Subject(s)
Dyskeratosis Congenita , Fibroblasts , Hematopoietic Stem Cell Transplantation , Lung Diseases , Lung , Oxidative Stress , Allografts , Dyskeratosis Congenita/metabolism , Dyskeratosis Congenita/pathology , Dyskeratosis Congenita/therapy , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Infant , Lung/metabolism , Lung/pathology , Lung Diseases/etiology , Lung Diseases/metabolism , Lung Diseases/pathology , MaleABSTRACT
Our group previously demonstrated a strong association between elevated plasma soluble CD13 enzyme activity and newly diagnosed extensive chronic GVHD (cGVHD) in children. As cytotoxic anti-CD13 Abs have been documented after blood and marrow transplant (BMT) in association with CMV infection and cGVHD, we hypothesized that soluble CD13 contributes to cGVHD pathogenesis by induction of CD13 reactive Abs and that anti-CD13 Abs could be additional biomarkers for newly diagnosed pediatric extensive cGVHD. Using prospectively collected plasma samples from pediatric allogeneic BMT (allo-BMT) subjects with cGVHD and controls without cGVHD enrolled in a large multi-institution Children's Oncology Group cGVHD therapeutic trial, we evaluated whether soluble CD13 correlates with induction of anti-CD13 Abs. We found that CD13 reactive Abs are present in a proportion of patients after allo-BMT, but did not seem to correlate with the presence of soluble CD13. Anti-CD13 Abs also did not meet our criteria as a diagnostic biomarker for cGVHD. These data do not confirm that induction of CD13 reactive Abs is a mechanism for cGVHD in children nor are part of the pathogenesis of cGVHD associated with elevated soluble CD13. The exact role of CD13 in cGVHD remains to be determined.
Subject(s)
Antibodies/immunology , Bone Marrow Transplantation/immunology , CD13 Antigens/immunology , Graft vs Host Disease/immunology , Adolescent , Antibodies/blood , Biomarkers/blood , CD13 Antigens/metabolism , Child , Child, Preschool , Chronic Disease , Double-Blind Method , Female , Graft vs Host Disease/blood , Graft vs Host Disease/drug therapy , Graft vs Host Disease/pathology , Humans , Hydroxychloroquine/therapeutic use , MaleABSTRACT
Pre-clinical studies have demonstrated that bone marrow ablation has a profound effect in decreasing erythropoietin (EPO) elimination. The study's objective was to determine in humans if EPO pharmacokinetics (PKs) are perturbed following bone marrow ablation. EPO PK studies were performed in eight subjects, aged 4 to 61 years, undergoing fully myeloablative hematopoietic stem cell transplantation. Serial PK studies using intravenous injection of recombinant human EPO (92+/-2.0 U/kg) (mean+/-SEM) were carried out during four periods of altered marrow integrity: baseline pre-ablation, post-ablation pre-transplant, early post-transplant pre-engraftment, and late post-transplant full engraftment. Compared with baseline, post-ablation pre-transplant and early post-transplant EPO PKs demonstrated declines in clearance increases in terminal elimination half-life of 36 and 95%, respectively. Clearance and half-life returned to baseline following full engraftment. The association of EPO elimination with decreased bone marrow activity in patients undergoing transplantation conclusively establishes the bone marrow as a key determinant of EPO elimination in humans.
Subject(s)
Erythropoietin/pharmacokinetics , Hematinics/pharmacokinetics , Hematopoietic Stem Cell Transplantation , Adult , Child , Child, Preschool , Female , Half-Life , Humans , Male , Metabolic Clearance Rate , Middle Aged , Recombinant ProteinsABSTRACT
Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic insufficiency and variable degrees of neutropenia. SDS patients are at risk of developing myelodysplasia, aplastic anemia, and leukemic transformation. The role and timing of allogeneic hematopoietic stem cell transplantation (HSCT) in SDS remain controversial. We report three SDS patients with severe aplasia transplanted using unrelated umbilical cord blood (UCB). Patients received melphalan (180 mg/m2), etoposide (1200 mg/m2), anti-thymocyte globulin (90 mg/kg), and total lymphoid irradiation (500 cGy); graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and prednisone. Myeloid engraftment occurred promptly with absolute neutrophil count >500 cells/mm3 on day 15 +/- 5 and all patients displayed 100% donor chimerism by 2 months post transplant. The major complication of transplant was GVHD, with all patients developing grade II or III acute GVHD, one progressing to chronic extensive GVHD. Patients are alive 309, 623, and 2029 days post transplant. Factors important in HSCT outcome for SDS may include transplantation at a young age, avoidance of cyclophosphamide, and adequate GVHD prophylaxis. Importantly, these cases also suggest that unrelated UCB, in the absence of a matched family member, is an excellent alternative stem cell source for SDS patients undergoing HSCT.
