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Biomedical subjects

R E Champlin

Publications and source records attributed to R E Champlin.

At least 109 records · Page 6Linked to original sources
PubMed1995

Radiation dose distribution within the bone marrow of patients receiving holmium-166-labeled-phosphonate for marrow ablation.

The primary objective of this work was to estimate the absorbed dose distribution to the bone marrow of six multiple myeloma patients who received holmium-166 (166Ho) DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid) for the purpose of bone marrow ablation. A methodology based on gamma camera images was developed to estimate the regional absorbed dose distributions delivered to the bone marrow, and this was compared with values calculated from the MIRD technique and bone marrow biopsies. The activity concentration in various skeletal regions was calculated from the activity in the region of interest (ROI) drawn on whole body gamma camera images, and the mass of bone in each ROI was derived from a dual x-ray absorptiometry image. The radiation absorbed dose to the bone marrow was calculated from this activity concentration using an adaptation of Bragg-Gray cavity theory. The radiation absorbed dose delivered to the bone marrow in the six patients calculated from the MIRD "S" factors ranged from 15.0 to 46.3 Gy. The gamma camera measured activity concentration in skeletal regions predominantly composed of trabecular bone was approximately five to six times higher than that in cortical regions. The skeletal activity concentration in each patient ranged from highs in such regions as the ribs to lows in such regions as the shin and foot by a factor of nearly 20, producing a heterogeneous distribution of absorbed dose within the marrow. Dose volume histograms calculated for these patients indicated that 15%-20% of the marrow received an absorbed dose significantly larger than the average value, while 5%-10% of the marrow received a substantially lower dose. Weighted mean dose estimates from the regional technique were typically 30% greater than the average dose estimates calculated with the MIRD "S" factors. Finally, absorbed dose estimates for the marrow calculated from the regional technique correlated more closely with the clinical response of blood cells and abnormal proteins measured in bone marrow aspirates and peripheral blood samples than estimates from the MIRD "S" factors.

Absorptiometry, Photon↗
PubMed1995

Pharmacokinetics, dosimetry and toxicity of holmium-166-DOTMP for bone marrow ablation in multiple myeloma.

UNLABELLED: In this Phase I clinical trial, six multiple myeloma patients who had not responded to conventional therapy and were scheduled for bone marrow transplantation received a bone-seeking radiopharmaceutical for bone marrow ablation. The pharmacokinetics, dosimetry, and toxicity of this radiopharmaceutical were studied. METHODS: Patients received from 519 mCi to 2.1 Ci (19.2 GBq to 77.7 GBq) of holmium-166 (166Ho) complexed with a bone-seeking agent, DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid). The reproducibility of pharmacokinetics from multiple injections of 166Ho-DOTMP administered to these myeloma patients was demonstrated from blood (r2 = 0.926) and whole-body retention (r2 = 0.983), which allowed therapeutic parameters to be determined from a diagnostic study. RESULTS: Over 50% of the 166Ho-DOTMP injected dose was excreted within 2-3 hr postinjection, increasing to 75%-85% over a 24-hr period. Rapid blood clearance minimized radiation dose to nontarget tissue: less than 10% of the injected activity was retained in the blood pool at 1 hr postinjection, and less than 2% remained after 5 hr. The total radiation absorbed dose delivered to the bone marrow for the six patients ranged from 7.9 Gy to 41.4 Gy. CONCLUSION: All patients demonstrated severe bone marrow toxicity with a white blood cell (WBC) count < 1,000 cells/microliters, two patients exhibited marrow ablation (WBC count < 100 cells/microliters), and no other toxicity > or = grade 2 was observed in any of the patients.

Bone Marrow↗
PubMed1995

Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus disease in adult bone marrow transplant recipients.

