < 0.0001), the volume-corrected mitotic index (P < 0.0001), histological grade (P < 0.0001), the apoptotic index (P < 0.0001), oestrogen and progesterose receptor content (P < 0.0001 for both) and p53 accumulation (P = 0.001). No correlation was found between Ki-67 expression and lymph node status (P = 0.25), metastasis at operation (n = 0.81) or tumour size (n = 0.38). The proliferation rate, as measured by image analysis of Ki-67 expression, predicted survival in the entire cohort (P = 0.001) and in axillary-lymph-node-negative (ANN) patients (P = 0.003). The difference in recurrence-free survival between the high- and low-expression groups was greatest in ANN tumours, 40% (P = 0.008). In axillary-lymph-node-positive tumours, the Ki-67 expression was not significantly related to recurrence-free survival (P = 0.723). The results of multivariate survival analysis showed that tumour size, axillary lymph node status, and mitotic index were independent prognostic factors in the entire series whereas, in ANN cases, tumour size and Ki-67 labelling were independent prognostic factors. These findings imply that Ki-67 expression could be an important prognostic determinant in breast cancer. Because of the evident loss of the predictive power of tumour size in the 1990s, the prognostic value of Ki-67 expression may even be accentuated in the currently diagnosed small breast carcinomas.

Breast Neoplasms↗
PubMed1996

Standardized mitotic counts in breast cancer. Evaluation of the method.

Twenty-one pathologists and technicians participated in a study evaluating the variation present in mitotic counts for prognostication of breast cancer. The participants counted the mitotic figures in 20 breast cancer samples from ten high power fields (mitotic activity index, MAI, giving the results in mitotic figures per 10 fields) and also made a correction for field size and area fraction of the neoplastic epithelium to get the standardized mitotic index (volume fraction corrected mitotic index, or M/VV index, giving the result in mitotic figures per square mm of neoplastic epithelium). The difference in variation between the two methods was not big, but the standardized mitotic index (SMI) showed consistently smaller variation among all participants and different subgroups. Experienced pathologists had the highest variation in mitotic counts, and specially trained technicians, the lowest. The efficiency of the mitotic counts in grading (the grading efficiency) was used to evaluate the mitotic counts. In groups without special training for mitotic counts the mean grading efficiency was lower (experienced and training pathologists both on average had the potential to grade 88% of the cases correctly) than in the group specially trained for the purpose (trained technicians had the potential to grade 95% of the cases correctly). Among the specially trained technicians, the grading efficiency was of the same magnitude as the grading efficiency achieved in determining the S-Phase fraction of cells from paraffin embedded breast cancers by flow cytometry in different laboratories. The results suggest that special training is helpful in making mitotic counts more reproducible, and that in trained hands, the mitotic counts give results comparable to more sophisticated methods of determining proliferative activity in breast cancer.

Breast Neoplasms↗
PubMed1996

Prognostic factors in gastric cancer: the value of vascular invasion, mitotic rate and lymphoplasmacytic infiltration.

A retrospective analysis of 321 gastric cancer patients was made to assess the prognostic value of TNM classification, tumour differentiation, Laurén classification, proliferative rate, inflammatory reaction and tumour invasion in vascular or neural structures of the gastric wall. The TNM classification showed the strongest correlation with survival in univariate and multivariate analyses (P < 0.0001). The invasion in lymphatic or vascular system and Laurén classification were also independent prognosticators in multivariate analysis (P < 0.05). In univariate analysis, the WHO-grade, the size and the location of the tumour and perinueral invasion were significant prognostic factors (P < 0.01), as were the infiltration of lymphocytes and plasma cells in the tumour (P < 0.05). On the other hand, the mitotic indices reflecting the proliferative activity of the tumour cells showed no significant correlation with the prognosis. The results indicate that the prognostic power of the TNM classification can be further increased by assessment of the above special histological features in gastric cancer.

Adult↗
PubMed1995

Life-long over-expression of ornithine decarboxylase (ODC) gene in transgenic mice does not lead to generally enhanced tumorigenesis or neuronal degeneration.

