Molecular mechanisms controlling vertebrate retinal patterning, neurogenesis, and cell fate specification.

This review covers recent advances in understanding the molecular mechanisms controlling neurogenesis and specification of the developing retina, with a focus on insights obtained from comparative single cell multiomic analysis. We discuss recent advances in understanding the mechanisms by which extrinsic factors trigger transcriptional changes that spatially pattern the optic cup (OC) and control the initiation and progression of retinal neurogenesis. We also discuss progress in unraveling the core evolutionarily conserved gene regulatory networks (GRNs) that specify early- and late-state retinal progenitor cells (RPCs) and neurogenic progenitors and that control the final steps in determining cell identity. Finally, we discuss findings that provide insight into regulation of species-specific aspects of retinal patterning and neurogenesis, including consideration of key outstanding questions in the field.

Deep Learning of Rhabdomyosarcoma Pathology Images for Classification and Survival Outcome Prediction.

Rhabdomyosarcoma (RMS), the most common malignant soft tissue tumor in children, has several histologic subtypes that influence treatment and predict patient outcomes. Assistance with histologic classification for pathologists as well as discovery of optimized predictive biomarkers is needed. A convolutional neural network for RMS histology subtype classification was developed using digitized pathology images from 80 patients collected at time of diagnosis. A subsequent embryonal rhabdomyosarcoma (eRMS) prognostic model was also developed in a cohort of 60 eRMS patients. The RMS classification model reached a performance of an area under the receiver operating curve of 0.94 for alveolar rhabdomyosarcoma and an area under the receiver operating curve of 0.92 for eRMS at slide level in the test data set (n = 192). The eRMS prognosis model separated the patients into predicted high- and low-risk groups with significantly different event-free survival outcome (likelihood ratio test; P = 0.02) in the test data set (n = 136). The predicted risk group is significantly associated with patient event-free survival outcome after adjusting for patient age and sex (predicted high- versus low-risk group hazard ratio, 4.64; 95% CI, 1.05-20.57; P = 0.04). This is the first comprehensive study to develop computational algorithms for subtype classification and prognosis prediction for RMS histopathology images. Such models can aid pathology evaluation and provide additional parameters for risk stratification.

Correction: Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group.

The authors have noticed that the final paragraph of the Results section contains errors in the number of patients involved. The correct number of patients is included in the text below. These errors do not affect the Figure referenced.In osteosarcoma, we focused on 8q gain as a specific biological feature of interest. Among the 41 patients with detectable ctDNA in the osteosarcoma cohort, 8q gain was detected in 73.2% (30/41). The 3-year EFS for patients with 8q gain (n = 30) in ctDNA was 60.0% (95% CI 40.5-75.0) compared to 80.8 (95% CI 42.4-94.9) in patients without 8q gain (n = 11) in ctDNA (p = 0.18; Fig. 3).

Prolonged response to sorafenib in a patient with refractory metastatic osteosarcoma and a somatic PDGFRA D846V mutation.

Outcome for patients with metastatic or recurrent/refractory osteosarcoma remains poor. Responses to sorafenib, a multikinase inhibitor, have been seen in recurrent/refractory osteosarcoma, although specific biomarkers of response have not been described. We report a partial response in a 7-year-old with refractory osteosarcoma treated with sorafenib 200 mg twice daily. Toxicities included Common Terminology Criteria for Adverse Events Grade 2 skin toxicities and growth suppression. After 51 months of therapy, he suffered a recurrence. Tumor sequencing later revealed a PDGFRA D846V mutation that was not identified in the relapse specimen. This case demonstrates prolonged partial response to sorafenib and provides a potential biomarker for response.

Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group.

BACKGROUND: New prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely to benefit from standard therapy. We describe the incidence and association with outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays. METHODS: A NGS hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with EWS and osteosarcoma, respectively. Patients were coded as positive or negative for ctDNA and tested for association with clinical features and outcome. RESULTS: The analytic cohort included 94 patients with EWS (82% from initial diagnosis) and 72 patients with primary localised osteosarcoma (100% from initial diagnosis). ctDNA was detectable in 53% and 57% of newly diagnosed patients with EWS and osteosarcoma, respectively. Among patients with newly diagnosed localised EWS, detectable ctDNA was associated with inferior 3-year event-free survival (48.6% vs. 82.1%; p = 0.006) and overall survival (79.8% vs. 92.6%; p = 0.01). In both EWS and osteosarcoma, risk of event and death increased with ctDNA levels. CONCLUSIONS: NGS assays agnostic of primary tumour sequencing results detect ctDNA in half of the plasma samples from patients with newly diagnosed EWS and osteosarcoma. Detectable ctDNA is associated with inferior outcomes.

The American Society of Pediatric Hematology/Oncology workforce assessment: Part 1-Current state of the workforce.

The American Society of Pediatric Hematology/Oncology (ASPHO) recognized recent changes in medical practice and the potential impact on pediatric hematology-oncology (PHO) workforce. ASPHO surveyed society members and PHO Division Directors between 2010 and 2016 and studied PHO workforce data collected by the American Board of Pediatrics and the American Medical Association to characterize the current state of the PHO workforce. The analysis of this information has led to a comprehensive description of PHO physicians, professional activities, and workplace. It is important to continue to collect data to identify changes in composition and needs of the PHO workforce.

Hope as a Predictor of Anxiety and Depressive Symptoms Following Pediatric Cancer Diagnosis.

Objective: To examine hope and its components of agency and pathways as predictors of anxiety and depressive symptoms in children receiving cancer treatment. Methods: Sixty patients (mean standard deviation age = 13.3 (2.7); 57% male) completed Snyder's Hope Scales, the Children's Depression Inventory, and the State-Trait Anxiety Inventory at diagnosis and 3 month intervals for 1 year following pediatric cancer diagnosis. Parents also completed Snyder's Hope Scales. Linear mixed-effect regression was used to assess hope's role in longitudinal models of symptoms of depression and anxiety. Results: Agency was a significant predictor of between-patient differences and within-patient changes in symptoms of depression and anxiety. Neither patient pathways nor either component of parent hope was predictive of symptoms of depression or anxiety. Patients who were more likely to have depressive symptoms at baseline were older, diagnosed with leukemia, and non-Hispanic White as opposed to Hispanic. Patient demographics were not predictive of anxiety. Conclusions: Patient agency is a potential target for intervention to prevent or reduce anxiety and depressive symptoms following pediatric cancer diagnosis.

Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial.

BACKGROUND: We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. METHODS: EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1-5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030. FINDINGS: Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. INTERPRETATION: EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. FUNDING: UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.

Humanism and professionalism education for pediatric hematology-oncology fellows: A model for pediatric subspecialty training.

BACKGROUND: Humanism and professionalism are virtues intrinsic to the practice of medicine, for which we lack a standard, evidence-based approach for teaching and evaluation. Pediatric hematology-oncology (PHO) fellowship training brings new and significant stressors, making it an attractive setting for innovation in humanism and professionalism training. PROCEDURE: We electronically surveyed a national sample of PHO fellows to identify fellows' educational needs in humanism and professionalism. Next, we developed a case-based, faculty-facilitated discussion curriculum to teach this content within pilot fellowship programs. We assessed whether fellowships would decide to offer the curriculum, feasibility of administering the curriculum, and satisfaction of fellow and faculty participants. RESULTS: Surveys were completed by 187 fellows (35%). A minority (29%) reported that their training program offers a formal curriculum in humanism and/or professionalism. A majority desires more formal teaching on balancing clinical practice and research (85%), coping with death/dying (85%), bereavement (78%), balancing work and personal life (75%), navigating challenging relationships with patients (74%), and depression/burn out (71%). These six topics were condensed into four case-based modules, which proved feasible to deliver at all pilot sites. Ten fellowship programs agreed to administer the novel curriculum. The majority (90%) of responding fellows and faculty reported the sessions touched on issues important for training, stimulated reflective communication, and were valuable. CONCLUSIONS: Pediatric hematology-oncology fellows identify numerous gaps in their training related to humanism and professionalism. This curriculum offers an opportunity to systematically address these educational needs and can serve as a model for wider implementation. Pediatr Blood Cancer 2015;62:335-340. © 2014 Wiley Periodicals, Inc.

Chemotherapy for Generalized Infantile Myofibromatosis With Visceral Involvement.

