c-CBL (CBL) encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by constitutional anomalies that include impaired growth, developmental delay, cryptorchidism, and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.Y371H mutant Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT, and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic, and functional consequences that are reminiscent of disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, and Noonan, Costello, cardiofaciocutaneous, and Legius syndromes.

Standard therapy in the United States for malignancy-associated hyperuricemia consists of hydration, alkalinization, and allopurinol. Urate oxidase catalyzes the enzymatic oxidation of uric acid to a 5 times increased urine soluble product, allantoin. Rasburicase is a new recombinant form of urate oxidase available for clinical evaluation. This multicenter randomized trial compared allopurinol to rasburicase in pediatric patients with leukemia or lymphoma at high risk for tumor lysis. Patients received the assigned uric acid-lowering agent for 5 to 7 days during induction chemotherapy. The primary efficacy end point was to compare the area under the serial plasma uric acid concentration curves during the first 96 hours of therapy (AUC 0-96 ). Fifty-two patients were randomized at 6 sites. In an intent-to-treat analysis, the mean uric acid AUC 0-96 was 128 ؎ 70 mg/dL.hour for the rasburicase group and 329 ؎ 129 mg/dL.hour for the allopurinol group (P < .0001). The rasburicase versus allopurinol group experienced a 2.6-fold (95% CI: 2.0-3.4) less exposure to uric acid. Four hours after the first dose, patients randomized to rasburicase compared to allopurinol achieved an 86% versus 12% reduction (P < .0001) of initial plasma uric acid levels. No antirasburicase antibodies were detected at day 14. This randomized study demonstrated more rapid control and lower levels of plasma uric acid in patients at high risk for tumor lysis who received rasburicase compared to allopurinol. For pediatric patients with advanced stage lymphoma or high tumor burden leukemia, rasburicase is a safe and effective alternative to allopurinol during initial chemotherapy. (Blood. 2001; 97:2998-3003)

Background Children surviving acute lymphoblastic leukemia (ALL) are at increased risk for overweight and obesity over that of the general population. Whether a generic or tailored approach to weight management is needed for cancer survivors has yet to be tested. Procedure Thirty-eight youth 8–18 years with BMI≥85% who had survived ALL were recruited for a randomized clinical trial evaluating a weight management intervention (WMI) tailored for childhood ALL survivors (Fit4Life). Fit4Life recipients received a 4-month web, phone, and text message-delivered WMI tailored for cancer survivorship. Controls received a general WMI delivered via phone and mail. Assessments were performed at baseline and 4 months. Outcome data were analyzed according to assigned treatment condition over time. Results Most (80% (70%,100%) [median (IQR)]) of the assigned curriculum was received by Fit4Life participants as compared to 50% (40%,65%) among controls. Fit4Life recipients ≥14 years demonstrated less weight gain (p=0.05) and increased moderate-to-vigorous physical activity (p<0.01) while all Fit4Life recipients reported reduced negative mood (p<0.05) over time as compared to control counterparts. Conclusions We demonstrated acceptable feasibility of a WMI tailored for overweight and obese children surviving ALL utilizing a multimodal technology approach. Improved weight, weight-related behavior, and psychological outcomes were demonstrated among Fit4Life intervention as compared to youth receiving a generic WMI. Data from this pilot trial may be used to design a larger trial to determine whether youth of all ages also can derive a benefit from a cancer-survivor tailored WMI and whether short-term outcomes translate into improved long-term outcomes for childhood ALL survivors.

Two cell lines were derived from an embryonal rhabdomyosarcoma. Cells of both lines grew as monolayers in liquid medium and formed colonies in agar medium. Each line consisted of 2 cytologic types resembling those of the original tumor—spindle cells and large multinucleated cells. No myofibrils could be demonstrated in the cells by light or by electron microscopy nor were virus particles detected. Cells of both lines probably contained myosin‐ATPase and cells of line #2 contained myoglobin. Chromosome studies of cell line #1 revealed a stem‐line of 51 chromosomes with a consistent karyotype. Three passages of cell line #2 were studied, and no evidence of a stem‐line was noted. Chromosome counts ranged from 45 to 170, and consistent marker chromosomes in most cells were present in the form of large metacentrics in the C group.