Assessing Sensitive Consumer Behavior Using the Item Count Response Technique

The authors propose a new truth-telling technique and statistical model called “item count response technique” (ICRT) to assess the prevalence and drivers of sensitive consumer behavior. Monte Carlo simulations and a large-scale application to self-reported cigarette consumption among pregnant women (n ¼ 1,315) demonstrate the effectiveness of the procedure. The ICRT provides more valid and precise prevalence estimates and is more efficient than direct self-reports and previous item count techniques. It accomplishes this by (1) incentivizing participants to provide truthful answers, (2) accounting for procedural nonadherence and differential

Allergic-like reactions to asparaginase: Atypical allergies without asparaginase inactivation

Background: Asparaginase is an important component of pediatric acute lymphoblastic leukemia (ALL) therapy. Unfortunately, this treatment is hampered by hypersensitivity reactions. In general, allergies – regardless of severity – cause complete inactivation of the drug. However, we report atypical allergic reactions without inactivation of asparaginase, here called allergic-like reactions. Procedure: Patients with an allergic-like reaction, who were treated according to the Dutch Childhood Oncology Group ALL-11 or the CoALL 08–09 protocol, were described. The reactions were identified by continual measurement of asparaginase activity levels. Characteristics, including timing of occurrence, symptoms, grade, and the presence of antiasparaginase antibodies, were compared to those of real allergies. Results: Fourteen allergic-like reactions occurred in nine patients. Five reactions were to PEGasparaginase and nine to Erwinia asparaginase. Allergic-like reactions occurred relatively late after the start of infusion compared to real allergies. Antibodies were absent in all but one patient with an allergic-like reaction, while they were detected in all patients with a real allergy. Symptoms and grade did not differ between the groups. Asparaginase was continued with the same formulation in six patients of whom four finished treatment with adequate activity levels. Conclusions: In conclusion, allergic-like reactions occur relatively late after the start of infusion and without antibodies. Despite these clinical differences, allergic-like reactions can only be distinguished from real allergies by continually measuring asparaginase activity levels. If clinically tolerated, formulations should not be switched in case of allergic-like reactions. Moreover, failure to recognize these reactions may lead to a less favorable prognosis if asparaginase therapy is terminated unnecessarily

Impaired dexamethasone-related increase of anticoagulants is associated with the development of osteonecrosis in childhood acute lymphoblastic leukemia

Coagulation alterations may be involved in osteonecrosis in childhood acute lymphoblastic leukemia. Retrospectively, we evaluated the available coagulation parameters at diagnosis and during induction treatment of 161 acute lymphoblastic leukemia patients: 24 with symptomatic osteonecrosis (median age: 13.8 years, range 4.0-17.2) and 137 without osteonecrosis (median age: 4.9 years, range 1.0-16.7). Coagulation parameters of both groups were similar at diagnosis. After four weeks of treatment including dexamethasone, levels of antithrombin and protein S were significantly less in osteonecrosis-positive than in osteonecrosis-negative patients. Subsequently, after four doses of asparaginase and tapering dexamethasone, these coagulation parameters equally decreased in both groups. Consequently, nadirs of antithrombin and protein S were significantly lower in osteonecrosis-positive than in osteonecrosis- negative patients, even reaching levels below lower normal limits in the osteonecrosis-positive group. A reduced dexamethasone related increase of antithrombin and protein S, and subsequent decline below normal levels after introduction of asparaginase, may result in a hypercoagulable state, contributing to development of symptomatic osteonecrosis

Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia

Resistance of leukemic cells to chemotherapeutic agents is associated with an unfavorable outcome in pediatric acute lymphoblastic leukemia (ALL). To investigate the underlying mechanisms of cellular drug resistance, the activation of various apoptotic parameters in leukemic cells from 50 children with ALL was studied after in vitro exposure with 4 important drugs in ALL therapy (prednisolone, vincristine, l-asparaginase, and daunorubicin). Exposure to each drug resulted in early induction of phosphatidylserine (PS) externalization and mitochondrial transmembrane (Deltapsim) depolarization followed by caspase-3 activation and poly(ADP-ribose) polymerase (PARP) inactivation in the majority of patients. For all 4 drugs, a significant inverse correlation was found between cellular drug resistance and (1) the percentage of cells with PS externalization (<.001 < P <.008) and (2) the percentage of cells with Deltapsim depolarization (.002 < P <.02). However, the percentage of cells with caspase-3 activation and the percentage of cells with PARP inactivation showed a significant inverse correlation with cellular resistance for prednisolone (P =.001; P =.001) and l-asparaginase (P =.01; P =.001) only. This suggests that caspase-3 activation and PARP inactivation are not essential for vincristine- and daunorubicin-induced apoptosis. In conclusion, resistance to 4 unrelated drugs is associated with defect(s) upstream or at the level of PS externalization and Deltapsim depolarization. This leads to decreased activation of apoptotic parameters in resistant cases of pediatric AL

Biological background of pediatric medulloblastoma and ependymoma: A review from a translational research perspective

Survival rates of pediatric brain tumor patients have significantly improved over the years due to developments in diagnostic techniques, neurosurgery, chemotherapy, radiotherapy, and supportive care. However, brain tumors are still an important cause of cancer-related deaths in children. Prognosis is still highly dependent on clinical characteristics, such as the age of the patient, tumor type, stage, and localization, but increased knowledge about the genetic and biological features of these tumors is being obtained and might be useful to further improve outcome for these patients. It has become clear that the deregulation of signaling pathways essential in brain development, for example, sonic hedgehog (SHH), Wnt, and Notch pathways, plays an important role in pathogenesis and biological behavior, especially for medulloblastomas. More recently, data have become available about the cells of origin of brain tumors and the possible existence of brain tumor stem cells. Newly developed array-based techniques for studying gene expression, protein expression, copy number aberrations, and epigenetic events have led to the identification of other potentially important biological abnormalities in pediatric medulloblastomas and ependymomas. Copyright 2008 by the Society for Neuro-Oncology

Acute lymphoblastic leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate linker

Polyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is essential for treatment of paediatric acute lymphoblastic leukaemia. We developed an assay identifying antibodies against the PEG-moiety, the linker and the drug itself in patients experiencing hypersensitivity reactions to PEGasparaginase. Eighteen patients treated according to the DCOG ALL-11 protocol, with a neutralizing hypersensitivity reaction to PEGasparaginase to the first PEGasparaginase doses in induction (12 patients) or during intensification after interruption of several months (6 patients) were included. ELISA was used to measure antibodies, coating with the succinimidyl succinate linker conjugated to BSA, PEGfilgrastim and Escherichia coli asparaginase, and using hydrolysed PEGasparaginase and mPEG5,000 for competition. Anti-PEG antibodies were detected in all patients (IgG 100%; IgM 67%) of whom 39% had anti-PEG antibodies exclusively. Pre-existing anti-PEG antibodies were also detected in patients who not previously received a PEGylated therapeutic (58% IgG; 21% IgM). Antibodies against the SS-linker were predominantly detected during induction (50% IgG; 42% IgM). Anti-asparaginase antibodies were detected in only 11% during induction but 94% during intensification. In conclusion, anti-PEG and anti-SS-linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Thus, switching to native E. coli asparaginase would be an option for adequate asparaginase treatment

Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia

We studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI(50, cont)) or short-term (3 hours; TSI(50, short)) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T, MTHFR 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC 80G>A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI(50, cont). In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL

MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations

Acute lymphoblastic leukemia (ALL) in infants is an aggressive malignancy with a poor clinical outcome, and is characterized by translocations of the Mixed Lineage Leukemia (MLL) gene. Previously, we identified RAS mutations in 14-24% of infant ALL patients, and showed that the presence of a RAS mutation decreased the survival chances even further. We hypothesized that targeting the RAS signaling pathway could be a therapeutic strategy for RAS-mutant infant ALL patients. Here we show that the MEK inhibitors Trametinib, Selumetinib and MEK162 severely impair primary RAS-mutant MLL-rearranged infant ALL cells in vitro. While all RAS-mutant samples were sensitive to MEK inhibitors, we found both sensitive and resistant samples among RAS-wildtype cases. We confirmed enhanced RAS pathway signaling in RASmutant samples, but found no apparent downstream over-activation in the wildtype samples. However, we did confirm that MEK inhibitors reduced p-ERK levels, and induced apoptosis in the RAS-mutant MLL-rearranged ALL cells. Finally, we show that MEK inhibition synergistically enhances prednisolone sensitivity,