A high-dimensional mediation model for a neuroimaging mediator: Integrating clinical, neuroimaging, and neurocognitive data to mitigate late effects in pediatric cancer.

Pediatric cancer treatment, especially for brain tumors, can have profound and complicated late effects. With the survival rates increasing because of improved detection and treatment, a more comprehensive understanding of the impact of current treatments on neurocognitive function and brain structure is critically needed. A frontline medulloblastoma clinical trial (SJMB03) has collected data, including treatment, clinical, neuroimaging, and cognitive variables. Advanced methods for modeling and integrating these data are critically needed to understand the mediation pathway from the treatment through brain structure to neurocognitive outcomes. We propose an integrative Bayesian mediation analysis approach to model jointly a treatment exposure, a high-dimensional structural neuroimaging mediator, and a neurocognitive outcome and to uncover the mediation pathway. The high-dimensional imaging-related coefficients are modeled via a binary Ising-Gaussian Markov random field prior (BI-GMRF), addressing the sparsity, spatial dependency, and smoothness and increasing the power to detect brain regions with mediation effects. Numerical simulations demonstrate the estimation accuracy, power, and robustness. For the SJMB03 study, the BI-GMRF method has identified white matter microstructure that is damaged by cancer-directed treatment and impacts late neurocognitive outcomes. The results provide guidance on improving treatment planning to minimize long-term cognitive sequela for pediatric brain tumor patients.

A retrospective investigation of the relationship between neuroblastoma response to anti-GD2 monoclonal antibodies and exposure to opioids for pain management.

OBJECTIVE: Recent increased awareness and research studies reflect possible associations between opioid exposure and cancer outcomes. Children with neuroblastoma (NB) often require opioid treatment for pain. However, associations between tumor response to chemotherapy and opioid exposure have not been investigated in clinical settings. METHODS: This is a single-institution retrospective review of patients with NB treated between 2013 and 2016. We evaluated opioid consumption quantified in morphine equivalent doses (mg/kg) based on nurse- or patient-controlled analgesia during antibody infusions. We also analyzed their associations with change in primary tumor volume and total tumor burden. RESULTS: Of 42 patients given opioids for pain related to anti-disialoganglioside monoclonal antibodies (anti-GD2 mAb), data completion was achieved for 36, and details of statistical analyses were entered. Median total weight-based morphine equivalent (over 8 days) was 4.71 mg/kg (interquartile range 3.49-7.96). We found a statistically insignificant weak negative relationship between total weight-based morphine equivalents and tumor volume ratio (correlation coefficient -.0103, p-value .9525) and a statistically insignificant weak positive relationship between total weight-based morphine equivalent and Curie score ratio (correlation coefficient .1096, p-value .5247). CONCLUSION: Our study found no statistically significant correlation between opioid consumption and natural killer (NK) cell-mediated killing of NB cells as measured by effects on tumor volume/tumor load.

Quality improvement knowledge in pediatric hematology/oncology physicians: A need for improved education.

Pediatric hematology/oncology fellows face unique quality improvement challenges given the danger of chemotherapy and caring for immunocompromised patients. Curricula to teach pediatric hematology/oncology fellows about quality improvement are lacking. We conducted a needs assessment of pediatric hematology/oncology physicians as a first step for creating a quality improvement curriculum for pediatric hematology/oncology fellows. Curricular topics were identified: root cause analysis, run charts, process mapping, chemotherapy/medication safety, implementation/adherence to guidelines. Identified barriers to curriculum implementation included a possible lack of quality improvement expertise, lack of awareness of quality improvement resources, and limited time.

A CT scan-based formula for predicting central venous catheter length in pediatric patients.