Subject(s)
Abnormalities, Multiple/therapy , Cord Blood Stem Cell Transplantation/methods , Anemia, Aplastic , Child , Cord Blood Stem Cell Transplantation/adverse effects , Disease-Free Survival , Exocrine Pancreatic Insufficiency , Female , Graft Survival , Graft vs Host Disease/drug therapy , Graft vs Host Disease/pathology , Humans , Infant , Neutropenia , Premedication , Survival Rate , Syndrome , Transplantation Chimera , Transplantation Conditioning/methodsABSTRACT
T cell depletion (TCD) of marrow is a proven method of graft-versus-host disease (GVHD) prophylaxis in allogeneic bone marrow transplantation (BMT). Nonetheless, TCD is associated with an increased risk of developing post transplant lymphoproliferative disorder (PTLD). Between 1986 and 1998, 241 pediatric patients at the University of Iowa underwent BMT using ex vivo TCD of marrow from mismatched related or matched unrelated donors. Additional GVHD prophylaxis included antithymocyte globulin (ATG) or anti lymphocyte globulin (ALG) post transplant (in vivo TCD). A total of 30 cases of PTLD were identified based upon a combination of clinical, histological, and immunological features. Nearly all cases occurred within 3 months post BMT. A statistically significant increase in PTLD incidence was noted for patients treated with ATG vs ALG (33 vs 9%). While grade I-II acute GVHD was more common in patients receiving ATG vs ALG, no difference in grade III-IV GVHD or overall survival was noted between the two groups. Assessment of immune recovery at various times post BMT revealed significantly fewer T cells in the ATG-treated group, suggesting the deleterious effect of ATG may be due to excessive depletion of donor-derived Epstein-Barr virus-specific cytotoxic T cells. Thus, caution should be exercised in the use of anti-T-cell antibody therapy for additional GVHD prophylaxis in the setting of TCD BMT.
Subject(s)
Bone Marrow Transplantation/adverse effects , Lymphocyte Depletion/adverse effects , Lymphoproliferative Disorders/etiology , Antilymphocyte Serum/adverse effects , Antilymphocyte Serum/therapeutic use , Bone Marrow Transplantation/methods , Child , Graft vs Host Disease/drug therapy , Graft vs Host Disease/prevention & control , Humans , Immunophenotyping , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Incidence , Retrospective Studies , Transplantation, HomologousABSTRACT
Shwachman-Diamond syndrome (SDS) is a rare genetic disorder characterized by pancreatic insufficiency, short stature, skeletal abnormalities and bone marrow dysfunction. Patients with SDS have varying degrees of marrow aplasia, which can be severe or progress to leukemic transformation. While allogeneic hematopoietic stem cell transplantation (HSCT) can be curative for the hematologic disturbances of SDS, a recent review of the literature reveals few survivors. Poor outcome with HSCT is often related to excessive cardiac and other organ toxicity from transplant preparative therapy. We describe two young children with SDS who developed aplastic anemia and subsequently underwent successful allografting using a non-cardiotoxic conditioning regimen. Case 1 received marrow from an HLA-identical sibling while case 2 received partially matched umbilical cord blood from an unrelated donor. Both patients are presently alive and well with sustained donor engraftment and excellent hematopoietic function at 36 and 22 months post-HSCT.
