Biomedical subjects

Eva C Guinan

Publications and source records attributed to Eva C Guinan.

18 recordsLinked to original sources

PubMed2007

An update on the management of severe idiopathic aplastic anaemia in children.

The current outlook for a child with severe idiopathic aplastic anaemia (AA) is very much better than in previous decades. In part, this may reflect better differentiation of idiopathic and inherited marrow failure. For children with idiopathic AA and a human leucocyte antigen (HLA)-matched sibling donor (MSD), allogeneic haematopoietic stem-cell transplantation (AHSCT) is the primary therapy of choice, offering long-term disease-free survival of 90%, although graft-versus-host disease remains a cause of long-term morbidity. A greater treatment challenge remains for those children without a MSD. Combination immunosuppressive therapy (IST) is associated with response rates of 70% or more. However, relapse and clonal evolution with transformation to myelodysplasia or acute myeloid leukaemia remain significant problems after IST and long-term event-free survival rates are less impressive. For children who do not have a sustained response to IST, alternate donor AHSCT should be considered. New HLA typing technologies, novel stem cell sources, reduced-intensity conditioning and graft engineering have reduced toxicity and improved the outcome after alternate donor AHSCT. Emerging therapies that capitalise on recent advances in our understanding of the pathophysiology of idiopathic AA and the immunobiology of AHSCT and IST may further improve the long-term outcome of this disease.

Anemia, Aplastic↗

PubMed2006

A novel pattern of transaminase elevation associated with autologous transplant for neuroblastoma.

To determine the pattern and degree of hepatic transaminitis experienced by children undergoing autologous transplantation for neuroblastoma. Sixty-four children with high-risk neuroblastoma received an autologous transplant with cyclophosphamide, etoposide, and carboplatin conditioning. Forty-eight went on to receive a second transplant with M and TBI conditioning. Charts were reviewed for evidence of hepatic regimen-related toxicity. A high rate of transaminitis was observed after both regimens. In each transplant, there was an early period of transaminitis during conditioning, from which patients recovered, followed by a second period of transaminase elevation. The degree of elevation was not associated with age, whether the administered dose was calculated based on a per kg or per M(2) basis or the presence of regimen-related severe mucositis. Elevated transaminases at admission were not associated with maximal hepatotoxicity during the first transplant although there was an association in the second transplant. However, the magnitude of transaminase elevation was less in the second transplant. VOD occurred in one and three patients in transplants 1 and 2, respectively. Both conditioning regimens were associated with an early and late elevation of transaminases without significant cholestasis. This biphasic pattern of transaminitis has not been reported previously. The high prevalence of transaminase elevation at time of both transplants was not associated with an increased incidence of VOD. We conclude that elevated transaminases should not preclude proceeding to a first or second autologous transplant with these regimens.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia.

Despite profound T-cell immunodeficiency, most patients treated with chemotherapy do not succumb to infection. The basis for residual protective immunity in lymphopenic patients is not known. We prospectively measured T-cell numbers, thymopoiesis, and T-cell memory in 73 children undergoing a 2-year chemotherapy regimen for acute lymphoblastic leukemia (ALL) and compared them to an age-matched cohort of 805 healthy children. Most patients had profound defects in CD4 and CD8 T-cell numbers at diagnosis that did not recover during the 2 years of therapy. Thymic output and the fraction of naive T cells were significantly lower than in healthy controls. However, the remaining T-cell compartment was enriched for antigen-experienced, memory T cells defined both by phenotype and by function. This relative sparing of T-cell memory may, in part, account for the maintenance of protective immunity in lymphopenic patients treated for ALL. Moreover, because the memory T-cell compartment is least affected by ALL and its treatment, strategies to induce immunity to pathogens or tumor antigens in cancer patients may be most successful if they seek to expand pre-existing memory T cells.

Adolescent↗

PubMed2005

Contribution of bone marrow-derived endothelial cells to human tumor vasculature.

