Biomedical subjects

D Radosavljević

Publications and source records attributed to D Radosavljević.

At least 19 recordsLinked to original sources

PubMed2001

Survival advantage for carboplatin substituting cisplatin in combination with vindesine and mitomycin C for stage IIIB and IV squamous-cell bronchogenic carcinoma: a randomized phase III study.

This communication represents the definitive report of a randomized phase III study comparing cisplatin and carboplatin, in combination with vindesine and mitomycin C in stage IIIB and IV squamous-cell bronchogenic carcinoma. A total of 221 patients entered the study and were randomized into two arms. Of these, 114 patients (109 evaluable for activity) were randomized to arm A, receiving cisplatin 120 mg/m(2), mitomycin C 8 mg/m(2) and vindesine 3 mg/m(2) per cycle; 107 patients (101 evaluable for activity) were randomized to arm B receiving carboplatin 500 mg/m(2) with the same doses of mitomycin C and vindesine per cycle. Patients with progressive disease (PD) were excluded from the study after the 2nd cycle, and those with stable disease (SD), partial response (PR) and complete response (CR) received six cycles of chemotherapy (or less in case of early progression). Patients were stratified according to the clinical stage (IIIB vs. IV), performance status (0+1 vs. 2+3) and tumor histological grade (I+II vs. III). In the cisplatin arm two patients (1.9%) achieved a CR, 38 (34.9%) a PR, 45 (41.2%) a SD and 24 (22.0%) had PD; the overall response rate was 40/109 (36.8%). In the carboplatin arm five patients (5.0%) achieved a CR, 31 (30.7%) a PR, 40 (39.6%) a SD, and 25 (24.7%) had PD; the overall response rate was 36/101 (35.7%). No statistically significant difference in response rate was present between the two arms, and the response rate was not influenced by performance status, histological grade or clinical stage. The Kaplan-Meyers curves displayed a significant advantage both for time to progression (P=0.005) and overall survival (P=0.008) for patients in the carboplatin arm. The advantage for patients receiving carboplatin instead of cisplatin appeared evident in univariate setting for patients with a good performance status and clinical stage IV, and occurred irrespectively of tumor histological grade; response duration and survival of responders was identical in the two arms. Patients achieving a stable disease survived longer in the carboplatin than in the cisplatin arm (P=0.012). Thus, substitution of cisplatin by carboplatin in the combination chemotherapy regimen, although more hematologically toxic (but less emetogenic) resulted in a similar response rate, but a significantly longer time to progression and overall survival.

Adult↗

PubMed2001

Tumor 'flare' hypercalcemia--an additional indication for bisphosphonates?

The most serious, potentially life-threatening manifestation of 'flare' is hypercalcemia, registered in 4-5% of breast cancer patients with bone metastases, usually during the first few weeks of tamoxifen treatment. There are no specific treatment recommendations for flare hypercalcemia, except tamoxifen withdrawal. There are no reports on the use of bisphosphonates in the treatment of flare hypercalcemia. Among 87 hypercalcemic patients with metastatic breast cancer observed during a 7-year period, 10 patients had tamoxifen-induced hypercalcemia. Diagnosis of flare hypercalcemia was based on the normal pretreatment values of serum calcium and the development of hypercalcemia within a maximum of 6 weeks of hormonal drug initiation. The median time from hormonal drug initiation to flare hypercalcemia was 14 days, the median duration 8.5 days, and the median calcium level was 3.09 mmol/l (range 2.79-4.46 mmol/l). All patients were treated with hydration, and 7 patients with calcium levels above 3.0 mmol/l were also treated with disodium pamidronate in various single doses (30-90 mg/24 h). Normocalcemia was achieved in all patients, and tamoxifen was continued without relapse of hypercalcemia. Median survival was 177 days (range 12-570 days). It seems that the use of bisphosphonates in the treatment of flare hypercalcemia could allow safe readministration of tamoxifen and prevent premature and unjustified tamoxifen discontinuation. Flare hypercalcemia might represent one more indication for the use of bisphosphonates.

Adult↗

PubMed2000

Eight-hour infusion versus bolus injection of doxorubicin in the EAP regimen in patients with advanced gastric cancer: a prospective randomised trial.

