Lack of effect of donor-recipient ABO mismatching on outcome following allogeneic hematopoietic stem cell transplantation.

Several recently published studies have suggested that patients who undergo ABO mismatched hematopoietic stem cell transplantation may be at increased risk for relapse, graft-versus-host disease, transplant-related mortality, and/or all-cause mortality. To investigate this issue further, we analyzed potential associations between the donor-recipient ABO mismatch pattern and the above outcome measures among 240 consecutive patients who underwent allogeneic hematopoietic stem cell transplantation at our institution. Our analyses uncovered no significant associations between donor-recipient ABO mismatch pattern and overall survival, event-free survival, transplant-related mortality, incidence of acute graft-versus-host disease (GVHD), or incidence of chronic GVHD. Our data do not support recent assertions that donor-recipient ABO mismatching is a major risk factor for patients undergoing allogeneic transplant, nor do they support recent assertions that ABO matching should be an important consideration in selecting allogeneic hematopoietic stem cell donors.

Relationships of physical activity with metabolic syndrome features and low-grade inflammation in adolescents.

AIMS/HYPOTHESIS: Physical activity has beneficial effects on symptoms of the metabolic syndrome and low-grade inflammation in adults. These associations have rarely been studied in adolescents. Moreover, it has not been established whether they depend on adiposity, fat localisation and adipokines. SUBJECTS, MATERIALS AND METHODS: We used cross-sectional data of 640 12-year-old adolescents participating in the Intervention Centred on Adolescents' Physical Activity and Sedentary Behaviour Study (ICAPS). Weight, height, body fat mass and WHR were measured. Metabolic syndrome components, two inflammatory markers (IL-6 and C-reactive protein), plasma leptin, adiponectin and soluble TNF-alpha receptor 1 (sTNF-alpha R1) were determined. Insulin resistance was estimated by homeostasis model assessment (HOMA) and energy expenditure due to organised leisure-time physical activity (PAE) assessed by questionnaire. RESULTS: The metabolic syndrome was present in 5.8% of the adolescents. After adjustment for sex, sexual maturity and socio-economic status, a beneficial relationship between PAE and all metabolic syndrome features was found, but only the associations with HOMA and IL-6 were independent of body fat mass and WHR. Adjusted means from the lowest to the highest tertile of PAE were 1.99, 1.80 and 1.78 for HOMA (p=0.04), and 0.88, 0.69 and 0.70 pg/ml for IL-6 (p=0.02). PAE was inversely associated with leptin, independently of body fat mass and WHR (p<10(-2)), but not with adiponectin or sTNF-alpha R1. Further adjustment for adipokines did not change the relationships of PAE with HOMA and IL-6. CONCLUSIONS/INTERPRETATION: In adolescents, physical activity is inversely related to HOMA and IL-6, independently of adiposity and fat localisation. These relationships are not accounted for by adipokines.

Measurable immune dysfunction and telomere attrition in long-term allogeneic transplant recipients.

This study was conducted to determine if the accelerated telomere attrition that occurs as a consequence of allogeneic stem cell transplantation leads to measurable functional defects. Telomere lengths in mononuclear leukocytes obtained from 15 long-term allogeneic stem cell transplant recipients and their respective donors were determined by Southern hybridization and densitometric analysis. Functional assays evaluated the ability of these cells to proliferate in response to a mitogenic stimulus and to differentiate under appropriate cytokine stimulation. Lymphocyte proliferation in response to phytohemagglutinin was determined by measurement of (3)[H]thymidine uptake. The ability of circulating myeloid cells to differentiate was determined after incubation of peripheral blood mononuclear cells with IL-3 and GM-CSF. A total of 13 patients demonstrated telomeric loss, ranging from 0.1 to 3.7 kbp. Strikingly, lymphocytes from 14 of the 15 patients demonstrated a significant decrease in proliferation when compared to their respective donors (68%+/-22, P=0.001). All patients demonstrated at least a 50% decrease in the number of myeloid colony-forming units when compared to their respective donors (P<0.0001). A decreased ability of hematopoietic cells to proliferate and differentiate is phenotypically consistent with an aged immune system. This may correlate with diminished clinically relevant immune responses to infection or vaccination, as seen in the elderly.