Infantile myofibromatosis (IM) is most commonly limited to cutaneous lesions that resolve spontaneously. However, generalized IM with visceral involvement, which has a reported mortality rate as high as 73%, has been successfully treated with a combination of methotrexate and vinblastine. Here we report the further efficacy of low-dose methotrexate and vinblastine in 2 pediatric patients with IM and visceral involvement and review the literature describing chemotherapy for these patients.

Hoping Is Coping: A Guiding Theoretical Framework for Promoting Coping and Adjustment Following Pediatric Cancer Diagnosis.

OBJECTIVE: To determine the pattern of resilience and adjustment following pediatric cancer diagnosis and to evaluate hope as a mediator of adjustment. METHODS: 61 participants with pediatric cancer completed measures of hope, depression, anxiety, and quality of life (QoL) within 4 weeks of cancer diagnosis and every 3 months for 1 year. RESULTS: Participants showed high and increasing levels of hope and QoL, as well as low and decreasing levels of depression and anxiety. Linear mixed-effects regression analyses revealed changes in depression, anxiety, and hope to be significant predictors of changes in QoL. Changes in hope were found to partially mediate the effects of depression and anxiety on QoL. CONCLUSIONS: While a variety of interventions are efficacious for treating anxiety and depression, hope theory provides a framework for choosing interventions that may more globally promote children's ability to maintain good functioning, adjustment, well-being, and QoL following cancer diagnosis.

Do pediatric hematology/oncology (PHO) fellows receive communication training?

PURPOSE: The Accreditation Council for Graduate Medical Education (ACGME) has established communication as a core competency for physicians in training. However, data suggest that most pediatric residents perceive inadequate training in the delivery of bad news and the majority of former trainees in pediatric oncology received no formal training in the delivery of bad news during fellowship. The study examines communication training in ACGME accredited US pediatric hematology-oncology (PHO) fellowship programs. METHODS: An online survey was distributed to 315 PHO fellows in training via the American Society of Pediatric Hematology/Oncology (ASPHO) fellow email registry. Each fellow received an initial request to participate and 2 reminders, while participation was encouraged through a random incentive drawing. RESULTS: One hundred and ten fellows (35%) responded. Eighty percent of respondents perceived communication training to be important to fellow education, however only 32% reported receiving communication training (other than direct observation). The most common reported teaching method of fellowship communication training was formal lecture (42%). Twenty-three percent of respondents reported neither communication training nor frequent feedback on their communication skills from faculty observation. This same group was the least satisfied with their programs' approach to teaching communication (P < 0.001). CONCLUSIONS: There is limited communication training in PHO fellowships despite ACGME requirements and fellows' interest in this training. Didactic learning remains the most frequently described training method, yet educational theory identifies the limitation of didactic lectures alone. Communication training employing novel teaching methods and emphasizing communication challenges identified by fellows should be developed and evaluated.

Bone scintigraphy in osteosarcoma: a single institution experience.

Bone scintigraphy is a well-established method to evaluate for metastatic disease in osteosarcoma. We identified a patient who had a negative (cold) bone scan at skeletal relapse and consequently reviewed the frequency of cold scans in osteosarcoma at our institution. No cold scans were identified at diagnosis, and only 1 patient had a cold scan at skeletal recurrence. No correlation was identified between clinical outcomes and bone scan features, other than identification of metastatic disease. Patients with skeletal recurrence were all symptomatic, thus we suggest that bone scintigraphy is not indicated in routine postchemotherapy surveillance for patients with osteosarcoma.

COVID-19 mRNA Vaccination Responses in Individuals With Sickle Cell Disease: ASH RC Sickle Cell Research Network Study.