It has been shown that bone marrow-derived stem cells can form a major fraction of the tumor endothelium in mouse tumors. To determine the role of such cells in human tumor angiogenesis, we studied six individuals who developed cancers after bone marrow transplantation with donor cells derived from individuals of the opposite sex. By performing fluorescence in situ hybridization (FISH) with sex chromosome-specific probes in conjunction with fluorescent antibody staining, we found that such stem cells indeed contributed to tumor endothelium, but at low levels, averaging only 4.9% of the total. These results illustrate substantial differences between human tumors and many mouse models with respect to angiogenesis and have important implications for the translation of experimental antiangiogenic therapies to the clinic.

Bone Marrow Cells↗

PubMed2005

Protective antibody responses to pneumococcal conjugate vaccine after autologous hematopoietic stem cell transplantation.

Patients undergoing autologous hematopoietic stem cell transplantation (autoHCT) are at increased risk for infection with Streptococcus pneumoniae and have impaired antibody responses to pneumococcal polysaccharide vaccines. We performed this study to examine the ability of autoHCT patients to respond to a heptavalent pneumococcal conjugate vaccine (PCV7) given after transplantation and to determine whether there was a potential benefit of immunizing these patients before stem cell collection. Sixty-one patients scheduled for autoHCT were randomized to receive either PCV7 or no vaccine before stem cell collection. After stem cell reinfusion, all study patients were immunized with PCV7 at 3, 6, and 12 months. Pneumococcal immunoglobulin G antibody concentrations were measured at the time of each immunization and 1 month after the 12-month dose. Serotype-specific pneumococcal antibody concentrations were significantly higher in patients immunized with PCV7 before stem cell collection compared with patients not immunized before their stem cells were collected for 6 of 7 serotypes at 3 months, 6 of 7 serotypes at 6 months, 4 of 7 serotypes at 12 months, and 3 of 7 serotypes at 13 months. After the 3-dose series of PCV7 after autoHCT, >60% of study patients had protective concentrations of antibody to all 7 vaccine serotypes regardless of immunization before stem cell collection. Pneumococcal conjugate vaccine is immunogenic in autoHCT patients and may be an effective strategy to prevent invasive disease after transplantation.

Adolescent↗

PubMed2005

Oral chronic graft-versus-host disease in pediatric patients after hematopoietic stem cell transplantation.

Chronic graft-versus-host disease (cGVHD) is a serious and potentially life-threatening complication of hematopoietic stem cell transplantation. This study, which is the largest single-center series of oral disease in pediatric patients with cGVHD, describes the oral findings in 49 consecutive patients seen in a pediatric multidisciplinary cGVHD clinic. All consecutive patients seen at the multidisciplinary pediatric hematopoietic stem cell transplantation/cGVHD clinic at the Dana-Farber Cancer Institute (Boston, MA) from July 2001 through October 2003 were included in this study. Subjective and objective assessments of mucosal, salivary gland, and sclerotic pathology were performed for each patient, and specific therapy was initiated when indicated. Oral mucosal cGVHD was identified in 22 (45%) of 49 patients. Only 4 (8%) of 49 patients reported mouth pain, and all patients reported being able to eat well. All patients who required specific therapy for their oral mucosal cGVHD (45%) were already taking at least 1 immunomodulatory agent; however, efficacy of treatment was difficult to assess because of inconsistent follow-up periods. Subjective and objective salivary gland and sclerotic disease were observed far less often. Oral mucosal pathology is common in these patients, and appropriate diagnosis and management of oral lesions is critical to reduce patient morbidity and to improve quality of life. The apparent lack of salivary gland involvement was notable. Developing validated age-appropriate evaluation strategies and identifying effective treatment guidelines will be invaluable in the future management of these patients.

Adolescent↗

PubMed2005

Failure to define window of time for autologous tumor vaccination in patients with newly diagnosed or relapsed acute lymphoblastic leukemia.

