Selenium-dependent GSH-Px in erythrocytes of patients with hypertension treated with ACE inhibitors.

This study is aimed at examining whether essential arterial hypertension (HTN) or ACE inhibitors have any effect on erythrocyte selenium (Se)-dependent and Se-non-dependent glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activity. Eleven patients with HTN (2 men and 9 women) and 9 healthy volunteers were included in this study after clinical examination and laboratory investigation. The activities of all three enzymes were determined and then the patients were assigned to receive ACE inhibitor therapy consisting of captopril, 25 to 50 mg daily, or enalapril, 10 to 40 mg daily. After 1 year, the determination of antioxidant enzymes was repeated. Our results showed that the initial values of Se-dependent GSH-Px in patients treated with ACE inhibitors were significantly lower (19.60 +/- 3.50 microM NADPH/min(-1)/mgHb(-1)) compared with the controls (28.64 +/- 4.93 microM NADPH/min(-1)/mgHb(-1); p < 0.001), whereas the activity of Se-non-dependent GSH-Px was significantly enhanced (13.55 +/- 1.46 microM NADPH/min(-1)/mgHb(-1); p < 0.001) compared with the control group (9.44 +/- 0.81 microM NADPH/min(-1)/mgHb(-1); p < 0.001). ACE inhibitors did not significantly change the activity of Se-dependent GSH-Px or Se-non-dependent GSH-Px. No significant alteration was observed in SOD activity.

Changes of lipid peroxides and antioxidative factors levels in blood of patients treated with ACE inhibitors.

In 14 patients (4 males and 10 females) with systemic hypertension plasma and erythrocyte lipid peroxides, plasma and erythrocyte catalase activity, plasma glutathione S-transferase (GST) activity, blood reduced glutathione (GSH) content and erythrocyte oxidant stress were investigated. All parameters were performed after clinical examination and then the patients were assigned to receive ACE inhibitor therapy, captopril (25-50 mg given twice per day) or enalapril (10-40 mg given twice per day). After six months the determination of lipid peroxides and antioxidative factors was repeated. At the beginning of the study both treated groups showed significantly higher plasma lipid peroxides compared to the control group. Both used ACE inhibitors produced significant decrease of plasma lipid peroxides after six months. Blood GSH content was also significantly higher in both patient groups before the treatment compared to the controls. Neither captopril nor enalapril produced any significant effect on GSH. Initial values of plasma GST activity in the patients were similar to the control group and did not significantly change after six month treatment. The patients assigned to receive enalapril showed significantly enhanced initial plasma catalase activity according to the controls. After six months treatment both ACE inhibitors significantly decreased plasma catalase activity. Erythrocyte lipid peroxides, erythrocyte catalase activity and oxidant stress of erythrocytes in both groups studied neither differ significantly at initial time of investigation according to the control group nor during or after six month treatment.

Serum levels of some acute phase proteins in kidney and urinary tract urothelial cancers.

Early diagnosis of kidney and urothelial cancer requires some new sensitive and specific methods. In this study the diagnostic use of serum alpha 1-acid glycoprotein (alpha 1-AG), coeruloplasmin, alpha 1-antitrypsin (alpha 1-AT), alpha 2-macroglobulin (alpha 2-MG) and albumin in patients with kidney, urinary bladder and upper tract urothelial cancer was evaluated. In kidney cancer patients the serum levels of alpha 1-AG, coeruloplasmin and alpha 1-AT were significantly increased over the controls (p < 0.001), however, albumin was decreased (p < 0.005). Sensitivity was relatively high for alpha 1-AG (85%), albumin (85%) and alpha 1-AT (77%). In patients with urinary tract urothelial cancer alpha 1-AG, alpha 1-AT and coeruloplasmin were also increased but not as much as in kidney cancer. Sensitivity of alpha 1-AG (63%), albumin (75%) and alpha 1-AT (66%) was also lower than in kidney cancer. This study has established the relative importance of alpha 1-AT and albumin determination in patients with kidney as well as with urothelial cancer.

Determination of the apparent synovial permeability in the knee joint of patients suffering from osteoarthritis and rheumatoid arthritis.

