Clinical Practice Guideline-Inconsistent Management of Fertility Preservation in Pediatric Cancer Patients in Community Settings: A Children's Oncology Group Study.

Background: The primary objective was to measure adherence to clinical practice guideline (CPG) recommendations for fertility preservation (FP) in pediatric cancer patients treated in National Cancer Institute Community Oncology Research Program (NCORP) sites. Secondary objectives were to describe factors such as site size associated with CPG-inconsistent care delivery and cryopreservation completion. Methods: This retrospective, multicenter study included patients 15 to 21 years old with a first cancer diagnosis from January 2014 through December 2015 who were previously enrolled to a Children's Oncology Group (COG) study and received care at a participating NCORP site. Patients were randomly selected from a list generated by the COG for chart review by participating sites. Primary outcome was care delivery that was inconsistent with a strong CPG recommendation on FP, namely discussion and offering of FP options before cancer treatment initiation, as adjudicated centrally by a panel. Results: A total of 129 patients from 25 sites were included. Among these, 48% (62/129) received CPG-inconsistent care. Most CPG-inconsistent care was due to lack of FP discussion documentation (93.5%, 58/62). Small site size, treatment at a pediatric (vs mixed adult/pediatric) site, and female sex were associated with higher odds of CPG-inconsistent care delivery. Conclusions: Newly diagnosed pediatric cancer patients often received CPG-inconsistent care for FP, with disproportionate gaps noted for females, and those treated at smaller or pediatric NCORP sites. The primary reason for CPG-inconsistent care is lack of FP discussion from clinicians. Opportunities to improve FP CPG implementation are highlighted.

Performance of ACR TI-RADS and the Bethesda System in Predicting Risk of Malignancy in Thyroid Nodules at a Large Children's Hospital and a Comprehensive Review of the Pediatric Literature.

While thyroid nodules are less common in children than in adults, they are more frequently malignant. However, pediatric data are scarce regarding the performance characteristics of imaging and cytopathology classification systems validated to predict the risk of malignancy (ROM) in adults and select those patients who require fine-needle aspiration (FNA) and possibly surgical resection. We retrospectively reviewed the electronic medical records of all patients 18 years of age or younger who underwent thyroid FNA at our institution from 1 July 2015 to 31 May 2022. Based on surgical follow-up from 74 of the 208 FNA cases, we determined the ROM for the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) ultrasound risk stratification system and The Bethesda System for Reporting Thyroid Cytopathology and added our results to those of pediatric cohorts from other institutions already published in the literature. We found the following ROMs for 1458 cases using ACR TI-RADS (TR): TR1. Benign: 2.2%, TR2. Not Suspicious: 9.3%, TR3. Mildly Suspicious: 16.6%, TR4. Moderately Suspicious: 27.0%, and TR5. Highly Suspicious 76.5%; and for 5911 cases using the Bethesda system: Bethesda I. Unsatisfactory: 16.8%, Bethesda II. Benign: 7.2%, Bethesda III: Atypia of Undetermined Significance: 29.6%, Bethesda IV. Follicular Neoplasm: 42.3%, Bethesda V. Suspicious for Malignancy: 90.8%, and Bethesda VI. Malignant: 98.8%. We conclude that ACR TI-RADS levels imply higher ROMs for the pediatric population than the corresponding suggested ROMs for adults, and, in order to avoid missing malignancies, we should consider modifying or altogether abandoning size cutoffs for recommending FNA in children and adolescents whose thyroid glands are smaller than those of adults. The Bethesda categories also imply higher ROMs for pediatric patients compared to adults.

Clinical practice guideline recommendation summaries for pediatric oncology health care professionals: A qualitative study.

OBJECTIVE: To develop a summary format of clinical practice guideline (CPG) recommendations to improve understandability among health care professionals. METHODS: We developed a summary format based on current research and used the "Think Aloud" technique in one-on-one cognitive interviews to iteratively improve it. Interviews of health care professionals from Children's Oncology Group-member, National Cancer Institute Community Oncology Research Program sites were conducted. After every five interviews (a round), responses were reviewed, and changes made to the format until it was well understood and no new, substantive suggestions for revision were raised. We took a directed (deductive) approach to content analysis of the interview notes to identify concerns related to recommendation summary usability, understandability, validity, applicability and visual appeal. RESULTS: During seven rounds of interviews with 33 health care professionals, we identified important factors that influenced understandability. Participants found understanding weak recommendations more challenging than strong recommendations. Understanding was improved when the term 'conditional' recommendation was used instead of 'weak' recommendation. Participants found a Rationale section to be very helpful but desired more information when a recommendation entailed a practice change. In the final format, the recommendation strength is clearly indicated in the title, highlighted, and defined within a text box. The rationale for the recommendation is in a column on the left, with supporting evidence on the right. In a bulleted list, the Rationale section describes the benefits and harms and additional factors, such as implementation, that were considered by the CPG developers. Each bullet under the supporting evidence section indicates the level of evidence with an explanation and the supporting studies with hyperlinks when applicable. CONCLUSIONS: A summary format to present strong and conditional recommendations was created through an iterative interview process. The format is straightforward, making it easy for organizations and CPG developers to use it to communicate recommendations clearly to intended users.

