Prospective External Validation of the Esbenshade Vanderbilt Models Accurately Predicts Bloodstream Infection Risk in Febrile Non-Neutropenic Children With Cancer.

PURPOSE: The optimal management of fever without severe neutropenia (absolute neutrophil count [ANC] ≥500/µL) in pediatric patients with cancer is undefined. The previously proposed Esbenshade Vanderbilt (EsVan) models accurately predict bacterial bloodstream infections (BSIs) in this population and provide risk stratification to aid management, but have lacked prospective external validation. MATERIALS AND METHODS: Episodes of fever with a central venous catheter and ANC ≥500/µL occurring in pediatric patients with cancer were prospectively collected from 18 academic medical centers. Variables included in the EsVan models and 7-day clinical outcomes were collected. Five versions of the EsVan models were applied to the data with calculation of C-statistics for both overall BSI rate and high-risk organism BSI (gram-negative and Staphylococcus aureus BSI), as well as model calibration. RESULTS: In 2,565 evaluable episodes, the BSI rate was 4.7% (N = 120). Complications for the whole cohort were rare, with 1.1% (N = 27) needing intensive care unit (ICU) care by 7 days, and the all-cause mortality rate was 0.2% (N = 5), with only one potential infection-related death. C-statistics ranged from 0.775 to 0.789 for predicting overall BSI, with improved accuracy in predicting high-risk organism BSI (C-statistic 0.800-0.819). Initial empiric antibiotics were withheld in 14.9% of episodes, with no deaths or ICU admissions attributable to not receiving empiric antibiotics. CONCLUSION: The EsVan models, especially EsVan2b, perform very well prospectively across multiple academic medical centers and accurately stratify risk of BSI in episodes of non-neutropenic fever in pediatric patients with cancer. Implementation of routine screening with risk-stratified management for non-neutropenic fever in pediatric patients with cancer could safely reduce unnecessary antibiotic use.

Identifying Barriers to HPV Vaccination for Patients With Sickle Cell Disease and Childhood Cancer Survivors.

Human papillomavirus (HPV) vaccination prevents the development of HPV-associated malignancies. Adolescent and young adult survivors of childhood cancers and patients with sickle cell disease (SCD) are vulnerable patient populations who would significantly benefit from HPV vaccination. In this multimethod study, a retrospective chart review found a notable difference between the rate of HPV vaccinations and other age-appropriate vaccinations in 177 childhood cancer survivors and in 70 patients with SCD. We then sought to describe patient and caregiver beliefs regarding HPV vaccination, through semistructured interviews with 21 patients and 48 caregivers. Interviews were analyzed with a thematic content approach to understand attitudes regarding the HPV vaccination. Qualitative interviews noted that many caregivers and adolescents had baseline misconceptions regarding the HPV vaccination in general and in context with their chronic illness. It was found that a strong recommendation from a trusted subspecialty provider would create reassurance about vaccination and reduce misconceptions and concerns about side effects in the context of a chronic illness. Counseling from subspecialists could have a strong impact on understanding the HPV vaccine in the context of chronic illness. This would likely help overcome many of the barriers to vaccination that are encountered by patients with SCD or oncology survivors.

Pediatric hematology and oncology physician and nurse practitioner views of the HPV vaccine and barriers to administration.

Rates of Human papilloma virus (HPV) vaccination among pediatric survivors of cancer and patients with sickle cell disease are lower than the national average. While recent attention has focused on patient HPV vaccine hesitancy and refusal, less is known about provider-level and system-level barriers to vaccinations in pediatric hematology/oncology (PHO) populations. Applying thematic analysis to qualitative interviews with 20 pediatric hematology/oncology physicians and nurse practitioners, we examine their views regarding HPV vaccination, with a focus on access and barriers to providing HPV vaccination in PHO practices. Results demonstrated that despite 90% of interviewees supporting HPV vaccination in their population, the number of pediatric hematology/oncology providers who reported that they counsel about HPV or provide HPV vaccination was 45%, even in stem cell and sickle cell clinics, where other childhood vaccines are commonly provided. Clinicians identified provider-level, clinic-level, and system-level barriers to giving the HPV vaccination, including but not limited to time/flow constraints, lack of resources, and continued education regarding the HPV vaccine. These barriers impede the ability for pediatric hematology/oncology providers to counsel and provide HPV vaccination to this specialized population.