Ornithine decarboxylase, the rate-controlling enzyme of the biosynthetic pathway of the polyamines, is one of the most inducible mammalian enzymes showing many of the features common to the oncoproteins. Ornithine decarboxylase activity is likewise strongly induced in response to various neurotoxic stimuli, and the enhanced enzyme activity is believed to be causally related to neuronal damage. We have generated several transgenic mouse lines over-expressing human ornithine decarboxylase gene. We have now subjected the animals to a long-term survival study in order to assess whether constitutively over-expressed ornithine decarboxylase would predispose them to enhanced tumorigenesis and neuronal degeneration. When the transgenic animals were 2 years old, their tissue ornithine decarboxylase activity was 20- to 50-fold that in their syngenic littermates. Macroscopic and microscopic examination of organs revealed no differences between syngenic and transgenic animals as regards spontaneous tumor incidence or age-related changes in brain.

Animals↗
PubMed1995

A comparison of diets with and without oats in adults with celiac disease.

BACKGROUND: Wheat, rye, and barley damage the small-intestinal mucosa of patients with celiac disease; maize and rice are harmless. The effects of a diet containing oats are uncertain. METHODS: In a randomized trial, we compared the effects of gluten-free diets without oats and with oats (with a goal of 50 to 70 g per day from three sources: two types of wheat-starch flour mixed with an equal amount of oats, muesli containing 60 percent oats, and rolled-oat breakfast cereal). Fifty-two adults with celiac disease in remission were followed for 6 months and 40 with newly diagnosed disease for 12 months. Endoscopy with duodenal biopsy was performed at the beginning and end of the study. RESULTS: The mean (+/- SD) oat intake in the oat group was 49.9 +/- 14.7 g per day at 6 months for patients in remission and 46.6 +/- 13.3 g per day at 12 months for patients with newly diagnosed disease. The oat and control groups did not differ significantly in nutritional status, symptoms, or laboratory measures. Patients in remission, regardless of diet, did not have worsening architecture of the duodenal villi or increased mononuclear-cell infiltration. All the patients with new diagnoses were in remission at one year, except for one in the control group. Six patients in the oat groups and five in the control group withdrew from the study. CONCLUSIONS: Moderate amounts of oats can be included in a gluten-free diet for most adult patients with celiac disease without adverse effects.

Adult↗
PubMed1995

Apoptosis suppressing protein bcl-2 is expressed in well-differentiated breast carcinomas with favourable prognosis.

The expression of bcl-2 protein was analysed immunohistochemically in 202 female breast carcinomas. The intensity of bcl-2 expression was inversely related to tumour grade (P < 0.0001), tumor necrosis (P < 0.0001), mitotic index (P < 0.0001), oestrogen receptor content (P < 0.0001), progesterone receptor content (P = 0.0007), S-phase fraction (P = 0.00047), and apoptotic index (P = 0.087). A high fraction of bcl-2-positive cells was related to ductal or lobular type (P = 0.03) and slight nuclear pleomorphism (P = 0.03). Heterogeneous expression of bcl-2 protein was associated with high grade (P = 0.02), severe nuclear pleomorphism (P = 0.02), DNA aneuploidy (P = 0.018), high S-phase fraction (P = 0.05), and early metastasis (P = 0.03). Intense expression of bcl-2 protein was significantly related to favourable outcome in the entire cohort (P = 0.0013), as well as in axillary lymph node-negative (ANN) tumours (P = 0.0124). Long recurrence-free periods in the entire cohort (P = 0.037) and in ANN tumours (P = 0.08) were confined to cases with intense expression of bcl-2 protein. In multivariate analysis, bcl-2 expression had no independent prognostic value in the entire cohort or in axillary lymph node-negative breast carcinomas, whereas it was a weak independent prognostic factor in axillary lymph node-positive breast carcinomas.

Adult↗
PubMed1995

Expression of p53 protein has no independent prognostic value in breast cancer.

