- Emmanuel Besa, MDDistinguished Professor Emeritus American Society of HematologyRetired Professor of Medical Oncolog... moreEmmanuel Besa, MDDistinguished Professor Emeritus American Society of HematologyRetired Professor of Medical OncologyKimmel Cancer CenterMDS Center of ExcellenceThomas Jefferson UniversityVisiting Professor for Research Development, Univ. of Philippines College of MedicineEditor-in-Chief, Hematology, Medscape Emedicineedit
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Twenty-one patients with B-cell chronic lymphocytic leukemia (B-CLL) have been followed for more than 2 years with serial cytogenetic studies, including 11 cases for more than 5 years and three others for more than 10 years. A... more
Twenty-one patients with B-cell chronic lymphocytic leukemia (B-CLL) have been followed for more than 2 years with serial cytogenetic studies, including 11 cases for more than 5 years and three others for more than 10 years. A chromosomally abnormal clone was present at the time of initial study in 10 of these patients, and neither these nor the 11 individuals with a normal karyotype had any cytogenetic evolution during the follow-up period, although clinical progression, requiring therapy, was observed in 13 cases. In an additional 12 B-CLL patients who had repeat chromosome studies but were followed for less than 2 years, two patients with advanced disease and multiple cytogenetic abnormalities developed minor additional karyotypic changes and died within 18 months, and two patients with a normal karyotype developed rapidly progressive disease associated with an emerging chromosomally abnormal clone and survived only 1 year. These results demonstrate that karyotypic evolution is rare in B-CLL. Its occurrence indicates a poor prognosis, but its rarity suggests that clinical progression in this disease is usually more dependent on other factors.
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A pilot study was performed to determine the efficacy of 13-cis-retinoic acid (CRA) and alpha-tocopherol (AT) with increasing doses of recombinant human erythropoietin (rHuEPO) in anemic patients with primary myelodysplastic syndrome... more
A pilot study was performed to determine the efficacy of 13-cis-retinoic acid (CRA) and alpha-tocopherol (AT) with increasing doses of recombinant human erythropoietin (rHuEPO) in anemic patients with primary myelodysplastic syndrome (MDS), to determine response rate and to determine the dose requirement and long-term effects of rHuEPO therapy on the transition to acute non-lymphocytic anemia and survival of these patients. Twenty-four consecutive MDS patients were entered into the study. Patients were stratified according to their FAB classification at study entry. Therapy consisted of a 6 month trial of CRA (100 mg m(-2) day(-1) and AT (800 mg day(-1)) with rHuEPO (150 units kg(-1) body weight subcutaneously three times a week). The rHuEPO dose was escalated to daily doses at 2 months, and 300 U kg(-1) body weight given three times a week for another 2 months and continuing therapy after 6 months in responsive patients. Response was measured by elimination of transfusions requirement (partial response, PR) and normal hemoglobin level and complete blood counts (complete response, CR). Observed responses for the 23 evaluable patients were 2 CR and 6 PR (34.8%). Odds ratio analysis showed that patients with anemia alone were 14 times more likely to respond than patients with pancytopenia (p = 0.06). In our study, two patients (8%) transformed to acute leukemia in CRA + AT + rHuEPO-treated patients. Median survival of 34 months with a median follow-up of 17 months (range 3-70 months) was observed. The response rates with the addition of rHuEPO to CRA and AT was similar but occurs earlier at 2 months compared to 6-10 months with CRA and AT alone and did not alter survival. There was no increase in the risk for leukemia in the group treated with rHuEPO. Response to either therapy appeared to be limited to patients in the early stages of MDS.
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Research Interests: Gastroenterology, Medicine, Hematopoiesis, Humans, Internal Medicine, and 12 morePlacebo, Blood, Skin Diseases, Clinical Sciences, Randomized Controlled Trial, Tretinoin, Sleep Stages, Random Allocation, Clinical Trials as Topic, Myelodysplastic syndromes, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
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A population of rats treated with a single dose of cortisol on their first day of life and a population of rats underfed since day sixteen of gestation until sacrificed have been studied. Body, brain and liver glycogen content have been... more
A population of rats treated with a single dose of cortisol on their first day of life and a population of rats underfed since day sixteen of gestation until sacrificed have been studied. Body, brain and liver glycogen content have been measured at eight, twelve and twenty-two days of life and compared to controls of the same age. Pituitary growth hormone and thyrotrophin content have also been measured in the same population of animals and at the same stages of life. Results are compared to those found in "neo-T4" rats -- which receive 30 micrograms T4 in 5 doses during the first days of life -- at the same ages.
