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Biomedical subjects

A Elias

Publications and source records attributed to A Elias.

At least 55 records · Page 3Linked to original sources
PubMed1996

Selective transgene expression for detection and elimination of contaminating carcinoma cells in hematopoietic stem cell sources.

Tumor contamination of bone marrow (BM) and peripheral blood (PB) may affect the outcome of patients receiving high dose chemotherapy with autologous transplantation of hematopoietic stem cell products. In this report, we demonstrate that replication defective adenoviral vectors containing the cytomegalovirus (CMV) or DF3/MUC1 carcinoma-selective promoter can be used to selectively transduce contaminating carcinoma cells. Adenoviral-mediated reporter gene expression in breast cancer cells was five orders of magnitude higher than that found in BM, PB, and CD34+ cells. Our results demonstrate that CD34+ cells have low to undetectable levels of integrins responsible for adenoviral internalization. We show that adenoviral-mediated transduction of a reporter gene can detect one breast cancer cell in 5 x 10(5) BM or PB cells with a vector containing the DF3/MUC1 promoter. We also show that transduction of the HSV-tk gene for selective killing by ganciclovir can be exploited for purging cancer cells from hematopoietic stem cell populations. The selective expression of TK followed by ganciclovir treatment resulted in the elimination of 6-logs of contaminating cancer cells. By contrast, there was little effect on CFU-GM and BFU-E formulation or on long term culture initiating cells. These results indicate that adenoviral vectors with a tumor-selective promoter provide a highly efficient and effective approach for the detection and purging of carcinoma cells in hematopoietic stem cell preparations.

Adenoviruses, Human↗
PubMed1996

Diagnostic value of anti-RA33 antibody, antikeratin antibody, antiperinuclear factor and antinuclear antibody in early rheumatoid arthritis: comparison with rheumatoid factor.

The goal of this prospective longitudinal study was to determine the serological profile of early rheumatoid arthritis (RA), and to test whether antikeratin antibody (AKA), antiperinuclear factor (APF), anti-RA33 antibody and antinuclear antibodies (ANA) had an additional diagnostic value when prescribed after rheumatoid factor (RF)-detecting methods. Sixty-nine patients with early polyarthritis suggestive of RA, seen between 1991 and 1993, were included. Five autoantibodies (i.e. RF, AKA, APF, RA33, ANA) were looked for at regular intervals. After 24 months follow-up, patients were classified as having RA (n = 49), unclassified polyarthritis (UP; n = 15) or other rheumatic diseases. Among patients with early RA, the sensitivity of these markers was 40.8% for RF, 36.7% for AKA, 28.6% for APF and 28.6% for anti-RA33. Among RF-negative RA patients, 51.7% were positive for AKA, APF, anti-RA33 antibodies and/or ANA. Positivity of the three recent markers usually persisted throughout follow-up, whereas RF was lost by 58% of patients with early, RF-positive, treated RA. Using multivariate analysis, only latex, RF test and AKA or APF had an independent and statistically significant diagnostic value for early RA. Our data suggest that RF and AKA (or APF) should be concomitantly determined for diagnosis in patients with suspected early RA.

Adolescent↗
PubMed1996

Double dose-intensive chemotherapy with autologous stem-cell support for metastatic breast cancer: no improvement in progression-free survival by the sequence of high-dose melphalan followed by cyclophosphamide, thiotepa, and carboplatin.