A series of 392 female breast carcinomas was analysed immunohistochemically for expression of p53 protein with special emphasis on the role of p53 as an independent prognostic factor. Altogether, 54.8 per cent of the carcinomas expressed p53 protein, with the mean [standard error (SE)] fraction of positive nuclei being 17.1 per cent (1.2 per cent). Expression of p53 protein was independent of tumour metastasis at diagnosis, axillary lymph node status, tumour diameter, histological type, tubule formation, proportion of intraductal growth, margin formation, necrosis, DNA ploidy, and S-phase fraction. A high fraction of p53-positive nuclei was significantly related to patient age under 70 years, high grade, severe nuclear pleomorphism, dense infiltration of tumour by lymphocytes, high mitotic index, and high apoptotic index (for all, P < 0.05). Impaired survival probability in the entire cohort (P = 0.05) and in the axillary lymph node-positive (ANP) tumours (P = 0.015) was associated with a fraction of p53-positive nuclei less than 25 per cent, while in the axillary lymph node-negative (ANN) tumours, expression of p53 had no prognostic value. In multivariate analysis, independent prognostic predictors included axillary lymph node status, tumour diameter, and mitotic index. In the ANN tumours, tumour diameter, fraction of p53-positive nuclei, and tumour grade were independent prognostic factors, whereas in the ANP tumours, diameter and mitotic index were the two independent prognostic factors. The results suggest that abnormal expression of p53 protein is only a weak independent prognostic factor in female breast cancer.

Adult↗
PubMed1995

Effects of simulated nuclear fuel particles on the histopathology and CYP enzymes in the rat lung and liver.

We studied both short-term (3 and 30 days) and long-term (3-24 months) effects of simulated nuclear fuel particles (neutron-activated UO2) on the rat lung and liver histopathology and cytochrome P450 (CYP) activities. In the short-term study, after a single intratracheal instillation with neutron-activated particles (administered activity 36 kBq), the lung histology revealed inflammation and a decrease in several lung testosterone hydroxylation levels. Liver exhibited normal histology but hepatic testosterone 7alpha-hydroxylase (T7alphaOH) was decreased by 30% at 3 days treatment with neutron-activated particles (9.3 kBq). At 30 days after treatment, hepatic T7alphaOH and testosterone 15alpha-hydroxylase activities were enhanced by 70 and 40%, respectively. At the long-term follow-up, benign and malignant lung tumors were observed but in the livers only slightly increased inflammation was found. At the 1.5-year follow-up (cumulated lung dose 0.4-0.66 Gy, 131 and 182 kBq), decreases in lung testosterone 6beta-hydroxylase (60%) and testosterone 6alpha-hydroxylase (30%) activities were found. In contrast to lungs, hepatic testosterone 16alpha-hydroxylase activity decreased by 60-75% with both nonactivated and neutron-activated particles. These findings indicate that when lung is exposed to nonactivated UO2 or beta-emitting UO2 particles they have differential effects on CYP enzymes in both the primary target organ (lung) and secondary tissue (liver).

Animals↗
PubMed1995

Subchronic toxicity of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in Wistar rats.

The subchronic (14-18 wk) toxicity of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a mutagenic by-product in chlorinated drinking water, was evaluated in Wistar rats. In a range-finding study, MX was administered daily for 14 days by gavage in deionized water to male rats (five animals per group) at doses of 12.5, 25, 50, 100 or 200 mg/kg body weight. The doses above 50 mg/kg were lethal and three out of five animals also died during treatment at 50 mg/kg. The range-finding study was repeated with doses of 5, 10 and 20 mg MX/kg, given on 5 days a week, to both males and females (10 animals per group). These doses were not overtly toxic but caused several changes in plasma clinical chemistry at 10 and 20 mg MX/kg in comparison with the controls. These included increased urea, creatinine and bilirubin and decreased inorganic phosphate and potassium in females and increased cholesterol in males. In the subchronic toxicity study, rats (15 per group, were given MX by gavage, on 5 days a week, at doses of 0 (controls) or 30 md/kg (low dose) for 18 wk, or, in the high-dose group, at doses increasing from 45 to 75 mg/kg over 14 wk. The high dose was finally lethal (two males and one female died) and caused hypersalivation, wheezing respiration, emaciation and tangled fur in animals. The body weights of the high-dose males decreased by 15%, and food consumption was decreased by 15 to 20%, but the water consumption increased by 15% to 60%. Plasma cholesterol and triglycerides were elevated and urine excretion was increased. Urine specific gravity was decreased and the relative weights of the liver and kidneys were increased in both sexes at both doses in comparison with the controls. At both doses, duodenal hyperplasia occurred in males and females, and slight focal epithelial hyperplasia in the forestomach was observed in males. Splenic atrophy and haemosiderosis were seen in two high-dose females, and epithelial cell atypia in the urinary bladder of one high-dose male and female. The frequency of bone marrow polychromatic erythrocytes with micronuclei was slightly increased in low-dose males. The results indicate that repeated administration of MX disturbs the fluid-electrolyte balance and induces diuresis, causes mucosal hyperplasia in the gastro-intestinal tract as a local effect, and affects lipid metabolism.