BACKGROUND: Doxorubicin (40 mg/m2/cycle), etoposide (360 mg/m2/cycle) and cisplatin (80 mg/m2/cycle) comprise an efficient regimen in patients with advanced gastric cancer (AGC). However, its excessive hematological toxicity led doctors to avoid using the combination. Doxorubicin is the main cause of myelotoxicity in the EAP regimen. The aim of this study was to compare an eight-hour infusion of doxorubicin (arm A) with intravenous injection of doxorubicin (arm B) in the EAP regimen with respect to toxicity, objective responses, time to progression (TTP) and survival in patients with AGC. PATIENTS AND METHODS: One-hundred twenty chemotherapy-naïve patients with measurable AGC were randomised between September 1994 and August 1998. Sixty patients in arm A and sixty patients in arm B were considered as fully evaluable. The arms were well balanced for age, sex distribution, previous therapy, histological grade and performance status. One-hundred eighty cycles were applied in arm A (median 2) and 201 in arm B (median 4). RESULTS: No difference was detected (P = 0.28) in the response rate of arm A 20% (CR 3; PR 9; 95% CI: 10-30) and B 28% (CR 3; PR 14; 95% CI: 17-40). But there was a significant difference in PD (P = 0.005) between arm A (51%) and arm B (36%). TTP (P = 0.01) and survival (P = 0.02) analyses detected an advantage for arm B vs. arm A. Grades 3-4 toxicity were as follows (arms A%/B%): anemia 8/10, leukopenia 24/26, thrombocytopenia 6/16 (significance, P = 0.05), nausea/vomiting 5/8, diarrhea 6/2, mucositis 8/5. Apart from the trombocytopenia, there was no significant difference in toxicity grades 3-4 between the two arms. Four treatment-related deaths occurred, two in each arm. CONCLUSIONS: Bolus injection of doxorubicin is superior to eight-hour doxorubicin infusion in the EAP regimen in terms of survival, TTP and PD without being significantly more toxic.

Adult↗

PubMed2000

Vitamin C induced apoptosis in human articular chondrocytes.

Chondrocytes present in articular cartilage survive as a resident cell population throughout the lifespan of the individual organism. However, articular chondrocytes as other cells also undergo apoptosis and there is an ever increasing list of diverse stimuli that can induce this phenomenon in vitro. Our main interest was to investigate potential cytotoxic effects of vitamin C (L-ascorbic acid) on human articular chondrocytes. The present study suggests that vitamin C can induce apoptosis in a cell culture of chondrocytes after 18 h of cultivation. Apoptosis-inducing activity of L-ascorbic acid is dose dependent and significantly affected by the presence of serum. The increased number of vitamin C induced apoptotic cells was associated with DNA fragmentation and morphological changes of the cells.

Apoptosis↗

PubMed1999

The role of stable disease in objective response assessment and its impact on survival in advanced colorectal cancer: is "stable disease" a homogenous response category?

Stable disease is a category which is not included in the evaluation of the overall treatment response rate. In many studies with a response rate below 20%, chemotherapy almost doubles the survival of patients. In the most chemotherapy trials with advanced colorectal cancer patients, about 30-50% had stable disease. Despite belonging to the same category of therapy response, some patients with stable disease have achieved symptom improvement, but some have not. The aim of the study was to investigate whether the stabilization of the disease with clinical benefit is associated with benefit in survival. A total of 99 patients with advanced colorectal cancer were treated with carboplatin (80 mg/m2, day 1-7), 5-FU (750 mg/m2, day 1-5), leucovorin (100 mg/m2, day 1-5) every 4 weeks. After 4 courses, in the case of stable disease (SD), the patients were stratified according to clinical benefit achievement in: Group A--patients with clinical benefit who continued with chemotherapy until 8 cycles or until disease progression; group B--patients without clinical benefit in whom chemotherapy was stopped after 4 cycles. Clinical benefit was a composite of assessment of pain, ECOG performance status, weight and temperature. Clinical benefit required a sustained improvement in at least one parameter without worsening in any other. Of 97 evaluable patients 48 achieved stable disease. Of 22 pts. with SD clinical benefit performance status improvement was recorded in 17, pain relief in 14, improvement in body weight in 14 and temperature disappearance in 8 pts. Of 26 pts. with SD without clinical benefit, 7 were asymptomatic from beginning of the chemotherapy. No difference was detected in the survival between responders and SD clinical benefit pts. (p = 0.24), but there was significant difference between responders and SD pts. without clinical benefit (p = 0.0004). SD clinical benefit pts. had significant difference in survival in comparison to pts. with progressive disease (p = 5.1 x 10(-6)). The results of our study indicate that under category "stable disease" there are two different subpopulations of patients with quite different symptom response to chemotherapy, different time to progression and possible different survival.

Adenocarcinoma↗

PubMed1999

Radio- and chemotherapy variably affect the general immunocompetence of lung cancer patients.

