Fausto R. Loberiza

Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study

BACKGROUND Although umbilical cord blood is an accepted alternative to bone marrow for transplantation, allele-matched bone marrow is generally regarded as the preferred graft source. Our aim was to assess leukaemia-free survival after transplantations of these alternatives compared with present HLA-matching practices, and to assess the relative effect of cell dose and HLA match, and their potential interaction on leukaemia-free survival after cord-blood transplantation. METHODS Outcomes of 503 children (<16 years) with acute leukaemia and transplanted with umbilical cord blood were compared with outcomes of 282 bone-marrow recipients. All transplantation took place in the USA. Recipients of umbilical cord blood were transplanted with grafts that were HLA-matched (n=35) or HLA-mismatched for one (n=201) or two antigens (n=267) (typing at antigen level for HLA-A and HLA-B, and allele level for HLA-DRB1). Bone-marrow recipients were transplanted with grafts that were matched at the allele level for HLA-A, HLA-B, HLA-C, and HLA-DRB (n=116), or mismatched (n=166). The primary endpoint was 5-year leukaemia-free survival. FINDINGS In comparison with allele-matched bone-marrow transplants, 5-year leukaemia-free survival was similar to that after transplants of umbilical cord blood mismatched for either one or two antigens and possibly higher after transplants of HLA-matched umbilical cord blood. Transplant-related mortality rates were higher after transplants of two-antigen HLA-mismatched umbilical cord blood (relative risk 2.31, p=0.0003) and possibly after one-antigen HLA-mismatched low-cell-dose umbilical-cord-blood transplants (1.88, p=0.0455). Relapse rates were lower after two-antigen HLA-mismatched umbilical-cord-blood transplants (0.54, p=0.0045). INTERPRETATION These data support the use of HLA-matched and one- or two-antigen HLA-mismatched umbilical cord blood in children with acute leukaemia who need transplantation. Because better HLA matching and higher cell doses significantly decrease the risk of transplant-related mortality after umbilical-cord-blood transplantation, greater investment in large-scale banking is needed to increase HLA diversity.

Flow-Induced Dilation of Human Coronary Arterioles Important Role of Ca2+-Activated K+ Channels

BackgroundFlow-induced vasodilation (FID) is a physiological mechanism for regulating coronary flow and is mediated largely by nitric oxide (NO) in animals. Because hyperpolarizing mechanisms may play a greater role than NO in the microcirculation, we hypothesized that hyperpolarization contributes importantly to FID of human coronary arterioles. Methods and ResultsArterioles from atria or ventricles were cannulated for videomicroscopy. Membrane potential of vascular smooth muscle cells (VSMCs) was measured simultaneously. After constriction with endothelin-1, increases in flow induced an endothelium-dependent vasodilation. N&ohgr;-Nitro-l-arginine methyl ester 10−4 mol/L modestly impaired FID of arterioles from patients without coronary artery disease (CAD), whereas no inhibition was seen in arterioles from patients with CAD. Indomethacin 10−5 mol/L was without effect, but 40 mmol/L KCl attenuated maximal FID. Tetraethylammonium 10−3 mol/L but not glibenclamide 10−6 mol/L reduced FID. Charybdotoxin 10−8 mol/L impaired both FID (15±3% versus 75±12%, P <0.05) and hyperpolarization (−32±2 mV [from −28±2 mV after endothelin-1] versus −42±2 mV [−27±2 mV], P <0.05). Miconazole 10−6 mol/L or 17-octadecynoic acid 10−5 mol/L reduced FID. By multivariate analysis, age was an independent predictor for the reduced FID. ConclusionsWe conclude that shear stress induces endothelium-dependent vasodilation, hyperpolarizing VSMCs through opening Ca2+-activated K+ channels in human coronary arterioles. In subjects without CAD, NO contributes to FID. NO and prostaglandins play no role in patients with CAD; rather, cytochrome P450 metabolites are involved. This is consistent with a role for endothelium-derived hyperpolarizing factor in FID of the human coronary microcirculation.

Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: The histocompatibility and alternate stem cell source working committee of the international bone marrow transplant registry

PURPOSE Peripheral-blood stem cells (PBSC) may be used as an alternative to bone marrow (BM) for allogeneic transplantation. Despite lack of data on PBSC transplantation in children, there has been a change in clinical practice, with increasing numbers of children receiving PBSC allografts. PATIENTS AND METHODS We compared the results of 143 PBSC and 630 BM transplants from human leukocyte antigen-identical sibling donors in children aged 8 to 20 years with acute leukemia. PBSC transplant recipients were older, and were more likely to have advanced leukemia, receive growth factors post-transplantation, and have undergone transplantation more recently. Risks of acute and chronic graft-versus-host disease (GVHD), treatment-related mortality, relapse, treatment failure (relapse or death), and overall mortality were compared using Cox proportional hazards regression to adjust for potentially confounding factors. RESULTS Hematopoietic recovery was faster after PBSC transplantation. Risks of grade 2 to 4 acute GVHD were similar, but chronic GVHD risk was higher after PBSC transplantation (relative risk [RR], 1.85; 95% CI, 1.28 to 2.66; P = .001). In contrast to reports in adults, treatment-related mortality (RR, 1.89; 95% CI, 1.28 to 2.80; P = .001), treatment failure (RR, 1.31; 95% CI, 1.03 to 1.68; P = .03), and mortality (RR, 1.38; 95% CI, 1.07 to 1.79; P = .01) were higher after PBSC transplantation. Risks of relapse were similar. CONCLUSION These data suggest poorer outcomes after PBSC compared with BM transplantation in children after adjusting for relevant risk factors. Given the trend toward increased use of PBSC allografts in children, prospective clinical trials are required to determine their appropriate role in this group of patients.

Association of Depressive Syndrome and Early Deaths Among Patients After Stem-Cell Transplantation for Malignant Diseases

PURPOSE The association of depression and increased mortality in the general population, and also various medical conditions, is well documented. However, depression is not well studied in the setting of hematopoietic stem-cell transplantation (HSCT). We examined the association between depressive syndrome and survival after HSCT. PATIENTS AND METHODS A total of 193 patients who received autologous or allogeneic HSCT from Brigham and Womens Hospital or Dana-Farber Cancer Institute were evaluated prospectively. The self-rated Likert-scaled symptom checklist, the SF-36, and the Spitzer Quality of Life Index Scale were administered. Outcomes evaluated included survival and quality of life. RESULTS Sixty-seven patients (35%) satisfied the criteria for depressive syndrome. The 1-year probability of survival for the depressed and nondepressed patients was 85% (95% confidence interval [CI], 74% to 92%) and 94% (95% CI, 89% to 97%), respectively (P =.04). In multivariable modeling, depressed patients have a three-fold greater risk of dying than nondepressed patients (95% CI, 1.07 to 8.30; P =.04) between 6 and 12 months after HSCT after adjusting for other prognostic factors. Global inferiority in quality of life was observed in the depressed cohort when last measured at 24 months after transplantation. CONCLUSION Depressive syndrome after HSCT is associated with decreased survival, at least from 6 to 12 months after transplantation. Persistence of this association after controlling for possible confounding factors suggests that depression may be more than simply a marker for concurrent ill health. This study raises an interesting hypothesis as to whether psychological or pharmacologic intervention for depression after HSCT can improve survival and/or quality of life.

A SAS macro for estimation of direct adjusted survival curves based on a stratified Cox regression model

Often in biomedical research the aim of a study is to compare the outcomes of several treatment arms while adjusting for multiple clinical prognostic factors. In this paper we focus on computation of the direct adjusted survival curves for different treatment groups based on an unstratified or a stratified Cox model. The estimators are constructed by taking the average of the individual predicted survival curves. The method of direct adjustment controls for possible confounders due to an imbalance of patient characteristics between treatment groups. This adjustment is especially useful for non-randomized studies. We have written a SAS macro to estimate and compare the direct adjusted survival curves. We illustrate the SAS macro through the examples analyzing stem cell transplant data and Ewings sarcoma data.

