Augmentation of natural chimerism with donor bone marrow in orthotopic liver recipients.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
G Rosner
Publications and source records attributed to G Rosner.
Randomized, double-blind comparison of a prochlorperazine-based versus a metoclopramide-based antiemetic regimen in patients undergoing autologous bone marrow transplantation.
BACKGROUND: Highly emetogenic combination alkylator therapy is routinely used in autologous bone marrow transplantation for treatment of eligible patients with solid tumors. Antiemetic therapy remains less than optimal in this setting. METHODS: One hundred twenty-six patients with cancer receiving high dose cisplatin, cyclophosphamide, and carmustine with autologous bone marrow support were randomized to receive one of four double-blinded antiemetic regimens: 4-day continuous infusion prochlorperazine (6 mg/m2 intravenous [i.v.] loading dose followed by 1.5 mg/m2/hour) or metoclopramide (80 mg/m2 iv loading dose followed by 20 mg/m2/hr) each with either dronabinol 5 mg/m2 or placebo capsules for two doses before carmustine on the last day of chemotherapy. All subjects received scheduled lorazepam and diphenhydramine throughout the 4-day study period. Efficacy was measured by the Emetic Process Rating Scale and the Rhodes Index of Nausea and Vomiting (INV) Form 2. RESULTS: One hundred six patients completed the study and were fully evaluable. The median number of emetic episodes on the metoclopramide study arm were: 1 (0-7, day -6), 1 (0-6, day -5), 2 (0-9, day -4), and 2 (0-10, with dronabinol day -3) or 2 (0-7, no dronabinol day -3) and on the prochlorperazine study arm were: 4 (0-12, day -6), 0 (0-8, day -5), 0 (0-12, day -4) and 2.5 (0-9, with dronabinol day -3) or 2 (0-12, no dronabinol day -3). Metoclopramide was significantly better on the first day of therapy (day -6, P < .002) and prochlorperazine was significantly better on the third day of therapy (day -4, P < 0.002). There was no significant difference among any of the four arms on the last day of chemotherapy (day -3), or when the median number of emetic episodes over the total study period were compared. The patients' assessment of nausea, vomiting, and retching on the INV Form 2 was consistent with the observer ratings. Toxicities requiring dose reduction or discontinuation of antiemetic drugs included diarrhea, cardiac arrhythmias, sedation, anxiety, and akathisia. CONCLUSIONS: Both metoclopramide and prochlorperazine in combination with lorazepam and diphenhydramine offer good control of nausea and vomiting although the sedation and low risk for cardiac toxicity limit the regimen to an inpatient setting with close monitoring. No regimen was clearly superior during the entire treatment period but prochlorperazine offered more consistent control after the first day.
Adult↗
Halothane, but not alpha-chloralose, blocks potassium-evoked cortical spreading depression in cats.
The effects of two anesthetics, halothane and alpha-chloralose, on induction of spreading depression and on extracellular glutamate elevation after intracortical potassium administration were investigated in artificially ventilated (30% oxygen/70% nitrous oxide) cats. High potassium concentrations were achieved using either direct KCl injections (7 microliters, 150 mM via a micropipette) or microdialysis by supplementing 100, 300 or 500 mM KCl, respectively, for 10 min to the perfusion solution (Ringer's). Changes of the cortical DC potential were recorded adjacent (1-2 mm: electrode DC1) and distant (6-7 mm: electrode DC2) to the injection site. Either under halothane (0.75% in the respiratory gas mixture) or under alpha-chloralose (60 mg/kg i.v.) anesthesia, prolonged negative shifts of the DC potential reflecting the elevated potassium levels after KCl injection were measured near the injection site (electrode DC1). In contrast, spreading depressions (transient short DC deflections) were almost exclusively observed under alpha-chloralose. Spreading depressions recorded with electrode DC1 were superimposed on the prolonged negative DC shifts and they propagated frequently to the more distant site (DC2). Upon KCl administration, dose dependent elevations of extracellular glutamate were measured. These elevations were not significantly altered by the type of anesthesia. Our results suggest that in cats, spreading depression induction is affected by anesthesia, i.e., spreading depression induction is inhibited by halothane as compared to alpha-chloralose. Furthermore, factors other than glutamate or high potassium seem to contribute to spreading depression induction.
