Pathologic Features of Down Syndrome Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML0431.

Context.—: Detailed diagnostic features of acute myeloid leukemia in Down syndrome are lacking, leading to potential misdiagnoses as standard acute myeloid leukemia occurring in patients with Down syndrome.

Objective.

Genotypic and clinical heterogeneity within NCCN favorable-risk acute myeloid leukemia.

The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF-KIT); and AML with normal cytogenetics and mutations in NPM1 (NPM1); or biallelic mutations in CEBPA (CEBPA), without FLT3-ITD. Although these AMLs are categorized as favorable risk by NCCN, clinical experience suggests that there are differences in clinical outcome amongst these cytogenetically and molecularly distinct leukemias. This study compared clinical and genotypic characteristics of 60 patients with favorable-risk AML, excluding APL, and demonstrated significant differences between them.

Data-Driven Iterative Refinement of Bone Marrow Testing Protocols Leads to Progressive Improvement in Cytogenetic and Molecular Test Utilization.

Objectives: To determine the effect of iterative refinement of standard ordering protocols on test utilization and results for bone marrow biopsy specimens.

Methods: Eighteen months of test utilization and result data were used to revise the protocols that determine cytogenetic and molecular test selection on bone marrow specimens and then compared with data obtained following protocol revision.

Results: Revision of protocols resulted in reduction in total tests and associated charges, due to a decrease in tests both concordant and discordant with the protocols.

Innovative analyses support a role for DNA damage and an aberrant cell cycle in myelodysplastic syndrome pathogenesis.

We used flow cytometry to analyze the cell cycle, DNA damage, and apoptosis in hematopoietic subsets in MDS marrow. Subsets were assigned using CD45, side scatter, CD34, and CD71. Cell cycle fractions were analyzed using DRAQ 5 (DNA content) and MPM-2 (mitoses).

Quantitative assessment of myeloid nuclear differentiation antigen distinguishes myelodysplastic syndrome from normal bone marrow.

By using flow cytometry, we analyzed myeloid nuclear differentiation antigen (MNDA) expression in myeloid precursors in bone marrow from patients with myelodysplastic syndrome (MDS) and control samples from patients undergoing orthopedic procedures. The median percentage of MNDA-dim myeloid precursors in MDS cases was 67.4% (range, 0.

PCR detection of Histoplasma capsulatum var. capsulatum in whole blood of a renal transplant patient with disseminated histoplasmosis.

We report the identification of Histoplasma capsulatum var. capsulatum from whole blood in a renal transplant patient with disseminated histoplasmosis using colorimetric microtiter-plate PCR. This modality demonstrated utility in reaching a definitive diagnosis in a timely manner.

Phase II evaluation of an intensified induction therapy with standard daunomycin and cytarabine followed by high dose cytarabine for adults with previously untreated acute myeloid leukemia: a Southwest Oncology Group study (SWOG-9500).

Induction therapy for acute myeloid leukemia (AML) usually consists of 7 days of cytarabine at 100-200 mg/m(2)/day and an anthracycline. Such combinations produce complete response (CR) rates of 60-80% in patients with de novo AML. On the basis of a previous report, suggesting a higher CR rate using a regimen of standard daunomycin and cytarabine followed by 3 days of high-dose cytarabine (HDAC), 101 eligible patients received this regimen in a phase II trial.

Dysregulated human myeloid nuclear differentiation antigen expression in myelodysplastic syndromes: evidence for a role in apoptosis.

Reduced levels of human myeloid nuclear differentiation antigen (MNDA) gene transcripts have been detected in both familial and sporadic cases of myelodysplastic syndromes (MDS). Numerous reports implicate elevated apoptosis/programmed cell death and death ligands and their receptors in the pathogenesis of MDS. MNDA and related proteins contain the pyrin domain that functions in signaling associated with programmed cell death and inflammation.

Age and acute myeloid leukemia.

We conducted a retrospective analysis of 968 adults with acute myeloid leukemia (AML) on 5 recent Southwest Oncology Group trials to understand how the nature of AML changes with age. Older study patients with AML presented with poorer performance status, lower white blood cell counts, and a lower percentage of marrow blasts. Multidrug resistance was found in 33% of AMLs in patients younger than age 56 compared with 57% in patients older than 75.

Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421.

Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction.

S100P is selectively upregulated in tumor cell lines challenged with DNA cross-linking agents.

Bifunctional alkylating agents that cross-link DNA are implicated in the pathogenesis of therapy related myelodysplastic syndromes (MDS) and MDS related acute myeloid leukemia (MDR-AML). We exposed HL60 cells to the highest level of bifunctional alkylating nitrogen mustard mechlorethamine (HN2) that was consistent with recovery following suppressed growth. Microarray analyses showed minor changes in transcripts in HN2 treated cells.

Overexpression of GSTA2 protects against cell cycle arrest and apoptosis induced by the DNA inter-strand crosslinking nitrogen mustard, mechlorethamine.

The effectiveness of bifunctional alkylating nitrogen mustard compounds in chemotherapy is related to their ability to form DNA inter-strand crosslinks. Patients exposed to DNA inter-strand crosslinking (ICL) agents subsequently experience an elevated incidence of myelodysplastic syndromes (MDS) and MDS related acute myeloid leukemia. Fanconi's anemia (FA) patients are deficient in the repair of crosslink DNA damage and they experience a high incidence of MDS.

Pulmonary hypertension complicating bone marrow transplantation for idiopathic myelofibrosis.

Idiopathic myelofibrosis is a rare hematologic disorder that is occasionally associated with pulmonary hypertension and has been cured with bone marrow transplantation (BMT). Most cases occur in older adults, but children with similar clinical and pathologic findings have been described. The authors describe a critically ill male infant with idiopathic myelofibrosis and subtle findings suggestive of pulmonary hypertension who was treated with BMT after failing to respond to chemotherapy.

Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia.

An International Working Group met to revise the diagnostic and response criteria for acute myelogenous leukemia originally published in 1990, as well as to provide definitions of outcomes and reporting standards to improve interpretability of data and comparisons among trials. Since the original publication, there have been major advances in our understanding of the biology and molecular genetics of acute leukemia that are clinically relevant and warrant incorporation into response definitions. Differences from the 1990 recommendations included a category of leukemia-free state, new criteria for complete remission, including cytogenetic and molecular remissions and remission duration.

Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase.

Chronic myeloid leukemia blast phase (CML-BP) cells commonly express the multidrug transporter, P-glycoprotein (Pgp). To determine whether Pgp inhibition improves treatment outcome in CML-BP, the Southwest Oncology Group performed a randomized, controlled trial testing the benefit of the Pgp modulator, cyclosporin A (CsA). Seventy-three eligible patients were assigned to treatment with cytarabine and infusional daunorubicin with or without intravenous CsA.

Retroviral mediated expression of the human myeloid nuclear antigen in a null cell line upregulates Dlk1 expression.

The human myeloid nuclear differentiation antigen (MNDA) is a hematopoietic cell specific nuclear protein. MNDA and other related gene products interact with and alter the activity of a large number of proteins involved in regulating specific gene transcription. MNDA and related genes exhibit expression characteristics, which suggest functions unique to specific lineages of cells, in addition to mediating the effects of interferons.

11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop.

Among 511 patients with therapy-related myelodysplastic syndrome or acute leukemia (t-MDS/t-AL) and balanced chromosome aberrations, 162 (32%) had translocations involving 11q23. The recurring translocation partners were 9p22 (48%), 19p13.3 (11%), 19p13.

Proposed changes in the definitions of acute myeloid leukemia and myelodysplastic syndrome: are they helpful?

For most of the 20th century, subclassification of acute myeloid leukemia (AML) was based on the resemblance of blasts to normal hematopoiesis. This approach was standardized by the French-American-British (FAB) group. Because of limited clinical relevance, clinicians resorted to other patient characteristics to determine treatment and predict outcome in AML.