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Biomedical subjects

N V Dimitrov

Publications and source records attributed to N V Dimitrov.

At least 37 records · Page 2Linked to original sources
PubMed1991

Plasma tocopherol concentrations in response to supplemental vitamin E.

Normal healthy volunteers were studied after various doses of dl-alpha-tocopherol were ingested on different schedules. Administration of 440, 880, or 1320 mg (400, 800, or 1200 IU) of dl-alpha-tocopherol as a single dose resulted in elevation of plasma alpha-tocopherol concentrations that peaked at 12-24 h. Chronic administration of dl-alpha-tocopherol (440, 880, or 1320 mg/d for 28 d) resulted in a steady state that occurred by days 4-5 of supplementation. Discontinuation of the treatment after day 28 was associated with a decline of plasma alpha-tocopherol, which returned to the pretreatment concentrations between 12 and 20 d. The plasma elevation of alpha-tocopherol was affected by dietary fat intake. Individuals consuming a high-fat diet showed significantly greater plasma alpha-tocopherol concentrations as compared with those fed a low-fat diet. The results of this study indicate that plasma kinetics of alpha-tocopherol are similar when supplements of 440, 880, or 1320 mg dl-alpha-tocopherol are given to normal, healthy individuals.

Adult↗
PubMed1990

Medullary cancer of the breast revisited.

Common as well as unusual, heretofore unmentioned histopathologic features observed in 336 typical and 273 atypical medullary breast cancers from 6404 patients enrolled in various stage I and II protocols of the National Surgical Adjuvant Breast and Bowel Projects (NSABP) are presented. Both medullary types exhibited comparable pathologic findings, except for the infiltrative border and/or slight or absent tumor lymphoid infiltrate which by definition characterize the atypical form. Both also demonstrated a similar, high proclivity to be aneuploid, and to lack estrogen and progesterone receptors and nodal metastases. After appropriate statistical adjustments, survival (analyzed for 198 patients with typical and 149 with atypical medullary cancers) was found to be better for untreated, node-negative and node-positive patients treated with L-PAM + 5Fu who had typical medullary cancers than those with the NOS histologic type. The magnitude of this difference was 6% at 5 and 17% at 10 years post-operatively (cumulative odds = 1.81 with a 95% confidence interval of 1.08 - 3.3) for the former group, and 4% at 5 and 16% at 10 years (cumulative odds = 1.56 with a 95% confidence interval of 1.08 - 2.23) for the latter. Survival was comparable for patients with atypical medullary and NOS types in both situations. No clear difference in survival was found in untreated, positive node patients with the 3 histologic types examined, although the sample sizes in this subset were relatively small. This information as well as other pertinent considerations indicate that the prognosis of typical medullary cancer is not as 'good' as previously perceived. It is also concluded that there is insufficient evidence at present to exclude the atypical medullary variant as a histologic type of breast cancer.

Biomarkers, Tumor↗
PubMed1990

Alteration of retinol-binding-protein concentrations by the synthetic retinoid fenretinide in healthy human subjects.

Normal subjects received fenretinide (HPR), 200 mg/d, on three schedules. Schedule 1 was treatment for 28 d. Schedule 2 consisted of 14 d of treatment, 3 d hiatus, and a second drug course of 14 d, 10,000 IU vitamin A was administered during the 3-d hiatus. Schedule 3 was 14 d of treatment followed by a rest period of 7 d and then 14 d of treatment. Increase in plasma HPR was accompanied by an even higher increase in the metabolite N-(4-methoxyphenyl)-all-trans-retinamide (MPR). The administration of HPR was associated with a significant reduction in retinol-binding protein (RBP), which returned to pretreatment values after the drug treatment was discontinued. Reduction of plasma retinol was also observed. Use of interrupted schedules with resting periods of 3 and 7 d changed HPR, MPR, and RBP concentrations in plasma. Addition of vitamin A did not affect the pattern of the measured variables in the plasma.

Adult↗
PubMed1990

Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a randomized clinical trial to determine whether tamoxifen (TAM) plus chemotherapy is more effective than TAM alone in improving disease-free survival (DFS), distant disease-free survival (DDFS), and survival (S) of positive-node, TAM-responsive patients aged greater than or equal to 50 years. Women were randomized among three treatment groups: (1) TAM alone, (2) Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cyclophosphamide, and TAM (ACT), or (3) melphalan (L-PAM), fluorouracil (5-FU), and TAM (PFT). The PFT arm was later modified so that new patients also received Adriamycin (PAFT). Findings from 1,124 eligible patients through 3 years of follow-up indicated a significantly better DFS for ACT-treated patients than for those receiving TAM alone (84% v 67%; P = .0004). An advantage in DDFS and S was also observed after ACT therapy (83% v 73% [P = .04 in the former] and 93% v 85% [P = .04 in the latter]). Both the DFS and DDFS of PAFT-treated patients were better than in those treated by TAM alone (83% v 66%, P = .0002 and 85% v 73%, P = .003). PFT patients also fared better in DFS and DDFS than TAM patients (81% v 72%, P = .07 and 85% v 74%, P = .02). Odds ratios consistently favored the three TAM-plus-chemotherapy groups. No significant S advantage is as yet evident in favor of the PAFT or PFT groups. Of importance is the failure of these studies to demonstrate an unfavorable interaction between the drug regimens used and the TAM, which was administered simultaneously. The findings related to the use of PAFT and PFT are of more biologic than clinical significance since L-PAM is rarely used in the treatment of breast cancer. The major conclusion from this study is the observance of a better outcome in positive-node breast cancer patients aged greater than or equal to 50 years from the use of postoperative prolonged TAM and short-course AC therapy (completed in 63 days) than from prolonged TAM therapy alone.

Aged↗
PubMed1990

Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented protocol B-15 to compare 2 months of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and cyclophosphamide (AC) with 6 months of conventional cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with breast cancer nonresponsive to tamoxifen (TAM, T). A second aim was to determine whether AC followed in 6 months by intravenous (IV) CMF was more effective than AC without reinduction therapy. Through 3 years of follow-up, findings from 2,194 patients indicate no significant difference in disease-free survival (DFS, P = .5), distant disease-free survival (DDFS, P = .5) or survival (S, P = .8) among the three groups. Since the outcome from AC and CMF was almost identical, the issue arises concerning which regimen is more appropriate for the treatment of breast cancer patients. AC seems preferable since, following total mastectomy, AC was completed on day 63 versus day 154 for conventional CMF; patients visited health professionals three times as often for conventional CMF as for AC; women on AC received therapy on each of 4 days versus on each of 84 days for conventional CMF; and nausea-control medication was given for about 84 days to conventional CMF patients versus for about 12 days to patients on AC. The difference in the amount of alopecia between the two treatment groups was less than anticipated. While alopecia was almost universally observed following AC therapy, 71% of the CMF patients also had hair loss and, in 41%, the loss was greater than 50%. This study and NSABP B-16, which evaluates the worth of AC therapy in TAM-responsive patients, indicate the merit of 2 months of AC therapy for all positive-node breast cancer patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Systemic therapy in patients with node-negative breast cancer. A commentary based on two National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials.

OBJECTIVE: To determine whether in the previous National Surgical Adjuvant Breast and Bowel Project (NSABP) studies of node-negative breast cancer there were either cohorts of patients with a prognosis favorable enough to preclude using systemic therapy or subsets of patients who failed to benefit from the treatments. DESIGN: Randomized clinical trials with stratification after surgery. SETTING: NSABP trials at institutions in the United States and Canada. PATIENTS: Data were collected on 731 eligible patients (Protocol B-13) with estrogen-receptor-negative tumors who randomly received either no therapy after surgery or sequential methotrexate and fluorouracil (M----F) followed by leucovorin. Data were also collected on 2834 patients (Protocol B-14) with estrogen-receptor-positive tumors who randomly received either placebo or tamoxifen treatment. The percentage of patients surviving disease-free was determined through 4 years of follow-up using life-table estimates. INTERVENTIONS: Protocol B-13 patients received 12 courses of M----F given intravenously on days 1 and 8 every 4 weeks. Leucovorin therapy was begun 24 hours after M----F administration. Protocol B-14 patients received 5-year treatment with either tamoxifen (10 mg twice daily by mouth) or placebo. RESULTS: When the outcome of untreated patients in either trial was related to the stratification variables, women were found to have a disease-free survival of less than 80% through 4 years of follow-up. This percentage is apt to decrease because the probability of treatment failure increases with time. In both trials, all subsets of women benefited from M----F or tamoxifen therapy. CONCLUSIONS: The disease-free survival of all cohorts of node-negative patients with estrogen-receptor-negative or estrogen-receptor-positive tumors was poor enough to justify systemic treatment. The benefits of the therapies used are insufficient to eliminate the need for assessing putatively better regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors.