Animals↗
Graft failure after an umbilical cord blood transplant in a patient with severe aplastic anemia.
Explore the source record for details and available documents.
Anemia, Aplastic↗
Unexpectedly slow decrease of Chernobyl-derived radiocesium in air and deposition in Bavaria/Germany.
Explore the source record for details and available documents.
Air Pollutants, Radioactive↗
Population pharmacodynamic study of amonafide: a Cancer and Leukemia Group B study.
PURPOSE: To determine if variability in toxicity of amonafide during phase II trials could be correlated with pharmacokinetic variability. PATIENTS AND METHODS: Seventy-three patients enrolled onto three Cancer and Leukemia Group B (CALGB) phase II trials of amonafide (300 mg/m2 daily for 5 days) were studied, using a limited sampling strategy (45 minutes and 24 hours) to estimate the amonafide area under the plasma concentration-time curve (AUC). Concentrations of N-acetyl-amonafide, an active metabolite, were also determined. RESULTS: The primary determinant of toxicity at a fixed dose of amonafide was the extent of N-acetylation. Fast acetylators (36% of patients) had significantly greater toxicity than slow acetylators (64% of patients), with median WBC nadirs of 500/microL and 3,400/microL, respectively (P < or = .001). In a multivariate analysis, lower pretreatment WBC count, lower albumin level, and nonwhite race were also independently associated with toxicity. Further analysis of interracial differences demonstrated that minority women had slower clearance of amonafide (P = .026) and a higher incidence of grade 4 leukopenia (P = .042). CONCLUSION: The highly variable toxicity of amonafide is primarily due to genetic differences in N-acetylation. Other genetic (race) and acquired factors (baseline WBC count and albumin level) also appear to influence the extent of toxicity observed following administration of this agent.
Acetylation↗
Detection of tumor cells in the bone marrow of stage IV breast cancer patients receiving high-dose chemotherapy: the role of induction chemotherapy.
High-dose chemotherapy and hematopoietic support can produce long-term, disease-free remissions in selected patients with metastatic breast cancer. Occult bone marrow involvement may contribute to late relapse. We used five anti-breast cancer monoclonal antibodies and flow cytometry with cytological analysis of sorted immunostained cells to detect tumor cells in the bone marrow in two cohorts of patients. The first (Upfront) cohort was treated with a single course of high-dose chemotherapy and autologous bone marrow support (ABMS) without induction chemotherapy. The second (AFM) cohort received induction chemotherapy with doxorubicin, 5-fluorouracil and methotrexate prior to high-dose chemotherapy and ABMS. Of the 15 Upfront patients, seven (47%) had immunostained cells in the harvested bone marrow by flow cytometry and 8/15 (53%) had positive cytologies. Of the 49 AFM patients studied, nine (18%) had immunostained cells in the bone marrow, and only 1/49 (2%) had positive cytologies. Induction chemotherapy significantly decreased bone marrow contamination as detected by flow cytometry and cytology in patients with breast cancer. The detection of immunostained cells in the bone marrow did not predict for relapse or overall survival.
Antineoplastic Combined Chemotherapy Protocols↗
Combination versus single agent therapy in effecting complete therapeutic response in human bladder cancer: analysis of cisplatin and/or 5-fluorouracil in an in vivo survival model.
