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The Journal of Visualized Experiments (JoVE) is a peer reviewed, PubMed-indexed video journal. Our mission is to increase the productivity of scientific research.

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Articles by Gregory Hale in JoVE

 JoVE General

Micro-drive Array for Chronic in vivo Recording: Drive Fabrication


JoVE 1094 4/20/2009

1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2

1Picower Institute for Learning and Memory, MIT - Massachusetts Institute of Technology, 2Department of Brain and Cognitive Science, MIT - Massachusetts Institute of Technology

In this protocol we demonstrate how to fabricate a micro-drive array for chronic electrophysiological recordings in rats.

 JoVE General

Micro-drive Array for Chronic in vivo Recording: Tetrode Assembly


JoVE 1098 4/22/2009

1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2

1Department of Brain and Cognitive Science, MIT - Massachusetts Institute of Technology, 2Picower Institute for Learning and Memory, MIT - Massachusetts Institute of Technology

In this protocol we demonstrate how to fabricate and condition tetrodes for use with a micro-drive array, which was designed for chronic electrophysiological recordings in rats. In addition, we illustrate the final stages of micro-drive array construction, which includes installing ground wires and a protective cone.

Other articles by Gregory Hale on PubMed

Human Leucocyte Antigen Alloimmunization After Bone Marrow Transplantation: an Association with Chronic Myelogenous Leukaemia

British Journal of Haematology. Jun, 2002  |  Pubmed ID: 12028035

Platelet refractoriness due to human leucocyte antigen (HLA) alloimmunization is a significant risk to allogeneic bone marrow transplant recipients. To identify factors contributing to this risk, we reviewed the records of 317 consecutive, paediatric, allogeneic bone marrow transplant recipients at a single institution. The 6-year estimated cumulative incidence of platelet refractoriness due to HLA alloimmunization was 2.6% +/- 0.9%. The incidence among patients with chronic myelogenous leukaemia (CML) 12.5% +/- 5.3% was significantly greater than that of other patients (1.1% +/- 0.6%, P < 0.001). Graft rejection (P = 0.003) and the number of platelet transfusions during the first 90 d after bone marrow transplantation (BMT) (P = 0.0025) were also significantly associated with alloimmunization. The association with CML and with graft rejection was not seen among patients alloimmunized before transplantation. Eight patients developed alloimmunization, of whom three had mismatched grafts and four had unrelated grafts. Alloantibody specificities, identified in seven patients, were unrelated to host or graft major histocompatibility complex (MHC). Host recognition of alloantigens in transfused blood products, not graft-host recognition, therefore seems predominantly responsible for the alloimmunization. These results show that paediatric CML patients have a significantly increased risk of platelet refractoriness due to HLA alloimmunization after BMT. Identifying the mechanism for the increased alloimmunization risk may assist in the development of therapies to prevent platelet refractoriness.

Autologous Stem Cell Transplantation for Small Cell Lung Cancer

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2002  |  Pubmed ID: 12064365

Small cell lung cancer usually responds to radiation and chemotherapy, but cures are infrequent. Autotransplantation attempts to increase cures by intensifying the effects of chemotherapy. We studied 103 patients receiving high-dose chemotherapy with autologous hematopoietic stem cell transplantation (SCT) for small cell lung cancer in 1989-1997 at 22 centers participating in the Autologous Blood and Marrow Transplant Registry. Median age at transplantation was 50 years (range, 30-74 years). Fifty-five percent of patients were men. Forty-seven percent of patients underwent transplantation in 1989-1993 and 53% in 1994-1997. Most patients received peripheral blood stem cells alone (39%) or with bone marrow (44%); 18% received bone marrow alone. The 2 most common preparative regimens were cyclophosphamide/carmustine/cisplatin (CBP) (60%) and ifosfamide/carboplatin/etoposide (ICE) (28%). Median time from diagnosis to transplantation was 6 months (range, 1-34 months). Most patients underwent transplantation after partial response (66%) or complete response (27%) to combination therapy. The 100-day mortality was 11% (95% confidence interval [CI], 6%-18%). Three-year probabilities of survival and progression-free survival (PFS) were 33% (95% CI, 24%-44%) and 26% (95% CI, 17%-36%), respectively, for all patients. Factors negatively associated with outcome in multivariate analysis were age greater than 50 years, extensive-stage disease at presentation, and preparative regimens other than CBP or ICE. Three-year survival and PFS rates were higher in patients with limited versus extensive disease, 43% versus 10% (P < .001) and 35% versus 4% (P < .001), respectively. Patients older than 50 years had nearly twice the risk of death or progression as younger patients (relative risk, 1.7; 95% CI, 1.1-2.8). Autologous SCT produces long-term survival in some patients with small cell lung cancer; SCT outcomes appear better in young patients with limited-stage disease. Transplantation for patients with extensive disease does not appear to produce substantial benefit.

Severity of Chronic Graft-versus-host Disease: Association with Treatment-related Mortality and Relapse

Blood. Jul, 2002  |  Pubmed ID: 12091329

Chronic graft-versus-host disease (cGVHD) is the leading cause of late treatment-related deaths among recipients of allogeneic bone marrow and blood transplants. However, cGVHD is also associated with fewer relapses. We sought to determine whether severity of cGVHD predicts the magnitude of these effects. One impediment to such an analysis is the current limited/extensive grading system for cGVHD because this classification was designed to identify patients likely to benefit from systemic immune suppression and does not capture the severity of multiorgan involvement. We, therefore, first developed a grading system predictive for survival by using data from 1827 HLA-matched sibling allotransplant recipients reported to the International Bone Marrow Transplant Registry (IBMTR). We found Karnofsky performance score, diarrhea, weight loss, and cutaneous and oral involvement to be independent prognostic variables, from which we generated a grading scheme. We tested this scheme, the limited/extensive classification system, and a classification based on clinical impression of overall cGVHD severity (mild/moderate/severe) in parallel analyses of 1092 HLA-matched sibling transplant recipients from the IBMTR and 553 recipients of unrelated donor marrow from the National Marrow Donor Program. Presence of cGVHD was associated with fewer relapses (relative risk [RR], 0.5-0.6) but more treatment-related mortality (RR, 1.8-2.8) in the 3 analyses. No grading scheme correlated cGVHD severity with relapse rates, but all schemes predicted treatment-related mortality. Survival and disease-free survival of the most favorable cGVHD group in each scheme were similar, or better, than those of patients without cGVHD; these patients may not need aggressive or extended immune suppression.

Decreased Treatment Failure in Recipients of HLA-identical Bone Marrow or Peripheral Blood Stem Cell Transplants with High CD34 Cell Doses

British Journal of Haematology. Jun, 2003  |  Pubmed ID: 12786798

We studied the association between CD34 cell dose and transplant outcomes in 359 bone marrow (BM) and 511 peripheral blood stem cell (PBSC) transplant recipients from human leucocyte antigen (HLA)-identical siblings, reported to the International Bone Marrow Transplant Registry (IBMTR). Transplants for leukaemia were performed between 1995 and 1998. Patients were divided into those receiving below or above the median CD34+ dose, for BM (3 x 106/kg) and PBSC (6 x 106/kg) grafts respectively. Cox proportional hazards regression was used to adjust for baseline patient-, disease- and transplant-related characteristics. Analysis of the BM recipients showed that high CD34 cell dose was associated with lower transplant-related mortality [relative risk (RR) = 0.60, P = 0.033] and treatment failure (inverse of leukaemia-free survival, RR = 0.69, P = 0.032). Among PBSC recipients, high CD34 dose was associated with faster recovery of neutrophils to > 0.5 x 109/l (RR = 1.38, P < 0.001) and platelets to > 20 x 109/l (RR = 1.34, P = 0.003), lower risk of relapse (RR = 0.62, P = 0.029) and treatment failure (RR = 0.74, P = 0.03). We conclude that higher CD34 cell doses decrease treatment failure in recipients of HLA-identical sibling BM and PBSC transplants.

T-cell Alloreactivity Dominates Natural Killer Cell Alloreactivity in Minimally T-cell-depleted HLA-non-identical Paediatric Bone Marrow Transplantation

British Journal of Haematology. Oct, 2003  |  Pubmed ID: 14531915

Natural killer (NK) cell alloreactivity resulting from killer immunoglobulin-like receptor (KIR) ligand incompatibility improves outcomes in patients receiving extensively T-cell-depleted bone marrow (BM) grafts. Patients with KIR ligand incompatibility are at risk for donor T-cell alloreactivity. We investigated the relative significance of NK-cell and T-cell alloreactivity in 105 paediatric patients who received a minimally T-cell-depleted human leucocyte antigen-non-identical BM transplantation. Donor NK-cell incompatibility did not improve patient outcome [engraftment, graft-versus-host disease (GVHD), relapse or overall survival]. In contrast, donor T-cell incompatibility was a risk factor for acute GVHD, chronic GVHD and death. Thus, T-cell alloreactivity dominated that of NK cells in minimally T-cell-depleted grafts.

Etiology and Outcome of Graft Failure in Pediatric Hematopoietic Stem Cell Transplant Recipients

Journal of Pediatric Hematology/oncology. Dec, 2003  |  Pubmed ID: 14663279

To determine the incidence, etiology and outcome of graft failure in pediatric allogeneic bone marrow transplant (BMT) recipients.

Comparison of Graft-versus-host-disease and Survival After HLA-identical Sibling Bone Marrow Transplantation in Ethnic Populations

Blood. Feb, 2005  |  Pubmed ID: 15486071

The association of ethnicity with the incidence of graft-versus-host disease (GVHD) and other clinical outcomes after transplantation is controversial. We compared the results of HLA-identical sibling bone marrow transplantations for leukemia, performed between 1990 and 1999, among different ethnic populations, including 562 Japanese, 829 white Americans, 71 African Americans, 195 Scandinavians, and 95 Irish. Results for adults and children were analyzed separately. Multivariate analyses of adult patients showed that white Americans, African Americans, and Irish cohorts were at significantly higher risk for acute GVHD than Japanese or Scandinavian cohorts (relative risk [RR] = 1.77, P < .001; RR = 1.84, P < .006; RR = 2.22, P < .001, respectively). White Americans, African Americans, and Irish, but not Scandinavians, were at significantly higher risk for early (within 3 months of transplantation) transplant-related mortality (TRM) compared with Japanese (RR = 2.99, P < .001; RR = 5.88, P < .001; RR = 2.66, P < .009, respectively). No differences in the risk for chronic GVHD, relapse, and overall survival were noted. In the pediatric cohort (limited to Japanese and white Americans), white Americans were at significantly higher risk for acute (RR = 1.93; P = .04) and chronic (RR = 3.16; P = .002) GVHD. No differences in other clinical outcomes were noted. Our findings suggest that ethnicity may influence the risk for GVHD, though overall survival rates after transplantation remain similar.

Atypical Teratoid/rhabdoid Tumors (ATRT): Improved Survival in Children 3 Years of Age and Older with Radiation Therapy and High-dose Alkylator-based Chemotherapy

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2005  |  Pubmed ID: 15735125

To describe clinical features, therapeutic approaches, and prognostic factors in pediatric patients with atypical teratoid/rhabdoid tumors (ATRT) treated at St Jude Children's Research Hospital (SJCRH).

