Publications by authors named "Yimei Li"

258 Publications

Limited Surgery and Conformal Photon Radiation Therapy for Pediatric Craniopharyngioma: Long-term Results from the RT1 Protocol.

Neuro Oncol 2022 May 12. Epub 2022 May 12.

Departments of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Background: Our aim was to estimate long-term disease control and complications after conformal radiation therapy (CRT) in children and adolescents with craniopharyngioma.

Materials And Methods: Pediatric patients with craniopharyngioma (n=101) were enrolled on or treated according to a phase II single institutional protocol from 1998. Surgery was individualized, and CRT (54Gy) was administered using a 1.0 cm or 0.5 cm clinical target volume margin. Patients were followed for 10 years by serial MR imaging and MR angiography and a battery of tests to measure the effects of treatment.

Results: Twenty patients had tumor progression. Twelve patients who had tumor progression died due to tumor (n=6) or complications related to tumor or treatment (n=6). With a median follow-up of 14.94 years for survivors, the 10-year estimates (±SE) of progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) were 78.84% ± 4.10%, 77.12% ± 4.19%, and 96.02% ± 1.95%, respectively. OS, EFS, and PFS were significantly associated with race, shunt status, and tumor volume. The 10-year cumulative incidence (±SE) of the secondary tumor (1.99% ± 1.40%), secondary malignant tumor (1.0% ± 1.0%), necrosis (1.98% ± 1.39%), vasculopathy (8.47% ± 2.90%), and permanent neurologic deficits (8.28% ± 3.37%) were estimated by competing risk analysis. Three patients required revascularization surgery. Salvage therapy was successful in 13 patients using surgery and radiosurgery.

Conclusions: Limited surgery and CRT using photons results in excellent tumor control. Tumor control and the incidence and severity of complications are associated with host, tumor, and treatment factors.
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http://dx.doi.org/10.1093/neuonc/noac124DOI Listing
May 2022

Sociodemographics, Health Competence, and Transition Readiness Among Adolescent/Young Adult Cancer Survivors.

J Pediatr Psychol 2022 Apr 28. Epub 2022 Apr 28.

Division of Oncology, The Children's Hospital of Philadelphia, USA.

Objective: Fewer than one-third of childhood cancer survivors receive follow-up from an adult provider, and adolescent and young adults (AYAs) from structurally minoritized sociodemographic groups often face health disparities that can impact transition to adult-oriented care. The primary aim of this study was to determine the relation among sociodemographic factors, cumulative effects, and transition beliefs/expectations and goals, and the moderating role of health competence beliefs in AYA survivors of childhood cancer.

Methods: A total of 195 AYAs (aged 15-29) reported sociodemographic information, completed the Transition Readiness Inventory assessing positive beliefs/expectations and goals related to transition, and completed the Health Competence Beliefs Inventory assessing health perceptions, healthcare satisfaction, cognitive competence, and autonomy. A cumulative sociodemographic factor variable was computed to investigate the potential additive effects of multiple sociodemographic factors associated with disparities. T-tests, Pearson correlations, and multivariate linear regressions were used.

Results: Cumulative sociodemographic factors were not related to transition readiness, and insurance type was the only factor associated with health competence beliefs and transition readiness, such that AYAs with public insurance reported lower healthcare satisfaction, cognitive competence, and transition goals relative to those with private insurance. There were no interaction effects; however, health competence beliefs were significantly associated with transition beliefs/expectations and goals.

Conclusion: Public insurance is a barrier to holding positive beliefs/expectations and goals about transition, yet other sociodemographic factors associated with risks for poor transfer were not related to transition readiness. Multi-level interventions to reduce disparities and improve transition readiness should target health competence beliefs and barriers created by insurance.
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http://dx.doi.org/10.1093/jpepsy/jsac039DOI Listing
April 2022

Endocrine Outcomes after Limited Surgery and Conformal Photon Radiation Therapy for Pediatric Craniopharyngioma: Long-term Results from the RT1 Protocol.

Neuro Oncol 2022 Apr 27. Epub 2022 Apr 27.

Department of Pediatrics, University of California, San Francisco, CA, USA.

Background: To estimate the incidence of endocrinopathy in children and adolescents with craniopharyngioma after treatment with photon-based conformal and intensity-modulated radiation therapy (CRT).

Methods: 101 pediatric patients were enrolled on a phase II single-institution protocol beginning in 1998 (n=76) or followed a similar non-protocol treatment plan (n=25). Surgery was individualized. CRT (54 Gy) was administered using a 1.0-cm or ≤0.5-cm clinical target volume margin. Patients underwent baseline and serial evaluation of the hypothalamic-pituitary axis.

Results: The 10-year cumulative incidence (CI) of growth hormone deficiency (GHD) was 68.42% (±11.27) for black patients and 94.23% (±3.57) for white patients (p=0.0286). The CI of thyroid stimulating hormone deficiency (TSHD) was 70.94% (±8.44) at 10 years for non-shunted patients and 91.67% (±10.40) at 6 years for shunted patients (p=0.0260). The CI of TSHD was 100% (±14.29) at 4 years for those with diabetes insipidus (DI) and 71.36% (±8.86) at 10 years for those without DI (p=0.0008). The 10-year CI of adrenocortical hormone deficiency was 70.00% (±16.15) for those with DI and 48.39% (±9.19) for those without DI (p=0.0080). The 10-year CI of LH/FSH deficiency was 43.33% (±9.32) age < 7 years, 61.29% (±9.11) aged 7-10 years, and 78.95% (±6.38) age ≥ 10 years (p<0.0001). BMI was significantly greater prior to CRT in white patients with DI (p=0.0004) and pre-existing GHD (p=0.0275).

Conclusions: Hormone deficiencies are common in pediatric patients with craniopharyngioma and associated with host, tumor, and treatment factors. Understanding the incidence and time to onset may facilitate intervention and patient selection for treatment.
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http://dx.doi.org/10.1093/neuonc/noac115DOI Listing
April 2022

Low-dose ketamine infusions reduce opioid use in pediatric and young adult oncology patients.

Pediatr Blood Cancer 2022 Apr 4:e29693. Epub 2022 Apr 4.

St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Ketamine is an NMDA-receptor antagonist with analgesic and opioid-sparing properties. Although well studied in adults, more robust evidence supporting ketamine's use for pediatric pain management is needed. This retrospective study evaluates ketamine's opioid-sparing effectiveness in pediatric and young adult oncology and hematology patients.

Procedure: Continuous ketamine infusions administered for pain management between 2010-2020 were reviewed. Data including demographic characteristics, oncology/hematology and pain diagnoses, concurrent pain medications, and ketamine infusions' dose and duration were collected. Opioid consumption data based on delivery via patient-controlled analgesia were collected 1 day before (D1), all days during (cumulatively named D2), and 1 day after (D3) ketamine infusions and calculated as morphine-equivalent doses (mg/kg/day). Data were reported for the entire study group as well as for distinct oncology and end-of-life categories, and short-term acute pain circumstances which included vaso-occlusive crises in hematology patients. Side effects were reviewed.