OBJECTIVES: We and others have shown that B cell precursor acute lymphoblastic leukemia cells (ALL) stimulated with CD40 ligand become efficient antigen-presenting cells (APC) capable of expanding autologous, tumor-specific T cells from patients. Translation of these preclinical findings to a novel treatment strategy required four separate issues to be determined: (1) if a CD40-ALL vaccine could be generated for clinical use; (2) whether clinical translation could be achieved; (3) whether the vaccination was safe; and (4) whether a window of time could be identified that would optimize the efficacy of vaccination. PATIENTS AND METHODS: Nine patients with relapsed/refractory ALL were enrolled in a phase I trial of vaccination with autologous CD40-ALL. Immunologic reconstitution was measured in a separate cohort of 23 patients with newly diagnosed ALL. RESULTS: We successfully prepared autologous vaccines for all nine patients in the phase I trial. CD40-ALL were potent APC, capable of stimulating allogeneic and peptide-specific T cells in vitro. Two patients were vaccinated without adverse events. Five patients died or progressed before vaccination, suggesting that rapid disease progression limits vaccination in patients with relapse disease, thus limiting clinical translation. We therefore sought to identify a window of time for vaccination during which this approach might be feasible. To achieve this end, we evaluated immunological reconstitution in newly diagnosed patients with ALL patients. Despite recovery of myelopoiesis, most patients had profound defects in T, B, and natural killer (NK) cell numbers that failed to recover at any point during therapy. CONCLUSION: Autologous tumor vaccination at a time of ALL relapse is not feasible. Alternative strategies for immunotherapy of ALL may require ex vivo generation of antigen specific T cells and adoptive therapy.

Adolescent↗

PubMed2005

Presence of anti-kinectin and anti-PMS1 antibodies in Japanese aplastic anaemia patients.

While anti-kinectin antibodies are frequently found in aplastic anaemia (AA) patients from the US (39%), we detected antibodies in only three of 30 (10%) of Japanese AA cases. Additionally, population differences in anti-postmeiotic segregation increased 1 (PMS1) responses were seen, with detectable antibody in 10% Japanese and 0% US AA patients. In one of the Japanese AA patients with detectible anti-kinectin antibodies, the autoantibody disappeared coincidentally with the partial resolution of pancytopenia. These results support the hypothesis that the epidemiology of AA is heterogeneous and suggest that anti-kinectin autoantibody titre may serve as a surrogate maker for the disease activity of AA.

Anemia, Aplastic↗

PubMed2005

Aplastic anemia: management of pediatric patients.

Aplastic anemia is a term describing the common findings of pancytopenia and marrow hypoplasia arising from a variety of disease states, including acquired aplastic anemia and a variety of congenital marrow failure states. The management of children with these disorders has been confounded by difficulties of diagnosis. The availability of molecular testing has assisted in partial resolution of this problem but has raised new issues, such as the potential of genetic predisposition and the management of asymptomatic individuals with molecular markers. Longitudinal data from large cohort studies and disease registries are providing a rational basis for making more informed treatment decisions for children with these disorders. In particular, the ability to subset patients more accurately has improved triage of treatments. Approaches to hematopoietic stem cell transplantation (SCT), using both conventional and alternative donors, are changing rapidly, and the long-term sequelae of newer approaches are not entirely clear. Improved diagnosis and longer survival have fostered an understanding of the multidisciplinary approach necessary to manage both the underlying problems and the significant sequelae of treatment in both acquired and congenital disease.

Adolescent↗

PubMed2004

A multiagent strategy to decrease regimen-related toxicity in children undergoing allogeneic hematopoietic stem cell transplantation.

