Pediatrics Commons^™

Changes In Family Functioning During The First Year Of Pediatric Cancer Treatment: A Mixed-Method Pilot Study, Carolyn Bates

Research Days

Background: A new diagnosis of pediatric cancer presents a sudden and tremendous stressor for families of all backgrounds and circumstances (Long & Marsland, 2011; Bemis et al., 2015). Although many families are resilient in the context of new cancer diagnosis, approximately 33% are at risk for negative outcomes due to psychosocial distress and difficulties with effective coping (Kazak et al., 2020; Pai et al., 2008), supporting the need for systematic assessment of psychosocial health as a standard of care in pediatric oncology (Kazak et al., 2015). Alongside heightened stress within the first year of diagnosis, parents may relax family rules …

Impact Of Covid-19 On Families With A Child In Cancer Treatment, Mirae J. Fornander

Research Days

Background: A new diagnosis of pediatric cancer diagnosis is a sudden and tremendous stressor to families (Long & Marsland, 2011). The COVID-19 pandemic presented an acute, universal stressor that impacted daily life around the world (Brooks et al., 2020). The impact of the COVID-19 pandemic on children with cancer and their families is not yet known.

Objectives/Goal: The current study is a pilot investigation of COVID-19 exposure and impact among a sample of families with a child being treated for cancer.

Methods/Design: Primary caregivers (N=22) of a child (M age=7.4, SD=4.6) who was diagnosed with cancer within the last 18 …

Survival Following Relapse In Children With Acute Myeloid Leukemia: A Report From Aml-Bfm And Cog., Mareike Rasche, Martin Zimmermann, Emma Steidel, Todd Alonzo, Richard Aplenc, Jean-Pierre Bourquin, Heidrun Boztug, Todd Cooper, A S. Gamis, Robert B. Gerbing, Iveta Janotova, Jan-Henning Klusmann, Thomas Lehrnbecher, Nora Mühlegger, Nils V. Neuhoff, Naghmeh Niktoreh, Lucie Sramkova, Jan Stary, Katharina Waack, Christiane Walter, Ursula Creutzig, Michael Dworzak, Gertjan Kaspers, Edward Anders Kolb, Dirk Reinhardt

Manuscripts, Articles, Book Chapters and Other Papers

Post-relapse therapy remains critical for survival in children with acute myeloid leukemia (AML). We evaluated survival, response and prognostic variables following relapse in independent cooperative group studies conducted by COG and the population-based AML-BFM study group. BFM included 197 patients who relapsed after closure of the last I-BFM relapse trial until 2017, while COG included 852 patients who relapsed on the last Phase 3 trials (AAML0531, AAML1031). Overall survival at 5 years (OS) was 42 ± 4% (BFM) and 35 ± 2% (COG). Initial high-risk features (BFM 32 ± 6%, COG 26 ± 4%) and short time to relapse (BFM …

Standardization Of Fertility Preservation Discussion Amongst Pediatric Oncology And Bone Marrow Transplant Patients: A Single Institution Experience, Chandni Dargan, Sarah E. Mc Dermott, Shelby Chesbro

Research Days

Background/Project Intent (Aim Statement): As treatment for pediatric malignancies improves long term survival, physicians are shifting focus to late effects of therapy such as infertility. Currently, options for fertility preservation include cryopreservation of mature oocytes, sperm, and gonadal tissue, although barriers remain present. Within our division, we lacked a standard approach to discussing fertility preservation options prior to initiation of treatment.

Methods (include PDSA cycles): Records from 474 pediatric patients with new oncologic diagnoses at CMH from 2014- 2020 were retrospectively reviewed. We evaluated the frequency that reproductive health discussions were documented in pubertal males and females requiring chemotherapy or …

Novel Mouse Model For Analysis Of Macrophage Function In Neuroblastoma, Gabrielle L. Brumfield, Shelby M. Knoche, Alaina C. Larson, Brittany Poelaert, Benjamin T. Goetz, Poomy Pandey, Don W. Coulter, Joyce C. Solheim

Child Health Research Institute Pediatric Research Forum

Background: Neuroblastoma is the third most common childhood cancer and accounts for 12% of cancer-associated deaths in children under the age of 15. Patients with high risk neuroblastoma have a poor 5-year survival rate of less than 50%. Neuroblastoma tumors treated with the histone deacetylase inhibitor (HDACi) vorinostat have increased infiltration of macrophages with upregulated immune cell-surface receptors. Neuroblastoma cells release VEGF and M-CSF, which may alter intratumoral macrophage populations. VEGF has also been implicated in alteration of amyloid precursor protein family processing. Our lab demonstrated that amyloid precursor protein 2 (APLP2), a member of the amyloid precursor protein …

Prospective Patient-Reported Symptom Profiles Associated With Pediatric Acute Lymphoblastic Leukemia Relapse, Austin L Brown, Kimberly P Raghubar, Olga A Taylor, Melanie Brooke Bernhardt, Lisa S Kahalley, Wei Pan, Philip J Lupo, Marilyn J Hockenberry, Michael E Scheurer

Faculty, Staff and Students Publications

PURPOSE: Despite improvements in frontline pediatric acute lymphoblastic leukemia (ALL) treatment, relapse remains a concern. Research in adult cancer patients suggests that patient-reported symptoms may predict survival, but the relationship between symptoms and relapse for pediatric ALL has received little attention.

METHODS: Pediatric patients with ALL (age 2-18 years) and/or their primary caregivers completed symptom surveys at the end of induction, start of delayed intensification (DI), start of maintenance cycle 1 (MC1), and start of maintenance cycle 2 (MC2). Symptom clusters for co-occurring fatigue, pain, sleep disruptions, and nausea were defined using latent profile analysis. Hazard ratios (HR) and 95% …

A Pedunculated Esophageal Chondromatous Hamartoma In A Child, Dan-Alexandru Iozsa, Maria Puscasu, Catalin Gabriel Cirstoveanu, Vlad Denis Constantin, Anca Silvia Dumitriu, Stana Paunica, Nicolae Sebastian Ionescu

Journal of Mind and Medical Sciences

Esophageal tumors are uncommon in pediatric population and most of them are benign. Esophageal hamartomas have been reported extremely rare in children. These can present as intramural tumors of the esophageal wall or as polyps. Dysphagia is the main symptom described in their case, but other specific symptoms are also reported. Such symptoms encountered in clinical practice are represented by obstructive apnea episodes and bradycardia, poor weight gain, epigastric or retrosternal pain, hematemesis or melena, dysphonia or tracheal sounds. Diagnosis can be delayed due to the insidious onset and non-specific symptoms, therefore patient’s compliance to follow-up and broad, careful evaluation …

Hemorrhagic Giant Cell Tumor Of The Occipital Skull Base: A Case Report And Literature Review, Cihan Kadipasaoglu, Andrew Wahba, Meenakshi B Bhattacharjee, Branko Cuglievan, Stephen A Fletcher

Faculty, Staff and Student Publications

Giant cell tumor of bone is a benign but locally aggressive osteolytic neoplasm that represents 3% to 5% of all primary bone tumors, primarily found at the epiphyses of long bones. Less than 1% are of calvarial origin. Herein, we report a rare case of a nine-year-old girl with a hemorrhagic giant cell tumor of the left occipital skull base.

Intramedullary Spinal Cord Lesions In Children, Ummey Hani, Sameer Saleem Tebha, Saqib Kamran Bakhshi, Muhammad Shahzad Shamim

Section of Neurosurgery

Paediatric intramedullary spinal cord lesions are uncommon pathologies, prone to result in dismal prognosis if not managed promptly and aggressively. While children usually present in good functional grades compared to adults, early recognition and treatment is important to improve outcomes. In this review, we present tumour demographics, patient factors, and treatment modalities of intramedullary spinal cord lesions in paediatric patients.

A Multidisciplinary Approach To Triage Patients With Breast Disease During The Covid-19 Pandemic: Experience From A Tertiary Care Center In The Developing World, Abida K. Sattar, Hania Shahzad, Adnan Abdul Jabbar, Azmina Tajdin Valimohammad, Sadaf Khan, Yasmin Vellani, Romana Idrees, Nasir Ali, Imrana Masroor, Humera Saeed, Gulzar S. Lakhani, Nadia Ayoub, Atif Waqar, Muhammad Zia-Ul Islam, Salman Kirmani, Asad Latif, Ather Enam

Section of General Surgery

Background: The COVID-19 pandemic has created a need to prioritize care because of limitation of resources. Owing to the heterogeneity and high prevalence of breast cancers, the need to prioritize care in this vulnerable population is essential. While various medical societies have published recommendations to manage breast disease during the COVID-19 pandemic, most are focused on the Western world and do not necessarily address the challenges of a resource-limited setting.
Aim: In this article, we describe our institutional approach for prioritizing care for patients presenting with breast disease.
Methods and results: The breast disease management guidelines were developed and approved …

Tisagenlecleucel Infusion In Patients With Relapsed/Refractory All And Concurrent Serious Infection., Erin Hall, Dwight E. Yin, Rakesh K. Goyal, Atif Ahmed, Grace S. Mitchell, Shawn D. St Peter, Terrie Flatt, Ibrahim A. Ahmed, Weijie Li, Richard J. Hendrickson, Keith August, Douglas Myers

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated durable efficacy and a manageable safety profile in pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) in the ELIANA pivotal trial and real-world experience. Experience from investigator-led studies prior to ELIANA suggests that infections and inflammatory conditions may exacerbate the severity of cytokine release syndrome (CRS) associated with CAR-T cell therapy, leading to extreme caution and strong restrictions for on-study and commercial infusion of tisagenlecleucel in patients with active infection. CRS intervention with interleukin (IL)-6 blockade and/or steroid therapy was introduced late in …

Comics For Pediatric Oncology Patients And Families: Education And Empowerment, Natalie Johns

Calvert Undergraduate Research Awards

The major objective is to develop the first book of a boxed set series of comic vignettes that will serve as a clinical educational tool for pediatric patients with a recent cancer diagnosis and their caregivers. These comics are hypothesized to improve patient and family understanding of the disease, its treatment, side effects, and outcomes in an engaging and aesthetically pleasing way. The overall goals of this project are to reduce anxiety and increase health literacy in patients and their families while assisting the oncology team in providing optimal medical care, thus improving the overall quality of treatment. Comics aimed …

Childhood Medulloblastoma, Naureen Mushtaq, Shahzadi Resham, Muhammad Shahzad Shamim, Bilal Mazhar Qureshi, Quratulain Riaz, Eric Bouffet

Section of Haematology/Oncology

Medulloblastoma is the most common malignant brain tumour in children and is a major cause of mortality and morbidity, particularly in low- and middle-income countries. It has been risk-stratified on the basis of clinical (age, metastasis and extent of resection) and histological subtypes (classic, desmoplastic and anaplastic). However, recently medulloblastoma has been sub-grouped by using a variety of different genomic approaches, such as gene expression profiling, micro-ribonucleic acid profiling and methylation array into 4 groups, namely Wingless, Sonic hedgehog, Group 3 and Group 4. This new sub-grouping has important therapeutic and prognostic implications. After acute leukaemia, brain tumour is the …

Morphologic Remission Status Is Limited Compared To Δn Flow Cytometry: A Children's Oncology Group Aaml0531 Report., Lisa Eidenschink Brodersen, Robert B. Gerbing, M Laura Pardo, Todd A. Alonzo, Dana Paine, Wayne Fritschle, Fan-Chi Hsu, Jessica A. Pollard, Richard Aplenc, Samir B. Kahwash, Betsy Hirsch, Susana Ramondi, Denise Wells, E Anders Kolb, Alan S. Gamis, Soheil Meshinchi, Michael R. Loken

Manuscripts, Articles, Book Chapters and Other Papers

Risk stratification for acute myeloid leukemia (AML) uses molecular and cytogenetic abnormalities identified at diagnosis. Response to therapy informs risk, and morphology continues to be used more frequently than flow cytometry. Herein, the largest cohort of pediatric patients prospectively assessed for measurable residual disease (MRD) by flow cytometry (N = 784) is reported. The "difference from normal" (ΔN) technique was applied: 31% of all patients tested positive (AML range, 0.02% to 91%) after the first course of treatment on Children's Oncology Group study AAML0531. Detection of MRD following initial chemotherapy proved the strongest predicator of overall survival (OS) in univariable …

Feasibility Of Treating High Grade Gliomas In Children With Tumor-Treating Fields: A Case Series., John Crawford, Marlon G Saria, Girish Dhall, Ashley Margol, Santosh Kesari

Articles, Abstracts, and Reports

Children diagnosed with high grade gliomas (HGG) have dismal prognoses and treatment options remain limited. Tumor treating fields (TTFields) in combination with temozolomide (TMZ) is approved for the treatment of newly diagnosed and recurrent glioblastoma (GBM) in adult patients. However, clinical experience with TTFields in the pediatric HGG population is lacking. This retrospective review of four clinical cases was undertaken to evaluate the feasibility of treating children diagnosed with HGG off-label with TTFields. Patients were evaluated for device compliance, safety, and outcome. Treatment with TTFields was delivered via four transducer arrays placed on the shaved scalp, which were connected to …

Intratumoral Translocation Positive Heterogeneity In Pediatric Alveolar Rhabdomyosarcoma Tumors Correlates To Patient Survival Prognosis, Katrina Gleditsch, Jorge Peñas, Danielle Mercer, Ayesha Umrigar, James Briscoe, Matthew Stark, Fern Tsien, Andrew D. Hollenbach

School of Medicine Faculty Publications

Alveolar rhabdomyosarcoma (ARMS) is characterized by one of three translocation states: t(2;13) (q35;q14) producing PAX3-FOXO1, t(1;13) (p36;q14) producing PAX7-FOXO1, or translocation-negative. Tumors with t(2;13) are associated with greater disease severity and mortality than t(1;13) positive or translocation negative patients. Consistent with this fact, previous work concluded that a molecular analysis of RMS translocation status is essential for the accurate determination of prognosis and diagnosis. However, despite this knowledge, most diagnoses rely on histology and in some cases utilize fluorescence in situ hybridization (FISH) probes unable to differentiate between translocation products. Along these same lines, diagnostic RT-PCR analysis, which can differentiate …

Cerebellar Mutism Syndrome After Surgical Resection Of Posterior Fossa Neoplastic Lesions, Saqib Kamran Bakhshi, Rida Mitha, Naureen Mushtaq, Muhammad Shahzad Shamim

Section of Neurosurgery

Cerebellar Mutism Syndrome (CMS) is a well-described clinical entity that complicates surgeries for posterior fossa tumours; more so in children than adults. This review focuses on the current understanding of CMS, its incidence and risk factors. Incidence showed a variable range in retrospective studies due to variety of definitions. Risk factors can be classified as either modifiable including surgical technique, or non-modifiable which include tumour related factors. A positive correlation has been associated between tumour pathology, brain stem invasion and size of tumour at time of presentation with development of CMS.

Investigation Of A Peculiar Case Of Childhood Lymphadenopathy, Chade Aribo, Alonso Al, Allison Woodall, Tommy Y. Kim

HCA Healthcare Journal of Medicine

Introduction: Lymphadenopathy is a common physical finding often associated with an infectious etiology. We present a case of a patient with generalized cervical and supraclavicular lymphadenopathy diagnosed with a rare malignancy. Health care providers should be aware of some uncommon historical or physical examination findings that warrant further investigation.

Clinical Findings: A 16-year-old female presented to the emergency department with 3 days of a fever, congestion and sore throat with swelling around the jaw. Her physical examination findings included bilateral mandibular swelling and generalized cervical lymphadenopathy with palpable supraclavicular lymph nodes.

Outcomes: Complete blood count showed pancytopenia with a white …

Ewing Sarcoma Family Of Tumors-Derived Small Extracellular Vesicle Proteomics Identify Potential Clinical Biomarkers., Glenson Samuel, Jennifer Crow, Jon B. Klein, Michael L. Merchant, Emily Nissen, Devin C. Koestler, Kris Laurence, Xiaobo Liang, Kathleen Neville, Vincent S. Staggs, Atif Ahmed, Safinur Atay, Andrew K. Godwin

Manuscripts, Articles, Book Chapters and Other Papers

Purpose: Ewing Sarcoma Family of Tumors (ESFT), the second most common pediatric osseous malignancy, are characterized by the pathognomonic chromosomal EWS-ETS translocation. Outside of tumor biopsy, no clinically relevant ESFT biomarkers exist. Additionally, tumor burden assessment at diagnosis, monitoring of disease responsiveness to therapy, and detection of disease recurrence are limited to radiographic imaging. To identify new, clinically relevant biomarkers we evaluated the proteome of a subset of ESFT-derived small extracellular vesicles (sEVs).

Materials and methods: We performed the first high quality proteomic study of ESFT-derived sEVs from 5 ESFT cell lines representing the most common EWS-ETS fusion types and …

A Pilot Study Of The Preliminary Efficacy Of Pain Buddy: A Novel Intervention For The Management Of Children’S Cancer-Related Pain, John F. Hunter, Amanda M. Acevedo, Sergio Gago-Masague, Alexandra Kain, Christine Yun, Lilibeth Torno, Brooke N. Jenkins, Michelle A. Fortier

Psychology Faculty Articles and Research

Objectives

Cancer‐related pain in children is prevalent and undermanaged. Mobile health (mHealth) applications provide a promising avenue to address the gap in pain management in children with cancer. Pain Buddy is a multicomponent mHealth application developed to manage cancer‐related pain in children. The goal of this paper is to present preliminary efficacy data of the impact of Pain Buddy on children's pain severity and frequency.

Methods

In a randomized controlled trial over 60 days, children (N = 48) reported daily pain on a tablet while receiving usual care. Those in the intervention group (N = 20) received remote …

Guided Imagery And Deep Breathing: Minimizing Anxiety Experienced By Pediatric Cancer Patients, Bethany Grace Aney

Graduate Theses/Dissertations

This particular research study examined the impact of guided imagery and deep breathing as coping tools to reduce the anxiety levels experienced by pediatric cancer patients ages 6-12 years of age at a children’s hospital in Central Pennsylvania. This quantitative study utilized a pretest-posttest design, in addition to utilizing the State-Trait Anxiety Inventory for Children (STAIC™) as the baseline and post-test assessment. The STAIC™ is a questionnaire tool that assesses individuals’ state and trait anxiety through a total of 40 questions. This particular study had a total of five patients, two male and three female that consented to undergoing three …

Bortezomib With Standard Chemotherapy For Children With Acute Myeloid Leukemia Does Not Improve Treatment Outcomes: A Report From The Children's Oncology Group., Richard Aplenc, Soheil Meshinchi, Lillian Sung, Todd Alonzo, John Choi, Brian Fisher, Robert Gerbing, Betsy Hirsch, Terzah Horton, Samir Kahwash, John Levine, Michael Loken, Lisa Brodersen, Jessica Pollard, Susana Raimondi, Edward Anders Kolb, A S. Gamis

Manuscripts, Articles, Book Chapters and Other Papers

New therapeutic strategies are needed for pediatric acute myeloid leukemia (AML) to reduce disease recurrence and treatment-related morbidity. The Children's Oncology Group Phase III AAML1031 trial tested whether the addition of bortezomib to standard chemotherapy improves survival in pediatric patients with newly diagnosed AML. AAML1031 randomized patients younger than 30 years of age with de novo AML to standard treatment with or without bortezomib. All patients received the identical chemotherapy backbone with either four intensive chemotherapy courses or three courses followed by allogeneic hematopoietic stem cell transplantation for high-risk patients. For those randomized to the intervention arm, bortezomib 1.3 mg/m2 …

Igf1r Immunohistochemistry In Ewing's Sarcoma As Predictor Of Response To Targeted Therapy., Elizabeth Gonzalez, Marilyn Bui, Atif Ahmed

Manuscripts, Articles, Book Chapters and Other Papers

Objectives: Ewing's sarcoma is an aggressive malignancy of bone and soft tissue in children and young adults. Despite advances in modern therapy, metastasis can occur and results in high mortality. The objective of this study was to identify whether the signaling transduction proteins, insulin growth factor receptor (IGF1R) and S6 kinase (S6K), can predict poor prognosis in Ewing's sarcoma.