Respiratory syncytial virus (RSV) infections in adult BMT recipients are frequently complicated by fatal pneumonias. Therapy of RSV pneumonia with aerosolized ribavirin alone has been reported to be associated with a 70% mortality rate. Because immune globulin therapy has been reported to be beneficial, we conducted a prospective trial of combination therapy with aerosolized ribavirin and intravenous immunoglobulin (IVIG). Aerosolized ribavirin was administered at 20 mg/ml for 18 h a day and IVIG was administered at 500 mg/kg every other day for the length of ribavirin therapy. Four lots of IVIG were chosen with RSV microneutralization Ab titers of 1:2048 to 1:8102. Between 8 January and 3 March 1993, during a community outbreak, 19 (45%) of 42 hospitalized adult BMT recipients with an acute respiratory illness were documented to have RSV disease. Two-thirds of these infections were hospital-acquired. All 19 patients presented with signs and symptoms of an upper respiratory tract illness. Sixteen patients developed pneumonia. The mortality was 22% in nine patients with pneumonia in whom therapy was initiated prior to the onset of profound respiratory failure. In contrast, the mortality was 100% in three patients with pneumonia in whom therapy was initiated within 24 h of respiratory failure requiring mechanical ventilation and in four untreated patients. We conclude that RSV may cause devastating outbreaks of severe pneumonia among hospitalized adult BMT recipients. Early diagnosis and combination therapy with ribavirin and IVIG was associated with a favorable outcome.

Administration, Inhalation↗
PubMed1995

Prevention of graft-versus-host disease with anti-CD5 ricin A chain immunotoxin after CD3-depleted HLA-nonidentical marrow transplantation in pediatric leukemia patients.

To determine if partial T cell depletion and intensive post-transplant immunosuppression is effective for the prevention of graft-versus-host disease (GVHD) in pediatric recipients of HLA-non-identical marrow transplants, 10 children with leukemia received high-dose thiotepa, cyclophosphamide and total body irradiation followed by transplantation of CD3-depleted marrow from matched unrelated or one-antigen mismatched related adult donors. To maximize the number of stem cells infused, a large volume (1-1.51) of marrow was harvested from the donors. After immunopurging, the marrow infused contained a median of 3.7 x 10(6) CD34+ cells/kg, 1.4 x 10(6) CD3+ cells/kg, and 1.6 x 10(6) CD5+ cells/kg as assessed by flow cytometry. Cyclosporine, methylprednisolone and anti-CD4 ricin A chain immunotoxin (XZ-CD5) were used for prevention of GVHD post-transplant. All patients achieved an ANC > 0.5 x 10(9)/l. No patient developed capillary leak syndrome or renal failure from XZ-CD5. Five developed grade 2-4 acute GVHD, and all responded to treatment with steroids. Five of nine evaluable patients developed chronic GVHD. Two patients relapsed, but the most common cause of death was infection with or without chronic GVHD. Four patients survive 10+ to 27+ months post-transplant. XZ-CD5 is well-tolerated in T cell-depleted marrow transplant recipients. However, partial T cell depletion and intensive post-transplant immunosuppression did not prevent moderate acute GVHD or chronic GVHD. This may have been due to the high number of T cells infused with the marrow.

Adolescent↗
PubMed1994

BCR-ABL protein expression in peripheral blood cells of chronic myelogenous leukemia patients undergoing therapy.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome (Ph1) in more than 95% of these patients. The Ph1 and the resulting BCR-ABL fused genes are markers for this type of leukemia. In CML, the product of the fused BCR-ABL gene is typically a protein of approximately 2,000 amino acids termed P210 BCR-ABL. We have developed an assay for the BCR-ABL protein involving Western blotting of circulating white blood cells (WBC) with an anti-ABL monoclonal antibody that can detect P210 BCR-ABL and P145 ABL in peripheral blood cells from chronic phase Ph1-positive leukemia patients. This assay was used to analyze the BCR-ABL protein content of circulating WBC from CML patients before and after various treatments. In parallel to changes in percentages of Ph1-positive blood cells as determined by cytogenetic analyses of bone marrow samples, BCR-ABL protein expression in blood cells decreased or increased as patients entered remission or underwent relapse. Of interest, six Ph1-negative CML patients were BCR-ABL protein-positive. All except one had a rearrangement in the major breakpoint cluster region and that patient expressed P185 BCR-ABL and not P210. Our results indicate that the BCR-ABL Western blotting assay has clinical applications for both diagnosis and prospective evaluation of Ph1-positive and Ph1-negative CML patients.

Fusion Proteins, bcr-abl↗
PubMed1994

Identical-twin bone marrow transplants for leukemia.

