High dose cyclophosphamide for severe refractory myasthenia gravis.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
I Brodsky
Publications and source records attributed to I Brodsky.
High-dose cyclophosphamide without stem-cell rescue for refractory CIDP.
Four patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who were refractory to conventional treatment were treated with high-dose cyclophosphamide (200 mg/kg over 4 days). All improved in functional status and muscle strength. Nerve conduction studies improved in three of four. Other immunomodulatory medications have been discontinued. High-dose cyclophosphamide can be given safely to patients with CIDP and patients with disease persistence after standard therapy may have a response that lasts for over 3 years and results in long-term disease remission.
Adult↗
High-dose cyclophosphamide for severe systemic lupus erythematosus.
Cytotoxic therapy is a cornerstone for patients with severe systemic lupus erythematosus (SLE). High-dose cyclophosphamide, 200 mg/kg, can induce a complete remission without the need for stem cell rescue in patients with autoimmune illnesses. Here we report on our first four patients treated for severe SLE with this treatment approach. Patients received cyclophosphamide, 200 mg/kg, divided over 4 days. Starting day 10, patients received filgrastim, 5 micrograms/kg/day, until their absolute neutrophil count (ANC) rose to 10.0 x 10(9)/l for two consecutive days. Disease activity as evaluated by scores from the Systemic Lupus Activity Measure-2, the SLE Disease Activity Index and the Responder Index for Lupus Erythematosus were completed before and after high-dose therapy. Before high-dose cyclophosphamide, SLE disease duration ranged from 8 to 21 (mean 12.5) years. Their average disease activity measured by SLAM-2 and SLEDAI was 15.5 (range 11-19) and 23.25 (range 20-26), respectively. At a median of 22 (range 12-39) months of follow-up, mean disease activity measured by SLAM-2 and SLEDAI decreased to 6.25 and 7.75, respectively. All patients experienced febrile neutropenia. No long-term morbidities or mortalities were observed. High dose cyclophosphamide is a therapy capable of decreasing disease severity in poor prognosis SLE patients. Future study is warranted for both refractory patients as well as primary therapy for patients with moderate to severe disease presentations.
Adult↗
Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia.
BACKGROUND: Severe aplastic anemia is a life-threatening bone marrow failure disorder. High-dose cyclophosphamide therapy followed by allogeneic bone marrow transplantation cures the disease. However, it requires a suitable donor and carries the risk for graft-versus-host disease. A small pilot study demonstrated that high-dose cyclophosphamide therapy without bone marrow transplantation leads to durable, treatment-free complete remission. OBJECTIVE: To confirm the safety and efficacy of high-dose cyclophosphamide therapy alone in patients with severe aplastic anemia. DESIGN: Uncontrolled clinical trial. SETTING: Three tertiary care hospitals. PATIENTS: 19 patients with untreated severe aplastic anemia. INTERVENTION: Cyclophosphamide, 50 mg/kg of body weight per day for 4 consecutive days. MEASUREMENTS: Probability of response and overall survival were measured. Complete remission was defined as normal blood count for age and sex. Partial remission was defined as independence from transfusion and an absolute neutrophil count greater than 0.5 x 10(9) cells/L without growth factor support. Nonresponders were patients who remained transfusion dependent or died. Relapse was defined as no longer meeting criteria for partial or complete remission. RESULTS: The median time to an absolute neutrophil count of 0.5 x 10(9) cells/L was 49 days. The probability of survival was 84% (95% CI, 59% to 95%) at 24 months. The probability of achieving treatment-free remission was 73% (CI, 51% to 91%) at 24 months, and the probability of achieving complete remission was 65% (CI, 39% to 89%) at 50 months. No responding patients have had relapse or have developed secondary clonal disorders. CONCLUSIONS: High-dose cyclophosphamide therapy without bone marrow transplantation produces durable treatment-free remission in severe aplastic anemia. This approach deserves further study in patients with severe aplastic anemia who are not suitable candidates for allogeneic bone marrow transplantation.
Adolescent↗
Use of granulocyte colony-stimulating factor after high-dose chemotherapy and autologous peripheral blood stem cell transplantation: what is the optimal timing?