Brain Parenchymal Damage After Haematopoietic Stem Cell Transplantation for Severe Sickle Cell Disease

British Journal of Haematology. May, 2005  |  Pubmed ID: 15877739

Prospective magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), neuropsychological testing and neurological examinations were performed to determine the long-term effect of successful haematopoietic stem cell transplantation on the neurological status of nine children with sickle cell disease. A scoring system for severity of brain parenchymal and vascular lesions was developed and applied. Neurological examinations and neuropsychometric tests were stable, but MRI and MRA studies were not. Transient changes occurred early in two patients. Persistent changes occurred in five. Parenchymal lesions occurred in zero of two patients without prior lacunae or infarcts and in all seven with prior lacunae or infarcts (P = 0.0278).

Variations in Working Memory Capacity Predict Individual Differences in General Learning Abilities Among Genetically Diverse Mice

Neurobiology of Learning and Memory. Nov, 2005  |  Pubmed ID: 16126418

Up to 50% of an individuals' performance across a wide variety of distinct cognitive tests can be accounted for by a single factor (i.e., "general intelligence"). Despite its ubiquity, the processes or mechanisms regulating this factor are a matter of considerable debate. Although it has been hypothesized that working memory may impact cognitive performance across various domains, tests have been inconclusive due to the difficulty in isolating working memory from its overlapping operations, such as verbal ability. We address this problem using genetically diverse mice, which exhibit a trait analogous to general intelligence. The general cognitive abilities of CD-1 mice were found to covary with individuals' working memory capacity, but not with variations in long-term retention. These results provide evidence that independent of verbal abilities, variations in working memory are associated with general cognitive abilities, and further, suggest a conservation across species of mechanisms and/or processes that regulate cognitive abilities.

Autologous Hematopoietic Stem Cell Transplantation for Pediatric Solid Tumors

Expert Review of Anticancer Therapy. Oct, 2005  |  Pubmed ID: 16221053

While advances in the treatment of pediatric cancers have increased cure rates, children with metastatic or recurrent solid tumors have a dismal prognosis despite initial transient responses to therapy. Autologous hematopoietic stem cell transplantation takes advantage of the steep dose-response relationship observed with many chemotherapeutic agents. While clearly demonstrated to improve outcomes in patients with metastatic neuroblastoma, autologous hematopoietic stem cell transplantation is also frequently used to treat patients with other high-risk diseases such as Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, Wilms' tumor, retinoblastoma, germ cell tumors, lymphomas and brain tumors. Most published experience consists of retrospective, single-arm studies; randomized clinical trials are lacking, due in part to the rarity of pediatric cancers treatable by autologous hematopoietic stem cell transplantation. These published literature demonstrate that autologous hematopoietic stem cell transplantation results in most cases in equivalent or superior outcomes when compared with conventional therapies. However, patient heterogeneity, patient selection, graft characteristics and processing and the varied conditioning regimens are additional factors to consider. Since the inception of autologous hematopoietic stem cell transplantation, regimen-related toxicity has markedly decreased and the vast majority of treatment failures are now due to disease recurrence. Prospective clinical trials are needed to identify specific high-risk patient populations, with randomization (when possible) to compare outcomes of patients undergoing autologous hematopoietic stem cell transplantation with those receiving standard therapy. In addition, investigators need to better define the role of autologous hematopoietic stem cell transplantation in these solid tumors, particularly in combination with other therapeutic modalities such as immunotherapy and novel cell processing methodologies.

Hemolytic Uremic Syndrome After Bone Marrow Transplantation: Clinical Characteristics and Outcome in Children

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Nov, 2005  |  Pubmed ID: 16275594

Hemolytic uremic syndrome (HUS) is an uncommon but potentially life-threatening complication of hematopoietic stem cell transplantation. We retrospectively studied the medical records of 293 children who underwent allogeneic bone marrow transplantation at St. Jude Children's Research Hospital between 1992 and 1999 to describe the clinical course of and to identify risk factors for transplant-associated HUS. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation for patients with hematologic malignancies (n = 244); patients with nonmalignant diseases (n = 49) received disease-specific regimens. Grafts from unrelated or mismatched related donors were depleted of T lymphocytes, whereas matched sibling grafts were unmanipulated. All patients received cyclosporine as prophylaxis for graft-versus-host disease. Recipients of grafts from matched siblings also received pentoxifylline or short-course methotrexate. HUS developed in 28 (9.6%) patients at a median of 171 days after transplantation. We identified older donor age (P = .029), use of antithymocyte globulin in the conditioning regimen (P = .008), and recipient CMV seronegativity (P = .011) as being associated with an increased risk of HUS. With a multiple regression analysis, the use of antithymocyte globulin (beta = .86; P = .04) and recipient cytomegalovirus seronegativity (beta = .93; P = .035) remained significant risk factors for the development of HUS.

Impact of Posttransplantation G-CSF on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation

Blood. Feb, 2006  |  Pubmed ID: 16239431

Granulocyte colony-stimulating factor (G-CSF) is often administered after hematopoietic-cell transplantation (HCT) to accelerate neutrophil recovery, but it is unclear what impact G-CSF has on long-term transplantation outcomes. We analyzed within the database of the Center for International Blood and Marrow Transplant Research the impact of giving posttransplantation G-CSF on the outcomes of allogeneic HCT for acute myelogenous leukemia and chronic myelogenous leukemia in 2719 patients who underwent transplantation between 1995 and 2000. These included 1435 recipients of HLA-identical sibling bone marrow (BM), 609 recipients of HLA-identical peripheral-blood stem cells (PBSCs), and 675 recipients of unrelated donor BM transplants. Outcomes were compared between patients receiving or not receiving G-CSF within 7 days of HCT according to graft type. Median follow-up was more than 30 months (range, 2-87 months). G-CSF shortened the posttransplantation neutropenic period, but did not affect days +30 and +100 treatment-related mortality (TRM). Probabilities of acute and chronic graft-versus-host disease (GVHD), leukemia-free survival (LFS), and overall survival were similar whether or not G-CSF was given. Multivariate analyses confirmed that giving G-CSF did not affect the risk of GVHD, TRM, LFS, or survival. In conclusion, results of this study found no long-term benefit or disadvantage of giving G-CSF after transplantation to promote hematopoietic recovery.

Outcome of Hematopoietic Stem Cell Transplantation for Pediatric Patients with Therapy-related Acute Myeloid Leukemia or Myelodysplastic Syndrome

Pediatric Blood & Cancer. Dec, 2006  |  Pubmed ID: 16155933

Therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) carry a poor prognosis. We analyzed the results of allogeneic HSCT in 38 children to determine which factors, if any, affected outcome.

Allogeneic Graft-versus-hepatoblastoma Effect

Pediatric Blood & Cancer. Apr, 2006  |  Pubmed ID: 15806543

Although the survival rate for pediatric patients with hepatoblastoma has improved, prognosis is still poor when the disease is unresectable and refractory to chemotherapy. Therefore, novel approaches are warranted. Herein, we describe a patient with recurrent metastatic hepatoblastoma who received a non-myeloablative hematopoietic stem cell transplantation from an HLA-matched unrelated donor. After withdrawal of immunosuppressant and establishment of full donor T-cell engraftment, the tumor regressed and serum alpha-fetoprotein level decreased in concurrence with the onset of graft-versus-host disease (GVHD). Her disease recurred when GVHD resolved. This patient's clinical course provides evidence for the probable existence of allogeneic graft-versus-hepatoblastoma effect.

Concomitant Administration of Vincristine, Doxorubicin, Cyclophosphamide, Ifosfamide, and Etoposide for High-risk Sarcomas: the St. Jude Children's Research Hospital Experience

Cancer. Apr, 2006  |  Pubmed ID: 16541446

Intensified chemotherapy may improve the outcome of patients with high-risk pediatric sarcomas. Vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide are highly effective against pediatric sarcomas. The authors investigated the feasibility of administering these agents concomitantly within a defined period.

Exploration in Outbred Mice Covaries with General Learning Abilities Irrespective of Stress Reactivity, Emotionality, and Physical Attributes

Neurobiology of Learning and Memory. Sep, 2006  |  Pubmed ID: 16650783

Across multiple learning tasks (that place different sensory, motor, and information processing demands on the animals), we have found that the performance of mice is commonly regulated by a single factor ("general learning") that accounts for 30-40% of the variance across individuals and tasks. Furthermore, individuals' general learning abilities were highly correlated with their propensity to engage in exploration in an open field, a behavior that is potentially stress-inducing. This relationship between exploration in the open field and general learning abilities suggests the possibility that variations in stress sensitivity/responsivity or related emotional responses might directly influence individuals' general learning abilities. Here, the relationship of sensory/motor skills and stress sensitivity/emotionality to animals' general learning abilities were assessed. Outbred (CD-1) mice were tested in a battery of six learning tasks as well as 21 tests of exploratory behavior, sensory/motor function and fitness, emotionality, and stress reactivity. The performances of individual mice were correlated across six learning tasks, and the performance measures of all learning tasks loaded heavily on a single factor (principal component analysis), accounting for 32% of the variability between animals and tasks. Open field exploration and seven additional exploratory behaviors (including those exhibited in an elevated plus maze) also loaded heavily on this same factor, although general activity, sensory/motor responses, physical characteristics, and direct measures of fear did not. In a separate experiment, serum corticosterone levels of mice were elevated in response to a mild environmental stressor (confinement on an elevated platform). Stress-induced corticosterone levels were correlated with behavioral fear responses, but were unsystematically related to individuals' propensity for exploration. In total, these results suggest that although general learning abilities are strongly related to individuals' propensity for exploration, this relationship is not attributable to variations in sensory/motor function or the individuals' physiological or behavioral sensitivity to conditions that promote stress or fear.

Cidofovir for the Treatment of Adenoviral Infection in Pediatric Hematopoietic Stem Cell Transplant Patients

Transplantation. May, 2006  |  Pubmed ID: 16732176

Adenovirus (ADV) infections are associated with significant morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The virus is endemic in the general pediatric population and frequently causes severe disease in immunocompromised patients, especially children. We report our experience with cidofovir (CDV) for treatment of ADV infection in 57 HSCT patients, median age 8 years (range 0.5-26).

Diagnostic Challenge in Recurrent Skin Rash After Autologous Bone Marrow Transplantation

Journal of Pediatric Hematology/oncology. Aug, 2006  |  Pubmed ID: 16912592

Engraftment syndrome, autologous graft-versus-host disease (GVHD), and infection after autologous hematopoietic cell transplantation can have similar clinical presentations. Here, we describe a patient with refractory Ewing sarcoma who had recurrent skin rash after autologous hematopoietic cell transplantation. Although the rash was diagnosed as GVHD histologically, this case illustrates the diagnostic dilemma of distinguishing engraftment syndrome, autologous GVHD, or concomitant viral infection. Because therapy for these entities is different, distinguishing them is important. Establishment of diagnostic criteria and understanding of the pathophysiology of these entities may lead to better management and to improved therapy of refractory cancer.

Rapid Immune Reconstitution After a Reduced-intensity Conditioning Regimen and a CD3-depleted Haploidentical Stem Cell Graft for Paediatric Refractory Haematological Malignancies

British Journal of Haematology. Nov, 2006  |  Pubmed ID: 17010105

The main obstacles to successful haploidentical haematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections and severe graft-versus-host disease (GvHD). We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin in order to expedite immune reconstitution after a CD3-depleted haploidentical stem cell transplant. This protocol was used to treat 22 paediatric patients with refractory haematological malignancies. After transplantation, 91% of the patients achieved full donor chimaerism. They also showed rapid recovery of CD3(+) T-cells, T-cell receptor (TCR) excision circle counts, TCRbeta repertoire diversity and natural killer (NK)-cells during the first 4 months post-transplantation, compared with those results from a group of patients treated with a myeloablative conditioning regimen. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.

