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Biomedical subjects

R E Sage

Publications and source records attributed to R E Sage.

At least 37 records · Page 2Linked to original sources
PubMed1993

Molecular detection of residual lymphoma cells in peripheral blood stem cell harvests and following autologous transplantation.

Twenty-seven patients with non-Hodgkin's lymphoma (NHL) have undergone peripheral blood stem cell (PBSC) harvesting for autologous transplantation (Tx). A molecular marker was found at presentation in 23/27 patients. Immunoglobulin heavy chain (IgH) or T cell receptor beta (TCR beta) rearrangements were detected by Southern blotting or the polymerase chain reaction (PCR) in 13 patients; PCR detected the bcl-2/JH fusion in 10 patients. Fifteen autologous PBSC transplants have been performed in 11 patients. In 5/11 patients, the marker was present in at least one PBSC collection (in four patients, every PBSC collection was positive). Survival data are available for nine patients (two early deaths); three patients relapsed and died (221 - 930 d), one is alive and in relapse (354 + d) and five are alive and in complete remission (330 - 1290 + d). These findings suggest that tumour cell contamination of PBSC harvests is not uncommon. Whether these cells are clonogenic and contribute to disease relapse remains to be elucidated. The presence of residual disease at the time of transplantation and the reappearance (or persistence) of marker positive cells post-transplantation both appear to be poor prognostic factors for disease-free survival.

Adult↗
PubMed1992

Reversal of human platelet aggregation by low concentrations of nitroglycerin in vitro in normal subjects.

The potential reversal of platelet aggregation in vitro by nitroglycerin in low concentrations was explored using both optical aggregometry and electron microscopy. Venous blood was collected from a cohort of normal volunteers (20 men and 10 women) aged 21 to 65 years. Aggregation in platelet-rich plasma was induced by adenosine diphosphate in concentrations just sufficient to maintain a steady state of aggregation, without a spontaneous disaggregation phase (3.5 to 5 microM). Administration of nitroglycerin after the induction of aggregation caused both inhibition of the primary wave of developing aggregation and marked disaggregation. This combined effect was maximal when nitroglycerin was added at 0.5 minute after the beginning of aggregation. The observed reversal of platelet aggregation by nitroglycerin was concentration-dependent. Significant effects occurred with nitroglycerin concentrations greater than or equal to 10(-8) M. Concentration associated with 50% reversal of aggregation was 1.52 +/- 0.24 (SEM) x 10(-6) M. Electron microscopy revealed that 10(-6) M nitroglycerin induced a significant reduction in both platelet clumping and morphologic changes associated with aggregation. The results of the current study suggest a beneficial antiplatelet effect of nitroglycerin in restoring homeostasis in the face of incipient platelet aggregation. The clinical use of nitroglycerin in patients with acute ischemic syndromes may rest on this action.

Adenosine Diphosphate↗
PubMed1992

Factors affecting blood stem cell collections following high-dose cyclophosphamide mobilization in lymphoma, myeloma and solid tumors.

Sixty patients with malignancy were enrolled in a study of high-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT). Stem cells were harvested prior to PBSCT using high-dose cyclophosphamide (CY) mobilization (4 or 7 g/m2) with collection of a median of 4.6 x 10(8)/kg mononuclear cells (range 0.2-9.5) and 21.6 x 10(4)/kg colony forming unit-granulocyte/macrophage (CFU-GM) (range 0.1-220). Forty-seven patients were mobilized once, 11 required two cycles and two required three cycles. Eight patients (13%) failed to reach the optimum CFU-GM target (greater than 15 x 10(4)/kg) following CY mobilization. A number of factors identified those patients who were likely to achieve optimum CFU-GM collections with CY mobilization. These included the use of the higher CY mobilization dose, a longer interval from last chemotherapy cycle to mobilization, and a higher premobilization bone marrow CFU-GM level. Patient's age, the degree of bone marrow infiltration, the nature of disease or the number of pre-mobilization chemotherapeutic cycles did not affect the ability to collect optimum CFU-GM numbers. Whilst the mobilization procedure was associated with moderate non-hematologic toxicity, significant hematological morbidity was observed primarily in patients mobilized using the 7 g/m2 dose. Refinements to the protocol, in particular the use of hematopoietic growth factors, are currently under investigation.