Subject(s)
Abnormalities, Multiple/therapy , Hematopoietic Stem Cell Transplantation/methods , Bone Marrow Diseases/therapy , Child, Preschool , Exocrine Pancreatic Insufficiency/therapy , Female , Humans , Musculoskeletal Abnormalities/therapy , Syndrome , Transplantation Chimera , Transplantation Conditioning/methods , Transplantation, Homologous/methods , Treatment OutcomeABSTRACT
Dyskeratosis congenita is a progressive bone-marrow failure syndrome that is characterized by abnormal skin pigmentation, leukoplakia and nail dystrophy. X-linked, autosomal recessive and autosomal dominant inheritance have been found in different pedigrees. The X-linked form of the disease is due to mutations in the gene DKC1 in band 2, sub-band 8 of the long arm of the X chromosome (ref. 3). The affected protein, dyskerin, is a nucleolar protein that is found associated with the H/ACA class of small nucleolar RNAs and is involved in pseudo-uridylation of specific residues of ribosomal RNA. Dyskerin is also associated with telomerase RNA (hTR), which contains a H/ACA consensus sequence. Here we map the gene responsible for dyskeratosis congenita in a large pedigree with autosomal dominant inheritance. Affected members of this family have an 821-base-pair deletion on chromosome 3q that removes the 3' 74 bases of hTR. Mutations in hTR were found in two other families with autosomal dominant dyskeratosis congenita.
Subject(s)
Chromosomes, Human, Pair 3 , Dyskeratosis Congenita/genetics , Mutation , RNA/genetics , Telomerase/genetics , Cell Line , Chromosome Mapping , DNA Mutational Analysis , Female , Genes, Dominant , Genetic Linkage , Humans , Male , Pedigree , Point Mutation , TelomereABSTRACT
Chronic graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. Both the disease and the medications used to treat it are associated with significant morbidity and mortality. The manifestations of chronic GVHD often resemble those of autoimmune disorders. Hydroxychloroquine (HCQ) is a 4-aminoquinoline antimalarial drug used for the treatment of autoimmune diseases. HCQ interferes with antigen processing and presentation, cytokine production, and cytotoxicity and is synergistic with cyclosporine and tacrolimus in vitro. Forty patients with steroid-resistant or steroid-dependent chronic GVHD were enrolled in a phase 2 trial of HCQ 800 mg (12 mg/kg) per day. Three complete responses and 14 partial responses were seen in 32 evaluable patients (53% response rate). All responders tolerated a >50% reduction in their steroid dose while receiving HCQ. Clinical response occurred at a median of 8 weeks (range, 4 to 24 weeks). No hematologic, hepatic, renal, or retinal toxicity was associated with HCQ. In light of its mechanisms of action, clinical activity for GVHD, and low toxicity profile, HCQ may be useful in a multiagent approach for the treatment of extensive chronic GVHD.
Subject(s)
Graft vs Host Disease/drug therapy , Hydroxychloroquine/therapeutic use , Immunosuppressive Agents/therapeutic use , Adolescent , Adrenal Cortex Hormones/therapeutic use , Adult , Bone Marrow Transplantation/adverse effects , Child , Child, Preschool , Chronic Disease , Drug Therapy, Combination , Female , Follow-Up Studies , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Histocompatibility , Humans , Infant , Male , Middle Aged , Remission Induction , Survival Rate , Transplantation, Homologous/adverse effects , Treatment OutcomeABSTRACT
The utility of bone marrow transplantation for childhood leukemia in patients unable to achieve a remission prior to transplant is controversial. To address this issue, we analyzed a subset of patients with advanced leukemia entered on prospective transplant trials at our hospital. Fifty-eight patients with ALL or AML (age 1-19) were identified. They had failed standard chemotherapy and were in relapse (22 in 1st, 27 in 2nd, three in 3rd, and three in 4th) or had never achieved an initial remission (three) at the time of transplant. Fifty-two patients received marrow from mismatched family members (haplo or DR-identical), while six received marrow from matched siblings. Most patients received myeloablative therapy consisting of total body irradiation, etoposide, cyclophosphamide, and cytosine arabinoside. Marrow from mismatched donors was T cell depleted. Only one of 52 patients transplanted with a mismatched donor survived long-term while three of six patients transplanted in relapse with a fully matched sibling donor are alive 6-10 years post BMT. The major causes of death were infection (39%) and relapse (28%). Acute GVHD grade III-IV was noted in 7% of patients. A comparable group of patients with leukemia transplanted at our center in remission using similarly mismatched family member donors (haplo or DR-identical) had an event-free survival of 28%. In conclusion, our data suggest that BMT utilizing mismatched family member donors is a poor option for patients in relapse at the time of transplant. New treatment strategies need to be developed to effectively manage these patients.
Subject(s)
Bone Marrow Transplantation , Leukemia/therapy , Adolescent , Adult , Female , Histocompatibility Testing , Humans , Infant , Leukemia/immunology , Leukemia/pathology , Leukemia/physiopathology , Lymphocyte Depletion , Male , Recurrence , T-Lymphocytes/immunology , Transplantation, Homologous , Treatment OutcomeABSTRACT
Hydroxychloroquine (HCQ), a lysosomotropic amine, is an immunosuppressive agent presently being evaluated in bone marrow transplant patients to treat graft-versus-host disease. While its immunosuppressive properties have been attributed primarily to its ability to interfere with antigen processing, recent reports demonstrate HCQ also blocks T-cell activation in vitro. To more precisely define the T-cell inhibitory effects of HCQ, the authors evaluated T-cell antigen receptor (TCR) signaling events in a T-cell line pretreated with HCQ. In a concentration-dependent manner, HCQ inhibited anti-TCR-induced up-regulation of CD69 expression, a distal TCR signaling event. Proximal TCR signals, including inductive protein tyrosine phosphorylation, tyrosine phosphorylation of phospholipase C gamma1, and total inositol phosphate production, were unaffected by HCQ. Strikingly, anti-TCR-crosslinking-induced calcium mobilization was significantly inhibited by HCQ, particularly at the highest concentrations tested (100 micromol/L) in both T-cell lines and primary T cells. HCQ, in a dose-dependent fashion, also reduced a B-cell antigen receptor calcium signal, indicating this effect may be a general property of HCQ. Inhibition of the calcium signal correlated directly with a reduction in the size of thapsigargin-sensitive intracellular calcium stores in HCQ-treated cells. Together, these findings suggest that disruption of TCR-crosslinking-dependent calcium signaling provides an additional mechanism to explain the immunomodulatory properties of HCQ.
Subject(s)
Calcium/physiology , Hydroxychloroquine/pharmacology , Receptors, Antigen, T-Cell/physiology , Signal Transduction/drug effects , T-Lymphocytes/physiology , Antigens, CD/genetics , Antigens, Differentiation, T-Lymphocyte/genetics , Gene Expression Regulation , Humans , Immunosuppressive Agents/pharmacology , Inositol Phosphates/metabolism , Jurkat Cells , Kinetics , Lectins, C-Type , Receptors, Antigen, T-Cell/drug effects , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Tetradecanoylphorbol Acetate/pharmacology , Tumor Cells, CulturedABSTRACT
BACKGROUND: Previous Phase II trials evaluating paclitaxel as a single agent have produced objective response rates of 38-40%. However, in these studies patients had recurrent disease and had received previous treatment with chemotherapy, radiation, surgery, or some combination of the same. To the authors' knowledge, the study reported here is the first to examine the role of paclitaxel in affecting objective antitumor response, as a single agent, in a previously untreated patient population. METHODS: Patients with untreated, resectable, advanced squamous cell carcinoma of the head and neck were eligible for this Phase II trial. The treatment plan included paclitaxel 250 mg/m(2) administered by 24-hour intravenous infusion every 21 days for a total of 3 courses and primary prophylaxis with colony stimulating factor during each course of chemotherapy. Surgical resection was performed after recovery from the final course of chemotherapy. After adequate wound healing, patients received external beam radiotherapy (median dose to primary site, 55.8 Gray [Gy]; median dose to neck sites, 50.4 Gy). RESULTS: Forty-five patients were registered. Thirty-eight patients completed the planned chemotherapy, 41 patients underwent surgical resection, and 37 patients completed the intended radiotherapy. The objective response rate was 50% (10% complete response; 40% partial response). Severe or life-threatening (Grade 3 or higher) granulocytopenia or thrombocytopenia occurred in 78% and 27% of patients, respectively. Two patients died of sepsis. Seventy-one percent, 67%, and 91% of patients were free of local, lymph node, and distant recurrence, respectively, with a median follow-up of 37 months. The 4-year overall survival and disease-related survival rates were 44.4% and 52.9%, respectively. CONCLUSION: The authors conclude that paclitaxel is an active agent in patients with advanced head and neck carcinoma. However, the overall disease control, achieved by using paclitaxel as induction therapy, did not appear to be better than that achieved with standard treatment methods. Combined modality regimens with concurrent chemotherapy and radiotherapy have demonstrated more promise.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Head and Neck Neoplasms/drug therapy , Paclitaxel/therapeutic use , Adult , Aged , Agranulocytosis/chemically induced , Antineoplastic Agents, Phytogenic/adverse effects , Carcinoma, Squamous Cell/radiotherapy , Carcinoma, Squamous Cell/surgery , Combined Modality Therapy , Head and Neck Neoplasms/radiotherapy , Head and Neck Neoplasms/surgery , Humans , Male , Middle Aged , Paclitaxel/adverse effects , Survival Analysis , Thrombocytopenia/chemically induced , Treatment OutcomeABSTRACT