Regimen-related toxicity (RRT) is a frequent cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). In this pilot study, we examined the feasibility and potential efficacy of administering a fixed combination of agents as a novel approach to reducing RRT in children undergoing HSCT. Thirty-seven patients were treated with ursodeoxycholic acid, folinic acid, vitamin E, and parenteral nutrition titrated to measured energy expenditure in the peritransplantation period. Outcomes were compared with those in historical controls (n = 131). Compliance with oral ursodeoxycholic acid and vitamin E of at least 90% was achieved in a mean of 86% (95% confidence interval, 75%-97%) of patients. In the study group, we observed (1) reduced prevalence and severity of mucositis (P = .008 and.004, respectively); (2) less severe hepatic toxicity (P = .007); and (3) shorter time to engraftment (P = .02) compared with the control group. These benefits appeared most pronounced among high-risk patients. The administration of this regimen, including oral medications, is feasible during the peritransplantation period, and it is well tolerated. The decreased RRT observed in comparison to historical controls suggests that combination approaches deserve exploration as a means of reducing the morbidity of HSCT.

Adolescent↗

PubMed2004

Dyskeratosis congenita vs. chronic graft versus host disease: report of a case and a review of the literature.

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome characterized by the triad of reticular pigmentation of the skin, nail dystrophy, and mucosal leukoplakia. DC is often associated with severe pancytopenia, and bone marrow failure is the principal cause of early mortality. Malignant transformation of mucosal leukoplakias may also occur. Rarely, aplastic anemia precedes the other clinical manifestations of the disease. We present a case of a 13-year-old boy who was diagnosed at age four with idopathic aplastic anemia, was treated successfully with an allogeneic bone marrow transplant, then subsequently developed skin, nail, and tongue lesions. While the initial impression was chronic graft-versus-host disease, additional work-up confirmed the diagnosis of DC.

Adolescent↗

PubMed2004

Measuring T cell immunity to influenza vaccination in children after haemopoietic stem cell transplantation.

Quantitative assessment of immunogen-specific T cell responses may provide a meaningful surrogate marker of functional immunity in patients following haemopoietic stem cell transplantation (HSCT). We developed a flow-cytometric assay to quantify antigen-specific T cell immunity to influenza-A and studied the T cell response to influenza vaccination in five children, 3-21 months post-HSCT. All patients showed an increase in influenza-A-specific CD4(+) immunity following vaccination while none had a detectable IgG response to the vaccine. This assay proved sufficiently sensitive to evaluate changes in T cell memory in immunocompromised individuals and could be used to better characterize post-HSCT immune reconstitution.

Adolescent↗

PubMed2003

Autoantibodies frequently detected in patients with aplastic anemia.

Although accumulating evidence strongly suggests that aplastic anemia (AA) is a T cell-mediated autoimmune disease, no target antigens have yet been described for AA. In autoimmune diseases, target autoantigens frequently induce not only cellular T-cell responses but also humoral B-cell responses. We hypothesized that the presence of antigen-specific autoantibodies could be used as a "surrogate marker" for the identification of target T-cell autoantigens in AA patients. We screened a human fetal liver library for serologic reactivity against hematopoietic stem/progenitor cell antigens and isolated 32 genes. In 7 of 18 AA patients, an immunoglobulin G (IgG) antibody response was detected to one of the genes, kinectin, which is expressed in all hematopoietic cell lineages tested including CD34+ cells. No response to kinectin was detected in healthy volunteers, multiply transfused non-AA patients, or patients with other autoimmune diseases. Epitope mapping of IgG autoantibodies against kinectin revealed that the responses to several of the epitopes were shared by different AA patients. Moreover, CD8+ cytotoxic T cells raised against kinectin-derived peptides suppressed the colony formation of granulocyte macrophage colony-forming units (CFU-GMs) in an HLA class I-restricted fashion. These results suggest that kinectin may be a candidate autoantigen that is involved in the pathophysiology of AA.

Anemia, Aplastic↗

PubMed2003

Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation.