Results: Significantly lower daily opioid consumption was noted in the oncology group, while decreases were not significant in the end-of-life group and in the overall study population. The acute pain group did not show an opioid reduction associated with the ketamine infusions. A largely tolerable side-effect profile was observed, with no differences among each group's incidence.

Conclusions: Ketamine infusions were associated with significantly reduced opioid consumption for oncology patients. The opioid-sparing effects of ketamine may vary according to clinical diagnoses and circumstances of use. Overall, low-dose ketamine infusions present an acceptable safety profile in pediatric and young adult patients; nevertheless, individual risks and benefits should be considered.
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http://dx.doi.org/10.1002/pbc.29693DOI Listing
April 2022

Variation in hospital costs and resource utilisation after congenital heart surgery.

Cardiol Young 2022 Apr 4:1-12. Epub 2022 Apr 4.

Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Children undergoing cardiac surgery have overall improving survival, though they consume substantial resources. Nationwide inpatient cost estimates and costs at longitudinal follow-up are lacking.

Methods: Retrospective cohort study of children <19 years of age admitted to Pediatric Health Information System administrative database with an International Classification of Diseases diagnosis code undergoing cardiac surgery. Patients were grouped into neonates (≤30 days of age), infants (31-365 days of age), and children (>1 year) at index procedure. Primary and secondary outcomes included hospital stay and hospital costs at index surgical admission and 1- and 5-year follow-up.

Results: Of the 99,670 cohort patients, neonates comprised 27% and had the highest total hospital costs, though daily hospital costs were lower. Mortality declined (5.6% in 2004 versus 2.5% in 2015, p < 0.0001) while inpatient costs rose (5% increase/year, p < 0.0001). Neonates had greater index diagnosis complexity, greater inpatient costs, required the greatest ICU resources, pharmacotherapy, and respiratory therapy. We found no relationship between hospital surgical volume, mortality, and hospital costs. Neonates had higher cumulative hospital costs at 1- and 5-year follow-up compared to infants and children.

Conclusions: Inpatient hospital costs rose during the study period, driven primarily by longer stay. Neonates had greater complexity index diagnosis, required greater hospital resources, and have higher hospital costs at 1 and 5 years compared to older children. Surgical volume and in-hospital mortality were not associated with costs. Further analyses comprising merged clinical and administrative data are necessary to identify longer stay and cost drivers after paediatric cardiac surgery.
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http://dx.doi.org/10.1017/S1047951122001019DOI Listing
April 2022

Risk factors associated with metastatic site failure in patients with high-risk neuroblastoma.

Clin Transl Radiat Oncol 2022 May 10;34:42-50. Epub 2022 Mar 10.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States.

Purpose: This retrospective study sought to identify predictors of metastatic site failure (MSF) at new and/or original (present at diagnosis) sites in high-risk neuroblastoma patients.

Methods And Materials: Seventy-six high-risk neuroblastoma patients treated on four institutional prospective trials from 1997 to 2014 with induction chemotherapy, surgery, myeloablative chemotherapy, stem-cell rescue, and were eligible for consolidative primary and metastatic site (MS) radiotherapy were eligible for study inclusion. Computed-tomography and I-123 MIBG scans were used to assess disease response and Curie scores at diagnosis, post-induction, post-transplant, and treatment failure. Outcomes were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) and CPH regression (CPHr) were used to identify covariates predictive of MSF at a site identified either at diagnosis or later.

Results: MSF occurred in 42 patients (55%). Consolidative MS RT was applied to 30 MSs in 10 patients. Original-MSF occurred in 146 of 383 (38%) non-irradiated and 18 of 30 (60%) irradiated MSs (p = 0.018). Original- MSF occurred in post-induction MIBG-avid MSs in 68 of 81 (84%) non-irradiated and 12 of 14 (85%) radiated MSs (p = 0.867). The median overall and progression-free survival rates were 61 months (95% CI 42.6-Not Reached) and 24.1 months (95% CI 16.5-38.7), respectively. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) and/or maintenance chemotherapy (HR 5.2, 95%CI 1.7-16.2, p = 0.005), and the presence of lung metastases at diagnosis (HR 4.4 95%CI 1.7-11.1, p = 0.002) as predictors of new MSF. The new MSF-free survival rate at 3 years was 25% and 87% in patients with and without high-risk factors.

Conclusions: Incremental improvements in systemic therapy influence the patterns and type of metastatic site failure in neuroblastoma. Persistence of MIBG-avidity following induction chemotherapy and transplant at MSs increased the hazard for MSF.
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http://dx.doi.org/10.1016/j.ctro.2022.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8956847PMC
May 2022

MRI sequences and interslice gap influence leptomeningeal metastasis detection in children with brain tumors.

Neuroradiology 2022 Mar 28. Epub 2022 Mar 28.

Department of Diagnostic Imaging, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 220, Memphis, TN, 38015, USA.

Purpose: Accurate detection of leptomeningeal metastasis (LM) is critical for risk stratification and treatment of pediatric brain tumors. Poor-quality staging MRI has been associated with decreased survival in this population, but technical factors differentiating good from poor quality screening MRIs remain undefined. To test the hypothesis that key technical factors are associated with accurate MRI diagnosis of leptomeningeal metastasis in children with leptomeningeal seeding brain tumors.

Methods: MRIs acquired at outside facilities and repeated in our institution within 35 days for 75 children with leptomeningeal seeding tumors were assessed for slice thickness and gap; use of T2 FLAIR + Contrast, acquisition plane of 3DT1WI + Contrast (brain); axial T1 + Contrast sequence, and use of pre-contrast T1 images (spine). Reported findings were recorded as positive, negative, or equivocal for LM and classified as true positive (TP; unequivocal metastasis), false negative (FN; not reported), false positive (FP; resolved without treatment), or true negative. Wilcoxon signed-rank and Fisher's exact test were used to assess technical differences between TP and FN MRIs.

Results: Rate of LM detection was greater with smaller interslice gap in brain (P = 0.003) and spine (P = 0.002); use of T2 FLAIR + Contrast (P = 0.005) and sagittal plane for 3DT1WI + Contrast (P = 0.028) in brain; and use of alternatives to axial TSE/FSE in spine (P = 0.048). Slice thickness was not significant. Pre-contrast T1WI did not contribute to LM diagnosis in spine.

Conclusion: Using post-contrast T2 FLAIR and sagittal 3DT1 in brain, small/no interslice gap, and avoiding TSE/FSE axials in spine may facilitate leptomeningeal metastasis detection in children with brain tumors.
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http://dx.doi.org/10.1007/s00234-022-02928-7DOI Listing
March 2022

Surgical outcomes in survivors of childhood cancer undergoing thyroidectomy: A single-institution experience.