The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.
Subject(s)
Antigens, CD19/metabolism , Antineoplastic Agents/pharmacokinetics , Genistein/pharmacokinetics , Lymphoma, Non-Hodgkin/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Adolescent , Adult , Age Factors , Child , Female , Humans , Immunoconjugates/pharmacokinetics , Lymphoma, Non-Hodgkin/ethnology , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/ethnology , Sex CharacteristicsABSTRACT
Children who require a marrow transplant may receive such hematopoietic cells from one of many sources. This study reviews the experience of one center with 58 children who received marrow from unrelated donors over a 10-year period. These children had a variety of malignant and non-malignant diseases. During that time period, only three of these children had failed to meet engraftment criteria. All donor marrow specimens were T-lymphocyte-depleted using an antibody/complement methodology. No difference was demonstrated in outcome between donors who were perfectly HLA-DR DNA matched versus those who were only partially matched. The increased size of various marrow donor registries has increased the number of potential donors available for these patients. The lack of a requirement for perfect matching means that there is an ever-increasing number of donors available. No graft-versus-host disease (GvHD) or grade III-IV GvHD was associated with a poorer outcome. Stable, long-term engraftment with minimal morbidity has been demonstrated in these children as evidenced by stability of survival curves by two years after marrow transplant.
Subject(s)
Bone Marrow Transplantation , Transplantation, Homologous , Adolescent , Bone Marrow Transplantation/adverse effects , Bone Marrow Transplantation/statistics & numerical data , Bone Marrow Transplantation/trends , Child , Child, Preschool , Graft vs Host Disease/etiology , Histocompatibility Testing , Hospitals, University , Humans , Infant , Iowa/epidemiology , Life Tables , Morbidity , Registries , Survival Analysis , Transplantation Conditioning/statistics & numerical data , Transplantation Conditioning/trends , Transplantation, Homologous/adverse effects , Transplantation, Homologous/statistics & numerical data , Transplantation, Homologous/trends , Treatment OutcomeABSTRACT
Seven children and eight adults with CD19+ B-lineage acute lymphoblastic leukemia, as well as one adult with chronic lymphocytic leukemia, were treated with the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein. All patients had failed previous chemotherapy regimens, and six patients had relapsed after bone marrow transplantation. B43-Genistein was administered as a 1-hour i.v. infusion at 0.1-0.32 mg/kg/day dose levels for 10 consecutive days or 3 consecutive days weekly for a total of nine doses. B43-Genistein was well tolerated by all patients with no life-threatening side effects. There were six episodes of grade 2-3 fever, two of which were clearly drug related, one episode each of grade 3 myalgia, grade 2 sinus tachycardia, and grade 2 vascular leak syndrome. There was one durable complete remission and two transient responses. Pharmacokinetic analyses in 12 patients revealed a plasma half-life of 20 +/- 5 h, mean residence time of 24 +/- 5 h, and a systemic clearance rate of 20 +/- 3 ml/h/kg. Moderate levels of human antimouse antibody (HAMA) ranging from 20-87 ng/ml were detected in the day 28 blood samples from three of nine cases examined. Treatment of these three HAMA-positive patients with a second course of B43-Genistein did not yield measurable immunoconjugate levels in the plasma, indicating that the administered B43-Genistein molecules were rapidly cleared from circulation due to the HAMA. On the basis of its acceptable toxicity profile and its ability to elicit objective responses at nontoxic dose levels, B43-Genistein may provide the basis for an effective treatment strategy for B-lineage acute lymphoblastic leukemia patients who have failed standard therapy.
Subject(s)
Antigens, CD19/immunology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Burkitt Lymphoma/drug therapy , Burkitt Lymphoma/enzymology , Enzyme Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Adolescent , Adult , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal/therapeutic use , Antibodies, Neoplasm/biosynthesis , Antigens, CD19/metabolism , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Burkitt Lymphoma/pathology , Child , Child, Preschool , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Female , Genistein/adverse effects , Genistein/pharmacokinetics , Genistein/therapeutic use , Humans , Immunotoxins/adverse effects , Immunotoxins/pharmacokinetics , Immunotoxins/therapeutic use , Male , Middle Aged , Pilot ProjectsABSTRACT
Severe combined immune deficiency (SCID) is a heterogeneous disorder characterized by profound defects in cellular and humoral immunity. We report here an infant with clinical and laboratory features of SCID and selective CD4 lymphopenia and lack of CD28 expression on CD8(+) T cells. T cells from this patient showed poor blastogenic responses to various mitogens and IL-2. Other T cell antigen receptor- induced responses, including upregulation of CD69, were similarly inhibited. However, more proximal T cell antigen receptor signaling events, such as anti-CD3 induced protein tyrosine phosphorylation, phosphorylation of mitogen-associated protein kinase, and calcium mobilization were intact. Although p59fyn and ZAP-70 protein tyrosine kinases were expressed at normal levels, a marked decrease in the level of p56lck was noted. Furthermore, this decrease was associated with the presence of an alternatively spliced lck transcript lacking the exon 7 kinase encoding domain. These data suggest that a deficiency in p56lck expression can produce a SCID phenotype in humans.
Subject(s)
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/deficiency , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics , Severe Combined Immunodeficiency/enzymology , Antigens, CD/biosynthesis , Antigens, Differentiation, T-Lymphocyte/biosynthesis , CD3 Complex/metabolism , CD4-CD8 Ratio , CD4-Positive T-Lymphocytes/cytology , Cell Division , Exons , Humans , Infant , Lectins, C-Type , Lymphopenia/blood , Lymphopenia/metabolism , Male , Phenotype , Phosphorylation , Receptors, Antigen, T-Cell/metabolism , Severe Combined Immunodeficiency/etiology , Severe Combined Immunodeficiency/genetics , Substrate Specificity , T-Lymphocytes/enzymology , Tyrosine/metabolismABSTRACT
An infant who received haploidentical BM for severe combined immunodeficiency (SCID) developed acute, reversible complete heart block in association with an exacerbation of GVHD. Respiratory distress and myocardial dysfunction were also seen with this and previous GVHD exacerbations. The patient had not received chemotherapy or radiation prior to BMT. The complete heart block resolved after 1 week of intensive immunosuppression. The association of complete heart block with GVHD is important because the heart block is potentially reversible with prompt, aggressive control of the GVHD.
