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Highlights • Extrapulmonary lymphangioleiomyomatosis is rare and can be associated with tuberous sclerosis. • Recognition of lymphangioleiomyomatosis is important for early disease screening and genetic testing. • Lymphangioleiomyomatosis in lower uterine segment is very rare and can be overlooked.

There are limiteddata on long-term changes in the gut microbiome after acute lymphoblastic leukemia (ALL) therapy. We compared the gut microbial composition in stool samples of nine survivors of childhood ALL with 10 healthy sibling controls using 16S rRNA gene sequencing. Analysis of beta diversity within family units demonstrated a significant difference in bacterial strains between patients and healthy siblings. A significant difference in alpha diversity between patients and their healthy siblings was noted using Pielou's evenness. The composition of the gut microbiome differs between pediatric ALL survivors and healthy sibling controls for years after completion of therapy.

Vincristine, a key agent in the treatment of many pediatric malignancies, causes sensory, motor and autonomic neuropathy. We report the clinical courses of 5 patients who required cessation of vincristine after developing severe neurotoxicity during treatment for acute lymphoblastic leukemia. All 5 patients lost the ability to ambulate and 3 had additional severe neurotoxic side effects including vision loss and vocal cord dysfunction. Although prior literature reports poor outcomes for children in whom vincristine was discontinued during acute lymphoblastic leukemia therapy, all 5 patients described here achieved and have maintained complete continuous remission.

11551 Background: Immune checkpoint inhibitors (ICI) have limited efficacy for most sarcomas. Yet, responses are seen in particular sarcoma subtypes, highlighting the need for better predictive biomarkers. The T cell inflamed score (TIS), a gene expression signature reflective of an active tumor immune microenvironment, is associated with ICI response in multiple solid tumors. We evaluated the TIS across a large database of sarcomas to identify which histologic subtypes may benefit from ICI. Methods: Next generation sequencing of DNA (592 gene or whole exome)/RNA (whole transcriptome) was performed for 3605 sarcoma patient samples, representing 45 histologic subtypes (Caris Life Sciences, Phoenix, AZ). TIS (18 gene weighted coefficient composite value; Cristescu 2018) was calculated and the Microenvironment Cell Populations-counter tool (Becht 2016) was used to quantify immune cell populations. Results were compared to melanoma (n = 1255), a representative immunogenic tumor type. High TIS was defined as a score within the upper quartile of melanoma TIS (> 5.5). Percentage with high TIS are reported with 95% CI. Results: Median TIS was highest in inflammatory myofibroblastic tumor (IMT), epithelioid sarcoma (EPIS), myxofibrosarcoma (MFS), well differentiated liposarcoma, and solitary fibrous tumor (SFT). These did not differ significantly from melanoma (p > 0.06). Median TIS was lowest in embryonal rhabdomyosarcoma, desmoid tumor (DES), synovial sarcoma (SYNS), and Ewing sarcoma (ES). Histologic subtypes where > 10% of samples had a high TIS included IMT (29.9% ± 21.7%), MFS (23.3% ± 12.6%), pleomorphic sarcoma (PLSARC) (21.9% ± 5.8%), cutaneous angiosarcoma (ANGS) (18.4% ± 13.9%), spindle cell sarcoma (17.5% ± 7.6%), liposarcoma (LPS) (17% ± 10.7%), EPIS (15.4% ± 19.6%), visceral ANGS (13.2% ± 10.7%), pleomorphic LPS (13.6% ± 14.3%), fibrosarcoma (12.5% ± 13.2%), leiomyosarcoma (11.6%± 3.4%), malignant peripheral nerve sheath tumor (MPNST) (10.2% ± 7.7%), and perivascular epithelioid cell tumor (PEComa) (10% ± 10.7%). The relative abundance of immune and stromal cell populations was highly variable across sarcoma subtypes, yet a strong positive correlation between TIS and immune cell populations was observed for most subtypes (e.g. T cells, Spearman R range: 0.56 [P = 0.08] - 0.96 [P < 0.0001]). A notable exception was SFT, which had a relatively high median TIS but low abundance of CD8+ T cells and B cells. Conclusions: We found high median TIS and/or significant proportions of samples with a high TIS in sarcoma subtypes with previously demonstrated responsiveness to ICI, including MFS, PLSARC, LPS, and ANGS, while unresponsive tumor types such as RMS, DES, SYNS, and ES had low TIS. We further identified subtypes with high TIS but limited prior clinical data supporting ICI use, such as IMT, EPIS, MPNST, SFT, and PEComa. Our results warrant prospective exploration of TIS as a predictive biomarker for ICI use in sarcoma.