Pediatr Blood Cancer 2022 06 26;69(6):e29674. Epub 2022 Mar 26.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Background: Childhood cancer survivors (CCS) are at increased risk for thyroid disease, and many require definitive management with thyroid surgery. Despite this, there is limited evidence on surgical outcomes among CCS. We sought to evaluate postoperative outcomes at our institution among CCS undergoing thyroid surgery compared to patients without a history of primary childhood malignancy.

Procedure: Medical records were reviewed for 638 patients treated at the Children's Hospital of Philadelphia Pediatric Thyroid Center between 2009 and 2020. Rates of surgical complications, including recurrent laryngeal nerve (RLN) paralysis and hypoparathyroidism, among CCS were compared to patients with sporadic/familial thyroid cancer, Graves' disease, and other benign thyroid conditions. Operative time and intraoperative parathyroid hormone levels were also evaluated.

Results: There were no significant differences in long-term surgical complication rates, such as permanent RLN paralysis and hypoparathyroidism, between CCS and patients without a history of primary childhood malignancy (all p > .05). For all surgical outcomes, there were no significant differences in complication rates when CCS were compared to those undergoing surgery for sporadic/familial thyroid cancer or Graves' disease (all p > .05). CCS with benign final pathology had significantly higher rates of transient hypoparathyroidism compared to patients with benign thyroid conditions (p < .001).

Conclusions: Our study suggests that CCS are not at higher risk of long-term complications from thyroid surgery when treated by high-volume surgeons within a multidisciplinary team.
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http://dx.doi.org/10.1002/pbc.29674DOI Listing
June 2022

Alzheimer's Disease Classification Through Imaging Genetic Data With IGnet.

Front Neurosci 2022 3;16:846638. Epub 2022 Mar 3.

Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, United States.

The application of deep learning techniques to the detection and automated classification of Alzheimer's disease (AD) has recently gained considerable attention. The rapid progress in neuroimaging and sequencing techniques has enabled the generation of large-scale imaging genetic data for AD research. In this study, we developed a deep learning approach, IGnet, for automated AD classification using both magnetic resonance imaging (MRI) data and genetic sequencing data. The proposed approach integrates computer vision (CV) and natural language processing (NLP) techniques, with a deep three-dimensional convolutional network (3D CNN) being used to handle the three-dimensional MRI input and a Transformer encoder being used to manage the genetic sequence input. The proposed approach has been applied to the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set. Using baseline MRI scans and selected single-nucleotide polymorphisms on chromosome 19, it achieved a classification accuracy of 83.78% and an area under the receiver operating characteristic curve (AUC-ROC) of 0.924 with the test set. The results demonstrate the great potential of using multi-disciplinary AI approaches to integrate imaging genetic data for the automated classification of AD.
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http://dx.doi.org/10.3389/fnins.2022.846638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8927016PMC
March 2022

Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.

EMBO J 2022 04 25;41(8):e108272. Epub 2022 Feb 25.

Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug-resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient-matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER-mitochondria-associated membranes (MAMs; ER-mitochondria contacts, ERMCs) in therapy-resistant cells, and genetically or biochemically reducing MAMs in therapy-sensitive tumors phenocopied resistance. MAMs serve as platforms to transfer Ca and bioactive lipids to mitochondria. Reduced Ca transfer was found in some but not all resistant cells, and inhibiting transfer did not attenuate apoptotic signaling. In contrast, reduced ceramide synthesis and transfer was common to resistant cells and its inhibition induced stress resistance. We identify ER-mitochondria-associated membranes as physiologic regulators of apoptosis via ceramide transfer and uncover a previously unrecognized mechanism for cancer multidrug resistance.
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http://dx.doi.org/10.15252/embj.2021108272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9016347PMC
April 2022

Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency.

J Transl Med 2022 02 23;20(1):103. Epub 2022 Feb 23.

Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN, USA.

Background: Pantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. PANK-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz disease, is a rare, life-threatening neurologic disorder that affects the CNS and arises from mutations in the human PANK2 gene. Pantazines, a class of small molecules containing the pantazine moiety, yield promising therapeutic effects in an animal model of brain CoA deficiency. A reliable technique to identify the neurometabolic effects of PANK dysfunction and to monitor therapeutic responses is needed.

Methods: We applied H magnetic resonance spectroscopy as a noninvasive technique to evaluate the therapeutic effects of the newly developed Pantazine BBP-671.

Results: H MRS reliably quantified changes in cerebral metabolites, including glutamate/glutamine, lactate, and N-acetyl aspartate in a neuronal Pank1 and Pank2 double-knockout (SynCre Pank1,2 dKO) mouse model of brain CoA deficiency. The neuronal SynCre Pank1,2 dKO mice had distinct decreases in Glx/tCr, NAA/tCr, and lactate/tCr ratios compared to the wildtype matched control mice that increased in response to BBP-671 treatment.

Conclusions: BBP-671 treatment completely restored glutamate/glutamine levels in the brains of the mouse model, suggesting that these metabolites are promising clinically translatable biomarkers for future therapeutic trials.
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http://dx.doi.org/10.1186/s12967-022-03304-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8867880PMC
February 2022

Inference for set-based effects in genetic association studies with interval-censored outcomes.

Biometrics 2022 Feb 14. Epub 2022 Feb 14.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

The rapid acceleration of genetic data collection in biomedical settings has recently resulted in the rise of genetic compendiums filled with rich longitudinal disease data. One common feature of these data sets is their plethora of interval-censored outcomes. However, very few tools are available for the analysis of genetic data sets with interval-censored outcomes, and in particular, there is a lack of methodology available for set-based inference. Set-based inference is used to associate a gene, biological pathway, or other genetic construct with outcomes and is one of the most popular strategies in genetics research. This work develops three such tests for interval-censored settings beginning with a variance components test for interval-censored outcomes, the interval-censored sequence kernel association test (ICSKAT). We also provide the interval-censored version of the Burden test, and then we integrate ICSKAT and Burden to construct the interval censored sequence kernel association test-optimal (ICSKATO) combination. These tests unlock set-based analysis of interval-censored data sets with analogs of three highly popular set-based tools commonly applied to continuous and binary outcomes. Simulation studies illustrate the advantages of the developed methods over ad hoc alternatives, including protection of the type I error rate at very low levels and increased power. The proposed approaches are applied to the investigation that motivated this study, an examination of the genes associated with bone mineral density deficiency and fracture risk.
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http://dx.doi.org/10.1111/biom.13636DOI Listing
February 2022

Association between timely targeted treatment and outcomes in patients with metastatic HER2-overexpressing gastroesophageal adenocarcinoma.

Cancer 2022 May 4;128(9):1853-1862. Epub 2022 Feb 4.

Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Timely targeted treatment initiation can be challenging because additional biomarker testing is needed for eligibility. The authors hypothesized that timely targeted treatment improves survival relative to nontimely initiation in metastatic HER2+ gastroesophageal adenocarcinoma (GEA).