Economic analysis of conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer.

We performed an economic analysis of data from 180 women in a clinical trial of conventional-dose chemotherapy vs high-dose chemotherapy plus stem-cell transplantation for metastatic breast cancer responding to first-line chemotherapy. Data on resource use, including hospitalizations, medical procedures, medications, and diagnostic tests, were abstracted from subjects' clinical trial records. Resources were valued using the Medicare Fee Schedule for inpatient costs at one academic medical center and average wholesale prices for medications. Monthly costs were calculated and stratified by treatment group and clinical phase. Mean follow-up was 690 days in the transplantation group and 758 days in the conventional-dose chemotherapy group. Subjects in the transplantation group were hospitalized for more days (28.6 vs 17.8, P=0.0041) and incurred higher costs (US dollars 84055 vs US dollars 28169) than subjects receiving conventional-dose chemotherapy, with a mean difference of US dollars 55886 (95% CI, US dollars 47298-US dollars 63666). Sensitivity analyses resulted in cost differences between the treatment groups from US dollars 36528 to US dollars 75531. High-dose chemotherapy plus stem-cell transplantation resulted in substantial additional morbidity and costs at no improvement in survival. Neither the survival results nor the economic findings support the use of this procedure outside of the clinical trial setting.

Severe cutaneous ulceration following treatment with thalidomide for GVHD.

We report two cases of severe leg ulcerations in patients being treated with thalidomide for graft-versus-host disease following bone marrow transplantation. Local wound care and debridement were attempted, but one patient required skin grafting to ensure healing. We propose that this complication may be due to the antiangiogenic properties of thalidomide and urge careful attention to skin breakdown in patients being treated with this compound.

Economic consequences of alterations in platelet transfusion dose: analysis of a prospective, randomized, double-blind trial.

BACKGROUND: In recent years, decreasing financial resources led to the use of lower-dose platelet components. However, the economic consequences of the use of such components have not been carefully studied. STUDY DESIGN AND METHODS: A formal economic analysis was conducted of a recently reported, prospective, randomized, double-blind study examining the platelet dose-response relationship in nonrefractory patients. The economic analysis used a decision analysis model, conducted from the hospital's perspective and based directly on the observed clinical data and on institutional cost structures. RESULTS: The decision analysis model estimated that a 38-percent reduction in mean platelet dose, within the commonly prescribed dose range, would result in the average patient's requiring approximately 60 percent more transfusions in the posttransplant period (8 vs. 5; p = 0.05), which would result in an estimated 60-percent increase in the median cost to the hospital ($4486/patient vs. $2804/patient [in 1996 US dollars], p = 0.05). CONCLUSION: Efforts to decrease costs by utilizing lower-dose single-donor platelet transfusions are predicted to result in a disproportionate increase in the number of transfusions per patient, with a corresponding increase in overall hospital transfusion costs.

Clinical consequences of alterations in platelet transfusion dose: a prospective, randomized, double-blind trial.

BACKGROUND: The dose-response relationship for platelet transfusion has become increasingly important as the use of platelet transfusion has grown. STUDY DESIGN AND METHODS: One hundred fifty-eight prophylactic apheresis platelet transfusions were administered to 46 patients undergoing high-dose therapy followed by hematopoietic progenitor cell transplantation in a prospective, randomized, double-blind, multiple-crossover study. Transfusions were administered in pairs, differing only in platelet content. Each pair consisted of a lower-dose platelet component (LDP) and a higher-dose platelet component (HDP) administered in random order to the same patient. LDPs contained a mean of 3.1 x 10(11) platelets (range, 2.3-3.5 x 10(11)), and HDPs contained a mean of 5.0 x 10(11) platelets (range, 4.5-6.1 x 10(11)). Patients with active bleeding and those who were refractory to platelet transfusions were excluded. RESULTS: The mean posttransfusion platelet count increment with LDP was 17,010 per microL, and that with HDP was 31,057 per microL (p<0.0001). Only 37 percent of LDPs resulted in platelet count increments of at least 20,000 per microL, whereas 81 percent of HDPs resulted in increments above this level (p<0.0001). The mean transfusion-free interval with LDP was 2.16 days, whereas that with HDP was 3.03 days (p<0.01). Administration of LDPs was associated with a 39 to 82 percent increase in the relative risk (per day) of requiring subsequent platelet transfusions (p<0.0001). CONCLUSION: As compared to the administration of HDPs, the administration of LDPs for prophylactic transfusion in hematopoietic progenitor cell transplant patients results in a lower platelet count increment, a lower likelihood of obtaining a posttransfusion platelet increment >20,000 per microL, a shorter transfusion-free interval, and a greater relative risk per day of requiring additional transfusions.