e22015 Background: GSK-3β overexpression is associated with aggressive malignancies, treatment resistance and poor prognosis. The GSK-3β inhibitor Elraglusib induces apoptosis via NFΚB and p53 pathways and has potent anti-fibrotic and immunomodulatory activity. Adult studies of elraglusib demonstrate clinical activity in pancreatic cancer, melanoma, lymphoma and sarcoma as a single agent or in combination with cytotoxic chemotherapy. Elraglusib is active in in vivo models of neuroblastoma (NBL) and malignant glioma. This first-in-pediatrics study (NCT04239092) is evaluating the safety, pharmacokinetics (PK), and efficacy of elraglusib monotherapy and in combination with chemotherapy in patients with refractory malignancies. Methods: Elraglusib is given intravenously (IV) twice-weekly at 3 dose levels (DL) (9.3, 12.4 and 15 mg/kg) as a single agent or in combination with irinotecan, cyclophosphamide/topotecan or temozolomide/irinotecan in 21-day cycles. A cohort of pts with refractory NBL will be treated at the recommended phase 2 dose (RP2D) of elraglusib with temozolomide/irinotecan. Results: As of January 2022, 23 pts (n = 7 female, median age 14.2 years) have received at least one dose of elraglusib. Tumor types: 5 NBL, 3 diffuse midline glioma (DMG), 3 osteosarcoma (OS), 3 ependymoma (EP), 2 alveolar rhabdomyosarcoma (aRMS), 1 angiosarcoma (AS), 1 Ewing sarcoma (ES), 1 glioblastoma (GBM), 1 hepatoblastoma (HB), 1 embryonal CNS tumor NOS, 1 NUT midline carcinoma, 1 pineoblastoma (PB). Median time from diagnosis is 26 months (range: 6.7 – 156.3) and median number of lines of prior systemic therapy is 2 (range 0-14). Two DLs of single agent (6 pts) have been completed (9.3 and 12.4 mg/kg) without elraglusib-attributable severe adverse events (SAEs). Of the 15 patients on the combination arm with irinotecan or cyclophosphamide/topotecan, a single adverse event (Grade 4 hypotension/infusion reaction) was reported. Grade 1/2 elraglusib attributable-AEs include: transient visual change (n = 10), nausea (n = 7), vomiting (n = 6), fatigue (n = 2), hypotension (n = 2) and infusion reaction (n = 1). One pt with recurrent ES had a radiographic and pathologic CR after 3 cycles of elraglusib/cyclophosphamide/topotecan. 6 pts (26.1%) had SD (2 NBL, 1 aRMS, 1 EP, 1 OS, 1 GBM). 8 pts (35%) remained on study treatment ≥ 3 months (2 NBL, 2 EP, 1 OS, 1 aRMS, 1 ES, 1 PB). Median treatment duration was 40 days (range 1 - 126). 4 pts remain on therapy. Conclusions: Elraglusib is well tolerated as a single agent and with several chemotherapy regimens in this heavily pretreated pediatric population with refractory cancers. It has encouraging antitumor activity, with 1 CR in a patient with recurrent ES. Enrollment is ongoing; a RPD2 has not been reached. Clinical trial information: NCT04239092.