Methods: The authors performed a retrospective cohort study of metastatic HER2+ GEA treated with first-line (1L) systemic therapy from January 2011 to December 2017 using a nationwide electronic health record-derived deidentified database. Timely targeted treatment-trastuzumab initiation within 14 days after starting 1L chemotherapy-was assessed as a time-varying exposure. Nontimely targeted treatment included patients who initiated trastuzumab after 14 days or who lacked documentation of receiving trastuzumab. Extended Cox regressions compared overall survival (OS) and progression-free survival (PFS) between timely and nontimely groups.

Results: A total of 320 patients were included; 59.1% received timely trastuzumab. Relative to nontimely initiation, timely trastuzumab was associated with significantly higher OS (2-year OS, 32.1% vs 15.3%; adjusted hazard ratio [HR], 0.67; 95% CI, 0.51-0.88) and PFS (2-year PFS, 9.2% vs 3.7%; adjusted HR, 0.71; 95% CI, 0.55-0.93). Results remained similar in sensitivity analyses 1) using alternative "timeliness" definitions up to 70 days after starting 1L chemotherapy, 2) comparing any trastuzumab, regardless of timing of initiation, to no trastuzumab, and 3) excluding patients lacking documentation of receiving trastuzumab.

Conclusions: Improved survival was observed among metastatic HER2+ GEA patients treated with trastuzumab versus those who were not, regardless of timing of initiation. Although these results reassure clinicians that modest targeted treatment delays may not be detrimental to outcomes, efforts should still ensure that all metastatic HER2+ GEA patients receive trastuzumab.
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http://dx.doi.org/10.1002/cncr.34117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007872PMC
May 2022

Toward MR-only proton therapy planning for pediatric brain tumors: Synthesis of relative proton stopping power images with multiple sequence MRI and development of an online quality assurance tool.

Med Phys 2022 Mar 11;49(3):1559-1570. Epub 2022 Feb 11.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Purpose: To generate synthetic relative proton stopping power (sRPSP) images from magnetic resonance imaging (MRI) sequence(s) and develop an online quality assurance (QA) tool for sRPSP to facilitate safe integration of magnetic resonance (MR)-only proton planning into clinical practice.

Materials And Methods: Planning computed tomography (CT) and MR images of 195 pediatric brain tumor patients were utilized (training: 150, testing: 45). Seventeen consistent-cycle generative adversarial network (ccGAN) models were trained separately using paired CT-converted RPSP and MRI datasets to transform a subject's MRI into sRPSP. T1-weighted (T1W), T2-weighted (T2W), and FLAIR MRI were permutated to form 17 combinations, with or without preprocessing, for determining the optimal training sequence(s). For evaluation, sRPSP images were converted to synthetic CT (sCT) and compared to the real CT in terms of mean absolute error (MAE) in Hounsfield units (HU). For QA, sCT was deformed and compared to a reference template built from training dataset to produce a flag map, highlighting pixels that deviate by >100 HU and fall outside the mean ± standard deviation reference intensity. The gamma intensity analysis (10%/3 mm) of the deformed sCT against the QA template on the intensity difference was investigated as a surrogate of sCT accuracy.

Results: The sRPSP images generated from a single T1W or T2W sequence outperformed that generated from multi-MRI sequences in terms of MAE (all p < 0.05). Preprocessing with N4 bias and histogram matching reduced MAE of T2W MRI-based sCT (54 ± 21 HU vs. 42 ± 13 HU, p = 0.002). The gamma intensity analysis of sCT against the QA template was highly correlated with the MAE of sCT against the real CT in the testing cohort (r = -0.89 for T1W sCT; r = -0.93 for T2W sCT).

Conclusion: Accurate sRPSP images can be generated from T1W/T2W MRI for proton planning. A QA tool highlights regions of inaccuracy, flagging problematic cases unsuitable for clinical use.
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http://dx.doi.org/10.1002/mp.15479DOI Listing
March 2022

Association of decreased muscle mass with reduced bone mineral density in patients with Graves' disease.

Endocrine 2022 Mar 22;75(3):916-926. Epub 2022 Jan 22.

Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong Road, Fuzhou, 350005, Fujian, China.

Aim: This study aimed to determine the association of decreased muscle mass with reduced bone mineral density in patients with Graves' disease.

Methods: A total of 758 patients with Graves' disease at diagnosis (mean age 41.2 years) were enrolled for a cross-sectional study; of these, 287 were enrolled for a cohort study with a median follow-up of 24 months. Meanwhile, 1164 age- and sex-matched healthy controls were recruited. All participants underwent dual-energy x-ray absorptiometry and muscle mass index (ASMI) measurements. The changes in ASMI and bone mineral density (BMD) were calculated from the measurements made at a gap of 2 years.

Results: The BMD of patients with Graves' disease was still significantly lower after normalizing serum thyroid hormone levels compared with that of healthy controls. ASMI positively correlated with BMD in patients with Graves' disease (lumbar BMD, r = 0.210; femoral neck BMD, r = 0.259; hip BMD, r = 0.235; P < 0.001), and this relationship persisted after successful anti-thyroid therapy (lumbar BMD, r = 0.169; femoral neck BMD, r = 0.281; hip BMD, r = 0.394; P < 0.001). Low muscle mass was associated with low BMD (OR, 1.436; 95% CI, 1.026-2.010). Improving the muscle mass led to changes in the bone mass of the femoral neck (OR, 0.420; 95% CI, 0.194-0.911) and hip (OR, 0.217; 95% CI, 0.092-0.511) during the follow-up. However, this phenomenon was not observed in lumbar and bone turnover markers.

Conclusions: The recovery of bone mass might be related to the recovery of the muscle mass. Patients with Graves' disease should be helped to regain their muscle mass and thus accelerate the recovery of bone mass while administering anti-thyroid therapy.
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http://dx.doi.org/10.1007/s12020-021-02960-2DOI Listing
March 2022

Risk Factors for Treatment Refractory and Relapsed Optic Pathway Glioma in Children with Neurofibromatosis Type 1.

Neuro Oncol 2022 Jan 9. Epub 2022 Jan 9.

Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, PA.

Background: Nearly one-third of patients with neurofibromatosis type 1-associated optic pathway glioma (NF1-OPG) fail frontline chemotherapy; however, little is known about risk factors for treatment failure.

Methods: We performed a retrospective multi-institutional cohort study to identify baseline risk factors for treatment-refractory/relapsed disease and poor visual outcome in children with NF1-OPG. Refractory/relapsed NF1-OPG was defined as requirement of two or more treatment regimens due to progression or relapse.

Results: Of 111 subjects eligible for inclusion, adequate clinical and visual data were available for 103 subjects from 7 institutions. Median follow-up from initiation of first chemotherapy regimen was 95 months (range 13-185). Eighty-four (82%) subjects received carboplatin-based frontline chemotherapy. Forty-five subjects (44%) experienced refractory/relapsed disease, with median time of 21.5 months (range 2-149) from initiation of first treatment to start of second treatment. The proportion of patients without refractory/relapsed disease at 2 and 5 years was 78% and 60%. In multivariable analyses, age less than 24 months at initial treatment, posterior tumor location, and familial inheritance were associated with refractory/relapsed NF1-OPG by 2 years. Both age less than 24 months and posterior tumor location were associated with refractory/relapsed NF1-OPG by 5 years. Subjects with moderate to severe vision loss at last follow-up were more likely to have posterior tumor location, optic disc abnormalities, or abnormal visual acuity at initial treatment.