An evaluation of the disparities affecting the underdiagnosis of pediatric cancer in Western Kenya.

INTRODUCTION: Western Kenya is home to approximately 24 million people, with 10 million children under the age of 15 years.1 Based on estimates of cancer incidence in similar populations from around the world, approximately 1500 patients should be diagnosed with pediatric cancer each year. This article describes the international collaboration that investigates potential barriers preventing the effective diagnosis of pediatric patients with cancer. METHODS: Here, we describe a multidisciplinary and sequential approach to better evaluate the complex factors affecting the lack of appropriate diagnosis of pediatric cancer in Western Kenya. RESULTS: Internal review at a large tertiary hospital noted 200-250 patients were diagnosed annually, suggesting the remaining 75%-80% of patients go undiagnosed and do not receive treatment. Following our screening process at a local referring hospital, 41 malaria slides demonstrated both morphologic and genetic evidence of leukemia. Knowledge assessments of local providers at referring institutions suggested a lack of education and training as the factors that contribute to lower rates of diagnosis. DISCUSSION: Through a multi-step approach, our teams were better able to isolate potential issues impeding the appropriate and timely diagnosis of pediatric cancer in Kenya.

Pediatric hematology/oncology physician and nurse practitioner attitudes towards the COVID-19 vaccines: A qualitative study.

As of 05/28/2021, SARS-CoV-2 (COVID-19) had caused 3.9 million infections in the United States (US) pediatric population since its discovery in December of 2019. The development and expansion of vaccination has markedly changed the shape of the epidemic. In this qualitative study, we report on pediatric hematology/oncology provider views on the COVID-19 vaccine prior to approval in the adolescent population <16 years of age. Results from interviews with 20 providers across the state of Indiana showed that most were supportive of the COVID-19 vaccine for healthy adults. However, the majority also expressed a need to see more data on the safety and effectiveness of COVID-19 vaccinations in pediatric hematology/oncology populations. While they recognized the public health importance of vaccination, their duty to protect their patients led to a need for more specific safety and efficacy data.

Social determinants of health and pediatric cancer survival: A systematic review.

Despite treatment advancements and improved survival, approximately 1800 children in the United States will die of cancer annually. Survival may depend on nonclinical factors, such as economic stability, neighborhood and built environment, health and health care, social and community context, and education, otherwise known as social determinants of health (SDoH). Extant literature reviews have linked socioeconomic status (SES) and race to disparate outcomes; however, these are not inclusive of all SDoH. Thus, we conducted a systematic review on associations between SDoH and survival in pediatric cancer patients. Of the 854 identified studies, 25 were included in this review. In addition to SES, poverty and insurance coverage were associated with survival. More studies that include other SDoH, such as social and community factors, utilize prospective designs, and conduct analyses with more precise SDoH measures are needed.

Prognostic factors for patients with relapsed central nervous system nongerminomatous germ cell tumors.

We aimed toidentify prognostic factors that may help better understand the behavior of relapsed central nervous system nongerminomatous germ cell tumors. We identified nine studies, including 101 patients; 33 patients (33%) were alive 12 months post-initial relapse. Sixty percent of patients with serum/cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) level ≤25 ng/mL at initial diagnosis were survivors compared with 28% among patients with serum/CSF AFP level >25 ng/mL (P = 0.01). Seventy-one percent of patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy at relapse were survivors compared with 7% among patients who had less than CR/CCR (P < 0.0001). Forty-eight percent of patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) following relapse were survivors compared with 12% among patients who did not receive HDCx/AuHCR (P = 0.0001). Local relapse site, gross total surgical resection, and radiotherapy at relapse were not associated with improved outcomes.

Cancer prevention, screening, and survivorship ECHO: A pilot experience with an educational telehealth program.

