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

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

Growth differentiation factor 15 (GDF15) elevation in children with newly diagnosed cancer.

Background: Growth differentiation factor 15 (GDF15), an inflammatory marker and mediator of adult cancer cachexia, remains largely unexplored in children. GDF15 increases nausea, vomiting, and anorexia in cancer and contributes to malnutrition, with the potential to be a cachexia therapeutic target. No studies have examined GDF15 in children with newly diagnosed cancer. Our pilot study compares GDF15 in children with newly diagnosed cancer to age- and sex-matched controls and correlates levels with anthropometric measurements and quality of life (QOL). Methods: Children with newly diagnosed cancer aged 2-21 years were enrolled with serum GDF15 ELISA, anthropometric measures [height, weight, and mid-upper arm circumference (MUAC)], and QOL assessments (using PedsQL™ Core and Gastrointestinal Modules), which were collected at baseline and repeated 3 months later. Serum GDF15 levels were obtained from age- and sex-matched controls for comparison. Results: A total of 57 participants enrolled (N=30, cancer group; N=27, control group) with a median age of 8.8 years (IQR 5.6-15.9 years). The participants were primarily male (54.4%), white (82.5%), and non-Hispanic (82.5%). Cancer diagnoses included acute lymphoblastic leukemia (N=8), lymphoma (N=8), neuroblastoma (N=5), soft tissue tumors (N=4), acute myeloid leukemia (N=2), and single participants with brain, kidney, and bone tumors. Baseline GDF15 was higher in the cancer cohort compared to the control cohort (median=614.6pg/mL and 320.5pg/mL, respectively; p<0.001). When examining participants with evaluable baseline and 3-month follow-up GDF15 levels (N=18), GDF15 was not statistically different (median=657.1pg/mL and 675.3pg/mL, respectively; p=0.702). A total of 13 of the 30 participants and 21 caregivers completed the PedsQL™ Core and Gastrointestinal symptom modules. QOL scores did not differ significantly at 3-month follow-up compared to baseline, but diarrhea worsened (p=0.017). Median participant response for diarrhea at baseline was 92.9 (IQR=92.9-96.4; N=13), which was significantly better than the follow-up (median=78.6; IQR= 71.4-92.9; p=0.017). There were no correlations between change in height, weight, or MUAC and change in GDF15 levels (p=0.351, 0.920, and 0.269 respectively). Conclusion: GDF15 was elevated in children with cancer at diagnosis compared to controls but did not correlate with anthropometric measurements or QOL. This pilot study will inform future prospective studies to better describe the natural history of GDF15 and its role in cachexia and as a potential therapeutic target.

In-person and virtual adaptation of an interprofessional palliative care communications skills training course for pediatric oncology clinicians.

Purpose: Effective, empathic communication is crucial for pediatric oncology clinicians when discussing palliative and end-of-life (PC/EOL) care with parents of children with cancer. Unfortunately, many parents report inadequate communication at these distressing times. This study evaluates the communication skills training (CST) clinicians received to deliver a PC/EOL communication intervention as part of a multi-site randomized-controlled trial (RCT). Methods: Clinicians from eight sites formed dyads (one physician and one nurse [RN] or advanced practice provider [APP]) and were trained over 3 days (in-person or virtually). Training was adapted from VitalTalk™ and included didactic instruction, videos, visual aids, and dedicated time to practice with simulated patients. Study participants completed a confidential, post-training online evaluation survey. A self-reported quality assurance checklist was used to measure fidelity to the communication protocol when delivered to parents during the RCT. Results: Thirty clinicians completed training; 26 completed post-training surveys including twelve (46.1%) physicians, 8 (30.8%) RNs and 6 (23.1%) APPs. Most were female (65.4%); white (80.8%), not Latinx (88.5%); 40-50 years old (53.9%); and in practice over 10 years (65.4%). Nine (34.6%) trained in-person; the rest trained virtually. Ninety-two percent reported the course was valuable or very valuable for developing their PC/EOL communication skills and 96% reported learning something new. Dyads trained virtually had similar fidelity to those trained in-person (95% and 90% respectively) when delivering the PC/EOL communication intervention to parents. Conclusion: This PC/EOL CST was valuable for improving pediatric oncology clinicians' communication skills, successfully implemented in-person and virtually, and translated effectively into practice.