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This study reports suggestive evidence for the ability of 3β-hydroxy-5β-pregnane-20-one, a steroid metabolite of testosterone, to trigger stem cells to a cell cycle stage responsive to the erythnoid differentiating effects of... more
This study reports suggestive evidence for the ability of 3β-hydroxy-5β-pregnane-20-one, a steroid metabolite of testosterone, to trigger stem cells to a cell cycle stage responsive to the erythnoid differentiating effects of erythropoietin (ESF). Erythropoiesis was suppressed by the hypenoxic method of ESF suppression, to create an animal sensitive to exogenous enythropoietic stimuli. Mice maintained in hyperoxia were injected daily with the metabolite while controls received diluent injections. A significant elevation in erythropoiesis, as measured by 59Fe incorporation into peripheral red blood cells, was observed in the metabolite-treated group 24, 48 and 72 hours after the initial injection. In another expeniment, mice receiving a single injection of the metabolite during hyperoxia were returned to ambient conditions 18 hours later. The observed erythropoietic response to the subsequent release of endogenous ESF, due to the temporary relative hypoxia of ambient conditions, was significantly higher in the metabolite-treated group than in the diluent-treated controls. The increment in erythropoietic response to the metabolite-, compared to the diluent-treated group, was greater in the posthyperoxic system, when rising titers of ESF are found, than in the hypenoxic system, suggesting that ESF may play a pimysioiogical role in the regulation of metabolite-induced erythropioesis.
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Using heat-killed, formalin-stabilized Staphylococcus aureus Cowan I suspension, it was possible to remove myeloma IgG and autoimmune anti-red blood cell antibodies from two patients' plasma following an extracorporeal procedure. The... more
Using heat-killed, formalin-stabilized Staphylococcus aureus Cowan I suspension, it was possible to remove myeloma IgG and autoimmune anti-red blood cell antibodies from two patients' plasma following an extracorporeal procedure. The arterial anticoagulated blood was processed through a cell separator machine. The separated plasma was pumped through a bacterial filter containing S. aureus suspension. The adsorbed plasma was then reunited with the blood cells and returned to the patient through the vein. S. aureus Cowan I could selectively remove the myeloma IgG and autoimmune anti-red cell antibodies from the patients' plasma prolonging the lives of these two terminal patients. The immunoadsorption procedure appears to be a safe, practical and quick method for the removal of pathological IgG from the patients' plasma.
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... Plans already in existence must be studied and evaluat-ed. ELAINE ALLEN, MD Staten Island Medical Group; Staten Island, NY 10301 REFERENCE 1. WAITZKIN H. A Marxist view of medical care. ... 1979;91:877-82. 2. KIMBERLY RP, BOWDEN RE,... more
... Plans already in existence must be studied and evaluat-ed. ELAINE ALLEN, MD Staten Island Medical Group; Staten Island, NY 10301 REFERENCE 1. WAITZKIN H. A Marxist view of medical care. ... 1979;91:877-82. 2. KIMBERLY RP, BOWDEN RE, KEISER HR, PLOTZ PH. ...
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Research Interests: Leukemia, Adolescent, Medicine, Humans, Child, and 8 morePubmed, Bone marrow, Aged, Middle Aged, Adult, Monocytes, Taurine, and Intracellular
A woman with thrombocytopenia that progressed to aplastic anemia, and her brother, who had persistent thrombocytopenia, both had a constitutional t(13;14) translocation. Six other family members, in three generations, had the same... more
A woman with thrombocytopenia that progressed to aplastic anemia, and her brother, who had persistent thrombocytopenia, both had a constitutional t(13;14) translocation. Six other family members, in three generations, had the same translocation, but no hematologic disorder. There was evidence suggestive of increased chromosomal fragility in lymphocyte cultures from two members of the kindred, but not in the two patients. The findings support a postulated association between the t(13;14) and hematologic disorders, but whether the mechanism involves an inherited defect in chromosomal stability is unproved.
Research Interests: Immunology, Biology, Medicine, Cancer Genetics, Humans, and 8 moreFemale, Male, Karyotyping, Pedigree, Middle Aged, Aplastic Anemia, Brother, and Thrombocytosis
1. Semin Hematol. 1994 Apr;31(2):134-45. Hematologic effects of androgens revisited: an alternative therapy in various hematologic conditions. Besa EC. Department of Medicine, Medical College of Pennsylvania, Philadelphia 19129. ...