OBJECTIVE: To compare outcomes of identical-twin with HLA-identical sibling bone marrow transplants for leukemia. DESIGN: Matched-pair analysis comparing relapse, treatment-related mortality, and leukemia-free survival in cohorts matched for disease and variables correlated with transplant outcome, with and without adjustment for graft-versus-host disease. SETTING: 163 institutions worldwide between 1978 and 1990, reporting to the International Bone Marrow Transplant Registry. PARTICIPANTS: 103 identical-twin transplants: 24 for acute lymphoblastic leukemia (ALL) in first remission, 45 for acute myelogenous leukemia (AML) in first remission, and 34 for chronic myelogenous leukemia (CML) in first chronic phase. Results were compared with those in 1030 concurrent HLA-identical sibling transplants matched for prognostic factors. RESULTS: Three-year probabilities of relapse after identical-twin compared with HLA-identical sibling transplants were as follows: ALL, 36% (95% CI, 17% to 55%) compared with 26% (CI, 20% to 32%); AML, 52% (CI, 37% to 67%) compared with 16% (CI, 12% to 20%); and CML, 40% (CI, 23% to 57%) compared with 7% (CI, 4% to 10%). Increased relapse risks in AML and CML persisted after adjusting for graft-versus-host disease (relative risk, 3.1 [CI, 1.9 to 5.1] and 5.5 [CI, 2.8 to 11.0], respectively). Although twins had less treatment-related mortality than HLA-identical siblings, leukemia-free survival was similar. Three-year leukemia-free survival probabilities after twin compared with HLA-identical sibling transplants were as follows: ALL, 57% (CI, 37% to 77%) compared with 58% (CI, 52% to 64%); AML, 42% (CI, 27% to 57%) compared with 55% (CI, 50% to 60%); and CML, 59% (CI, 42% to 76%) compared with 61% (CI, 56% to 66%). CONCLUSIONS: Identical-twin transplants in AML and CML are associated with increased relapse risk compared with HLA-identical sibling transplants. A similar trend was observed in ALL but was not statistically significant. Increased relapse in twin transplants is not explained by lack of graft-versus-host disease. Leukemia-free survival after twin and HLA-identical sibling transplants is similar because increased relapse in twins is offset by decreased treatment-related mortality.

Bone Marrow Transplantation↗
PubMed1994

Analysis of interphase cells for the Philadelphia translocation using painting probe made by inter-Alu-polymerase chain reaction from a radiation hybrid.

Fluorescence in situ hybridization (FISH) probe for the identification of the Philadelphia (Ph) translocation [t(9;22) (q34;q11)] in chronic myelogenous leukemia cells was developed by inter-Alu-polymerase chain reaction of DNA from an interspecific somatic cell hybrid containing approximately 5 Mb of human DNA covering the ABL gene region on human chromosome 9q34. This probe was large enough to be effective in identifying the genomic domains yet small enough to resolve them in more than 90% of bone marrow interphase cells. Combination of the probe with a cosmid contig probe for the BCR region of chromosome 22 in two-color FISH reduced the frequency of false-positive identification of the Ph chromosome to less than 1%. The procedure allows detection of as few as 1% Ph+ cells independent of the cycling status or BCR/ABL expression level of cells, and the quantitation of non-Ph chromosome-containing interphase nuclei in the marrow of patients judged 100% Ph+ by standard cytogenetics.

Humans↗
PubMed1994

B cell dysfunction after bone marrow transplantation is associated with decreased Ca2+ flux upon membrane Ig crosslinking.

Patients undergoing bone marrow transplantation have a long-lasting defect of B cell-mediated immunity. Both quantitative (decreased blood B cell counts) and qualitative (decreased Ig production) abnormalities of B cells have been described. To better understand the mechanism of the qualitative defect and its potential relation to B cell immaturity, we studied the in vitro responsiveness of B cells to polyclonal stimuli in patients at 2-12 months post-transplant and in normal neonates. Several key steps of the B cell program were deficient in the patients while they were relatively normal in the neonates. These included (i) early activation as assessed by Ca2+ flux; (ii) late activation as assessed by the increase in cell size and upregulation of the activation antigens CD25 and CD71; and (iii) proliferation as assessed by the number of cycling cells after stimulation. We conclude that the functional B cell defect during the early (< 1 year) post-transplant period extends back to the level of early activation and cannot be simply attributed to the relative immaturity of post-transplant B cells.