The concentrations of alpha 1-acid glycoprotein (alpha 1-antitrypsin (alpha 1-AT), ceruloplasmin (Cp) and alpha 2-macroglobulin (alpha 2-MG) in serum and in knee joint synovial fluid of patients suffering from rheumatoid arthritis (RA) and osteoarthritis (OA) were determined and apparent synovial permeability (SP) to each protein calculated. The results showed that the rheumatoid synovia were significantly more permeable (P < 0.001) than the osteoarthritic synovia. Cp and alpha 2-MG showed the greatest average increase in apparent SP, about five times the values for OA joints. Apparent SP reflected disease activity rather well, since the patients with the more active disease had the highest values, six times that of the OA values. Although the values for the small proteins alpha 1-AGP and alpha 1-AT were greater in RA joints, more intense inflammation resulted in a greater increase in apparent SP to larger proteins, so that the apparent SP for alpha 2-MG and Cp are more reliable for evaluating disease activity. Apparent SP as determined by this and previous studies appeared to be a much more accurate and sensitive measure than the synovial fluid/plasma protein concentration ratio. Knowledge of the apparent SP could be a useful parameter in evaluating synovitis since the exudative flare-ups usually parallel the intensity of the inflammation.

[Erythrocyte catalase activity in patients with endemic nephropathy and in their family members]. / Aktivnost katalaze eritrocita kod bolesnika s endemskom nefropatijom i clanova njihovih porodica

Etiology and pathogenesis of endemic nephropathy (EN) are unknown and in this work the possible pathogenetic role of disturbed antioxidant protection, estimated by the activity of erythrocyte catalase, was evaluated. In patients with EN as well as in clinically healthy members of their families a statistically significant increase in catalase activity (16.7 +/- 0.63 x 10(4) U/g Hb) compared to the control group of the blood bank donors from the city of Nish (11.7 +/- 0.69 x 10 U/g Hb) was found. Increased catalase activity, at the level of significance, was also found in clinically healthy members of EN patients families. The increase of catalase activity was considered compensatory to the increased oxydative capacity.

Lactate dehydrogenase activity and its isoenzymes in serum and synovial fluid of patients with rheumatoid arthritis and osteoarthritis.

By determining the total activity of total lactate dehydrogenase (LDH-T) and its isoenzymes in serum and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and osteo-arthritis (OA) we demonstrated in RA serum increased (p less than 0.02) activity of hepatic LDH (LDH-H) and a shift of the LDH isoenzymatic profile towards the M forms; in rheumatoid SF increased (p less than 0.001) activity of the total LDH-T and LDH-H which makes possible the use of these markers of inflammation in assessing RA activity. Values for LDH-T and LDH-H of 400-700 U/l and 300-500 U/l, respectively, correspond to moderate disease activity, while values exceeding 750 U/l and 550 U/l, respectively, correspond to high RA activity. The anaerobic isoenzymatic distribution of LDH in rheumatoid SF results in a significant (p less than 0.001) decrease in LDH1 and LDH2 and an increase (p less than 0.001) in LDH4 and LDH5.

Twenty years experience of interstitial iridium brachytherapy in the management of soft tissue sarcomas.

From February 1968 to February 1988, 50 patients above 10 years of age with a soft tissue sarcoma were treated with interstitial brachytherapy, combined with a wide excision. After pathologic review, 48 were included in the final analysis. A pathological grading was made possible in 41, which showed a majority of high grades (2 + 3 = 86%). Patients presented mainly with small (less than 5 cm: 36) or mid-size lesions (greater than 5 cm: 12). The tumor was located in the limbs (32), trunk (9), and head and neck (7). Four patients had metastases at the time of treatment. Brachytherapy was part of the initial treatment in 22 cases, and of a salvage procedure after previous excision(s) combined or not with another form of treatment in 26. A uniform technique of iridium 192 wires after-loaded in plastic tubing was used. Sixty Gy median doses were delivered with brachytherapy alone (44) or combined with external beam (4). Sixteen patients also received an adjuvant chemotherapy. Follow up ranged from 16 months to 20 years (median 82 months). At the time of analysis, two patients (4%) only had failed in the irradiated volume, but the marginal failures rate (14:31%) was unexpectedly high. Seven of the patients who failed (43%) were salvaged by a second similar procedure. The 5-year survival was 62% in non-previously treated patients and 56.5% in previously treated ones (pNS). By multivariate analysis, only the tumor location appeared predictive of LF (p less than 0.01), which in turn was strongly correlated with the metastatic outcome (p less than 0.01). Necroses were observed in 17 cases (35%) and associated with a benign course in most of them. High dose brachytherapy combined with conservative surgery is highly effective in small and mid-size soft tissue sarcomas located in the extremities and head and neck, whereas in trunk and in recurrent tumors, the adjunction of large fields external radiotherapy and/or possibly polychemotherapy appears necessary.

Risk factors for male breast cancer: a Franco-Swiss case-control study.

