Daniel A. Weiser

Background: Infertility following gonadotoxic chemotherapy is among the most distressing late effects experienced by childhood cancer survivors, highlighting the importance of fertility preservation (FP) counseling at the time of diagnosis. We aimed to improve the frequency and consistency of FP counseling and provider comfort with infertility‐related discussions through implementation of a standardized multidisciplinary workflow. Procedure: Interventions were implemented through two sequential Plan‐Do‐Study‐Act (PDSA) cycles to standardize fertility counseling practices. The first focused on provider education, workflow reminders, and standardized documentation. The second established a multidisciplinary FP team (FPT) to provide individualized patient counseling and facilitate FP. Documented FP counseling was assessed through chart review, and provider comfort regarding infertility and FP discussions was evaluated through anonymous surveys. Results: Documented fertility counseling improved from 43% at baseline to 65% following the first PDSA cycle and to 93.2% following implementation of the FPT in PDSA Cycle 2. Provider comfort improved most notably when counseling pubertal patients. Provider self‐reported comfort with fertility‐related discussions increased from 70% to 82% for pubertal male patients and from 56% to 82% for pubertal female patients. Comfort discussing FP with prepubertal patients remained comparatively lower throughout the study. Conclusion: A multidisciplinary FPT with standardized workflow resulted in sustained improvement of documented fertility counseling, while also improving provider comfort with fertility‐related discussions. These interventions were also associated with increased utilization of FP services. This represents an effective strategy to reduce missed opportunities for FP, ensuring timely counseling and access to FP options to all patients undergoing gonadotoxic therapy.

Children with severe neutropenia are advised to avoid activities and public spaces where they may be exposed to potential sources of infection, due to the risk of neutropenic fever, an oncologic emergency. The influence of exposure to environmental infectious disease risk factors (IDRFs) on the incidence of bacteremia has been difficult to study. Lockdowns enforced during the COVID-19 pandemic resulted in widespread social distancing and were associated with reduced opportunities for exposure to such environmental risk factors. We performed a retrospective chart review to compare the incidence of fever and bloodstream infection in patients with chemotherapy-induced neutropenia before (March 15, 2019 to March 14, 2020) and during the COVID-19 pandemic (March 15, 2020 to March 14, 2021). Before COVID-19, there were 219 episodes of neutropenia, 79 episodes with fever, and 12 episodes with bacteremia. During COVID-19, there were 236 episodes of neutropenia, 80 episodes with fever, and 13 episodes with bacteremia. In this small retrospective study, we did not observe a statistically significant difference in the incidence of either febrile neutropenia or febrile neutropenic bloodstream infection across 2 years with differing levels of exposure to environmental IDRFs (febrile neutropenia: IRR=0.89, P =0.38; bloodstream infection: IRR=1.01, P =0.99). Further multicenter studies are needed to better define the risks of exposure to potential environmental sources of infection, which may ultimately impact provider guidance for children with severe neutropenia.

Background: Hepatic veno-occlusive disease (VOD) is an endothelial injury seen after stem cell transplantation that can also occur with conventional chemotherapies. Morbidity can be significant, highlighting the need for effective supportive care. Case Report: We present a pediatric patient with Wilms tumor who developed VOD after dactinomycin and vincristine. Management included a molecular adsorbent recirculating system (MARS) for acute liver failure and irinotecan with vincristine (VI) as bridging chemotherapy before gradual reintroduction of dactinomycin. Conclusion: The patient remains in remission without long-term VOD complications. MARS facilitated hepatic recovery, and disease control was maintained with VI serving as a low-hepatotoxic bridging regimen before rechallenging with dactinomycin.

Next-generation sequencing (NGS) tests are integral to oncology care. To address the need for clinical and NGS data management, interpretation, and reporting, we developed iCatalog for the multi-institutional Individualized Cancer Therapy 2/Genomic Assessment Informs Novel Therapy Consortium (GAIN) pediatric precision oncology (PO) study. We designed iCatalog as a secure, web-based clinical decision support application that stores and integrates clinical, specimen, and molecular data from multiple sources at the patient level. The knowledge base (KB) and centralized patient/test database are intended to manage information for the 825 patients expected to enroll in the GAIN study. User permissions and access are controlled. Gene- and variant-level interpretation is facilitated through linked external resources and an internal KB that can be updated during application use. iCatalog generates editable, study-specific patient reports for each molecular test. Launched to support the GAIN study, iCatalog integrates genomic data from eight NGS platforms, generates 1002 clinical interpretation reports, and stores data for 1194 tests involving 777 patients with pediatric solid tumors across 133 diagnoses. The KB contains pediatric cancer-specific curations, authored by the research team, spanning 581 genes and 2659 variants (including 2146 single-nucleotide variants and insertions-deletions, 235 copy-number variants, 278 structural variants). iCatalog is a robust tool designed and proven to support a PO study. It integrates clinical and genomic data to facilitate the clinical interpretation and reporting of variants identified through NGS testing while maintaining a pediatric-specific KB generated during the study. As a scalable, modular platform, iCatalog can accelerate clinical decision-making and elevate PO insights across studies.