Adolescent↗
PubMed1994

Thiotepa, busulfan, and cyclophosphamide as a preparative regimen for marrow transplantation: risk factors for early regimen-related toxicity.

One hundred twenty-seven adults with advanced hematologic malignancies received thiotepa 450-750 mg/m2, busulfan 10 or 12 mg/kg, and cyclophosphamide 120 or 150 mg/kg as a preparative regimen for autologous (86 patients) or allogeneic (41 patients) marrow transplantation. Early regimen-related toxicity (RRT) was scored according to the Seattle toxicity grading system. Grade 1-4 RRT occurred in 94% of the patients. Grade 3-4 RRT was noted in 19 patients (9% of the autologous and 27% of the allogeneic marrow recipients) and included 6% hepatic, 5% pulmonary, 3% renal, 2% mucosal, 2% bladder, 2% cardiac, and 1% CNS toxicity at the grade 3 or 4 level. No patient experienced life-threatening or fatal gastrointestinal or cutaneous toxicity. A stepwise logistic regression analysis suggested that the higher busulfan dose, Zubrod performance status of 2 or 3, and ten or more previous cycles of chemotherapy were factors predictive of grade 3-4 RRT. The regimen-related mortality for all patients was 8% (95% Cl 4-14%). The incidence and spectrum of RRT for this novel drug combination are similar to those reported for the standard preparative regimens. Heavily pretreated patients with poor performance status receiving the higher busulfan dose have a higher incidence of severe or fatal RRT.

Adult↗
PubMed1994

Evaluation of the neurobehavioral functioning of patients before, during, and after bone marrow transplantation.

PURPOSE: To evaluate the cognitive and emotional functioning of patients undergoing bone marrow transplantation (BMT) in the protected environment (PE). PATIENTS AND METHODS: Patients were given tests of cognition and mood before their hospitalization in the PE, after 2 weeks, at discharge, and at 8 months post-BMT. Locus of control, degree of social support, previous biotherapy, and on-treatment psychiatric consultation were also analyzed. RESULTS: Before BMT, 20% of patients had mild cognitive dysfunction, and nearly 40% had significant anxiety. Although few patients developed problems with cognition or mood during the study, short-term memory deficits nearly doubled at follow-up compared with baseline. Anxiety decreased significantly during hospitalization and remained low at follow-up. In contrast, depression increased throughout hospitalization, but decreased at follow-up. Pre-BMT emotional status and cognitive functioning were highly related to long-term outcome. Type of BMT, locus of control, and degree of social support were related to psychologic distress and cognitive functioning, both during and after BMT. Patient age was not a predictor of neurobehavioral symptoms during or after BMT. CONCLUSION: Pretransplant emotional and cognitive functioning are important determinants of long-term outcome and quality of life (QOL) in BMT patients. In addition, a few patients undergoing BMT develop short-term memory difficulties and mood disturbance that may persist. Pretransplant identification of patients at risk for neurobehavioral difficulties may guide early interventions during hospitalization. Posttransplant assessment may then be used to develop rehabilitation programs and other interventions for individuals with persisting complaints.

Adult↗
PubMed1994

Large-scale preparation of highly purified, frozen/thawed CD34+, HLA-DR- hematopoietic progenitor cells by sequential immunoadsorption (CEPRATE SC) and fluorescence-activated cell sorting: implications for gene transduction and/or transplantation.

The purification of early hematopoietic progenitor cells for autologous transplantation is based on two rationales: (1) elimination of clonogenic tumor cells, and/or (2) gene transfer into indefinitely self-replicating hematopoietic stem cells. Primitive CD34+ stem cells can be separated from more mature stem cells, or probably from clonogenic tumor cells, by differences in HLA-DR surface antigen expression. The objective of this study was to establish a large-scale technique for purification of CD34+, DR- progenitor cells from a large volume marrow harvest. In five different experiments, CD34+ cells were purified to between 76% and 91% by avidin-biotin immunoadsorption (CEPRATE SC) as a first step. This was followed by fluorescence-activated cell sorting to separate DR+ and DR- cells, which resulted in the generation of between 1.75 and 11.3 x 10(5) CD34+, DR- cells. The purity of DR- cells increased from between 0.5% and 4.3% in the immuno-adsorbed fraction up to 99% in the DR- sorted fraction. As shown in a single experiment, the purity of CD34+, DR- cells immediately after thawing increased from 0.01% to 94.3% while losing 99% of those early progenitor cells during the multistep purification procedure. We were able to physically separate one CD34+, DR- cell from up to 8000 nucleated cells in the prepurified cell suspension. One million highly purified CD34+, DR- progenitor cells is potentially an adequate cell dose for autologous transplantation equivalent to what is contained in an unselected and functioning marrow autograft.