In order to evaluate risk factors in male breast cancer, a case-control study of 91 histologically diagnosed cases and 255 cancer controls, matched for age and year of diagnosis, was conducted in Villejuif (France) and Geneva (Switzerland). Factors studied included marital history, occupational exposure, associated diseases, family history of breast cancer, history of radiation exposure and drugs which increase or are suspected of increasing prolactin or estrogen levels. Cases were significantly more likely to be bachelors or to work as butchers than were the controls. Other statistically significant risk factors identified were family history of breast cancer and therapeutic use of digitalis. Elevated risks, although not significant, were observed for individuals with a past history of tuberculosis, hyperthyroidism, liver cirrhosis or gallstone, who had been treated with isoniazid, or who had worked in high environmental temperatures. Further studies are needed to confirm our results particularly as regards hormonal imbalance and genetic factors.

Growth rate, kinetics of tumor cell proliferation and long-term outcome in human breast cancer.

Thymidine labelling index (LI) was prospectively assayed in vitro in a series of 128 consecutive patients with breast cancer. The follow-up was longer than 15 years for all patients. The distribution of LI was log normal and patients were subdivided into 3 groups (patients with LI = m +/- sigma, lower than m - sigma and greater than m + sigma where m is the geometrical mean). The incidence of relapse and death remained significantly lower in the group with a low LI than in the 2 other groups, whereas the difference between the 2 other groups faded away when follow-up exceeded 10 years. Multivariate analyses show that LI is one of the two most important independent prognostic indicators for relapse or death, the other being histological grading. Data concerning 2,648 patients treated at our Institute, prior to the introduction of chemotherapy into treatment protocols, have been used to investigate the influence of tumor growth rate on the probability of distant dissemination. A model of the natural history was used, in order to generate metastasis appearance curves, in 3 subgroups of patients, according to the value of the tumor doubling time (TDT). Our results show that after a follow-up exceeding 8 years, there is no longer any difference between the subgroups of patients with rapid or intermediate growth rate, whereas after 25 years large and highly significant differences in relapse and survival between the slow-growing tumors and the other two subgroups still remain. These two sets of data concur to show that tumor growth rate or proliferation rate correlates with the probability of metastatic dissemination.

Radiation dose and breast cancer risk in patients treated for cancer of the cervix.

The relationship between breast cancer and radiation treatment for cervical cancer was evaluated in an international study of 953 women who subsequently developed breast cancer and 1,806 matched controls. Radiation doses to the breast (average 0.31 Gy) and ovaries (average 32 Gy) were reconstructed for exposed subjects on the basis of their original radiotherapy records. Overall, 88% of the breast cancer cases and 89% of the controls received radiation treatment [relative risk (RR) = 0.88; 95% confidence interval (CI) = 0.7-1.2]. Among women with intact ovaries (561 cases, 1,037 controls), radiotherapy was linked to a significant 35% reduction in breast cancer risk, attributable in all likelihood to the cessation of ovarian function. Ovarian doses of 6 Gy were sufficient to reduce breast cancer risk but larger doses did not reduce risk further. This saturation-type response is probably due to the killing of a critical number of ovarian cells. Cervical cancer patients without ovaries (145 cases, 284 controls) were analyzed separately because such women are at especially low natural risk for breast cancer development. In theory, any effect of low-dose breast exposure, received incidentally during treatment for cervical cancer, should be more readily detectable. Among women without ovaries, there was a slight increase in breast cancer risk (RR = 1.07; 95% CI = 0.6-2.0), and a suggestion of a dose response with the RR being 1.0, 0.7, 1.5 and 3.1 for breast doses of 0, 0.01-0.24, 0.25-0.49 and 0.50+ Gy, respectively. However, this trend of increasing RR was not statistically significant. If low-dose radiation increases the risk of breast cancer among women over age 40 years, it appears that the risk is much lower than would be predicted from studies of younger women exposed to higher doses.

Lymphography in the initial evaluation of endometrial carcinoma.

Two hundred eighty-eight patients with endometrial carcinoma underwent a bipedal lymphography. The proportion of positive lymphangiograms is related to the clinical stage, the histologic grade, and the depth of myometrial invasion. Lymphography is not a significant predictor of survival taking into account the other prognostic factors. A histological examination of the lymph nodes was carried out for 138 patients. Lymphography is not very sensitive but is highly specific, detecting only 50% of metastases with a false positive rate that is too high. It therefore is of little diagnostic and prognostic value for operable patients. It is, however, useful for the followup of lymph nodes of patients treated by radiation therapy.

Radiation dose and second cancer risk in patients treated for cancer of the cervix.

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

Prognostic factors in gestational trophoblastic tumors. A multivariate analysis.

