Cassie Kline

Bio: Cassie Kline is an academic researcher from Children's Hospital of Philadelphia. The author has contributed to research in topics: Cancer & Precision medicine. The author has an hindex of 4, co-authored 9 publications receiving 89 citations. Previous affiliations of Cassie Kline include University of California, San Francisco & Boston Children's Hospital.

Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy

Abstract: Purpose: Pediatric diffuse midline glioma (DMG) are highly malignant tumors with poor clinical outcomes. Over 70% of patients with DMG harbor the histone 3 p.K27M (H3K27M) mutation, which correlates with a poorer clinical outcome, and is also used as a criterion for enrollment in clinical trials. Because complete surgical resection of DMG is not an option, biopsy at presentation is feasible, but rebiopsy at time of progression is rare. While imaging and clinical-based disease monitoring is the standard of care, molecular-based longitudinal characterization of these tumors is almost nonexistent. To overcome these hurdles, we examined whether liquid biopsy allows measurement of disease response to precision therapy. Experimental Design: We established a sensitive and specific methodology that detects major driver mutations associated with pediatric DMGs using droplet digital PCR (n = 48 subjects, n = 110 specimens). Quantification of circulating tumor DNA (ctDNA) for H3K27M was used for longitudinal assessment of disease response compared with centrally reviewed MRI data. Results: H3K27M was identified in cerebrospinal fluid (CSF) and plasma in 88% of patients with DMG, with CSF being the most enriched for ctDNA. We demonstrated the feasibility of multiplexing for detection of H3K27M, and additional driver mutations in patient9s tumor and matched CSF, maximizing the utility of a single source of liquid biome. A significant decrease in H3K27M plasma ctDNA agreed with MRI assessment of tumor response to radiotherapy in 83% (10/12) of patients. Conclusions: Our liquid biopsy approach provides a molecularly based tool for tumor characterization, and is the first to indicate clinical utility of ctDNA for longitudinal surveillance of DMGs. Clin Cancer Res; 1–10. ©2018 AACR.

Effects of a unique pediatric hematology–oncology palliative care program on medical decision-making and communication between healthcare providers and families: Results of a supportive care survey

Abstract: PurposeThe purpose of this study was to evaluate family satisfaction with an embedded pediatric hematology–oncology (Hem-Onc) palliative care program and its decision-making tool (DMT). A secondary aim was to identify factors that play an important role in family medical decision-making.MethodsFamilies were asked to complete a self-administered questionnaire within 4 weeks of participating in a Supportive Care Team (SCT) conference and receiving a DMT.ResultsTwenty parents or guardians of pediatric Hem-Onc patients participated in the study. All of the patients had approached a major treatment-related change; all of the study participants had attended a SCT medical decision-making conference and received a DMT. The most important considerations to the study participants regarding treatment decisions were their child's quality of life, their child's chance of improving, perception of their child's wishes, and the hospital staff's advice. Of the people and services that were most useful in guiding m...

Advances in Targeted Therapies for Pediatric Brain Tumors

Abstract: Over the last years, our understanding of the molecular biology of pediatric brain tumors has vastly improved. This has led to more narrowly defined subgroups of these tumors and has created new potential targets for molecularly driven therapies. This review presents an overview of the latest advances and challenges of implementing targeted therapies into the clinical management of pediatric brain tumors, with a focus on gliomas, craniopharyngiomas, and medulloblastomas. Pediatric low-grade gliomas (pLGG) show generally a low mutational burden with the mitogen-activated protein kinase (MAPK) signaling presenting a key driver for these tumors. Direct inhibition of this pathway through BRAF and/or MEK inhibitors has proven to be a clinically relevant strategy. More recently, MEK and IL-6 receptor inhibitors have started to be evaluated in the treatment for craniopharyngiomas. Aside these low-grade tumors, pediatric high-grade gliomas (pHGG) and medulloblastomas exhibit substantially greater molecular heterogeneity with various and sometimes unknown tumor driver alterations. The clinical benefit of different targeted therapy approaches to interfere with altered signaling pathways and restore epigenetic dysregulation is undergoing active clinical testing. For these multiple pathway-driven tumors, combination strategies will most likely be required to achieve clinical benefit. The field of pediatric neuro-oncology made tremendous progress with regard to improved diagnosis setting the stage for precision medicine approaches over the last decades. The potential of targeted therapies has been clearly demonstrated for a subset of pediatric brain tumors. However, despite clear response rates, questions of sufficient blood-brain barrier penetration, optimal dosing, treatment duration as well as mechanisms of resistance and how these can be overcome with potential combination strategies need to be addressed in future investigations. Along this line, it is critical for future trials to define appropriate endpoints to assess therapy responses as well as short and long-term toxicities in the growing and developing child.

Radiation in Combination With Targeted Agents and Immunotherapies for Pediatric Central Nervous System Tumors - Progress, Opportunities, and Challenges.