High Prevalence of Gene Fusions and Copy Number Alterations in Pediatric Radiation Therapy-Induced Papillary and Follicular Thyroid Carcinomas.

Background: Childhood cancer survivors and bone marrow transplant recipients treated with radiation therapy (RT) are at increased risk for subsequent thyroid cancer. However, the genetic landscape of pediatric thyroid cancer, both primary and RT-induced, remains poorly defined, as pediatric papillary thyroid carcinoma (PTC) has been understudied compared with adults and data on pediatric follicular thyroid carcinoma (FTC) are virtually nonexistent. The objective of this study was to characterize and compare the molecular profiles of pediatric RT-induced PTC and FTC cases with primary pediatric thyroid cancers. Methods: A total of 41 differentiated thyroid carcinomas (11 RT cases and 30 primary cases) from 37 patients seen at Phoenix Children's Hospital between January 1, 2010 and December 31, 2019 were evaluated by targeted next-generation sequencing and/or BRAF immunohistochemistry. Results: Eighty-six percent (6/7) of RT-PTC harbored a gene fusion (GF) compared with 56% (14/25) of primary PTC; 14% (1/7) of RT-PTC had a single-nucleotide variant (SNV; specifically, a point mutation in the DICER1 gene) compared with 44% (11/25) of primary PTC (all of the latter had the BRAFV600E mutation). An exceedingly rare ROS1 fusion was identified in a child with RT-PTC. With respect to FTC, copy number alterations (CNAs) were seen in 75% (3/4) of RT cases compared with 40% (2/5) of primary cases. None of the RT-FTC had SNVs compared with 100% (5/5) of primary FTC. Conclusions: In children, the molecular profile of subsequent RT-induced thyroid cancers appears to differ from primary (sporadic and syndromic) cases, with a high prevalence of GFs in RT-PTC (similar to PTC occurring after the Chernobyl nuclear reactor accident) and CNAs in RT-FTC. A better understanding of the molecular mechanisms underlying these cancers may lead to more accurate diagnosis, prognosis, and treatment, as some of the genomic alterations are potentially targetable.

Facilitators and barriers to clinical practice guideline-consistent supportive care at pediatric oncology institutions: a Children's Oncology Group study.

BACKGROUND: Clinical practice guideline (CPG)-consistent care improves patient outcomes, but CPG implementation is poor. Little is known about CPG implementation in pediatric oncology. This study aimed to understand supportive care CPG implementation facilitators and barriers at pediatric oncology National Cancer Institute (NCI) Community Oncology Research Program (NCORP) institutions. METHODS: Healthcare professionals at 26 pediatric, Children's Oncology Group-member, NCORP institutions were invited to participate in face-to-face focus groups. Serial focus groups were held until saturation of ideas was reached. Supportive care CPG implementation facilitators and barriers were solicited using nominal group technique (NGT), and implementation of specific supportive care CPG recommendations was discussed. Notes from each focus group were analyzed using a directed content analysis. The top five themes arising from an analysis of NGT items were identified, first from each focus group and then across all focus groups. RESULTS: Saturation of ideas was reached after seven focus groups involving 35 participants from 18 institutions. The top five facilitators of CPG implementation identified across all focus groups were organizational factors including charging teams with CPG implementation, individual factors including willingness to standardize care, user needs and values including mentorship, system factors including implementation structure, and implementation strategies including a basis in science. The top five barriers of CPG implementation identified were organizational factors including tolerance for inconsistencies, individual factors including lack of trust, system factors including administrative hurdles, user needs and values including lack of inclusivity, and professional including knowledge gaps. CONCLUSIONS: Healthcare professionals at pediatric NCORP institutions believe that organizational factors are the most important determinants of supportive care CPG implementation. They believe that CPG-consistent supportive care is most likely to be delivered in organizations that prioritize evidence-based care, provide structure and resources to implement CPGs, and eliminate implementation barriers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02847130. Date of registration: July 28, 2016.

Creation of a chemotherapy-induced nausea/vomiting dashboard to improve outcomes for pediatric cancer patients.