An in vivo study of cisplatin (CDDP) and 5-fluorouracil (5FU) cytotoxicity was performed using a multidose matrix with a human bladder transitional cell carcinoma xenograft tumor line (DU4284) tested by subrenal capsule assay in 154 nude mice (NM-SRCA). Statistical analysis of initial growth inhibition at 20 days and host survival demonstrates therapeutic, cooperative interaction. Toxic doses of either CDDP or 5FU alone as well as low-dose combinations provided modest or no survival benefit. The single dose of CDDP (7 mg/kg) and of 5FU (100 mg/kg) was best (by analysis of efficacy and toxicity) of those tested and caused > 97% initial regression. While 94% of controls incurred tumor deaths by 225 days, 75% treated at this dose were tumor free and likely cured. Our conclusions were: (a) NM-SRCA human xenograft testing is excellent for rapid in vivo screening of promising treatment strategies to evaluate for efficacy at acceptable toxicity, but confirmation of true therapeutic impact should be sought by correlating initial growth inhibition with host survival; (b) enhanced survival seen only when CDDP/5FU are used together (versus either single agent) supports the value of pursuing histiotype-specific screening of potentially synergistic drug combinations; and (c) of clinical relevance, human transitional cell carcinoma is now identified as a histiotype in which a therapeutic, cooperative interaction between CDDP/5FU has been demonstrated in vivo.
Animals↗
Dynamic penumbra demonstrated by sequential multitracer PET after middle cerebral artery occlusion in cats.
Experimental models of focal cerebral ischemia have provided important data on early circulatory and biochemical changes, but typically their correspondence with metabolic and hemodynamic findings in stroke patients has been poor. To fill the gap between experimental studies at early time points and rather late clinical studies, we repeatedly measured CBF, CMRO2, oxygen extraction fraction (OEF), cerebral blood volume (CBV), and CMRglc in six cats before and up to 24 h after permanent middle cerebral artery (MCA) occlusion (MCAO), using the 15O steady state and [18F]fluorodeoxy-glucose methods and a high-resolution positron emission tomography (PET) scanner. Likewise, three sham-operated control cats were studied during the same period. Final infarct size was determined on serial histologic sections. In the areas of final glucose metabolic depression that were slightly larger than the histologic infarcts, mean CBF dropped to approximately 40% of control values immediately on arterial occlusion. If further decreased to < 20% during the course of the experiment. This progressive ischemia was most conspicuous in border zones. CMRO2 fell to a lesser degree (55%), eventually reaching approximately 25% of its control level. At early stages, OEF increased mainly in the center of ischemia. With time, areas of increased OEF moved from the center to the periphery of the MCA territory. Concurrently, progressive secondary decreases in OEF in conjunction with further reductions of CBF and CMRO2 indicated the development of central necrosis. The findings are highly suggestive of a dynamic penumbra. In five cats with complete MCA infarcts, CBF decreased and OEF increased in the contralateral hemisphere after 24 h, suggesting whole-brain damage. This effect may be explained by the widespread brain edema found histologically in addition to the nonspecific CBF reductions and OEF elevations observed also in the sham-operated controls after 1 day in the experimental condition. In one cat, cortical OEF increased only transiently. Normal CMRO2 and CMRglc were eventually restored, and the final infarct was small. This study demonstrates that acute regional pathophysiologic changes can be repeatedly assessed by multivariate PET in cats. Viable tissue can be detected up to several hours after MCA occlusion, and the transition of misery-perfused regions into necrosis or preserved tissue can be followed over time. The present results support the concept of a dynamic penumbra, in which for up to 24 h tissue damage spreads progressively from the center to the periphery of ischemia. Sequential high-resolution PET provides insight into the dynamics of regional pathophysiology and may thus further the development of rational therapeutic strategies.
Animals↗
[The reliability of data in ecopathologic investigations].
The reliability of information gathered during ecopathological investigations is a constant concern, requiring a rigorous strategy to limit risks of error. These risks are all the more important when there are human shortcomings (farmer or investigator) as opposed to technical shortcomings (results of laboratory tests). A dual strategy can be implemented to guarantee reliability: ensuring reliable collection of data by attention to the human element (selection of farmers, training of investigators, organisation of professional partners), and ensuring the collection of reliable data by attention to facts (quality of the questionnaire, harmonization of procedures, objective interpretation of qualitative findings, quality of data-processing support, timing of data collection, verification procedures). The argument is supported by numerous examples provided by teams of ecopathologists.
Animals↗
Collection of data by non-professionals in ecopathology surveys.
In the course of the surveys carried out by the Centre d'Ecopathologie Animale, the collection of data is performed by interviewers who are specialists in cattle breeding (eg, technicians, veterinary surgeons, and inseminators). This practice improves the reliability of the collected data but gives rise to constraints. To get round these difficulties, a number of methods improving the feasability of surveys by numerous and various interviewers have been developed and adapted: setting up surveys by interdisciplinary groups; preliminary surveys and validation of survey procedures and aids; and training interviewers about the ecopathological approach and the constraints of data collection.
Animal Diseases↗
Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: a Cancer and Leukemia Group B study.
BACKGROUND: Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression. PURPOSE: The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclophosphamide administered every 2 weeks with GM-CSF support. METHODS: For this trial by the Cancer and Leukemia Group B (CALGB), cohorts of patients were treated with cyclophosphamide as a 1-hour intravenous infusion every 14 days; GM-CSF was given subcutaneously on days 3-10. Four dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and three dose levels of GM-CSF (2.5, 5.0, and 10.0 micrograms/kg per day) were evaluated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 and minimal prior radiotherapy were eligible for analysis. Drug clearance and area under the curve for plasma drug concentration x time (AUC) were estimated at completion of the infusion and at 4 and 24 hours after the start of the infusion. RESULTS: Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more resulted in neutropenia (absolute neutrophil counts < 100/microL) in all cycles of therapy. At those doses, blood cell count recovery adequate for re-treatment occurred in 67%-85% of cycles (median, 16 days). Doses of 6.0 g/m2 were associated with the greatest degree of myelosuppression and frequent hospitalization (88% of cycles); requirements for blood transfusion prohibited further dose escalation. Nonhematologic toxic effects were tolerable, with two episodes of reversible cardiotoxicity and four episodes of hemorrhagic cystitis that precluded further therapy. Degree of myelosuppression was not correlated with cyclophosphamide AUC or clearance. CONCLUSIONS: The recommended phase II dose of cyclophosphamide is 4.5 g/m2 administered every 2 weeks with GM-CSF given at 5.0 micrograms/kg per day of GM-CSF. Our results suggest that, with GM-CSF support, high cumulative doses of cyclophosphamide can be given to achieve optimal dose intensity, with reproducible blood cell count recovery and without the need for autologous bone marrow transplantation. IMPLICATIONS: Phase II studies of this intensive regimen in malignant diseases sensitive to alkylating agents are currently being done in CALGB.
Adult↗
Comparative effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on priming peripheral blood progenitor cells for use with autologous bone marrow after high-dose chemotherapy.
Two hematopoietic colony-stimulating factors, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), have been shown to accelerate leukocyte and neutrophil recovery after high-dose chemotherapy and autologous bone marrow (BM) support. Despite their use, a prolonged period of absolute leukopenia persists during which infections and other complications of transplantation occur. We collected large numbers of peripheral blood (PB) progenitors after CSF administration using either G-CSF or GM-CSF and tested their ability to affect hematopoietic reconstitution and resource utilization in patients undergoing high-dose chemotherapy and autologous BM support. Patients with breast cancer or melanoma undergoing high-dose chemotherapy and autologous BM support were studied in sequential nonrandomized trials. After identical high-dose chemotherapy, patients received either BM alone, with no CSF; BM with either G-CSF or GM-CSF; or BM with G-CSF or GM-CSF and G-CSF or GM-CSF primed peripheral blood progenitor cells (PBPC). Hematopoietic reconstitution, as well as resource utilization, was monitored in these patients. The use of CSF-primed PBPC led to a highly significant reduction in the duration of leukopenia with a white blood cell (WBC) count under 100 and 200 cells/mL, and neutrophil count under 100 and 200 cells/mL with both GM- and G-CSF primed PB progenitor cells, compared with the use of the CSF with BM or with historical controls using BM alone. In addition, the use of CSF-primed PBPC resulted in a significant reduction in median number of antibiotics used, days in the Bone Marrow Transplant Unit, and hospital resources used. Patients receiving G-CSF primed PBPC also experienced a reduction in the median number of days in the hospital, red blood cell (RBC) transfusions, platelet transfusions, days on antibiotics, and discounted hospital charges. Phenotypic analysis of the CSF-primed PBPC indicated the presence of cells bearing antigens associated with both early and late hematopoietic progenitor cells. The use of CSF-primed PBPC can significantly improve hematopoietic recovery after high-dose chemotherapy and autologous BM support. In addition, the use of G-CSF-primed PBPC was associated with a significant reduction in hospital resource utilization, and a reduction in hospital charges.