Malnutrition screening and treatment in pediatric oncology: a scoping review.

BACKGROUND: Malnutrition and cachexia during pediatric cancer treatment worsen toxicity and quality-of-life. Clinical practice varies with lack of standard malnutrition definition and nutrition interventions. This scoping review highlights available malnutrition screening and intervention data in childhood cancer and the need for standardizing assessment and treatment. METHODS: Ovid Medline, CINAHL, and Cochrane Library were searched for studies containing malnutrition as the primary outcome with anthropometric, radiographic, or biochemical measurements. Secondary outcomes included validated nutritional assessment or screening tools. Two authors reviewed full manuscripts for inclusion. Narrative analysis was chosen over statistical analysis due to study heterogeneity. RESULTS: The search yielded 234 articles and 17 articles identified from reference searching. Nine met inclusion criteria with six nutritional intervention studies (examining appetite stimulants, nutrition supplementation, and proactive feeding tubes) and three nutritional screening studies (algorithms or nutrition support teams) each with variable measures and outcomes. Both laboratory evaluations (albumin, prealbumin, total protein) and body measurement (weight loss, mid-upper arm circumference) were used. Studies demonstrated improved weight, without difference between formula or appetite stimulant used. Screening studies yielded mixed results on preventing weight loss, weight gain, and survival. CONCLUSION: Our review demonstrated a paucity of evidence for malnutrition screening and intervention in pediatric cancer treatment. While a variety of malnutrition outcomes, interventions, and screening tools exist, nutritional interventions increased weight and decreased complications. Screening tools decreased malnutrition risk and may improve weight gain. Potential age- and disease-specific nutritional benefits and toxicities also exist, further highlighting the benefit of standardizing malnutrition definitions, screening, and interventions.

Constipation and GI diagnoses in children with solid tumours: prevalence and management.

OBJECTIVES: Despite continued development of targeted therapies for children with cancer, patients continue to experience an array of unwanted side effects. Children with solid tumours may experience constipation as a result of vinca alkaloid therapy, psychological stressors, periods of inactivity and opioid use. Our objective was to investigate the prevalence and treatment of constipation in hospitalised children with solid tumours treated with chemotherapy. METHODS: We retrospectively analysed data from 48 children's hospitals in the Pediatric Health Information System, extracting patients 0-21 years of age with a solid tumour diagnosis hospitalised from October 2015 through December 2019. RESULTS: We identified 13 375 unique patients with a solid tumour diagnosis receiving chemotherapy. Constipation was the most common gastrointestinal complaint with 8658 (64.7%; 95% Cl: 63.9% to 65.5%) having a constipation diagnosis or having received at least two laxatives during admission. Bone cancers had the highest percentage (69.9%) of patients with constipation, while Hodgkin's lymphoma had the lowest, although 52.1% of patients were affected. A total of 44% (n=35 301) of encounters received an opioid at some point during admission. Of patients receiving constipation medications, the most commonly prescribed was polyethyl glycol (n=25 175, 31.7%), followed by docusate (n=11 297, 14.2%), senna (n=10 325, 13.0%) and lactulose (n=5501, 6.9%). CONCLUSIONS: Constipation is the most common gastrointestinal issue that children with solid tumours experience while receiving chemotherapy in the inpatient setting. Increased attention should be given to constipation prophylaxis and treatment in children with solid tumours undergoing chemotherapy, particularly those identified as high risk.

The urgent need to improve childhood cancer cachexia.

Clinical care and research around cancer cachexia in children is lacking. Cachexia increases treatment-related toxicity and long-term morbidity and potentially affects mortality. We highlight the urgent need for specific focus on childhood cancer cachexia and discuss potential solutions to inform cachexia therapeutics for children.

Malnutrition identification and management variability: An administrative database study of children with solid tumors.