OBJECTIVE: The evaluation of the effects of radiotherapy and chemotherapy on the immune status of lung cancer patients. EXPERIMENTAL DESIGN: Prospective nonrandomized study. SETTING: Hospitalized care. PATIENTS: 121 patients with unresectable non-small-cell lung cancer (Stage IIIb or IV), who were planned for radiotherapy (n = 81) or chemotherapy (n = 40). MEASURES: The relative and absolute numbers of blood T lymphocytes and monocytes, as well as the mitogen-induced proliferative response of the former, and phagocyting capacity of the latter cell subpopulation, were determined in patients before starting any therapy. In radiotherapy (RT)-treated group, the immune parameters were evaluated after 45 Gy and 60 Gy had been given. In chemotherapy (ChT)-treated group, the same parameters were determined three weeks after the 2nd and 4th cycle of ChT. RESULTS: The number and proliferative response of T lymphocytes were significantly (p < 0.001) lower, while the number and phagocyting capacity of monocytes were significantly (p < 0.001) higher in all patients before therapy, in comparison to the controls. After RT, the T cell number and proliferative response were significantly (p < 0.001) decreased, while the number of monocytes and their phagocyting capacity remained unchanged, when compared to the pretreatment values. Unlike RT, chemotherapy did not change any investigated parameter, except for the phagocyting activity of monocytes, which was significantly (p < 0.02) decreased, in comparison to the pretreatment value, after four cycles of ChT only. CONCLUSIONS: Two cancer treatment modalities--radio- and chemotherapy--variably affect the immune status of lung cancer patients. The initial great disturbances of general immunity parameters are further aggravated by radiotherapy. Unlike RT, chemotherapy exerts no suppression at all; on the contrary, it tends to normalize some of the parameters of cellular immunity of lung cancer patients.

Adult↗

PubMed1997

Androgen level variations, clinical response to LHRH agonists and changes in the quality of life subscales in metastatic prostate cancer--speculations about possible role of the monoamine system.

The aim of this study was to investigate the effect of goserelin-acetat (Zoladex) on testosterone suppression, to compare achieved suppression with clinical effects in patients with prostate cancer with bone metastases and consequent painful syndrome, to study the behavior of adiol during treatment and to assess life quality with emphases on the physical and psychological domain in relation to clinical and biological treatment effects. Fifteen patients were treated by Zoladex in one dose every 28 days, and followed-up for 12 months. All patients had several metastatic localizations in the bones, initial high prostate specific antigen (PSA), and high acid (AP) and alkaline phosphatase (ALP). PSA, testosterone, adiol (delta-5-androstenediol), luteinizing hormone (LH), foliculostimulating hormone (FSH), ALP and AP were also measured before every cycle. For evaluation of the life quality Rotterdam Symptom Checklist was used. Clinical progression was not registered during follow-up, with drop of PSA, ALP and AP. Testosterone and adiol displayed mainly inverse trends during treatment. The complete testosterone suppression was never achieved. It seems that Zoladex has quite different influence on LH and FSH, as levels of those hormones have shown opposite trend. Some of the observed hormonal effects could be attributed to stimulation of the monoamine system. Suppression of LH level provoked by administration of LHRH agonists increases level of dopamine in hypothalamus which inhibits releasing of its hormones. By inhibition of corticotropic releasing factor and ACTH, and by its influence on adrenal gland, we could explain drop of adiol levels in the first months of administration of LHRH agonists. Testosterone increase and adiol drop in the first months, and adiol increase following testosterone level drop in the fourth to eight month, may be explained by negative feed back mechanism between different androgens which could be stimulated or provoked by LHRH therapy. The question of effects which are results of LHRH agonists modulation of the monoamine system and consequent activation of other central mechanisms of hormonal regulation is still open. Patients' quality of life under therapy was improved for about 30% in psychological and functional domains. There were no significant changes on physical subscale, during treatment. It seems that the obtained positive psychological treatment effect is not only a consequence of pain decrease, but it could be the result of the change in the level of monoamines in CNS under Zoladex.

Acid Phosphatase↗

PubMed1996

[A pilot study of high-dose zorubicin in advanced stages of soft tissue sarcoma in adults].

High-dose anthracyclines, doxorubicin 75 mg/m2 and epirubicin 150-180 mg/m2, are the most active drugs in the treatment of advanced soft tissue sarcoma. These dosages are associated with significant hematological toxicity for both drugs and a high risk of cardiotoxicity for doxorubicin. The aim of this pilot study was to investigate the activity of zorubicin in advanced soft tissue sarcoma, with a dosage supposed to be equihematotoxic to epirubicin 180 mg/m2. Twenty of 21 patients who had been included in the study were evaluable for response, 15 males and five females, median age 41 (range 20-67) years. All patients received zorubicin 600 mg/m2 per cycle divided in 3 days, the intercycle interval being 4 weeks. The cardiac function was monitored by determinations of left ventricular ejection fraction before each cycle. Therapeutic response was the following: 2/20 patients (10%) complete response, 6/20 (30%) partial response, 6/20 (30%) stable disease and 6/20 (30%) progressive disease, the overall response rate being 8/20 (40%). Complete responses were observed in a patient with undifferentiated sarcoma of the mediastinum and in a patient with unresectable angiosarcoma of subcutaneous tissues. The major toxicity was hematological, with granulocytopenia grade 4 occurring in 42/66 cycles, and the nadir on day 10 of the treatment cycle. Nine of 66 cycles were complicated by febrile neutropenia and stomatitis of any grade was recorded in only 1/66 cycles. No cumulative cardiotoxicity was observed up to a total cumulative zorubicin dose of 3,000 mg/m2.