PURPOSE: Twenty-one percent of responding metastatic breast cancer patients remain progression-free a median 50 months following one intensification cycle of cyclophosphamide (6,000 mg/m2), thiotepa (500 mg/ m2), and carboplatin (800 mg/m2) (CTCb) with autologous bone marrow transplantation (ABMT). This trial studied whether the sequence of high-dose melphalan followed by CTCb resulted in improved disease response and duration. METHODS: Women with at least partial responses (PRS) to induction received melphalan (140 or 180 mg/ m2) with peripheral-blood progenitor cell (PBPC) and granulocyte colony-stimulating factor (G-CSF) support. They were monitored as outpatients. After recovery, patients were hospitalized for CTCb with marrow, PBPC, and G-CSF support. RESULTS: Data on 67 women, at a median of 25 months from CTCb, were examined. After melphalan, 49 (73%) required admission for fever (89%), mucositis (35%), or infection (15%) (median stay, 8 days). All received CTCb. For the first 33 patients, the median days from start of melphalan to CTCb was 24. After liver toxicity (one death from venoocclusive disease [VOD]) developed in 11 patients during CTCb, the interval between intensifications was increased to 35 days without incident. Twenty-three patients (34%) are progression-free a median of 16 months post-CTCb. The median progression-free survival (PFS) and survival times for the whole group are estimated at 11 and 20 months, respectively. CONCLUSION: Treatment with this sequence of high-dose melphalan followed by CTCb has not resulted in superior PFS to date, when compared with single-intensification CTCb. This report discusses factors related to patient selection, the role of induced drug resistance, and the schedule of administration of alkylating agenting that may adversely influence outcome.

Adolescent↗
PubMed1996

Predicting daily maintenance dose of fluindione, an oral anticoagulant drug.

Due to large inter-individual variations, the dose of vitamin K antagonist required to target the desired hypocoagulability is hardly predictible for a given patient, and the time needed to reach therapeutic equilibrium may be excessively long. This work reports on a simple method for predicting the daily maintenance dose of fluindione after the third intake. In a first step, 37 patients were delivered 20 mg of fluindione once a day, at 6 p.m. for 3 consecutive days. On the morning of the 4th day an INR was performed. During the following days the dose was adjusted to target an INR between 2 and 3. There was a good correlation (r = 0.83, p < 0.001) between the INR performed on the morning of day 4 and the daily maintenance dose determined later by successive approximations. This allowed us to write a decisional algorithm to predict the effective maintenance dose of fluindione from the INR performed on day 4. The usefulness and the safety of this approach was tested in a second prospective study on 46 patients receiving fluindione according to the same initial scheme. The predicted dose was compared to the effective dose soon after having reached the equilibrium, then 30 and 90 days after. To within 5 mg (one quarter of a tablet), the predicted dose was the effective dose in 98%, 86% and 81% of the patients at the 3 times respectively. The mean time needed to reach the therapeutic equilibrium was reduced from 13 days in the first study to 6 days in the second study. No hemorrhagic complication occurred. Thus the strategy formerly developed to predict the daily maintenance dose of warfarin from the prothrombin time ratio or the thrombotest performed 3 days after starting the treatment may also be applied to fluindione and the INR measurement.

Administration, Oral↗
PubMed1996

[Adventitial cyst of the popliteal artery. Imaging and percutaneous treatment].

Adventitial cystic disease of the popliteal artery is a rare cause of calf claudication in young patients. A case explored by magnetic resonance imaging is reported: a water rich mass around the popliteal artery compressed the arterial lumen. Treatment consisted in CT-guided percutaneous aspiration. Good functional outcome except for severe efforts, despite persistance of cystic images was observed. Echography, computed tomography or magnetic resonance imaging are more useful to establish the diagnosis than arteriography because these techniques can directly visualize the arterial wall. Percutaneous treatment preserves the intima and can be performed in out-patients. When feasible, it could be preferred to conventional surgery.

Adult↗
PubMed1996

D-dimer test and diagnosis of deep vein thrombosis: a comparative study of 7 assays.

