M. Monica Gramatges

Germline mutations in shelterin complex genes are associated with familial glioma

Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.

The Adolescent and Young Adult with Cancer: State of the Art-- Acute Leukemias

Despite survival gains over the past several decades, adolescent and young adult (AYA) patients with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) demonstrate a consistent survival disadvantage. The AYA population exhibits unique disease and host characteristics, and further study is needed to improve their outcomes. This review will highlight distinctive aspects of disease biology in this population, as well as salient treatment-related toxicities including osteonecrosis, pancreatitis, thromboembolism, hyperglycemia, and infections. The impact of obesity and differences in drug metabolism and chemotherapy resistance will also be discussed, as well as optimal treatment considerations for the AYA population.

Absolute lymphocyte counts refine minimal residual disease-based risk stratification in childhood acute lymphoblastic leukemia

Several studies have demonstrated the prognostic utility of absolute lymphocyte count (ALC) during therapy for a range of malignancies, with low ALC associated with adverse outcome. Here we investigated whether ALC retained independent prognostic significance with respect to minimal residual disease (MRD) status in children with acute lymphoblastic leukemia (ALL).

Reply to "peripheral blood lymphocyte recovery and overall survival in pediatric acute lymphoblastic leukemia"

To the Editor: Hatzipantelis et al. report on the prognostic impact of absolute lymphocyte count (ALC) recovery at day þ29 after induction chemotherapy in a retrospective study of 117 children treated with the BFM/ALLIC 2009 chemotherapy protocol at their institution in Greece. They found that a cut-off value of ALC 350 cells/ml was associated with a significantly more favorable prognosis (5-year OS 92.3% vs. 69.2%, HR 2.2, P1⁄4 0.05), providing further evidence of the association between high ALC and improved outcome that has been previously demonstrated in pediatric ALL, as well as numerous other adult and pediatric malignancies. In assessing their review of the literature on the prognostic significance of ALC (Table I), it is important to consider that the exact numeric ALC cutoff that is most predictive of prognosis would be expected to differ depending on the induction treatment regimen. Moreover, the optimal time point at which to assess ALC recovery will differ depending on the intensity of the induction regimen and hence the kinetics of marrow recovery. The specifics of the induction regimen in the study by Hatzipantelis et al. are not referenced in their communication, but differences from the regimens used in our prior studies likely account for the differences they observed in both the ALC cutoff (350 vs. 1,500 cells/ml [1]) and the time point (induction day 29 vs. day 15 [2]) that were predictive of outcome. Similarly, treatment differences likely account for the lack of independent prognostic significance of ALC in recent reports by Alkayed et al. [3] and Rubnitz et al. [4]. The modified St. Jude induction regimen used in Ref. [3] included seven drugs, with ALC assessment at day 36. The St. Jude Total XV induction regimen used in Ref. [4] included eight drugs, with modification (three extra doses of L-asparaginase) during induction based on early bone marrow response at day 19. While the prognostic significance of specific ALC numeric cutoffs and measurement time points may differ somewhat across studies, we and others believe that the bulk of evidence in ALL and other malignancies affirms that early ALC recovery is a useful and independent marker of favorable prognosis [2,5–7]. It appears that timing and cutoffs for lymphocyte counts will need to be defined for different treatment regimens and different patient populations. To this end, the Children’s OncologyGroup is prospectively evaluating ALC at day 29 of a four-drug induction on the current high risk ALL study AALL1131. In addition to its potential role in the context of MRD-based risk stratification, we also note that ALC has particular potential as a clinical tool contributing to risk stratification in developing countries. Many of these countries use a standard threeor four-drug induction regimen such as those studied in our prior report [1], and do not have access to MRD analysis to guide risk stratification. Use of ALC as a proxy for MRD assessment (when MRD is not available) may improve ALL outcomes in developing countries by identifying those patients who would benefit from a more intensive treatment regimen.

An overview of disparities in childhood cancer: Report on the Inaugural Symposium on Childhood Cancer Health Disparities, Houston, Texas, 2016

ABSTRACT The Inaugural Symposium on Childhood Cancer Health Disparities was held in Houston, Texas, on November 2, 2016. The symposium was attended by 109 scientists and clinicians from diverse disciplinary backgrounds with interests in pediatric cancer disparities and focused on reviewing our current knowledge of disparities in cancer risk and outcomes for select childhood cancers. Following a full day of topical sessions, everyone participated in a brainstorming session to develop a working strategy for the continued expansion of research in this area. This meeting was designed to serve as a springboard for examination of childhood cancer disparities from a more unified and systematic approach and to enhance awareness of this area of need.

Inherited and Acquired Myeloid Neoplasms of Childhood

Acute myeloid leukemias (AML), myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and myelodysplastic syndromes (MDS) account for approximately 20–25% of neoplastic hematologic diagnoses in pediatric populations. The 2016 revision of the World Health Organization (WHO) classification now contains a section dedicated to myeloid neoplasms with germline predisposition, which includes cases of MDS, MDS/MPN, MPN, and acute leukemias that occur in the setting of a predisposing inherited genetic alteration. Although rare, pediatric myeloid neoplasms encompass a unique diagnostic and therapeutic spectrum due to their tendency to associate with underlying inherited genetic alterations. This chapter will discuss myeloid neoplasms that present in childhood, and highlight pertinent clinical, laboratory, and molecular findings, as well as components of the diagnostic work-up and clinical management. Particular emphasis will be placed on the molecular alterations that characterize inherited MPN, MDS, MDS/MPN, and AML, and their relevance to the pediatric patient and family, pathologists, and clinicians.