PURPOSE: Two of the most common acute side effects of chemotherapy are nausea and vomiting. Nausea and vomiting impact quality of life, nutritional status, and ability to tolerate further chemotherapy. Parents of pediatric oncology patients rank nausea as one of the most bothersome treatment-related symptoms. METHODS: Utilizing Quality Improvement methodology, we developed a dashboard interface to facilitate extraction of data from the electronic medical record (EMR), which is presented via a visual display that summarizes the type of chemotherapy and antiemetic medications, use of as needed medications, and number of episodes of emesis. RESULTS: This dashboard interface allows for rapid and efficient identification of patients whose antiemetic regimen is mismatched for the emetogenicity of ordered chemotherapy, thus providing a timely opportunity to modify the antiemetic regimen based on published guidelines before administration of chemotherapy drugs. It also allows measurement of the effectiveness of the antiemetic regimen in terms of the number of break through emesis and the need for as needed medications. CONCLUSIONS: A novel CINV dashboard was created, which visually conveys complex information about antiemetics, chemotherapy emetogenicity, as needed medications, and breakthrough vomiting for inpatient pediatric oncology patients.

Pediatric Chronic Myeloid Leukemia Presenting With Extreme Thrombocytosis Simulating Essential Thrombocythemia.

A 10-year-old boy presented with spontaneous bruising and was found to have extreme thrombocytosis without neutrophilia/shift to immaturity, basophilia or eosinophilia. While the peripheral blood and bone marrow findings initially suggested essential thrombocythemia, BCR-ABL1 translocation was detected and chronic myeloid leukemia, chronic phase, was diagnosed. Apheresis for platelet depletion was performed as a bridge given the delayed effects of medical therapy.

Exogenous immunoglobulin downregulates T-cell receptor signaling and cytokine production.

Intravenous immune globulin (IVIG), a polyvalent solution of pooled human immunoglobulin, is a potent immunomodulating agent. It is currently approved to treat autoimmune diseases, including idiopathic thrombocytopenia purpura, autoimmune hemolytic anemia, and Kawasaki disease. The basis of IVIG's immunomodulatory properties is not entirely understood. Proposed mechanisms include Fc receptor blockade, interference with cytokine network, and provision of anti-idiotypic antibodies. IVIG has also been shown to affect T-lymphocyte function, although a direct effect has been difficult to reconcile given the lack of immunoglobulin or Fc-receptors on T cells. Experiments were thus carried out to determine whether IVIG was acting on a specific T-cell subset and at the level of the T-cell receptor (TCR), and whether cytokine expression patterns were modulated. T lymphocytes obtained from adult peripheral blood and umbilical cord blood were cultured over a 1-wk time course in the presence of pharmacological IVIG concentrations (Gamunex(®) , 0-2.0 mg/ml). Cells were exposed to various stimulation conditions, and TCR signaling competence was assessed by quantifying activation-induced upregulation of CD25 and CD69, as well as production of specific T-cell cytokines. IVIG was found to significantly decrease T-lymphocyte proliferation, in a dose and time-dependent manner, in both cord and adult blood. IVIG markedly reduced phytohemagglutinin and anti-CD3-induced upregulation of CD25 and CD69 in both CD4 and CD8 T-cell subsets, although phorbol ester-induced responses were intact, suggesting a defect in the CD3/TCR signaling pathway. IVIG also inhibited anti-CD3-induced cytokine production of IL-10, IL-2, and IFN-γ in a dose-dependent manner. These data suggest that IVIG may have direct T-cell immunomodulatory properties by dampening TCR responses. Further studies are needed to more precisely define the molecular targets of IVIG.

Response to radiation in renal medullary carcinoma.

Renal medullary carcinoma (RMC) is a rare and highly aggressive malignancy arising from the renal medulla and found mostly in patients with sickle cell trait. RMC usually presents with widely metastatic disease. We describe a young man diagnosed with metastatic RMC who sustained a complete response to systemic chemotherapy but developed brain metastases with leptomeningeal involvement and subsequently had a partial response to brain irradiation. The use of radiation in the management of RMC is reviewed. Due to the apparent propensity for RMC to spread to the central nervous system, prophylactic treatment such as craniospinal irradiation should be considered along with chemotherapy in patients with metastatic RMC to potentially improve the progression-free interval.

A surfactant copolymer facilitates functional recovery of heat-denatured lysozyme.

The triblock copolymer poloxamer 188 is a non-cytotoxic, nonionic surfactant with both hydrophobic and hydrophilic domains. We show that P188 is able to facilitate the recovery of catalytic activity of heat-denatured lysozyme in dilute solution at low molar ratios of P188:enzyme. Heat-denatured enzyme retained 55% of native activity. After treatment with P188, the enzyme's activity was 85% of native. Because of the low molar ratios used and the non-cytotoxic nature of the compound, P188 may be of potential use in burn therapy.