Conclusion: Young age, posterior tumor location, and optic disc abnormalities may identify patients with the greatest likelihood of refractory/relapsed NF1-OPG and poor visual outcomes, and who may benefit from newer treatment strategies.
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http://dx.doi.org/10.1093/neuonc/noac013DOI Listing
January 2022

Outcomes of children and young adults with T-cell acute lymphoblastic leukemia/lymphoma who present in critical status.

Pediatr Blood Cancer 2022 04 8;69(4):e29457. Epub 2022 Jan 8.

Perelman School of Medicine, Philadelphia, Pennsylvania.

Background: Patients with T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/LLy) commonly present with critical features such as hyperleukocytosis and mediastinal mass, which complicates completing a diagnostic and staging workup and prevents clinical trial enrollment.

Procedure: Consecutive patients with T-ALL/LLy from 1999 to 2019 at the Children's Hospital of Philadelphia were analyzed for pediatric intensive care unit (PICU) admission and various high-risk features as well as clinical trial enrollment and outcome.

Results: We identified 153 patients newly diagnosed with T-ALL/LLy, 53 (35%) required PICU-level care within 24 hours and 73 (48%) within 7 days. Non-PICU patients had a significantly higher clinical trial enrollment rate (79.4%) versus PICU patients (56.1%, P = 0.016). Patients who enrolled on a clinical trial had similar relapse risk to those who did not enroll (relapse rate 20% vs 29%, P = 0.523). Nineteen patients were precluded from trial participation. Risk of relapse was increased for patients admitted to the PICU within 24 hours (26% vs 13%, P = 0.048). Forty-four patients with T-ALL presented with hyperleukocytosis, of which 30% relapsed versus 14% without (P = 0.082). Patients who underwent apheresis for hyperleukocytosis were statistically more likely to relapse (47% vs 15%, P = 0.007). Patients with elevated uric acid (20% vs 16%, P = 0.278), mediastinal mass (20% vs 14%, P = 0.501), or required emergent steroids (20% vs 16%, P = 0.626) had a similar relapse risk. A single second relapse patient survived.

Conclusions: Almost half of T-ALL/LLy patients required PICU-level care at diagnosis, making enrollment on clinical trials challenging, but trial enrollment predicted better outcome. Physicians should balance maintaining eligibility with safety to offer patients all options.
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http://dx.doi.org/10.1002/pbc.29457DOI Listing
April 2022

Pre- and Posttherapy Risk Factors for Vasculopathy in Pediatric Patients With Craniopharyngioma Treated With Surgery and Proton Radiation Therapy.

Int J Radiat Oncol Biol Phys 2022 05 3;113(1):152-160. Epub 2022 Jan 3.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: Vasculopathy (VAS) is a significant complication associated with radiation therapy in patients treated for brain tumors. We studied the type, location, severity, timing, and resolution of VAS in children with craniopharyngioma treated with proton radiation therapy (PRT) and evaluated predictors of stenosis (STN) using a novel patient and imaging-based modeling approach.

Methods And Materials: Children with craniopharyngioma (n = 94) were treated with 54 Gy relative biological effectiveness PRT in a clinical trial, NCT01419067. We evaluated VAS type, location, severity, and resolution. VAS events were segmented and related to their location, operative corridor, PRT dose, and vascular territory to facilitate mixed effect logistic regression modeling of spatial predictors of STN events.

Results: Forty-five (47.9%) patients had 111 instances of confirmed VAS (pre-PRT n = 37, 33.3%). The median time to post-PRT VAS was 3.41 years (95% confidence interval, 1.86-6.11). STN events were observed post-PRT in 23.4% (n = 22) of patients. Post-PRT VAS was detected by cerebral angiogram in 9.6% (n = 9), severe in 4.3% (n = 4), and compensated on perfusion in 2.1% (n = 2). Revascularization was required for 5 (5.3%) patients. Postsurgical, pre-PRT VAS, and PRT dose to unperturbed vessels were predictive of STN. The effect of PRT on STN was negligible within the surgical corridor.

Conclusions: VAS often precedes PRT and was the strongest predictor of post-PRT STN. The adverse effect of PRT on STN was only apparent in unperturbed vasculature beyond the operative corridor.
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http://dx.doi.org/10.1016/j.ijrobp.2021.12.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018579PMC
May 2022

The Emerging Role of FUNDC1-Mediated Mitophagy in Cardiovascular Diseases.

Front Physiol 2021 17;12:807654. Epub 2021 Dec 17.

Interdisciplinary Center of Cell Response, State key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.

Mitochondria are highly dynamic organelles and play essential role in ATP synthase, ROS production, innate immunity, and apoptosis. Mitochondria quality control is critical for maintaining the cellular function in response to cellular stress, growth, and differentiation Signals. Damaged or unwanted mitochondria are selectively removed by mitophagy, which is a crucial determinant of cell viability. Mitochondria-associated Endoplasmic Reticulum Membranes (MAMs) are the cellular structures that connect the ER and mitochondria and are involved in calcium signaling, lipid transfer, mitochondrial dynamic, and mitophagy. Abnormal mitochondrial quality induced by mitophagy impairment and MAMs dysfunction is associated with many diseases, including cardiovascular diseases (CVDs), metabolic syndrome, and neurodegenerative diseases. As a mitophagy receptor, FUNDC1 plays pivotal role in mitochondrial quality control through regulation of mitophagy and MAMs and is closely related to the occurrence of several types of CVDs. This review covers the regulation mechanism of FUNDC1-mediated mitophagy and MAMs formation, with a particular focus on its role in CVDs.
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http://dx.doi.org/10.3389/fphys.2021.807654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718682PMC
December 2021

Late effects in survivors of high-risk neuroblastoma following stem cell transplant with and without total body irradiation.

Pediatr Blood Cancer 2022 03 31;69(3):e29537. Epub 2021 Dec 31.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Background: Neuroblastoma is the most common extracranial solid tumor in children. Those with high-risk disease are treated with multimodal therapy, including high-dose chemotherapy, stem cell transplant, radiation, and immunotherapy that have led to multiple long-term complications in survivors. In the late 1990s, consolidation therapy involved myeloablative conditioning including total body irradiation (TBI) with autologous stem cell rescue. Recognizing the significant long-term toxicities of exposure to TBI, more contemporary treatment protocols have removed this from conditioning regimens. This study examines an expanded cohort of 48 high-risk neuroblastoma patients to identify differences in the late effect profiles for those treated with TBI and those treated without TBI.

Procedure: Data on the study cohort were collected from clinic charts, provider documentation in the electronic medical record of visits to survivorship clinic, including all subspecialists, and ancillary reports of laboratory and diagnostic tests done as part of risk-based screening at each visit.

Results: All 48 survivors of BMT for high-risk neuroblastoma had numerous late effects of therapy, with 73% having between five and 10 late effects. TBI impacted some late effects significantly, including growth hormone deficiency (GHD), bone outcomes, and cataracts.

Conclusion: Although high-risk neuroblastoma survivors treated with TBI have significant late effects, those treated without TBI also continue to have significant morbidity related to high-dose chemotherapy and local radiation. A multidisciplinary care team assists in providing comprehensive care to those survivors who are at highest risk for significant late effects.
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http://dx.doi.org/10.1002/pbc.29537DOI Listing
March 2022

Disease Burden Affects Outcomes in Pediatric and Young Adult B-Cell Lymphoblastic Leukemia After Commercial Tisagenlecleucel: A Pediatric Real-World Chimeric Antigen Receptor Consortium Report.

J Clin Oncol 2022 03 9;40(9):945-955. Epub 2021 Dec 9.

Stanford University School of Medicine, Stanford, CA.

Purpose: Tisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration-approved for children, adolescents, and young adults (CAYA) with relapsed and/or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel.

Methods: We conducted a retrospective, multi-institutional study of CAYA with RR B-ALL across 15 US institutions, who underwent leukapheresis shipment to Novartis for commercial tisagenlecleucel. A total of 200 patients were included in an intent-to-treat response analysis, and 185 infused patients were analyzed for survival and toxicity.

Results: Intent-to-treat analysis demonstrates a 79% morphologic CR rate (95% CI, 72 to 84). The infused cohort had an 85% CR (95% CI, 79 to 89) and 12-month OS of 72% and EFS of 50%, with 335 days of median follow-up. Notably, 48% of patients had low-disease burden (< 5% bone marrow lymphoblasts, no CNS3, or other extramedullary disease), or undetectable disease, pretisagenlecleucel. Univariate and multivariate analyses associate high-disease burden (HB, ≥ 5% bone marrow lymphoblasts, CNS3, or non-CNS extramedullary) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%; < .0001 for OS and EFS). Grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 21% and 7% overall and 35% and 9% in patients with HB, respectively.

Conclusion: Commercial tisagenlecleucel in CAYA RR B-ALL demonstrates efficacy and tolerability. This first analysis of commercial tisagenlecleucel stratified by disease burden identifies HB preinfusion to associate with inferior OS and EFS and increased toxicity.
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http://dx.doi.org/10.1200/JCO.20.03585DOI Listing
March 2022

Carboplatin During Craniospinal Radiotherapy for Children With Group 3 Medulloblastoma-A New Standard of Care?-Reply.

JAMA Oncol 2022 02;8(2):302-303

Cancer and Blood Disorders Center, Seattle Children's, Fred Hutchinson Cancer Research Center, University of Washington, Seattle.

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http://dx.doi.org/10.1001/jamaoncol.2021.6526DOI Listing
February 2022

Unrelated donor α/β T cell- and B cell-depleted HSCT for the treatment of pediatric acute leukemia.

Blood Adv 2022 Feb;6(4):1175-1185

Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.

Unrelated donor (URD) hematopoietic stem cell transplant (HSCT) is associated with an increased risk of severe graft-versus-host disease (GVHD). TCRαβ/CD19 depletion may reduce this risk, whereas maintaining graft-versus-leukemia. Outcome data with TCRαβ/CD19 depletion generally describe haploidentical donors, with relatively few URDs. We hypothesized that TCRαβ/CD19-depletion would attenuate the risks of GVHD and relapse for URD HSCT. Sixty pediatric and young adult (YA) patients with hematologic malignancies who lacked a matched-related donor were enrolled at 2 large pediatric transplantation centers between October 2014 and September 2019. All patients with acute leukemia had minimal residual disease testing, and DP typing was available for 77%. All patients received myeloablative total body irradiation- or busulfan-based conditioning with no posttransplant immune suppression. Engraftment occurred in 98%. Four-year overall survival was 69% (95% confidence interval [CI], 52%-81%), and leukemia-free survival was 64% (95% CI, 48%-76%), with no difference between lymphoid and myeloid malignancies (P = .6297 and P = .5441, respectively). One patient (1.7%) experienced primary graft failure. Relapse occurred in 11 patients (3-year cumulative incidence, 21%; 95% CI, 11-34), and 8 patients (cumulative incidence, 15%; 95% CI, 6.7-26) experienced nonrelapse mortality. Grade III to IV acute GVHD was seen in 8 patients (13%), and 14 patients (26%) developed chronic GVHD, of which 6 (11%) had extensive disease. Nonpermissive DP mismatch was associated with higher likelihood of acute GVHD (odds ratio, 16.50; 95% CI, 1.67-163.42; P = .0166) but not with the development of chronic GVHD. URD TCRαβ/CD19-depleted peripheral HSCT is a safe and effective approach to transplantation for children/YAs with leukemia. This trial was registered at www.clinicaltrials.gov as #NCT02323867.
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http://dx.doi.org/10.1182/bloodadvances.2021005492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864664PMC
February 2022

Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy.

Blood 2022 Apr;139(14):2173-2185

Division of Oncology and Cancer Immunotherapy Program, Children's Hospital of Philadelphia, Philadelphia, PA.

Chimeric antigen receptor (CAR) T-cell therapy can induce durable remissions of relapsed/refractory B-acute lymphoblastic leukemia (ALL). However, case reports suggested differential outcomes mediated by leukemia cytogenetics. We identified children and young adults with relapsed/refractory CD19+ ALL/lymphoblastic lymphoma treated on 5 CD19-directed CAR T-cell (CTL019 or humanized CART19) clinical trials or with commercial tisagenlecleucel from April 2012 to April 2019. Patients were hierarchically categorized according to leukemia cytogenetics: High-risk lesions were defined as KMT2A (MLL) rearrangements, Philadelphia chromosome (Ph+), Ph-like, hypodiploidy, or TCF3/HLF; favorable as hyperdiploidy or ETV6/RUNX1; and intermediate as iAMP21, IKZF1 deletion, or TCF3/PBX1. Of 231 patients aged 1 to 29, 74 (32%) were categorized as high risk, 28 (12%) as intermediate, 43 (19%) as favorable, and 86 (37%) as uninformative. Overall complete remission rate was 94%, with no difference between strata. There was no difference in relapse-free survival (RFS; P = .8112), with 2-year RFS for the high-risk group of 63% (95% confidence interval [CI], 52-77). There was similarly no difference seen in overall survival (OS) (P = .5488), with 2-year OS for the high-risk group of 70% (95% CI, 60-82). For patients with KMT2A-rearranged infant ALL (n = 13), 2-year RFS was 67% (95% CI, 45-99), and OS was 62% (95% CI, 40-95), with multivariable analysis demonstrating no increased risk of relapse (hazard ratio, 0.70; 95% CI, 0.21-2.90; P = .7040) but a higher proportion of relapses associated with myeloid lineage switch and a 3.6-fold increased risk of all-cause death (95% CI, 1.04-12.75; P = .0434). CTL019/huCART19/tisagenlecleucel are effective at achieving durable remissions across cytogenetic categories. Relapsed/refractory patients with high-risk cytogenetics, including KMT2A-rearranged infant ALL, demonstrated high RFS and OS probabilities at 2 years.
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http://dx.doi.org/10.1182/blood.2021012727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990372PMC
April 2022

Center Variation in Indication and Short-Term Outcomes after Pediatric Heart Transplantation: Analysis of a Merged United Network for Organ Sharing - Pediatric Health Information System Cohort.