Administration of granulocyte colony-stimulating factor to patients undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation accelerates neutrophil recovery and decreases hospitalization time. The optimal timing for granulocyte colony-stimulating factor infusion remains unknown. In this retrospective, case-controlled, two-armed study, we reviewed our experience at Hahnemann University Hospital to determine whether initiating granulocyte colony-stimulating factor infusions on posttransplant day 0 versus day 8 affects neutrophil recovery time, posttransplant discharge date, total hospital days after high-dose chemotherapy, and autologous peripheral blood stem cell transplantation. All patients hospitalized between 1994 and 1998 at Hahnemann University Hospital, Bone Marrow Transplantation Unit with breast cancer or non-Hodgkin's lymphoma, who underwent high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation and received granulocyte colony-stimulating factor either on posttransplant day 0 (16 patients) or day 8 (16 patients). The day 0 and day 8 groups had no statistically significant differences in age, sex, weight, height, body surface area, disease characteristics, pretransplant harvesting or conditioning regimens, or transplant CD34+ cell counts. Our main outcome measure was the mean time to reach absolute neutrophil count greater than or equal to 0.5 x 10(9)/l, the number of hospital days after transplant, and the total hospital days. The mean days to neutrophil recovery (10.56 versus 9.68, p = 0.48), posttransplant hospital days (13.62 versus 12.81, p = 0.39), and total hospital days (20.25 versus 20.25, p = 1.00) were not significantly different between day 8 and day 0 groups, respectively. No significant effects on neutrophil recovery time, posttransplant hospital days, or total hospital days were observed with the initial granulocyte colony-stimulating factor infusion on day 0 versus day 8 after transplant. Delayed administration may allow substantial cost savings (US$200 x 8 approximately equal to US $1,600 per patient) without affecting clinical outcome. More studies are needed to determine whether greater delay is feasible.
Adult↗
Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group.
BACKGROUND: We conducted a randomized trial in which we compared high-dose chemotherapy plus hematopoietic stem-cell rescue with a prolonged course of monthly conventional-dose chemotherapy in women with metastatic breast cancer. METHODS: Women 18 to 60 years of age who had metastatic breast cancer received four to six cycles of standard combination chemotherapy. Patients who had a complete or partial response to induction chemotherapy were then randomly assigned to receive either a single course of high doses of carboplatin, thiotepa, and cyclophosphamide plus transplantation of autologous hematopoietic stem cells or up to 24 cycles of cyclophosphamide, methotrexate, and fluorouracil in conventional doses. The primary end point was survival. RESULTS: The median follow-up was 37 months. Of 553 patients who enrolled in the study, 58 had a complete response to induction chemotherapy and 252 had a partial response. Of these, 110 patients were assigned to receive high-dose chemotherapy plus hematopoietic stem cells and 89 were assigned to receive conventional-dose chemotherapy. In an intention-to-treat analysis, we found no significant difference in survival overall at three years between the two treatment groups (32 percent in the transplantation group and 38 percent in the conventional-chemotherapy group). There was no significant difference between the two treatments in the median time to progression of the disease (9.6 months for high-dose chemotherapy plus hematopoietic stem cells and 9.0 months for conventional-dose chemotherapy). CONCLUSIONS: As compared with maintenance chemotherapy in conventional doses, high-dose chemotherapy plus autologous stem-cell transplantation soon after the induction of a complete or partial remission with conventional-dose chemotherapy does not improve survival in women with metastatic breast cancer.
Adolescent↗
Autologous stem cell transplantation for acute myeloid leukemia in first remission.
We studied the feasibility, toxicity, and efficacy of a 2-step approach to autologous stem cell transplantation for patients with acute myeloid leukemia in first remission. Step 1 consisted of consolidation chemotherapy including cytarabine 2000 mg/m2 twice daily for 4 days concurrent with etoposide 40 mg/kg by continuous infusion over 4 days. During the recovery from this chemotherapy, peripheral blood stem cells were collected under granulocyte colony-stimulating factor stimulation. Step 2, autologous stem cell transplantation, involved the preparative regimen of busulfan 16 mg/kg followed by etoposide 60 mg/kg and reinfusion of unpurged peripheral blood stem cells. A total of 128 patients were treated. During step 1, there was 1 treatment-related death. A median CD34+ cell dose of 14 (x10(6)/kg) was collected in 3 aphereses. Ten patients suffered relapse before transplantation, and 117 patients (91%) proceeded to transplantation. During step 2, there were 2 treatment-related deaths, and 35 patients subsequently suffered relapse. With median follow-up of 30 months, 5-year disease-free survival for all patients entered in the study is projected to be 55%. By cytogenetic risk group, 5-year disease-free survival is 73% for favorable-risk patients, 51% for intermediate-risk patients, and 0% for poor-risk patients. We conclude that this 2-step approach to autologous transplantation produces excellent stem cell yields and allows a high percentage of patients to receive the intended therapy. Preliminary efficacy analysis is very encouraging, with outcomes that appear superior to those of conventional chemotherapy.