Outcome of autologous transplantation for mantle cell lymphoma: a study by the European Blood and Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries

Summary. Mantle cell lymphoma (MCL) has an aggressive clinical course with a median survival < 3 years and is incurable with conventional chemotherapy. A large multicentre study with adequate follow‐up may clarify the role of significant factors affecting outcome in autologous stem cell transplantation for MCL. Patients receiving an autologous transplant for MCL between 1988 and 1998, and reported to the European Blood and bone Marrow Transplant (EBMT) registry or Autologous Blood and Marrow Transplant Registry (ABMTR), were included. Expert haematopathology review was required on all identified patients. Disease and transplant details were requested from the transplant centres, and the final cohort of patients with verified pathology, adequate clinical information and follow‐up was analysed. One hundred and ninety‐five patients were included in the analyses (149 EBMT, 46 ABMTR) with a median follow‐up of 3·9 years. The 2 year and 5 year overall survival were 76% and 50%, and progression free survival was 55% and 33% respectively. Disease status at transplant was the most significant factor affecting survival: patients with chemosensitive disease but not in first complete remission (CR1) were 2·99 times (95% CI: 1·66–5·38, P < 0·001) more likely to die than patients transplanted in CR1. Autologous transplantation probably improves survival in patients with MCL especially if performed in first CR.

Diabetes Mellitus Impairs Vasodilation to Hypoxia in Human Coronary Arterioles Reduced Activity of ATP-Sensitive Potassium Channels

Abstract— ATP-sensitive K+ channels (KATP) contribute to vasomotor regulation in some species. It is not fully understood the extent to which KATP participate in regulating vasomotor tone under physiological and pathophysiological conditions in the human heart. Arterioles dissected from right atrial appendage were studied with video microscopy, membrane potential recordings, reverse transcription–polymerase chain reaction, and immunohistochemistry. Hypoxia produced endothelium-independent vasodilation and membrane hyperpolarization of vascular smooth muscle cells, both of which were attenuated by glibenclamide. Aprikalim, a selective KATP opener, also induced a potent endothelium-independent and glibenclamide-sensitive vasodilation with membrane hyperpolarization. Reverse transcription–polymerase chain reaction detected mRNA expression for KATP subunits, and immunohistochemistry confirmed the localization of the inwardly rectifying Kir6.1 protein in the vasculature. In patients with type 1 or type 2 diabetes mellitus (DM), vasodilation was reduced to both aprikalim (maximum dilation, DM(+) 90±2% versus DM(−) 96±1%, P <0.05) and hypoxia (maximum dilation, DM(+) 56±8% versus DM(−) 85±5%, P <0.01) but was not altered to sodium nitroprusside or bradykinin. Baseline myogenic tone and resting membrane potential were not affected by DM. We conclude that DM impairs human coronary arteriolar dilation to KATP opening, leading to reduced dilation to hypoxia. This reduction in KATP function could contribute to the greater cardiovascular mortality and morbidity in DM.

Syngeneic Hematopoietic Stem-Cell Transplantation for Non-Hodgkin’s Lymphoma: A Comparison With Allogeneic and Autologous Transplantation—The Lymphoma Working Committee of the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation

PURPOSE To compare results of syngeneic, allogeneic, and autologous hematopoietic stem-cell transplantation for non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS The databases of the International Bone Marrow Transplant Registry (IBMTR) and the European Group for Blood and Marrow Transplantation were used to identify 89 NHL patients who received syngeneic transplants. These patients were compared with NHL patients identified from the IBMTR and the Autologous Blood and Marrow Transplant Registry who received allogeneic (T-cell depleted and T-cell replete) and autologous (purged and unpurged) transplants. RESULTS No significant differences in relapse rates were observed when results of allogeneic transplantation were compared with syngeneic transplantation for any histology. T-cell depletion of allografts was not associated with a higher relapse risk, but was associated with improved overall survival for patients with low-grade and intermediate-grade histology. Patients who received unpurged autografts for low-grade NHL had a five-fold (P =.008) greater risk of relapse than recipients of syngeneic transplants, and recipients of unpurged autografts had a two-fold (P =.0009) greater relapse risk than patients who received purged autografts. Among low-grade NHL patients, the use of purging was associated with significantly better disease-free survival (P =.003) and overall survival (P =.04) when compared with patients who received unpurged autografts. CONCLUSION These analyses failed to find evidence of a graft-versus-lymphoma effect, but do provide indirect evidence to support the hypothesis that tumor contamination may contribute to lymphoma relapse, and that purging may be beneficial for patients undergoing autologous hematopoietic stem-cell transplantation for low-grade NHL.

Health‐related quality of life in children with sickle cell disease: child and parent perception

Health‐related quality of life (HRQL) is an outcome that may be used to measure the impact of sickle cell disease on the child and their family but has not been routinely assessed in this disease. The objective of this study was to describe the HRQL of children with sickle cell disease as reported by the parent and the child, to compare the relationship between the two, and to determine the association of parent, child and disease characteristics on HRQL. Ninety‐five parents completed the Child Health Questionnaire (CHQ)‐Parent Form28 and 53 children completed the CHQ‐Child Form87. Compared with the child report, parents reported worse HRQL in the overall perception of health, physical functioning, behaviour and self esteem domains of HRQL (P < 0·005). Parent and child reports of HRQL correlated strongly in assessment of the impact of bodily pain (r = 0·58) on HRQL and moderately in physical functioning (r = 0·44), behaviour (r = 0·45), general health (r = 0·44), self esteem (r = 0·40) and changes in health (r = 0·33) domains. Disease status, neurobehavioral co‐morbidities, and parent education were associated with the HRQL of the child. Both the parent and child perspectives are needed to fully understand the impact of sickle cell disease on the HRQL of the child and effect of this disease on the family.

Significant Improvement in Survival After Allogeneic Hematopoietic Cell Transplantation During a Period of Significantly Increased Use, Older Recipient Age, and Use of Unrelated Donors

PURPOSE Over the past four decades, allogeneic hematopoietic cell transplantation (alloHCT) has evolved as a curative modality for patients with hematologic diseases. This study describes changes in use, technique, and survival in a population-based cohort. PATIENTS AND METHODS The study included 38,060 patients with hematologic malignancies or disorders who underwent first alloHCT in a US or Canadian center from 1994 to 2005 and were reported to the Center for International Blood and Marrow Transplant Research. RESULTS AlloHCT as treatment for acute lymphoblastic (ALL) and myeloid leukemias (AML), myelodysplastic syndrome (MDS), and Hodgkin and non-Hodgkin lymphomas increased by 45%, from 2,520 to 3,668 patients annually. From 1994 to 2005, use of both peripheral (7% to 63%) [corrected] and cord blood increased (2% to 10%), whereas use of marrow decreased (90% to 27%). Despite a median age increase from 33 to 40 years and 165% [corrected] increase in unrelated donors for alloHCT, overall survival (OS) at day 100 significantly improved for patients with AML in first complete remission after myeloablative sibling alloHCT (85% to 94%; P < .001) and unrelated alloHCT (63% to 86%; P < .001); 1-year OS improved among those undergoing unrelated alloHCT (48% to 63%; P = .003) but not among those undergoing sibling alloHCT. Similar results were seen for ALL and MDS. Day-100 OS after cord blood alloHCT improved significantly from 60% to 78% (P < .001) for AML, ALL, MDS, and chronic myeloid leukemia. Use of reduced-intensity regimens increased, yielding OS rates similar to those of myeloablative regimens. CONCLUSION Survival for those undergoing alloHCT has significantly improved over time. However, new approaches are needed to further improve 1-year OS.