Risk-adapted Craniospinal Radiotherapy Followed by High-dose Chemotherapy and Stem-cell Rescue in Children with Newly Diagnosed Medulloblastoma (St Jude Medulloblastoma-96): Long-term Results from a Prospective, Multicentre Trial

The Lancet Oncology. Oct, 2006  |  Pubmed ID: 17012043

Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma.

Establishing the Use of Body Mass Index As an Indicator of Nutrition Risk in Children with Cancer

JPEN. Journal of Parenteral and Enteral Nutrition. Jan-Feb, 2007  |  Pubmed ID: 17202441

The negative health consequences of malnutrition in the pediatric oncology patient are well known. The purpose of this study was to determine the usefulness of body mass index (BMI) for age as a tool to prospectively identify pediatric cancer patients at risk for malnutrition and to determine the BMI percentile that would be required to identify at-risk patients.

Selective Attention is a Primary Determinant of the Relationship Between Working Memory and General Learning Ability in Outbred Mice

Learning & Memory (Cold Spring Harbor, N.Y.). Jan-Feb, 2007  |  Pubmed ID: 17272650

A single factor (i.e., general intelligence) can account for much of an individuals' performance across a wide variety of cognitive tests. However, despite this factor's robustness, the underlying process is still a matter of debate. To address this question, we developed a novel battery of learning tasks to assess the general learning abilities (GLAs) of mice. Using this battery, we previously reported a strong relationship between GLA and a task designed to tax working memory capacity (i.e., resistance to competing demands). Here we further explored this relationship by investigating which aspects of working memory (storage or processing) best predict GLAs in mice. We found that a component of working memory, selective attention, correlated with GLA comparably to working memory capacity. However, this relationship was not found for two other components of working memory, short-term memory capacity and duration. These results provide further evidence that variations in aspects of working memory and executive functions covary with general cognitive abilities.

Feasibility and Outcome of Reduced-intensity Conditioning in Haploidentical Transplantation

Annals of the New York Academy of Sciences. Jun, 2007  |  Pubmed ID: 17442774

Allogeneic stem cell transplantation is for a number of patients with malignant and nonmalignant diseases the only curative approach. For those patients who do not have an HLA-identical-related or -unrelated stem cell donor, a related three-loci mismatch haploidentical stem cell transplantation with T cell-depleted stem cells is a viable option. T cell depletion either by CD34(+) positive selection or by CD3-negative depletion strategies is available and has been investigated. We have shown that reduced-intensity conditioning haploidentical transplantation using mobilized peripheral stem cells negatively depleted from T and B lymphocytes is associated with a rapid immune reconstitution, a low transplant-related mortality rate, and a favorable outcome in patients in remission at the time of transplant. For chemorefractory patients, additional posttransplant cellular and humoral immunotherapeutic strategies are needed for prevention of relapse after transplantation.

CD34(+) Hematopoietic Progenitor Cell Selection of Bone Marrow Grafts for Autologous Transplantation in Pediatric Patients

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. May, 2007  |  Pubmed ID: 17448921

CD34(+)-selection of hematopoietic grafts for patients undergoing autologous hematopoietic stem cell transplantation (HSCT) is frequently used to obtain a tumor-free graft. The majority of published experience is with peripheral blood stem cell (PBSC) products; only scant information has been published on bone marrow (BM) grafts. We reviewed our experience using CD34(+) selection of BM grafts in children undergoing autologous BM transplantation. After obtaining institutional approval, we performed a retrospective review of the medical records of patients who underwent autologous stem cell collection at St. Jude. From January 1, 1999, to December 31, 2003, 373 patients underwent autologous HSCT; 131 received marrow grafts, 237 received PBSC grafts, and 5 received a combination. Seventeen patients underwent BM harvests for CD34(+) selection of their stem cell grafts. Sixteen patients received 19 CD34 purified grafts processed on the Isolex 300i Magnetic Cell Selection System device. Four patients were not included in the engraftment analysis as 1 did not receive the collected product, 1 received a tandem product, and 2 received products that were composed of 2 or 3 combined purified products. Following selection, marrow grafts contained a median of 1.4 x 10(6) CD34(+) cells/kg (range: 0.09-8.3 x 10(6)/kg) and a median of 0.014 x10(8) total nucleated cell cells/kg (range: 0.001-0.09 x 10(8)/kg). The median CD34% recovery was 30.9% (range: 9.3%-57.1%), with the median CD34 purity being 95.5% (range: 62.2%-98.8%). All patients engrafted. The median time to absolute neutrophil count > or = 500/mm(3) was 19 days (range: 12-35 days), and to platelet recovery was 28 days (range 18-37 days). No patient died from transplant-related complications. Our study demonstrates that CD34(+)-selection of marrow grafts is feasible, and these grafts are able to successfully reconstitute hematopoiesis in patients undergoing autologous BMT.

Matched-related Donor Transplantation for Sickle Cell Disease: Report from the Center for International Blood and Transplant Research

British Journal of Haematology. Jun, 2007  |  Pubmed ID: 17459050

We report outcomes after myeloablative haematopoietic cell transplantation (HCT) from human leucocyte antigen (HLA)-matched sibling donors in 67 patients with sickle cell disease transplanted between 1989 and 2002. The most common indications for transplantation were stroke and recurrent vaso-occlusive crisis in 38% and 37% of patients respectively. The median age at transplantation was 10 years and 67% of patients had received >10 red blood cell transfusions before HCT. Twenty-seven percent of patients had a poor performance score at transplantation. Ninety-four percent received busulfan and cyclophosphamide-containing conditioning regimens and bone marrow was the predominant source of donor cells. Most patients achieved haematopoietic recovery and no deaths occurred during the early post-transplant period. Rates of acute and chronic graft-versus-host disease were 10% and 22% respectively. Sixty-four of 67 patients are alive with 5-year probabilities of disease-free and overall survival of 85% and 97% respectively. Nine patients had graft failure with recovery of sickle erythropoiesis, eight of who had recurrent sickle-related events. This report confirms and extends earlier reports that HCT from HLA-matched related donors offers a very high survival rate, with few transplant-related complications and the elimination of sickle-related complications in the majority of patients who undergo this therapy.

A Novel Approach for the Analysis of T-cell Reconstitution by Using a T-cell Receptor Beta-based Oligonucleotide Microarray in Hematopoietic Stem Cell Transplantation

Experimental Hematology. May, 2007  |  Pubmed ID: 17577931

Analysis of T-cell population diversity is important to hematopoietic stem cell transplantation (HSCT). The millions of specificities in T-cell receptor (TCR) hypervariable complementarity- determining region 3 (CDR3) precludes detection of all T-cell populations by antibody-based flow cytometry. An alternative method, the TCR CDR3 spectratyping assay, involves multiple polymerase chain reaction (PCR) analyses and is interpreted only qualitatively. In this study, we designed the first TCRbeeta-based oligonucleotide microarray and investigated its specificity, clonality discrimination, sensitivity of detection, and feasibility for monitoring T-cell population diversity in HSCT.

Diagnostic Yield of Bronchoalveolar Lavage is Low in Allogeneic Hematopoietic Stem Cell Recipients Receiving Immunosuppressive Therapy or with Acute Graft-versus-host Disease: the St. Jude Experience, 1990-2002

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Jul, 2007  |  Pubmed ID: 17580261

Management of pulmonary complications after hematopoietic stem cell transplantation (HSCT) often includes bronchoalveolar lavage (BAL), but the diagnostic yield of BAL remains unclear in pediatric HSCT patients. We reviewed the records of 78 allogeneic and 11 autologous transplant recipients who underwent BAL after HSCT at St. Jude Children's Research Hospital (1990-2002). We analyzed donor and recipient information, clinical variables, adverse events during bronchoscopy, outcome, and medical management at the time of the procedure to determine the diagnostic yield of BAL and factors that affect its success. Seventy-eight allogeneic and 11 autologous transplant recipients underwent BAL at a median of 68 days (range, 6-528 days) and 23 days (range, 6-705 days) after HSCT, respectively. The median age at the time of BAL was 12.2 years (0.8-23.5 years) in allogeneic patients and 16.9 years (4.8-26.2 years) in autologous patients. The most common indications for BAL in both populations were fever, hypoxia, and abnormality on chest auscultation. BAL identified an etiology in 53 allogeneic (67.9%) and 7 autologous (63.6%) patients (BAL positive); only 1 etiology was identified in 30 of the 53 allogeneic patients (56.6%). The most common finding was bacterial infection in both allogeneic (59.0%) and autologous (71.4%) patients. Of 39 allogeneic patients who had concurrent extrapulmonary infection, 30 (76.9%) had a positive BAL. Seven (9.0%) allogeneic patients experienced hypoxia (generally transient) during bronchoscopy. Approximately 68% of those with a positive BAL were receiving immunosuppressive therapy, whereas 96% of patients with a negative BAL were receiving immunosuppressive therapy (P = .008). Further, 26.4% of the BAL-positive cohort had grade II-IV acute graft-versus-host disease (aGVHD), whereas 60% of the BAL-negative group had grade II-IV aGVHD (P = .004). In our experience, the safety and diagnostic yield of BAL in this set of patients is relatively high, but the likelihood of informative findings is reduced among allogeneic recipients with grade II-IV aGVHD and those receiving immunosuppressive therapy.

A Prospective Cohort Study of Late Sequelae of Pediatric Allogeneic Hematopoietic Stem Cell Transplantation

Medicine. Jul, 2007  |  Pubmed ID: 17632263

As survivors of pediatric allogeneic hematopoietic stem cell transplantations (HSCTs) increase in number, it is increasingly important to evaluate their well-being. We conducted this prospective cohort study to evaluate the cumulative incidence and risk factors for late sequelae of HSCT. Comprehensive surveillance tests were performed annually on every participant, regardless of signs and symptoms, to obtain accurate information on the time-of-onset of each late event to allow hazard function analyses. All participants included in this report had been followed for at least 3 years after HSCT. With a median follow-up of 9 years and a current age of 18.5 years, only 20 of the 155 participants (13%) had no late sequelae; 18 survivors (12%) had 1 chronic health condition, 71 (46%) had 2-4 conditions, and 46 (30%) had 5-9 conditions. Risk factors for increasing number of chronic conditions included young age at the time of HSCT, female sex, high radiation dose, and history of chronic graft-versus-host disease. The cumulative incidence at 10 years for common late events was as follows (ordered by the median time-of-onset): osteonecrosis 13.8%, chronic renal insufficiency 26.8%, hypothyroidism 45.1%, growth hormone deficiency 31.2%, female hypogonadism 57.4%, osteopenia 47.7%, cataracts 43.4%, pulmonary dysfunction 63.2%, and male hypogonadism 20.3%. Coexistence of multiple late sequelae was common in HSCT survivors. Our findings provide a basis for more effective patient counseling, optimal surveillance, and early intervention.