BACKGROUND: Malnutrition during cancer treatment increases treatment-related morbidity and mortality. Our study better characterizes variability in malnutrition identification and treatment by examining nutrition-related diagnoses and support for children with central nervous system (CNS) and non-CNS solid tumors during therapy. We examined diagnosis of malnutrition, use of tube feeding or parenteral nutrition (PN), and appetite stimulants. METHODS: We retrospectively reviewed 0 to 21-year-old patients in the Pediatric Health Information System from 2015 to 2019. Patients were classified as having (1) billed malnutrition diagnosis, (2) malnutrition diagnosis or using PN and enteral nutrition ("functional malnutrition"), and (3) any previous criteria or prescribed appetite stimulants ("possible malnutrition"), as well as associated risk factors. RESULTS: Among 13,375 unique patients, CNS tumors were most common (24.4%). Overall, 26.5% of patients had malnutrition diagnoses, 45.4% met functional malnutrition criteria, and 56.0% had possible malnutrition. Patients with adrenal tumors had highest billed, functional, and possible malnutrition (36.6%, 64.1%, and 69.4%, respectively) followed by CNS tumors (29.1%, 52.4%, and 64.1%). Patients with adrenal tumors had highest rates of PN use (47.4%) and those with CNS tumors had the highest tube feeding use (26.8%). Hospital admissions with malnutrition had a longer hospital length of stay (LOS) (6 vs 3 days, P < 0.0001), more emergency department admissions (24.4% vs 21.8%, P < 0.0001), and more opioid use (58.6% vs 41.4%, P < 0.0001). CONCLUSIONS: Variability in malnutrition diagnoses hinders clinical care and nutrition research in pediatric oncology. Improving disease-specific recognition and treatment of malnutrition can target nutrition support, ensure appropriate reimbursement, and potentially improve outcomes for children with solid tumors.

Features Associated With Weight Loss and Growth Stunting for Young Children During Cancer Therapy.

Features associated with malnutrition are poorly elucidated in pediatric cancer care. We aimed to better understand characteristics associated with weight-for-height (WHZ) and height-for-age (HAZ) changes for infants and young children during cancer treatment. This retrospective study included 434 patients diagnosed <3 years old from 2007 to 2015 at a large pediatric cancer center. Patients starting treatment outside our center, those with relapsed or secondary malignancies, or with inaccurate information were excluded. Abstracted weights and heights for a 24-month period after treatment initiation were converted to sex-specific and age-specific z scores. Although not statistically different at baseline, patients with hematologic malignancies gained weight over time, while other tumor types did not. Higher treatment intensity and younger age at diagnosis increased odds of clinically significant weight loss. Older children had higher HAZ at diagnosis and HAZ also significantly decreased over time for all examined risk factors, which is distinctly different from patterns in WHZ over time. In conclusion, WHZ and HAZ are affected differently by cancer treatment in infants and young children. We identify key risk factors for weight loss and growth stunting which will be necessary to develop prospective trials to examine anthropometric, biochemical, and patient recorded outcomes around nutrition.

Normalized measures and patient characteristics to identify undernutrition in infants and young children treated for cancer.

BACKGROUND: Various measures and definitions for undernutrition are used in pediatrics. Younger children treated for cancer are at high risk, but lack well-defined risk-based screening and intervention. METHODS: A retrospective study collected weight longitudinally for patients less than three years-old over two years after initiating cancer treatment. We included those diagnosed 2007-2015 at a large pediatric cancer center. Exclusion criteria included treatment starting outside our system, secondary or relapsed malignancy, or incomplete information. A decrease ≥1 in weight-for-age or weight-for-height z-score signified clinically significant weight loss. Univariate and multivariate models assessed hazards for developing first episode of clinically significant weight loss. RESULTS: Of 372 patients, only 24.6% of patients lost 10% of weight, but 58.6% lost weight-for-age z-score ≥1 and 64.8% lost ≥1 weight-for-height z-score within two years of treatment initiation. Patients who lost weight were younger (median age 15 vs. 24 months, p < 0.001). Compared to patients diagnosed in the first year of life, those diagnosed 24-35 months were less likely to lose weight (HR 0.62, p < 0.001) and lost weight later (median time to weight loss 144 vs. 35 days). Higher treatment intensity increased weight loss risk (HR 2.30, p < 0.001) and decreased time to weight loss (35 vs. 154 days). No differences were found based on sex, diagnosis, enteral or parenteral nutrition, gastroenterology consults, or intensive care admissions. CONCLUSIONS: Using normalized z-scores is more sensitive for identifying weight loss. Younger children are more likely to lose weight with higher intensity cancer therapy. Patient and treatment specific information should be used in risk stratifying weight loss screening and nutritional interventions.