One hundred sixty-two gestational trophoblastic tumors (GTT) were treated at the Institute Gustave-Roussy, Villejuif, France, from 1975 to 1985. Sustained complete remission (CR) was obtained in 146 patients (90%). All 97 patients with no histologic diagnosis of choriocarcinoma were cured, including 19 patients considered at high risk initially. Among 65 histologic chariocarcinoma patients, 16 died (CR, 75.5%) including seven initially nonmetastatic patients. Using a univariate analysis, all factors tested in the whole group of patients were more or less significant except for age and parity. However, when the same variables were tested in patients considered at high risk initially, only three factors were statistically significant. Those three factors were the only ones associated with a statistically significant higher relative death risk (RR) on multivariate analysis and are as follows: an antecedent nonmolar pregnancy (RR = 4.3; P less than 0.01); initial presentation with more than one metastatic organ (RR = 7.4; P less than 0.01); and primary resistance to single agent (RR = 18.8; P less than 0.0001) or multi-agent chemotherapy (RR = 26.1; P less than 0.0001). It seems that those three factors, together with a histologic diagnosis of choriocarcinoma, are the prognostic factors that discriminate patients with unfavorable outcomes among the high-risk group.

Feasibility study of an alternating schedule of radiotherapy and chemotherapy in advanced uterine cervical carcinoma.

From July 1981 to April 1982, 36 patients with advanced cervical carcinoma stage III (24 patients) and stage IV (12 patients) entered a feasibility study of a radiotherapy and chemotherapy combination. The first three chemotherapy courses consisted of cis-platinum alone (50 mg/m2) and were interdigitated with radiotherapy. Six more courses composed of an association of cis-platinum (50 mg/m2) and cyclophosphamide (400 mg/m2) were given after the completion of radiotherapy. Radiotherapy was delivered in two courses of 25 Gy separated by a gap of 2 weeks. The overall 4-year survival rate was 35% (95% CI: 22%). The 4-year survival rate, cumulative loco-regional failure rate, and cumulative metastasis rate were respectively 44% (95% CI: 20%), 56% (95% CI: 21%), and 30% (95% CI: 21%) in stage III and 28% (95% CI: 27%), 83% (95% CI: 21%) and 74% (95% CI: 30%) in stage IV. The incidence of immediate and late complications was low: no patient had her radiotherapy stopped because of an intolerance and two patients had their chemotherapy stopped because of an haematological intolerance. Only one patient presented a severe late clinical complication (small bowel injury).

Is prophylactic para-aortic irradiation worthwhile in the treatment of advanced cervical carcinoma? Results of a controlled clinical trial of the EORTC radiotherapy group.

From November 1977 to July 1981, 441 patients with cervical carcinoma were randomized between pelvic irradiation and pelvic and para-aortic irradiation. Included were patients with stage I and IIB with proximal vaginal and/or parametrial involvement with positive pelvic lymph nodes either on lymphangiogram or at surgery, and stage IIB with distal vaginal and/or parametrial involvement and III regardless of pelvic node status on lymphangiogram. Patients with clinically or surgically involved para-aortic nodes were not included. The external beam dose to the para-aortic area was fixed at 45 Gy. There was no statistically significant difference between the two treatment arms in terms of local control, overall distant metastases and survival with no evidence of disease (NED), although the incidence of para-aortic metastases and distant metastases without tumor at pelvic sites was significantly higher in patients receiving pelvic irradiation alone (pelvic group). The 4-year NED survival rate was 51%. The incidence of severe digestive complications was significantly higher in patients receiving para-aortic irradiation (para-aortic group). Routine para-aortic irradiation for all high risk patients with cervical carcinoma is of limited value, but patients with a high probability of local control can benefit from extended field irradiation, despite an increase in severe digestive complications.

Radiation dose and leukemia risk in patients treated for cancer of the cervix.

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.

A method of analysis taking into account competing events: application to the study of digestive complications following irradiation for cervical cancer.

Over the past 20 years, mortality rates from uterine cervix carcinoma have been decreasing owing to earlier diagnosis and improved treatment. The incidence of secondary effects from radiation therapy has spurred some interest and injuries resulting from 'over'-treatment have been of some concern. The present study concerns the evaluation of bowel complications following treatment for the 272 stage IIb and III patients treated in our centre between 1967 and 1973. Competing risk methodology is applied and the influence of radiotherapy parameters is evaluated by a log-linear model of the event-specific failure rates. A single parameter (NSD) which summarized total dose, total number of sessions and total treatment time is found to be related to the occurrence of complications.