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We investigated the role of copy number alterations to refine risk stratification in adult Philadelphia chromosome positive (Ph) + acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors (TKIs) and allogeneic stem cell transplantation (aSCT). Ninety-seven Ph + ALL patients (median age 41 years; range 18-64 years) within the prospective multicenter German Multicenter ALL Study Group studies 06/99 (n = 8) and 07/2003 (n = 89) were analyzed. All patients received TKI and aSCT in first complete remission (CR1). Copy number analysis was performed with single nucleotide polymorphism arrays and validated by multiplex ligation-dependent probe amplification. The frequencies of recurrently deleted genes were: IKZF1, 76%; CDKN2A/2B, 45%; PAX5, 43%; BTG1, 18%; EBF1, 13%; ETV6, 5%; RB, 14%. In univariate analyses, the presence of CDKN2A/2B deletions had a negative impact on all endpoints: overall survival ( P = .023), disease-free survival ( P = .012), and remission duration ( P = .036). The negative predictive value of CDKN2A/2B deletions was retained in multivariable analysis along with other factors such as timing of TKI therapy, intensity of conditioning, achieving remission after induction phase 1 and BTG1 deletions. We therefore conclude that acquired genomic CDKN2A/2B deletions identify a subgroup of Ph + ALL patients, who have an inferior prognosis despite aSCT in CR1. Their poor outcome was attributable primarily to a high relapse rate after aSCT., (© 2018 by The American Society of Hematology.)

Clonal evolution is believed to be a main driver for progression of various types of cancer and implicated in facilitating resistance to drugs. However, the hierarchical organization of malignant clones in the hematopoiesis of myelodysplastic syndromes (MDS) and its impact on response to drug therapy remain poorly understood. Using high-throughput sequencing of patient and xenografted cells, we evaluated the intratumoral heterogeneity (n= 54) and reconstructed mutational trajectories (n = 39) in patients suffering from MDS (n = 52) and chronic myelomonocytic leukemia-1 (n = 2). We identified linear and also branching evolution paths and confirmed on a patient-specific level that somatic mutations in epigenetic regulators and RNA splicing genes frequently constitute isolated disease-initiating events. Using high-throughput exome- and/or deep-sequencing, we analyzed 103 chronologically acquired samples from 22 patients covering a cumulative observation time of 75 years MDS disease progression. Our data revealed highly dynamic shaping of complex oligoclonal architectures, specifically upon treatment with lenalidomide and other drugs. Despite initial clinical response to treatment, patients' marrow persistently remained clonal with rapid outgrowth of founder-, sub-, or even fully independent clones, indicating an increased dynamic rate of clonal turnover. The emergence and disappearance of specific clones frequently correlated with changes of clinical parameters, highlighting their distinct and far-reaching functional properties. Intriguingly, increasingly complex mutational trajectories are frequently accompanied by clinical progression during the course of disease. These data substantiate a need for regular broad molecular monitoring to guide clinical treatment decisions in MDS., (© 2016 by The American Society of Hematology.)

Objective: To compare the behavior of macrosomic newborns who were vaginally delivered of healthy mothers without diabetes with that of non-macrosomic, appropriate-for-gestational-age (AGA) newborns., Design/setting: Newborns were recruited conveniently from a tertiary hospital. Newborns were examined at 12-24 and 36-48 hours of age, using the Brazelton Neonatal Behavioral Assessment Scale (NBAS)., Participants: Thirty macrosomic newborns who were delivered vaginally were matched with AGA newborns for ethnicity, maternal education, parity, and obstetric medications., Main Outcome Measures: Dimensions scores derived from the individual NBAS items measured reflex functioning, response decrement, orientation, motor processes, range of state, autonomic stability, and regulation of state., Results: Macrosomic newborns performed weaker than AGA newborns on the reflex and motor dimensions. Both groups displayed improved motor scores on Day 2, but regulation of state scores were weaker. For orientation, AGA newborns scored higher on Day 1, and macrosomic newborns scored higher on Day 2., Conclusions: Increased head, limb, and body mass of macrosomic newborns, compared with adjacent and overall muscle strength, might have interfered with the execution of coordinated movements. Nurses can inform mothers of changes they can expect in their newborns' behavior.