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Biomedical subjects

R Leff

Publications and source records attributed to R Leff.

13 recordsLinked to original sources
PubMed1999

Adjuvant dose-intense chemotherapy with peripheral blood stem cell support in stage II-III breast cancer with five to nine involved axillary lymph nodes.

The purpose of this study is to determine outcomes for patients with high-risk nonmetastatic breast cancer undergoing high-dose chemotherapy with peripheral blood stem cell support. Forty-three patients with stage II-III disease, five to nine positive axillary lymph nodes, and a median age of 44 years (range, 27-60 years) were enrolled in a study that included: 1) standard dose doxorubicin, 5-fluorouracil, and methotrexate adjuvant therapy; 2) cyclophosphamide, etoposide, filgrastim, and peripheral blood stem cell harvest; and 3) high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) followed by peripheral blood stem cell infusion. All 43 patients received doxorubicin, 5-fluorouracil, and methotrexate, 42 (98%) received etoposide, and 41 (95%) received CTCb. Thirty-two patients (74%) are alive, 28 (65%) without relapse at a median of 55 months (range, 41-87 months). Two died (5%) of treatment-related causes, (subclavian catheter complication after etoposide and late radiation pneumonitis), and nine other deaths (21%) were associated with recurrent breast cancer. The probabilities of overall and event-free survival at 4 years were 0.77 and 0.67, respectively, compared with 0.82 and 0.69, respectively, for 72 similar patients with 10 or more positive axillary nodes receiving the same sequence of therapy. Thus, patients with five to nine positive axillary lymph nodes have a similar risk of failure after high-dose chemotherapy and peripheral blood stem cell support as patients with 10 or more positive axillary lymph nodes.

Adult↗
PubMed1999

Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group.

PURPOSE: To assess whether pamidronate can reduce the frequency of skeletal morbidity in women with lytic bone metastases from breast cancer treated with hormone therapy. PATIENTS AND METHODS: Three hundred seventy-two women with breast cancer who had at least one lytic bone lesion and who were receiving hormonal therapy were randomized to receive 90 mg of pamidronate or placebo as a 2-hour intravenous infusion given in double-blind fashion every 4 weeks for 24 cycles. Patients were evaluated for skeletal complications: pathologic fractures, spinal cord compression, irradiation of or surgery on bone, or hypercalcemia. The skeletal morbidity rate (the ratio of the number of skeletal complications to the time on trial) was the primary efficacy variable. Bone pain, use of analgesics, quality of life, performance status, bone tumor response, and biochemical parameters were also evaluated. RESULTS: One hundred eighty-two patients who received pamidronate and 189 who received placebo were assessable. The skeletal morbidity rate was significantly reduced at 12, 18, and 24 cycles in patients treated with 90 mg of pamidronate (P = .028, .023, and .008, respectively). At 24 cycles, the proportion of patients having had any skeletal complication was 56% in the pamidronate group and 67% in the placebo group (P = .027). The time to the first skeletal complication was longer for patients receiving pamidronate than for those given placebo (P = .049). There was no statistical difference in survival or in objective bone response rate. Pamidronate was well tolerated. CONCLUSION: Treatment with 90 mg of pamidronate as a 2-hour intravenous infusion every 4 weeks in addition to hormonal therapy significantly reduces skeletal morbidity from osteolytic metastases.

Adolescent↗
PubMed1998

Phase I-II evaluation of rapid sequence tandem high-dose melphalan with peripheral blood stem cell support in patients with multiple myeloma.

This study was designed to determine the maximum tolerated dose (MTD) of high-dose melphalan (HDM), with peripheral blood stem cell support, that could be given twice within 90 days to patients with multiple myeloma. Twenty patients received tandem HDM at 160, 180 or 200 mg/m2 and a total of 55 were treated at the estimated MTD of 200 mg/m2. Seventeen of 55 (31%) did not receive cycle 2; six because of low CD34+ cell yields, three because of severe (n = 1) or fatal toxicities (n = 2) and eight for other reasons. The median interval between doses for 38 patients was 70 days (range 41-225). Three of 55 patients (5%) died of treatment-related causes. In patients completing two cycles of HDM, at any dose level, the complete remission rate improved from 15% following cycle 1 to 55% following cycle 2. The probabilities of survival, event-free survival and relapse or progression at 18 months for the 55 patients treated at the MTD were 0.84, 0.76 and 0.20, respectively, with a median follow-up of 19 months (range 9-36) from mobilization chemotherapy. It was concluded that two cycles of HDM, 200 mg/m2, could be administered to approximately 70% of patients under the age of 66 with multiple myeloma in a median interval of 70 days, with improvement in CR rates.