Pharmacological Modulation of Stress Reactivity Dissociates General Learning Ability from the Propensity for Exploration

Behavioral Neuroscience. Oct, 2007  |  Pubmed ID: 17907827

It has previously been reported that general learning ability (GLA) correlates positively with exploratory tendencies in individual outbred mice. This finding suggests the possibility that variations in stress reactivity modulate GLA and thus its relationship to exploratory tendencies. Here, the authors investigated the potential role of stress reactivity in regulating this relationship by assessing the effects of the anxiolytic chlorodiazepoxide (CDP; 10 mg/kg) on subjects' performance in a battery of diverse learning tasks as well as exploratory behaviors and stress reactivity. CDP-treated mice exhibited reductions in stress-induced corticosterone levels and behavioral reactivity to mild stressors and a corresponding increase in exploration. However, CDP-treated mice did not exhibit facilitated acquisition of any of the learning tasks and expressed GLA comparable to controls. Results indicate that although reduced stress reactivity promotes exploration, this does not translate into an up-regulation of GLA, suggesting that the relationship between GLA and exploration is not mediated by stress reactivity. The authors propose that variations in GLA reflect individuals' propensity for novelty seeking, whereas exploration reflects both stress reactivity and novelty seeking, the latter of which may underlie the relationship between exploration and GLA.

EBV Lymphoproliferative Disease of Host Origin After Haploidentical Stem Cell Transplantation

Pediatric Blood & Cancer. Nov, 2007  |  Pubmed ID: 16421900

Post-transplant lymphoproliferative disease (PTLPD), due to the reactivation of Epstein-Barr virus (EBV), is a serious complication. The risk of the disorder increases with T-cell depletion methods, mismatched hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD), and immunosuppression. In contrast to solid organ transplantation, where EBV is typically of recipient origin, the source of the EBV in HSCT recipients is donor-derived B-lymphocytes. In this report, we describe a 15-year-old girl who underwent HSCT from her father as treatment for acute myeloid leukemia (AML). She subsequently developed disseminated PTLPD involving multiple organ and nodal sites. Her neoplastic lymphoblasts were host-derived and refractory to rituximab treatment due to lack of CD20 expression.

Perspective on the Role of Haploidentical Transplantation in the Management of Hematologic Malignancies: Why Do It?

Current Hematologic Malignancy Reports. Jul, 2007  |  Pubmed ID: 20425370

Haploidentical hematopoietic stem cell transplantation (HSCT) using mismatched family member donors has historically been complicated by high rates of nonrelapse toxicity and the need for laboratory expertise in depleting grafts of T lymphocytes. Over the past decade, improvements in supportive care, the increased use of peripheral-blood stem cell grafts, and improved T-cell depletion techniques have reduced the incidence of graft failure and lowered the rate of nonrelapse mortality. In addition, clinical studies have demonstrated that the donor-recipient mismatch may be beneficial in this setting, stimulating an immunologic cell-mediated antileukemia effect that results in lower disease recurrence rates. All of these advances have led to improvements in outcomes following haploidentical HSCT, making it an attractive option available to some patients. Because most patients do not have a matched related donor available and time to identify an unrelated donor may be excessive, haploidentical HSCT is a potentially curative option for these patients.

Alternative Allogeneic Donor Sources for Transplantation for Childhood Diseases: Unrelated Cord Blood and Haploidentical Family Donors

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Jan, 2008  |  Pubmed ID: 18162220

Allogeneic stem cell transplantation has been demonstrated to be curative in a wide variety of pediatric malignant and nonmalignant diseases, and can be traced back over 50 years ago to the original report of Thomas et al. HLA matched sibling donors have been the gold standard for pediatric recipients requiring allogeneic donors for both nonmalignant and malignant conditions. However, only 25% of potential pediatric recipients possesses an HLA-matched sibling donor, and the frequency is even less in those with genetic nonmalignant conditions because of genetically affected other siblings within the family. Therefore, 75% to 90% of potential pediatric recipients require alternative allogeneic donor cells for treatment of their underlying conditions. Potential alternative allogeneic donor sources include unrelated cord blood donors, unrelated adult donors, and haploidentical family donors. In this article we review the experience of both unrelated cord blood donor and haploidentical family donor transplants in selected pediatric malignant and nonmalignant conditions.

Allogeneic Transplants in Follicular Lymphoma: Higher Risk of Disease Progression After Reduced-intensity Compared to Myeloablative Conditioning

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Feb, 2008  |  Pubmed ID: 18215784

Reduced-intensity conditioning (RIC) regimens have been increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in follicular lymphoma (FL). We compared traditional myeloablative conditioning regimens to RIC in FL. Outcomes of HLA-identical sibling HSCT for FL in 208 recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1997 and 2002 were studied. Conditioning regimens were categorized as myeloablative (N = 120) or RIC (N = 88). Use of RIC regimens increased from <10% of transplants in 1997 to >80% in 2002 signaling a major shift in practice. Patients receiving RIC were older and had a longer interval from diagnosis to transplant. These differences did not correlate with outcomes. Median follow-up of survivors was 50 months (4-96 months) after myeloablative conditioning versus 35 months (4-82 months) after RIC (P < .001). At 3 years, overall survival (OS) for the myeloablative and RIC cohorts were 71 (63%-79%) and 62 (51%-72%; P = .15) and progression free survival (PFS), 67 (58%-75%) and 55 (44%-65%; P = .07), respectively. Lower Karnofsky performance score (KPS) and resistance to chemotherapy were associated with higher treatment-related mortality (TRM) and lower OS and PFS. On multivariate analysis, an increased risk of lymphoma progression after RIC was observed (relative risk = 2.97, P = .04). RIC has become the de facto standard in allogeneic HSCT for FL, and appears to result in similar long-term outcomes. Although disease-free survival (DPS) is similar compared to myeloablative conditioning, an increased risk of late disease progression after RIC is concerning.

High-dose Chemotherapy with Autologous Stem Cell Rescue for Children with Recurrent Malignant Brain Tumors

Cancer. Mar, 2008  |  Pubmed ID: 18224664

High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been reported to be effective in treating children with recurrent central nervous system (CNS) malignancies.

Unrelated Donor Transplants in Adults with Philadelphia-negative Acute Lymphoblastic Leukemia in First Complete Remission

Blood. Jul, 2008  |  Pubmed ID: 18398065

We report the retrospective outcomes of unrelated donor (URD) transplants in 169 patients with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) who received transplants between 1995 and 2004. Median age was 33 years (range, 16-59 years). A total of 50% had a white blood cell count (WBC) more than 30 x 10(9)/L, 18% extramedullary disease, 42% achieved CR more than 8 weeks from diagnosis, 25% had adverse cytogenetics, and 19% had T-cell leukemia. A total of 41% were HLA well-matched, 41% partially matched with their donors, and 18% were HLA-mismatched. At 54-month median follow-up, incidences of acute grade 2-IV, III to IV, and chronic graft-versus-host disease were 50%, 25%, and 43%, respectively. Five-year treatment-related mortality (TRM), relapse, and overall survival were 42%, 20%, and 39%, respectively. In multivariate analyses, TRM was significantly higher with HLA-mismatched donors and T-cell depletion. Relapse risk was higher if the diagnostic WBC was more than 100 x 10(9)/L. Factors associated with poorer survival included WBC more than 100 x 10(9)/L, more than 8 weeks to CR1, cytomegalovirus seropositivity, HLA mismatching, and T-cell depletion. Nearly 40% of adults with ALL in CR1 survive 5 years after URD transplantation. Relapse risks were modest; TRM is the major cause of treatment failure. Selecting closely HLA-matched URD and reducing TRM should improve results.

Molecular Monitoring of Immune Reconstitution After Haploidentical Stem Cell Transplantation

Current Stem Cell Research & Therapy. May, 2008  |  Pubmed ID: 18473872

Haploidentical hematopoietic stem cell transplantation from a mismatched family member is an alternative treatment for transplant candidates who lack a HLA-matched related or an appropriate unrelated donor. One of main obstacles to successful haploidentical transplantation is slow immune reconstitution which significantly increases the risk of opportunistic infections, graft-vs-host-disease and disease relapse. Immune reconstitution is conventionally estimated by phenotypic recovery of immune cells according to lineage and/or by in vitro evidence of cell function. The limitations of these approaches include the sensitivity and specificity of phenotype markers, the availability of antibodies, the instability of long-term cell culture and the laborious nature of cell-function assays. Investigators have sought alternative approaches that are more sensitive, specific and simple, and that allow high-throughput testing for use in clinical transplantation. In this mini-review, we briefly introduce the concept of "molecular monitoring of immune-reconstitution" and discuss recent progress in this field achieved by our laboratory and other groups. We also propose future directions for clinical research incorporating these novel concepts.

Leucoencephalopathy, Transverse Myelopathy, and Peripheral Neuropathy in Association with Glutamic Acid Decarboxylase-65 (GAD) Antibodies in Children with Cancer

Journal of Child Neurology. Nov, 2008  |  Pubmed ID: 18474930

Neurologic toxicity may occur as a direct effect of cancer and its therapy or indirectly because of a dysfunctional immune system. The authors report the development of axonal neuropathy, myelopathy, and leucoencephalopathy associated with glutamic acid decarboxylase-65 (GAD) antibodies in 4 children with progressive cancer who were heavily pretreated. Three patients with refractory leukemia and 1 with Ewing sarcoma developed paraplegia with sensory level and dorsal column dysfunction. Three developed leucoencephalopathy and 1 died of neurologic disease. All had high serum titers of GAD antibodies during the progressive phase of the illness, and the antibody levels returned to normal with the stability of the neurologic disease. Three survivors are showing gradual recovery. This syndrome of central and peripheral nervous system toxicity may have resulted from chemotherapy toxicity or from immune dysfunction, as suggested by the high GAD antibody titers.

Up-regulation of Exploratory Tendencies Does Not Enhance General Learning Abilities in Juvenile or Young-adult Outbred Mice

Neurobiology of Learning and Memory. Sep, 2008  |  Pubmed ID: 18555705

"General cognitive ability" describes a trait that transcends specific learning domains and impacts a wide range of cognitive skills. Individual animals (including humans) exhibit wide variations in their expression of this trait. We have previously determined that the propensity for exploration is highly correlated with the general cognitive abilities of individual outbred mice. Here, we asked if inducing an increase in exploratory behaviors would causally promote an increase in animals' general learning abilities. In three experiments, juvenile and young-adult male CD-1 outbred mice were exposed to 12 novel environments starting at post-natal days 39 (juvenile) and 61 (young adult), after which they underwent a series of cognitive and exploratory tests as adults (beginning at post-natal day 79). Exposure to novel environments promoted increases in exploration (across multiple measures) on two different tasks, including an elevated plus maze. However, a subsequent test of general learning abilities (aggregate performance across five distinct learning tasks) determined that exposure to novel environments as juveniles or young-adults had no effect on general learning abilities in adulthood. Therefore, while exposure to novel environments promotes long-lasting increases in mice's exploratory tendencies, these increases in exploration do not appear to causally impact general learning abilities.