Subject(s)
Bone Marrow Transplantation/adverse effects , Graft vs Host Disease/complications , Heart Block/etiology , Humans , Immunosuppressive Agents/therapeutic use , Infant , MaleABSTRACT
OBJECTIVE: To evaluate complications and sequelae of maxillary removal and reinsertion for anterior cranial base tumors. DESIGN: A retrospective review of patients who underwent maxillary removal and reinsertion from 1990 to 1996. SETTING: The Arthur G. James Cancer Hospital and Research Institute at The Ohio State University, Columbus. PATIENTS: A consecutive sample of 46 patients who underwent maxillary removal and reinsertion. The patients ranged in age from 11 to 77 years and were followed up for as long as 6 years after surgery. There were 16 benign and 30 malignant lesions. MAIN OUTCOME MEASURES: Intraoperative, postoperative (1-10 days), short-term (11 days through 3 months), and long-term (>3 months) complications; survival status of patients; and adjuvant therapy. RESULTS: Four patients (9%) had undergone previous radiotherapy; 9 (20%) received intraoperative radiation therapy; and 23 (50%) received planned postoperative radiotherapy. No intraoperative complications were noted. The most common short-term complication found was transient diplopia, affecting 9 patients (20%). Diplopia resolved within 3 months in all but 2 patients, in whom the condition was permanent. There were 4 patients (9%) who required removal of the nasal dorsum plate, and 4 (9%) who required removal of maxillary plates that were exposed intranasally. Midface asymmetry as reported by the patient or noted on the physical examination was documented in only 2 patients. The most common long-term complication was nasal asymmetry, affecting 13 patients (28%). CONCLUSIONS: Maxillary removal allows improved visualization and access to anterior skull base lesions, while reinsertion of the maxillary fragment provides functional preservation and excellent cosmesis with few short- or long-term complications, even when adjuvant radiotherapy is used.
Subject(s)
Maxilla/surgery , Postoperative Complications/epidemiology , Skull Base Neoplasms/surgery , Adolescent , Adult , Aged , Child , Combined Modality Therapy , Esthetics , Female , Follow-Up Studies , Humans , Male , Middle Aged , Retrospective Studies , Skull Base Neoplasms/radiotherapy , Treatment OutcomeABSTRACT
The authors present results of long-term follow-up of seven patients whose degenerative disease of the first metatarsophalangeal joint was treated with irradiated chondral graft implantation arthroplasty. In appropriate candidates, this procedure is a reasonable alternative to Keller arthroplasty alone, arthrodesis, and nonbiologic implant arthroplasty.
Subject(s)
Arthroplasty, Replacement/methods , Bioprosthesis , Joint Diseases/surgery , Metatarsophalangeal Joint/surgery , Adult , Aged , Cartilage/surgery , Female , Follow-Up Studies , Humans , Joint Diseases/physiopathology , Middle Aged , Movement , Radiation , Retrospective StudiesABSTRACT
Ligation of the CD4 receptor by HIV envelope glycoprotein gp120 inhibits T cell activation and signaling through the TCR complex. Recent reports suggest CD4 ligation by gp120 + anti-gp120 Abs uncouples protein tyrosine kinases (PTKs) from the TCR signal-transduction cascade. This finding and other observations led us to hypothesize that the effects of gp120 are mediated through p56(lck), a PTK noncovalently associated with CD4. To test this hypothesis, we first examined the kinetics of gp120/anti-gp120-induced TCR signaling defects in the Jurkat T cell line. Pretreating cells with gp120/anti-gp120 for 1 to 4 h before stimulation prevented TCR-directed PTK activation. Coincident with TCR desensitization, pretreatment with gp120/anti-gp120 also decreased the amount of p56(lck) that could be immunoprecipitated from the Nonidet P-40 detergent-soluble fraction of cellular lysates, while simultaneously increasing the recovery of p56(lck) from the Nonidet P-40 detergent-insoluble fraction (or cytoskeleton). To assess the potential role of the actin in this process, experiments were conducted in the presence of cytochalasin D. Cytochalasin D restored TCR signaling in cells previously desensitized with gp120/anti-gp120 and prevented translocation of p56lck from the Nonidet P-40 detergent-soluble fraction of cell lysates. Furthermore, p56(lck) was found to coimmunoprecipitate with anti-actin. These data suggest that gp120/anti-gp120 may inhibit TCR signaling by sequestering p56(lck) to the cytoskeleton.