Pleuropulmonary blastoma-like peritoneal sarcoma: a newly described malignancy associated with biallelic DICER1 pathogenic variation.

Since the original description of pathogenic germline DICER1 variation underlying pleuropulmonary blastoma (PPB), the spectrum of extrapulmonary neoplasms known to be associated with DICER1 has continued to expand and now includes tumors of the ovary, thyroid, kidney, eye, and brain among other sites. This report documents our experience with another manifestation: a primitive sarcoma that resembles PPB and DICER1-associated sarcoma of the kidney. These tumors are distinguished by their unusual location in the peritoneal cavity, associated with visceral and/or parietal mesothelium. A total of seven cases were identified through pathology review in children presenting at a median age of 13 years (range 3-14 years). Primary sites of origin included the fallopian tube (four cases), serosal surface of the colon (one case), and pelvic sidewall (two cases). One case had pathologic features of type I PPB, another type Ir (regressed) PPB, and the remaining five had features of type II or III PPB with a mixed primitive sarcomatous pattern with or without cystic elements. All had a pathogenic DICER1 variation identified in germline and/or tumor DNA. PPB-like peritoneal tumors represent a newly described manifestation of DICER1 pathogenic variation whose pathologic features are also recapitulated in DICER1-related renal sarcoma, cervical embryonal rhabdomyosarcoma, and some Sertoli-Leydig cell tumors with heterologous elements. Tumors arising from the fallopian tube or elsewhere in the abdomen/pelvis, especially those with heterogeneous rhabdomyosarcomatous and/or cartilaginous differentiation, should prompt consideration of germline and tumor DICER1 testing.

Nutrition & Exercise Interventions in Pediatric Patients with Brain Tumors: A Narrative Review.

Brain tumors have been the most common pediatric solid tumor and leading cause of morbidity and mortality. Improved survival emphasizes the importance of adverse treatment effects especially related to nutrition and exercise. Although studies have examined nutrition and exercise outcomes, few randomized trials exist. This narrative review included a systematic literature search with analysis of controlled or single group studies examining clinical and quality-of-life impact of nutrition or exercise interventions. Seven articles were included. Three nutrition studies demonstrated improvement with proactive feeding tubes, nutritional supplementation, and nutritional status. Two exercise studies showed improvement in measures of fitness and neuroanatomy with exercise in pediatric brain tumor survivors; two cohort studies demonstrated a link between quality of life and physical activity. Preliminary studies show nutrition and exercise may improve physical well-being and quality of life, suggesting future controlled studies are warranted to inform clinical care of children with brain tumors.

Hyperleukocytosis in infant acute leukemia: a role for manual exchange transfusion for leukoreduction.