The current D-Dimer ELISA methods provide high sensitivity and negative predictive value for the diagnosis of deep vein thrombosis but these methods are not suitable for emergency or for individual determination. We have evaluated the performance of 3 newly available fast D-Dimer assays (Vidas D-Di, BioMérieux; Instant IA D-Di, Stago; Nycocard D-Dimer, Nycomed) in comparison with 3 classic ELISA methods (Stago, Organon, Behring) and a Latex agglutination technique (Stago). One-hundred-and-seventy-one patients suspected of presenting a first episode of deep vein thrombosis were investigated. A deep vein thrombosis was detected in 75 patients (43.8%) by ultrasonic duplex scanning of the lower limbs; in 11 of them the thrombi were distal and very limited in size (< 2 cm). We compared the performance of the tests by calculating their sensitivity, specificity, positive and negative predictive value for different cut-off levels and by calculating the area under ROC curves. The concordance of the different methods was evaluated by calculating the kappa coefficient. The performances of the 3 classic ELISA and of the Vidas D-Di were comparable and kappa coefficients indicated a good concordance between the results provided by these assays. Their sensitivity slightly declined for detection of the very small thrombi. Instant IA D-Di had a non-significantly lower sensitivity and negative predictive value than the 4 previous assays; however its performance was excellent for out-patients. As expected, the Latex assay had too low a sensitivity and negative predictive value to be recommended. In our hands, Nycocard D-Dimer also exhibited low sensitivity and negative predictive value, which were significantly improved when the plasma samples were tested by the manufacturer. Thus significant progress has been made, allowing clinical studies to be planned to compare the safety and cost-effectiveness of D-Dimer strategy to those of the conventional methods for the diagnosis of venous thrombosis.

Adolescent↗
PubMed1995

Analysis of 4-hydroxycyclophosphamide in human blood.

Cyclophosphamide is a prodrug activated by cytochrome P450 isozymes in the liver. The product of hepatic activation of cyclophosphamide is 4-hydroxycyclophosphamide. Previously reported methods for determining 4-hydroxycyclophosphamide were either impractical or unreliable for monitoring infusion pharmacokinetics in conjunction with clinical trials. One procedure in which a fluorescent hydroxyquinoline derivative was prepared from 4-hydroxycyclophosphamide and analyzed by HPLC appeared to work at first, but gradually lost its selectivity due to degradation of the column by the strongly acidic mobile phase. An alternative procedure was developed using a weakly acidic eluent and postcolumn treatment with trifluoroacetic acid. This provided for protonation of the hydroxyquinoline, required for sensitive fluorescence detection, but spared the column. The resulting assay was sensitive, selective, reproducible, and accurate. The method was used to monitor 4-hydroxycyclophosphamide pharmacokinetics during and after 4 day infusions of 1.5 g/m2-day of cyclophosphamide given to three patients. It was also used to measure the time-dependent disappearance of acrolein and 4-hydroxycyclophosphamide added to human blood from healthy donors and that of metabolically derived 4-hydroxycyclophosphamide in the blood of a patient treated with cyclophosphamide. Slower decomposition was observed in the latter two cases than in the blood spiked with acrolein. Reliable data were obtained from > 1000 determinations using the same column without significant degradation of its stationary phase.

Chromatography, High Pressure Liquid↗
PubMed1995

High-dose ifosfamide, carboplatin, and etoposide pharmacokinetics: correlation of plasma drug levels with renal toxicity.

An autologous bone marrow transplant regimen of ifosfamide, carboplatin, and etoposide (ICE) has been developed as treatment for certain malignancies. At maximum tolerated doses renal insufficiency precludes dose escalation. The objective was to examine whether measurement of plasma drug levels early during treatment would provide warning of renal failure. Nine patients received a 96-h continuous infusion of ifosfamide 16,000 mg/m2, carboplatin 1600 mg/m2, and etoposide 1200 mg/m2. Pharmacokinetics, including drug levels and plasma concentration-time curves, of ifosfamide, ultrafiltrable platinum (uPt) and etoposide were analyzed and correlated with renal function. One of the nine patients developed anuric renal failure requiring hemodialysis. By 17 h from the start of infusion, this patient showed substantially higher drug levels of ifosfamide (200 vs mean 217 microM) and uPt (19 vs mean 10 microM) than those patients with preserved renal function. The 95% confidence intervals suggested that a 16-22 h ifosfamide level > 153 microM and an uPt level > microM predict the development of significant renal dysfunction. Although drug levels were substantially higher at 56 h, the serum creatinine did not yet reflect kidney injury. This study suggests that high plasma ifosfamide and uPt levels, analyzed early in the course of a 96-h infusion of high-dose ICE, provide warning of severe and potentially fatal renal injury. Since ICE has substantial activity in a number of malignancies, but significant renal morbidity, real-time pharmacokinetic-guided dosing may reduce treatment-related toxicity.