Second Autologous Stem Cell Transplantation for Relapsed Lymphoma After a Prior Autologous Transplant

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Aug, 2008  |  Pubmed ID: 18640574

We determined treatment-related mortality, progression-free survival (PFS), and overall survival (OS) after a second autologous HCT (HCT2) for patients with lymphoma relapse after a prior HCT (HCT1). Outcomes for patients with either Hodgkin lymphoma (HL, n = 21) or non-Hodgkin lymphoma (NHL, n = 19) receiving HCT2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) were analyzed. The median age at HCT2 was 38 years (range: 16-61) and 22 (58%) patients had a Karnofsky performance score <90. HCT2 was performed >1 year after HCT1 in 82%. The probability of treatment-related mortality at day 100 was 11% (95% confidence interval [CI], 3%-22%). The 1-, 3-, and 5-year probabilities of PFS were 50% (95% CI, 34%-66%), 36% (95% CI, 21%-52%), and 30% (95% CI, 16%-46%), respectively. Corresponding probabilities of survival were 65% (95% CI, 50%-79%), 36% (95% CI, 22%-52%), and 30% (95% CI, 17%-46%), respectively. At a median follow-up of 72 months (range: 12-124 months) after HCT2, 29 patients (73%) have died, 18 (62%) secondary to relapsed lymphoma. The outcomes of patients with HL and NHL were similar. In summary, this series represents the largest reported group of patients with relapsed lymphomas undergoing SCT2 following failed SCT1, and with long-term follow-up. Our series suggests that SCT2 is feasible in patients relapsing after prior HCT1, with a lower treatment-related mortality than that reported for allogeneic transplant in this setting. HCT2 should be considered for patients with relapsed HL or NHL after HCT1 without alternative allogeneic stem cell transplant options.

Impact of Prior Imatinib Mesylate on the Outcome of Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia

Blood. Oct, 2008  |  Pubmed ID: 18664621

Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM(+)) and 900 subjects who did not receive IM before HCT (IM(-)) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM(+) and IM(-) groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.

Clinical and CT Features of Benign Pneumatosis Intestinalis in Pediatric Hematopoietic Stem Cell Transplant and Oncology Patients

Pediatric Radiology. Oct, 2008  |  Pubmed ID: 18665358

Pneumatosis intestinalis in children is associated with a wide variety of underlying conditions and often has a benign course. The CT features of this condition have not been systematically investigated.

Amifostine Protects Against Cisplatin-induced Ototoxicity in Children with Average-risk Medulloblastoma

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Aug, 2008  |  Pubmed ID: 18669462

To determine the role of amifostine as a protectant against cisplatin-induced ototoxicity in patients with average-risk (AR) medulloblastoma treated with craniospinal radiotherapy and four cycles of cisplatin-based, dose-intense chemotherapy and stem-cell rescue.

HLA-matched Sibling Hematopoietic Stem Cell Transplantation for Fanconi Anemia: Comparison of Irradiation and Nonirradiation Containing Conditioning Regimens

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Oct, 2008  |  Pubmed ID: 18804044

Related to the underlying DNA repair defect that is the hallmark of Fanconi anemia (FA), preparatory regimen-related toxicities have been obstacles to hematopoietic cell transplantation (HCT). In an attempt to decrease the risk and severity of regimen-related toxicities, nonirradiation regimens have been explored. The aim of this study is to compare outcomes after irradiation and nonirradiation regimens in 148 FA patients and identify risk factors impacting upon HCT outcomes. Hematopoietic recovery, acute and chronic graft-versus-host disease (aGVHD, GVHD), and mortality were similar after irradiation and nonirradiation regimens. In both groups of recipients aged >10 years, prior use of androgens and cytomegalovirus seropositivity in either the donor or recipient were associated with higher mortality. With median follow-ups >5 years, the 5-year probability of overall survival, adjusted for factors impacting overall mortality was 78% and 81% after irradiation and nonirradiation regimens, P = .61. In view of the high risk of cancer and other radiation-related effects on growth and development, these results support the use of nonirradiation preparatory regimens. As the peak time for developing solid tumors after HCT is 8 to 9 years, longer follow-up is required before definitive statements can be made regarding the impact of nonirradiation regimens on cancer risk.

Advances in Pediatric Hematopoietic Stem Cell Transplantation

Cancer Biology & Therapy. Oct, 2008  |  Pubmed ID: 18927494

Allogeneic and autologous hematopoietic stem cell transplantation (HSCT) has become a therapeutic option for an increasing number of patients with otherwise incurable leukemias, solid tumors, immunodeficiencies, hemoglobinopathies and metabolic diseases. For patients requiring an allogeneic transplant, the addition of unrelated cord blood units and partially matched family member donors as alternate stem cell sources has increased the chances that an appropriate donor can be identified. In addition, new approaches to stem cell graft engineering are yielding insights into potential cellular immune therapies, which may decrease the adverse effects of HSCT such as graft-versus-host disease (GVHD) and harness the alloimmune graft-versus-leukemia effect. Novel conditioning regimens, primarily reduced intensity and non-myeloablative regimens, allow patients with significant co-morbidities to undergo transplantation with reduced morbidity and mortality. Combinations of immune-modulatory cytokines and monoclonal antibodies with autologous and allogeneic transplantation are among the advances being explored in contemporary HSCT.

Risk Factors for Acute Graft-versus-host Disease After Human Leukocyte Antigen-identical Sibling Transplants for Adults with Leukemia

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Dec, 2008  |  Pubmed ID: 18981462

Acute graft-versus-host disease (GVHD) causes substantial morbidity and mortality after human leukocyte antigen (HLA)-identical sibling transplants. No large registry studies of acute GVHD risk factors have been reported in two decades. Risk factors may have changed in this interval as transplant-related techniques have evolved.

Influence of Age and Histology on Outcome in Adult Non-Hodgkin Lymphoma Patients Undergoing Autologous Hematopoietic Cell Transplantation (HCT): a Report from the Center For International Blood & Marrow Transplant Research (CIBMTR)

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Dec, 2008  |  Pubmed ID: 19041053

To compare the clinical outcomes of older (age > or =55 years) non-Hodgkin lymphoma (NHL) patients with younger NHL patients (<55 years) receiving autologous hematopoietic cell transplantation (HCT) while adjusting for patient-, disease-, and treatment-related variables, we compared autologous HCT outcomes in 805 NHL patients aged > or =55 years to 1949 NHL patients <55 years during the years 1990-2000 using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). In multivariate analysis, older patients with aggressive histologies were 1.86 times (95% confidence interval [CI] 1.43-2.43, P < .001) more likely than younger patients to experience treatment-related mortality (TRM). Relative death risks were 1.33 times (CI 1.04-1.71, P = .024) and 1.50 times (CI 1.33-16.9, P < .001) higher in older compared to younger patients with follicular grade I/II and aggressive histologies, respectively. Autologous HCT in older NHL patients is feasible, but most disease-related outcomes are statistically inferior to younger patients. Studies addressing supportive care particular to older patients, who are most likely to benefit from this approach, are recommended.

The Graft-versus-leukemia Effect Using Matched Unrelated Donors is Not Superior to HLA-identical Siblings for Hematopoietic Stem Cell Transplantation

Blood. Mar, 2009  |  Pubmed ID: 19059878

Do some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]-matched, n=941) or HLA-identical sibling donor (n=3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P< .001) and relapse (RR, 1.50; P< .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P< .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect.

Total and Active Rabbit Antithymocyte Globulin (rATG;Thymoglobulin) Pharmacokinetics in Pediatric Patients Undergoing Unrelated Donor Bone Marrow Transplantation

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Feb, 2009  |  Pubmed ID: 19167688

Rabbit antithymocyte globulin (rATG; Thymoglobulin) is currently used to prevent or treat graft-versus-host disease (GVHD) during hematopoietic stem cell transplantation (HSCT). The dose and schedule of rATG as part of the preparative regimen for unrelated donor (URD) bone marrow transplantation (BMT) have not been optimized in pediatric patients. We conducted a prospective study of 13 pediatric patients with hematologic malignancies undergoing URD BMT at St. Jude Children's Research Hospital from October 2003 to March 2005, to determine the pharmacokinetics and toxicities of active and total rATG. The conditioning regimen comprised total body irradiation (TBI), thiotepa, and cyclophosphamide (Cy); cyclosporine (CsA) and methotrexate (MTX) were administered as GVHD prophylaxis. Patients received a total dose of 10 mg/kg rATG, and serial blood samples were assayed for total rATG by enzyme linked immunosorbent assay (ELISA) and active rATG by florescein activated cell sorting (FACS). We found that our weight-based dosing regimen for rATG was effective and well tolerated by patients. The half-lives of total and active rATG were comparable to those from previous studies, and despite high doses our patients had low maximum concentrations of active and total rATG. There were no occurrences of grade iii-iv GVHD even in patients having low peak rATG levels, and the overall incidence of grade II GVHD was only 15%. None of the patients had serious infections following transplantation. These data support the use of a 10 mg/kg dose of rATG in children with hematologic malignancies because it can be administered without increasing the risk of graft rejection, or serious infection in pediatric patients with a low rate of GVHD. These conclusions may not apply to patients with nonmalignant disorders.

Clinical Utility of Computed Tomography Screening of Chest, Abdomen, and Sinuses Before Hematopoietic Stem Cell Transplantation: the St. Jude Experience

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Apr, 2009  |  Pubmed ID: 19285637

All allogeneic (allo) and autologous (auto) hematopoietic stem cell transplantation (HSCT) recipients at St. Jude Children's Research Hospital undergo pre-HSCT computed tomography (CT) of the sinuses, chest, and abdomen because they are at significant risk for opportunistic infections. We studied whether this extensive routine imaging is warranted to detect infection despite the risk of additional radiation exposure. We reviewed the medical records of all children receiving allo- and auto-HSCT at St. Jude in 2004 and 2005. Of the 184 eligible patients who received 187 transplants, 131 received allografts and 56 autografts. Solid tumors and lymphomas were removed from the final analysis of the chest and abdomen CT as this imaging is typically warranted as part of disease restaging; thus, 111 allogeneic participants were included in this analysis. Both auto- and allo-recipients were evaluated by sinus CT and included in this final analysis. Most allo- and auto-HSCT recipients (> or =80%) did not have sinus, pulmonary, cardiac, or gastrointestinal symptoms; >85% of the evaluable allo-recipients had no prior fungal infection. Eighty-eight allo- and 31 auto-HSCT recipients had abnormal sinus CT findings, all unrelated to the underlying disease. Sixty-two (55.9%) of the allo-recipients had normal chest CT and 85 (76.6%) had normal abdominal CT. Of the 18 allo-recipients who began new therapy based on these findings, only 2 (11.1%) were related to chest CT findings and the other 16 were related to sinus findings. Our findings suggest that pre-HSCT routine CT imaging of the abdomen may not be warranted in a subset of allogeneic recipients who are asymptomatic and without previous infectious findings. Thus, these patients may be spared unnecessary radiation exposure. Recipients undergoing auto-HSCT or allo-HSCT for lymphomas or solid tumors will routinely undergo chest and abdominal CT imaging as part of their disease evaluation. The decision to perform chest CT should be made judiciously based on a careful history and physical examination. Sinus imaging, which was frequently abnormal, may be justified in all patients to plan post-HSCT care.

