Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921

PURPOSE Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m$^{2}$ once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. RESULTS Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m$^{2}$, 11 at 350 mg/m$^{2}$ (one DLT), and 10 at 400 mg/m$^{2}$ (one DLT). The mean AUCs at 300 mg/m$^{2}$, 350 mg/m$^{2}$, and 400 mg/m$^{2}$ were 2.20 μg h/mL, 2.52 μg h/mL, and 2.66 μg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m$^{2}$ once daily (max 600 mg/d) with food in R/I patients and 300 mg/m$^{2}$ once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience

Use and perceived helpfulness of smoking cessation methods: results from a population survey of recent quitters

<p>Abstract</p> <p>Background</p> <p>Increasing rates of smoking cessation is one of the most effective measures available to improve population health. To advance the goal of increasing successful cessation at the population level, it is imperative that we understand more about smokers' use of cessation methods, as well as the helpfulness of those methods in real-world experiences of quitting. In this survey of recent quitters, we simultaneously examined rates of use and perceived helpfulness of various cessation methods.</p> <p>Methods</p> <p>Recent quitters (within 12 months; n = 1097) completed a telephone survey including questions relating to 13 cessation methods. Indices of use and perceived helpfulness for each method were plotted in a quadrant analysis. Socio-demographic differences were explored using bivariate and multivariate analyses.</p> <p>Results</p> <p>From the quadrant analysis, cold turkey, NRT and gradual reduction before quitting had high use and helpfulness; GP advice had high use and lower helpfulness. Prescribed medication and online programs had low use but high helpfulness. Remaining methods had low use and helpfulness. Younger quitters were more likely to use unassisted methods such as cold turkey; older or less educated quitters were more likely to use assisted methods such as prescribed medication or advice from a general practitioner.</p> <p>Conclusions</p> <p>The majority of recent quitters quit cold turkey or cut down before quitting, and reported that these methods were helpful. Efforts to influence population smoking prevalence should attempt to provide support and motivation for smokers choosing these methods, in addition to assessing the effectiveness and accessibility of other methods for smokers who need or choose them.</p

Dasatinib in pediatric patients with chronic myeloid leukemia in chronic phase:results from a phase II trial

PurposeSafe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I study determined suitable dosing for children with Philadelphia chromosome-positive (Ph+) leukemias.MethodsCA180-226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients < 18 years of age receiving dasatinib. There are three cohorts: (1) imatinib-resistant/intolerant CML-CP, (2) imatinib-resistant/intolerant CML in accelerated/blast phase or Ph+ acute lymphoblastic leukemia (n = 17), and (3) newly diagnosed CML-CP treated with tablets or powder for oral suspension. Major cytogenetic response > 30% for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest.ResultsOf 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, respectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial hypertension were reported. Bone growth and development events were reported in 4% of patients.ConclusionIn the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Lancaster, Jeanette interview for the Miami Valley College of Nursing and Health Oral History Project

Donna Miles Curry interviewed Jeanette Lancaster about the founding of the Wright State University College of Nursing and Health. In the interview Dr. Lancaster discusses her career and her decision to come to Wright State as faculty with the College of Nursing and Health

Chitosan nanoparticle antigen uptake in epithelial monolayers can predict mucosal but not systemic in vivo immune response by oral delivery

This study compared in vitro and in vivo antigen delivery effects of ultrapure chitosan (CS) chloride. CS nanoparticles were formulated to incorporate ovalbumin (OVA) as a model antigen and characterised for size, charge, OVA complexation and release. The effect of CS:OVA nanoparticles on cell viability, epithelial tight junctions and transepithelial permeation of OVA was tested on Caco-2 monolayer in vitro intestinal model. The system’s ability to elicit immune responses was subsequently tested in vivo. The work confirmed that CS complexes with OVA into nano-size entities. Nanocomplexes displayed favourable delivery properties, namely OVA release and no notable cytotoxicity. CS:OVA markedly enhanced antigen delivery across Caco-2 monolayers. However, the system did not elicit notable in vivo immune responses (some mucosal response was apparent) following oral delivery. The study highlights that a clear effect on antigen permeability across epithelial monolayers in vitro may predict the in vivo mucosal but not systemic immune response following oral delivery

Leukaemia survival trends in children with Down's syndrome in Great Britain, 1971-2000: a population-based study

Background: Children with Down's syndrome (DS) who developed leukaemia have had a worse prognosis than other children with leukaemia in the past. In the 1970s and early 1980s, some children with DS who developed leukaemia received fewer cycles of chemotherapy or were advised not to have treatment. Methods: In this population-based study, trends in 5-year survival with leukaemia were evaluated for children with and without DS who were diagnosed in Great Britain during 1971-2000 and followed to the end of 2004. Results: For all children, with and without DS, survival has increased dramatically over the 30 year study period. For lymphoid leukaemia, survival in children with DS increased, but remains lower than for other children (5-year survival 59% vs 83% during 1996-2000). For acute non-lymphoblastic leukaemia (ANLL), however, 5-year survival improved substantially for children with DS, from less than 1% in the early 1970s to over 80% in the 1990s. For other children, survival increased from 6% to 64% during the same period. Conclusion: Survival for all children diagnosed with leukaemia has improved during the last three decades. For lymphoid leukaemia, the inferior outcome observed on more recent treatment protocols in children with DS remains an area for concern. For ANLL, the improvement in survival for children with DS is due to a number of factors, namely increased recruitment of these children to clinical trials, changes in clinical practice and important differences in the biology of myeloid leukaemia in young children with DS, resulting in a better response to some chemotherapeutic agents

Symptomatic severe hypertriglyceridaemia with asparaginase therapy in acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma:is rechallenging safe?

Severe hyperlipidaemia with asparaginase therapy is rare. We report six cases, four of which developed significant problems with severe hyperlipidaemia during induction therapy for ALL and lymphoblastic lymphoma. The median triglyceride level was 22.3 mmol/L and the median cholesterol level was 12.3 mmol/L. None of the patients showed signs or symptoms of pancreatitis. Three children were re-exposed with Peg asparaginase, and one with Erwinia asparaginase, without recurrence of hyperlipidaemia or other symptoms. These cases highlight the dilemma in managing such rare cases of symptomatic hypertriglyceridaemia secondary to asparaginase and steroid therapy