Value of the pretransplant evaluation in predicting toxic day-100 mortality among blood stem-cell and bone marrow transplant recipients.

PURPOSE: To determine the value of pretransplant studies in predicting day 100 nonrelapse toxic mortality following high-dose therapy. PATIENTS AND METHODS: A retrospective review of 383 consecutive hematopoietic stem-cell transplants was performed with attention to toxic mortality and pretransplant factors. Univariate log-rank analysis was used to yield the most significant cut-off values for individual factors. Multivariate analysis using Cox proportional hazards regression determined factors independently predictive of early toxic death. RESULTS: Nonrelapse toxic mortality before day 100 occurred in 23 of 383 (6.0%) transplant recipients. Factors associated with an increased risk of toxic death by univariate analysis included forced expiratory volume in 1 second (FEV1) less than 78% of predicted (P = .0002), allogeneic versus autologous transplant (P = .0003), diffusion capacity of carbon monoxide less than 52% of predicted (P = .002), serum creatinine concentration greater than 1.1 mg/dL (P = .003), Eastern Cooperative Oncology Group performance status greater than 0 (P = .006), preparative regimen containing total-body irradiation versus chemotherapy alone (P = .006), marrow versus blood stem cell (P = .01), serum ALT greater than 50 IU/L (P = .02), diagnosis of hematologic disorder versus solid tumor (P = .06), serum bilirubin level greater than 1.1 mg/dL (P = .08), left ventricular ejection fraction (P = .09), and growth factor use (P = .09). In the multivariate model, transplant type (relative risk, 4.2), FEV1 (relative risk, 4.5), performance status (relative risk, 3.7), serum creatinine (relative risk, 3.8), and serum bilirubin (relative risk, 3.7) were found to be independent predictors of early toxic mortality. CONCLUSION: The pretransplant evaluation is a useful tool to identify patients at risk for early toxic mortality following high-dose therapy.

The erythroid leukemias: a comparative study of erythroleukemia (FAB M6) and Di Guglielmo disease.

Pure erythroid malignancies, such as Di Guglielmo disease (DG), in which the predominant immature elements are proerythroblasts, are excluded from the French-American-British (FAB) classification for acute leukemia and do not fit neatly into any of the categories of myelodysplasia. This retrospective review compares the clinical and laboratory features of DG and erythroleukemia (FAB M6) among 37 cases treated at a single institution over a 7-year period. DG was defined as >30% proerythroblasts and the absence of a myeloblastic component. Clinical and laboratory features were similar in both subtypes. High proportions of secondary leukemias and prior myelodysplastic syndromes (MDS) were noted (M6, 13 of 26 cases; DG, five of 11 cases; p = 0.85). Pancytopenia was common at presentation in both groups [median white blood cells (WBC), 2,600/mm3; HgB, 8.65 gm/dl; platelets, 38,000/microl]. Two-thirds of studied cases had chromosomal abnormalities typified by major karyotypic abnormalities (MAKA) involving three or more chromosomes. Abnormalities involving chromosome 5 and/or 7 occurred in 47% (48% M6 and 45% DG). Both erythroid malignancies carried a poor prognosis (M6, 6.0-month median survival; DG, 4-month survival; p = 0.74). Among those patients choosing aggressive rather than palliative therapy, higher remission rate (80 versus 25%) and survival advantage (11.5 versus 2.5 months) were seen in M6 compared to DG. However, only two long-term survivors exist. The similar clinical and laboratory features, cytogenetic patterns, and poor survival data suggest that the FAB classification schema should be modified to include DG.