Acute Disease↗
Immunoablative high-dose cyclophosphamide without stem-cell rescue for refractory, severe autoimmune disease.
BACKGROUND: Immunoablative high-dose cyclophosphamide without stem-cell rescue induces durable, complete remission in most patients with aplastic anemia. OBJECTIVE: To determine the efficacy of high-dose cyclophosphamide in various refractory, severe autoimmune diseases. DESIGN: Prospective phase II study. SETTING: Johns Hopkins University (Baltimore, Maryland) and Hahnemann University (Philadelphia, Pennsylvania). PATIENTS: Eight patients with refractory, severe autoimmune disease. INTERVENTION: Immunoablative high-dose cyclophosphamide (50 mg/kg of body weight per day) for 4 consecutive days. MEASUREMENTS: Clinical and laboratory variables of autoimmune disease. RESULTS: Seven patients improved markedly: Five achieved complete remission and two achieved partial remission. Four patients have remained in continuous complete remission for 3 to 21 months, and two patients in partial remission continue to improve after 14 and 19 months of follow-up. High-dose cyclophosphamide was well tolerated; median times to a neutrophil count of 0.5 x 10(9) cells/L and platelet transfusion independence were 17 and 16 days, respectively. CONCLUSIONS: Immunoablative high-dose cyclophosphamide without stem-cell rescue can induce complete remission in patients with refractory, severe autoimmune disease. Reemergence of marrow function is similar to that seen after autologous transplantation and does not carry the risk for reinfusion of autoaggressive lymphocytes with the autograft.
Adult↗
Infrared Study of the Intercalation of Kaolinite by Caesium Bromide and Caesium Iodide.
CsBr- and CsI-kaolinite intercalation complexes were synthesized by gradually heating caesium halide disks of the DMSO-kaolinite intermediate up to 330 degreesC. Infrared spectroscopy revealed two types of complexes with the caesium salts: almost nonhydrous, obtained during thermal treatment of the DMSO complex, and hydrated, produced by regrinding the disk in air. Comparison of band positions for CsBr-kaolinite and CsI-kaolinite with those for the CsCl complex (observed in a previous study) shows that the strength of the hydrogen bond between the intercalated halide and the inner surface hydroxyl decreases on the order CsCl > CsBr > CsI. The nonreactivity of CsI in mechanochemical intercalation may arise from weak interaction between I- and inner surface hydroxyl groups, resulting from the fact that caesium is a very soft acid and iodide is a very soft base. Consequently, the very strong interaction between the two ions in the crystal is not disrupted during mechanochemical treatment. Copyright 1998 Academic Press and Minister of Natural Resources, Canada.
Journal Article↗
mdm2-P2 transcript levels predict the functional activity of the p53 tumor suppressor in primary leukemic cells.
The mdm2-P2 promoter is a transcriptional target of the p53 tumor suppressor. The aim of this study was to determine if there is an association between the level of these transcripts and the status of the p53 gene in human leukemic cells. A correlation between mdm2-P2 transcript levels and p53 gene status was observed in all cell lines examined. Primary malignant cells from 10 leukemic patients were also analysed for both mdm2-P2 levels and p53 gene status. All five patients with detectable mdm2-P2 transcripts possessed wild-type p53 alleles. However, only two of five patients with undetectable mdm2-P2 transcripts possessed mutant p53. mdm2-P2 levels were also determined in primary leukemic cells from 14 additional cases both before and after in vitro exposure to cisplatin. The p53 gene was found to be wild-type in all cases where mdm2-P2 levels were induced by cisplatin. There were four cases where no, or only modest, increases in mdm2-P2 levels were detected after cisplatin exposure. Two of these patients were found to harbor mutant p53 while one other possessed leukemic cells with elevated levels of mdm2 protein. These results show that induction of mdm2-P2 transcripts can be used to predict the presence of transcriptionally active p53 in primary leukemic cells.
Alleles↗
Busulfan versus hydroxyurea in the treatment of polycythemia vera (PV) and essential thrombocythemia (ET)
Explore the source record for details and available documents.
Antineoplastic Agents↗
Effect of clinical outcomes data on intensive care unit utilization by bone marrow transplant patients.