We evaluated the postoperative use of sequential methotrexate and fluorouracil followed by leucovorin in 679 patients with primary breast cancer, histologically negative axillary nodes, and estrogen-receptor-negative (less than 10 fmol) tumors. No survival advantage was observed with this therapy as compared with no postoperative therapy during four years of follow-up (87 percent vs. 86 percent; P = 0.8). However, there was a significant prolongation of disease-free survival among women who received this therapy as compared with those who did not (80 percent vs. 71 percent; P = 0.003). An advantage was observed in both the patients less than or equal to 49 years old and those greater than or equal to 50. At four years, treatment failure was reduced by 24 percent in the younger group and by 50 percent in the older group. The rates of both local and regional and distant metastases were decreased. These benefits, achieved without the use of an alkylating agent, were associated with tolerable side effects. Multivariate analysis testing for potential interactions failed to identify subgroups of patients who did not benefit from the therapy. These results, although promising, do not obviate the need for additional trials to evaluate potentially better regimens of therapy, but they do suggest that sequential methotrexate-fluorouracil should be used in the control arm in such studies. Their use is also justified for the treatment of patients who refuse to participate in clinical trials, provided the patients meet the eligibility criteria of the present study. Since women with tumors too small for conventional analysis of estrogen-receptor and progesterone-receptor concentrations were not included in this study, we do not recommend systemic treatment for them outside of a clinical trial.

Aged↗
PubMed1989

A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors.

We conducted a randomized, double-blind, placebo-controlled trial of postoperative therapy with tamoxifen (10 mg twice a day) in 2644 patients with breast cancer, histologically negative axillary nodes, and estrogen-receptor-positive (greater than or equal to 10 fmol) tumors. No survival advantage was observed during four years of follow-up (92 percent for placebo vs. 93 percent for tamoxifen; P = 0.3). There was a significant prolongation of disease-free survival among women treated with tamoxifen, as compared with those receiving placebo (83 percent vs. 77 percent; P less than 0.00001). This advantage was observed in both the patients less than or equal to 49 years old (P = 0.0005) and those greater than or equal to 50 (P = 0.0008), particularly in the former, among whom the rate of treatment failure was reduced by 44 percent. Multivariate analysis indicated that all subgroups of patients benefited. Tamoxifen significantly reduced the rate of treatment failure at local and distant sites, tumors in the opposite breast, and the incidence of tumor recurrence after lumpectomy and breast irradiation. The benefit was attained with a low incidence of clinically appreciable toxic effects. The magnitude of the improvement obtained does not preclude the need for future trials in which patients given tamoxifen could serve as the control group in an evaluation of potentially better therapies. Tamoxifen treatment is justified in patients who meet the eligibility criteria of the present study and who refuse to participate in those trials. Since patients with tumors too small for conventional analysis of estrogen-receptor and progesterone-receptor concentrations were not eligible for this study, no information is available to indicate that such patients should receive tamoxifen.

Adult↗
PubMed1989

A phase II trial of intermittent leukocyte interferon and high dose chlorambucil in the treatment of non-Hodgkin's lymphoma resistant to conventional therapy.

Thirteen patients with advanced non-Hodgkin's lymphoma who previously failed conventional chemotherapy protocols were treated with a combination of alpha-interferon (IFN) 6,000,000 units i.m. days 1-5 and 8, plus chlorambucil (CLB) 16 mg/m2 days 5-9 repeated every 4 weeks. There were five complete responses (CRs) and one partial response (PR) (46% total responses) with mean duration of remission of 456+ days. Responses were obtained in low and intermediate grade lymphomas. Toxicity was acceptable and easily managed. It is unlikely that IFN alone using this low dose intermittent schedule is responsible for the remissions. The combination of the two agents appears to be an effective treatment modality. IFN may be functioning as a biological response modifier when used in combination with a cytotoxic agent.