Acute Kidney Injury↗
PubMed1995

Weak immunogenicity of the preS2 sequence and lack of circumventing effect on the unresponsiveness to the hepatitis B virus vaccine.

The preS2 sequence is known to circumvent immunological unresponsiveness to the S protein and to induce a 'carrier' effect on the anti-S antibody production, in mice. In humans, an anti-S response was found in 100% and 97% of healthy subjects vaccinated with the S and S + preS2 preparations, respectively, whereas less than 50% of drinkers responded whatever the vaccine used. Anti-preS2 were found in 44% of healthy recipients of the S + preS2 vaccine, whereas there were no anti-preS2 responders in drinkers. Anti-preS2 remained undetectable in 32% of the blood donors hyperimmunized with the S + preS2 vaccine, whereas anti-S antibody boosted in all cases. In humans, in contrast to mice, immunogenicity of the preS2 sequence appears weak and the preS sequence does not circumvent the anti-S unresponsiveness.

Adult↗
PubMed1995

The collection and evaluation of peripheral blood progenitor cells sufficient for repetitive cycles of high-dose chemotherapy support.

BACKGROUND: The development of an optimized peripheral blood progenitor cell (PBPC) harvest protocol to provide support for repetitive chemotherapy cycles is described. STUDY DESIGN AND METHODS: PBPCs mobilized by cyclophosphamide plus granulocyte-colony-stimulating factor (G-CSF) were studied in 163 leukapheresis harvests from 26 lymphoma patients. Harvested cells were transfused with two chemotherapy cycles and with an autologous bone marrow transplant. Progenitor cell content was examined in the context of hematopoietic engraftment. RESULTS: Mobilization allowed the harvest of large numbers of PBPCs. Peak harvests tended to occur after the recovering white cell count exceeded 10 x 10(9) per L. CD34+ lymphomononuclear cell (MNC) and colony-forming units-granulocyte-macrophage (CFU-GM) counts correlated poorly, but both measures peaked within 24 hours of each other in 21 of 26 patients, which demonstrated PBPC mobilization. Engraftment of platelets (> 50 x 10(9)/L) and granulocytes (> 500 x 10(6)/L) was achieved in a median of 20.5 and 16 days, respectively. A minimum number of progenitors necessary to ensure engraftment could be derived. CONCLUSION: Cyclophosphamide and G-CSF allowed the harvest of sufficient PBPCs to support multiple rounds of chemotherapy. Harvest should commence when the recovery white cell count exceeds 10 x 10(9) per L. PBPC harvest CD34+MNC counts are as useful as CFU-GM results in the assessment of PBPC content, and they may allow harvest protocols to be tailored to individual patients.

Adult↗
PubMed1995

Prognostic factors for prolonged progression-free survival with high-dose chemotherapy with autologous stem-cell support for advanced breast cancer.

