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Langerhans cell histiocytosis (LCH) remains a poorly understood disorder with heterogeneous clinical presentations characterized by focal or disseminated lesions that contain excessive CD1a+ langerin+ cells with dendritic cell features known as "LCH cells." Two of the major questions investigated over the past century have been (i) the origin of LCH cells and (ii) whether LCH is primarily an immune dysregulatory disorder or a neoplasm. Current opinion is that LCH cells are likely to arise from hematopoietic precursor cells, although the stage of derailment and site of transformation remain unclear and may vary in patients with different extent of disease. Over the years, evidence has provided the view that LCH is a neoplasm. The demonstration of clonality of LCH cells, insufficient evidence alone for neoplasia, is now bolstered by finding driver somatic mutations in BRAF in up to 55% of patients with LCH, and activation of the RAS-RAF-MEK-ERK (where MEK and ERK are mitogen-activated protein kinase and extracellular signal-regulated kinase, respectively) pathway in nearly 100% of patients with LCH. Herein, we review the evidence that recurrent genetic abnormalities characterized by activating oncogenic mutations should satisfy prerequisites for LCH to be called a neoplasm. As a consequence, recurrent episodes of LCH should be considered relapsed disease rather than disease reactivation. Mapping the complete genetic landscape of this intriguing disease will provide additional support for the conclusion that LCH is a neoplasm and is likely to provide more potential opportunities for molecularly targeted therapies., (© 2016 Wiley Periodicals, Inc.)

Purpose: Academic laboratories are developing increasingly large amounts of data that describe the genomic landscape and gene expression patterns of various types of cancers. Such data can potentially identify novel oncology molecular targets in cancer types that may not be the primary focus of a drug sponsor's initial research for an investigational new drug. Obtaining preclinical data that point toward the potential for a given molecularly targeted agent, or a novel combination of agents requires knowledge of drugs currently in development in both the academic and commercial sectors., Methods: We have developed the DrugPath database ( http://www.drugpath.org ) as a comprehensive, free-of-charge resource for academic investigators to identify agents being developed in academics or industry that may act against molecular targets of interest. DrugPath data on molecular targets overlay the Michigan Molecular Interactions ( http://mimi.ncibi.org ) gene-gene interaction map to facilitate identification of related agents in the same pathway., Results: The database catalogs 2,081 drug development programs representing 751 drug sponsors and 722 molecular and genetic targets., Conclusions: DrugPath should assist investigators in identifying and obtaining drugs acting on specific molecular targets for biological and preclinical therapeutic studies.

Background: Platinum agents have been used for a variety of cancers, including pivotal use in pediatric tumors for many years. Oxaliplatin, a third generation platinum, has a different side effect profile and may provide improved activity in pediatric cancers., Procedure: Patients 21 years or younger with progressive or refractory malignant solid tumors, including tumors of the central nervous system were enrolled on this multi-center open label, non-randomized Phase 1 dose escalation study. The study used a standard 3 + 3 dose escalation design with 2 dose levels (85 and 100 mg/m(2) ) with an expansion cohort of 15 additional patients at the recommended dose. Patients received oxaliplatin at the assigned dose level and 5-fluorouracil (5-FU) bolus 400 mg/m(2) followed by a 46-hour 5-FU infusion of 2,400 mg/m(2) every 14 days. The leucovorin dose was fixed at 400 mg/m(2) for all cohorts., Results: Thirty-one evaluable patients were enrolled, 8 at 85 mg/m(2) and 23 at 100 mg/m(2) for a total of 121 courses. The median age was 12 years (range 2-19 years). The main toxicities were hematologic, primarily neutrophils and platelets. The most common non-hematologic toxicities were gastrointestinal. Stable disease was noted in 11 patients (54% of evaluable patients) and 1 confirmed partial response in a patient with osteosarcoma., Conclusions: The maximum planned dose of oxaliplatin at 100 mg/m(2) per dose in combination with 5-FU and leucovorin was safe and well tolerated and in this patient population. This combination demonstrated modest activity in patients with refractory or relapsed solid tumor and warrants further study. Pediatr Blood Cancer 2013;60:230-236. © 2012 Wiley Periodicals, Inc., (Copyright © 2012 Wiley Periodicals, Inc.)