Adult↗
PubMed1998

A randomized trial of two doses of cyclophosphamide with etoposide and G-CSF for mobilization of peripheral blood stem cells in 318 patients with stage II-III breast cancer.

The purpose of this study was to develop a less toxic outpatient chemotherapy regimen for mobilizing peripheral blood stem cells (PBSC). Three hundred eighteen patients with newly diagnosed stage II-III breast cancer who had received conventional dose adjuvant chemotherapy were randomized to receive intermediate-dose cyclophosphamide (2 g/m2), etoposide (600 mg/m2), and granulocyte colony-stimulating factor (G-CSF) 6 micrograms/kg/day (ID-Cy, n = 162) or high-dose cyclophosphamide (4 g/m2) and the same doses of etoposide and G-CSF (HD-Cy, n = 156) followed by collection of PBSC. Three hundred seventeen of 318 patients had apheresis performed, and 315 received high-dose chemotherapy (HDC) followed by PBSC support. The median numbers of CD34+ cells collected in a median of two apheresis following ID-Cy and HD-Cy were 19.9 and 22.2 x 10(6)/kg, respectively (p = 0.04). The fractions of patients achieving CD34+ cell doses > or = 2.5 or > or = 5.0 x 10(6)/kg were not different between the two regimens. More patients receiving HD-Cy had grade 3-4 nausea (p = 0.001), vomiting (p = 0.03), and mucositis (p = 0.04). The fractions of patients having a neutrophil nadir < 0.5 x 10(9)/L following ID-Cy and HD-Cy were 0.83 and 0.95, respectively (p = < 0.001). The fractions of patients having a platelet nadir < 25 x 10(9)/L following ID-Cy and HD-Cy were 0.13 and 0.51, respectively (p = < 0.001). More patients in the HD-Cy group received platelet (p < 0.001) and red blood cell (p < 0.001) transfusions and were admitted to the hospital more frequently (p = 0.03) than patients receiving ID-Cy. Three hundred fifteen patients received HDC followed by infusion of PBSC. There were no significant differences in the incidence of transplant-related death or early survival between patients receiving ID-Cy or HD-Cy followed by HDC. It was concluded that a regimen of Cy 2 g/m2 with etoposide and G-CSF was effective for mobilization of PBSC with low morbidity and resource utilization in patients with limited prior chemotherapy exposure.

Adult↗
PubMed1998

Sequential treatment including high-dose chemotherapy with peripheral blood stem cell support in patients with high-risk stage II-III breast cancer: outpatient administration in community cancer centers.

The authors determined outcomes for patients with localized high-risk breast cancer undergoing sequential outpatient treatment with conventional-dose adjuvant therapy, chemotherapy, and growth factor mobilization of peripheral blood stem cells (PBSC) and high-dose chemotherapy (HDC) with PBSC support in community cancer centers. Ninety-six patients with stage II-IIIB noninflammatory breast cancer with 10 or more positive lymph nodes and a median age of 46 years (range, 22-60 years) were treated with: 1) doxorubicin, 5-fluorouracil, and methotrexate (AFM), four courses at 2-week intervals; 2) cyclophosphamide (4 g/m2) and etoposide (600 mg/m2) (CE), followed by filgrastim (6 microg/kg per day) and PBSC harvest; and 3) cyclophosphamide (6 g/m2), thiotepa (500 mg/m2), and carboplatin (800 mg/m2) (CTCb), followed by PBSC infusion. All 96 patients received AFM, 95 (99%) received CE, and 95 (99%) received CTCb with a median hospital stay of 12 days (5-34 days) for all phases of treatment. Sixty-nine patients (72%) are alive, 55 (57%) without relapse at a median follow-up of 53 months (range, 37-77 months). One patient (1%) died of acute myeloid leukemia and all other deaths were associated with recurrent breast cancer. The probabilities of event-free survival (EFS) at 4 years for patients with or without locally advanced disease were 0.37 and 0.69, respectively (p = 0.004), and 0.71 and 0.48 for patients who were estrogen/progesterone receptor (ER/PR) positive or ER/PR negative, respectively (p = 0.016). In multivariate analyses, locally advanced disease (relative risk, 2.3; p = 0.021) and ER/PR-negative hormone receptor status (relative risk, 2.2; p = 0.014) were the only adverse risk factors for EFS identified. Patients with zero, one, or two of these adverse risk factors had 4-year EFS of 0.80, 0.56, and 0.33, respectively. The sequential administration of AFM, CE, and CTCb followed by PBSC in an outpatient community setting was well tolerated in patients with high-risk stage II-III breast cancer. More intensive or more novel treatment strategies will be required to decrease relapses in patients who have ER/PR-negative tumors and/or have locally advanced disease.