Adolescent↗
PubMed1991

A rare translocation (4;11)(q21;p14-15) in an acute lymphoblastic leukemia expressing T-cell and myeloid markers.

A 21-year-old male presented with a large mediastinal mass and a white cell count of 420 x 10(9)/L. A diagnosis of acute lymphoblastic leukemia (ALL) was made, with 90% of cells in the bone marrow (BM) and 99% in the peripheral blood (PB) being lymphoblasts (FAB L1). Cytogenetic analysis of these cells revealed a rare variant of the t(4;11) translocation involving chromosome arm 11p rather than 11q, namely t(4;11)(q21;p14-15). The standard form of the (4;11) translocation has been associated with leukemias with mixed-lineage phenotypes. Three cases of ALL with t(4q;11p) have previously been reported. One of these cases showed phenotypic heterogeneity involving myeloid and lymphoid lineages. The leukemia reported here also exhibits lymphoid/myeloid features. Immunophenotyping of the blasts showed that most of the cells were positive for CD2, CD5, CD7, CD10 (CALLA), CD34, and HLA-DR. A significant proportion of the cells expressed CD33. These results suggest a biphenotypic rather than a biclonal disease. Molecular analysis showed rearrangement of both immunoglobulin heavy-chain genes (JH) and of a single allele of the T-cell receptor (TCR) gamma 1 gene, while retaining germline TCR beta genes.

Adult↗
PubMed1991

Mobilization of haemopoietic stem cells by cyclophosphamide into the peripheral blood of patients with haematological malignancies.

Thirty one peripheral blood stem cell mobilizations using cyclophosphamide, followed by leucapheresis, were performed in 25 patients with a variety of haematological malignancies. Cyclophosphamide at doses ranging from 0.25 g/M2/day x 4 days to 4 g/M2 on one day were given. Total doses of cyclophosphamide less than 4 g/M2 failed to induce a significant mobilization of stem cells into the peripheral blood. This compares to cyclophosphamide doses of 4 g/M2 given over one or two days where 70%-75% of patients yielded adequate stem cells for transplantation (greater than 20 x 10(4) CFU-GM/kg). Both the presence of tumour cells in the bone marrow and previous chemotherapy within 12 months of cyclophosphamide infusion significantly diminished the patients stem cell mobilizations. The rate of recovery of the patient's leucocyte count following cyclophosphamide was highly correlated to the peak level of PB CFU-GM and is a good indicator of the total stem cell yield. Fever in 50% of patients during the period of cytopaenia was the only complication seen in our patients and thus high dose cyclophosphamide is a suitable and safe agent for mobilizing haemopoietic stem cells.

Adult↗
PubMed1990

Novel translocations in acute nonlymphocytic leukemia. Two cases involving chromosome 21, band q22.

We present two cases in which translocations involving 21q22 were found at presentation in acute nonlymphocytic leukemia (ANLL). The first of these translocations, t(3;21)(q26-q27;q22), is previously unknown in ANLL, but appears indistinguishable from that reportedly associated with Philadelphia-positive chronic myelogenous leukemia. The second case involves t(15;21)(q21-q22;q22), a translocation previously undescribed in ANLL. Both of these exchanges involve 21q22 plus another chromosome region associated with leukemogenesis. We attempted to interrelate these cytogenetic data with the oncogenic significance of 21q22.

Chromosome Banding↗
PubMed1990

Single high doses of cyclophosphamide enable the collection of high numbers of hemopoietic stem cells from the peripheral blood.