BACKGROUND: Marrow stromal cells (MSC) can differentiate into multiple mesenchymal tissues. To assess the feasibility of human MSC transplantation, we evaluated the in vitro immunogenicity of MSC and their ability to function as alloantigen presenting cells (APC). METHODS: Human MSC were derived and used in mixed cell cultures with allogeneic peripheral blood mononuclear cells (PBMC). Expression of immunoregulatory molecules on MSC was analyzed by flow cytometry. An MSC-associated suppressive activity was analyzed using cell-proliferation assays and enzyme-linked immunoassays. RESULTS: MSC failed to elicit a proliferative response when cocultured with allogeneic PBMC, despite provision of a costimulatory signal delivered by an anti-CD28 antibody and pretreatment of MSC with gamma-interferon. MSC express major histocompatibility complex (MHC) class I and lymphocyte function-associated antigen (LFA)-3 antigens constitutively and MHC class II and intercellular adhesion molecule (ICAM)-1 antigens upon gamma-interferon treatment but do not express CD80, CD86, or CD40 costimulatory molecules. MSC actively suppressed proliferation of responder PBMC stimulated by third-party allogeneic PBMC as well as T cells stimulated by anti-CD3 and anti-CD28 antibodies. Separation of MSC and PBMC by a semipermeable membrane did not abrogate the suppression. The suppressive activity could not be accounted for by MSC production of interleukin-10, transforming growth factor-beta1, or prostaglandin E2, nor by tryptophan depletion of the culture medium. CONCLUSIONS: Human MSC fail to stimulate allogeneic PBMC or T-cell proliferation in mixed cell cultures. Unlike other nonprofessional APC, this failure of function is not reversed by provision of CD28-mediated costimulation nor gamma-interferon pretreatment. Rather, MSC actively inhibit T-cell proliferation, suggesting that allogeneic MSC transplantation might be accomplished without the need for significant host immunosuppression.

Apoptosis↗

PubMed2002

Donor immunization with pneumococcal conjugate vaccine and early protective antibody responses following allogeneic hematopoietic cell transplantation.

Patients undergoing hematopoietic cell transplantation (HCT) are at increased risk for infections with Streptococcus pneumoniae and have long-lasting, impaired antibody responses to pneumococcal polysaccharide vaccines. We examined whether donor immunization with a heptavalent pneumococcal conjugate vaccine (PCV7) would elicit protective antibody responses to additional doses of vaccine administered early after transplantation. Ninety-six patients scheduled to receive an allogeneic hematopoietic cell transplant were randomized with their donors to receive either a dose of PCV7 vaccine or no vaccine before transplantation. All patients received PCV7 at 3 months, 6 months, and 12 months following transplantation, and serotype-specific antibody concentrations were determined after each dose. Following HCT, geometric mean antibody concentrations of patients in the immunized donor group were significantly higher for 5 of the 7 vaccine serotypes after one dose (P <.05) and for 4 of the 7 serotypes after 2 doses of vaccine (P <.03). Sixty-seven percent of patients in the immunized donor group had presumed protective IgG concentrations more than or equal to 0.50 microg/mL to all 7 serotypes following the first dose of vaccine compared to 36% in the unimmunized donor group (P =.05). After the third dose of vaccine, both groups had more than 60% of patients with concentrations at least 0.50 microg/mL to all vaccine serotypes. Donor immunization enhances early antibody responses of patients undergoing HCT to pneumococcal conjugate vaccine. A 3-dose schedule of PCV7 vaccine at 3, 6, and 12 months is immunogenic in these patients regardless of donor immunization.

Adolescent↗

PubMed2002

Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome.