PURPOSE: Placement of a central venous catheter (CVC) is the most commonly performed pediatric procedure. This study aims to develop simple formulas to calculate intravascular length of CVCs prior to insertion to minimize reliance on fluoroscopic and radiographic imaging, which may not be uniformly available. METHODS: We performed a single-institution, retrospective review of 115 pediatric patients who received both CVC placement and computed tomography (CT) imaging of the chest within 3 months of the procedure. Using measurements from the CT imaging, formulas calculating the length of the intravascular component of the CVC based on height and insertion laterality were developed and compared to previously published formulas. These formulas were then trialed prospectively to validate reliability and application. RESULTS: Formulas were developed for right-sided and left subclavian insertion. The right-side formula accurately predicted CVC length in 52.6% of patients, compared to 47.4% by the Andropoulos formula. The left subclavian formula accurately estimated 62.5%, compared to 34.5% by the Stroud formula. CONCLUSIONS: The optimal intravascular length of central venous catheters may be determined by simple formulas based on patient height and insertion site. LEVEL OF EVIDENCE: III.

Clinical and organizational risk factors for mortality during deterioration events among pediatric oncology patients in Latin America: A multicenter prospective cohort.

BACKGROUND: Hospitalized pediatric hematology-oncology (PHO) patients have frequent clinical deterioration events (CDE) requiring intensive care unit (ICU) admission, particularly in resource-limited settings. The objective of this study was to describe CDEs in hospitalized PHO patients in Latin America and to identify event-level and center-level risk factors for mortality. METHODS: In 2017, the authors implemented a prospective registry of CDEs, defined as unplanned transfers to a higher level of care, use of ICU-level interventions on the floor, or nonpalliative floor deaths, in 16 PHO centers in 10 countries. PHO hospital admissions and hospital inpatient days were also reported. This study analyzes the first year of registry data (June 2017 to May 2018). RESULTS: Among 16 centers, 553 CDEs were reported in PHO patients during 11,536 admissions and 119,414 inpatient days (4.63 per 1000 inpatient days). Event mortality was 29% (1.33 per 1000 inpatient days) but ranged widely across centers (11%-79% or 0.36-5.80 per 1000 inpatient days). Significant risk factors for event mortality included requiring any ICU-level intervention on the floor and not being transferred to a higher level of care. Events with organ dysfunction, a higher severity of illness, and a requirement for ICU intervention had higher mortality. In center-level analysis, hospitals with a higher volume of PHO patients, less floor use of ICU intervention, lower severity of illness on transfer, and lower rates of floor cardiopulmonary arrest had lower event mortality. CONCLUSIONS: Hospitalized PHO patients who experience CDEs in resource-limited settings frequently require floor-based ICU interventions and have high mortality. Modifiable hospital practices around the escalation of care for these high-risk patients may contribute to poor outcomes. Earlier recognition of critical illness and timely ICU transfer may improve survival in hospitalized children with cancer.

Perianesthetic neurological adverse events in children: A review of the Wake-Up Safe Database.

BACKGROUND: Perianesthetic neurological adverse events are rare in children and have been studied in detail in the settings of cardiac surgery and regional anesthesia. Our study aims to characterize perianesthetic neurological adverse events in children in the setting of all types of surgery and diagnostic or interventional procedures, to evaluate anesthesia's role, and to identify factors amenable to prevention. METHODS: We conducted a retrospective study by reviewing all the anesthetic encounters reported in the Wake-Up Safe database between January 2010 and December 2017. RESULTS: The rate of perianesthetic neurological adverse events was 0.49 per 10 000 pediatric anesthetic encounters. The odds of NAE were significantly higher in children who were older than 6 months; had American Society of Anesthesiologists physical status (ASA PS) of 3, 4, or 5; or had American Society of Anesthesiologists Emergency (ASA E) status. Seizures were the most common NAE. Overall, 23 (18.1%) children with neurological adverse events died, and 33 (26%) experienced permanent or severe permanent harm. The risk of death was higher in infants and in children with ASA PS of 3, 4, or 5; ASA E status; preexisting neurological abnormality; or preexisting neurological deficit and in events associated with cardiac arrest or trauma. Anesthesia contributed to 24 (18.9%) events; patient disease was the primary causative factor in 95 (74.8%) adverse events, and 37 (29.1%) events were preventable, including 2 deaths. Preventable factors broadly included inadequate preoptimization, complications during airway management and central venous catheter placement, and suboptimal patient positioning. CONCLUSION: Perianesthetic neurological adverse events are rare in children and have a poor outcome. Our study has described pediatric perianesthetic neurological injury in detail and identified contributing factors that can be optimized during various phases of perianesthetic care. This information can be utilized during the informed consent process and to enhance the quality of care in children receiving anesthesia.

Revealing Opinions for COVID-19 Questions Using a Context Retriever, Opinion Aggregator, and Question-Answering Model: Model Development Study.

BACKGROUND: COVID-19 has challenged global public health because it is highly contagious and can be lethal. Numerous ongoing and recently published studies about the disease have emerged. However, the research regarding COVID-19 is largely ongoing and inconclusive. OBJECTIVE: A potential way to accelerate COVID-19 research is to use existing information gleaned from research into other viruses that belong to the coronavirus family. Our objective is to develop a natural language processing method for answering factoid questions related to COVID-19 using published articles as knowledge sources. METHODS: Given a question, first, a BM25-based context retriever model is implemented to select the most relevant passages from previously published articles. Second, for each selected context passage, an answer is obtained using a pretrained bidirectional encoder representations from transformers (BERT) question-answering model. Third, an opinion aggregator, which is a combination of a biterm topic model and k-means clustering, is applied to the task of aggregating all answers into several opinions. RESULTS: We applied the proposed pipeline to extract answers, opinions, and the most frequent words related to six questions from the COVID-19 Open Research Dataset Challenge. By showing the longitudinal distributions of the opinions, we uncovered the trends of opinions and popular words in the articles published in the five time periods assessed: before 1990, 1990-1999, 2000-2009, 2010-2018, and since 2019. The changes in opinions and popular words agree with several distinct characteristics and challenges of COVID-19, including a higher risk for senior people and people with pre-existing medical conditions; high contagion and rapid transmission; and a more urgent need for screening and testing. The opinions and popular words also provide additional insights for the COVID-19-related questions. CONCLUSIONS: Compared with other methods of literature retrieval and answer generation, opinion aggregation using our method leads to more interpretable, robust, and comprehensive question-specific literature reviews. The results demonstrate the usefulness of the proposed method in answering COVID-19-related questions with main opinions and capturing the trends of research about COVID-19 and other relevant strains of coronavirus in recent years.

Natural Language Processing and Machine Learning Methods to Characterize Unstructured Patient-Reported Outcomes: Validation Study.

BACKGROUND: Assessing patient-reported outcomes (PROs) through interviews or conversations during clinical encounters provides insightful information about survivorship. OBJECTIVE: This study aims to test the validity of natural language processing (NLP) and machine learning (ML) algorithms in identifying different attributes of pain interference and fatigue symptoms experienced by child and adolescent survivors of cancer versus the judgment by PRO content experts as the gold standard to validate NLP/ML algorithms. METHODS: This cross-sectional study focused on child and adolescent survivors of cancer, aged 8 to 17 years, and caregivers, from whom 391 meaning units in the pain interference domain and 423 in the fatigue domain were generated for analyses. Data were collected from the After Completion of Therapy Clinic at St. Jude Children's Research Hospital. Experienced pain interference and fatigue symptoms were reported through in-depth interviews. After verbatim transcription, analyzable sentences (ie, meaning units) were semantically labeled by 2 content experts for each attribute (physical, cognitive, social, or unclassified). Two NLP/ML methods were used to extract and validate the semantic features: bidirectional encoder representations from transformers (BERT) and Word2vec plus one of the ML methods, the support vector machine or extreme gradient boosting. Receiver operating characteristic and precision-recall curves were used to evaluate the accuracy and validity of the NLP/ML methods. RESULTS: Compared with Word2vec/support vector machine and Word2vec/extreme gradient boosting, BERT demonstrated higher accuracy in both symptom domains, with 0.931 (95% CI 0.905-0.957) and 0.916 (95% CI 0.887-0.941) for problems with cognitive and social attributes on pain interference, respectively, and 0.929 (95% CI 0.903-0.953) and 0.917 (95% CI 0.891-0.943) for problems with cognitive and social attributes on fatigue, respectively. In addition, BERT yielded superior areas under the receiver operating characteristic curve for cognitive attributes on pain interference and fatigue domains (0.923, 95% CI 0.879-0.997; 0.948, 95% CI 0.922-0.979) and superior areas under the precision-recall curve for cognitive attributes on pain interference and fatigue domains (0.818, 95% CI 0.735-0.917; 0.855, 95% CI 0.791-0.930). CONCLUSIONS: The BERT method performed better than the other methods. As an alternative to using standard PRO surveys, collecting unstructured PROs via interviews or conversations during clinical encounters and applying NLP/ML methods can facilitate PRO assessment in child and adolescent cancer survivors.

Total Hip Arthroplasty in Adolescents and Young Adults for Management of Advanced Corticosteroid-Induced Osteonecrosis Secondary to Treatment for Hematologic Malignancies.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a potentially severe toxicity associated with glucocorticoid treatment for pediatric hematologic malignancy. We examined clinical outcomes of THA in adolescents and young adults treated for hematologic malignancies who developed advanced ONFH. METHODS: In a single-institution cohort, we retrospectively reviewed medical records and imaging for perioperative complications, reoperations, functional assessment at last follow-up, and radiological outcomes. Twenty-seven patients (41 hips) underwent THA (bilateral in 14 patients). There were 11 males. Median (interquartile range [IQR]) age at primary diagnosis was 14.9 years [1.8-18.9]. The median (IQR) age at THA was 19.8 years [14.6-30.3]. Mean (range) post-THA follow-up was 111.5 months (65.4-165.8). RESULTS: Perioperative complications included one intraoperative calcar fracture that was secured with a cerclage wire and one posterior hip dislocation that occurred 6 days postoperatively, requiring closed reduction. One hip required a revision 21.1 months post-THA due to a fractured ceramic liner. The radiographic review was available for 38 of 41 hips and demonstrated none with loosening, subsidence, or osteolysis; nine developed periacetabular stress shielding. Incidence of stress shielding was associated with increased postoperative pain (P = .0130). There was a significant functional improvement in range of motion (ROM), pain, use of supports, participation in school, work, and sports, and use of pain medication from preoperative to postoperative clinical visits (P < .001). DISCUSSION: Total hip arthroplasty in adolescents and young adults offers symptomatic and functional improvement in patients with ONFH. We found it to be safe with low perioperative complication rates even in patients undergoing active treatment for malignancy. LEVEL OF EVIDENCE: Level IV, case series study. See Instructions for authors for a complete description of levels of evidence.

Barriers to the early integration of palliative care in pediatric oncology in 11 Eurasian countries.

BACKGROUND: The early integration of palliative care significantly improves quality of life for children with cancer. However, cultural, structural, and socioeconomic barriers can delay the integration of palliative care into cancer care, particularly in low-income and middle-income countries. To date, little is known regarding the timing of and barriers to palliative care integration in Eurasia. METHODS: The Assessing Doctors' Attitudes on Palliative Treatment (ADAPT) survey evaluates physician perceptions regarding palliative care integration into pediatric oncology in Eurasia. This evidence-based survey was adapted to the regional context; iteratively reviewed by US and regional panelists; and piloted in English, Russian, and Mongolian. After distribution to physicians caring for children with cancer, statistical analysis was complemented by qualitative analysis of open-ended responses. RESULTS: A total of 424 physician responses were received from 11 countries in the Eurasian region. Study findings demonstrated wide variability in access to palliative care experts across countries (18%-96%), with the majority of providers (64%) reporting that the initial palliative care consultation typically occurs when curative options are no longer available. Providers desired an earlier initial palliative care consultation than what currently occurs in their setting (P < .001). Primary barriers to timely consultation included limited access to palliative care services and specialists, lack of physician education, and perceived family resistance. CONCLUSIONS: The current study is the first to identify physician perceptions of the delayed timing of palliative care integration into childhood cancer care and associated barriers in Eurasia. These findings will inform the development of targeted interventions to mitigate local structural and cultural barriers to access and facilitate earlier palliative care integration in the region.

A multicountry assessment in Eurasia: Alignment of physician perspectives on palliative care integration in pediatric oncology with World Health Organization guidelines.

BACKGROUND: The World Health Organization (WHO) advocates for early integration of palliative care for all children with life-threatening illness. Provider awareness and misperceptions, however, can impede this imperative. In the Eurasian region, little is known about physician knowledge and perspectives on palliative care. METHODS: The Assessing Doctors' Attitudes on Palliative Treatment survey was developed as an evidence-based and culturally relevant assessment of physician perceptions on palliative care integration into childhood cancer care in Eurasia. Iteratively tested by American and Eurasian palliative care experts, the survey was culturally adapted, translated, and piloted in English, Russian, and Mongolian. The survey was distributed to physicians caring for children with cancer. Fifteen statements were scored in accordance with WHO guidelines to evaluate provider knowledge. The statistical analysis was complemented by a qualitative analysis of open-ended responses. RESULTS: This study received 424 responses from 11 countries in Eurasia. The mean alignment between provider perspectives and WHO recommendations was 70% (range, 7%-100%). Significant independent predictors of higher alignment included country, prior palliative care education, and greater experience with patient death. Respondents primarily described palliative care as end-of-life care and symptom management. Two-thirds of respondents (67%) reported not feeling confident about delivering at least 1 component of palliative care. CONCLUSIONS: This is the first study assessing physician perspectives and knowledge of palliative care in Eurasia and reveals wide variability in alignment with WHO guidelines and limited confidence in providing palliative care. Study findings will inform targeted educational interventions, which must be tailored to the local political, economic, and cultural context.

Predictors of narcolepsy and hypersomnia due to medical disorder in pediatric craniopharyngioma.

PURPOSE: Several studies describe sleep-wake disturbances in pediatric craniopharyngioma, but none have determined the prevalence or associated predictors of excessive sleepiness in this group after diagnosis and prior to post-operative observation or adjuvant radiotherapy. In this study, we report sleep-wake disturbances in children and adolescents with craniopharyngioma and associated clinical and treatment variables. METHODS: After surgery and prior to radiotherapy or observation, pediatric patients (n = 110) with craniopharyngioma ≥ 3 years old completed a baseline sleep clinic evaluation by a pediatric sleep specialist, polysomnography (PSG) and next-day multiple sleep latency test (MSLT). MSLT was limited to those ≥ 6 years old. Logistic regression models were used to determine the relationship between patient characteristics and the presence and type of hypersomnia. RESULTS: Amongst patients completing PSG and MSLT, 80% had polygraphic evidence of excessive daytime sleepiness. Hypersomnia due to medical condition was diagnosed in 45% and narcolepsy in 35%. Overweight or obese patients were more likely to be diagnosed with hypersomnia (P = 0.012) or narcolepsy (P = 0.009). Grade 2 hypothalamic involvement (HI) at diagnosis was associated with the diagnosis of narcolepsy (P = 0.0008). CONCLUSIONS: This study describes the prevalence and associated predictors of hypersomnia for patients with craniopharyngioma after surgical resection. HI was predictive of narcolepsy diagnosis, and a higher body mass index z-score was associated with hypersomnia due to medical condition and narcolepsy. We recommend that sleep assessment and intervention begin after surgical resection, especially in overweight or obese patients and those with extensive tumors.

Are we meeting the informational needs of cancer patients and families? Perception of physician communication in pediatric oncology.

BACKGROUND: High-quality oncology care is marked by skillful communication, yet little is known about patient and family communication perceptions or content preferences. Our study sought to elicit pediatric oncology patient and parent perceptions of early cancer communication to establish whether informational needs were met and identify opportunities for enhanced communication throughout cancer care. METHOD: An original survey instrument was developed, pretested, and administered to 129 patients, age 10-18 years, and their parents at 3 cancer centers between 2011 and 2015. Statistical analysis of survey items about perceived communication, related associations, and patient/parent concordance was performed. RESULTS: A greater percentage of participants reported "a lot" of discussion about the physical impact of cancer (patients, 58.1% [n = 75]; parents, 69.8% [n = 90]) compared with impact on quality of life (QOL) (patients, 44.2% [n = 57]; parents, 55.8% [n = 72]) or emotional impact (patients, 31.8% [n = 41]; parents, 43.4% [n = 56]). One fifth of patients (20.9% [n = 27]) reported they had no up-front discussion about the emotional impact of cancer treatment. Parents indicated a desire for increased discussion regarding impact on family life (27.9% [n = 36]), long-term QOL (27.9% [n = 36]), and daily activities (20.2% [n = 26]). Patients more frequently than parents indicated a desire for increased physician/patient discussion around the impact on daily activities (patients, 40.3% [n = 52]; parents, 21.7% [n = 28]; P < .001), long-term QOL (patients, 34.9% [n = 45]; parents, 16.3% [n = 21]; P < .001), pain management (patients, 23.3% [n = 30]; parents, 7% [n = 9]; P < .001), physical symptom management (patients, 24% [n = 31]; parents, 7.8% [n = 10]; P < .001), short-term QOL (patients, 23.3% [n = 30]; parents, 9.3% [n = 12]; P = .001), and curative potential (patients, 21.7% [n = 28]; parents, 8.5% [n = 11]; P = .002, P values calculated using McNemar's test). CONCLUSION: Oncologists may not be meeting the informational needs of many patients and some parents/caregivers. Communication could be enhanced through increased direct physician-patient communication, as well as proactive discussion of emotional symptoms and impact of cancer on QOL.

Speaking genomics to parents offered germline testing for cancer predisposition: Use of a 2-visit consent model.

BACKGROUND: Patients with cancer are increasingly offered genomic sequencing, including germline testing for cancer predisposition or other disorders. Such testing is unfamiliar to patients and families, and clear communication is needed to introduce genomic concepts and convey risk and benefit information. METHODS: Parents of children with cancer were offered the opportunity to have their children's tumor and germline examined with clinical genomic sequencing. Families were introduced to the study with a 2-visit informed consent model. Baseline genetic knowledge and self-reported literacy/numeracy were collected before a study introduction visit, during which basic concepts related to genomic sequencing were discussed. Information was reinforced during a second visit, during which informed consent was obtained and a posttest was administered. RESULTS: As reflected by the percentage of correct answers on the pretest and posttest assessments, this model increased genetic knowledge by 11.1% (from 77.8% to 88.9%; P < .0001) in 121 parents participating in both the study introduction and consent visits. The percentage of parents correctly identifying the meaning of somatic and germline mutations increased significantly (from 18% to 59% [somatic] and from 31% to 64% [germline]; P < .0001). Nevertheless, these concepts remained unfamiliar to one-third of the parents. No relation was identified between the change in the overall percentage of correct answers and self-reported literacy, numeracy, or demographics. CONCLUSIONS: The use of a 2-visit communication model improved knowledge of concepts relevant to genomic sequencing, particularly differences between somatic and germline testing; however, these areas remained confusing to many participants, and reinforcement may be necessary to achieve complete understanding.

Noninferiority testing for matched-pair ordinal data with misclassification.

New treatments that are noninferior or equivalent to-but not necessarily superior to-the reference treatment may still be beneficial to patients because they have fewer side effects, are more convenient, take less time, or cost less. The noninferiority test is widely used in medical research to provide guidance in such situation. In addition, categorical variables are frequently encountered in medical research, such as in studies involving patient-reported outcomes. In this paper, we develop a noninferiority testing procedure for correlated ordinal categorical variables based on a paired design with a latent normal distribution approach. Misclassification is frequently encountered in the collection of ordinal categorical data; therefore, we further extend the procedure to account for misclassification using information in the partially validated data. Simulation studies are conducted to investigate the accuracy of the estimates, the type I error rates, and the power of the proposed procedure. Finally, we analyze one substantive example to demonstrate the utility of the proposed approach.

Predictors of Location of Death for Children with Cancer Enrolled on a Palliative Care Service.

BACKGROUND: In the U.S., more children die from cancer than from any other disease, and more than one third die in the hospital setting. These data have been replicated even in subpopulations of children with cancer enrolled on a palliative care service. Children with cancer who die in high-acuity inpatient settings often experience suffering at the end of life, with increased psychosocial morbidities seen in their bereaved parents. Strategies to preemptively identify children with cancer who are more likely to die in high-acuity inpatient settings have not been explored. MATERIALS AND METHODS: A standardized tool was used to gather demographic, disease, treatment, and end-of-life variables for 321 pediatric palliative oncology (PPO) patients treated at an academic pediatric cancer center who died between 2011 and 2015. Multinomial logistic regression was used to predict patient subgroups at increased risk for pediatric intensive care unit (PICU) death. RESULTS: Higher odds of dying in the PICU were found in patients with Hispanic ethnicity (odds ratio [OR], 4.02; p = .002), hematologic malignancy (OR, 7.42; p < .0001), history of hematopoietic stem cell transplant (OR, 4.52; p < .0001), total number of PICU hospitalizations (OR, 1.98; p < .0001), receipt of cancer-directed therapy during the last month of life (OR, 2.96; p = .002), and palliative care involvement occurring less than 30 days before death (OR, 4.7; p < .0001). Conversely, lower odds of dying in the PICU were found in patients with hospice involvement (OR, 0.02; p < .0001) and documentation of advance directives at the time of death (OR, 0.37; p = .033). CONCLUSION: Certain variables may predict PICU death for PPO patients, including delayed palliative care involvement. Preemptive identification of patients at risk for PICU death affords opportunities to study the effects of earlier palliative care integration and increased discussions around preferred location of death on end-of-life outcomes for children with cancer and their families. IMPLICATIONS FOR PRACTICE: Children with cancer who die in high-acuity inpatient settings often experience a high burden of intensive therapy at the end of life. Strategies to identify patients at higher risk of dying in the pediatric intensive care unit (PICU) have not been explored previously. This study finds that certain variables may predict PICU death for pediatric palliative oncology patients, including delayed palliative care involvement. Preemptive identification of patients at risk for PICU death affords opportunities to study the effects of earlier palliative care integration and increased discussions around preferred location of death on end-of-life outcomes for children with cancer and their families.

Prevalence, risk factors, and response to treatment for hypersomnia of central origin in survivors of childhood brain tumors.

Daytime sleepiness is recognized in childhood brain tumor survivors. Our objective was to determine prevalence, risk factors for PSG/MLST proven hypersomnia/narcolepsy, and response to stimulants in childhood brain tumor survivors. Standard PSG/MSLT criteria were used to diagnose hypersomnia/narcolepsy. Medical records of brain tumor survivors having undergone a PSG/MSLT were reviewed for the diagnostic code of hypersomnia/narcolepsy. Survivors with hypersomnia/narcolepsy were matched with 2-3 survivors without reported hypersomnia/narcolepsy by age at tumor diagnosis, gender, and time from tumor diagnosis. Between January 2000 to April 2015, 39 of the 2336 brain tumor patients treated at our institution were diagnosed with hypersomnia/narcolepsy for a prevalence rate of 1670/100,000. Hypersomnia/narcolepsy was diagnosed at a median of 6.1 years (range 0.4-13.2) from tumor diagnosis and 4.7 years (range - 1.5 to 10.4) from cranial radiation. Midline tumor location (OR 4.6, CI 1.7-12.2, p = 0.002) and anti-epilepsy drug (AED) use (OR 11, CI 2.4-54) correlated with hypersomnia/narcolepsy while radiation dose > 30 Gray trended towards significance (OR 1.8, CI 0.9-3.6); posterior fossa tumor location reduced the risk (OR 0.1, CI 0.04-0.5, p = 0.002). AED use also correlated with midline tumor location. Thirty-seven survivors were treated with stimulants and reported improved wakefulness and school performance [response rate CI 0.97 (0.86-0.99) and 0.83 (0.65-0.94)]. Prevalence of hypersomnia/narcolepsy among childhood brain tumor survivors was higher than the general population. Tumor location and radiation dose were possible risk factors, and stimulants were reported to be beneficial.

Illness and end-of-life experiences of children with cancer who receive palliative care.

BACKGROUND: The field of pediatric palliative oncology is newly emerging. Little is known about the characteristics and illness experiences of children with cancer who receive palliative care (PC). METHODS: A retrospective cohort study of 321 pediatric oncology patients enrolled in PC who died between 2011 and 2015 was conducted at a large academic pediatric cancer center using a comprehensive standardized data extraction tool. RESULTS: The majority of pediatric palliative oncology patients received experimental therapy (79.4%), with 40.5% enrolled on a phase I trial. Approximately one-third received cancer-directed therapy during the last month of life (35.5%). More than half had at least one intensive care unit hospitalization (51.4%), with this subset demonstrating considerable exposure to mechanical ventilation (44.8%), invasive procedures (20%), and cardiopulmonary resuscitation (12.1%). Of the 122 patients who died in the hospital, 44.3% died in the intensive care unit. Patients with late PC involvement occurring less than 30 days before death had higher odds of dying in the intensive care unit over the home/hospice setting compared to those with earlier PC involvement (OR: 4.7, 95% CI: 2.47-8.97, P < 0.0001). CONCLUSIONS: Children with cancer who receive PC experience a high burden of intensive treatments and often die in inpatient intensive care settings. Delayed PC involvement is associated with increased odds of dying in the intensive care unit. Prospective investigation of early PC involvement in children with high-risk cancer is needed to better understand potential impacts on cost-effectiveness, quality of life, and delivery of goal concordant care.

Structural and Maturational Covariance in Early Childhood Brain Development.

Brain structural covariance networks (SCNs) composed of regions with correlated variation are altered in neuropsychiatric disease and change with age. Little is known about the development of SCNs in early childhood, a period of rapid cortical growth. We investigated the development of structural and maturational covariance networks, including default, dorsal attention, primary visual and sensorimotor networks in a longitudinal population of 118 children after birth to 2 years old and compared them with intrinsic functional connectivity networks. We found that structural covariance of all networks exhibit strong correlations mostly limited to their seed regions. By Age 2, default and dorsal attention structural networks are much less distributed compared with their functional maps. The maturational covariance maps, however, revealed significant couplings in rates of change between distributed regions, which partially recapitulate their functional networks. The structural and maturational covariance of the primary visual and sensorimotor networks shows similar patterns to the corresponding functional networks. Results indicate that functional networks are in place prior to structural networks, that correlated structural patterns in adult may arise in part from coordinated cortical maturation, and that regional co-activation in functional networks may guide and refine the maturation of SCNs over childhood development.

Impact of Demographic and Obstetric Factors on Infant Brain Volumes: A Population Neuroscience Study.

Individual differences in neuroanatomy are associated with intellectual ability and psychiatric risk. Factors responsible for this variability remain poorly understood. We tested whether 17 major demographic and obstetric variables were associated with individual differences in brain volumes in 756 neonates assessed with MRI. Gestational age at MRI, sex, gestational age at birth, and birthweight were the most significant predictors, explaining 31% to 59% of variance. Unexpectedly, earlier born babies had larger brains than later born babies after adjusting for other predictors. Our results suggest earlier born children experience accelerated brain growth, either as a consequence of the richer sensory environment they experience outside the womb or in response to other factors associated with delivery. In the full sample, maternal and paternal education, maternal ethnicity, maternal smoking, and maternal psychiatric history showed marginal associations with brain volumes, whereas maternal age, paternal age, paternal ethnicity, paternal psychiatric history, and income did not. Effects of parental education and maternal ethnicity are partially mediated by differences in birthweight. Remaining effects may reflect differences in genetic variation or cultural capital. In particular late initiation of prenatal care could negatively impact brain development. Findings could inform public health policy aimed at optimizing child development.