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Progressive and severe autoimmune hemolytic anemia developed in a patient with chronic lymphocytic leukemia (CLL) despite treatment with chlorambucil, high doses of corticosteroids and attempts to transfuse packed red blood cells.... more
Progressive and severe autoimmune hemolytic anemia developed in a patient with chronic lymphocytic leukemia (CLL) despite treatment with chlorambucil, high doses of corticosteroids and attempts to transfuse packed red blood cells. Splenectomy was not performed because of severe coronary artery disease. Direct antiglobulin tests revealed a warm red blood cell autoantibody of IgG-type with anti-e specificity. The patient was treated by extracorporeal immunoadsorption of plasma IgG using a cell separator and protein A as the immunoadsorbent. The patient responded by an increase in the hemoglobin levels and platelet counts after two treatments. Specificity of the procedure was shown by a decrease in the serum IgG and by the demonstration of the same reactivity to ficin-treated reagent red blood cell panel of the eluate from the protein A. Antibody titers of the patient's red blood cell eluate decreased from 1:128 to 1:64 and eventually the anti-e specificity was lost. This is a report of a novel approach to treatment of the acute phase of an autoimmune hemolytic anemia.
Research Interests: Immunology, Medicine, Cell separation, Adsorption, Humans, and 14 moreChronic Lymphocytic Leukemia, Male, Aged, Antibody, Platelet Count, Hemoglobins, immunoglobulin G, The American, Hemolytic Anemia, Chlorambucil, Autoimmune hemolytic anemia, Staphylococcal protein A, Prednisone, and Medical and Health Sciences
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The responses of 23 patients with agnogenic myeloid metaplasia (AMM) to androgen therapy were studied. Various clinical and laboratory parameters were analyzed for their value in determining response to therapy and length of survival.... more
The responses of 23 patients with agnogenic myeloid metaplasia (AMM) to androgen therapy were studied. Various clinical and laboratory parameters were analyzed for their value in determining response to therapy and length of survival. Fifty-seven percent of patients responded, as determined by a sustained increase in hematocrit within three months of therapy which thus eliminated the need for transfusions. Chromosome study of the abnormal hemic population was the best predictor of response: 92% of patients with normal chromosomes responded, while 78% of patients with chromosomal abnormalities did not. Responders had a mean survival time of five and a half years from the time of diagnosis as compared with two years for the nonresponders. The degree of thrombocytopenia, suppression of the ferrokinetic, and lack of activity in axial skeleton on bone marrow scans indicated severely compromised hemopoiesis in the nonresponders. The results suggest that in some patients with AMM, more extensive cytogenetic alterations in the abnormal hematopoietic cells result in an inability to respond to androgen therapy and that the chromosome study is the test most accurate for predicting the outcome of therapy.
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This paper describes the design and evaluation of a computer-based instruction (CBI) program that was integrated into a multidisciplinary cancer curriculum at the Medical College of Pennsylvania. Instruction took place in a cancer... more
This paper describes the design and evaluation of a computer-based instruction (CBI) program that was integrated into a multidisciplinary cancer curriculum at the Medical College of Pennsylvania. Instruction took place in a cancer learning center. Modules contained literature, posters, slide sets, videocassette films, and "see, touch, and feel" models to teach and practice breast, testicular, rectal, laryngeal, and colonoscopic examinations. The CBI (programmed on HyperCard) contained tutorials divided into three levels of learning objectives: level one, epidemiology and prevention; level two, diagnosis and staging; and level three, management and prognosis. Simulated cases and test items were developed for each level. To evaluate students' perceptions of the program and provide them with feedback about their performances, the authors designed a questionnaire, held a focus group, and developed a built-in tracking system for the CBI. Results showed that the program was well received, the students answered the test items correctly, and the students wanted more time to study cancer. A description of some of the problems encountered with technology and equipment is provided for faculty who may be interested in designing and implementing similar CBI programs.
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Interstitial lung disease has been reported in association with numerous alkylating agents and other chemotherapeutic drugs. Chlorambucil has only rarely been implicated in this complication. We report a case of a 74-year-old man with... more
Interstitial lung disease has been reported in association with numerous alkylating agents and other chemotherapeutic drugs. Chlorambucil has only rarely been implicated in this complication. We report a case of a 74-year-old man with chronic lymphocytic leukemia who received high-dose intermittent chlorambucil and prednisone every two weeks. Following several of these courses of therapy, respiratory distress occurred 9 to 12 days after the chlorambucil was given. During the final episode, open lung biopsy was performed and demonstrated typical changes of drug-induced pneumonitis, with interstitial infiltrates and fibrosis and proliferation of type II alveolar lining cells.