Prior Rituximab Correlates with Less Acute Graft-versus-host Disease and Better Survival in B-cell Lymphoma Patients Who Received Allogeneic Peripheral Blood Stem Cell Transplantation

British Journal of Haematology. Jun, 2009  |  Pubmed ID: 19344418

Prior therapy with rituximab might attenuate disparate histocompatibility antigen presentation by B cells, thus decreased the risk of acute graft-versus-host disease (GVHD) and improved survival. We tested this hypothesis by comparing the outcomes of 435 B-cell lymphoma patients who received allogeneic transplantation from 1999 to 2004 in the Center for International Blood and Marrow Transplant Research database: 179 subjects who received rituximab within 6 months prior to transplantation (RTX cohort) and 256 subjects who did not receive RTX within 6 months prior to transplantation (No-RTX cohort). The RTX cohort had a significantly lower incidence of treatment-related mortality (TRM) [relative risk (RR) = 0.68; 95% confidence interval (CI), 0.47-1.0; P = 0.05], lower acute grade II-IV (RR = 0.72; 95% CI, 0.53-0.97; P = 0.03) and III-IV GVHD (RR = 0.55; 95% CI, 0.34-0.91; P = 0.02). There was no difference in the risk of chronic GVHD, disease progression or relapse. Progression-free survival (PFS) (RR = 0.68; 95% CI 0.50-0.92; P = 0.01) and overall survival (OS) (RR = 0.63; 95% CI, 0.46-0.86; P = 0.004) were significantly better in the RTX cohort. Prior RTX therapy correlated with less acute GVHD, similar chronic GVHD, less TRM, better PFS and OS.

Risk Factors Affecting Outcome of Second HLA-matched Sibling Donor Transplantations for Graft Failure in Severe Acquired Aplastic Anemia

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. May, 2009  |  Pubmed ID: 19361755

We examined transplantation outcomes after a second HLA-matched sibling transplantation for primary (16%) or secondary (84%) graft failure in 166 patients with severe acquired aplastic anemia (AA). Two-thirds of these patients has a performance score < 90. In most cases (88%), the same donor was used for both transplants, for both transplantations, and 84% of the second transplantations used bone marrow grafts. We identified 2 prognostic factors: intertransplantation interval (surrogate for primary graft failure and early secondary graft failure) and performance status. Shorter intertransplantation interval ( 3 months from first transplantation was 56% and 76%, respectively. The corresponding probabilities in patients with lower performance scores were 33% and 61%. The predominant cause of failure after second transplantation was nonengraftment (in 72 of 166 patients), most commonly in patients with primary or early secondary graft failure (51 of 72; 71%). Our data indicate that novel approaches, including conditioning regimens with greater immunosuppression, should be explored for these patients.

Iron Overload in Survivors of Childhood Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

Pediatric Transplantation. May, 2009  |  Pubmed ID: 18518909

Iron overload has not been studied extensively and prospectively in pediatric survivors of allogeneic hematopoietic stem cell transplantation (HSCT); therefore, we conducted a prospective long-term study of 133 survivors of childhood leukemia to assess the incidence of and risk factors for iron overload and to investigate its association with organ dysfunction. One yr after HSCT, the mean serum ferritin level was 1158 ng/mL (range, 22-3264 ng/mL), with 124 patients (93.2%) having a serum ferritin level that exceeded the upper limit of the normal range (110 ng/mL). Thereafter, the serum ferritin level declined over time. There was a positive correlation between the level of serum ferritin and that of total bilirubin (r = 0.21, p < 0.001) and glutamate pyruvate transaminase (r = 0.17, p < 0.001). A high concentration of serum ferritin was associated with low cardiac fractional shortening (r = -0.15, p = 0.047). In addition, patients with hypothyroidism and GH deficiency had a higher level of serum ferritin than those without (p < 0.02). We conclude that iron overload is common after HSCT and is associated with hepatic, cardiac, and endocrine dysfunction.

Race and Socioeconomic Status Influence Outcomes of Unrelated Donor Hematopoietic Cell Transplantation

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Dec, 2009  |  Pubmed ID: 19896078

Success of hematopoietic cell transplantation (HCT) can vary by race, but the impact of socioeconomic status (SES) is not known. To evaluate the role of race and SES, we studied 6207 unrelated-donor myeloablative (MA) HCT recipients transplanted between 1995 and 2004 for acute or chronic leukemia or myelodysplastic syndrome (MDS). Patients were reported by transplant center to be White (n = 5253), African American (n = 368), Asian/Pacific-Islander (n = 141), or Hispanic (n = 445). Patient income was estimated from residential zip code at time of HCT. Cox regression analysis adjusting for other significant factors showed that African American (but not Asian or Hispanic) recipients had worse overall survival (OS) (relative-risk [RR] 1.47; 95% confidence interval [CI] 1.29-1.68, P < .001) compared to Whites. Treatment-related mortality (TRM) was higher in African Americans (RR 1.56; 95% CI 1.34-1.83, P < .001) and in Hispanics (RR 1.30; 95% CI 1.11-1.51, P = .001). Across all racial groups, patients with median incomes in the lowest quartile (<$34,700) had worse OS (RR 1.15; 95% CI 1.04-1.26, P = .005) and higher risks of TRM (RR 1.21; 1.07-1.36, P = .002). Inferior outcomes among African Americans are not fully explained by transplant-related factors or SES. Potential other mechanisms such as genetic polymorphisms that have an impact on drug metabolism or unmeasured comorbidities, socioeconomic factors, and health behaviors may be important. Low SES, regardless of race, has a negative impact on unrelated donor HCT outcomes.

Deletion of PEA-15 in Mice is Associated with Specific Impairments of Spatial Learning Abilities

BMC Neuroscience. 2009  |  Pubmed ID: 19917132

PEA-15 is a phosphoprotein that binds and regulates ERK MAP kinase and RSK2 and is highly expressed throughout the brain. PEA-15 alters c-Fos and CREB-mediated transcription as a result of these interactions. To determine if PEA-15 contributes to the function of the nervous system we tested mice lacking PEA-15 in a series of experiments designed to measure learning, sensory/motor function, and stress reactivity.

Impact of Pre-transplant Rituximab on Survival After Autologous Hematopoietic Stem Cell Transplantation for Diffuse Large B Cell Lymphoma

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Nov, 2009  |  Pubmed ID: 19822306

Incorporation of the anti-CD20 monoclonal antibody rituximab into front-line regimens to treat diffuse large B cell lymphoma (DLBCL) has resulted in improved survival. Despite this progress, however, many patients develop refractory or recurrent DLBCL and then undergo autologous hematopoietic stem cell transplantation (AuHCT). It is unclear to what extent pre-transplant exposure to rituximab affects outcomes after AuHCT. Outcomes of 994 patients receiving AuHCT for DLBCL between 1996 and 2003 were analyzed according to whether rituximab was (n = 176; +R cohort) or was not (n = 818; -R cohort) administered with front-line or salvage therapy before AuHCT. The +R cohort had superior progression-free survival (PFS; 50% vs 38%; P = .008) and overall survival (OS; 57% vs 45%; P = .006) at 3 years. Platelet and neutrophil engraftment were not affected by exposure to rituximab. Nonrelapse mortality (NRM) did not differ significantly between the 2 cohorts. In multivariate analysis, the +R cohort had improved PFS (relative risk of relapse/progression or death, 0.64; P < .001) and improved OS (relative risk of death, 0.74; P = .039). We conclude that pre-transplant rituximab is associated with a lower rate of progression and improved survival after AuHCT for DLBCL, with no evidence of impaired engraftment or increased NRM.

Outcomes of Hematologic Malignancies After Unrelated Donor Hematopoietic Cell Transplantation According to Place of Residence

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Mar, 2010  |  Pubmed ID: 19879951

Studies suggest that patients who live in rural areas may have worse clinical outcomes compared with patients living in urban areas. We studied whether place of residence (rural versus urban) is associated with clinical outcomes of patients with leukemia or myelodysplastic syndrome (MDS) who received an unrelated donor hematopoietic cell transplantation (HCT). Patients' residential ZIP code at the time of transplant was used to determine rural or urban designation based on the Rural Urban Commuting Codes. The study included 6140 patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 121 U.S. HCT centers: 1179 (19%) came from rural areas, whereas 4961 (81%) came from urban areas. Rural and urban patients were similar in patient-, disease-, and transplant-related characteristics aside from household income and distance traveled to the HCT center. After adjusting for income and other significant patient, disease, and transplant-related variables, the risk of overall mortality between patients residing in rural and urban areas were not statistically significant (relative risk 1.01, 95% confidence intervals 0.93-1.10, P = .74). Similar outcomes were noted for treatment-related mortality (TRM), disease-free survival (DFS), and relapse. Patient's income, derived from the U.S. Census and based on their residential ZIP code, was independently associated with outcomes. In summary, our study showed no differences in the clinical outcomes of patients from rural or urban areas after unrelated donor HCT.

Long-term Outcome of EBV-specific T-cell Infusions to Prevent or Treat EBV-related Lymphoproliferative Disease in Transplant Recipients

Blood. Feb, 2010  |  Pubmed ID: 19880495

T-cell immunotherapy that takes advantage of Epstein-Barr virus (EBV)-stimulated immunity has the potential to fill an important niche in targeted therapy for EBV-related cancers. To address questions of long-term efficacy, safety, and practicality, we studied 114 patients who had received infusions of EBV-specific cytotoxic T lymphocytes (CTLs) at 3 different centers to prevent or treat EBV(+) lymphoproliferative disease (LPD) arising after hematopoietic stem cell transplantation. Toxicity was minimal, consisting mainly of localized swelling at sites of responsive disease. None of the 101 patients who received CTL prophylaxis developed EBV(+) LPD, whereas 11 of 13 patients treated with CTLs for biopsy-proven or probable LPD achieved sustained complete remissions. The gene-marking component of this study enabled us to demonstrate the persistence of functional CTLs for up to 9 years. A preliminary analysis indicated that a patient-specific CTL line can be manufactured, tested, and infused for $6095, a cost that compares favorably with other modalities used in the treatment of LPD. We conclude that the CTL lines described here provide safe and effective prophylaxis or treatment for lymphoproliferative disease in transplantation recipients, and the manufacturing methodology is robust and can be transferred readily from one institution to another without loss of reproducibility.

High-dose Chemotherapy with Blood or Bone Marrow Transplants for Rhabdomyosarcoma

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Apr, 2010  |  Pubmed ID: 19961947

Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, is cured with conventional therapy in 70%. However, the 5-year survival for those who relapse is about 30%, and drops to about 15% for those with unfavorable histologies (alveolar/undifferentiated subtypes). We describe outcomes of 62 subjects receiving autologous blood/bone marrow (BM) transplants for RMS between 1989 and 2003, and reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR). Histologic subtype was confirmed by reviewing pathology reports. Treatment-related mortality (TRM), progression-free survival (PFS), and overall survival (OS) were evaluated. Overall, 73% of subjects were <20 years; 39% had cancer bulk >5 cm, 63% had metastasis at diagnosis, 55% had unfavorable histologies, 92% had cancer responsive to chemotherapy pretransplant, and 67% were in first remission. The 1-year TRM was 5% (95% confidence interval [CI], 1%-12%) and the 5-year PFS and OS were 29% (95% CI, 18%-41%) and 32% (95% CI, 21%-44%), respectively. There was only a 4% relapse rate after the first year. There were no differences in 5-year PFS or survival based on histological subtype, transplant in first remission versus relapse (36% versus 29%; P = .5), or transplantation for poor-risk histologies in first remission versus relapse (34% versus 33%; P = .9). Our data indicate that autotransplants for RMS disease are typically done in patients with disease responsive to chemotherapy pretransplant, with approximately one-third long-term survivors. Despite high-risk factors, we also found a low TRM, perhaps reflecting the migration from marrow to blood stem cells as the graft source. Even when performed after relapse for alveolar/undifferentiated histologies, long-term survivals were seen seemingly better than results with conventional therapies.

