Retired Physician scientist and acid mic researcher, now editor for Emedicine, Traveller, and writer, teaching as an adjunct professor in Medicine in the University of the Philippines.
To determine the mechanism of the aplastic crisis in a patient with autoimmune hemolytic anemia (... more To determine the mechanism of the aplastic crisis in a patient with autoimmune hemolytic anemia (AIHA) and reticulocytopenia who developed red cell aplasia simultaneously, serum- and IgG-separated fractions were examined for the presence of erythroid progenitor cell inhibitors. The patient's red cell autoantibody was a complement-independent IgG that reacted with the little-e antigen of the Rh complex. A complement-dependent serum IgG inhibitor directed against erythroid colony- and burst-forming units but not granulocyte-macrophage units was detected in samples before treatment with extracorporeal staphylococcal protein-A immunoadsorption and corticosteroids. The erythroid progenitor cell inhibitor persisted in samples multiply adsorbed against type-ee red cells and was not detected in heat eluates prepared from these red cells. A reticulocytosis occurred when serum IgG levels were reduced to 27% of pretreatment values. At this point, the erythroid progenitor cell inhibitor was...
Endothelial damage is thought to be a contributing factor in the pathogenesis of Thrombotic Throm... more Endothelial damage is thought to be a contributing factor in the pathogenesis of Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndromes (TTP/HUS). The present studies measured two markers of endothelial cell stimulation and/or activation [von Willebrand Factor (vWF:Ag) and thrombomodulin (TM)] in patients with TTP/HUS disorders and compared them to controls. The patient groups consisted of adults with TTP/HUS, with (n = 13) and without (n = 14) peak Cr levels >2.0 mg/dl. Additionally, 52 patients with Bone Marrow Transplant-associated Thrombotic Microangiopathy (BMT-TM) following allogeneic BMT were evaluated. Both vWF:Ag and TM were elevated in all patient groups compared to controls. TTP/HUS patients with peak Cr >2.0 mg/dl had higher TM levels (P < 0.001) than did those with peak Cr levels below 2 mg/dl. However, thrombomodulin/ creatinine (TM/Cr) ratios did not differ in these two groups nor did they differ from controls. BMT-TM pts had higher vWF:Ag levels and higher TM/Cr ratios than controls and TTP/ HUS, P < 0.001. The median TM/Cr ratio in BMT-TM was 91 (range = 34-229) compared to 38 (range = 29-50) in controls, P < 0.001 and 38 (range = 6 to 156) in TTP/HUS, P < 0.001. Additionally both TM (P < 0.001) and TM/Cr (P < 0.02) were higher in patients with Grades 3 and 4 BMT-TM compared to those with Grade 2 BMT-TM. These results suggest that endothelial cell activation occurs in TTP/HUS and BMT-TM. Since TM/Cr ratios were higher in BMT-TM compared to TTP/HUS, these findings suggest that the mechanism of elevated TM in BMT-TM cannot be explained solely by altered renal excretion. Taken together, these findings strongly indicate a role of endothelial cell damage in BMT-TM.
7071 Background: Bortezomib is a proteasome inhibitor known to effect multiple signaling pathways... more 7071 Background: Bortezomib is a proteasome inhibitor known to effect multiple signaling pathways. In hematologic malignancies, the inhibition of nuclear factor KB (NF-KB) activation and the induction of apoptosis in cells that overexpress bcl-2 have been implicated. The combination of mitoxantrone and etoposide has been successful in relapsed/refractory acute myeloid leukemia with complete remission (CR) rates of 35–45%, with median duration of CR of 4–5 months. Based on the ability to inhibit NF-KB, the addition of bortezomib should render malignant cells more susceptible to mitoxantrone and etoposide. Methods: Patients with relapsed or refractory acute leukemia were offered enrollment on a phase I study of escalating doses of bortezomib (0.7, 1.0, 1.3 mg/m2) on days 1 and 4, in combination with mitoxantrone 10 mg/m2 days 1–5 and etoposide 100 mg/m2 days 1–5. Dose escalation was allowed if not patient in the previous cohort had dose limiting toxicity defined as >grade 3 toxicity that was definitely rela...