PURPOSE: With a median observation time of 50 months from transplant, 13 (22%) of 62 women with metastatic breast cancer treated with high-dose chemotherapy at the Dana-Farber Cancer Institute (DFCI)/Beth Israel Hospital (BIH) remain progression-free. This study determined factors prognostic for prolonged progression-free survival (PFS). METHODS: From June 1988 to January 1992, women who responded to standard chemotherapy received high-dose cyclophosphamide, thiotepa, and carboplatin with autotransplantation. Data encompassing initial breast cancer diagnosis, metastatic presentation, and response to induction treatment were examined for correlations with improved PFS. RESULTS: The 5-year PFS rate for the entire group is estimated to be 21% (95% confidence interval [CI], 10% to 32%). For those patients who attained a complete response (CR) to induction therapy, the 5-year PFS rate is estimated to be 31% (95% CI, 0% to 63%). In univariate analyses, a single metastatic site, CR to induction therapy, prolonged interval from primary diagnosis to first metastases, estrogen receptor (ER)-negative tumors, and older age (> or = 40 years) were associated with prolonged PFS. In multivariate analyses, single metastatic site (P = .002) and attainment of a CR to induction chemotherapy (P = .04) were the most significant predictors for PFS, with a strong trend observed for an interval from primary diagnosis to onset of metastatic disease of 24+ months (P = .066). CONCLUSION: We and others have shown that 10% to 25% of women with metastatic breast cancer are progression-free after high-dose chemotherapy with autotransplantation. Those with chemosensitive disease, minimal tumor bulk, and a prolonged disease-free interval appear to benefit most. Emphasis should continue to focus on the development of more effective cytotoxic regimens and biologic approaches to increase the percentage of patients who may benefit from this approach.

Adolescent↗
PubMed1994

Continuous-infusion cisplatin, 5-fluorouracil, and leucovorin for advanced non-small cell lung cancer.

BACKGROUND: Cisplatin, 5-fluorouracil, and leucovorin (PFL) have demonstrated synergistic activity in preclinical models. Continuous infusion of these agents maximizes the potential for synergistic interaction and forms the basis of the PFL regimen. METHODS: Sixty-one patients with advanced (Stages IIIB and IV) non-small cell lung cancer were entered into the study. Thirty-one were treated with cisplatin 25 mg/m2/day on days 1-5, 5-fluorouracil 800 mg/m2/day on days 2-6, and calcium leucovorin 500 mg/m2/day on days 1-6. Because of severe mucositis, the final 30 patients were treated with the same dosage of cisplatin but with the deletion on day 6 of leucovorin and 5-fluorouracil. Cycles were repeated every 28 days. Response was assessed after two cycles. Responding patients received an additional two cycles. Patients with Stage IIIB disease received radiation therapy to the mediastinum and sites of involved disease. RESULTS: PFL had an overall response rate of 41%. Median survival was 8.1 months, and median time to treatment failure was 4.2 months. Importantly, 68% (17 of 25) of responses were maximal after just two cycles of chemotherapy. Notable toxicities included mucositis (43% > or = Grade 3) and myelosuppression. Response, time to failure, or survival did not differ between the two schedules. Mucositis was less severe with 4-day PFL. CONCLUSIONS: PFL as given in this manner is an active regimen for the treatment of patients with advanced non-small cell lung cancer. The rapidity of response makes it a regimen for incorporation into protocols for Stage IIIA disease. A neoadjuvant study using PFL is underway.

Adult↗
PubMed1994

Hepatitis C virus (HCV) viremia in human immunodeficiency virus-seronegative and -seropositive patients with indeterminate HCV recombinant immunoblot assay.

Positivity of recombinant immunoblot assay (RIBA) for detection of antibodies to hepatitis C virus (anti-HCV) is usually associated with HCV viremia. The significance of an indeterminate RIBA result, defined by reactivity to only one HCV antigen, is unclear. Whether anti-human immunodeficiency virus (HIV)-negative or -positive subjects with an indeterminate RIBA have HCV viremia detectable by polymerase chain reaction was investigated. An indeterminate RIBA was found in 48 (15%) of 318 anti-HIV-negative and 38 (23%) of 167 anti-HIV-positive subjects (P < .05). Clinical stage was IV-C-1 or IV-C-2 in 82% of those anti-HIV-positive. HCV viremia was found more frequently in anti-HIV-positive (89%) than in anti-HIV-negative subjects (50%) with an indeterminate RIBA (P < .05). These results suggest an impaired anti-HCV response associated with HIV infection.