Introduction: There is a lack of high-quality data regarding optimal chemotherapy dosage regimens among infants. Dosing regimens for chemotherapy during the first year of life are commonly based on empiric recommendations extrapolated from older children; however, balancing efficacy and toxicity is critical as severe adverse drug reactions may lead to treatment failure or reduced adherence to needed medications., Areas Covered: This review describes pharmacokinetic and pharmacogenetic considerations when administering chemotherapeutic agents to infants. Examples of commonly used agents are provided with practical recommendations for dosing adjustments., Expert Opinion: Optimal chemotherapy for children and infants in particular has lagged behind the remarkable progress in cancer treatment and it is clear that far more basic and clinical research are needed with respect to the mechanistic basis of age-dependent differences in pharmacokinetic parameters. More recent studies which have combined pharmacokinetic data with clinical toxicity and outcome data have resulted in a number of more evidence-based guidelines at least for the initial chemotherapy dosing; however, at present, the dosing of chemotherapy drugs in neonates and infants remains largely empiric.

Purpose: To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors., Patients and Methods: This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m(2)) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m(2)/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected., Results: Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m(2) weekly plus irinotecan 16 mg/m(2)/d (pediatric) or 20 mg/m(2)/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%)., Conclusion: The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.

Purpose: Heat shock protein 90 (Hsp90) is essential for the posttranslational control of many regulators of cell growth, differentiation, and apoptosis. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) binds to Hsp90 and alters levels of proteins regulated by Hsp90. We conducted a phase I trial of 17-AAG in pediatric patients with recurrent or refractory neuroblastoma, Ewing's sarcoma, osteosarcoma, and desmoplastic small round cell tumor to determine the maximum tolerated dose, define toxicity and pharmacokinetic profiles, and generate data about molecular target modulation., Experimental Design: Escalating doses of 17-AAG were administered i.v. over 1 to 2 h twice weekly for 2 weeks every 21 days until patients experienced disease progression or toxicity. harmacokinetic and pharmacodynamic studies were done during cycle 1., Results: Fifteen patients were enrolled onto dose levels between 150 and 360 mg/m(2); 13 patients were evaluable for toxicity. The maximum tolerated dose was 270 mg/m(2). DLTs were grade 3 transaminitis and hypoxia. Two patients with osteosarcoma and bulky pulmonary metastases died during cycle 1 and were not evaluable for toxicity. No objective responses were observed. 17-AAG pharmacokinetics in pediatric patients were linear; clearance and half-life were 21.6 +/- 6.21 (mean +/- SD) L/h/m(2) and 2.6 +/- 0.95 h, respectively. Posttherapy increases in levels of the inducible isoform of Hsp70, a marker of target modulation, were detected in peripheral blood mononuclear cells at all dose levels., Conclusion: 17-AAG was well tolerated at a dose of 270 mg/m(2) administered twice weekly for 2 of 3 weeks. Caution should be used in treatment of patients with bulky pulmonary disease.

There is reason to believe that the unfolding revolution in molecular biology and translational research will allow selective targeting of tumor cells, and radically change the way general practitioners and pediatric oncologists treat and follow children with cancer. This article highlights some of the most promising approaches being tested in the field. By learning about the underlying biology, the remaining hurdles, the projected timeline, and the possible impact of new therapies on the practice of pediatric oncology, health care professionals and patients should be better prepared for the future of pediatric oncology.

The primary reason for the failure to cure patients with cancer remains the development of multiple mechanisms of resistance to cytotoxic agents. The two major effectors of tumor cell killing include genotoxic agents and cell-mediated immunity. Genotoxic agents function primarily by initiating pathways leading to apoptosis or programmed cell death, whereas immune-mediate cytotoxicity utilizes both programmed cell death-promoting as well as cytolytic processes. The mechanisms leading to treatment resistance initially involve alterations in the way tumor cells transport, metabolize, and provide substrates for cytotoxic agents. Beyond these specific mechanisms, tumor cells may also express alterations in the regulators and effectors of apoptotic death, thus creating a more generalized resistance pattern. Through a variety of other mechanisms, tumor cells may also decrease specific antigen expression or the ability to costimulate T lymphocytes. The result of antigen recognition in the absence of costimulation can lead to antigen-specific tolerance, which may also represent a major form of escape from immune-mediated killing. The elucidation of these mechanisms of resistance to therapy and tumor cell survival should form the basis for the development of more effective therapies.

The failure to cure patients with cancer continues to be primarily because of the development of treatment resistance. Both normal and malignant cells die by either programmed cell death (apoptosis) or by cytolysis. Malignant cells have developed mechanisms of resistance that prevent them from entering the programmed cell death pathway as well as mechanisms of escaping immune recognition and cytolysis. These mechanisms include specific protective adaptations involving drug transport, metabolism, and target interactions. Malignant cells may also become resistant to therapy through alterations in genes encoding proteins involved in the initiation of apoptotic pathways. Finally, tumor cells may develop mechanisms to escape immune recognition, making them resistant to T-cell destruction. This article provides an overview of these mechanisms, with emphasis on published articles reported within the past year.