Adult↗

PubMed1991

DNA sequencing by hybridization: 100 bases read by a non-gel-based method.

Determination of the sequences of human and other complex genomes requires much faster and less expensive sequencing processes than the methods in use today. Sequencing by hybridization is potentially such a process. In this paper we present hybridization data sufficient to accurately read a known sequence of 100 base pairs. In independent reactions, octamer and nonamer oligonucleotides derived from the sequence hybridized more strongly to this DNA than to controls. The 93 consecutive overlapping probes were derived from a 100-base-pair segment of test DNA and additional probes were generated by incorporation of a noncomplementary base at one of the ends of 12 of the basic probes. These 12 additional probes also had a full-match target in one of the control DNAs. The test and one of five control DNAs spotted on nylon filters were hybridized with 83 octamers and 22 nonamers under low-temperature conditions. A stronger signal in DNA containing a full-match target compared to DNA with only mismatched targets was obtained with all 105 probes. In 3 cases (2.9%), the difference of signals was not significant (less than 2-fold) due to inefficient hybridization and the consequently higher influence of background. The hybridization pattern obtained enabled us to resequence the 100 base pairs by applying an algorithm that tolerates an error rate much higher than was observed in the experiment. With this result, the technological components of large-scale DNA sequencing using the sequencing by hybridization method are in place.

Base Sequence↗

PubMed1991

Deletion analysis of Duchenne muscular dystrophy using cDNA probes and multiplex PCR.

The authors studied Duchenne muscular dystrophy (DMD) in 14 Yugoslav families with 16 diseased men. All the sixteen patients showed typical phenotypic features of DMD. The linkage analysis was done with five probes 754, C7, PERT87.15, pERT87.30, and pERTBir. A deletion with pERT87.15 (DX 164) in one family was found. Deletion analysis was mainly performed using cDNA probes and multiplex PCR analysis. Preferential deletions were in the hot spot deletion region covered by cDNA probe 8. Among 14 examined patients with cDNA hybridization deletions were found in 5 cases (5/14). For quick and prenatal analysis the authors used multiplex PCR. With this methods deletions were found in 4 cases (4/15). The percentage of the observed deletions cases was 50% (8/16) in Yugoslav population, which shows good correlation with other European and American populations studied. Prenatal diagnosis was done for two consultants with highly ambiguous carrier risk, and no deletions were found.

Child↗

PubMed1990

Origin of rat beta-globin haplotypes containing three and five genes.

We have reported in rat three adult beta-gene haplotypes containing either five or three genes. Detailed sequence analysis reveals that the leftmost gene is the major gene and that at the opposite end downstream lies the minor gene. All of the genes lying between them are minor-major hybrids indicating their origin by unequal crossing-over. In two haplotypes beta-globin genes were found with an L1(1) element inserted directly into IVS2. The described results allow the formulation of a pathway of mutational events leading from the ancient two-beta-gene rodent ancestor through a three-gene haplotype to five-gene haplotypes, one of which is postulated to have arisen in common laboratory strains since their capture in the wild.

Animals↗

PubMed1989

Variant chromosomal arrangement of adult beta-globin genes in rat.

The genomic organization of three haplotypes of beta-globin genes was determined to resolve the question of the number of those genes in rat. Haplotype a, found in inbred strain DA, has three genes or pseudogenes, while haplotypes b, found in AO, Y5 and Wistar strains, and c, found in Wistar strain, have five genes or pseudogenes each. In haplotypes b and c, the first gene is of beta major type and the remaining four are of beta minor type. Partial sequencing of six out of 13 genes shows that duplications of beta minor genes are causing polymorphism in a number of genes. Also, in haplotype b two beta minor genes have a 6.5-kb intron 2, while in haplotype c only one beta minor gene contains such a large intron 2. The three structurally different haplotypes described are not interconvertible by single recombination events. The results indicate that the rat has the highest number of adult beta-globin genes found in mammals so far.

Amino Acid Sequence↗

PubMed1989