Animals↗
PubMed1995

Expression of retinoblastoma gene protein (Rb) in breast cancer as related to established prognostic factors and survival.

The expression of retinoblastoma gene product (Rb protein) was studied by immunohistochemical analysis of 205 cases of breast cancer. Rb protein was invariably expressed in non-neoblastic breast epithelium, in dysplastic and hyperblastic lesions adjacent to tumours, and none of the breast tumours was totally negative for Rb protein. According to the scoring system used, the expression of Rb protein was abnormal in 36.6% of cases. Abnormal expression of Rb protein was significantly related to grade (P < 0.00004), type (P = 0.0183), margin formation (P = 0.0116), DNA ploidy (P < 0.0002) and nuclear pleomorphism (P < 0.0001). Abnormal expression of Rb protein was related to high S phase fraction (P = 0.004), high mitotic index (P < 0.001) and high morphometric nuclear factor values (P < 0.01). The expression of Rb protein had no prognostic value in univariate or multivariate analysis. The results show that the tumour suppressor gene Rb participates in the growth regulation of breast cancer cells in vivo, but immunohistochemical assessment of the expression of Rb protein has no prognostic significance in clinical breast cancer over already established prognostic factors.

Adult↗
PubMed1995

Biokinetics of nuclear fuel compounds and biological effects of nonuniform radiation.

Environmental releases of insoluble nuclear fuel compounds may occur at nuclear power plants during normal operation, after nuclear power plant accidents, and as a consequence of nuclear weapons testing. For example, the Chernobyl fallout contained extensive amounts of pulverized nuclear fuel composed of uranium and its nonvolatile fission products. The effects of these highly radioactive particles, also called hot particles, on humans are not well known due to lack of reliable data on the extent of the exposure. However, the biokinetics and biological effects of nuclear fuel compounds have been investigated in a number of experimental studies using various cellular systems and laboratory animals. In this article, we review the biokinetic properties and effects of insoluble nuclear fuel compounds, with special reference to UO2, PuO2, and nonvolatile, long-lived beta-emitters Zr, Nb, Ru, and Ce. First, the data on hot particles, including sources, dosimetry, and human exposure are discussed. Second, the biokinetics of insoluble nuclear fuel compounds in the gastrointestinal tract and respiratory tract are reviewed. Finally, short- and long-term biological effects of nonuniform alpha- and beta-irradiation on the gastrointestinal tract, lungs, and skin are discussed.

Air Pollutants, Radioactive↗
PubMed1994

Distribution and short-term effects of intratracheally instilled neutron-irradiated UO2 particles in the rat.