Adult↗
PubMed1997

Induction, mobilization of peripheral blood stem cells (PBSC), high-dose chemotherapy and PBSC infusion in patients with untreated stage IV breast cancer: outcomes by intent to treat analyses.

We investigated the outcomes of patients with breast cancer undergoing induction chemotherapy, mobilization of peripheral blood stem cells (PBSC) and high-dose chemotherapy (HDC) with PBSC infusion. One hundred and fourteen patients with untreated stage IV breast cancer, with a median age of 46 years (range 24-62), were entered on a phase II trial consisting of; (1) doxorubicin, 5-flurouracil, methotrexate (AFM) x 4 courses at 2 week intervals; (2) cyclophosphamide (4 g/m2), etoposide (600 mg/m2), cisplatin (105 mg/m2) (CEP), filgrastim (6 micrograms/kg/day) and PBSC collection; (3) cyclophosphamide (6 g/m2), thiotepa (500 mg/m2), carboplatin (800 mg/m2), (CTCb) followed by PBSC infusion. All patients received AFM, 107 (94%) received CEP, 93 (82%) received CTCb and PBSC as per protocol and 99 (87%) ultimately received HDC and PBSC. There was one infectious death after AFM and all other deaths were associated with progressive disease. Fifty-two patients (46%) are alive, 21 (18%) without progression, at a median 31 months (range 22-47). The probabilities of survival and progression-free survival at 3.5 years were 0.40 and 0.17, respectively. All 62 patients with visceral disease and/or a prior history of doxorubicin adjuvant therapy have relapsed or progressed. We conclude that the sequential administration of AFM, CEP and CTCb followed by PBSC resulted in long-term PFS only in patients who were NED, had bone-only disease or had lymph node or soft tissue disease with or without bone disease. Other strategies, aimed at improving responses to initial therapy, improving HDC regimens and/or developing immunomodulatory therapies, will be necessary to improve PFS for patients who fail doxorubicin adjuvant or who have visceral disease.

Adult↗
PubMed1997

High-dose chemotherapy and peripheral blood stem cell infusion in patients with non-Hodgkin's lymphoma: results of outpatient treatment in community cancer centers.

The outcomes for patients with non-Hodgkin's lymphoma (NHL) treated with high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) infusion by practicing oncologists in community cancer centers in the United States were determined. Eighty-three patients with NHL, who had failed conventional chemotherapy, underwent mobilization of PBSC with chemotherapy and a recombinant growth factor in an outpatient facility. At a median of 40 days (range 26-119) after mobilization chemotherapy all received carmustine (300 mg/m2 x 1), etoposide (150 mg/m2 twice a day x 4 days), cytarabine (100 mg/m2 twice a day x 4 days) and cyclophosphamide (35 mg/kg x 4 days) (BEAC) followed by infusion of unmanipulated PBSC in an outpatient facility. The probabilities of treatment-related mortality, relapse/progression, overall survival (OS) and event-free survival (EFS) at 3 years for all 83 patients were 0.07, 0.57, 0.49 and 0.38, respectively. The probabilities of relapse/progression, OS and EFS at 3 years for 28 patients who had failed primary induction chemotherapy were 0.55, 0.42 and 0.38, respectively. The probabilities of OS and EFS for 27 patients in untreated first relapse were 0.52 and 0.44, respectively, as compared to 0.56 and 0.32, respectively, for 18 patients who had reinduction attempts prior to receiving mobilization chemotherapy (P = 0.81 for OS and 0.99 for EFS). No significant risk factors for the outcomes of TRM, relapse/progression, OS or EFS could be identified. These data demonstrate that approximately 40% of patients with NHL who have failed conventional chemotherapy become long-term disease-free survivors after mobilization chemotherapy, high-dose BEAC and PBSC infusion administered in an outpatient setting in community cancer centers, with the major cause of failure being relapse. Results obtained in this study are comparable to published data in similar patient populations receiving therapy as inpatients, suggesting that clinical trials involving well-tested HDC regimens can be carried out safely in this setting.