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Research Interests: Endocrinology, Chemistry, DNA replication, Medicine, Biological Sciences, and 14 moreHematopoietic Stem Cells, Internal Medicine, Mice, Female, Animals, Iron, Erythropoiesis, Androgen Receptor, Androgen, Species Specificity, Erythrocytes, Dihydrotestosterone, Flutamide, and Medical and Health Sciences
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Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder primarily affecting CD34+ cells, characterized by ineffective hematopoiesis, often transforming into acute myelogenous leukemia (AML). A subset of patients has 5q... more
Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder primarily affecting CD34+ cells, characterized by ineffective hematopoiesis, often transforming into acute myelogenous leukemia (AML). A subset of patients has 5q deletion (del(5q)) as the culprit pathogenetic trigger. Del(5q) affects critical regions 5q31 and 5q33, leading to gene haplodeficiency with subsequent RPS14 haplodeficiency and P53 activation. Subsequent to P53 activation, erythroid cell apoptosis and ineffective erythropoiesis occur. Other pathogenetic elements include protein phosphatase 2a and CDC25C haplodeficiency and decreased miR-145 and miR-146a expression. Lenalidomide is an immunomodulatory agent that selectively suppresses the del(5q) clone. While the mechanism is not fully understood, it is associated with diverse molecular changes including stabilization of MDM2 with subsequent enhanced P53 degradation. Lenalidomide showed success in low- and intermediate-1-risk MDS as reported in the 002, 003, and 004 trials. However, in higher-risk MDS, the results of lenalidomide monotherapy were modest, mandating the use of combination therapy. The role and priority of lenalidomide varies between different guidelines, and accordingly, future efforts are necessary to reach a unified therapeutic algorithm. TP53 mutations are important predictors of AML progression and possible resistance to lenalidomide. It is recommended to identify TP53 mutation early in the disease since it may change the decision regarding choice of therapy. Challenges with lenalidomide therapy remain the long-term effects and timing of its discontinuation.
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Excerpt High doses of androgens have increased hemoglobin concentration in patients and animals. Verwilghen and associates demonstrated a fall in plasma volume in nonhematologic patients treated wi...
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ABSTRACT Neonatal alloimmune thrombocytopenia (NAIT) most commonly involves antibodies directed against the PlA1 antigen, but other platelet specific alloantigens have been associated with it. We describe the case of a mother whose first... more
ABSTRACT Neonatal alloimmune thrombocytopenia (NAIT) most commonly involves antibodies directed against the PlA1 antigen, but other platelet specific alloantigens have been associated with it. We describe the case of a mother whose first three infants developed NAIT secondary to anti-Bak(a) antibodies, while her fourth infant did not. The three affected infants were treated postnatally with platelet transfusions. The fourth infant was treated antenatally with one dose of intravenous immunoglobulin (IVIg) given to the mother. Postpartum analysis revealed the infant's platelets to be Bak(a)-positive but negative for elevated IgG. Maternal serum reacted with neonatal platelets in vitro, but cord serum was negative for antiplatelet antibodies. These clinical observations do not prove the efficacy of IVIg; however, they raise several questions: Why wasn't this infant thrombocytopenic? Why didn't the umbilical cord contain maternal antibody? Was the single dose of IVIg responsible for preventing NAIT? IVIg is currently under investigation in a clinical trial evaluating its effectiveness in preventing NAIT in mothers with anti-PlA1 antibodies, where it has shown some success. There have been no reports of the use against anti-Bak(a) antibodies. We suggest that a weekly dose schedule may not be necessary for all affected pregnancies, and antibodies with specificity other than anti-PlA1 may require less vigorous therapy.
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Taurine is a highly acidic sulfur-containing amino acid which is not incorporated into protein, but appears to be an end product of methionine metabolism. Its high acidity (pKa 1.5 or less) and its oxidized nature suggest that by normal... more
Taurine is a highly acidic sulfur-containing amino acid which is not incorporated into protein, but appears to be an end product of methionine metabolism. Its high acidity (pKa 1.5 or less) and its oxidized nature suggest that by normal mechanisms it might be a readily excreted molecule and, thus, not to found in wide abundance. However, taurine is found to be widely distributed in animal tissues, especially during periods of cellular growth (15).
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We encountered two patients who presented with hypochromic-microcytic anemia and were refractory to iron therapy. The symptoms were suggestive of anemia of chronic disease (ACD); however, there was no evidence of any such disease, either... more
We encountered two patients who presented with hypochromic-microcytic anemia and were refractory to iron therapy. The symptoms were suggestive of anemia of chronic disease (ACD); however, there was no evidence of any such disease, either inflammatory or malignant. These patients were reminiscent of patients originally described as having primary defective iron reutilization. The hematologic picture consisted of hypochromic-microcytic anemia, low serum iron, low to normal iron binding capacity, high serum ferritin, and increased bone marrow iron in the absence of ringed sideroblasts. These patients had symptomatic anemia and received danazol (200 mg orally) three times per day to which they responded very well with an increase of approximately 3 g in the hemoglobin concentration over 1 year and amelioration of their symptoms. Danazol was well tolerated and did not cause any virilizing side effects. Doses were lowered in maintenance after 1 year to 200 mg once per week, and responses were sustained up to 36 months of follow-up duration. In the differential diagnosis of hypochromic-microcytic anemia, especially in postmenopausal women, one has to consider this type of treatable anemia when more common types such as iron deficiency, chronic inflammation, malignancy, sideroblastic anemia, or thalassemia have been ruled out.