Protein S is a vitamin K–dependent anticoagulant protein that was first discovered in Seattle, Wa... more Protein S is a vitamin K–dependent anticoagulant protein that was first discovered in Seattle, Washington in 1979and arbitrarily named after the city of its discover. The major function of protein S is as a cofactor to facilitate theaction of activated protein C (APC) on its substrates, activated factor V (FVa) and activated factor VIII (FVIIIa).Protein S deficiencies are associated with thrombosis.Protein S deficiency may be hereditary or acquired; the latter is usually due to hepatic diseases or a vitamin Kdeficiency. Protein S deficiency usually manifests clinically as venous thromboembolism (VTE). The association ofprotein S deficiency with arterial thrombosis appears coincidental or weak at best. Arterial thrombosis is not evidentwith other hereditary anticoagulant abnormalities (eg, protein C or antithrombin III deficiency, factor V Leiden genemutation).Hereditary protein S deficiency is an autosomal dominant trait. Thrombosis is observed in both heterozygous andhomozygous gen...
INTRODUCTION: The majority of patients (pts) with MDS become red blood cell (RBC) transfusion dep... more INTRODUCTION: The majority of patients (pts) with MDS become red blood cell (RBC) transfusion dependent with escalating risk for transfusional hemosiderosis and its adverse effect on morbidity and mortality. The US03 trial is designed to evaluate long-term efficacy and safety of the oral iron chelator, deferasirox (DFX), in pts with lower risk MDS. In this ongoing study 53 pts have completed 12 months’ (mos) treatment. METHODS: US03 is a Phase II, open-label, 3-year trial in pts with Low- or Int-1 IPSS risk MDS and transfusional iron overload (SF ≥1000 μg/L and >20 units RBC transfusions [tx]), with serum creatinine (SCr) ≤2-fold the upper limit of normal (ULN). Initial DFX dose was 20 mg/kg/day and could be increased to 40 mg/kg/day based on tolerability and response. SF was monitored monthly; LPI, the reactive species of non-transferrin-bound iron, was assessed quarterly. BASELINE FEATURES: 176 pts were enrolled at 45 centers. Mean age was 70 years (range, 21−90), including 102...
Lenalidomide was approved by the US Food and Drug Administration in December of 2005 for the trea... more Lenalidomide was approved by the US Food and Drug Administration in December of 2005 for the treatment (tx) of transfusion-dependent anemia (TDA) in patients (pts) with MDS and chromosome 5q deletions (del5q). In the trial that secured the approval, 67% of 148 pts achieved red blood cell (RBC) transfusion independence (TI) with a median time to TI of 44 weeks. 90% of pts who achieved TI did so by completion of 3 months of therapy. In a companion study (MDS-002) pts lacking del5q the frequency of TI was only 26%. We report three cases of IPSS Low risk myelodysplasia MDS with a delayed response to lenalidomide. The patient characteristics are outlined in Table 1. Following a 6 to 11 month trial of lenalidomide for TDA in IPSS Low risk MDS delayed TI can occur 1 to 4 months after discontinuation of lenalidomide. Delayed TI was not associated with a cytogenetic response. The duration of response can last from 11 months to 16 months. Lenalidomide, a thalidomide analogue, is an immunomodu...
Treating Acquired von Willebrand’s Syndrome (AVWS) is a challenge requiring multiple therapeutic ... more Treating Acquired von Willebrand’s Syndrome (AVWS) is a challenge requiring multiple therapeutic modalities to achieve success in controlling and preventing bleeding episodes. From review of the literature, clinical use of rituximab, an anti-CD20 monoclonal antibody, in AVWS has not been reported. We present our experience with four patients treated with rituximab for steroid or intravenous immunoglobulin (IVIG) refractory and/or dependent AVWS associated with IgG monoclonal gammopathy of undetermined significance. Rituximab at a dose of 375mg/m2 was administered intravenously weekly for 4 consecutive weeks in the first patient. After 3 cycles of rituximab, we observed a correction of her bleeding time to normal, improvement of her prolonged aPTT, a decrease in her monoclonal IgG and cessation of her bleeding episodes for 29 months. She relapsed and was retreated with rituximab at the same dose for 3 cycles with no improvement in aPTT and bleeding time. She has had no further bleedi...
INTRODUCTION: The majority of patients (pts) with MDS require red blood cell transfusions, which ... more INTRODUCTION: The majority of patients (pts) with MDS require red blood cell transfusions, which can result in iron overload and its clinical sequelae. The US03 trial is designed to evaluate the long-term efficacy and safety of the once-daily, oral iron chelator, deferasirox (DFX), in pts with lower-risk MDS. In this ongoing study 93/176 pts have now completed 12 months of treatment. METHODS: US03 is a Phase II, open-label, 3-year trial in pts with Low- or Int-1 IPSS-risk MDS and transfusional iron overload (serum ferritin [SF] 1000 μg/L and >20 units RBC transfusions), with serum creatinine (SCr) 2-fold the upper limit of normal (ULN). Initial DFX dose was 20 mg/kg/day and could be increased to 40 mg/kg/day based on tolerability and response. SF was monitored monthly; labile plasma iron (LPI), the reactive species of non-transferrin-bound iron, was assessed quarterly. BASELINE FEATURES: 176 pts were enrolled at 45 centers. Mean age: 70 years (range 21–90); 105 men and 71 women; ...
7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxama... more 7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single agent activity in AML and both Hodgkin’s and non-Hodgkin’s lymphomas. Preclinical evaluation demonstrating in vitro and in vivo synergy and antileukemic activity with demethylating agents, including 5-azacitidine (AZA), prompted clinical evaluation of mocetinostat + AZA in MDS and AML. Methods: This open-label, Phase II trial enrolled patients with MDS or AML. Patients received AZA (75 mg/m2SC; days 1-7 every 28 days) and mocetinostat (90-110 mg 3x/wk starting on AZA day 5). Anticancer activity, safety and pharmacokinetics and pharmacodynamics were evaluated. We report here on the MDS cohort. Results: Twenty patients with MDS were enrolled. Eight patients had received prior therapy for MDS including decitabine (n=1), lenalidomide (n=3), tipifarnib (n=2) and cytarabine (n=2). Median age was 70.5 yrs (range 41-81). Disease control...
To determine the mechanism of the aplastic crisis in a patient with autoimmune hemolytic anemia (... more To determine the mechanism of the aplastic crisis in a patient with autoimmune hemolytic anemia (AIHA) and reticulocytopenia who developed red cell aplasia simultaneously, serum- and IgG-separated fractions were examined for the presence of erythroid progenitor cell inhibitors. The patient's red cell autoantibody was a complement-independent IgG that reacted with the little-e antigen of the Rh complex. A complement-dependent serum IgG inhibitor directed against erythroid colony- and burst-forming units but not granulocyte-macrophage units was detected in samples before treatment with extracorporeal staphylococcal protein-A immunoadsorption and corticosteroids. The erythroid progenitor cell inhibitor persisted in samples multiply adsorbed against type-ee red cells and was not detected in heat eluates prepared from these red cells. A reticulocytosis occurred when serum IgG levels were reduced to 27% of pretreatment values. At this point, the erythroid progenitor cell inhibitor was...
Endothelial damage is thought to be a contributing factor in the pathogenesis of Thrombotic Throm... more Endothelial damage is thought to be a contributing factor in the pathogenesis of Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndromes (TTP/HUS). The present studies measured two markers of endothelial cell stimulation and/or activation [von Willebrand Factor (vWF:Ag) and thrombomodulin (TM)] in patients with TTP/HUS disorders and compared them to controls. The patient groups consisted of adults with TTP/HUS, with (n = 13) and without (n = 14) peak Cr levels >2.0 mg/dl. Additionally, 52 patients with Bone Marrow Transplant-associated Thrombotic Microangiopathy (BMT-TM) following allogeneic BMT were evaluated. Both vWF:Ag and TM were elevated in all patient groups compared to controls. TTP/HUS patients with peak Cr >2.0 mg/dl had higher TM levels (P < 0.001) than did those with peak Cr levels below 2 mg/dl. However, thrombomodulin/ creatinine (TM/Cr) ratios did not differ in these two groups nor did they differ from controls. BMT-TM pts had higher vWF:Ag levels and higher TM/Cr ratios than controls and TTP/ HUS, P < 0.001. The median TM/Cr ratio in BMT-TM was 91 (range = 34-229) compared to 38 (range = 29-50) in controls, P < 0.001 and 38 (range = 6 to 156) in TTP/HUS, P < 0.001. Additionally both TM (P < 0.001) and TM/Cr (P < 0.02) were higher in patients with Grades 3 and 4 BMT-TM compared to those with Grade 2 BMT-TM. These results suggest that endothelial cell activation occurs in TTP/HUS and BMT-TM. Since TM/Cr ratios were higher in BMT-TM compared to TTP/HUS, these findings suggest that the mechanism of elevated TM in BMT-TM cannot be explained solely by altered renal excretion. Taken together, these findings strongly indicate a role of endothelial cell damage in BMT-TM.
7071 Background: Bortezomib is a proteasome inhibitor known to effect multiple signaling pathways... more 7071 Background: Bortezomib is a proteasome inhibitor known to effect multiple signaling pathways. In hematologic malignancies, the inhibition of nuclear factor KB (NF-KB) activation and the induction of apoptosis in cells that overexpress bcl-2 have been implicated. The combination of mitoxantrone and etoposide has been successful in relapsed/refractory acute myeloid leukemia with complete remission (CR) rates of 35–45%, with median duration of CR of 4–5 months. Based on the ability to inhibit NF-KB, the addition of bortezomib should render malignant cells more susceptible to mitoxantrone and etoposide. Methods: Patients with relapsed or refractory acute leukemia were offered enrollment on a phase I study of escalating doses of bortezomib (0.7, 1.0, 1.3 mg/m2) on days 1 and 4, in combination with mitoxantrone 10 mg/m2 days 1–5 and etoposide 100 mg/m2 days 1–5. Dose escalation was allowed if not patient in the previous cohort had dose limiting toxicity defined as >grade 3 toxicity that was definitely rela...
Protein S is a vitamin K–dependent anticoagulant protein that was first discovered in Seattle, Wa... more Protein S is a vitamin K–dependent anticoagulant protein that was first discovered in Seattle, Washington in 1979and arbitrarily named after the city of its discover. The major function of protein S is as a cofactor to facilitate theaction of activated protein C (APC) on its substrates, activated factor V (FVa) and activated factor VIII (FVIIIa).Protein S deficiencies are associated with thrombosis.Protein S deficiency may be hereditary or acquired; the latter is usually due to hepatic diseases or a vitamin Kdeficiency. Protein S deficiency usually manifests clinically as venous thromboembolism (VTE). The association ofprotein S deficiency with arterial thrombosis appears coincidental or weak at best. Arterial thrombosis is not evidentwith other hereditary anticoagulant abnormalities (eg, protein C or antithrombin III deficiency, factor V Leiden genemutation).Hereditary protein S deficiency is an autosomal dominant trait. Thrombosis is observed in both heterozygous andhomozygous gen...
INTRODUCTION: The majority of patients (pts) with MDS become red blood cell (RBC) transfusion dep... more INTRODUCTION: The majority of patients (pts) with MDS become red blood cell (RBC) transfusion dependent with escalating risk for transfusional hemosiderosis and its adverse effect on morbidity and mortality. The US03 trial is designed to evaluate long-term efficacy and safety of the oral iron chelator, deferasirox (DFX), in pts with lower risk MDS. In this ongoing study 53 pts have completed 12 months’ (mos) treatment. METHODS: US03 is a Phase II, open-label, 3-year trial in pts with Low- or Int-1 IPSS risk MDS and transfusional iron overload (SF ≥1000 μg/L and >20 units RBC transfusions [tx]), with serum creatinine (SCr) ≤2-fold the upper limit of normal (ULN). Initial DFX dose was 20 mg/kg/day and could be increased to 40 mg/kg/day based on tolerability and response. SF was monitored monthly; LPI, the reactive species of non-transferrin-bound iron, was assessed quarterly. BASELINE FEATURES: 176 pts were enrolled at 45 centers. Mean age was 70 years (range, 21−90), including 102...