OBJECTIVE: To determine if a program to educate referring physicians as to the poor outcome of mechanically ventilated bone marrow transplant patients would result in a change in intensive care unit (ICU) utilization. DESIGN: Retrospective chart review. SETTING: Medical ICU at an urban university hospital. PATIENTS: Patients undergoing bone marrow transplantation in the interval before (n = 236) vs. the interval after (n = 144) a physician education program. INTERVENTIONS: Two separate educational programs were conducted for oncologists and intensivists to review the findings of an earlier study demonstrating the outcome of bone marrow transplant patients in the ICU. MEASUREMENTS AND MAIN RESULTS: The results demonstrated that this physician education intervention did not result in a change in the utilization of medical ICU resources by these patients. Comparing the time periods before and after the intervention, there were no statistically significant differences in the proportion of patients who were admitted to the medical ICU, the proportion who received mechanical ventilation, or the medical ICU lengths of stay. Similarly, the two groups did not differ regarding the 100-day survival rate of all bone marrow transplant patients studied, all bone marrow transplant patients admitted to the medical ICU, or all bone marrow transplant patients intubated. CONCLUSION: Simple educational interventions are not a powerful mechanism by which to alter the practice of physicians regarding the utilization of scarce and expensive resources, even when the physicians generally agree that the use of those resources results in dismal patient outcomes.
Adult↗
Evidence for copurification of HERV-K-related transcripts and a reverse transcriptase activity in human platelets from patients with essential thrombocythemia.
We have previously reported that particles resembling retroviral particles and possessing an RNA-directed DNA polymerase activity can be prepared from platelets. Furthermore, we and others have shown that these particles are present at higher levels in patients with essential thrombocythemia and polycythemia vera. We show here that these particles package RNA molecules that encode HERV-K-related pol genes. A subset of the RNA molecules that are packaged are likely to encode the RNA directed DNA polymerase activity and, because these RNAs possess long/full-length open reading frames for the reverse transcriptase and RNaseH (also for part of the integrase domains in genomic clones) of HERV-K, we propose that these transcripts are indeed strong candidates for encoding the enzyme activity found in these particles. Moreover, by using a modification of the polymerase chain reaction-based reverse transcriptase assay in which activated DNA is added during cDNA synthesis to suppress DNA polymerase-mediated RNA-directed DNA synthesis, we have found that the particle-associated enzyme behaves like a retroviral reverse transcriptase, further supporting the conclusion that retrovirus-like, perhaps HERV-K sequences, encode this enzyme activity.
Adult↗
Microsecond atomic force sensing of protein conformational dynamics: implications for the primary light-induced events in bacteriorhodopsin.
In this paper a new atomic force sensing technique is presented for dynamically probing conformational changes in proteins. The method is applied to the light-induced changes in the membrane-bound proton pump bacteriorhodopsin (bR). The microsecond time-resolution of the method, as presently implemented, covers many of the intermediates of the bR photocycle which is well characterized by spectroscopical methods. In addition to the native pigment, we have studied bR proteins substituted with chemically modified retinal chromophores. These synthetic chromophores were designed to restrict their ability to isomerize, while maintaining the basic characteristic of a large light-induced charge redistribution in the vertically excited Franck-Condon state. An analysis of the atomic force sensing signals lead us to conclude that protein conformational changes in bR can be initiated as a result of a light-triggered redistribution of electronic charge in the retinal chromophore, even when isomerization cannot take place. Although the coupling mechanism of such changes to the light-induced proton pump is still not established, our data question the current working hypothesis which attributes all primary events in retinal proteins to an initial trans<==>cis isomerization.
Bacteriorhodopsins↗
Cytokine mRNA expression in human platelets and a megakaryocytic cell line and cytokine modulation of platelet function.
Platelet formation and function are regulated, in vivo, to varying degrees by cytokines in the micro-environment. While white blood cells are the major source of cytokines within the cardiovascular system, the question addressed in this study was whether platelets and the platelet precursor, the megakaryocyte, may also serve as a source of cytokines. Cytokines produced by or carried within platelets could be released at sites of vascular injury and participate in wound healing. Platelets and a human megakaryocyte-like cell line, HU3, were found to express message for interleukin 7 (IL-7), stem cell factor (SCF), transforming growth factor beta (TGF-beta), cMpl, the IgE receptor subunits Fc epsilon RI alpha gamma and the transcription factor, NF-E2. Other cytokines expressed in HU3 cells but not in platelets included IL-1 beta, IL-6, IL-10, IL-13, TNF-alpha and the FC epsilon RI beta subunit. The HU3 cell line seemed to be further along the maturation/differentiation pathway to platelet formation than a second blood derived bipotential cell line, MB02. The MB02 cell line did not express IL-6, IL-10, SCF, TNF-omega nor cMpl. Furthermore, culturing the HU3 cells in TPO appeared to repress expression of Fc epsilon RI beta directing the cell closer to the platelet phenotype. In light of the presence of cytokine expression in platelets/megakaryocytes, agonist-induced platelet aggregation was measured in the presence of added cytokines as a means to evaluate potential cytokine modulation of platelet function. Collagen-induced aggregations were significantly enhanced by IL-6, SCF and TPO. Other cytokines tested significantly stimulated the thrombin receptor activating peptide, SFLLRNP-, U46619- and ADP-induced platelet aggregations with TPO being the most consistent activator. It is possible that cytokines released from platelets act in concert with cytokines released from other cellular sources to modulate haemostasis and thrombosis differentially depending upon the site of injury.