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Measurement of blood volume is an important clinical tool in establishing a diagnosis as in polycythemia vera, in assessing the true significance of a low blood count in a patient with splenomegaly, and in evaluating a bleeding patient.... more
Measurement of blood volume is an important clinical tool in establishing a diagnosis as in polycythemia vera, in assessing the true significance of a low blood count in a patient with splenomegaly, and in evaluating a bleeding patient. In theory, blood volume measurements should be of great value in treating acute blood loss, but this is often too time-consuming to be practicable. The main value of blood volume studies so far has been in clinical research where it is essential for correct interpretation of the peripheral blood measurements. Estimates using the hematocrit (packed cell volume) could be misleading since this measurement does not take into account total blood volume and changes in the plasma volume. A variety of isotopes that tag the red blood cell have been used to measure total blood volume and red cell mass. Most commonly used at present is autologous 51-Cr labeled red cells, thus eliminating the risk of hepatitis in transfusion to the subjects. Radio labeled albumin and other plasma proteins were used to measure plasma volume. A large molecular protein is ideal to eliminate overestimation from extravascular diffusion of labeled material for accurate determination of plasma volume. Physiologic changes in the newborn, in pregnant women, during exercise, bed rest, and altitude in the nonpathologic state are discussed. Studies in the normal subject's adaptation in different physiologic conditions have revealed a variety of factors that regulate blood volume.
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Blood volumes before and at five-week intervals during nandrolone decanoate therapy were measured in 30 patients. In nine nonanemic but impotent male patients, an increase in hematocrit value was due to hemoconcentration during the first... more
Blood volumes before and at five-week intervals during nandrolone decanoate therapy were measured in 30 patients. In nine nonanemic but impotent male patients, an increase in hematocrit value was due to hemoconcentration during the first five weeks; red blood cell (RBC) mass increased the tenth week. In ten patients with malignant disease and four patients with sickle cell anemia, this response in plasma volume and RBC mass occurred as early as five to ten weeks. Of seven patients with refractory anemia, blood volume changes ocurred in two patients as late as the 30th week of therapy. In previous studies, testosterone enanthate has been shown to increase plasma volume. This unique property of nandrolone decanoate in decreasing plasma volume appears to be a physiologic response, probably similar to that found in acclimatization to high altitude in man. Nandrolone decanoate therapy may be desirable when fluid retention is contraindicated.
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The effect of an androgen, 19-nortestosterone decanoate (19-ND), on radioironincorporation into peripheral red blood cells wastested in the plethoric (PCT) and the plethorichyperoxic(PCT-HOX) mouse. When 19-ND wasinjected 24 hr prior to... more
The effect of an androgen, 19-nortestosterone decanoate (19-ND), on radioironincorporation into peripheral red blood cells wastested in the plethoric (PCT) and the plethorichyperoxic(PCT-HOX) mouse. When 19-ND wasinjected 24 hr prior to the administration of exogenouserythropoietin (ESF), it was observedthat these mice responded with significantlygreater levels of erythropoiesis, as measured by50Fe incorporation into peripheral red blood cells,as compared to identical mice injected with ESFalone. Additional observations showed that hyperoxia(HOX) was capable of significantly decreasingthe already minimal levels of erythropoiesisnormally found in PCT mice and that this PCTHOXanimal did not respond as markedly toandrogen therapy as the PCT animal. The additionof assayable minimal amount of ESF didnot cause further augmentation of radioiron incorporationin the groups receiving ESF only.Since plasma ESF activity was not found to beelevated to detectable levels following androgenadministration in PCT-HOX mice,...