BACKGROUND: Hyperleukocytosis is a serious, life-threatening complication of pediatric acute leukemia that can cause neurologic injury, pulmonary leukostasis, metabolic derangements, and coagulopathy. Acute leukemia has the highest risk of mortality and morbidity at presentation when associated with hyperleukocytosis. Infant leukemia presents unique challenges and treatment considerations due to the disease itself and size and overall health of the patient. While medical management of hyperleukocytosis in older patients with acute leukemia has been described, including cytoreductive procedures with automated leukapheresis (AL) or manual whole blood (WB) exchange transfusion, very little data exist for standardized management of hyperleukocytosis in infant leukemia patients. CASE REPORTS: We describe four cases of infant acute leukemia presenting with hyperleukocytosis and leukostasis who each received manual WB exchange transfusions in conjunction with induction chemotherapy and review the existing literature on the use of procedural leukoreduction in infants with hyperleukocytosis. Special attention is given to challenges and technical aspects of leukapheresis in infants: when to perform manual WB exchange versus AL, optimal vascular access, blood product selection, exchange rates, and the monitoring for complications. Using published cases, we outline benefits versus risks of manual WB exchange and AL in infants less than 10 kg. CONCLUSION: If providers perform procedural leukoreduction, the literature and our experience demonstrate manual WB exchange transfusion is favored over AL in infants less than 10 kg because of technical and complication risks associated with AL. Additional studies are needed to understand the impact of cytoreduction on long-term outcomes.

Ethical Barriers in Adolescent Oncofertility Counseling.

Adult survivors of pediatric cancers are at substantial risk for infertility. Oncofertility is an emerging field in medicine that has focused on the fertility preservation of these patients. As the field continues to develop, there are several areas in which our practice has improved. However, several ethical concerns still exist involving beneficence, nonmaleficence, informed consent, adolescent assent, and posthumous use of reproductive tissues. Because the field is still developing, great disparities exist in available options depending on age, ability to pay, and geographic location. Such discrepancies in access may lead to health disparities in the adolescent patient population. As the science continues to make future fertility more feasible, the ethical questions will continue to be more complex. The purpose of this article is to review some of the developments regarding oncoferility and address future directions for research and inquiry in specific areas.

Gentian violet and ferric ammonium citrate disrupt Pseudomonas aeruginosa biofilms.

OBJECTIVE/HYPOTHESIS: Bacterial biofilms are resistant to antibiotics and may contribute to persistent infections including chronic otitis media and cholesteatoma. Discovery of substances to disrupt biofilms is necessary to treat these chronic infections. Gentian violet (GV) and ferric ammonium citrate (FAC) were tested against Pseudomonas aeruginosa biofilms to determine if either substance can reduce biofilm volume. STUDY DESIGN: The biofilm volume and planktonic growth of PAO1 and otopathogenic P. aeruginosa (OPPA8) isolated from an infected cholesteatoma was measured in the presence of GV or FAC. METHODS: OPPA8 and PAO1 expressing a green fluorescent protein plasmid (pMRP9-1) was inoculated into a glass flow chamber. Biofilms were grown under low flow conditions for 48 hours and subsequently exposed to either GV or FAC for an additional 24 hours. Biofilm formation was visualized by confocal laser microscopy and biofilm volume was assayed by measuring fluorescence. Planktonic cultures were grown under standard conditions with GV or FAC. Statistical analysis was performed by Student t test and one-way ANOVA. RESULTS: GV reduced PAO1 and OPPA8 biofilm volume (P < .01). GV delayed the onset and rate of logarithmic growth in both strains. FAC reduced OPPA8 biofilm volume (P < .01), but did not effect of PAO1 biofilms. FAC had no effect on planktonic growth. CONCLUSIONS: The efficacy of GV in disrupting biofilms in vitro suggests that it may disrupt biofilms in vivo. The effect of FAC on Pseudomonas aeruginosa biofilms is strain dependent. Strain differences in response to increasing iron concentration and biofilm morphology stress the importance of studying clinically isolated strains in testing antibiofilm agents.

Mapping out spatial ability: sex differences in way-finding navigation.

This study examined how navigational strategies, map drawing, and map reading skills may be related in spatial perception performance of 124 U.S. undergraduate men and women who completed one of two versions of Collaer and Nelson's Judgment of Line Angle and Position-15 test and Piaget's Water Level Test. Analysis indicated sex differences in performance were eliminated when self-perceptions of map reading, map drawing, and navigational skills were used as covariates. The men used an orientation (cardinal), whereas the women used a landmark way-finding strategy. Introducing a fine motor skill to solve the Judgment of Line Angle and Position-15 eliminated the sex difference. The data suggest spatial perception is in part influenced by map reading and way-finding strategies.