In the present study we investigated the radionuclide distribution and histopathological effects of neutron-irradiated UO2 particles in the rat after intratracheal instillation. The kinetics and short-term effects of uranium fission products (95Zr, 95Nb, 103Ru, and 141Ce) were examined during a 3-month follow-up period. A rapid clearance (about 21%) of particles occurred via the gastrointestinal tract within 24 hr after the instillation. Autoradiographic and histological examinations revealed that the retained particles were nonuniformly distributed in the lungs. Translocation of the fission products from the lung to various other tissues was slow; 3 months after the instillation, the activity of the total body burden was below 1% in the liver, kidney, and spleen, whereas in the lungs it was 83%. Clearance of particles appeared to be mainly due to tracheobronchial mucociliary mechanisms. Translocation of the fission products to the bone and liver was significantly less than that reported by the ICRP, indicating that the clearance of uranium-matrix-associated fission products is preferably dependent on the physical characteristics of the particulate material. The cumulative lung doses ranging from 170 to 550 mSv caused slight or moderate local inflammatory reactions in the lungs, but at smaller dose levels there were no histopathological changes observed.

Animals↗
PubMed1994

Toxic effects and excretion in urine of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in the after a single oral dose.

Toxic effects and excretion in urine of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), the potent mutagenic compound in chlorinated drinking water, was evaluated in male Wistar rats by the up-and-down method. MX was dosed by gavage in deionized water at doses between 200 mg/kg and 600 mg/kg, for one animal at a time, and effects were observed for 14 days. Urine was collected in metabolism cages up to 72 h after dosing for chemical analysis of MX in urine. The animals receiving 200 mg/kg did not display clear clinical signs but at higher doses the signs of ill effects included dyspnea, laborious, wheezing and gasping breathing, decreased spontaneous motor activity, ataxia, nostril discharges, catalepsia and cyanosis. In necropsy bronchi contained foamy liquid and the lungs appeared edematous and spongy. The stomach cavity was expanded due to accumulation of fluid and gas and the gastrointestinal tract from stomach to caecum was reddish. Microscopically, the main target organ of toxicity was the gastrointestinal tract (diffuse congestion and necrosis in the mucosa). Signs of toxicity were recorded also in lungs (slight edema) and kidneys (dilated tubules, thin tubular epithelium, brownish tubular and interstitial concretion). The LD50 in 48 h was 230 mg/kg. Only 0.03-0.07% of the dose (200 mg/kg or 300 mg/kg) was excreted in urine as intact MX. The results indicate that at high doses MX has a strong local irritating effect in the gastrointestinal tract and it probably increases liquid permeability in lungs. MX may also cause tubular damage in kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Apoptosis in breast cancer as related to histopathological characteristics and prognosis.

Apoptotic cells were quantitated by light microscopy in a series of 288 breast carcinomas, and their number (cells/mm2 of neoplastic epithelium, i.e., the apoptotic index, AI) was related to various histopathological features and disease outcome. High AI was associated with tumour necrosis (P = 0.003), lack of tubule formation (P = 0.03), dense stromal lymphocyte infiltration (P = 0.0009), high grade of the tumour (P < 0.0001), DNA aneuploidy (P = 0.049), high S-phase fraction (P = 0.010), high mitotic rate (P < 0.0001), lack of sex steroid receptors (P = 0.004), expression of p53 tumour suppressor gene (P = 0.004), and high values of morphometrically measured nuclear factors (P < 0.05). In survival analysis, an AI greater than 3/mm2 was related to short recurrence-free survival in the entire cohort (P = 0.0079) as well as in the axillary lymph node-negative tumours (P = 0.0253). Survival of the patients with node-negative tumours (P = 0.0356), node-positive tumours (P = 0.0085) and in the entire cohort (P = 0.004) was related to AI. Recurrence-free survival was related to the mitotic index (P = 0.0012), ductal type (P = 0.011), S.D. of the nuclear area (P = 0.075), and axillary lymph node status (P = 0.096). Cox's analysis showed that only the tumour diameter (P < 0.001), axillary lymph node status (P = 0.001), progesterone receptor content (P = 0.004) and ductal type (P = 0.041) had independent prognostic value, whereas AI did not.

Adult↗
PubMed1994

The influence of dichloromethylene bisphosphonate on the healing of a long bone fracture, composition of bone mineral and histology of bone in the rat.