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Summary. Erythropoiesis was suppressed in mice by hyperoxia (HOX) and/or post‐hypoxic plethora (PCT), the cytocidal effects of actinomycin‐D (ACT), or by a combination of these techniques.When 19‐nortestosterone decanoate (19‐ND) was... more
Summary. Erythropoiesis was suppressed in mice by hyperoxia (HOX) and/or post‐hypoxic plethora (PCT), the cytocidal effects of actinomycin‐D (ACT), or by a combination of these techniques.When 19‐nortestosterone decanoate (19‐ND) was injected during HOX and 24 hr 59Fe incorporation was measured during and following HOX, the increment in androgen‐induced erythropoiesis compared to vehicle‐treated controls was significantly greater in the post‐HOX assay system, where erythropoietin (ESF) titres were increased as compared to the response seen in the ESF suppressed mouse maintained in HOX. When erythropoiesis was suppressed by HOX and ACT, erythropoiesis was sustained in the 19‐ND‐treated mouse for a longer period than in the vehicle‐treated controls. In addition, when these mice were removed from HOX to ambient conditions and all injections were terminated, erythropoiesis recovered more rapidly in the groups previously treated with the androgen. When ESF was injected to PCT‐HOX mice only 24 hr after they received a single 19‐ND injection, it was observed that these mice had significantly greater levels of 59Fe incorporation than identical mice injected with ESF alone. In addition, it was found that HOX was capable of significantly decreasing the already minimal levels of erythropoiesis found in the plethoric mouse and that this PCT‐HOX animal did not respond as markedly to androgen administration as the plethoric animal maintained at ambient conditions. It was concluded that the data presented in this report are compatible with the concept that the androgenic steroid, 19‐ND, has a direct affect on the haematopoietic stem cell pool by increasing the size of a stem cell population capable of responding to ESF and that further differentiation of these elements is dependent on the availability of ESF to the target tissue.
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Five patients with clinical stage III and IV chronic lymphocytic leukemia were treated with a five-day infusion of high-dose intravenous immunoglobulin for either autoimmune hemolytic anemia or immune thrombocytopenic purpura or by a dose... more
Five patients with clinical stage III and IV chronic lymphocytic leukemia were treated with a five-day infusion of high-dose intravenous immunoglobulin for either autoimmune hemolytic anemia or immune thrombocytopenic purpura or by a dose of intravenous immunoglobulin G every three to four weeks for prevention and control of infections associated with hypogammaglobulinemia. The hematocrit level stabilized with a decrease in red blood cell destruction by intravenous immunoglobulin G in chronic lymphocytic leukemia patients with AIHA without altering red blood cell autoantibody titers, but severe hemolysis recurred after 21 days. A long-term remission was observed when intravenous immunoglobulin G was combined with steroids, chemotherapy, plasmapheresis, and splenectomy. The platelet count increased and platelet transfusion requirement was eliminated in a chronic lymphocytic leukemia patient with immune thrombocytopenic purpura by the intravenous immunoglobulin G, and chemotherapy was administered and a complete remission resulted. An interesting observation was the lymphocytopenic effects observed in the five patients during a daily infusion of intravenous immunoglobulin for five days. Furthermore, the maintenance intravenous immunoglobulin G given every three weeks controlled both infections and lymphocyte counts with the chemotherapy. Changing the schedule to every four weeks resulted in poor control of the lymphocyte counts with chemotherapy. These observations indicate a direct macrophage blocking effect in autoimmune hemolytic anemia and immune thrombocytopenic purpura, but the lymphocytopenic effect suggests immunomodulating effects of intravenous immunoglobulin G, which may alter the response of chronic lymphocytic leukemia cells to chemotherapy.
Research Interests: Immunology, Medicine, Humans, Chronic Lymphocytic Leukemia, Female, and 12 moreMale, Aged, Middle Aged, Antibody, Lymphocytes, Thrombotic Thrombocytopenic Purpura, Intravenous Immunoglobulin, immunoglobulin G, Autoimmune hemolytic anemia, Hypogammaglobulinemia, Medical and Health Sciences, and leukocyte Count
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Research Interests: Biology, Medicine, Lymphoma, Population, Humans, and 15 moreArticles, Mutation, Polymerase Chain Reaction, The, Experimental Medicine, Amino Acid Sequence, Base Sequence, Germline, Oligonucleotides, Autoantigens, Clonal Selection, Molecular Sequence Data, Diffuse large B cell lymphoma, Medical and Health Sciences, and B cell
In general, the use of granulocyte colony-stimulating factor (G-CSF) has been relatively safe with only occasional reports of inducing adult respiratory distress syndrome. 1 The mechanism for this complication is relatively unknown. A... more