We used single high doses of cyclophosphamide (4 g/m2) to produce rebound increases in peripheral blood (PB) stem cells (PBSC) during recovery from myelosuppression, enabling their collection by apheresis for later autotransplantation. Thirty-three courses of cyclophosphamide were given to 30 patients with malignant lymphoma, multiple myeloma, or solid tumors. The neutrophil count was less than 0.5 x 10(9)/liter for a mean of 6.9 days (median 7 days), and fever occurred in 17 of 33 courses. Positive blood cultures occurred in two patients, one of whom died. The mean peak level of PB granulocyte-macrophage colony-forming units (CFU-GM) was 1517 x 10(3)/liter (median 2447 x 10(3)/liter), a 14-fold increase above the mean in normal subjects. The peak occurred at a mean of 16.6 days (median 16 days) after cyclophosphamide, generally coinciding with the time to reach 1.0 x 10(9) neutrophils per liter. Normal or minimally involved bone marrow and a rapid rise in leukocyte count during recovery were independent variables correlated to the peak of the rebound increase in PB CFU-GM levels. Previous chemotherapy and the duration of neutropenia were additional independent variables in the group with peak PB CFU-GM levels of greater than 1000 x 10(3)/liter. The mean total CFU-GM collected after a mean of five aphereses was 43.8 x 10(4)/kg body weight (BW) (median 35.5 x 10(4)/kg BW), significantly correlated with the mononuclear cell yield. We conclude that single 4 g/m2 doses of cyclophosphamide effectively produce high levels of PBSC, particularly but not exclusively in patients with normal or minimally involved bone marrow and who have not had intensive recent chemotherapy.

Adult↗
PubMed1989

Alteration in doxorubicin and doxorubicinol plasma concentrations with repeated courses to patients.

Fifteen cancer patients were studied following repeated courses of doxorubicin (12-44 mg/m2) (together with other anticancer agents) to consider the possibility of enhanced metabolism as a cause of the previously reported reduction in doxorubicin plasma concentrations with repeated courses. Plasma doxorubicin and doxorubicinol concentrations were measured by a modified high-performance liquid chromatography/fluorescence method. The results presented confirmed the significant decline in doxorubicin plasma concentration-dose ratios measured 3 h after the 1-h infusion. Although the degree of this reduction varied markedly between patients, it was shown not to be associated with a rise in the plasma concentration-dose ratio of the major metabolite doxorubicinol or with altered renal and/or hepatic function, which may have influenced disposition. Alternative mechanisms that might explain the reduction in doxorubicin concentrations, such as increased doxorubicin clearance or volume of distribution, were not considered in the present study.

Adolescent↗
PubMed1988

Renal clearance and protein binding of melphalan in patients with cancer.

The renal clearance of melphalan and the fraction unbound in plasma were determined after intravenous infusion of 5 mg/m2 over 5 min in nine patients with cancer to obtain information regarding the mechanism of renal handling of melphalan. Four of the patients underwent bone marrow transplantation and also received an IV dose of 220 mg/m2. Total melphalan clearance after the 5 mg/m2 dose ranged from 66.0 to 272 ml/min per m2; the percentage of the dose excreted unchanged in urine, from 2.5% to 92.8%; renal clearance, from 4.1 to 188 ml/min per m2; the fraction unbound in plasma, from 0.0598 to 0.460; and t1/2 beta, from 39.4 to 84.3 min. Unbound melphalan clearance and renal clearance calculated from the unbound fraction in plasma for each patient ranged from 441 to 3356 ml/min per m2 and 15 to 961 ml/min per m2 respectively and were not related to serum albumin, serum creatinine or creatinine clearance. The percentage of the dose excreted and melphalan renal clearance were not related to urine flow. There was evidence of active secretion of melphalan in the kidney an possible reabsorption. There were no significant paired differences in melphalan disposition between the high- and low-dose studies. Highly variable renal clearance involving active secretion may contribute in part to large interpatient differences in the total plasma clearance of melphalan in patients with cancer.

Adult↗
PubMed1987

Effect of L-leucine on oral melphalan kinetics in patients.

Melphalan uptake in the intestine has recently been shown to be an energy-dependent process which is affected by metabolic inhibitors. It is therefore theoretically possible that amino acids in food could reduce melphalan absorption by competing for uptake at the sites of absorption in the intestine. Since L-leucine has been shown to be the most potent inhibitor of melphalan transport into cells in vitro, this amino acid was chosen for the present study in patients. Oral melphalan (4.5 +/- 0.5 mg/m2) was given to ten fasting patients with and without a 2-g oral dose of L-leucine on separate randomized occasions at least 1 week apart. Melphalan plasma levels were measured by high-performance liquid chromatography (HPLC) for 5-h after dosing. L-Leucine plasma levels were measured by HPLC before and at 1 h after dosing. The area under the curve for melphalan was lower in seven of the patients after L-leucine. Plasma L-leucine levels 1 h after melphalan administration were 15.4 +/- 3.7 micrograms/ml fasting and 35.4 +/- 5.2 micrograms/ml after L-leucine. The results indicate that L-leucine can reduce plasma melphalan levels in some patients, probably through a reduction in absorption of the drug from the gastrointestinal tract. However, the effect, like that of food, is highly variable.

