Citations

Purpose Randomized comparisons of idarubicin (IDA) with daunorubicin (DNR) show that in adults with acute myeloid leukemia (AML), IDA achieves higher remission rates and longer remission durations. In Children's Cancer Group Pilot Study CCG-2941, we assessed toxicity and feasibility of substituting 4 mg of DNR with 1 mg of IDA in intensive-timing daunorubicin-based induction therapy (DNR/DNR) used in CCG-2891. Patients and Methods On days 1 through 3 and 10 through 14, patients received two courses of dexamethasone, cytarabine, 6-thioguanine, etoposide, and IDA (IDA/IDA). After enrollment of 65 patients, toxicity prompted replacement of IDA with DNR (IDA/DNR) on days 10 through 14 for the remaining 28 patients. Outcomes were compared with those of intensive timing in CCG-2891. Results Treatment-related mortality after two courses of induction was not significantly different among the three regimens: 14% with IDA/IDA, 7% with IDA/DNR, and 9% with DNR/DNR. In course 1 of CCG-2941 IDA/IDA, 11% of patients withdrew compared with 1.5% in CCG-2891 (P < .001) and 5% in CCG-2941 IDA/DNR (P = not significant). Compared with CCG-2891 DNR/DRN, CCG-2941 IDA/IDA increased days in hospital (43 v 36 days; P = .007), mean duration of course 1 by a week (P = .002), and risk of grade 3 or 4 hyperbilirubinemia (18% v 5%; P = .02). Toxicity of IDA/DNR was not different from that of DNR/DNR in CCG-2891. The mean day 7 marrow blast percentage was 11.4% in CCG-2941 versus 21.1% in CCG-2891 (P = .004). Remission induction, survival, and event-free survival rates were not significantly different from those of CCG-2891. Conclusion In CCG-2941, excessive toxicity and withdrawals outweighed potential benefits of early response with IDA.

Albuminuria increases the risk of cardiovascular events in patients with essential hypertension and diabetic subjects. The heritability (h 2 ) of albuminuria in multiplex hypertensive families is unknown. We calculated the familial aggregation of urine albumin:creatinine ratio (ACR) and performed a genome-wide scan to assess for loci contributing to ACR in participants enrolled in the Hyper tension G enetic E pidemiology N etwork (HyperGEN). To perform the genome scan, we analyzed genotype results from 2589 individuals from 805 families in the Family Blood Pressure Program. ACR and covariates were available in 1727 individuals (mean age, 57.1 years). Estimates of h 2 were obtained by using variance component methodology as implemented in the SOLAR software package. Linkage was tested between 387 markers spanning the genome at an average interval of 9.32 cM, using SOLAR multipoint analysis. The h 2 of log urine ACR was 0.49 ( P <1×10 −7 ) after controlling for significant main and interactive effects of age, gender, race, body mass index, blood pressure, and use of ACE inhibitors or angiotensin-2 receptor blockers. The genome-wide scan revealed a maximum LOD score of 2.73 on chromosome 19 (robust corrected LOD, 2.40; P =0.0009) at marker D19S591 and a LOD score of 2.0 on chromosome 12 (robust corrected LOD, 1.75; P =0.005) at marker PAH. These analyses demonstrate the marked heritability of urine ACR in families enriched for the presence of members with essential hypertension. They suggest that a gene(s) associated with urinary ACR may be present on human chromosomes 19 and 12.

ABSTRACT An aspartyl protease, Beta‐Site APP cleaving enzyme (BACE), was identified as the β‐secretase responsible for generating the Amyloid β protein that is believed to cause Alzheimer's disease. BACE has a short propeptide domain that is absent in the mature enzyme because of proteolytic cleavage after the sequence RLPR. This sequence is a predicted substrate for proprotein convertases such as furin. To determine the role of furin and other proprotein convertases, we expressed proBACE in a furin‐deficient mutant Chinese hamster ovary (CHO‐K1) line, RPE.40. ProBACE signal was higher in RPE.40 than in the CHO‐K1 parent, which confirmed that furin plays a role in propeptide removal. However, two independent approaches showed that proBACE is cleaved to mature BACE in RPE.40: proBACE was rapidly turned over in RPE.40 although total BACE was stable, and decanoyl‐RVKR‐chloromethylketone, an inhibitor of the proprotein convertase family, substantially increased proBACE levels in both RPE40 and CHO‐K1. Transient transfection shows that furin, PACE4, PC5/6, and PC7 mediate BACE cleavage in vivo , at least when overexpressed. RPE.40 is proficient in BACE activity despite its furin deficiency. Therefore, our finding that proBACE is cleaved in this mutant leaves open the possibility that maturation is an important regulatory step and a therapeutic target.

Ectomesenchymomas (EM) are rare malignant neoplasms usually consisting of rhabdomyosarcoma (RMS) with a neural component. Only 21 cases have been previously reported. Here we extend the clinicopathologic spectrum of EM by describing our findings in 15 cases. Only 5 patients were infants; 10 were ≤3 years old and 5 were ≥6 years old. No male predilection was observed; 7 were female. The originating institutional diagnoses were; RMS (12), undifferentiated sarcoma (1), or EM (2), suggesting underdiagnosis of this entity. The primary tumor sites included external genital (5), pelvis/abdomen (6), head and neck (3), and extremity (1). The size of the primary neoplasm was usually ≥5 cm at diagnosis but dissemination only occurred in a minority. Local infiltration was not uncommon. These neoplasms were typically multilobate, thinly encapsulated, hemorrhagic, and necrotic. Light microscopic features were highly variable, but embryonal RMS with scattered or clustered ganglion cells, often in lacunae, was characteristic. In some cases, primitive neuroblastic or neuroectodermal areas were found and/or a component of alveolar RMS was seen. Focal anaplasia was occasionally observed. Mitotic activity appears higher than previously appreciated and some necrosis was invariably present. Electron microscopy was performed in 11 cases, which confirmed skeletal muscle ± neural differentiation. Cytogenetic studies performed in five cases revealed no specific abnormality. Monoclonal neuron-specific enolase was the best marker of ganglion cells and primitive neural elements. MIC-2 (CD99) membrane expression was not definitively present in any of the six cases examined. A number of the above parameters appear to be of some prognostic significance, but overall, these neoplasms appear to have a similar outcome as would be predicted for their RMS element alone (exclusive of any neural component), with respect to the RMS subtype, age of the patient, and anatomic location of the neoplasm.