Base Sequence↗
Atomic Force Sensing of Light-Induced Protein Dynamics with Microsecond Time Resolution in Bacteriorhodopsin and Photosynthetic Reaction Centers
This paper reports on experiments that have monitored protein microsecond dynamics with a cantilevered near-field optical glass fiber. In these experiments two photoactive proteins, bacteriorhodopsin (bR) and the photosynthetic reaction center (PS I), are used to demonstrate that such probes can measure light-induced microsecond protein dynamics even though the resonance frequencies of the glass cantilevers used are on the order of a few hundred kilohertz. In the case of the light-driven proton pump, bR, the light-induced atomic force sensing (AFS) signal is negative (indicating contraction) in the microsecond time domain of the L photointermediate and becomes positive (corresponding to expansion) in the subsequent M intermediate that lives for milliseconds. Double pulse experiments from M to bR show that the latter process reverses the AFS signal. Thus, the AFS structural changes are coupled with the (optical) photocycle intermediates. Light-induced contraction and expansion phenomena are also observed in the case of PS I. In both systems the time regime of the dynamic phenomena that have been measured with AFS is five orders of magnitude faster than the fastest previously recorded atomic force detection of dynamic phenomena. This advance portends a new era in dynamic imaging of protein conformational changes.
Journal Article↗
Na(+)-K(+)-ATPase in frog esophagus mucociliary cell membranes: inhibition by protein kinase C activation.
We examined protein kinase C (PKC)-dependent regulation of Na(+)-K(+)-ATPase in frog mucociliary cells. Activation of PKC by 12-O-tetradecanoylphorbol-13-acetate (TPA) or 1,2-dioctanoyl-sn-glycerol (diC8) either in intact cells or isolated membranes resulted in a specific inhibition of Na(+)-K(+)-ATPase activity by approximately 25-45%. The inhibitory effects in membranes exhibited time dependence and dose dependence [half-maximal inhibition concentration (IC50) = 0.5 +/- 0.1 nM and 2.4 +/- 0.2 microM, respectively, for TPA and diC8] and were not influenced by Ca2+. Analysis of the ouabain inhibition pattern revealed the presence of two Na(+)-K(+)-ATPase isoforms with IC50 values for cardiac glycoside of 2.6 +/- 0.8 nM and 409 +/- 65 nM, respectively. Most importantly, the isoform possessing a higher affinity for ouabain was almost completely inhibited by TPA, whereas its counterpart was hardly sensitive to the PKC activator. The results suggest that, in frog mucociliary cells, PKC regulates Na(+)-K(+)-ATPase and that this action is related to the specific Na(+)-K(+)-ATPase isoform.
4-Nitrophenylphosphatase↗
Altered expression of p53 and mdm-2 proteins at diagnosis is associated with early treatment failure in childhood acute lymphoblastic leukemia.
PURPOSE: To determine whether potential alteration in p53 function through p53 gene mutation or mdm-2 overexpression correlates with early treatment failure in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Diagnostic marrow samples from 34 children were analyzed for p53 gene alterations by western blot and SSCP/DNA sequence analysis and for mdm-2 overexpression by western blot analysis. These samples were derived from two groups of children with ALL: 17 good outcome patients who are in long-term continuous complete remission and 17 poor outcome patients who did not achieve a complete remission or relapsed within 6 months of achieving remission. RESULTS: Two children within the poor outcome group were found to have p53 gene mutations. Furthermore, five poor outcome patients were shown to have greater than 10-fold overexpression of mdm-2 protein compared with the mean level of mdm-2 protein measured in the good outcome group. Aberrant p53 protein expression was found in only one good outcome patient, whereas no good outcome children were found to have elevated levels (> 10-fold) of mdm-2 protein. CONCLUSION: We show for the first time that potential alteration in p53 function in childhood ALL is more common (P = .036) in cases of early treatment failure than in children who remain in long-term continuous remission.
Child↗