Antigens, CD↗
PubMed1994

Evaluation of anti-CD5 ricin A chain immunoconjugate for prevention of acute graft-vs.-host disease after HLA-identical marrow transplantation.

Anti-CD5 ricin A chain immunoconjugate (XZ-CD5) is an immunotoxin that inhibits proliferative and cytotoxic responses to alloantigen in vitro and has activity in the treatment of acute graft-vs.-host disease (GVHD). To determine if XZ-CD5 could be used to prevent acute GVHD, 11 adult recipients of HLA-identical allogeneic marrow received XZ-CD5 0.1 mg kg-1 day-1 intravenously with high-dose methyl-prednisolone for 10, 14 or 17 doses early post-transplant. Six additional patients received 17 doses of XZ-CD5 and cyclosporine (CSA). All patients engrafted. Severe capillary leak syndrome was the most common serious toxicity and occurred more frequently in patients receiving CSA (5/5 vs. 3/11, P = 0.03). All evaluable patients developed acute GVHD; 88% had grade II-IV GVHD. Flow cytometric analysis demonstrated a substantial number of circulating CD5+ and CD3+ lymphocytes during and early after administration of XZ-CD5. These results suggest that the immunotoxin did not eliminate alloreactive T cells in this setting.

Acute Disease↗
PubMed1994

Radiobiology of total body radiation.

The first bone marrow transplants (BMTs) in human patients were performed after conditioning with total body irradiation (TBI). TBI remains an important part of BMT protocols. The morbidity and mortality of BMT remains significant, but can be decreased by the introduction of optimized TBI regimens. This requires dosimetric control and a detailed analysis and description of the physics of the TBI procedure in every BMT center that utilizes TBI. Recommendations for such procedures are given. Radiobiological models are of help in developing less toxic TBI procedures, but can only be effective after dosimetric control has been obtained and if the influence of other variables on the outcome of BMT are taken into account. Fractionated TBI (fraction size over 3.0 Gy or higher) appears to be more effective and better tolerated than single fraction TBI. Lung shielding is possible during TBI. Smaller organs or organs that cannot be imaged easily are not recommended for shielding. Radiolabeled immunoglobulins are but low molecular weight bone seeking radioisotopes and are not expected to improve the therapeutic ratio of TBI. Other variables in BMT are more difficult to quantify and model than TBI (e.g. high-dose chemotherapy, graft-versus-host disease) and will be more difficult to optimize.

Animals↗
PubMed1994

Influenza A virus infections among hospitalized adult bone marrow transplant recipients.

Although influenza virus continues to cause annual epidemics of respiratory diseases, surprisingly little is known about the frequency and clinical course of influenza among adult patients with cancer. During the 1991-92 influenza epidemic in Houston, Texas, we followed all adult BMT recipients hospitalized at M.D. Anderson Cancer Center. None of these 68 patients had received prophylaxis for influenza. Influenza virus type A was isolated from 8 (29%) of 28 BMT recipients with an acute respiratory illness. Five of these infections were acquired in the hospital. All 8 patients presented with an upper respiratory tract illness. In 6 patients, the infection was complicated by pneumonia. The frequency of influenza was similar among autologous (5 of 18) and allogeneic (3 of 10) BMT recipients. The risk of developing pneumonia was not related to the type of transplant or to the engraftment status. All patients received broad-spectrum antibiotics. The 2 patients who did not develop pneumonia also received amantadine. The mortality with pneumonia was 17%. During community outbreaks, influenza is a frequent cause of acute respiratory illness among hospitalized adult BMT recipients and is frequently complicated by pneumonia. Studies are needed to define the optimal means of preventing and treating influenza in BMT recipients.

Adult↗