A Comparison of HLA-identical Sibling Allogeneic Versus Autologous Transplantation for Diffuse Large B Cell Lymphoma: a Report from the CIBMTR

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Jan, 2010  |  Pubmed ID: 20053330

We compared outcomes of 916 diffuse large B cell lymphoma (DLBCL) patients aged >or=18 years undergoing first autologous (n = 837) or myeloablative (MA) allogeneic hematopoietic cell transplant (HCT) (n = 79) between 1995 and 2003 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Median follow-up was 81 months for allogeneic HCT versus 60 months for autologous HCT. Allogeneic HCT recipients were more likely to have high-risk disease features including higher stage, more prior chemotherapy regimens, and resistant disease. Allogeneic HCT was associated with a higher 1 year treatment-related mortality (TRM) (relative risk [RR] 4.88, 95% confidence interval [CI], 3.21-7.40, P < .001), treatment failure (RR 2.06, 95% CI, 1.54-2.75, P < .001), and mortality (RR 2.75, 95% CI, 2.03-3.72, P < .001). Risk of disease progression was similar in the 2 groups (RR 1.12, 95% CI, 0.73-1.72, P = .59). In fact, for 1-year survivors, no significant differences were observed for TRM, progression, progression-free (PFS) or overall survival (OS). Increased risks of TRM and mortality were associated with older age (>50 years), lower performance score, chemoresistance, and earlier year of transplant. In a cohort of mainly high-risk DLBCL patients, upfront MA allogeneic HCT, although associated with increased early mortality, was associated with a similar risk of disease progression compared to lower risk patients receiving autologous HCT.

Second Unrelated Donor Hematopoietic Cell Transplantation for Primary Graft Failure

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Aug, 2010  |  Pubmed ID: 20172038

Failure to engraft donor cells is a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We describe the results of 122 patients reported to the National Marrow Donor Program between 1990 and 2005, who received a second unrelated donor HCT after failing to achieve an absolute neutrophil count of >or=500/microL without recurrent disease. Patients were transplanted for leukemia (n = 83), myelodysplastic disorders (n = 16), severe aplastic anemia (n = 20), and other diseases (n = 3). The median age was 29 years. Twenty-four patients received second grafts from a different unrelated donor. Among 98 patients who received a second graft from the same donor, 28 received products that were previously collected and cryopreserved for the first transplantation. One-year overall survival (OS) after second transplant was 11%, with 10 patients alive at last follow-up. We observed no differences between patients who received grafts from the same or different donors, or in those who received fresh or cryopreserved product. The outcomes after a second allogeneic HCT for primary graft failure are dismal. Identifying risk factors for primary graft failure can decrease the incidence of this complication. Further studies are needed to test whether early recognition and hastened procurement of alternative grafts can improve transplant outcomes for primary graft failure.

Outcomes of Pediatric Bone Marrow Transplantation for Leukemia and Myelodysplasia Using Matched Sibling, Mismatched Related, or Matched Unrelated Donors

Blood. Nov, 2010  |  Pubmed ID: 20671124

Although some trials have allowed matched or single human leukocyte antigen (HLA)-mismatched related donors (mmRDs) along with HLA-matched sibling donors (MSDs) for pediatric bone marrow transplantation in early-stage hematologic malignancies, whether mmRD grafts lead to similar outcomes is not known. We compared patients < 18 years old reported to the Center for International Blood and Marrow Transplant Research with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome undergoing allogeneic T-replete, myeloablative bone marrow transplantation between 1993 and 2006. In total, patients receiving bone marrow from 1208 MSDs, 266 8/8 allelic-matched unrelated donors (URDs), and 151 0-1 HLA-antigen mmRDs were studied. Multivariate analysis showed that recipients of MSD transplants had less transplantation-related mortality, acute graft-versus-host disease (GVHD), and chronic GVHD, along with better disease-free and overall survival than the URD and mmRD groups. No differences were observed in transplant-related mortality, acute and chronic GVHD, relapse, disease-free survival, or overall survival between the mmRD and URD groups. These data show that mmRD and 8/8 URD outcomes are similar, whereas MSD outcomes are superior to the other 2 sources. Whether allele level typing could identify mmRD recipients with better outcomes will not be known unless centers alter practice and type mmRD at the allele level.

Impact of Age on Outcomes After Bone Marrow Transplantation for Acquired Aplastic Anemia Using HLA-matched Sibling Donors

Haematologica. Dec, 2010  |  Pubmed ID: 20851870

Transplantation from an HLA-matched sibling is the treatment of choice for young patients with acquired severe aplastic anemia. For older patients, the acceptable upper age limit for transplantation as first-line treatment varies. The current analysis, therefore, sought to identify age or ages at transplantation at which survival differed.

Outcome of Patients with IgD and IgM Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation: a Retrospective CIBMTR Study

Clinical Lymphoma, Myeloma & Leukemia. Dec, 2010  |  Pubmed ID: 21156462

Immunoglobulin D (IgD) and IgM multiple myeloma represent uncommon immunoglobulin isotypes, accounting for 2% and 0.5% of cases, respectively. Limited information is available regarding the prognosis of these isotypes, but they have been considered to have a more aggressive course than the more common immunoglobulin G (IgG) and IgA isotypes. In particular, the outcome after autologous hematopoietic stem cell transplantation (auto-HCT) has not been well defined.

Hematopoietic Stem Cell Transplantation for Refractory or Recurrent Non-Hodgkin Lymphoma in Children and Adolescents

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Feb, 2010  |  Pubmed ID: 19800015

We examined the role of hematopoietic stem cell transplantation (HSCT) for patients aged< or =18 years with refractory or recurrent Burkitt (n=41), lymphoblastic (n=53), diffuse large B cell (DLBCL; n=52), and anaplastic large cell lymphoma (n=36), receiving autologous (n=90) or allogeneic (n=92; 43 matched sibling and 49 unrelated donor) HSCT in 1990-2005. Risk factors affecting event-free survival (EFS) were evaluated using stratified Cox regression. Characteristics of allogeneic and autologous HSCT recipients were similar. Allogeneic donor HSCT was more likely to use irradiation-containing conditioning regimens, bone marrow (BM) stem cells, be performed in more recent years, and for lymphoblastic lymphoma. EFS rates were lower for patients not in complete remission at HSCT, regardless of donor type. After adjusting for disease status, 5-year EFS were similar after allogeneic and autologous HSCT for DLBCL (50% vs 52%), Burkitt (31% vs 27%), and anaplastic large cell lymphoma (46% vs 35%). However, EFS was higher for lymphoblastic lymphoma, after allogeneic HSCT (40% vs 4%; P < .01). Predictors of EFS for progressive or recurrent disease after HSCT included disease status at HSCT and use of allogeneic donor for lymphoblastic lymphoma. These data were unable to demonstrate a difference in outcome by donor type for the other histological subtypes.

Reducing the Risk for Transplantation-related Mortality After Allogeneic Hematopoietic Cell Transplantation: How Much Progress Has Been Made?

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2011  |  Pubmed ID: 21220593

Transplantation-related mortality (TRM) is a major barrier to the success of allogeneic hematopoietic cell transplantation (HCT).

Clinical Options After Failure of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Hematologic Malignancies

Expert Review of Clinical Immunology. Jul, 2011  |  Pubmed ID: 21787195

Disease recurrence is the single most common cause of death after allogeneic or autologous hematopoietic stem cell transplantation (HSCT). Disease status and chemosensitivity at the time of transplantation, as well as the development of graft-versus-host disease (GVHD), are factors known to influence the risk of relapse post-HSCT. Both acute and chronic GVHD have been associated with decreased relapse rates; however, owing to toxicity, overall survival is not consistently improved in these patients. Furthermore, there is a transient period of immunodeficiency after HSCT, which may permit residual malignant cells to proliferate early in the post-transplant course, before the donor immune system can establish a graft-versus-tumor response. Patients who fail an initial HSCT have an extremely poor outcome; therefore, maneuvers to prevent, identify and treat recurrent disease as early as possible in these situations are necessary. Strategies to distinguish graft-versus-tumor from GVHD, to enhance both general and disease-specific immune reconstitution after transplantation, and to increase donor-mediated anti-host immune reactions are being investigated in clinical trials. Single agent nontoxic post-HSCT chemotherapy, cellular therapies and second allogeneic HSCT using reduced intensity regimens are among the modalities under investigation.

HLA-C Antigen Mismatch is Associated with Worse Outcome in Unrelated Donor Peripheral Blood Stem Cell Transplantation

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Jun, 2011  |  Pubmed ID: 20870028

The association between HLA matching and outcome in unrelated-donor peripheral blood stem cell (PBSC) transplantation has not yet been established. In the present study, a total of 1933 unrelated donor-recipient pairs who underwent PBSC transplantation between 1999 and 2006 for acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia and received high-resolution HLA typing for HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 were included in the analysis. Outcomes were compared between HLA-matched and HLA-mismatched pairs, adjusting for patient and transplant characteristics. Matching for HLA-A, -B, -C, and -DRB1 alleles (8/8 match) was associated with better survival at 1 year compared with 7/8 HLA-matched pairs (56% vs 47%). Using 8/8 HLA-matched patients as the baseline (n = 1243), HLA-C antigen mismatches (n = 189) were statistically significantly associated with lower leukemia-free survival (relative risk [RR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = .0010), and increased risk for mortality (RR, 1.41; 95% CI, 1.16-1.70; P = .0005), treatment-related mortality (RR, 1.61; 95% CI, 1.25-2.08; P = .0002), and grade III-IV graft-versus-host disease (RR, 1.98; 95% CI, 1.50-2.62; P < .0001). HLA-B antigen or allele mismatching was associated with an increased risk for acute GVHD grade III-IV. No statistically significant differences in outcome were observed for HLA-C allele (n = 61), HLA-A antigen/allele (n = 136), HLA-DRB1 allele (n = 39), or HLA-DQ antigen/allele (n = 114) mismatches compared with 8/8 HLA-matched pairs. HLA mismatch was not associated with relapse or chronic GVHD. HLA-C antigen-mismatched unrelated PBSC donors were associated with worse outcomes compared with 8/8 HLA-matched donors. The study's limited power due to small sample size precludes conclusions about other mismatches.

Comparison of Outcomes After Transplantation of G-CSF-stimulated Bone Marrow Grafts Versus Bone Marrow or Peripheral Blood Grafts from HLA-matched Sibling Donors for Patients with Severe Aplastic Anemia

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Jul, 2011  |  Pubmed ID: 21034842

We compared outcomes of patients with severe aplastic anemia (SAA) who received granulocyte-colony stimulating factor (G-CSF)-stimulated bone marrow (G-BM) (n = 78), unstimulated bone marrow (BM) (n = 547), or peripheral blood progenitor cells (PBPC) (n = 134) from an HLA-matched sibling. Transplantations occurred in 1997 to 2003. Rates of neutrophil and platelet recovery were not different among the 3 treatment groups. Grade 2-4 acute graft-versus-host disease (aGVHD) (relative risk [RR] = 0.82, P = .539), grade 3-4 aGVHD (RR = 0.74, P = .535), and chronic GVHD (cGVHD) (RR = 1.56, P = .229) were similar after G-BM and BM transplants. Grade 2-4 aGVHD (RR = 2.37, P = .012) but not grade 3-4 aGVHD (RR = 1.66, P = .323) and cGVHD (RR = 5.09, P < .001) were higher after PBPC transplants compared to G-BM. Grade 2-4 (RR = 2.90, P < .001), grade 3-4 (RR = 2.24, P = .009) aGVHD and cGVHD (RR = 3.26, P < .001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR = 0.63, P = .05). These data suggest no advantage to using G-BM and the observed higher rates of aGVHD and cGVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA-matched sibling transplants for SAA.