Phase II study of high-dose cyclophosphamide, etoposide, and carboplatin (CEC) followed by autologous hematopoietic stem cell rescue in women with metastatic or high-risk non-metastatic breast cancer: multivariate analysis of factors affecting survival and engraftment.

Seventy women with high-risk stage II (n = 10), IIIA (n = 12), IIIB (n = 11), or IV (n = 37) breast cancer received cyclophosphamide 6000 mg/m2, etoposide 2400 mg/m2, and carboplatin 1200 mg/m2 followed by infusion of autologous hematopoietic stem cells (AHSC). Women with high-risk stage II disease had eight or more involved axillary lymph nodes (n = 9) or axillary and breast relapse following lumpectomy, chemotherapy, and radiation therapy (n = 1). Women with measurable stage III or stage IV disease were required to demonstrate complete or partial response to conventional-dose chemotherapy prior to transplant. The overall (complete plus partial) response rate for the 31 patients not in complete remission at the time of transplant was 55%. With a median follow-up of 545 days, the 2-year actuarial progression-free survival rates for patients with stage II, IIIA, IIIB and IV are 86, 75, 42 and 13%, respectively. Factors independently predictive of longer progression-free survival by multivariate analysis included lower stage disease, status of disease at transplant (in CR vs not in CR), and positive estrogen receptor status. Factors predictive of more rapid neutrophil engraftment by multivariate analysis included post-transplant administration of hematopoietic growth factors, greater number of infused CFU-GM, mobilization with G-CSF or cyclophosphamide/G-CSF (vs mobilization with GM-CSF or no mobilization), and lower stage disease. Only one patient (1.4%) died prior to day 100 from any cause. High-dose cyclophosphamide, etoposide, and carboplatin followed by infusion of AHSC constitutes an active and well-tolerated regimen in the treatment of women with high-risk non-metastatic or metastatic breast cancer.

Detection of a dormant 20q- leukemia clone in bone marrow cultures with hematopoietic growth factors: implications for secondary leukemia post-transplant.

A patient developed secondary acute myelogenous leukemia with a 20q- marker chromosome abnormality six years following chemotherapy and radiation for Hodgkins disease (HD). Routine cytogenetics on the bone marrow which had been harvested and cryopreserved immediately following completion of initial therapy for HD showed no cytogenetic abnormality. However, a 20q- clonal marker was detected after culturing bone marrow with hematopoietic growth factors (HGF). The marrow was used successfully for an autotransplant. Post-transplant, the 20q- marker was again detected in HGF cultured samples. The patient relapsed at 165 days post-transplant with the 20q- marker and trisomy 21. These data suggest that standard cytogenetic assays may not detect abnormal clones which can cause leukemia post-transplant.

Association between antibodies reactive with neutrophils, rate of neutrophil engraftment, and incidence of post-engraftment neutropenia following BMT.

Previous reports have suggested that antibodies reactive with neutrophils (ARN) are frequently detectable in patients undergoing bone marrow or blood stem cell transplantation (BMT), and that such antibodies result in steroid-responsive delayed neutrophil engraftment or steroid-responsive post-engraftment neutropenia in some patients. However, the true incidence and significance of ARN in the BMT setting remain poorly established because most of the published data are in the form of retrospective case reports. Therefore, we prospectively studied the incidence of ARN, the rate of neutrophil engraftment, and the incidence of post-engraftment neutropenia in a cohort of 40 BMT candidates. Sixteen of the 36 evaluable patients (44%) had detectable ARN following transplant vs none of 25 concurrently studied healthy controls (P < 0.0001). Patients with detectable ARN in the post-transplant period recovered to an absolute neutrophil count (ANC) of 500 x 10(9)/l a median of 3.5 days later than patients without detectable ARN; multivariate analysis controlling for the potential effects of diagnosis, conditioning regimen, amount of prior therapy, and other factors revealed that only the administration of hematopoietic growth factors (P = 0.008) and the presence of ARN in the post-transplant period (P = 0.016) were independently predictive of the rate of neutrophil engraftment following BMT. Four of the 16 patients with detectable ARN (25%) satisfied previously published criteria for post-engraftment neutropenia, ie a fall in the ANC to less than 500 x 10(9)/l for at least 2 consecutive days, following initial engraftment to an ANC of at least 1000 x 10(9)/l for at least 2 consecutive days. In contrast, none of the 20 patients without detectable post-transplant ARN developed post-engraftment neutropenia. Multivariate analysis revealed that only the presence of ARN in the post-transplant period (P = 0.022) was independently predictive of post-engraftment neutropenia. All four patients with ARN-associated post-engraftment neutropenia responded to steroid-based therapy. These prospectively gathered data support previously published primarily case report data suggesting that ARN occur frequently following BMT and are associated with an increased incidence of delayed neutrophil engraftment and post-engraftment neutropenia. As is the case in the non-transplant setting, ARN-associated neutropenia occurring following BMT may respond to steroid-based therapy.