Adult↗
A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model.
This laboratory has previously used a window chamber model to measure red blood cell velocity in mammary tumors and normal granulation tissues of the F-344 rat. Because red cell flux and hematocrit more accurately reflect the oxygen carrying potential of blood, we used this model to measure these parameters. Red blood cells were labelled with fluorescein isothiocyanate, and 0.2 ml. packed cells were injected intravenously into rats bearing an 8 to 10 day old R-3230 mammary carcinoma. beta-phycoerythrin (0.15 mg.) was also injected and served as a plasma dye to outline the blood vessels. A sample of peripheral blood was then taken and analyzed by flow cytometry to determine the labeled fraction of red blood cells. Flowing tumor and normal tissue vessels were recorded onto a VCR, and these video images were used to determine vascular length and diameter, RBC flux and velocity, and hematocrit. Median vessel diameter and loge (red blood cell flux) were significantly greater in tumors than in normal tissues (p = 0.007 and p < 0.025, respectively). After controlling for these variables, the median tumor hematocrit of 19% was not significantly greater than the median normal tissue hematocrit of 15%. This technique provides a nontoxic and reproducible method that is now being used to assist in the in vivo definition of tumor oxygenation.
Animals↗
Measurement of material extravasation in microvascular networks using fluorescence video-microscopy.
We have developed a new method using fluorescence videomicroscopy to quantitate the extravasation of intravenously injected materials. This method can measure the relative plasma concentration of, and the vascular permeability to, these materials in microcirculatory preparations which contain multiple blood vessels in a field of view. The image of a tissue area containing multiple blood vessels is recorded via a SIT camera immediately before, and for an extended period after, the intravenous injection of a bolus of fluorescent test tracers. The videotape is analyzed off-line. At various time points, the light intensities of the entire tissue area and of several spots over selected vessels are measured. These measurements are then used to calculate the fluorescent light intensities arising from the tracers inside vessels (Iv) and in the interstitial region (Ii). Iv represents the relative amount of the tracers in the plasma, and Ii represents that in the interstitium. Iv and Ii are used to calculate an average permeability (P) for the vessels in the observed region. The benefit of this method is that it can be used to compare permeability of various tissues of interest or to serially evaluate changes in P in the same tissue over time. In this study, it was applied to measuring P to albumin as well as to liposomes in granulating and implanted tumor tissues in a rat skin flap window chamber. Changes in permeability to a small molecule (sulforhodamine B) before and during bradykinin application were also measured. The results of these experiments indicate that the relative plasma concentrations predicted by this method conformed well to those measured directly from blood samples, and the measured permeability values were consistent with previously published data. Therefore, this method provides a valid approach for quantitatively measuring the extravasation of intravenously injected molecular and colloidal materials in microcirculatory preparations. The method has a set of defined experimental conditions and assumptions that cannot be violated, however, or erroneous results can be obtained.
Animals↗
Elevation of neuroactive substances in the cortex of cats during prolonged focal ischemia.