HLA-matched Sibling Bone Marrow Transplantation for β-thalassemia Major

Blood. Feb, 2011  |  Pubmed ID: 21119108

We describe outcomes after human leukocyte antigen-matched sibling bone marrow transplantation (BMT) for 179 patients with β-thalassemia major. The median age at transplantation was 7 years and the median follow-up was 6 years. The distribution of Pesaro risk class I, II, and III categories was 2%, 42%, and 36%, respectively. The day 30 cumulative incidence of neutrophil recovery and day 100 platelet recovery were 90% and 86%, respectively. Seventeen patients had graft failure, which was fatal in 11. Six of 9 patients with graft failure are alive after a second transplantation. The day 100 probability of acute graft-versus-host disease and 5-year probability of chronic graft-versus-host disease was 38% and 13%, respectively. The 5-year probabilities of overall- and disease-free survival were 91% and 88%, respectively, for patients with Pesaro risk class II, and 64% and 62%, respectively, for Pesaro risk class III. In multivariate analysis, mortality risks were higher in patients 7 years of age and older and those with hepatomegaly before BMT. The leading causes of death were interstitial pneumonitis (n = 7), hemorrhage (n = 8), and veno-occlusive disease (n = 6). Proceeding to BMT in children younger than 7 years before development of end-organ damage, particularly in the liver, should improve results after BMT for β-thalassemia major.

Outcomes of Allogeneic Hematopoietic Cell Transplantation for Adolescent and Young Adults Compared with Children and Older Adults with Acute Myeloid Leukemia

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Oct, 2011  |  Pubmed ID: 22040843

Adolescents and young adults (AYAs) with cancer have not experienced improvements in survival to the same extent as children and older adults. We compared outcomes among children (<15 years), AYAs (15-40 years) and older adults (>40 years) receiving allogeneic hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML). Our cohort consisted of 900 children, 2,708 AYA, and 2,728 older adult recipients of HLA-identical sibling or unrelated donor (URD) transplantation using myeloablative or reduced-intensity/nonmyeloablative conditioning. Outcomes were assessed over three time periods (1980-1988, 1989-1997, 1998-2005) for siblings and two time periods (1989-1997, 1998-2005) for URD HCT. Analyses were stratified by donor type. Results showed overall survival for AYAs using either siblings or URD improved over time. Although children had better and older adults had worse survival compared with AYAs, improvements in survival for AYAs did not lag behind those for children and older adults. After sibling donor HCT, 5-year adjusted survival for the three time periods was 40%, 48%, and 53% for children, 35%, 41%, and 42% for AYAs, and 22%, 30%, and 34% for older adults. Among URD HCT recipients, 5-year adjusted survival for the two time periods was 38% and 37% for children, 24% and 28% for AYAs, and 19% and 23% for older adults. Improvements in survival occurred because of a reduction in risk of treatment-related mortality. The risk of relapse did not change over time. Improvements in survival among AYAs undergoing allogeneic HCT for AML have paralleled those among children and older adults.

Alternate Donor Hematopoietic Cell Transplantation (HCT) in Non-Hodgkin Lymphoma Using Lower Intensity Conditioning: A Report from the CIBMTR

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Dec, 2011  |  Pubmed ID: 22155506

We analyzed the outcomes of 248 (61% male) adult recipients of HLA-matched unrelated and HLA-mismatched related donor hematopoietic cell transplantation (HCT) for non-Hodgkin lymphoma (NHL) after reduced or lower intensity conditioning (RIC), reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1997 to 2004. Median age was 52 (range: 18-72 years); 31% had a Karnofsky performance score <90. Follicular NHL (43%) was the major histology. Incidence of grades II-IV acute graft-versus-host disease (aGVHD) was 43% at 100 days; and chronic GVHD (cGVHD) was 44% at 3 years. Treatment-related mortality (TRM) at 100 days was 24%. Three-year overall survival (OS) and progression-free survival (PFS) were 41% and 32%, respectively. In multivariate analysis, use of antithymocyte globulin (ATG) and HLA mismatch were associated with increased TRM. High-grade histology, ATG use, and chemotherapy resistance were associated with lower PFS. Older age, shorter interval from diagnosis to HCT, non-total body irridiation (TBI) conditioning regimens, ex vivo T cell depletion, and HLA-mismatched unrelated donors were associated with mortality. GVHD did not influence relapse or PFS. Older age, aggressive histology, and chemotherapy resistance correlated with poorer survival. For selected patients with NHL, lack of an available sibling donor should not be a barrier to allogeneic HCT.

Outcome of Lower-Intensity Allogeneic Transplantation in Non-Hodgkin Lymphoma After Autologous Transplantation Failure

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Dec, 2011  |  Pubmed ID: 22198543

We studied the outcome of allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning regimens (reduced-intensity conditioning and nonmyeloablative) in patients with non-Hodgkin lymphoma who relapsed after autologous hematopoietic stem cell transplantation. Nonrelapse mortality, lymphoma progression/relapse, progression-free survival (PFS), and overall survival were analyzed in 263 patients with non-Hodgkin lymphoma. All 263 patients had relapsed after a previous autologous hematopoietic stem cell transplantation and then had undergone allogeneic hematopoietic stem cell transplantation from a related (n = 26) or unrelated (n = 237) donor after reduced-intensity conditioning (n = 128) or nonmyeloablative (n = 135) and were reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2006. The median follow-up of survivors was 68 months (range, 3-111 months). Three-year nonrelapse mortality was 44% (95% confidence interval [CI], 37%-50%). Lymphoma progression/relapse at 3 years was 35% (95% CI, 29%-41%). Three-year probabilities of PFS and overall survival were 21% (95% CI, 16%-27%) and 32% (95% CI, 27%-38%), respectively. Superior Karnofsky Performance Score, longer interval between transplantations, total body irradiation-based conditioning regimen, and lymphoma remission at transplantation were correlated with improved PFS. Allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning is associated with significant nonrelapse mortality but can result in long-term PFS. We describe a quantitative risk model based on pretransplantation risk factors to identify those patients likely to benefit from this approach.

One-antigen Mismatched Related Versus HLA-matched Unrelated Donor Hematopoietic Stem Cell Transplantation in Adults with Acute Leukemia: Center for International Blood and Marrow Transplant Research Results in the Era of Molecular HLA Typing

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. May, 2011  |  Pubmed ID: 20674756

Approximately 13% of patients lacking an HLA-identical sibling have a one-antigen-mismatched related donor (MMRD). Historically, outcomes from the use of a one-antigen MMRD were considered equivalent to those from the use of a matched unrelated donor (UD). Recent improvements in UD stem cell transplantation (SCT) resulting from better molecular HLA matching justifies investigating whether UD should be preferred over MMRD in adult patients with acute leukemia. Here, we compared the outcomes of MMRD (n = 89) and HLA-A, -B, -C, and -DRB1 allele-matched UD (n = 700) SCT reported to the Center for International Blood and Marrow Transplant Research between 1995 and 2005. The patients underwent transplantation for acute myelogenous leukemia or acute lymphoblastic leukemia in first or second complete remission. Donor type was not associated with hematologic recovery. Univariate and multivariate comparisons of MMRD versus HLA-matched UD transplants showed no statistically significant differences in overall survival, disease-free survival, treatment-related mortality, relapse, or 100-day grade III-IV acute graft-versus-host disease (GVHD). MMRD SCT was associated with a lower rate of chronic GVHD at 1 year (35% vs 47%; P = .03), which was confirmed by multivariate analysis (relative risk, 0.58; 95% confidence interval, 0.39-0.85; P < .01). According to our data, HLA-matched UD and MMRD SCT are associated with comparable survival. Given that less chronic GVHD was observed in the MMRD transplantations, this option, when available, remains the first choice in patients with acute leukemia without an HLA-identical sibling in need of allogeneic SCT.

Childhood Obesity and Outcomes After Bone Marrow Transplantation for Patients with Severe Aplastic Anemia

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. May, 2011  |  Pubmed ID: 20817111

The prevalence of obesity in the pediatric population has increased in the last 2 decades and represents a serious health concern, with potential impact on outcomes of hematopoietic cell transplantation (HCT). We studied the effect of weight by age-adjusted body mass index (BMI) percentile in 1,281 pediatric patients (age 2-19 years) with severe aplastic anemia who underwent HCT between 1990 and 2005. The study population was divided into 5 weight groups-underweight, risk of underweight, normal BMI range, risk of overweight, and overweight-according to age-adjusted BMI percentiles. Cox proportional hazards regression models for survival and acute graft-versus-host disease (aGVHD), performed using weight groups as the main effect and the normal BMI range (26th-75th percentile) as the baseline comparison, found higher mortality among overweight children (>95th percentile adjusted for age). Weight at transplantation did not increase the adjusted risk of grade III-IV aGVHD. The 1-year and 2-year overall survival rates were 60% and 59% for overweight children, compared with >70% in children with lower BMI at both time points (P < .001). Other significant factors associated with survival included race and region, donor type, conditioning regimens in related donor transplants, performance score, and year of transplantation. In conclusion, overweight children with aplastic anemia have worse outcomes after HCT. The impact of obesity on survival outcomes in children should be discussed during pretransplantation counseling.

Pregnancy After Hematopoietic Cell Transplantation: a Report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR)

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Feb, 2011  |  Pubmed ID: 20659574

Preservation of fertility after hematopoietic cell transplantation (HCT) can have a significant influence on the quality of life of transplant survivors. We describe 178 pregnancies in HCT recipients that were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2002 and 2007. There were 83 pregnancies in female HCT recipients and 95 pregnancies in female partners of male HCT recipients. Indications for transplantation included hematologic and other malignancies (N = 99) and nonmalignant disorders (N = 79, of which 75 patients had severe aplastic anemia). The cohort included recipients of autologous HCT (20 women, 13 men), myeloablative (MA) allogeneic HCT (12 women, 50 men), and nonmyeloablative allogeneic HCT (2 women, 2 men). Age at HCT was <20 years for 50% of women and 19% of men. Conditioning regimens included total body irradiation (TBI) in 16% of women and 19% of men; doses were MA in 10% of women and in 16% of men. Live births were reported in 86% of pregnancies in partners of male transplant patients and 85% of pregnancies in female transplant patients, with most pregnancies occurring 5 to 10 years after HCT. We conclude that some HCT recipients can retain fertility, including patients who have received TBI and/or MA conditioning. Young patients undergoing HCT should be counseled both before and after HCT about potential loss of fertility, methods for preserving fertility, and planning for future pregnancy. Fertility and outcomes of pregnancy after HCT need prospective evaluation in large transplant cohorts.

Bexarotene is Active Against Subcutaneous Panniculitis-like T-cell Lymphoma in Adult and Pediatric Populations

Clinical Lymphoma, Myeloma & Leukemia. Feb, 2012  |  Pubmed ID: 22001256

Subcutaneous panniculitis-like T-cell lymphoma (SPTL-AB) and cutaneous gamma/delta T-cell lymphoma (CGD-TCL) are rare T-cell lymphomas with varying clinical courses. There is no standard treatment, although chemotherapy and hematopoietic stem cell transplantation are commonly used. We describe results using bexarotene for children and adults with these disorders.

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