Treatment of hepatic veno-occlusive disease with low-dose tissue plasminogen activator: impact on coagulation profile.

An 18-year-old white male developed severe hepatic veno-occlusive disease (VOD) during an autologous bone marrow transplant for primary refractory nodular sclerosing Hodgkin's disease. As a result of VOD-induced hepatic dysfunction, coagulation studies revealed depression of vitamin K dependent procoagulant factor VII. Intravenous recombinant tissue plasminogen activator 20 mg over h on 4 consecutive days and continuous heparin infusion (1000 unit bolus followed by 150 units/kg/day) resulted in rapid reversal of the VOD syndrome. During treatment, procoagulant factors II, VII, IX and X levels increased indicating the return of hepatic synthesizing capacity. Factor V levels, which were elevated pre-therapy, also rose dramatically. Plasma antigen levels of protein C, a natural anticoagulant, remained severely depressed. No clinical evidence of bleeding and only minimal systemic fibrinolysis was noted. Despite concerns regarding the use of lytic therapy in a thrombocytopenic post-BMT patient, serial measurements of coagulation parameters during severe VOD suggested that low dose rt-PA improved portions of the systemic hemostatic profile.

Factors associated with response to platelet transfusion following hematopoietic stem cell transplantation.

We studied 526 consecutive post-transplant platelet transfusions to determine the factors associated with response to platelet transfusion in the BMT setting. Poor responses to platelet transfusions occurred frequently, with 310 of the 484 evaluable transfusions (64%) resulting in post-infusion corrected count increments of less than 7500. Factors associated with poor response to platelet transfusion by both univariate and multivariate analysis included, (1) presence of serum lymphocytotoxic antibodies; (2) male sex; (3) body surface area greater than 1.7 m2; (4) transfusion of red cells on the day of the platelet infusion; (5) concurrent administration of steroids; (6) major ABO mismatch between the recipient and the platelet product; and (7) (among women) a history of one or more pregnancies prior to transplant. Paradoxically, a history of greater than 25 blood product exposures prior to transplant, and evidence of prior CMV infection in either the bone marrow donor or recipient were associated with higher CCIs by both univariate and multivariate analysis. Factors that showed little correlation with response to platelet transfusion included, (1) age of the infused platelet product; (2) concurrent fever; (3) recent administration of intravenous immunoglobulin; and (4) absolute neutrophil count at the time of the infusion. The factors associated with response to platelet transfusion in BMT patients appear to be different from those observed in the non-transplant setting.

Malignant myoepithelioma of the parotid gland: case report and review of the literature.

A 62-year-old male with a myoepithelioma of the right parotid gland was treated with surgical excision followed by adjuvant radiation therapy. Prior to the completion of radiation therapy, the patient developed progressive disease at local, regional, and distant metastatic sites. Combined modality treatment with radiation and chemotherapy resulted in a significant but transient shrinkage of the tumours at all sites. The patient succumbed to metastatic disease 212 days following the diagnostic biopsy. This case illustrates several of the distinctive clinical and pathological characteristics of this rare tumour.