Kristin Schroeder

Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology

Diffuse intrinsic pontine glioma (DIPG) is a high-grade glioma that originates in the pons and is seen exclusively in children. Despite numerous efforts to improve treatment, DIPG remains incurable with 90% of children dying within 2 y of diagnosis, making it one of the leading causes of death in children with brain tumors. With the advent of new genomic tools, the genetic landscape of DIPG is slowly being unraveled. The most common genetic alterations include a K27M mutation in H3.3 or H3.1, which are found in up to 78% of DIPGs, whereas p53 mutations are found in up to 77%. Other recently discovered alterations include amplification of components of the receptor tyrosine kinase/Ras/phosphatidylinositol 3-kinase signaling pathway, particularly platelet-derived growth factor receptor A. Recapitulating such alterations, genetically engineered DIPG preclinical models have been developed, and DIPG xenograft models have also been established. Both models have strengths and weaknesses but can help with the prioritization of novel agents for clinical trials for children with DIPG. As we move forward, it is important that we continue to study the complex and unique biology of DIPG and develop improved preclinical models to increase our understanding of DIPG pathogenesis, allowing translation into successful therapies in the not too distant future.

A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent.

Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 μM, significant inhibition of proliferation at a concentration of 1.5 μM, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.

Molecular variants and mutations in medulloblastoma.

Medulloblastoma is the commonest malignant brain tumor in children. Treatment with surgery, irradiation, and chemotherapy has improved outcomes in recent years, but patients are frequently left with devastating neurocognitive and other sequelae following such therapy. While the prognosis has traditionally been based on conventional histopathology and clinical staging (based on age, extent of resection, and presence or absence of metastasis), it has become apparent in recent years that the inherent biology of the tumor plays a significant part in predicting survival and sometimes supersedes clinical or pathologic risk factors. The advent of deep sequencing gene technology has provided invaluable clues to the molecular makeup of this tumor and allowed neuro-oncologists to understand that medulloblastoma is an amalgamation of several distinct disease entities with unique clinical associations and behavior. This review is a concise summary of the pathology, genetic syndromes, recent advances in molecular subgrouping, and the associated gene mutations and copy number variations in medulloblastoma. The association of molecular alterations with patient prognosis is also discussed, but it should be remembered that further validation is required in prospective clinical trials utilizing uniform treatment approaches.

Central nervous system tumor distribution at a tertiary referral center in Uganda.

ancer has become the leading cause of death and disability in the developing world, with more than 55% of Cthe 12.7 million known cancer cases globally and 64% of the known 7.6 million cancer related deaths worldwide occurring in lowerand middle-income countries (LMICs) (43). Of these cancer diagnoses, up to 20% are central nervous system (CNS) tumors. Significant variation exists between the reported incidence of primary CNS tumors in the United States and other highincome countries (HICs) and LMIC worldwide: 20.1 per 100,000 and 3.2 3.9 per 100,000 respectively (3, 7, 15). Although there is known geographic variation in cancer incidence, the 5-fold lower comparative rate for global CNS tumors is likely an underestimate because of limited diagnostic health infrastructure in many LMICs (37). In East Africa, there is 1 neurosurgeon per 9million people, compared with 1 per 62,500 people in the United States, with even fewer pathologists and radiation oncologists (9). In Uganda, before 2007 only 5 neurosurgeonswere available to serve a population of more than 36 million people (12, 17, 22). With restricted neurosurgical services, CNS tumor biopsies are not routinely performed, contributing to the limited availability of epidemiologic data and treatment options in the East African Population. In 2007, a collaborative effort between Duke University Department of Neurosurgery and Mulago Hospital in Kampala, Uganda, expanded neurosurgical capabilities with delivery of surplus equipment and establishment of neurosurgical training camps. As a result, Mulago Hospital began to offer more complex surgical treatment for patients, including an increased number of craniotomies for intracranial tumors (17). It is now the only neurosurgical referral center in Uganda, treating patients from all 13 municipalities, providing a more comprehensive patient population to evaluate CNS tumor distribution. This study is a retrospective review of clinically diagnosed neurosurgical masses at Mulago Hospital in Kampala, Uganda from

Cost-Effectiveness of Pediatric Cancer Treatment in Tanzania: An Economic Analysis

Abstract 52Background:Despite the high burden of pediatric cancer in low- and middle-income countries, the number of facilities at which children can obtain treatment remains distressingly low. Understanding the costs and economic value of pediatric cancer treatment may assist policy makers to maximize the value of investments in health with informed resource allocation decisions. We examined the direct and indirect costs, cost-effectiveness, and societal economic benefit of diagnosing and treating children with cancer in Tanzania at the Bugando Medical Center, one of only two hospitals in the country with a pediatric oncology unit.Methods:A retrospective chart review of hospital admissions and clinic visits from January 2010 to August 2014 was performed. Costs were recorded for all items that were billed to the patient for laboratory studies, medications, imaging, pathology, surgeries, and hospital stay. Travel costs were estimated for each patient on the basis of a self-reported home address. All costs ...