INTRODUCTION: The American Cancer Society, Inc. (ACS) estimates that 37,940 Indiana residents were diagnosed with cancer in 2020, which remains the leading cause of death in the state. Across the cancer continuum, national goals have been established targeting recommended benchmarks for states in prevention, screening, treatment, and survivorship. Indiana consistently falls below most goals for each of these targeted categories. METHODS: To address these disparities, we implemented Project ECHO (Extension for Community Healthcare Outcomes) as a virtual telehealth educational platform targeted at local healthcare providers. ECHO programs utilize a novel tele-mentoring approach to the education of clinicians in a hub/spoke design. Sessions occurred twice monthly from September 2019 to September 2020 and consisted of a traditional didactic lecture and a case-based discussion led by participating providers. RESULTS: During the pilot year there were a total of 22 ECHO sessions with 140 different participants. On average, 15.5 spokes attended each session with increasing participation at the end of the year. Post-session surveys suggested generally favorable perception with 72% of respondents finding the quality "excellent." DISCUSSION: Given the increasing rate of recurrent participation toward the end of the pilot year in conjunction with the favorable survey responses following each session, it was felt that the program was overall successful and warranted continued implementation. CONCLUSION: The Project ECHO platform is a validated telehealth education platform that has the potential to impact cancer care at multiple points along the cancer continuum at the regional level.

Accuracy of central neuro-imaging review of DIPG compared with histopathology in the International DIPG Registry.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, <50% pontine involvement, focally exophytic morphology, sharply defined margins, and/or marked diffusion restriction throughout. RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

The state of neuro-oncology during the COVID-19 pandemic: a worldwide assessment.

BACKGROUND: It remains unknown how the COVID-19 pandemic has changed neuro-oncology clinical practice, training, and research efforts. METHODS: We performed an international survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents, April 24-May 17, 2020. We assessed clinical practice and research environments, institutional preparedness and support, and perceived impact on patients. RESULTS: Of 582 respondents, 258 (45%) were US-based and 314 (55%) international. Ninety-four percent of participants reported changes in their clinical practice. Ninety-five percent of respondents converted at least some practice to telemedicine. Ten percent of practitioners felt the need to see patients in person, specifically because of billing concerns and pressure from their institutions. Sixty-seven percent of practitioners suspended enrollment for at least one clinical trial, including 62% suspending phase III trial enrollments. More than 50% believed neuro-oncology patients were at increased risk for COVID-19. Seventy-one percent of clinicians feared for their own personal safety or that of their families, specifically because of their clinical duties; 20% had inadequate personal protective equipment. While 69% reported increased stress, 44% received no psychosocial support from their institutions. Thirty-seven percent had salary reductions and 63% of researchers temporarily closed their laboratories. However, the pandemic created positive changes in perceived patient satisfaction, communication quality, and technology use to deliver care and mediate interactions with other practitioners. CONCLUSIONS: The pandemic has changed treatment schedules and limited investigational treatment options. Institutional lack of support created clinician and researcher anxiety. Communication with patients was satisfactory. We make recommendations to guide clinical and scientific infrastructure moving forward and address the personal challenges of providers and researchers.

Evaluation of the Pediatric Neuro-Oncology Resources Available in Chile.