Children and adults with sickle cell disease (SCD) have increases in morbidity and mortality with COVID-19 infections. The ASH Research Collaborative Sickle Cell Disease Research Network performed a prospective COVID-19 vaccine study to assess antibody responses and analyze whether mRNA vaccination precipitated any adverse effects unique to individuals with SCD. Forty-one participants received two doses of the Pfizer-BioNTech vaccine and provided baseline blood samples prior to vaccination and 2 months after the initial vaccination for analysis of IgG reactivity against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Six month IgG reactivity against the viral RBD was also available in 37 patients. Post-vaccination reactogenicity was common and similar to the general population. There were no fevers that required inpatient admission. Vaso-occlusive pain within 2-3 days of 1st or 2nd vaccination was reported by 5 (12%) participants including 4 (10%) who sought medical care. Twenty-seven participants (66%) were seropositive at baseline, and all 14 (34%) initially seronegative participants converted to seropositive post vaccination. Overall, mRNA vaccination had a good risk benefit-profile in individuals with sickle cell disease.This mRNA vaccine study also marks the first evaluation of vaccine safety and antibody response in very young children with sickle cell disease. NCT05139992.

IL-8 predicts pediatric oncology patients with febrile neutropenia at low risk for bacteremia.

INTRODUCTION: Despite a low bacteremia rate, pediatric oncology patients are frequently admitted for febrile neutropenia. A pediatric risk prediction model with high sensitivity to identify patients at low risk for bacteremia is not available. We performed a single-institution prospective cohort study of pediatric oncology patients with febrile neutropenia to create a risk prediction model using clinical factors, respiratory viral infection, and cytokine expression. MATERIALS AND METHODS: Pediatric oncology patients with febrile neutropenia were enrolled between March 30, 2010 and April 1, 2011 and managed per institutional protocol. Blood samples for C-reactive protein and cytokine expression and nasopharyngeal swabs for respiratory viral testing were obtained. Medical records were reviewed for clinical data. Statistical analysis utilized mixed multiple logistic regression modeling. RESULTS: During the 12-month period, 195 febrile neutropenia episodes were enrolled. There were 24 (12%) episodes of bacteremia. Univariate analysis revealed several factors predictive for bacteremia, and interleukin (IL)-8 was the most predictive variable in the multivariate stepwise logistic regression. Low serum IL-8 predicted patients at low risk for bacteremia with a sensitivity of 0.9 and negative predictive value of 0.98. CONCLUSIONS: IL-8 is a highly sensitive predictor for patients at low risk for bacteremia. IL-8 should be utilized in a multi-institution prospective trial to assign risk stratification to pediatric patients admitted with febrile neutropenia.

Osteosarcoma Explorer: A Data Commons With Clinical, Genomic, Protein, and Tissue Imaging Data for Osteosarcoma Research.

PURPOSE: Osteosarcoma research advancement requires enhanced data integration across different modalities and sources. Current osteosarcoma research, encompassing clinical, genomic, protein, and tissue imaging data, is hindered by the siloed landscape of data generation and storage. MATERIALS AND METHODS: Clinical, molecular profiling, and tissue imaging data for 573 patients with pediatric osteosarcoma were collected from four public and institutional sources. A common data model incorporating standardized terminology was created to facilitate the transformation, integration, and load of source data into a relational database. On the basis of this database, a data commons accompanied by a user-friendly web portal was developed, enabling various data exploration and analytics functions. RESULTS: The Osteosarcoma Explorer (OSE) was released to the public in 2021. Leveraging a comprehensive and harmonized data set on the backend, the OSE offers a wide range of functions, including Cohort Discovery, Patient Dashboard, Image Visualization, and Online Analysis. Since its initial release, the OSE has experienced an increasing utilization by the osteosarcoma research community and provided solid, continuous user support. To our knowledge, the OSE is the largest (N = 573) and most comprehensive research data commons for pediatric osteosarcoma, a rare disease. This project demonstrates an effective framework for data integration and data commons development that can be readily applied to other projects sharing similar goals. CONCLUSION: The OSE offers an online exploration and analysis platform for integrated clinical, molecular profiling, and tissue imaging data of osteosarcoma. Its underlying data model, database, and web framework support continuous expansion onto new data modalities and sources.

Graduate medical education changes: yes we can or enough already?

The Accreditation Council for Graduate Medical Education (ACGME) established new duty hour recommendations for pediatric subspecialty trainees in July 2011. Short-term and long-term implications to Pediatric Hematology/Oncology (PHO) are reviewed. Other modifications have been introduced by the ACGME and the American Board of Pediatrics (ABP) in the last decade, including the introduction of the six core competencies and an expansion in the definition of scholarship for fellows. The effect of these on fellows are discussed with suggested strategies for PHO to prepare for further change likely to result from a new ABP initiative to evaluate subspecialty training and certification over the next 3 years. Pediatr Blood Cancer 2012; 59: 1168-1172. © 2012 Wiley Periodicals, Inc.