Pediatr Cardiol 2022 Mar 15;43(3):636-644. Epub 2021 Nov 15.

Division of Oncology, Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

The relationship between center-specific variation in indication for pediatric heart transplantation and short-term outcomes after heart transplantation is not well described. We used merged patient- and hospital-level data from the United Network for Organ Sharing and the Pediatric Health Information Systems to analyze outcomes according to transplant indication for a cohort of children (≤ 21 years old) who underwent heart transplantation between 2004 and 2015. Outcomes included 30-day mortality, transplant hospital admission mortality, and hospital length of stay, with multivariable adjustment performed according to patient and center characteristics. The merged cohort reflected 2169 heart transplants at 20 U.S. centers. The median number of transplants annually at each center was 11.6, but ranged from 3.5 to 22.6 transplants/year. Congenital heart disease was the indication in the plurality of cases (49.2%), with cardiomyopathy (46%) and myocarditis (4.8%) accounting for the remainder. There was significant center-to-center variability in congenital heart disease as the principal indication, ranging from 15% to 66% (P < 0.0001). After adjustment, neither center volume nor proportion of indications for transplantation were associated with 30-day or transplant hospital admission mortality. In this large, merged pediatric cohort, variation was observed at center level in annual transplant volume and prevalence of indications for heart transplantation. Despite this variability, center volume and proportion of indications represented at a given center did not appear to impact short-term outcomes.
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http://dx.doi.org/10.1007/s00246-021-02768-xDOI Listing
March 2022

Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning.

J Clin Oncol 2022 01 29;40(1):83-95. Epub 2021 Oct 29.

Department of Radiation Oncology, St Jude Children's Research Hospital, Memphis, TN.

Purpose: To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03.

Patients And Methods: Patients age 3-21 years with medulloblastoma were treated at a single institution on a phase III study. The craniospinal RT dose was 23.4 Gy for average-risk patients and 36-39.6 Gy for high-risk patients. The boost dose was 55.8 Gy to the tumor bed. Patients underwent cognitive testing at baseline and once yearly for 5 years. Performance on tests of memory (associative memory and working memory) and processing speed (composite processing speed and perceptual speed) was analyzed. Mixed-effects models were used to estimate longitudinal trends in neurocognitive outcomes. Reliable change index and logistic regression were used to define clinically meaningful neurocognitive decline and identify variables associated with decline.

Results: One hundred and twenty-four patients were eligible for inclusion, with a median neurocognitive follow-up of 5 years. Mean right and left hippocampal doses were significantly associated with decline in associative memory in patients without posterior fossa syndrome (all < .05). Mean CC and frontal WM doses were significantly associated with decline in both measures of processing speed (all < .05). Median brain substructure dose-volume histograms were shifted to the right for patients with a decline in associative memory or processing speed. The odds of decline in associative memory and composite processing speed increased by 23%-26% and by 10%-15% for every 1-Gy increase in mean hippocampal dose and mean CC or frontal WM dose, respectively.

Conclusion: Increasing RT dose to the CC or frontal WM and hippocampus is associated with worse performance on tests of processing speed and associative memory, respectively. Brain substructure-informed RT planning may mitigate neurocognitive impairment.
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http://dx.doi.org/10.1200/JCO.21.01480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683226PMC
January 2022

Medical Outcomes, Quality of Life, and Family Perceptions for Outpatient vs Inpatient Neutropenia Management After Chemotherapy for Pediatric Acute Myeloid Leukemia.

JAMA Netw Open 2021 10 1;4(10):e2128385. Epub 2021 Oct 1.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Importance: Pediatric acute myeloid leukemia (AML) requires multiple courses of intensive chemotherapy that result in neutropenia, with significant risk for infectious complications. Supportive care guidelines recommend hospitalization until neutrophil recovery. However, there are little data to support inpatient over outpatient management.

Objective: To evaluate outpatient vs inpatient neutropenia management for pediatric AML.

Design, Setting, And Participants: This cohort study used qualitative and quantitative methods to compare medical outcomes, patient health-related quality of life (HRQOL), and patient and family perceptions between outpatient and inpatient neutropenia management. The study included patients from 17 US pediatric hospitals with frontline chemotherapy start dates ranging from January 2011 to July 2019, although the specific date ranges differed for the individual analyses by design and relative timing. Data were analyzed from August 2019 to February 2020.

Exposures: Discharge to outpatient vs inpatient neutropenia management.

Main Outcomes And Measures: The primary outcomes of interest were course-specific bacteremia incidence, times to next course, and patient HRQOL. Course-specific mortality was a secondary medical outcome.

Results: Primary quantitative analyses included 554 patients (272 [49.1%] girls and 282 [50.9%] boys; mean [SD] age, 8.2 [6.1] years). Bacteremia incidence was not significantly different during outpatient vs inpatient management (67 courses [23.8%] vs 265 courses [29.0%]; adjusted rate ratio, 0.73; 95% CI, 0.56 to 1.06; P = .08). Outpatient management was not associated with delays to the next course compared with inpatient management (mean [SD] 30.7 [12.2] days vs 32.8 [9.7] days; adjusted mean difference, -2.2; 95% CI, -4.1 to -0.2, P = .03). Mortality during intensification II was higher for patients who received outpatient management compared with those who received inpatient management (3 patients [5.4%] vs 1 patient [0.5%]; P = .03), but comparable with inpatient management at other courses (eg, 0 patients vs 5 patients [1.3%] during induction I; P = .59). Among 97 patients evaluated for HRQOL, outcomes did not differ between outpatient and inpatient management (mean [SD] Pediatric Quality of Life Inventory total score, 70.1 [18.9] vs 68.7 [19.4]; adjusted mean difference, -2.8; 95% CI, -11.2 to 5.6). A total of 86 respondents (20 [23.3%] in outpatient management, 66 [76.7%] in inpatient management) completed qualitative interviews. Independent of management strategy received, 74 respondents (86.0%) expressed satisfaction with their experience. Concerns for hospital-associated infections among caregivers (6 of 7 caregiver respondents [85.7%] who were dissatisfied with inpatient management) and family separation (2 of 2 patient respondents [100%] who were dissatisfied with inpatient management) drove dissatisfaction with inpatient management. Stress of caring for a neutropenic child at home (3 of 3 respondents [100%] who were dissatisfied with outpatient management) drove dissatisfaction with outpatient management.