Methods: After the Institutional Research Board approval, immunohistochemical experiments on tissue microarray slides containing 32 archived Ewing's sarcoma tumor samples were performed with antibodies against IGF1Rb and p-S6K. Immunohistochemical staining results were correlated with patients' clinical data including clinical stage and …

Bilateral Pulmonary Metastases Of Papillary Thyroid Carcinoma In A 12-Year-Old Child-A Case Report And Review Of The Literature., V Thirumala, C O'Souji, S Thirumala

Articles, Abstracts, and Reports

Metastatic disease of the lung has been extensively documented in the adult patient population. The most common primary sources for pulmonary metastases include breast, colon gastrointestinal including pancreas and urinary bladder. Malignant lung tumors in pediatric population is extremely rare. However, like in adult patient population, metastases are more common than primary tumors in lung in pediatric patients. Metastatic spread of tumors can occur both by way of hematogenous spread and lymphatic pathways. We present a rare case of biopsy proven metastatic thyroid carcinoma in the lung in a 12-year-old male child masquerading as bilateral miliary nodules on imaging studies. …

Transcriptional Analyses Of Adult And Pediatric Adamantinomatous Craniopharyngioma Reveals Similar Expression Signatures Regarding Potential Therapeutic Targets., Eric Prince, Ros Whelan, Andrew Donson, Susan Staulcup, Astrid Hengartner, Trinka Vijmasi, Chibueze Agwu, Kevin O Lillehei, Nicholas K Foreman, James M Johnston, Luca Massimi, Richard C E Anderson, Mark M Souweidane, Robert P Naftel, David D Limbrick, Gerald Grant, Toba N Niazi, Roy Dudley, Lindsay Kilburn, Eric M Jackson, George I Jallo, Kevin Ginn, Amy Smith, Joshua J Chern, Amy Lee, Annie Drapeau, Mark D Krieger, Michael H Handler, Todd C Hankinson, Advancing Treatment For Pediatric Craniopharyngioma Consortium

Manuscripts, Articles, Book Chapters and Other Papers

Adamantinomatous craniopharyngioma (ACP) is a biologically benign but clinically aggressive lesion that has a significant impact on quality of life. The incidence of the disease has a bimodal distribution, with peaks occurring in children and older adults. Our group previously published the results of a transcriptome analysis of pediatric ACPs that identified several genes that were consistently overexpressed relative to other pediatric brain tumors and normal tissue. We now present the results of a transcriptome analysis comparing pediatric to adult ACP to identify biological differences between these groups that may provide novel therapeutic insights or support the assertion that potential …

Increasing Palliative Care Team Involvement In Pediatric Oncology Patients, Sana Farooki

Research Days

No abstract provided.

Parents' Experiences Of Camp For Siblings Of Pediatric Oncology Patients, Kristen Lauren Krueger

Graduate Theses/Dissertations

The diagnosis and treatment of childhood cancer is oftentimes a stressful experience for individuals other than the patient, such as parents and siblings of pediatric oncology patients. Parents and siblings may be impacted in many ways, but there are interventions to help. The purpose of this qualitative study was to understand parents’ lived experiences of having a child who has attended a camp designed for siblings of pediatric oncology patients. Parents (n=5) of siblings that have attended camp for siblings were interviewed with open-ended questions. Data was analyzed using phenomenology procedures. Results from this study indicated that mothers and fathers …

Extracorporeal Membrane Oxygenation As A Bridge To Chimeric Antigen Receptor T-Cell Therapy For Severe Refractory Sepsis In The Setting Of Relapsed Refractory Pediatric Acute Lymphoblastic Leukemia: A Case Report., Alyssa Stoner, Jenna Miller, Terrie Flatt, Jessica S. Wallisch

Manuscripts, Articles, Book Chapters and Other Papers

Pediatric oncology patients with sepsis are at higher risk of morbidity and mortality compared with pediatric patients without malignancy. Historically, patients with relapsed and/or refractory disease were not considered candidates for aggressive life support strategies including extracorporeal membrane oxygenation support.

Case Summary: We report a 4-year-old female with relapsed refractory pre-B cell acute lymphoblastic leukemia preparing for chimeric antigen receptor T cell therapy with tisagenlecleucel who was admitted with fever and neutropenia. She progressed to refractory septic shock secondary to

Conclusion: The ability to provide chimeric antigen receptor T-cell therapy at designated institutions can augment extracorporeal membrane oxygenation candidacy discussions …

Atrx Loss In Pediatric Glioma Results In Epigenetic Dysregulation Of G2/M Checkpoint Maintenance And Sensitivity To Atm Inhibition, Brendan Mullan, Tingting Qin, Ruby Siada, Carla Danussi, Jacqueline Brosnan-Cashman, Drew Pratt, Taylor Garcia, Viveka Nand Yadav, Xinyi Zhao, Meredith Morgan, Sriram Venneti, Alan Meeker, Alnawaz Rehemtulla, Pedro Lowenstein, Maria Castro, Carl Koschmann

Medical Student Research Symposium

ATRX is a histone chaperone protein recurrently mutated in pediatric glioma. The mechanism which mediates the proliferative advantage of ATRX loss in pediatric glioma remains unexplained. Recent data revealed a distinct pattern of DNA binding sites of the ATRX protein using ChIP-seq in mouse neuronal precursor cells (mNPCs). Using the ATRX peaks identified in p53^-/- mNPCs, we confirmed that ATRX binding sites were significantly enriched in gene promoters (p < 0.0001) and CpG islands (p < 0.0001) compared with random regions. Gene set enrichment (GSE) analysis identified that cell cycle and regulation of cell cycle were among the most significantly enriched gene sets (p=2.52e-16 and 1.61e-9, respectively). We found that ATRX loss resulted in dysfunction of G2/M checkpoint maintenance: (1) ATRX-deficient pediatric glioblastoma (GBM) cells exhibited a seven-fold increase in mitotic index at 16 hours after sub-lethal radiation, and (2) murine GBM cells with ATRX knockdown demonstrated impaired pChk1 signaling on western blot at multiple time points after radiation compared to controls (p=0.0187). Notably, the ATM signaling (pChk2) remained intact in those cells, suggesting a potential therapeutic target. ATRX-deficient mouse cells were uniquely sensitive to ATM inhibitors at 1 uM alongside 8 Gy radiation compared to controls with intact ATRX (AZD0156: p=0.0027 and AZD01390: p=0.0436). Mice intra-cranially implanted with ATRX-deficient GBM cells showed improved survival (n=10, p=0.0018) when treated with AZD0156 combined with radiation. Our findings suggest that ATRX loss in glioma results in unique sensitivity to ATM inhibition via epigenetic dysregulation of G2/M checkpoint maintenance.

Suppressing Stat5 Signaling Affects Osteosarcoma Growth And Stemness., Dharmalingam Subramaniam, Pablo Angulo, Sivapriya Ponnurangam, Prasad Dandawate, Prabhu Ramamoorthy, Pugazhendhi Srinivasan, Tomoo Iwakuma, Scott J. Weir, Katherine Chastain, Shrikant Anant

Manuscripts, Articles, Book Chapters and Other Papers

Osteosarcoma (OS) is the most common primary bone tumor that primarily affects children and adolescents. Studies suggested that dysregulation JAK/STAT signaling promotes the development of OS. Cells treated with pimozide, a STAT5 inhibitor suppressed proliferation and colony formation and induced sub G0/G1 cell cycle arrest and apoptosis. There was a reduction in cyclin D1 and CDK2 expression and Rb phosphorylation, and activation of Caspase-3 and PARP cleavage. In addition, pimozide suppressed the formation of 3-dimensional osteospheres and growth of the cells in the Tumor in a Dish lung organoid system. Furthermore, there was a reduction in expression of cancer stem …