Brian A.

abstract title released April 21, to be presented June 2 at ASCO 2014

J Clin Oncol 31, 2013 (suppl 6; abstr 127)

Poster.

The data on front-line use of dastanib in the treatment of chronic phase CML are reviewed.

Hematopoietic cells isolated from patients with Bcr-Abl-positive leukemia exhibit multiple abnormalities of cytoskeletal and integrin function. These abnormalities are thought to play a role in the pathogenesis of leukemia; however, the molecular events leading to these abnormalities are not fully understood. We show here that the Abi1 pathway is required for Bcr-Abl to stimulate actin cytoskeleton remodeling, integrin clustering and cell adhesion. Expression of Bcr-Abl induces tyrosine… Show more

Hematopoietic cells isolated from patients with Bcr-Abl-positive leukemia exhibit multiple abnormalities of cytoskeletal and integrin function. These abnormalities are thought to play a role in the pathogenesis of leukemia; however, the molecular events leading to these abnormalities are not fully understood. We show here that the Abi1 pathway is required for Bcr-Abl to stimulate actin cytoskeleton remodeling, integrin clustering and cell adhesion. Expression of Bcr-Abl induces tyrosine phosphorylation of Abi1. This is accompanied by a subcellular translocation of Abi1/WAVE2 to a site adjacent to membrane, where an F-actin-enriched structure containing the adhesion molecules such as beta1-integrin, paxillin and vinculin is assembled. Bcr-Abl-induced membrane translocation of Abi1/WAVE2 requires direct interaction between Abi1 and Bcr-Abl, but is independent of the phosphoinositide 3-kinase pathway. Formation of the F-actin-rich complex correlates with an increased cell adhesion to fibronectin. More importantly, disruption of the interaction between Bcr-Abl and Abi1 by mutations either in Bcr-Abl or Abi1 not only abolished tyrosine phosphorylation of Abi1 and membrane translocation of Abi1/WAVE2, but also inhibited Bcr-Abl-stimulated actin cytoskeleton remodeling, integrin clustering and cell adhesion to fibronectin. Together, these data define Abi1/WAVE2 as a downstream pathway that contributes to Bcr-Abl-induced abnormalities of cytoskeletal and integrin function. Show less

Discusses the dose reductions used to successfully obtain a complete remission in an HIV patient presenting with acute hepatic failure and large cell NHL.

The 42nd Annual Meeting of the American Society of Clinical Oncology was held in Atlanta, GA, June 2-6, 2006. Some of the presentations pertaining to the diagnosis and management of non-Hodgkin's lymphoma are summarized in this review. Principal issues in indolent lymphoma included the role of maintenance therapy, novel agents such as bendamustine and pixantrone, and updates of predictive factors. Studies in aggressive lymphomas included standard regimens, such as rituximab-based chemotherapy… Show more

The 42nd Annual Meeting of the American Society of Clinical Oncology was held in Atlanta, GA, June 2-6, 2006. Some of the presentations pertaining to the diagnosis and management of non-Hodgkin's lymphoma are summarized in this review. Principal issues in indolent lymphoma included the role of maintenance therapy, novel agents such as bendamustine and pixantrone, and updates of predictive factors. Studies in aggressive lymphomas included standard regimens, such as rituximab-based chemotherapy and radioimmunotherapy, as well as novel salvage regimens. Advances in the management of mantle cell lymphoma with radioimmunotherapy, hyper-CVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) and emerging agents, such as bortezomib and temsirolimus, were presented. Show less

Chronic lymphocytic leukemia is a low-grade B-lineage lymphoid malignancy. Based on recent findings, the disease appears to be more heterogeneous than previously thought. Many cases may require no treatment at all unless patients become symptomatic or develop signs of rapid progression. Even in this setting, treatment is noncurative and is directed at reducing the symptoms. Recently described molecular risk features may help delineate at initial diagnosis which patients will have a more… Show more

Chronic lymphocytic leukemia is a low-grade B-lineage lymphoid malignancy. Based on recent findings, the disease appears to be more heterogeneous than previously thought. Many cases may require no treatment at all unless patients become symptomatic or develop signs of rapid progression. Even in this setting, treatment is noncurative and is directed at reducing the symptoms. Recently described molecular risk features may help delineate at initial diagnosis which patients will have a more aggressive course. Newer treatment regimens incorporating purine nucleoside analogs and monoclonal antibodies have increased the rate of molecular complete remissions, which may lead to increased survival. Reduced intensity conditioning regimens have made the potentially curative modality of allogeneic transplantation more widely available. All of these recent treatments have significant risks of infectious complications, which must be carefully weighed against the risks posed by the underlying disease, and many low-risk asymptomatic patients do not require any treatment. A proposed risk-based treatment algorithm will be discussed. Show less

ABCG2 is a member of the adenosine triphosphate-binding cassette (ABC) family of cell surface transport proteins. ABCG2 is expressed in many types of primitive repopulating cells, and may be a marker of tumor stem cells. The physiologic role of ABCG2 seems to be excretion of genotoxic substances from the body and from primitive repopulating cell populations. A unifying hypothesis is presented, linking the expression of ABCG2 in normal and malignant stem cells with a physiologic role for… Show more

ABCG2 is a member of the adenosine triphosphate-binding cassette (ABC) family of cell surface transport proteins. ABCG2 is expressed in many types of primitive repopulating cells, and may be a marker of tumor stem cells. The physiologic role of ABCG2 seems to be excretion of genotoxic substances from the body and from primitive repopulating cell populations. A unifying hypothesis is presented, linking the expression of ABCG2 in normal and malignant stem cells with a physiologic role for protection of stem cells. Future studies will explore the possible role of ABCG2 in tumor stem cells and how this may influence the selection of new cancer therapeutic strategies. Show less

To determine the clinical significance of central nervous system (CNS) involvement at the time of diagnosis of pediatric acute myeloid leukemia (AML), we analyzed clinical features and outcomes of 290 patients treated consecutively on four institutional trials (AML80, AML83, AML87, and AML91). CNS status was classified as CNS1 (no blast cells in CSF; n=205), CNS2 (<5 WBC/mul CSF with blast cells; n=37), or CNS3 (>/=5 WBC/mul CSF with blast cells, or signs of CNS involvement; n=48)… Show more

To determine the clinical significance of central nervous system (CNS) involvement at the time of diagnosis of pediatric acute myeloid leukemia (AML), we analyzed clinical features and outcomes of 290 patients treated consecutively on four institutional trials (AML80, AML83, AML87, and AML91). CNS status was classified as CNS1 (no blast cells in CSF; n=205), CNS2 (<5 WBC/mul CSF with blast cells; n=37), or CNS3 (>/=5 WBC/mul CSF with blast cells, or signs of CNS involvement; n=48). Patients with CNS3 status were significantly younger than others (P=0.016) and significantly more likely to have the favorable cytogenetic features t(9;11), t(8;21), or inv(16) (P<0.001). The CNS3 group had a significantly greater probability (+/-s.e.) of 5-year event-free survival (43.7+/-7.0%) than did the CNS1 (27.8+/-3.2%, P=0.015) and CNS2 (24.3+/-7.5%, P=0.032) groups. However, after adjustment for favorable genetic features, there was no significant difference in EFS between the CNS3 and the combined CNS1+CNS2 groups (P=0.075). In all, 10 of 151 patients treated on AML80 and AML83, but none of 139 treated on AML87 and AML91, had primary CNS relapse. CNS involvement had no adverse prognostic significance, and patients with CNS2 status had similar outcome to CNS1 patients in this large group of pediatric patients with AML, treated at a single institution. Show less

Previous reports have suggested that the adenosine triphosphate-binding cassette protein ABCG2 (breast cancer resistance protein [BCRP], mitoxantrone resistance [MXR]) is associated with drug resistance in acute myeloid leukemia (AML). The aims of this study were to determine the level of ABCG2 mRNA expression necessary to produce drug resistance and to define the ABCG2 levels in normal bone marrow (BM), peripheral blood (PB), cord blood (CB), and adult AML blast cell populations. First, using… Show more

Previous reports have suggested that the adenosine triphosphate-binding cassette protein ABCG2 (breast cancer resistance protein [BCRP], mitoxantrone resistance [MXR]) is associated with drug resistance in acute myeloid leukemia (AML). The aims of this study were to determine the level of ABCG2 mRNA expression necessary to produce drug resistance and to define the ABCG2 levels in normal bone marrow (BM), peripheral blood (PB), cord blood (CB), and adult AML blast cell populations. First, using transduced clonal cell lines expressing varying levels of ABCG2, we found that ABCG2 expression conferred resistance to mitoxantrone and topotecan, but not to idarubicin. Next, we developed a real-time reverse transcription-polymerase chain reaction assay for measuring ABCG2 mRNA expression levels in clinical samples. Normal BM and PB contained low levels of ABCG2 mRNA, while higher levels were measured in CB mononuclear cells, CD34(+), and Ac133(+) populations, consistent with the known stem cell enrichment in these populations. Next, we studied the ABCG2 mRNA levels in 40 specimens from newly diagnosed adult AML patients. Only 7% of these samples contained ABCG2 mRNA levels within the range of our drug-resistant clone, although another 78% were higher than normal blood and bone marrow. Flow cytometry revealed very small subpopulations of ABCG2-expressing cells in the cases we examined. Our data suggest that high levels of ABCG2 mRNA expression in adult AML blast specimens are relatively uncommon and that ABCG2 expression may be limited to a small cell subpopulation in some cases. Show less