Adult↗
PubMed1988

Bioavailability of beta-carotene in humans.

Normal healthy volunteers were studied after they ingested various beta-carotene doses. Daily administration of 15 or 45 mg beta-carotene resulted in significant increase in plasma beta-carotene levels. The extent of increase and the pattern of plasma beta-carotene levels showed substantial interindividual variation. Absorption of beta-carotene was affected by dietary fat concentration. Individuals placed on a high-fat diet showed significant increases in plasma beta-carotene as compared with those placed on a low-fat diet. Pharmacological doses of beta-carotene (45 and 90 mg) were used in intermittent schedules (5-6 d intervals) without altering the steady state of beta-carotene plasma levels. Yellowing of the skin occasionally occurred during daily dosing with 45 mg beta-carotene without evidence of toxicity. The observed individual variation in bioavailability of beta-carotene raises questions regarding clinical use of this micronutrient. It appears that determination of target plasma beta-carotene concentrations is essential for effective use of this compound in prevention or treatment.

Adult↗
PubMed1988

High-dose folinic acid and 5-fluorouracil in the treatment of advanced colon cancer.

Forty-eight patients with measurable metastatic colorectal cancer were treated with leucovorin (FA), 80 mg/m2 as an intravenous (i.v.) infusion over 20 h, followed by 5-fluorouracil (5-FU), 400 mg/m2, i.v. push on days 1-3. This same dose of FA was then administered as a 1-h infusion on day 11 and weekly thereafter, followed by 5-FU, 400 mg/m2, slow intravenous (i.v.) push. Thirty patients had received no prior chemotherapy, and 18 patients had received chemotherapy with various other regimens. The drugs were well tolerated, with minimal hematologic toxicity and mild to moderate gastrointestinal and mucosal toxicity. Three complete responses (CRs) and nine partial responses (PRs) were observed. Nineteen additional patients remained stable for prolonged periods of time, and 12 patients continued to progress through treatment. The median survival for responders was 52.5 weeks. The patients who had received prior chemotherapy had lower response rates than the previously untreated patients, but responses were seen in both subsets. The CR plus PR rate in previously untreated patients was 30%, with 40% having stabilization of disease. The CR plus PR rate in patients previously treated with other chemotherapy regimens was 19%, with an additional 50% having stabilization of disease. Patients with stable disease appeared to have a clinical benefit similar to that of patients with PR. Toxicity was generally mild and acceptable and consisted mainly of nausea, vomiting, and mucositis. At these dosage levels, diarrhea was not a limiting toxicity. CRs and PRs occurred only in patients with Eastern Cooperative Oncology Group (ECOG) performance status 1 and 2. Carcinoembryonic antigen (CEA) levels generally reflected the type of clinical response and could often predict responders early on in the course of treatment, but did not quantitatively correlate with the degree of response. This regimen has efficacy at least similar to that of standard 5-FU regimens, and appears to have activity as a "salvage therapy" also. The minimal toxicity of this regimen, its convenience for outpatient use, and the relatively low expense as compared with regimens employing a higher dose of FA recommend it for further investigation.

Adenocarcinoma↗
PubMed1987

Changes in calcium channel activity in membranes from cis-diammine-dichloroplatinum(II)-resistant and -sensitive L1210 cells.

Ca2+ channels from lipid and proteolipid fractions of cisplatin-sensitive and cisplatin-resistant cells were reconstituted and characterized in bilayer lipid membranes formed at the tips of patch-clamp micropipets. The characteristics of the Ca2+ channels were typical for the endoplasmic reticulum membrane channel activity. They had a relatively large unit conductance and were modified by typical activators (nucleotides) and inhibitors (ruthenium red, verapamil). Different doses of nifedipine did not inhibit Ca2+ channel activity. A substantial difference between the single-channel properties of the two types of investigated membranes was observed. The mean open time and the open state probability of channels reconstituted in bilayer lipid membranes from the membrane components of cisplatin-resistant cells were larger than those in bilayer lipid membranes made from components of cisplatin-sensitive cells. Ruthenium red (7 X 10(-7) M) inhibited the channel activity in both types of membranes to the same level. The observed effects could be related to an increased Ca2+ release from the intracellular Ca2+ stores (endoplasmic reticulum system) accompanied by an enhanced intracytoplasmic Ca2+ concentration in cisplatin-resistant cells. These changes in the Ca2+ concentration level may be responsible for the higher antitumor drug efflux rate and the development of the drug resistance. The suggestion is made that specific inhibitors of the Ca2+ transport across the membranes of the subcellular Ca2+-storing organelles may be tested as agents for overcoming the antitumor drug resistance.