Administration, Oral↗
PubMed1986

A five-year experience with central nervous system lymphoma.

The experience with central nervous system (CNS) non-Hodgkin's lymphoma at a 700-bed teaching hospital over five years (1979-1983) is reported. During this period 222 patients with non-Hodgkin's lymphoma were seen. Ten new cases (eight patients with secondary and two patients with primary CNS lymphoma) were diagnosed during this period, representing an overall incidence of 4.5%. The clinical, pathological and neuroradiological findings of this group are described with special emphasis on the varied appearances that were found on computer-assisted tomographic scans.

Adult↗
PubMed1986

The effect of food on oral melphalan absorption.

Fifteen patients receiving oral melphalan (4.2-5.3 mg/m2) for a variety of neoplastic disorders were studied. Ten patients received the drug on separate occasions, with and without a standardized breakfast. Eight of these patients also received an IV bolus dose (5 mg/m2) to determine bioavailability. Serial melphalan plasma samples were taken over 5 h after administration and assayed by high-performance liquid chromatography. The median area under the curve (AUC) when taken fasting was 179 (range 95-336) ng X h X ml-1, and when taken with food, 122 (47-227) ng X h X ml-1, the median reduction being 39% (P less than 0.01). In one patient, who died before completing the study, the drug was not detectable at all after being taken with food. In the eight patients who were also given IV melphalan, the median terminal melphalan half-life (57 min, range 38-71) was no different from its oral half-life [55 (27-104) min fasting; 55 (30-72) min with food] (P greater than 0.1). In these patients bioavailability was 85% (26-96)% when the drug was taken fasting and 58% (7-99)% when taken with food (P less than 0.025). Median clearance following IV administration was 362 ml/min/m2 (range 104-694). It was found that the melphalan level in a single plasma sample drawn 1.5 h after administration was highly predictive of oral melphalan AUC (rs = 0.915, P less than 0.1). This study suggests that to ensure optimum absorption of the drug, melphalan should not be taken with food.

Absorption↗
PubMed1986

Aleukaemic leukostasis in a case of large cell non-Hodgkin's lymphoma: report of a case with a distinctive central nervous system involvement.

A 52-year-old man with large cell non-Hodgkin's lymphoma developed a unique pattern of central nervous system involvement by lymphoma while in apparent systemic remission. Despite intermittent neurological episodes suggestive of CNS involvement by lymphoma no evidence of CNS lymphoma was found on repeated cerebrospinal fluid and brain CT scan examinations. At necropsy widespread occlusion of cerebral blood vessels by malignant lymphoid cells was observed with extensive tissue necrosis and haemorrhages. Leukaemic involvement of peripheral blood was not detected on repeated blood film examinations during life.

Brain↗
PubMed1986

Hemoglobin Woodville: alpha (2)6(A4) aspartic acid----tyrosine.

Hemoglobin Woodville was detected in a Vietnamese woman during antenatal and cord blood screening programs for families of South East Asian origin. The variant constitutes 9% of total hemoglobin and structural analysis demonstrated the substitution alpha 6 Asp----Tyr. Hematological data on the proposita were normal. No apparent clinical or pathological findings were associated with this abnormal hemoglobin.

Adult↗
PubMed1986

DNA binding by adriamycin, melphalan, cis-dichloro-diammineplatinum (II) and nornitrogen mustard assessed by restriction enzyme block.

The ability of a number of DNA binding drugs to block the action of selected restriction enzymes has been used to determine the nucleotide base binding preference of these drugs. The three alkylating agents studied all displayed guanine-cytosine (G-C) base binding preference which accords with previous results for cis-DDP and with the preferred sites of alkylation being the N7 and O6 of guanine bases. Adriamycin was markedly more reactive in this assay system compared to the alkylating drugs and in contrast to these drugs showed an adenine-thymine (A-T) base binding preference.

Cisplatin↗