PURPOSE: Sepsis is the leading cause of mortality in patients with childhood cancer receiving cytotoxic chemotherapy. Pediatric hematology/oncology and transplant (PHOT) providers must counsel their patients on the safety of public activities and weigh the risk of infection exposure with the social and developmental benefits of in-person school and social outings. We hypothesize that there is significant variability in recommendations given by PHOT providers. METHODS: An electronic anonymous survey was developed and piloted by a group of PHOT providers to assess current methods for educating patients and families on limiting infectious exposures. Five clinical vignettes were created by the study team to explore how providers balance the competing priorities of safety and health-related quality of life (HRQoL). The electronic survey was institutional review board–approved and disseminated via email to all PHOT providers affiliated with the Children's Oncology Group across the United States. RESULTS: In total, 545 clinicians completed the survey. Most respondents were attending physicians (393, 72%), followed by fellows (61, 11%), advanced practice providers (APPs; 38, 7%), and nurses (37, 7%). On average, nurses and fellows made more conservative recommendations for avoiding infectious exposures compared with the recommendations from attending physicians and APPs ( P < .0001). On average, providers with more years of clinical experience expressed less cautious recommendations, whereas those with less years of experience provided more cautious recommendations for avoiding infectious exposures ( P = .0072). CONCLUSION: This survey demonstrates the importance of collaboration between all members of the care team in defining priorities for balancing safety risk and HRQoL to provide consistent messaging to patients. The variations in survey responses highlight the need for universal guidelines to standardize physician recommendations for limiting infectious exposures in pediatric patients on chemotherapy.

Summary: The novel use of blood-based biospecimens from a retrospective cohort of 50 patients with osteosarcoma was recently studied. The potential clinical utility of sorting cell-free DNA by fragment size was defined, with shorter tumor-specific DNA enrichment providing prognostic value and allowing for streamlined molecular profiling of circulating tumor material. See related article by Udomruk et al., p. 2085

PURPOSE: Osteosarcoma risk stratification, on the basis of the presence of metastatic disease at diagnosis and histologic response to chemotherapy, has remained unchanged for four decades, does not include genomic features, and has not facilitated treatment advances. We report on the genomic features of advanced osteosarcoma and provide evidence that genomic alterations can be used for risk stratification. MATERIALS AND METHODS: In a primary analytic patient cohort, 113 tumor and 69 normal samples from 92 patients with high-grade osteosarcoma were sequenced with OncoPanel, a targeted next-generation sequencing assay. In this primary cohort, we assessed the genomic landscape of advanced disease and evaluated the correlation between recurrent genomic events and outcome. We assessed whether prognostic associations identified in the primary cohort were maintained in a validation cohort of 86 patients with localized osteosarcoma tested with MSK-IMPACT. RESULTS: In the primary cohort, 3-year overall survival (OS) was 65%. Metastatic disease, present in 33% of patients at diagnosis, was associated with poor OS ( P = .04). The most frequently altered genes in the primary cohort were TP 53, RB1, MYC, CCNE1, CCND3, CDKN2A/B, and ATRX. Mutational signature 3 was present in 28% of samples. MYC amplification was associated with a worse 3-year OS in both the primary cohort ( P = .015) and the validation cohort ( P = .012). CONCLUSION: The most frequently occurring genomic events in advanced osteosarcoma were similar to those described in prior reports. MYC amplification, detected with clinical targeted next-generation sequencing panel tests, is associated with poorer outcomes in two independent cohorts.

Background: Patients with relapsed and refractory solid and central nervous system (CNS) tumors have poor outcomes and need novel therapeutic options. Vincristine, irinotecan, and temozolomide (VIT) is a common chemotherapy regimen in relapsed pediatric tumors with an established toxicity profile. Metformin shows preclinical anti‐cancer activity through multiple pathways.Methods: The objective of this Phase I trial was to establish the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of metformin in combination with VIT in children with relapsed and refractory solid and CNS tumors. A 3 + 3 design was used to test the addition of metformin at five dose levels (666, 999, 1333, 1666, and 2000 mg/m²/day). Therapy toxicity, pharmacokinetics, and radiologic response to treatment were evaluated.Results: Twenty‐six patients (median age 13 years, range 2–18 years) were enrolled with 22 evaluable for toxicity. The most common diagnoses were Ewing sarcoma (n = 8), rhabdomyosarcoma (n = 3) and atypical teratoid/rhabdoid tumor (n = 3). The MTD was exceeded at Dose Level 5 due to two dose‐limiting toxicities; both were Grade 3 diarrhea requiring prolonged hospitalization and intravenous fluids. The MTD was not determined due to study closure with less than six patients enrolled at Dose Level 4. Frequently observed toxicities were gastrointestinal (most notably diarrhea) and hematologic. Amongst 16 patients evaluable for best overall response, there was one complete response (Ewing sarcoma), three partial responses (Ewing sarcoma, glioblastoma multiforme, and alveolar rhabdomyosarcoma), and five patients with stable disease.Conclusions: The MTD of VIT with metformin was not determined due to premature study closure. We recommend an RP2D of Dose Level 4, 1666 mg/m²/day. Radiographic responses were seen in multiple tumor types. Further evaluation for efficacy could be investigated in a Phase II trial.

To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0–27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors.