Acute pseudobulbar palsy due to methotrexate with rapid response to intravenous immunoglobulin.
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Adult↗
Biomedical subjects
H Enright
Publications and source records attributed to H Enright.
Erythroid hypoplasia associated with leptospirosis.
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Adult↗
A novel t(15;17) translocation in acute myeloid leukaemia not associated with PML/RARalpha rearrangement.
We report a novel t(15;17)(q15;q11) translocation in acute myeloid leukaemia (AML M4) which was not associated with PML/RARalpha rearrangement or with acute promyelocytic leukaemia (APL) morphology. The leukaemia behaved in refractory fashion, with 70% blasts in the bone marrow after the first course of chemotherapy. In view of the refractory behaviour of the leukaemia, the patient was treated with high dose chemotherapy and autologous stem cell rescue. The patient is alive and well 22 months post-autologous stem cell transplant. This case demonstrates that while cytogenetic analysis provides important diagnostic and prognostic information, the precise location of the chromosomal breakpoints is critical in the interpretation of cytogenetic results.
Adult↗
Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial therapy for chronic graft-versus-host disease.
Chronic graft-versus-host disease (CGVHD) is a major cause of morbidity following allogeneic bone marrow transplantation. Thalidomide is active in salvage therapy for high-risk or resistant CGVHD. In a prospective randomized trial, we tested initial therapy with thalidomide. Patients with extensive CGVHD were randomized to receive either cyclosporine and alternate-day prednisone (n = 27, no-thalidomide [no-thal] group) or cyclosporine, prednisone, and thalidomide (200-800 mg/day; n = 27, thal group). Although most patients responded, initial therapy with thalidomide did not improve control of CGVHD. Response rates were 83% versus 89% at 2 months (P = .7), 88% versus 84% at 6 months (P > .8) and 85% versus 73% at 1 year (P = .5) in the thal and no-thal groups, respectively. Multivariate analysis revealed related donor transplant (odds ratio [OR] = 11.3; P =.03) and de novo or quiescent onset of CGVHD (OR = 7.7; P =.04) to be significant predictors of good early response, whereas a platelet count of > or =100,000/microL was a significant predictor of good response (OR = 10.4; P =.04) at 1 year. Survival for the thal and no-thal groups was similar at 1 year (66% versus 74%) and 2 years (66% versus 54%, P = .85). Multivariate analysis revealed progressive onset CGVHD (relative risk [RR] = 4.2; P =.01), unrelated donor (RR = 5.7; P < .01), sex mismatch (RR = 7.9; P < .01), and platelet counts of <100,000/microL (RR = 3.8; P = .01) as significant predictors of poorer survival. These data suggest that despite a high response rate (79% response and 53% complete response) and encouraging survival rates (70% at 1 year and 60% at 2 years), thalidomide offers no clinical benefit when incorporated into initial therapy for CGVHD. The value of thalidomide as salvage therapy requires further study.
Bone Marrow Transplantation↗
Chronic myelomonocytic leukemia revealed by uncontrollable hematuria.
Nephrectomy was performed for uncontrollable unilateral hematuria in an apparently healthy 72-year-old man. The suburothelial connective tissue of the kidney was infiltrated by primitive myeloid cells with associated acute vasculitis and foci of extramedullary hematopoiesis. Subsequently, the patient was shown to have chronic myelomonocytic leukemia. Although renal involvement and vasculitis have been recorded previously in chronic myelomonocytic leukemia, this is the first occasion, to our knowledge, where their concurrence resulted in such a spectacular presentation.
Aged↗
Effective progenitor cell mobilization in lymphoproliferative disorders using ifosfamide, epirubicin and etoposide (IEV).
The combination of ifosfamide, epirubicin and etoposide (IEV) is an effective salvage regimen for lymphoproliferative disease. We report our experience with this combination in mobilization of peripheral blood stem cells (PBSC) in patients with relapsed or refractory/high-risk lymphoma. The median time to leukapheresis was 14 days, with 85% of patients commencing PBSC collection in the range of 13-15 days. Mobilization was successful in 26 of 28 patients (93%), who achieved the minimum transplant dose of 2 x 10(6)/kg CD34+ cells in a median of 2 leukaphereses. Overall, the median CD34+ cell yield was 6.94 x 10(6)/kg (range 0.73-27.4). In 15 of 27 patients (54%), the yield was sufficient (> 6 x 10(6)/kg) to permit CD34+ cell selection and/or a second autograft. IEV was given as an inpatient in all cases. Patients were scheduled for discharge after chemotherapy. This was achieved in 71%, with readmission 1 week later for harvest. Therapy was complicated by neutropenic fever in 13 patients and mild nausea. In autografts carried out using IEV-mobilized PBSC (n = 20), the median time to neutrophils > 0.5 x 10(9)/L was 10 days (range 7-13 days), and to platelets > 20 x 10(9)/L was 13 days (range 11-18 days). There was no mobilization- or transplant-related mortality. We conclude that IEV is a safe, predictable and highly effective mobilization regimen in patients with lymphoma.
Adolescent↗
Fortification of foods with folic acid.
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Adult↗
Response to thalidomide therapy in refractory chronic graft-versus-host disease.
Chronic graft-versus-host disease (GVHD) refractory to standard immunosuppressive therapy remains a major cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT). Thalidomide may be effective in some patients with high-risk or refractory chronic GVHD. We report a single-institution study of thalidomide in 37 BMT patients with extensive chronic GVHD refractory to standard immunosuppressive therapy. Acute GVHD occurred in 34 (91%) of patients and evolved progressively into chronic GVHD in 23 (62%) patients. Thalidomide was added to standard immunosuppressive therapy a median of 11 months (range 0-105 months) after the diagnosis of chronic GVHD. Fourteen of 37 (38%) patients responded after introduction of thalidomide (one complete, 13 partial). Ten of 21 (46%) children and four of 16 (25%) adults responded. Responses were seen in eight of 17 (47%) recipients of related donor marrow and six of 20 (30%) recipients of unrelated donor marrow. Eight of 23 (34%) patients with progressive onset of chronic GVHD showed a response. There were no deaths among the responders. The remaining 23 patients (62%) did not respond and of these only two survive, one with progressive scleroderma, and the other with bronchiolitis obliterans. Chronic GVHD with associated infection (most commonly disseminated fungal infection) was a major contributor to mortality in all cases. Overall, after initiation of thalidomide, the 2-year Kaplan-Meier survival was 41% (95% C.I. 24%-59%). We conclude that thalidomide is a useful and well-tolerated therapy for patients with previously treated refractory chronic GVHD, including those with progressive onset of chronic GVHD, recipients of unrelated donor marrow, and children. Earlier introduction of thalidomide as an adjunct to standard immunosuppressive therapy may lead to more frequent responses and possible better survival.
Chronic Disease↗
The iron chelator L1 potentiates oxidative DNA damage in iron-loaded liver cells.
Iron-mediated carcinogenesis is thought to occur through the generation of oxygen radicals. Iron chelators are used in attempts to prevent the long term consequences of iron overload. In particular, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), has shown promise as an effective chelator. Using an established hepatocellular model of iron overload, we studied the generation of iron-catalyzed oxidative DNA damage and the influence of iron chelators, including L1, on such damage. Iron loading of HepG2 cells was found to greatly exacerbate hydrogen peroxide-mediated DNA damage. Desferrithiocin was protective against iron/hydrogen peroxide-induced DNA damage; deferoxamine had no effect. In contrast, L1 exposure markedly potentiated hydrogen peroxide-mediated oxidative DNA damage in iron-loaded liver cells. However, when exposure to L1 was maintained during incubation with hydrogen peroxide, L1 exerted a protective effect. We interpret this as indicating that L1's potential toxicity is highly dependent on the L1:iron ratio. In vitro studies examining iron-mediated ascorbate oxidation in the presence of L1 showed that an L1:iron ratio must be at least 3 to 1 for L1 to inhibit the generation of free radicals; at lower concentrations of L1 increased oxygen radical generation occurs. In the clinical setting, such potentiation of iron-catalyzed oxidative DNA damage at low L1:iron ratios may lead to long-term toxicities that might preclude administration of L1 as an iron chelator. Whether this implication in fact extends to the in vivo situation will have to be verified in animal studies.
Cell Line↗
Intracellular targets in heme protein-induced renal injury.