In general, the use of granulocyte colony-stimulating factor (G-CSF) has been relatively safe with only occasional reports of inducing adult respiratory distress syndrome. 1 The mechanism for this complication is relatively unknown. A possible mechanism include the superoxide production by G-CSF causing neutrophil leakage resulting in pulmonary epithelial damage. We are reporting a 63 year old woman with a medical history of severe psoriasis and chronic thrombocytopenia with splenomegaly who presented to the emergency room with epistaxis and excessive bruising with a platelet count of 5 x 10 9 /L. She received weekly injections of efalizumab (Raptiva) for six months for treatment of severe psoriasis and was stopped five weeks prior to presentation. Methotrexate and dexamethasone were started approximately one week prior to admission for continued refractory psoriasis. G-CSF was started at 480 mcq subcutaneous once a day on day 4 of admission for neutropenia induced by either efalizumab or methotrexate. When her white blood cell (WBC) count rose from 1.9 x10 9 /L to 6.3 x10 9 /L the G-CSF was stopped on hospital day 8. Her absolute monocyte count also rose from 0 to 3.78 x 10 9 /L (normal range from 0.1 x10 9 /L to 0.9 x10 9 /L) with a left shift in the peripheral blood. The WBC and monocyte counts continued to rise and she was transferred to our hospital for further care on hospital day 11. The WBC count peaked at 147.9 x 10 9 /L on hospital day 12, with a differential of 17% monocytes, 16% metamyelocytes, 4% myelocytes, and 1% promyelocytes. The patient gradually became short of breath at rest, requiring 2–4 liters of oxygen and developed bibasilar crackles on exam. Bibasilar infiltrates were detected on chest radiographs at the outside hospital. Upon arrival to our hospital a CT of thorax showed diffuse bilateral ground glass attenuation. WBC count decreased to 119 x10 9 /L on hospital day 15, with a differential of 47% monocytes, 2% metamyelocytes, 3% myelocytes, and 1% blasts. A bone marrow examination showed morphologic findings consistent with acute monocytic leukemia with monocytoid cells greater than 50%. Since the WBC count continued to decrease with improvement of her respiratory symptoms no chemotherapy was given. When the WBC reached 7.4 x 10 9 /L another bone marrow examination showed a hypercellular marrow with full maturation and no excess of blasts and no evidence of acute leukemia. A background of mature monocytes (12%) and increased reticulin fibers were noted. Chronic myelomonocytic leukemia was her final diagnosis. The laboratory and bone marrow studies while under the effects of G-CSF mimicked those of acute myeloid leukemia. The use of G-CSF in this patient appeared to have unmasked an underlying CMML from an undifferentiated myeloproliferative disorder. Her development of pulmonary infiltrates, hypoxia, leukocytosis and monocytosis after receiving G-CSF appeared to be a differentiation-like syndrome. This resolved after stopping G-CSF and without high dose steroid therapy. Physicians should be aware that G-CSF can cause a syndrome that mimics AML and should refrain from starting cytotoxic chemotherapy based on bone marrow findings under the influence of growth factors.
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The myelodysplastic syndrome (MDS) occurs in a heterogenous group of patients with varying degrees of cytopenia and an associated morphologic change in their peripheral blood and bone marrow cells which indicate an abnormality in cellular... more
The myelodysplastic syndrome (MDS) occurs in a heterogenous group of patients with varying degrees of cytopenia and an associated morphologic change in their peripheral blood and bone marrow cells which indicate an abnormality in cellular maturation. This condition is also considered to be a preleukemic state because of the tendency to progress into acute myelogenous leukemia in approximately 40% of the patients. A significant number of these patients succumb to the complications of bone marrow failure such as infection and hemorrhage from the resulting cytopenia. Currently, there is no satisfactory specific therapy available for MDS.
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Our objectives were to measure and compare plasminogen activator inhibitor levels (PAI-1) in primary adult thrombotic thrombocytopenic purpura (TTP) and in secondary TTP associated with bone marrow transplantation (BMT)-TTP. PAI-1 antigen... more
Our objectives were to measure and compare plasminogen activator inhibitor levels (PAI-1) in primary adult thrombotic thrombocytopenic purpura (TTP) and in secondary TTP associated with bone marrow transplantation (BMT)-TTP. PAI-1 antigen levels were measured by an enzyme linked immunosorbent assay on platelet poor plasma samples obtained from patients at the time of diagnosis of the TTP disorder and from a group of normal volunteers. The samples were frozen at -70 degrees C. Patients with TTP secondary to bone marrow transplantation had their grade determined by percentage fragmented cells and lactate dehydrogenase levels. The primary TTP samples were contributed by investigators in the multi-institutional North American TTP Group, and the bone marrow transplant samples were obtained from an adult bone marrow transplant program. Nineteen patients with adult TTP, and 47 patients with bone marrow transplant-TTP were evaluated. Of the latter, 14 had Grade 2, 13 had Grade 3, and 20 had Grade 4 BMT-TTP. PAI-1 levels were elevated compared to control volunteers in both primary adult TTP and BMT-TTP, P < 0.001. Levels did not differ from normal in Grade 2 BMT-TTP (median = 16 ng/ml; quartiles = 9-20). PAI-1 levels were similar in primary TTP (median = 32 ng/ml; quartiles = 25-51) and Grade 3 BMT-TTP (median = 35 ng/ml; quartiles = 19-48 ng/ml), P = 0.7. However, PAI-1 levels were significantly higher in Grade 4 BMT-TTP (median = 83 ng/ml; quartiles = 60-143) than Grade 3 BMT-TTP, and primary TTP, P < 0.001. PAI-1 levels are high in primary TTP and secondary bone marrow transplant-TTP (Grades 3-4). In contrast, normal levels are seen in Grade 2 BMT-TTP, which is a self-limited disorder. Therefore, high PAI-1 levels may contribute to hypofibrinolysis in the pathogenesis of primary TTP and of moderate to severe TTP (Grades 3-4) following bone marrow transplantation.
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3529 Hematologic malignancies in older patients are often characterized by resistant phenotypes which would ideally be treated by allogeneic hematopoietic stem cell transplant (HSCT). However, allogeneic HSCT in this age group is... more
3529 Hematologic malignancies in older patients are often characterized by resistant phenotypes which would ideally be treated by allogeneic hematopoietic stem cell transplant (HSCT). However, allogeneic HSCT in this age group is associated with greater regimen-related toxicity than in younger patients limiting its application. In addition, older patients have a smaller matched related donor pool due to the age and comorbidities of their siblings, but often have haploidentical offspring donor options. In order to extend the application of HSCT to older patients…
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Using (a) somatic cell hybrids retaining partial chromosome 5 and (b) clinical samples from patients with acquired deletions of the long arm of chromosome 5, combined with chromosome 5-linked DNA probes, some of which exhibited RFLPs, we... more
Using (a) somatic cell hybrids retaining partial chromosome 5 and (b) clinical samples from patients with acquired deletions of the long arm of chromosome 5, combined with chromosome 5-linked DNA probes, some of which exhibited RFLPs, we have determined the order of a series of genes on chromosome 5. The order established is 5pter----MLVI-2----cen----HEXB----DHFR----Pi227- --- cp12.6----(IL5,IL4)----IL3----GMCSF---- FGFA---- (CSF1R,PDGFR)----(treC,ADRBR)----(ARH-H9,CSF1 )----qter. The suggested order and orientation for the closely linked IL3/GMCSF gene pair is cen----5' IL3 3'----5' GMCSF 3'----qter, on the basis of analysis of the GMCSF rearrangement in HL60 DNA. The map position of the GRL locus, which was consistent with both somatic cell hybrid and 5q- analyses, was telomeric to GMCSF and centromeric to CSF1R/PDGFR, near FGFA. Long-range restriction-enzyme analysis of 5q- DNAs did not detect rearrangements of 5q-linked probes except in HL60 DNA, but it did revea...
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The observation of increasing myelofibrosis has been interpreted as a sign of progression in the course of low risk patients with myelodysplastic syndrome (MDS). We report here a 64 year old, Caucasian woman who was diagnosed to have... more
The observation of increasing myelofibrosis has been interpreted as a sign of progression in the course of low risk patients with myelodysplastic syndrome (MDS). We report here a 64 year old, Caucasian woman who was diagnosed to have refractory anemia in 5/19/03 with a bone marrow findings showing hypercellularity of 95%, erythroid dysplastic changes with 1% myeloblasts with no ringed sideroblasts. Her cytogenetic study show normal chromosomes and she had an IPSS score of 0. However, she began to require red cell transfusions with no response to EPO and G-CSF therapy for 5 months when she was entered into an open label, multi-center clinical trial using Revlimid at 10 mg/day given orally in tablet form. Her growth factors were discontinued 4 weeks before entry and a baseline bone marrow study on 10/7/04 show a 90% cellular marrow with same abnormalities. In addition, she now has developed a grade III/IV diffuse reticulin fibers as shown by silver stains indicating increased myelofibrosis. She tolerated the treatment well with very little side effects and by second month of therapy, she had her last red cell transfusion and her hemoglobin level started to increase from 8.3 to 9.7 g/dl. Other than a mild neutropenia with ANC between 800 to 900/μL, she tolerated treatment well. She attained a normal hemoglobin of 12 g/dl at the 4th month. Repeat BM done at this time shows a normal cellularity of 50% but erythroid cells show persistence of dysplasia but overall fibrosis has reversed to Grade I/IV. She currently remains in remission 21 months on Revlimid treatment. Demonstration of reversal of myelofibrosis in MDS indicate that this drug may be effective in primary myelofibrosis and agnogenic myeloid metaplasia.