11525 Background: Osteosarcoma (OS) incidence is characterized by a bimodal age distribution, with peaks in early adolescence and in adults > 65 years of age. In contrast to adolescents, OS in adults is frequently considered as a secondary neoplasm (i.e., transformation of Paget´s disease of the bone, radiation induced). Yet, the literature is scarce regarding the impact of age on the molecular landscape of OS. Herein, we sought to explore the association between age and the genomic profile as well as the tumor immune microenvironment (TME) in a large cohort of OS patients. Methods: 208 specimens were centrally analysed at the Caris Life Sciences laboratory with DNA seq (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), RNA seq (Archer fusion panel or whole-transcriptome sequencing) and immunohistochemistry (IHC). RNA deconvolution and differential expression analyses were performed using the Microenvironment Cell Populations counter method for quantification of immune cell populations and gene expression profiling. The cohort was stratified into three distinct age groups (< 25 years [n = 83], 25-45 years [n = 58], > 45 years [67]). Results: Overall, the most frequently detected mutations were in TP53 (37%), RB1 (13%), ATRX (9%), TERT (6%), PTEN (5%), PIK3CA (4%) and KMT2D (3%). Copy number alterations were most frequently detected in CDK4 (12%), LRIG3 (11%), FLCN (11%), MDM2 (9%), CCND3 (9%), VEGFA (8%), TFEB (8%). Interestingly, age-based stratification revealed an increased frequency of FLCN (19.7 vs 4.7%, p < 0.01), CCND3 (13.9 vs 3.1%, p < 0.05), and HSP90AB1 (11.3 vs 0.0%, p < 0.01), alterations in patients < 25 years compared to > 45 years. TME analysis revealed that patients > 45 years have decreased B-cell abundance compared to patients < 25 years (2.9-fold decrease, p < 0.05) and 25-45 years (4.8-fold decrease, p < 0.05). Although not statistically significant, median transcriptional expression of PD-L1 was numerically increased in patients > 45 years (1.8-fold compared to 25-45 years, p = 0.17; 2.0-fold compared to < 25 years, p = 0.27), which was consistent with increasing rates of IHC PD-L1 expression with age (5.3%, 9.4%, and 17.5%, respectively, p = 0.06). Conclusions: To the best of our knowledge, this study represents the largest cohort of molecularly characterized OS. Age-associated differences in the genetic landscape and TME composition, including increased gene amplifications observed in younger patients and decreased B-cell abundance in older patients, might suggest fundamental underlying molecular and biological differences.

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma that presents most commonly in the extremities of adolescents and young adults. Involvement of the head and neck is more common in younger patients. A 2-year-old found to have localized lingual ASPS and was treated successfully with partial glossectomy. We describe this rare form of sarcoma, discuss management options, review updated literature and present our patient's outcome after 5 years of close follow-up.

Objectives To evaluate the cost-effectiveness of screening children born at extremely low birth weight (ELBW) for hepatoblastoma using serial serum alpha-fetoprotein measurements. Study design We created a decision tree to evaluate the cost effectiveness of screening children born at ELBW between 3 and 48 months of age compared with current standard of care (no screening). Our model used discounted lifetime costs and monetary benefits in 2018 US dollars, based on estimates in the published literature. The effects of uncertainty in model parameters were also assessed using univariate sensitivity analyses, in which we changed the values for one parameter at a time to assess the effect on the estimated incremental cost-effectiveness ratio. Results For the estimated 55 699 children born at ELBW in the US each year, this screening is associated with 77.7 additional quality-adjusted life-years (QALYs) at a cost of $8.7 million. This results in an incremental cost-effectiveness ratio of about $112 000/QALY, which is considered cost effective from a US societal perspective. For children diagnosed with hepatoblastoma, our model finds that the screening regimen is associated with a 10.1% increase in survival, a 4.18% increase in expected QALYs, and a $245 184 decrease in expected cost. Conclusions Screening ELBW children for hepatoblastoma between 3 and 48 months of age dominates the alternative and is cost effective from a societal perspective.