Sustained accumulation of excitatory amino acids and other neuroactive substances may contribute to the delayed progression of infarction in focal ischemia. Following occlusion of the left middle cerebral artery (MCAO), extracellular amino acid and purine catabolite concentrations as well as local CBF were repeatedly monitored for up to 15 h in auditory (A) and somatosensory (SF) cortices of seven halothane-anesthetized cats using microdialysis/HPLC and hydrogen clearance. MCAO resulted in persistent reduction of local CBF, which was more severe in A (n = 6) than in SF (n = 6). Accordingly, higher transmitter amino acid and purine catabolite concentrations were found in A than in SF during ischemia. Aspartate, glutamate, and gamma-aminobutyrate (GABA) as well as hypoxanthine and inosine reached maximum levels 1-2 h after onset of ischemia (15-, 7-, 31-, 8-, and 14-fold increases, respectively). Maximum levels remained almost constant, with the exception of inosine, which decreased subsequently. Glycine seemed to increase with prolonged ischemia and reached maximum levels (10-fold) 15 h after occlusion. Adenosine peaked 30 min after occlusion (54-fold) and decreased thereafter to control levels within 1-2 h. One hour after occlusion, CBF thresholds for amino acid elevation were lower (glutamate and GABA approximately 20 ml 100 g-1 min-1 and glycine approximately 10 ml 100 g-1 min-1) than 6 and 15 h after occlusion (thresholds for all amino acids at approximately 30 ml 100 g-1 min-1). These results indicate that in prolonged ischemia, excitotoxicity is an important factor, particularly in border zones of ischemic foci.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acids↗
Large-scale oligonucleotide typing for HLA-DRB1/3/4 and HLA-DQB1 is highly accurate, specific, and reliable.
DNA typing of HLA class II alleles of the DRB1/3/4 and DQB1 loci using sequence-specific oligonucleotide probes and polymerase chain reaction-amplified DNA was used for the large-scale typing of donors for the National Marrow Donor Program unrelated donor registry. The results of quality control analysis for the first 7 months of the project show the typing to be highly accurate, specific, and reliable. The percent of correctly classified HLA oligotypes based on 1652 DRB1 and 1652 DQB1 assignments was greater than 99% for DRB1/DRB3/DRB4 and greater than 98% for DQB1. This level of accuracy is particularly remarkable because the quality control samples could not be distinguished from 9011 donor samples tested at the same time by the laboratories.
Alleles↗
Ischemia-induced accumulation of extracellular amino acids in cerebral cortex, white matter, and cerebrospinal fluid.
In a global model of brain ischemia, accumulation of amino acids was studied in the extracellular space of the auditory cortex and the internal capsule using microdialysis, and in CSF of halothane anesthetized cats. In both brain regions, blood flow determined by hydrogen clearance decreased below 10 ml/100 g/min after extracranial multiple-vessel occlusion, and extracellular potassium activity (Ke) measured in the dialysate increased significantly. A delayed rise in Ke was observed in CSF. In contrast, ischemic amino acid accumulation differed markedly between the two brain regions investigated. In cortex, transmitter amino acids glutamate, aspartate, and gamma-aminobutyric acid (GABA) rose almost immediately after onset of ischemia, and increased 30-, 25-, and 250-fold, respectively, after 2 h of ischemia. The nontransmitter amino acids taurine, alanine, and serine increased 10-, seven-, and fourfold, respectively, whereas glutamine and essential amino acids (valine, phenylalanine, isoleucine, and leucine) increased only 1.5-fold. In the internal capsule, increases in amino acids, if any, were delayed and much smaller than in cortex. The largest alteration was a fivefold elevation of GABA. In CSF, changes in amino acids were small and comparable to those in the internal capsule. Our results demonstrate that ischemia-induced extracellular amino acid accumulation is a well localized phenomenon restricted to gray matter structures that possess release and reuptake systems for these substances. We assume that amino acids diffuse slowly into adjacent while matter structures, and into CSF.
Amino Acids↗