The effects of dichloromethylene bisphosphonate (clodronate) on the composition of bone mineral, morphology and histology of a long bone with an artificial femoral fracture were studied in a 22 week experiment. Two hundred twenty-four female rats were allocated to dose groups of 0, 3, 10, and 30 mg/kg clodronate daily subcutaneously. Bone calcium, phosphorus and magnesium concentrations remained stable and fluoride concentration rose with time. There were no statistical differences between different groups. Clodronate did not alter the histology of the callus nor delayed the healing of the fracture. It caused mild to moderate prominence of the metaphyseal area in the fractured bone in a dose- and time-dependent manner. Serum osteocalcin levels were lowered in the treated animals dose-dependently. Other serological as well as haematological values were within normal range. Clodronate seems in this experimental arrangement to be a safe agent to administer in different pathological conditions of bone even when they are complicated by fractures of long bones.

Animals↗
PubMed1993

Effects of 2-ethylhexanoic acid on reproduction and postnatal development in Wistar rats.

Reproductive toxicity of 2-ethylhexanoic acid (2-EHA) was studied in Wistar rats. The animals (24 animals per sex per group) were given 2-EHA as a sodium salt in drinking water at daily doses of 100, 300, or 600 mg/kg. Control animals received plain water. Male rats were exposed to 2-EHA for 10 weeks and females for 2 weeks prior to mating, both sexes during the mating period and females during the entire gestation and lactation period. 2-EHA caused a slight but dose-dependent decrease in fertility; time to mating increased at 300 and 600 mg/kg and even total infertility ensued. 2-EHA slightly decreased sperm quality in males. The spermatozoa were significantly less motile at 100 and 600 mg/kg and abnormal sperm occurred more frequently at the two highest dose levels. The average litter size was reduced by 16% in the dose group receiving 600 mg/kg. The birth weights of the pups were unaffected but the body weight gain was transiently slower during lactation at 600 mg/kg. Several pups appeared abnormal (kinky tail, lethargic, slightly paralyzed legs) and the physical development assessed by several landmarks (opening of eyes, eruption of teeth, hair growth) and reflexes (grip reflex, cliff avoidance) was delayed at 300 and 600 mg/kg. In another experiment, a single dose of 600 mg/kg 2-EHA was given to pregnant females by gavage on Gestational Day 4, 5, 6, or 7 and the number of implantations were counted on Gestational Day 10. Administration on Day 6 decreased the number of implantations and caused resorptions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Comparison of classic and quantitative prognostic factors in hormone receptor-positive and hormone receptor-negative female breast cancer.

The prognostic variables of 281 women with breast carcinoma (followed up for more than 8 years) were studied using Cox's analysis. Clinical and histologic features, nuclear morphometric variables, and mitotic indices were analyzed separately in progesterone receptor-negative (PR-) and -positive tumors (PR+). In PR- tumors, axillary lymph node status (p = 0.0025) and tumor size (p = 0.03) were predictors of survival in the univariate analysis. Tumor size (p < 0.0001), axillary lymph node status (p = 0.0006), the volume-corrected mitotic index (M/V index) (p = 0.0023), and the mitotic activity index (MAI) (p = 0.0067) were found to be related to survival according to univariate analysis of PR+ tumors. In PR- tumors, axillary lymph node status (p = 0.002), year of treatment (p = 0.017), and circumscription of the tumor margin (p = 0.02) had independent predictive value. In PR+ tumors, tumor size (p < 0.001), the MAI (p = 0.001), and axillary lymph node status (p = 0.04) predicted survival independently in Cox's analysis. In PR- tumors, histologic type (p = 0.008) was an independent predictor of recurrence-free survival, whereas in PR+ tumors, the M/V index (p < 0.001), tumor size (p = 0.007), and the standard deviation of the nuclear perimeter (p = 0.026) were independently related to recurrence-free survival. The results indicated that mitotic indices and nuclear morphometric variables are of limited value in predicting patient survival in breast carcinomas that are hormone receptor negative. Thus, a separate analysis is advocated for hormone receptor-positive and -negative tumors when the predictive value of quantitative measurements and histologic variables is tested in patients with breast cancer.

Aged↗