Predictive value of interleukin-5 and monocyte chemotactic protein-1 for bacteremia in children with febrile neutropenia.

A variety of clinical and laboratory parameters have been used to predict bacteremia. We hypothesize that the generation of a cytokine profile could be used to identify patients at higher risk of bacteremia at the time of presentation with febrile neutropenia. We prospectively evaluated children with cancer who presented with an episode of febrile neutropenia. A multiplexed flow cytometric assay was performed which measured 15 cytokines and chemokines obtained before the initiation of antibiotics. Fifty-eight episodes of chemotherapy-induced febrile neutropenia were included in this study during which 4 patients (7%) had bacteremia. An interleukin-5 level of >8 pg/dL had a sensitivity of 67% and a specificity of 96% to predict bacteremia. An monocyte chemotactic protein-1 level >1650 pg/dL had a sensitivity of 80% and a specificity of 82% to predict bacteremia. Erythrocyte sedimentation rate, C-reactive protein, protein C, and other cytokines/chemokines were not predictive of bacteremia. Elevations of interleukin-5 and monocyte chemotactic protein-1 are predictive of bacteremia in children with cancer who have febrile neutropenia. Prospective studies should be undertaken to determine whether these parameters retain predictive value in a larger series of patients and can select children for outpatient management or early discharge.

Correlation of histopathology and multi-modal magnetic resonance imaging in childhood osteosarcoma: Predicting tumor response to chemotherapy.

BACKGROUND: Osteosarcoma, which is the most common malignant pediatric bone cancer, remains dependent on an imprecise systemic treatment largely unchanged in 30 years. In this study, we correlated histopathology with magnetic resonance imaging (MRI), used the correlation to extract MRI-specific features representative of tumor necrosis, and subsequently developed a novel classification model for predicting tumor response to neoadjuvant chemotherapy in pediatric patients with osteosarcoma using multi-modal MRI. The model could ultimately serve as a testable biomarker for a high-risk malignancy without successful precision treatments. METHODS: Patients with newly diagnosed high-grade appendicular osteosarcoma were enrolled in a single-center observational study, wherein patients underwent pre-surgical evaluation using both conventional MRI (post-contrast T1-weighted with fat saturation, pre-contrast T1-weighted, and short inversion-time inversion recovery (STIR)) and advanced MRI (diffusion weighted (DW) and dynamic contrast enhanced (DCE)). A classification model was established based on a direct correlation between histopathology and MRI, which was achieved through histologic-MR image co-registration and subsequent extraction of MR image features for identifying histologic tumor necrosis. By operating on the MR image features, tumor necrosis was estimated from different combinations of MR images using a multi-feature fuzzy clustering technique together with a weighted majority ruling. Tumor necrosis calculated from MR images, for either an MRI plane of interest or whole tumor volume, was compared to pathologist-estimated necrosis and necrosis quantified from digitized histologic section images using a previously described deep learning classification method. RESULTS: 15 patients were enrolled, of whom two withdrew, one became ineligible, and two were subjected to inadequate pre-surgical imaging. MRI sequences of n = 10 patients were subsequently used for classification model development. Different MR image features, depending on the modality of MRI, were shown to be significant in distinguishing necrosis from viable tumor. The scales at which MR image features optimally signified tumor necrosis were different as well depending on the MR image type. Conventional MRI was shown capable of differentiating necrosis from viable tumor with an accuracy averaging above 90%. Conventional MRI was equally effective as DWI in distinguishing necrotic from viable tumor regions. The accuracy of tumor necrosis prediction by conventional MRI improved to above 95% when DCE-MRI was added into consideration. Volume-based tumor necrosis estimations tended to be lower than those evaluated on an MRI plane of interest. CONCLUSIONS: The study has shown a proof-of-principle model for interpreting chemotherapeutic response using multi-modal MRI for patients with high-grade osteosarcoma. The model will continue to be evaluated as MR image features indicative of tumor response are now computable for the disease prior to surgery.