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The outcome for children with cancer has improved significantly over the past 60 years, with greater than 80% of patients today becoming 5-year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States, and significant short-term and long-term treatment toxicities continue to impact the majority of children with cancer. The development of targeted new agents offers the prospect of potentially more effective and less toxic treatment for children. More than a decade since imatinib mesylate was introduced into the treatment of children with Philadelphia chromosome-positive acute lymphoblastic leukemia, transforming its outcome, a range of targeted agents has undergone study in pediatric cancer patients. Early lessons learned from these studies include a better understanding of the adverse event profile of these drugs in children, the challenge of developing pediatric-specific formulations, and the continued reliance on successful development for adult cancer indications on pediatric drug development. The collaborative research infrastructure for children with cancer in the United States is well positioned to advance novel treatments into clinical investigations for a spectrum of rare and ultra-rare childhood cancers. A greater investment of resources in target discovery and validation can help drive much needed development of new, more effective treatments for children with cancer.

The addition of rituximab to standard combination chemotherapy in children with high-grade (mainly Burkitt’s) lymphoma improved 3-year event-free survival (94% vs. 82%). The incidence of myelotoxic effects was somewhat higher, without a higher incidence of death from toxic effects; the incidence of hypogammaglobulinemia was higher.

This book brings together the study of two great disciplines of the Islamic world: law and philosophy. In both sunni and shiite Islam, it became the norm for scholars to acquire a high level of expertise in the legal tradition. Thus some of the greatest names in the history of Aristotelianism were trained jurists, like Averroes, or commented on the status and nature of law, like al-F♯1r♯1b♯±. While such authors sought to put law in its place relative to the philosophical disciplines, others criticized philosophy from a legal viewpoint, like al-Ghaz♯1l♯± and Ibn Taymiyya. But this collection of papers does not only explore the relative standing of law and philosophy. It also looks at how philosophers, theologians, and jurists answered philosophical questions that arise from jurisprudence itself. What is the logical structure of a well-formed legal argument? What standard of certainty needs to be attained in passing down judgments, and how is that standard reached? What are the sources of valid legal judgment and what makes these sources authoritative? May a believer be excused on grounds of ignorance? Together the contributions provide an unprecedented demonstration of the close connections between philosophy and law in Islamic society, while also highlighting the philosophical interest of texts normally studied only by legal historians.

How do we judge whether we should be willing to follow the views of experts or whether we ought to try to come to our own, independent views? This book seeks the answer in medieval philosophical thought. In this engaging study into the history of philosophy and epistemology, Peter Adamson provides an answer to a question as relevant today as it was in the medieval period: how and when should we turn to the authoritative expertise of other people in forming our own beliefs? He challenges us to reconsider our approach to this question through a constructive recovery of the intellectual and cultural traditions of the Islamic world, the Byzantine Empire, and Latin Christendom. Adamson begins by foregrounding the distinction in Islamic philosophy between taqlīd , or the uncritical acceptance of authority, and ijtihād , or judgment based on independent effort, the latter of which was particularly prized in Islamic law, theology, and philosophy during the medieval period. He then demonstrates how the Islamic tradition paves the way for the development of what he calls a \"justified taqlīd ,\" according to which one develops the skills necessary to critically and selectively follow an authority based on their reliability. The book proceeds to reconfigure our understanding of the relation between authority and independent thought in the medieval world by illuminating how women found spaces to assert their own intellectual authority, how medieval writers evaluated the authoritative status of Plato and Aristotle, and how independent reasoning was deployed to defend one Abrahamic faith against the other. This clear and eloquently written book will interest scholars in and enthusiasts of medieval philosophy, Islamic studies, Byzantine studies, and the history of thought.

Peter Adamson offers an accessible, humorous tour through a period of eight hundred years when some of the most influential of all schools of thought were formed: from the third century BC to the sixth century AD. He introduces us to Cynics and Skeptics, Epicureans and Stoics, emperors and slaves, and traces the development of Christian and Jewish philosophy and of ancient science. Chapters are devoted to such major figures as Epicurus, Lucretius, Cicero, Seneca, Plotinus, and Augustine. But in keeping with the motto of the series, the story is told 'without any gaps,' providing an in-depth look at less familiar topics that remain suitable for the general reader. For instance, there are chapters on the fascinating but relatively obscure Cyrenaic philosophical school, on pagan philosophical figures like Porphyry and Iamblichus, and extensive coverage of the Greek and Latin Christian Fathers who are at best peripheral in most surveys of ancient philosophy. A major theme of the book is in fact the competition between pagan and Christian philosophy in this period, and the Jewish tradition also appears in the shape of Philo of Alexandria. Ancient science is also considered, with chapters on ancient medicine and the interaction between philosophy and astronomy. Considerable attention is paid also to the wider historical context, for instance by looking at the ascetic movement in Christianity and how it drew on ideas from Hellenic philosophy. From the counter-cultural witticisms of Diogenes the Cynic to the subtle skepticism of Sextus Empiricus, from the irreverent atheism of the Epicureans to the ambitious metaphysical speculation of Neoplatonism, from the ethical teachings of Marcus Aurelius to the political philosophy of Augustine, the book gathers together all aspects of later ancient thought in an accessible and entertaining way.

Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma. In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2 per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials.gov, NCT00939770. 79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10·1 years (range 1·1–21·4); 43 patients were included in the dose escalation phase (A1), 25 patients in part A2, and 11 patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m2 twice daily. Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1–6). Objective tumour responses were documented in 14 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC). The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted. Pfizer and National Cancer Institute grant to the Children's Oncology Group.

Peter Adamson introduces the most important philosopher of the Islamic world, Ibn Sina. After describing the historical context in which he lived, what we know of the man, and his surviving works, Adamson discusses the different areas of Ibn Sina's thought.

In this randomized trial of three common treatments for childhood absence epilepsy, ethosuximide and valproic acid were more effective than lamotrigine, and adverse effects on attention were less frequent with ethosuximide than with valproic acid. These findings suggest that ethosuximide has the best efficacy and safety profile. The findings of this randomized trial of three common treatments for childhood absence epilepsy suggest that ethosuximide has the best efficacy and safety profile. Childhood absence epilepsy accounts for 10 to 17% of all cases of childhood-onset epilepsy, making it the most common form of pediatric epilepsy. 1 , 2 The syndrome is characterized by daily frequent but brief staring spells, typically beginning at 4 to 8 years of age, in an otherwise apparently healthy child. 3 The classic electroencephalogram (EEG) shows generalized spike-wave bursts (of 3 Hz) with normal background activity. 3 , 4 Often misperceived as a benign form of epilepsy, childhood absence epilepsy is associated with variable remission rates; affected children have cognitive deficits and long-term psychosocial difficulties. 5 – 7 Three medications are commonly used as initial . . .