We examined two potential intracellular targets in the glycerol model of acute renal failure, namely, the mitochondrion and the nucleus. Within three hours, alterations in mitochondrial function are already apparent. With either glutamate/malate or succinate/rotenone, state 3 and uncoupled respirations were decreased at three hours, and at 24 hours, such decrements were quite pronounced; in the presence of glutamate/malate, state 2 respiration was also depressed at 24 hours, while with succinate/rotenone state 2 was increased. Marked ultrastructural changes were observed in mitochondria studied at three hours, including the novel finding of degenerate mitochondria in autophagic vacuoles. Since the heme content in mitochondria was increased some tenfold within three hours, mitochondrial function was studied after exposure to concentrations of heme that reproduced such contents of heme: mitochondria initially displayed increased respiration, and subsequently, a persistent decline in oxygen consumption until oxygen consumption was virtually undetectable. With higher concentrations of heme, the early increase in oxygen consumption was blunted and the progressive decline in oxygen consumption was hastened. The antioxidant iron chelator, deferoxamine, prevented the early rise in oxygen consumption but did not prevent or delay the subsequent decline. We also assessed nuclear damage as a potential lesion in the glycerol model. DNA laddering was not observed at any time point. At 3 and 24 hours there was DNA injury by the TUNEL technique in the distal nephron but not in the proximal nephron. The 8-hydroxydeoxyguanosine/deoxyguanosine content was increased in the glycerol kidneys at 24 hours but not at three hours. At neither time point was evidence of apoptosis observed by light or electron microscopy. In studies undertaken in cell culture models, heme, at concentrations of 10 microM, failed to evince any such changes in LLC-PK1 cells, a cell line from the proximal tubule, or in MDCK cells, a cell line derived from the distal tubule. At concentrations of 50 microM, heme induced approximately 20% positivity in MDCK cells but none in LLC-PK1 cells by the TUNEL technique. We conclude that mitochondria and nuclei are prominent targets for injury in the glycerol model of acute renal failure. The presence of TUNEL-positive cells in the distal nephron but not at proximal sites in vivo underscores the increasing appreciation of the distinct responses of these nephron sites to nephrotoxic insults.
Acute Kidney Injury↗
Bone marrow transplantation for chronic myelogenous leukemia.
Chronic myelogenous leukemia (CML) is a hematologic malignancy characterized by an initial chronic phase of expanded clonal myelopoiesis followed by inevitable progression to accelerated phase and finally to fatal blast crisis. Although interferon therapy results in hematologic control of disease in most patients and major cytogenetic responses in 30% to 35%, resulting in better survival than with conventional therapy with hydroxyurea or busulfan, most patients have residual disease detectable by molecular methods. Allogeneic bone marrow transplantation may cure selected patients with CML and should be considered early in the course of disease. Newer approaches to therapy include autografting using mobilized peripheral blood stem cells. Selection and expansion of nonleukemic progenitors may improve outcome following autologous transplantation. Advances in understanding of mechanisms of action of antisense oligonucleotides, ribozymes, and tyrosine kinase inhibitors and the immunologic responses to CML cells are also likely to lead to novel approaches to therapy.
Bone Marrow Transplantation↗
Autoimmune phenomena in patients with myelodysplastic syndromes.
Autoimmune syndromes are common in patients with myelodysplastic syndromes (MDS). Clinical manifestations include an acute systemic vasculitic syndrome (characterized by skin vasculitis, fever, arthritis and sometimes associated with pulmonary infiltrates and peripheral edema), chronic autoimmune disorders, including chronic cutaneous vasculitis, polyneuropathy, inflammatory bowel disease and glomerulonephritis, and classical connective tissue disorders, most notably relapsing polychondritis. Asymptomatic immunologic abnormalities are also common and include hypergammaglobulinemia and a positive FANA. Autoimmune syndromes may be the primary cause of death in some patients with MDS. However, these syndromes frequently respond to immunosuppressive agents and occasional dramatic hematologic responses to steroid therapy are seen. We review the incidence, nature, course and response to therapy of these manifestations and discuss potential pathogenic mechanisms.
Autoimmune Diseases↗
Relapse after non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an unrelated donor, and chronic graft-versus-host disease are protective.
We analyzed the incidence of posttransplant chronic myelogenous leukemia (CML) relapse in 283 consecutive related-donor (n = 177) and unrelated-donor (n = 106) allogeneic transplant recipients. Twenty-two of 165 related-donor recipients with stable or advanced disease at the time of transplant had hematologic relapse of CML following transplant (5-year Kaplan-Meier estimate of relapse, 20%; 95% confidence interval [CI], 11 to 30%). One of 12 patients transplanted in second stable phase following blast crisis also relapsed. Fifteen related-donor transplant recipients relapsed within 5 years of transplant; however, seven relapsed between 5 and 9 years after transplant. Factors independently associated with an increased risk of posttransplant relapse for related-donor recipients included prolonged interval between diagnosis and transplant (relative risk, [RR], 3.81; P = .009) and bone marrow basophilia (RR, 5.62; P = .01). Related-donor recipients with posttransplant chronic graft-versus-host disease (CGVHD) had a decreased risk of relapse (RR, 0.24; P = .005). Only two of 106 unrelated-donor transplant recipients relapsed following transplant (5-year Kaplan-Meier estimate of relapse, 3%; 95% CI, 0% to 7%). When both related- and unrelated-donor recipients were considered, the use of an unrelated donor was independently associated with a decreased risk of relapse (RR, 0.24; P = .07). Twelve of 16 relapsing patients who received further therapy (nine of 13 who underwent second transplant and three of three who received donor leukocyte infusions) remain alive. This analysis shows that relapse, sometimes occurring long after transplant, is an important adverse outcome in allogeneic transplantation for CML. Early transplant, posttransplant CGVHD, and use of an unrelated donor are associated with a reduced incidence of relapse, perhaps due to allogeneic disparities enhancing the graft-versus-leukemia effect.
Adolescent↗
Preferential targeting of oxidative base damage to internucleosomal DNA.
The structure of nuclear chromatin may limit the accessibility of carcinogenic agents to DNA. In the case of oxidative DNA strand cleavage mediated by the physiologically relevant iron chelate, iron-ADP, histone-associated nucleosomal DNA is protected while internucleosomal DNA is susceptible to damage. We now find that the distribution of iron-ADP-generated 8-hydroxydeoxyguanosine, a potentially mutagenic oxidative base change, shows relative targeting to internucleosomal sites (3.5-fold increased oxidative modification of internucleosomal compared with nucleosomal DNA as the minimal degree of enrichment). In contrast, iron-EDTA, which generates hydroxyl radical in the 'fluid phase', does not target internucleosomal DNA. Thus, physiologic iron chelates may promote site-specific damage and thereby be relevant to mechanisms of iron-dependent oxidative mutagenesis and carcinogenesis.
8-Hydroxy-2'-Deoxyguanosine↗
Chronic myelogenous leukemia.
Chronic myelogenous leukemia involves clonal expansion of hematopoietic progenitor cells associated with the characteristic translocation between chromosomes 9 and 22, resulting in the generation of an aberrant bcr-abl protein with enhanced tyrosine kinase activity. The bcr-abl protein can induce cell proliferation, induce transformation of immature hematopoietic cells, and suppress apoptosis in vitro. Abnormalities of stromal cell and progenitor cell interaction may be central to the pathogenesis of the abnormal hematopoiesis in chronic myelogenous leukemia. Therapy with interferon alpha in chronic-phase chronic myelogenous leukemia can result in hematologic responses in up to 70% to 80% of patients and partial or complete cytogenetic responses in up to 50%; many studies show a significant overall survival advantage for patients treated with interferon. Allogeneic marrow transplantation can result in long-term survival for patients with chronic myelogenous leukemia, particularly younger patients undergoing transplantation early in the course of disease, and unrelated donor or autologous marrow transplantation may be an option for patients without a matched sibling donor. Future therapy will likely involve selection and expansion ex vivo of Ph- stem cells for reinfusion as part of a strategy for autologous marrow transplantation. Other areas of current investigation include in vitro assessment of the activity of antisense oligonucleotides and of the immunologic responses to chronic myelogenous leukemia cells.
Humans↗
Unrelated donor bone marrow transplantation for hematological malignancies-current status.
We have explored the efficacy and toxicity of hematopoietic stem cell transplantation from unrelated donors for hematologic malignancies and other disorders. While most marrow donors have been identified through the National Marrow Donor Program in cooperation with many international registries, the recent development of unrelated donor umbilical cord blood (UCB) banks has allowed us to also evaluate this stem cell source. Analysis of the first 211 URD BMT performed at the University of Minnesota shows an overall survival of 33%, with older recipient age and transplant from a donor with a major HLA-A or B mismatch independently associated with poorer survival. Analysis of engraftment of URD marrow shows increasing risk of delayed or incomplete engraftment with increasing HLA disparity between URD and recipient. GVHD is increased in recipients of URD marrow compared with recipients of related donor marrow. Malignant relapse, however, is less frequent in URD marrow recipients, perhaps due to an increased graft-versus-leukemia effect. Formal assessment shows quality of life in long term URD BMT survivors (beyond 2 years) is excellent, and not different from that seen in sibling marrow recipients. Data from patients receiving unrelated donor UCB transplantation at the University of Minnesota indicate that UCB is an acceptable alternate source of stem cells, at least for young recipients, and may be associated with a reduced incidence of GVHD. Ongoing studies at the University of Minnesota include examination of the applicability of unrelated UCB transplantation to adult recipients, and of the degree of HLA-incompatibility which can be tolerated in UCB transplantation. Studies to identify the optimal GVHD prophylaxis for URD BMT, and to examine the role of class II matching in transplant outcome are in progress.
Bone Marrow Transplantation↗
Outcome of second bone marrow transplantation following a uniform conditioning regimen as therapy for malignant relapse.
Twenty-three second bone marrow transplants (BMT) were performed between October 1987 and January 1994 for patients with malignant relapse following initial BMT. For first BMT, twenty-one of 23 (91%) were conditioned with cyclophosphamide plus total body irradiation. For second BMT, a uniform conditioning regimen consisting of busulfan and cyclophosphamide was used. Eleven patients had chronic myelogenous leukemia, seven acute leukemia, four lymphoma, and one myelodysplastic syndrome. Median patient age at second BMT was 32 years, the median time between first BMT and relapse was 22 months, and the median time to second BMT after relapse was 5 months. The second BMT marrow source included: autologous marrow (1), unrelated donors (4), new matched sibling donors (5) and same matched sibling donors as the first BMT (13). The Kaplan-Meier disease-free survival and survival rates at 3 years were 38 and 43%, respectively (median follow-up of survivors was 45 and 48 months, respectively), and five patients survive disease-free at 4-6 years. Nine of the 13 deaths occurred within 100 days after second BMT; eight had relapsed within 1 year of the first BMT. We conclude that: (1) second BMT can offer durable long-term survival in certain patients, especially those who relapse late after first transplant; (2) busulfan and cyclophosphamide is a suitable conditioning regimen for second BMT.
Adolescent↗
Related donor marrow transplant for chronic myeloid leukemia: patient characteristics predictive of outcome.
Pre-transplant characteristics of 137 consecutive patients (including 103 patients with one or more features suggesting advanced disease) undergoing related donor marrow transplant for chronic myeloid leukemia (CML) were analyzed to determine their association with outcome. Multivariate analysis identified increased recipient age (relative risk (RR) for patients over 30 years of relapse or death 2.37; P = 0.004), and longer interval between diagnosis and transplant (RR 1.20; P = 0.0001) as significant adverse influences on disease-free survival (DFS). The 5-year DFS for patients transplanted within 1 year of diagnosis (¿early transplant', n = 71) was significantly higher (51%) than that for patients transplanted beyond 1 year from diagnosis ('delayed transplant', n = 55) (34%; log rank P = 0.02). For early transplant patients, poor prognostic features included myelofibrosis (RR 3.53; P = 0.018), splenomegaly (RR 2.22; P = 0.029) and the use of a female donor (RR 3.16; P = 0.002). The 5-year DFS for patients transplanted within 1 year of diagnosis and without signs of advanced disease was 67%. The presence of increasing numbers of features suggesting acceleration prior to transplant had a cumulative adverse influence of DFS. The risk of relapse (5 year estimate 20%) was also independently and significantly increased in association with a longer interval from diagnosis to transplant (P = 0.012). Early transplant is an important influence on DFS and relapse after related donor transplant therapy for CML, although additional patient characteristics influencing outcome can be identified and may have cumulative adverse effects.
Adolescent↗