A Tri-Institutional Approach to Address Disparities in Children's Oncology Group Clinical Trial Accrual for Adolescents and Young Adults and Underrepresented Minorities.

Purpose: Enrollment in Children's Oncology Group (COG) clinical trials has led to significant improvements in survival; however, disparities in survival persist, particularly among ethnic minorities, adolescents and young adults (AYAs), and the underinsured, partly due to inadequate access to cooperative group cancer clinical trials. In 2008, two COG sites University of Illinois at Chicago (UIC) and Rush University Medical Center, and a nonmember institution, John H Stroger Hospital, created a unified COG program utilizing one lead Institutional Review Board and research team. This study assesses the impact that the tri-institutional COG program had on clinical trial accrual for minority, AYA, and uninsured patients. Methods: Analysis and comparison of COG enrollment data from 2002 to 2008 (pre-merger) and 2008 to 2017 (post-merger) by age, ethnicity, insurance type, clinical trial type, oncologic diagnosis, and specialty of the enrolling physician were completed. Results: Following the merger, the total studies open to enrollment increased by 100%, enrollments increased by 446%, and, for each diagnoses, increased by more than 200%. Enrollment of ethnic minorities rose by 533%, most significantly for Hispanic patients by 925%. AYA enrollments increased by 822%. There was a 28-fold increase in enrollment of uninsured patients. Significantly more providers from various oncology specialties were engaged in enrolling patients and a consistent increase in the percentile standing of the program occurred after the merger. Conclusions: Creation of a tri-institutional COG research program was associated with significant increases in clinical trial enrollments, especially for underrepresented minorities, AYAs, and uninsured patients. The UIC/Rush/Stroger COG Program provides a novel and exemplary approach to address cancer health disparities for these vulnerable populations.

A Rare Case of Spontaneous Remission of Terminal Deoxynucleotidyl Transferase Negative B-acute Lymphoblastic Leukemia.

Spontaneous remission of untreated pediatric leukemia is an extremely rare occurrence. The underlying mechanism may be because of an immune-mediated process or increased cortisol production during stress or infection. We describe a rare case of terminal deoxynucleotidyl transferase negative B-acute lymphoblastic leukemia with concurrent infection that went into remission without treatment with chemotherapy or corticosteroids. Though B-acute lymphoblastic leukemia can rarely go into spontaneous remission, these patients require close follow-up as most patients will eventually develop recurrence.

Methotrexate-Induced Neurotoxicity in Hispanic Adolescents with High-Risk Acute Leukemia-A Case Series.

Intrathecal methotrexate (IT MTX) and high-dose intravenous methotrexate (HD MTX) are important components of treatment in high-risk acute leukemia. We describe five Hispanic adolescents with high-risk acute leukemia at our institution who experienced MTX-induced neurotoxicity. All patients were eventually rechallenged with MTX. Two of the five patients had a second episode of neurotoxicity, but all patients recovered. Further studies should be performed to determine whether Hispanic patients are more susceptible to MTX neurotoxicity.

Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110α inhibition.

The PIM family of proteins encodes serine/threonine kinases with important roles in protein synthesis and cancer cell metabolism. In glioblastoma (GBM) cell lines, siRNA-mediated knockdown of PIM kinases or pharmacological inhibition of PIM kinases by SGI-1776 or AZD-1208 results in reduced phosphorylation of classic PIM effectors and also elements of the PI3K/mTOR pathway, suggesting interplay between PIM and mTOR signals in GBM cells. Combination of PIM kinase inhibitors with BYL-719, an inhibitor specific for the PI3K catalytic isoform p110α, results in enhanced antineoplastic effects in GBM cells. Additionally, pharmacologic inhibition of PIM kinases impairs growth of patient-derived glioma sphere cells, suggesting an important role for PIM kinases in cancer stem cell (CSC) function and survival. Such effects are further enhanced by concomitant inhibition of PIM kinase and p110α activities. Altogether these findings suggest that pharmacological PIM targeting in combination with PI3K inhibition may provide a unique therapeutic approach for the treatment of heterogeneous tumors containing populations of therapy-resistant CSCs in GBM.

A simple, low-cost staining method for rapid-throughput analysis of tumor spheroids.

Tumor spheroids are becoming an important tool for the investigation of cancer stem cell (CSC) function in tumors; thus, low-cost and high-throughput methods for drug screening of tumor spheroids are needed. Using neurospheres as non-adherent three-dimensional (3-D) cultures, we developed a simple, low-cost acridine orange (AO)-based method that allows for rapid analysis of live neurospheres by fluorescence microscopy in a 96-well format. This assay measures the cross-section area of a spheroid, which corresponds to cell viability. Our novel method allows rapid screening of a panel of anti-proliferative drugs to assess inhibitory effects on the growth of cancer stem cells in 3-D cultures.

Rechallenging With Intrathecal Methotrexate After Developing Subacute Neurotoxicity in Children With Hematologic Malignancies.

Methotrexate is associated with neurologic side effects. It is recommended that patients who developed neurotoxicity be rechallenged with methotrexate, but little is known about the safety of this approach. We performed a chart review to identify patients who received high-dose or intrathecal (IT) methotrexate. Twenty-one of 298 patients (7%) experienced neurologic symptoms attributed to methotrexate treatment in the premaintenance phase. Seventeen of these patients were rechallenged with IT methotrexate and 13 (76%) had no further neurotoxic events. No patients rechallenged during maintenance (n = 9) experienced recurrence of neurotoxic events. It is safe to rechallenge with IT methotrexate in maintenance.

Regulatory effects of a Mnk2-eIF4E feedback loop during mTORC1 targeting of human medulloblastoma cells.

The mTOR pathway controls mRNA translation of mitogenic proteins and is a central regulator of metabolism in malignant cells. Development of malignant cell resistance is a limiting factor to the effects of mTOR inhibitors, but the mechanisms accounting for such resistance are not well understood. We provide evidence that mTORC1 inhibition by rapamycin results in engagement of a negative feedback regulatory loop in malignant medulloblastoma cells, involving phosphorylation of the eukaryotic translation-initiation factor eIF4E. This eIF4E phosphorylation is Mnk2- mediated, but Mnk1-independent, and acts as a survival mechanism for medulloblastoma cells. Pharmacological targeting of Mnk1/2 or siRNA-mediated knockdown of Mnk2 sensitizes medulloblastoma cells to mTOR inhibition and promotes suppression of malignant cell proliferation and anchorage-independent growth. Altogether, these findings provide evidence for the existence of a Mnk2-controlled feedback loop in medulloblastoma cells that accounts for resistance to mTOR inhibitors, and raise the potential for combination treatments of mTOR and Mnk inhibitors for the treatment of medulloblastoma.