Validation and Quality Assessment of the Kilimanjaro Cancer Registry

Purpose Global cancer burden has increasingly shifted to low- and middle-income countries and is particularly pronounced in Africa. There remains a lack of comprehensive cancer information as a result of limited cancer registry development. In Moshi, Tanzania, a regional cancer registry exists at Kilimanjaro Christian Medical Center. Data quality is unknown. Our objective was to evaluate the completeness and quality of the Kilimanjaro Cancer Registry (KCR). Methods In October 2015, we conducted a retrospective review of KCR by validating the internal consistency of registry records with medical and pathology records. We randomly sampled approximately 100 total registry cases. Four reviewers not associated with the KCR manually collected data elements from medical records and compared them with KCR data. Results All 100 reviewed registry cases had complete cancer site and morphology included in the registry. Six had a recorded stage. For the majority (n = 92), the basis of diagnosis was pathology. Pathology reports were found in the medical record for 40% of patients; for the remainder, these were stored separately in the pathology department. Of sampled registry cases, the KCR and medical records were 98% and 94% concordant for primary cancer site and morphology, respectively. For 28%, recorded diagnosis dates were within 14 days of what was found in the medical record, and for 32%, they were within 30 days. Conclusion The KCR has a high level of concordance for classification and coding when data are retrieved for validation. This parameter is one of the most important for measuring data quality in a regional cancer registry.

Pediatric Cancer in Northern Tanzania: Evaluation of Diagnosis, Treatment, and Outcomes

Purpose The majority of new diagnoses of pediatric cancer are made in resource-poor countries, where survival rates range from 5% to 25% compared with 80% in high-resource countries. Multiple factors, including diagnostic and treatment capacities and complex socioeconomic factors, contribute to this variation. This study evaluated the available resources and outcomes for pediatric patients with cancer at the first oncology treatment center in northern Tanzania. Methods Qualitative interviews were completed from July to August 2015 to determine available staff, hospital, diagnostic, treatment, and supportive care resources. A retrospective review of hospital admissions and clinic visits from January 2010 to August 2014 was completed. A total of 298 patients were identified, and data from 182 patient files were included in this review. Results Diagnostic, treatment, and supportive capacities are limited for pediatric cancer care. The most common diagnoses were Burkitt lymphoma (n = 32), other non-Hodgkin lymphoma (n = 26), and Wilms tumor (n = 25). A total of 40% of patients (n = 72) abandoned care. There was a 20% 2-year event-free survival rate, which was significantly affected by patient age, method of diagnosis, and year of diagnosis. Conclusion To our knowledge, this is the first review of pediatric cancer outcomes in northern Tanzania. The study identified areas for future development to improve pediatric cancer outcomes, which included strengthening of training and diagnostic capacities, development of registries and research databases, and the need for additional research to reduce treatment abandonment.

Qualitative Analysis of Palliative Care for Pediatric Patients With Cancer at Bugando Medical Center: An Evaluation of Barriers to Providing End-of-Life Care in a Resource-Limited Setting

Purpose Palliative care remains an urgent, neglected need in the developing world. Global disparities in end-of-life care for children, such as those with advanced cancers, result from barriers that are complex and largely unstudied. This study describes these barriers at Bugando Medical Center, one of three consultant hospitals in Tanzania, to identify areas for palliative care development suitable to this context. Methods In-depth interviews were conducted with 20 caregivers of pediatric patients with cancer and 14 hospital staff involved in pediatric end-of-life care. This was combined with 1 month of participant observation through direct clinical care of terminally ill pediatric patients. Results Data from interviews as well as participant observation revealed several barriers to palliative care: financial, infrastructure, knowledge and cultural (including perceptions of pediatric pain), and communication challenges. Although this study focused on barriers, what also emerged were the unique advantages of end-of-life care in this setting, including community cohesiveness and strong faith background. Conclusion This study provides a unique but focused description of barriers to palliative care common in a low-resource setting, extending beyond resource needs. This multidisciplinary qualitative approach combined interviews with participant observation, providing a deeper understanding of the logistical and cultural challenges in this setting. This new understanding will inform the design of more effective—and more appropriate—palliative care policies for young patients with cancer in the developing world.

Feasibility of Using a Digital Case Management Application to Expand the Patient Navigator System at Bugando Medical Centre

Abstract 36PurposeEach year, more than 200,000 children globally are diagnosed with cancer, more than 80% of which occurs in low- to middle-income countries. Pediatric cancer survival rates in low- to middle-income countries are 5% to 25% compared with 80% in high-income countries, with treatment abandonment accounting for one third of the survival gap. A mobile case management system can improve patient communication and reduce treatment abandonment. The current proposal evaluated the feasibility and acceptability of a mobile phone–based case management system at Bugando Medical Centre (BMC) in Mwanza, Tanzania.MethodsWe surveyed 40 families of children with cancer who attended BMC and 10 pediatric oncology providers at BMC to assess mobile phone ownership, use patterns, communication preferences (eg, voice v text messaging), and the advantages and disadvantages of a mobile case management system.ResultsIn all, 85% of families owned a mobile phone and 100% of providers owned smart phones. Of families, 98...

Impact of a Patient Navigator on Time to Diagnosis Among Pediatric Oncology Patients in Tanzania

Abstract 12Background:Oncology patient navigation programs have been successfully implemented at hospitals throughout the United States and have enhanced the quality of care through financial guidance, treatment coordination, and psychosocial support. In low-resource settings, barriers to receiving cancer care are increased and a patient navigator in this setting has the potential to significantly impact outcomes; however, there is limited research on the efficacy of such programs in these settings. At Bugando Medical Centre in Mwanza, Tanzania, a patient navigation program was established to identify potential pediatric oncology patients, then assist these patients and their families throughout the diagnosis and treatment process with the goals of reducing time to oncology evaluation and diagnosis and, ultimately, improving survival outcomes.Methods:A retrospective analysis of hospital records was conducted of all pediatric oncology patients who were evaluated at Bugando Medical Centre from 2010 to 2016,...