Alanine Transaminase↗
PubMed1994

Recombinant human erythropoietin for the treatment of the anaemia associated with autologous bone marrow transplantation.

Patients with solid tumours undergoing high-dose chemotherapy with autologous bone marrow transplantation use an average of 10 units of packed red blood cells (PRBC) while awaiting haemopoietic reconstitution. They are also known to have inappropriately low endogenous erythropoietin levels for their degree of anaemia. This pilot study was designed to determine the effects of recombinant human erythropoietin (rHuEPO) on erythroid recovery and PRBC transfusion requirements. Ten patients received high-dose chemotherapy (days -7 to -3), bone marrow reinfusion (day 0), and then rHuEPO (day 1 onward). RHuEPO (200 units/kg intravenous bolus daily), along with iron supplementation, was administered for 28 d or until a haematocrit (Hct) of 35% (independent of transfusions) was reached, whichever occurred first. PRBCs were routinely given for Hct < or = 25% and platelets for counts < 20,000/microliters. Eight (80%) patients developed a brisk reticulocytosis (median peak reticulocyte count 0.32 x 10(9)/l) and a haematocrit > or = 30% independent of red blood cell transfusions within 32 d of receiving marrow, as compared to 20/37 (54%) similarly treated controls. An unexpected finding was the more rapid engraftment in myeloid and platelet lineages in a subset of rHuEPO-treated patients. Quick return of red blood cells (17 v 33 d) (P = 0.0001), platelets (14 v 19 d) (P = 0.04), and neutrophils (13 v 25 d) (P = 0.01) (with circulating myeloblasts and early myeloid forms) characterized recovery from an ifosfamide-based intensification with rHuEPO support. Similar trilineage enhancement of haemopoiesis did not occur with the possibly more myeloablative cyclophosphamide-based regimens. Despite the enhancement by rHuEPO on reticulocytosis, there was no significant decrease in PRBC transfusion requirements. RHuEPO proved to be a well-tolerated agent in enhancing reticulocytosis following high-dose chemotherapy. Further study to elucidate the activity of erythropoietin on both erythroid and non-erythroid growth and maturation appears warranted.

Adult↗
PubMed1994

Effect of recombinant human interleukin-3 on haematological recovery from chemotherapy-induced myelosuppression.

Patients with non-small-cell lung cancer (NSCLC) were treated with ICE chemotherapy (ifosfamide 2000 mg/m2, days 1-3; carboplatin 300 mg/m2, day 1; etoposide 75 mg/m2, days 1-3) intravenously (i.v.) during the first 3 d of a maximum of four 28 d treatment cycles. Interleukin-3 (IL-3) was administered in cycles 2 and 4 as a daily subcutaneous (s.c.) injection on days 5-18. Cohorts of three patients were treated at dosage levels of 0.5, 1.25, 2.5, 5.0, 10.0 and 15.0 micrograms/kg/d. At 15.0 micrograms/kg/d a 'flu-like' syndrome of myalgias, arthralgias and fatigue was considered dose-limiting. Other toxicities were headache, fever, urticaria, arrhythmia, chills and flushing. Subsequently, nine patients were added to the group receiving 10 micrograms/kg/d. 27 patients received IL-3 after their second course of ICE. At 10 and 15 micrograms/kg/d, IL-3 in cycle 2 was associated with enhanced haematological recovery. Depth of neutrophil nadir and days of neutropenia (ANC < 0.5 x 10(9)/l) were reduced in 9/13 patients and in 8/11 patients, respectively. No effect was seen on platelet nadir or days of thrombocytopenia. IL-3 was well tolerated up to 10 micrograms/kg/d when given as a daily s.c. injection. Results suggest IL-3 as a potential adjunct to chemotherapy, and further studies to explore administration of IL-3 in combination with other cytokines in this setting are warranted.

Adolescent↗