Citations

The biological changes that occur in the brains of Alzheimer's disease (AD) patients are thought to begin long before the onset of clinical symptoms. Although current therapeutic agents have been approved only for patients with mild to moderate AD, Alzheimer‐type pathology in patients with mild to moderate AD is already quite advanced. One impetus for the development of the concept of mild cognitive impairment (MCI) was the attempt to recognize AD early in its clinical expression and to determine whether it is possible through therapeutic interventions to improve the memory impairment at this stage or delay further progression to dementia. To this end, several clinical trials have been conducted in patients with MCI. On September 8 and 9, 2004 a meeting of the Alzheimer's Association Research Roundtable was held at which experts in the field of MCI convened to review the collective experience from these trials and to consider potential approaches that might improve MCI clinical trials in the future. This article summarizes the presentations and discussions of that meeting.

Abstract Activating FLT3 mutations are the most common genetic aberrations in acute myeloid leukemia (AML), resulting in the constitutive activation of this receptor tyrosine kinase (RTK), but such mutations are rarely found in acute lymphoblastic leukemia (ALL). Here we describe a unique subset of de novo adult T-cell ALL (T-ALL) cases that coexpress CD117/KIT and cytoplasmic CD3 (CD117/KIT+ ALL). Activating mutations in the FLT3 RTK gene were found in each of 3 CD117/KIT+ cases that were analyzed, but not in 52 other adult T-ALL samples from the same series that lacked CD117/KIT expression. Our results indicate the need for clinical trials to test the efficacy of drugs that inhibit the FLT3 RTK in this subset of patients with T-ALL. (Blood. 2004;104:558-560)

Purpose To determine whether adding the multidrug resistance gene-1 (MDR-1) modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to chemotherapy provided clinical benefit to patients with poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Patients and Methods A phase III randomized study was performed using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC; n = 66) versus MEC (n = 63) to treat patients with relapsed or refractory AML and high-risk MDS. Results For the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus 25% of patients, respectively (P = not significant). For patients who had not received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS), the CR rate was increased—35% versus 15% for the remaining patients (P = .018); CR rates did not differ between treatment arms. The median disease-free survival in those achieving CR was similar in the two arms (10 versus 9.3 months) as was the patients’ overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of patients) versus MDR− patients were similar for those receiving either chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic patients (45% of patients) was 13% compared to the remainder, 28% (P = .09). Population pharmacokinetic analysis demonstrated that the clearances of mitoxantrone and etoposide were decreased by 59% and 50%, respectively, supporting the empiric dose reductions in the PSC-MEC arm designed in anticipation of drug interactions between valspodar and the chemotherapeutic agents. Conclusion CR rates and overall survival were not improved by using PSC-MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high-risk MDS.

AbstractThese cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at‐risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in this document is derived from extensivereview of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provid information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Key components include the intake (medical and family histories), psychosocial assessment (assessment of risk perception), cancer risk assessment (determination and communication of risk), molecular testing for hereditary cancer syndromes (regulations, informed consent, and counseling process), and follow‐up considerations. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a client.

Purpose Acute monocytic leukemia is a distinct subtype of acute myeloid leukemia (AML) with characteristic biologic and clinical features. This study was designed to compare the outcome of patients with M5 to that of other subtypes of AML, and to identify differences in M5a and M5b. Patients and Methods We reviewed all patients with AML M5 entered in three clinical trials for newly diagnosed AML conducted by the Eastern Cooperative Oncology Group between 1989 and 1998. Eighty-one patients, 21 with M5a and 60 with M5b, were identified. Results The complete remission rate was 62% for all patients with M5; 52% for patients with M5a and 65% for patients with M5b (P = .3), and 60% for the 1,122 patients with non-M5 AML entered on the same clinical trials (P = .8 for M5 v non-M5). The 3-year disease-free survival was 26% for all M5 patients; 18% for M5a and 28% for M5b (P = .31), and 33% for non-M5 patients (P = .13 for M5 v non-M5). The 3-year overall survival was 31% for all M5 patients; 33% for M5a and 30% for M5b (P = .65), and 30% for non-M5 (P = .74 for M5 v non-M5). The karyotypes of patients with AML M5 were heterogeneous. CD11b was the only leukemic cell antigen expressed differently in M5a (53%) compared to M5b (77%) to a significant degree (P = .02). Conclusion AML M5 represents an immunologically heterogeneous population similar to non-M5 AML with a prognosis that is not dependent on morphology. The disease-free survival and overall survival of patients with M5a, M5b, and non-M5 appear not to differ with currently available therapy.

AbstractThe optimal induction for older adults with acute myeloid leukemia (AML) is unknown. Several anthracyclines have been proposed, but the data remain equivocal. Additionally, few prospective trials of priming with hematopoietic growth factors to cycle leukemia cells prior to induction chemotherapy have been conducted. Three hundred and sixty-two older adults with previously untreated AML were randomized to either daunorubicin, idarubicin or mitoxantrone with a standard dose of cytarabine as induction therapy. In addition, 245 patients were also randomized to receive granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo beginning 2 days prior to induction chemotherapy and continuing until marrow aplasia. No difference was observed in the disease-free overall survival or in toxicity among patients receiving any of the 3 induction regimens or among those receiving growth factor or placebo for priming. However, the complete remission rate for the first 113 analyzable patients, who did not participate in the priming study and started induction therapy 3 to 5 days earlier than those who did, was significantly higher (50% versus 38%; P = .03). None of the anthracyclines is associated with improved outcome in older adults. Priming with hematopoietic growth factor did not improve response when compared with placebo. Furthermore, delaying induction therapy in older adults may lead to a lower complete remission rate.

▪ Abstract Genetic disorders of mitochondrial fatty acid β-oxidation have been recognized within the last 20 years as important causes of morbidity and mortality, highlighting the physiological significance of fatty acids as an energy source. Although the mammalian mitochondrial fatty acid-oxidizing system was recognized at the beginning of the last century, our understanding of its exact nature remains incomplete, and new components are being identified frequently. Originally described as a four-step enzymatic process located exclusively in the mitochondrial matrix, we now recognize that long-chain-specific enzymes are bound to the inner mitochondrial membrane, and some enzymes are expressed in a tissue-specific manner. Much of our new knowledge of fatty acid metabolism has come from the study of patients who were diagnosed with single-gene autosomal recessive defects, a situation that seems to be further evolving with the emergence of phenotypes determined by combinations of multiple genetic and environmental factors. This review addresses the normal process of mitochondrial fatty acid β-oxidation and discusses the clinical, metabolic, and molecular aspects of more than 20 known inherited diseases of this pathway that have been described to date.