Adult↗
PubMed1994

A motif in human histidyl-tRNA synthetase which is shared among several aminoacyl-tRNA synthetases is a coiled-coil that is essential for enzymatic activity and contains the major autoantigenic epitope.

In myositis, disease-specific autoantibodies may be directed against an aminoacyl-tRNA synthetase, usually histidyl-tRNA synthetase. To explore the basis for this phenomenon, we have made recombinant histidyl-tRNA synthetase in the baculovirus system. It was enzymatically active and recognized by human autoantibodies. A truncated protein lacking the first 60 amino acids was inactive as an antigen and as an enzyme. This region is within the first two exons, is predicted to have a coiled-coil configuration, and is found in some other synthetases but not in Escherichia coli or yeast histidyl-tRNA synthetase. Circular dichroism showed that the peptides from this region (amino acids 1-60 and 1-47) have the predicted high alpha-helical content, but smaller fragments (1-30, 14-45, and 31-60) do not. The peptides with a high alpha-helical content could inhibit autoantibodies almost completely, whereas the smaller peptides were unable to do so. The amino acid sequence of this coiled-coil domain in human histidyl-tRNA synthetase resembles the sequence of the extended this coiled-coil arm near the NH2 terminus of bacterial seryl-tRNA synthetase as well as similar regions in some eukaryotic aminoacyl-tRNA synthetases, raising the possibility that this domain serves a similar tRNA-stabilizing role and has been preserved from a common ancestor.

Amino Acid Sequence↗
PubMed1982

The effects of diazoxide upon fetal and maternal hemodynamics and fetal brain function and metabolism.

The effects of maternal infusion of Diazoxide (D) were evaluated in two groups of experiments: Nine ewes and their five nonhypoxic fetuses; the remaining four fetuses were excluded because of the development of hypoxia prior to the study. D was directly administered intravenously (IV) to the six fetuses. In group 1 maternal and fetal observations were made at 0, 5, 15, 30, and 45 minutes. A 60-minute observation was also made for the maternal infusion studies. Maternal infusion of 5 mg/kg maternal weight significantly reduced maternal pH from the control value at 5 minutes. Maternal metabolic acidosis was indicated by concomitant significant reductions in base deficit (BD) and total bicarbonate (HCO3), both of which remained low for all subsequent time periods. Maternal lactic acid concentration also increased at 15 minutes, although not significantly. Maternal PO2 also fell significantly at 5 minutes, remaining significantly low for the remaining observations. A profound maternal hypotension was elicited at 5 minutes. All following observations for maternal blood pressure (MBP) were also significantly low. Fetal carotid arterial (FCA) pH declined significantly from the control period value at 15 minutes, remaining significantly low for the remaining observations. FCA O2% saturation (O2%) also witnessed a significant decline from baseline for all observations. FCA serum lactate level rose at 15 minutes; however, this was not deemed significant. No significant changes were seen in fetal brain metabolic rate of oxygen or glucose. Fetal electroencephalogram (EEG) revealed a definite hypoxic change in a majority of cases. In group 2, the effects of a direct fetal IV administration of 30 mg D (mean dose = 7.97 mg/kg fetal weight) were studied in six experiments. No significant changes in fetal acid base status or fetal blood pressure (FBP) were witnessed for the 45 minutes under scrutiny. Fetal heart rate (FHR) showed a short transient rise from baseline at 5 and 15 minutes, returning to normal thereafter. A slight significant decrease in O2% saturation and O2 content were seen only for the 5-minute observation. There were no significant changes of fetal brain function and metabolism observed following D administration to the fetus. The significant fetal hypoxia and acidosis witnessed through the maternal infusion but not in the direct fetal bolus administration were probably owing to profound maternal hypotension resulting in deterioration of uteroplacental perfusion and fetal "gas exchange."

Animals↗