Veno-occlusive disease (VOD) is the most common regimen-related toxicity accompanying stem cell transplantation (SCT). Severe VOD complicated by multisystem organ failure (MOF) remains almost uniformly fatal. Preliminary experience with defibrotide (DF), a single-stranded polydeoxyribonucleotide with fibrinolytic, antithrombotic, and anti-ischemic properties, in the treatment for severe VOD has suggested safety and activity. Eighty-eight patients who developed severe VOD after SCT were treated with DF under a defined treatment plan. At diagnosis, median bilirubin was 76.95 microM (4.5 mg/dL), median weight gain was 7%, ascites was present in 84%, and abnormal hepatic portal venous flow was present in 35%. At DF initiation, median bilirubin had increased to 215.46 microM (12.6 mg/dL), and MOF was present in 97%. DF was administered intravenously in doses ranging from 5 to 60 mg/kg per day for a median of 15 days. No severe hemorrhage or other serious toxicity related to DF was reported. Complete resolution of VOD was seen in 36%, with 35% survival at day +100. Predictors of survival included younger age, autologous SCT, and abnormal portal flow, whereas busulfan-based conditioning and encephalopathy predicted worse outcome. Decreases in mean creatinine and plasminogen activator inhibitor 1(PAI-1) levels during DF therapy predicted better survival. The complete response rate, survival to day +100, and absence of significant DF-associated toxicity in this largest patient cohort reported to date confirm the results of earlier studies. Certain features associated with successful outcome may correlate with DF-related treatment effects, and prospective evaluation of DF therapy for severe VOD should allow better definition of predictors of response or failure.

Adolescent↗

PubMed2002

Neutrophil defense in patients undergoing bone marrow transplantation: bactericidal/permeability-increasing protein (BPI) and defensins in graft-derived neutrophils.

BACKGROUND: Even after neutrophil counts return to near normal levels, patients undergoing myeloablative chemotherapy and bone marrow transplantation (BMT) are at risk for invasive bacterial infections, raising the possibility that their neutrophil function might be impaired. To assess potential qualitative defects in neutrophil function in patients undergoing BMT, we measured neutrophil content of the antimicrobial (poly)peptides BPI and defensins. METHODS: Neutrophil extracts were analyzed for content of BPI by Western blotting and ELISA and for defensin peptides by acid-urea polyacrylamide gel electrophoresis (PAGE). Antibacterial activity of neutrophil extracts was measured against Escherichia coli K1/r, a clinical isolate sensitive to synergistic killing by BPI and defensins. RESULTS: Neutrophil extract BPI content on post-BMT days +20, +30, and +100 (169+/-35, 232+/-57, and 160+/-55 ng per 106 neutrophils, respectively) was similar to the neutrophil BPI content of normal controls (163+/-35 ng per 106 neutrophils). Neutrophil defensin content also did not vary during this time-span. Activity of neutrophil extracts against E. coli K1/r did not differ between BMT patients and controls. CONCLUSION: At post-BMT days +20 to +100, neutrophils derived from engrafted marrow contain normal quantities of BPI and defensins. Any deficiencies of neutrophil function during this phase are not due to inadequate expression of these antimicrobial (poly)peptides but could reflect abnormalities in other aspects of neutrophil function.

Adolescent↗

PubMed2002

Marrow failure.

This chapter describes the clinical presentation and molecular basis of two inherited bone marrow failure syndromes, Fanconi anemia (FA), and Diamond-Blackfan anemia (DBA). It also provides an update on diagnostic and therapeutic approaches to bone marrow failure of all types (inherited and acquired) in pediatric patients. In Section I, Dr. Alan D'Andrea reviews the wide range of clinical manifestations of Fanconi anemia. Significant advances have been made in understanding the molecular pathogenesis of FA. On the basis of these advances, new diagnostic assays and treatment options are now available. In Section II, Dr. Niklas Dahl examines the clinical features and molecular pathogenesis of Diamond-Blackfan anemia. The possible links between the RPS19 gene (DBA gene) and the erythropoiesis defect are considered. In Section III, Drs. Eva Guinan and Akiko Shimamura provide an algorithm for the diagnostic evaluation and treatment of children with inherited or acquired aplastic anemia. Through the presentation of a case study of a pediatric patient with bone marrow failure, he provides an overview of the newest tests and treatment options.

Adult↗