Approximately 1 in 285 children in the United States (US) will be diagnosed with cancer before the age of 20.1 More than 80% of children diagnosed with cancer will become long-term survivors.2 As of January, 2010, there are more than 380,000 adult survivors of childhood cancer in the US.3 More than two-thirds of survivors will develop chronic conditions.4 Professional organizations have advocated for specialized risk-based care of survivors.5 Locally and nationally, lack of transition services and insurance coverage are barriers to care of these adult survivors.6 We describe one such case to illustrate these challenges and their impact. [Full article available at http://rimed.org/rimedicaljournal-2016-08.asp, free with no login].

Targeted next-generation sequencing (NGS) identified a novel loss of function mutation in GARS, a gene linked to Charcot–Marie–Tooth disease (CMT), in a paediatric acute lymphoblastic leukaemia patient with severe chemotherapy-induced peripheral neuropathy (CIPN) due to vincristine. The patient was clinically asymptomatic, and lacked a family history of neuropathy. The effect of the mutation was modelled in a zebrafish knockdown system that recapitulated the symptoms of the patient both prior to and after treatment with vincristine. Confocal microscopy of pre- and post-synaptic markers revealed that the GARS knockdown results in changes to peripheral motor neurons, acetylcholine receptors and their co-localisation in neuromuscular junctions (NMJs), whereas a sensitive and reproducible stimulus–response assay demonstrated that the changes correlating with the GARS mutation in themselves fail to produce peripheral neuropathy symptoms. However, with vincristine treatment the GARS knockdown exacerbates decreased stimulus response and NMJ lesions. We propose that there is substantial benefit in the use of a targeted NGS screen of cancer patients who are to be treated with microtubule targeting agents for deleterious mutations in CMT linked genes, and for the screening in zebrafish of reagents that might inhibit CIPN. Studying a young cancer patient’s DNA in a zebrafish model helped reveal why she experienced a severe complication of chemotherapy. The 12-year-old girl developed back pain, muscle weakness and other symptoms of nerve damage after receiving two doses of a chemotherapy drug called vincristine to treat her acute lymphoblastic leukemia. To determine the cause of the problem, a team led by Michael Holloway from the Warren Alpert Medical School at Brown University, USA, sequenced 15 genes linked to Charcot-Marie-Tooth disease, the most common hereditary explanation for this kind of nerve damage. They found a novel mutation in a gene called GARS. The researchers knocked down this gene’s function in zebrafish, and saw no obvious signs of disease until they added vincristine and observed disruption of neuromuscular junctions.

Neuroblastoma is an embryonal tumor of childhood with a heterogenous clinical presentation that reflects differences in activation of complex biological signaling pathways. Protein phosphorylation is a key component of cellular signal transduction and plays a critical role in processes that control cancer cell growth and survival. We used shotgun LC/MS to compare phosphorylation between a human MYCN amplified neuroblastoma cell line (NB10), modeling a resistant tumor, and a human neural precursor cell line (NPC), modeling a normal baseline neural crest cell. 2181 unique phosphorylation sites representing 1171 proteins and 2598 phosphopeptides were found. Protein kinases accounted for 6% of the proteome, with a predominance of tyrosine kinases, supporting their prominent role in oncogenic signaling pathways. Highly abundant receptor tyrosine kinase (RTK) phosphopeptides in the NB10 cell line relative to the NPC cell line included RET, insulin-like growth factor 1 receptor/insulin receptor (IGF-1R/IR), and fibroblast growth factor receptor 1 (FGFR1). Multiple phosphorylated peptides from downstream mediators of the PI3K/AKT/mTOR and RAS pathways were also highly abundant in NB10 relative to NPC. Our analysis highlights the importance of RET, IGF-1R/IR and FGFR1 as RTKs in neuroblastoma and suggests a methodology that can be used to identify potential novel biological therapeutic targets. Furthermore, application of this previously unexploited technology in the clinic opens the possibility of providing a new wide-scale molecular signature to assess disease progression and prognosis.