Lenalidomide was approved by the US Food and Drug Administration in December of 2005 for the trea... more Lenalidomide was approved by the US Food and Drug Administration in December of 2005 for the treatment (tx) of transfusion-dependent anemia (TDA) in patients (pts) with MDS and chromosome 5q deletions (del5q). In the trial that secured the approval, 67% of 148 pts achieved red blood cell (RBC) transfusion independence (TI) with a median time to TI of 44 weeks. 90% of pts who achieved TI did so by completion of 3 months of therapy. In a companion study (MDS-002) pts lacking del5q the frequency of TI was only 26%. We report three cases of IPSS Low risk myelodysplasia MDS with a delayed response to lenalidomide. The patient characteristics are outlined in Table 1. Following a 6 to 11 month trial of lenalidomide for TDA in IPSS Low risk MDS delayed TI can occur 1 to 4 months after discontinuation of lenalidomide. Delayed TI was not associated with a cytogenetic response. The duration of response can last from 11 months to 16 months. Lenalidomide, a thalidomide analogue, is an immunomodu...
Treating Acquired von Willebrand’s Syndrome (AVWS) is a challenge requiring multiple therapeutic ... more Treating Acquired von Willebrand’s Syndrome (AVWS) is a challenge requiring multiple therapeutic modalities to achieve success in controlling and preventing bleeding episodes. From review of the literature, clinical use of rituximab, an anti-CD20 monoclonal antibody, in AVWS has not been reported. We present our experience with four patients treated with rituximab for steroid or intravenous immunoglobulin (IVIG) refractory and/or dependent AVWS associated with IgG monoclonal gammopathy of undetermined significance. Rituximab at a dose of 375mg/m2 was administered intravenously weekly for 4 consecutive weeks in the first patient. After 3 cycles of rituximab, we observed a correction of her bleeding time to normal, improvement of her prolonged aPTT, a decrease in her monoclonal IgG and cessation of her bleeding episodes for 29 months. She relapsed and was retreated with rituximab at the same dose for 3 cycles with no improvement in aPTT and bleeding time. She has had no further bleedi...
INTRODUCTION: The majority of patients (pts) with MDS require red blood cell transfusions, which ... more INTRODUCTION: The majority of patients (pts) with MDS require red blood cell transfusions, which can result in iron overload and its clinical sequelae. The US03 trial is designed to evaluate the long-term efficacy and safety of the once-daily, oral iron chelator, deferasirox (DFX), in pts with lower-risk MDS. In this ongoing study 93/176 pts have now completed 12 months of treatment. METHODS: US03 is a Phase II, open-label, 3-year trial in pts with Low- or Int-1 IPSS-risk MDS and transfusional iron overload (serum ferritin [SF] 1000 μg/L and >20 units RBC transfusions), with serum creatinine (SCr) 2-fold the upper limit of normal (ULN). Initial DFX dose was 20 mg/kg/day and could be increased to 40 mg/kg/day based on tolerability and response. SF was monitored monthly; labile plasma iron (LPI), the reactive species of non-transferrin-bound iron, was assessed quarterly. BASELINE FEATURES: 176 pts were enrolled at 45 centers. Mean age: 70 years (range 21–90); 105 men and 71 women; ...
7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxama... more 7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single agent activity in AML and both Hodgkin’s and non-Hodgkin’s lymphomas. Preclinical evaluation demonstrating in vitro and in vivo synergy and antileukemic activity with demethylating agents, including 5-azacitidine (AZA), prompted clinical evaluation of mocetinostat + AZA in MDS and AML. Methods: This open-label, Phase II trial enrolled patients with MDS or AML. Patients received AZA (75 mg/m2SC; days 1-7 every 28 days) and mocetinostat (90-110 mg 3x/wk starting on AZA day 5). Anticancer activity, safety and pharmacokinetics and pharmacodynamics were evaluated. We report here on the MDS cohort. Results: Twenty patients with MDS were enrolled. Eight patients had received prior therapy for MDS including decitabine (n=1), lenalidomide (n=3), tipifarnib (n=2) and cytarabine (n=2). Median age was 70.5 yrs (range 41-81). Disease control...
This is a professional memoir of an established physical scientist and Hematologist work during h... more This is a professional memoir of an established physical scientist and Hematologist work during his tenure in the Medical College of Pennsylvania and its mutations to MCP-Hahnemann University and Drexel College of Medicine (DUCOM) and finally at Thomas Jefferson University. It written for nos specialist including lay readers. The second part includes essays on new research in the field and essays on art and music.
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