PURPOSE: Pediatric neuro-oncology resources are mostly unknown in Chile. We report the human and material resources available in Chilean hospitals providing pediatric neuro-oncology services. METHODS: A cross-sectional survey was distributed to 17 hospitals providing pediatric neuro-oncology services (Programa Infantil Nacional de Drogas Antineoplásicas [PINDA] hospitals, 11; private, 6). RESULTS: Response rate was 71% (PINDA, 8; private, 4). Pediatric neuro-oncology services were mainly provided within general hospitals (67%). Registries for pediatric CNS tumors and chemotherapy-related toxicities were available in 100% and 67% of hospitals, respectively. CNS tumors were treated by pediatric oncologists in 92% of hospitals; none were formally trained in neuro-oncology. The most used treatment protocols were the national PINDA protocols. All WHO essential medicines for childhood cancer were available in more than 80% of the hospitals except for gemcitabine, oxaliplatin, paclitaxel, and procarbazine. The median number of pediatric neurosurgeons per hospital was two (range, 2-6). General neuroradiologists were available in 83% of the centers. Pathology specimens were sent to neuropathologists (58%), adult pathologists (25%), and pediatric pathologists (17%). Intensity-modulated radiotherapy, conformal radiotherapy, and cobalt radiotherapy were used by 67%, 58%, and 42% of hospitals, respectively. Only one private hospital performed autologous hematopoietic cell transplant for children with CNS tumors. CONCLUSION: A wide range of up-to-date treatment modalities are available for children with CNS tumors. Our survey highlights future directions to improve the pediatric neuro-oncology services available in Chile such as the expansion of multidisciplinary clinics, palliative care services, long-term cancer survivorship programs, dedicated clinical research support teams, establishing standardized mechanism for sending pathologic specimen for second opinion to international specialized centers, and establishing specialized neuro-oncology training program.

Venous thromboembolism in children with central nervous system tumors: Comparison of an institutional cohort to a national administrative database.

BACKGROUND: Central nervous system (CNS) tumors are the second most common malignancy of childhood, and published data on venous thromboembolism (VTE) rate and risk factors for these patients are outdated or incomplete. Here, we determine the cumulative incidence and risk factors for VTE in this population. PROCEDURE: VTE diagnosis and associated clinical risk factors were abstracted and analyzed for two cohorts of children (0-21 years) diagnosed with CNS tumors between January 1, 2010 to September 30, 2018. The first study was a retrospective single institution cohort study. The initial observations were confirmed across multiple pediatric hospitals using the Pediatric Health Information System (PHIS) administrative database. RESULTS: The single-institution cohort included 338 patients aged 3 days to 20.9 years (median age, 8.6 years); VTE developed in eight (2.4%) patients. The PHIS cohort included 17 634 patients aged from 0 to 21.9 years (median: 9.5 years); VTE developed in 354 (2.0%) patients. Univariate analysis for the single-institution cohort identified central venous catheter (CVC) placement as a risk factor for VTE (odds ratio [OR] 8.40, 95% confidence interval [CI] 1.43-49.41, P = .0186). Multivariable analysis of the PHIS dataset identified CVC placement (OR 1.97, 95% CI 1.57-2.46; P < .0001), obesity (OR 2.96, 95% CI 1.21-7.26; P = .0177), and more than one hospital admission (OR 3.54, 95% CI 2.69-4.64; P < .0001) as significant predictors of VTE. VTE diagnosis was not associated with increased mortality in either cohort. CONCLUSIONS: The VTE rate in children with CNS tumors is low (2%). CVC placement was identified as a modifiable risk factor in both cohorts.

Pineal teratoma with nephroblastic component in a newborn male: Case report and review of the literature.

Neonatal germ cell tumors are rare and comprise both benign and malignant neoplasms. Teratoma with nephroblastoma is a malignant subset defined pathologically by the presence of nephroblastoma and teratoma elements. Although teratoma with nephroblastoma is most often found in the kidney, 24 of 59 reported cases are associated with extrarenal locations, such as the mediastinum or retroperitoneum. To our knowledge, this is the first patient in the literature with intracranial/pineal teratoma with nephroblastoma, which was managed with staged transcranial approaches resulting in gross total resection and no adjuvant therapy (surveillance observation imaging). We further augmented the patient's management by comprehensive genomic profiling of the tumor to better understand the molecular biology and explore options for targeted therapy.

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition.

PURPOSE: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P = .02). CONCLUSION: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

A Quality Improvement Approach to Increase Exercise Assessment in Survivors of Childhood Leukemia.

INTRODUCTION: Survivors of childhood cancer are at increased risk of treatment-related cardiovascular disease, the severity of which is impacted by the level of regular exercise. Exercise assessments (EAs) are not a routine component of follow-up care. METHODS: We incorporated a quantitative EA tool into the clinic triage during follow-up visits for survivors of acute lymphoblastic leukemia. The nursing staff was surveyed on the use of the EA tool to gauge understanding and level of comfort with addressing patient questions. RESULTS: Over 27 months, the percentage of off-therapy acute lymphoblastic leukemia patients with documented EA increased from 0% to 80%. We noted degradation in EA completions in the last 6 months of the project, which we attributed to project nursing staff transition and failure to maintain education. Interventions that improved the percentage of completed EA included the incorporation the assessment tool into the electronic medical record and weekly reminders of scheduled eligible patients. A nurse incentive plan did not impact project success. Survey results revealed that the nursing staff were comfortable with the EA and did not view the new process as hurting patient flow. CONCLUSION: Implementation of an EA tool into routine clinic follow-up was successful. We met the project goal of assessing greater than 50% of the follow-up patients. This work will serve as the foundation for the next phase of the project, which will be to provide education on the importance of exercise and earlier intervention when a sedentary lifestyle is identified.

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

Genome sequencing identifies somatic BRAF duplication c.1794_1796dupTAC;p.Thr599dup in pediatric patient with low-grade ganglioglioma.

Gangliogliomas (WHO grade I) are rare tumors affecting the central nervous system and are most frequently observed in children. Next-generation sequencing of tumors is being utilized at an increasing rate in both research and clinical settings to characterize the genetic factors that drive tumorigenesis. Here, we report a rare BRAF somatic mutation (NM_004333.4:c.1794_1796dupTAC; p.Thr599dup) in the tumor genome from a pediatric patient in her late teens, who was initially diagnosed with low-grade ganglioglioma at age 13. This duplication of 3 nt introduces a second threonine residue at amino acid 599 of the BRAF protein. Based on previous studies, this variant is likely to increase kinase activity, similar to the well-characterized BRAF p.Val600Glu (V600E) pathogenic variant. In addition, although the p.T599dup somatic mutation has been documented rarely in human cancers, the variant has not been previously reported in ganglioglioma. The identification of this variant presents an opportunity to consider targeted therapy (e.g., BRAF inhibitor) for this patient.

Delays in diagnosis for children with newly diagnosed central nervous system tumors.

BACKGROUND: United States studies documenting time interval from symptom onset to definitive diagnosis for childhood central nervous system (CNS) tumors are more than a quarter-century old. The purpose of this study is to establish an accurate and contemporary Ohio baseline of the diagnostic interval for children with newly diagnosed CNS tumors. METHODS: Medical records were retrospectively reviewed for 301 children with newly diagnosed CNS tumors from January 2004 to August 2015 at Nationwide Children's Hospital. We obtained comprehensive data on 171 patients (56.8%). Records were reviewed for age, gender, tumor type, presenting symptoms, number of health care visits prior to diagnosis, time interval (in months) from onset of symptoms to definitive diagnosis, and any associated genetic syndromes. RESULTS: Of the 171 patients with newly diagnosed CNS tumors, 25 children (14.6%) had a known cancer predisposition syndrome (all with neurofibromatosis type 1). Among the remaining 146 children, the median and mean time intervals from symptom onset to definitive diagnosis were 42 days and 138 days (range < 1 to 2190 days), respectively. CONCLUSIONS: We have documented and quantified the contemporary delays in diagnosis of childhood brain tumors in central Ohio to serve as a benchmark for our future planned interventions to reduce the time interval from symptom onset to diagnosis through adaptation of the United Kingdom HeadSmart program throughout the state of Ohio and ultimately throughout the United States.

Acanthamoeba granulomatous amoebic encephalitis after pediatric hematopoietic stem cell transplant.

Acanthamoeba encephalitis is a rare, often fatal condition, particularly after HSCT, with 9 reported cases to date in the world literature. Our case was originally diagnosed with ALL at age 3 years, and after several relapses underwent HSCT at age 9 years. At 17 years of age, he was diagnosed with secondary AML for which he underwent a second allogeneic HSCT. He presented with acute-onset worsening neurological deficits on day +226 after the second transplant and a post-mortem diagnosis of Acanthamoeba encephalitis was established, with the aid of the CDC.