Conclusions And Relevance: This cohort study found that outpatient neutropenia management was not associated with higher bacteremia incidence, treatment delays, or worse HRQOL compared with inpatient neutropenia management among pediatric patients with AML. While outpatient management may be safe for many patients, course-specific mortality differences suggest that outpatient management in intensification II should be approached with caution. Patient and family experiences varied, suggesting that outpatient management may be preferred by some but may not be feasible for all families. Further studies to refine and standardize safe outpatient management practices are warranted.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.28385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554641PMC
October 2021

Understanding Adolescent and Young Adult 6-Mercaptopurine Adherence and mHealth Engagement During Cancer Treatment: Protocol for Ecological Momentary Assessment.

JMIR Res Protoc 2021 Oct 22;10(10):e32789. Epub 2021 Oct 22.

Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States.

Background: Adolescents and young adults (AYAs) with cancer demonstrate suboptimal oral chemotherapy adherence, increasing their risk of cancer relapse. It is unclear how everyday time-varying contextual factors (eg, mood) affect their adherence, stalling the development of personalized mobile health (mHealth) interventions. Poor engagement is also a challenge across mHealth trials; an effective adherence intervention must be engaging to promote uptake.

Objective: This protocol aims to determine the temporal associations between daily contextual factors and 6-mercaptopurine (6-MP) adherence and explore the proximal impact of various engagement strategies on ecological momentary assessment survey completion.

Methods: At the Children's Hospital of Philadelphia, AYAs with acute lymphoblastic leukemia or lymphoma who are prescribed prolonged maintenance chemotherapy that includes daily oral 6-MP are eligible, along with their matched caregivers. Participants will use an ecological momentary assessment app called ADAPTS (Adherence Assessments and Personalized Timely Support)-a version of an open-source app that was modified for AYAs with cancer through a user-centered process-and complete surveys in bursts over 6 months. Theory-informed engagement strategies will be microrandomized to estimate the causal effects on proximal survey completion.

Results: With funding from the National Cancer Institute and institutional review board approval, of the proposed 30 AYA-caregiver dyads, 60% (18/30) have been enrolled; of the 18 enrolled, 15 (83%) have completed the study so far.

Conclusions: This protocol represents an important first step toward prescreening tailoring variables and engagement components for a just-in-time adaptive intervention designed to promote both 6-MP adherence and mHealth engagement.

International Registered Report Identifier (irrid): DERR1-10.2196/32789.
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http://dx.doi.org/10.2196/32789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571686PMC
October 2021

Arterial spin labeling as an ancillary assessment to postoperative conventional angiogram in pediatric moyamoya disease.

J Neurosurg Pediatr 2022 Jan 1;29(1):40-47. Epub 2021 Oct 1.

8Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.

Objective: Digital subtraction angiography (DSA) is commonly performed after pial synangiosis surgery for pediatric moyamoya disease to assess the degree of neovascularization. However, angiography is invasive, and the risk of ionizing radiation is a concern in children. In this study, the authors aimed to identify whether arterial spin labeling (ASL) can predict postoperative angiogram grading. In addition, they sought to determine whether patients who underwent ASL imaging without DSA had similar postoperative outcomes when compared with patients who received ASL imaging and postoperative DSA.

Methods: The medical records of pediatric patients who underwent pial synangiosis for moyamoya disease at a quaternary children's hospital were reviewed during a 10-year period. ASL-only and ASL+DSA cohorts were analyzed. The frequency of preoperative and postoperative symptoms was analyzed within each cohort. Three neuroradiologists assigned a visual ASL grade for each patient indicating the change from the preoperative to postoperative ASL perfusion sequences. A postoperative neovascularization grade was also assigned for patients who underwent DSA.

Results: Overall, 21 hemispheres of 14 patients with ASL only and 14 hemispheres of 8 patients with ASL+DSA were analyzed. The groups had similar rates of MRI evidence of acute or chronic stroke preoperatively (61.9% in the ASL-only group and 64.3% in the ASL+DSA group). In the entire cohort, transient ischemic attack (TIA) (p = 0.027), TIA composite (TIA or unexplained neurological symptoms; p = 0.0006), chronic headaches (p = 0.035), aphasia (p = 0.019), and weakness (p = 0.001) all had decreased frequency after intervention. The authors found a positive association between revascularization observed on DSA and the visual ASL grading (p = 0.048). The visual ASL grades in patients with an angiogram indicating robust neovascularization demonstrated improved perfusion when compared with the ASL grades of patients with a poor neovascularization.

Conclusions: Noninvasive ASL perfusion imaging had an association with postoperative DSA neoangiogenesis following pial synangiosis surgery in children. There were no significant postoperative stroke differences between the ASL-only and ASL+DSA cohorts. Both cohorts demonstrated significant improvement in preoperative symptoms after surgery. Further study in larger cohorts is necessary to determine whether the results of this study are validated in order to circumvent the invasive catheter angiogram.
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http://dx.doi.org/10.3171/2021.7.PEDS21302DOI Listing
January 2022

Outcomes of intensification of induction chemotherapy for children with high-risk acute myeloid leukemia: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2021 12 1;68(12):e29281. Epub 2021 Oct 1.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Background: High-risk pediatric acute myeloid leukemia confers a poor prognosis, and alternative strategies are needed to improve outcomes. We hypothesized that intensifying induction on the AAML1031 clinical trial would improve outcomes compared to the predecessor trial AAML0531.

Methods: Patients on AAML0531 received cytarabine (1600 mg/m )/daunorubicin (150 mg/m )/etoposide (ADE) for induction II and patients on AAML1031 received mitoxantrone (48 mg/m )/cytarabine (8000 mg/m ) (MA). Stem cell transplant (SCT) conditioning included busulfan/cyclophosphamide on AAML0531, whereas AAML1031 used busulfan/fludarabine and liberalized donor eligibility. Patients were included in this analysis if they met high-risk criteria common to the two trials by cytogenics or poor disease response after induction I ADE.

Results: MA provided no benefit over ADE at: induction II response (complete response [CR]: 64% vs. 62%, p = .87; measurable residual disease [MRD]+: 57% vs. 46%, p = .34); or intensification I response (CR: 79% vs. 94%, p = .27; MRD+: 27% vs. 20%, p = 1.0). When considered with altered SCT approach, MA did not improve 5-year disease-free survival (24% ± 9% vs. 18% ± 15%, p = .63) or 5-year overall survival (35% ± 10% vs. 38% ± 18%, p = .66). MA was associated with slower neutrophil recovery (median 34 vs. 27 days, p = .007) and platelet recovery (median 29 vs. 24.5 days, p = .04) and longer hospital stay (32 vs. 28 days, p = .01) during induction II.

Conclusion: Intensification of induction II did not improve treatment response or survival, but did increase toxicity and resource utilization. Alternative strategies are urgently needed to improve outcomes for pediatric patients with high-risk acute myeloid leukemia (trials registered at clinicaltrials.gov NCT01371981, NCT00372593).
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http://dx.doi.org/10.1002/pbc.29281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717610PMC
December 2021
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