Animals↗
PubMed1987

cis-platinum, 5-fluorouracil, and hydroxyurea in the treatment of advanced non-small-cell lung cancer. A phase II study.

Sixteen patients with advanced non-small-cell lung cancer were treated with the combination of cis-platinum, 5-fluorouracil, and hydroxyurea. There were two complete responses (lasting 16 weeks each) and one partial response (lasting 12 weeks). Toxicity was manageable, but responders were unable to tolerate further therapy. Despite the obtaining of complete responses, the overall benefit of this particular combination requires further clinical investigation.

Adenocarcinoma↗
PubMed1987

Abrogation of adriamycin-induced cardiotoxicity by selenium in rabbits.

Adriamycin-induced cardiomyopathy in rabbits was produced by intravenous injections of the drug with a short therapeutic schedule (3 mg/kg body wt administered as four intermittent doses). Animals receiving selenium supplementation of Adriamycin showed preservation of the normal pattern of the heart histologic picture. The protective effect of selenium was accompanied by increased selenium levels in the plasma and the heart muscle. An eventual interaction between the antitumor effect of Adriamycin and the protective effect of selenium was ruled out by in vitro experiments using the L1210 cell line. Selenium did not abrogate the antiproliferative effect of Adriamycin when the cells were treated simultaneously with both agents. The results from this study indicate that Adriamycin-induced cardiotoxicity could be prevented by selenium if the animals were pretreated with selenium, rather than simultaneous administration of both agents. The mechanism of this effect is not entirely understood.

Animals↗
PubMed1986

Cell-mediated tumor-killing effect studied by using bilayer lipid membranes.

The bilayer lipid membrane (BLM) system was used to investigate the tumor killing effect of natural killer (NK) cells under various experimental conditions. It was found that NK cells interact specifically with BLMs made from lipids and proteolipids isolated from target K562 cells inducing an increase of the membrane conductance. This effect was more pronounced when the NK cells were pretreated with interferon. A similar effect was observed when NK cells were pretreated with sodium selenite. The results suggest that changes in membrane conductance and permeability are involved in the mechanism of the tumor-killing effect mediated by NK cells.

Cell Membrane↗
PubMed1985

Chemotherapeutic agents and modulation of natural killer cell activity in vitro.

This study investigated the effect of various clinically used chemotherapeutic agents on non-modulated and human alpha Interferon (IFN) modulated natural killer cell (NK) activity. The inhibitors of DNA synthesis, Adriamycin, Cis-Platinum, 5-Fluorouracil and Methotrexate, did not alter NK cell activity at comparable clinically used doses. Similarly, Vincristine and Vinblastine, which are antimitotic agents, did not affect the NK activity. Only inhibitors of RNA synthesis L-Asparaginase and Actinomycin D reduced non-modulated and IFN modulated NK cell activity.

Antineoplastic Agents↗
PubMed1984

Malignant mesothelioma of the tunica vaginalis testis.

Eighteen patients with malignant mesothelioma of the tunica vaginalis testis have been previously reported. These and the six patients reported here are reviewed for natural history and response to treatment. This tumor should be considered in men of any age with scrotal masses that include a hydrocele. Staging procedures should include computerized tomography scanning of the chest and abdomen. Inguinal orchiectomy appears to be the optimal primary surgical approach. Intraabdominal disease found at diagnostic laparotomy may be effectively treated by surgery and/or abdominal radiotherapy. Clinical features such as a long asymptomatic interval from initial presentation to clinical recurrence were observed and are also worthy of emphasis. Thus, serial follow-up is advised. Upon recurrence, treatment remains unsatisfactory but some responsiveness to chemotherapy has been noted. Doxorubicin-containing regimens were administered to five patients with measurable pulmonary nodules resulting in two partial regressions by standard criteria.

Adult↗