Abstract: Pediatric brain tumors are the most common solid tumors in children and represent a heterogenous group of diagnoses. While some are treatable with current standard of care, relapsed/refractory disease is common and some high-risk diagnoses remain incurable. A growing number of therapy options are under development for treatment of CNS tumors, including targeted therapies that disrupt key tumor promoting processes and immunotherapies that promote anti-tumor immune function. While these therapies hold promise, it is likely that single agent treatments will not be sufficient for most high-risk patients and combination strategies will be necessary. Given the central role for radiotherapy for many pediatric CNS tumors, we review current strategies that combine radiation with targeted therapies or immunotherapies. To promote the ongoing development of rational combination treatments, we highlight 1) mechanistic connections between molecular drivers of tumorigenesis and radiation response, 2) ways in which molecular alterations in tumor cells shape the immune microenvironment, and 3) how radiotherapy affects the host immune system. In addition to discussing strategies to maximize efficacy, we review principles that inform safety of combination therapies.

Harmonization of postmortem donations for pediatric brain tumors and molecular characterization of diffuse midline gliomas

Abstract: Children diagnosed with brain tumors have the lowest overall survival of all pediatric cancers. Recent molecular studies have resulted in the discovery of recurrent driver mutations in many pediatric brain tumors. However, despite these molecular advances, the clinical outcomes of high grade tumors, including H3K27M diffuse midline glioma (H3K27M DMG), remain poor. To address the paucity of tissue for biological studies, we have established a comprehensive protocol for the coordination and processing of donated specimens at postmortem. Since 2010, 60 postmortem pediatric brain tumor donations from 26 institutions were coordinated and collected. Patient derived xenograft models and cell cultures were successfully created (76% and 44% of attempts respectively), irrespective of postmortem processing time. Histological analysis of mid-sagittal whole brain sections revealed evidence of treatment response, immune cell infiltration and the migratory path of infiltrating H3K27M DMG cells into other midline structures and cerebral lobes. Sequencing of primary and disseminated tumors confirmed the presence of oncogenic driver mutations and their obligate partners. Our findings highlight the importance of postmortem tissue donations as an invaluable resource to accelerate research, potentially leading to improved outcomes for children with aggressive brain tumors.

The somatic genomic landscape of glioblastoma

Abstract: We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

Barriers and facilitators of pediatric shared decision-making: a systematic review

Abstract: Shared decision-making (SDM) is rarely implemented in pediatric practice. Pediatric health decision-making differs from that of adult practice. Yet, little is known about the factors that influence the implementation of pediatric shared decision-making (SDM). We synthesized pediatric SDM barriers and facilitators from the perspectives of healthcare providers (HCP), parents, children, and observers (i.e., persons who evaluated the SDM process, but were not directly involved). We conducted a systematic review guided by the Ottawa Model of Research Use (OMRU). We searched MEDLINE, EMBASE, Cochrane Library, CINAHL, PubMed, and PsycINFO (inception to March 2017) and included studies that reported clinical pediatric SDM barriers and/or facilitators from the perspective of HCPs, parents, children, and/or observers. We considered all or no comparison groups and included all study designs reporting original data. Content analysis was used to synthesize barriers and facilitators and categorized them according to the OMRU levels (i.e., decision, innovation, adopters, relational, and environment) and participant types (i.e., HCP, parents, children, and observers). We used the Mixed Methods Appraisal Tool to appraise study quality. Of 20,008 identified citations, 79 were included. At each OMRU level, the most frequent barriers were features of the options (decision), poor quality information (innovation), parent/child emotional state (adopter), power relations (relational), and insufficient time (environment). The most frequent facilitators were low stake decisions (decision), good quality information (innovation), agreement with SDM (adopter), trust and respect (relational), and SDM tools/resources (environment). Across participant types, the most frequent barriers were insufficient time (HCPs), features of the options (parents), power imbalances (children), and HCP skill for SDM (observers). The most frequent facilitators were good quality information (HCP) and agreement with SDM (parents and children). There was no consistent facilitator category for observers. Overall, study quality was moderate with quantitative studies having the highest ratings and mixed-method studies having the lowest ratings. Numerous diverse and interrelated factors influence SDM use in pediatric clinical practice. Our findings can be used to identify potential pediatric SDM barriers and facilitators, guide context-specific barrier and facilitator assessments, and inform interventions for implementing SDM in pediatric practice. PROSPERO CRD42015020527

Response assessment in paediatric low-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group

Abstract: Response criteria for paediatric high-grade glioma vary historically and across different cooperative groups. The Response Assessment in Neuro-Oncology working group developed response criteria for adult high-grade glioma, but these were not created to meet the unique challenges in children with the disease. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric high-grade glioma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric high-grade gliomas to various treatments. For areas in which scientific investigation was scarce, consensus was reached through an iterative process. RAPNO response assessment recommendations include the use of MRI of the brain and the spine, assessment of clinical status, and the use of corticosteroids or antiangiogenics. Imaging standards for brain and spine are defined. Compared with the recommendations for the management of adult high-grade glioma, for paediatrics there is inclusion of diffusion-weighted imaging and a higher reliance on T2-weighted fluid-attenuated inversion recovery. Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted.

A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: A report from the Pacific Pediatric Neuro-Oncology Consortium.

Abstract: This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA-certified laboratory. Patient-derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA-approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES-based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe.