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BackgroundMaternal migraine has been linked to adverse birth outcomes including low birth weight and preterm birth, as well as congenital anomalies in offspring. It has been speculated that this may be due to the use of medications in pregnancy, but lifestyle, genetic, hormonal, and neurochemical factors could also play a role. There is evidence for varying cancer incidences among adults with migraine. Here, we utilized data from national registries in Denmark to examine associations between maternal diagnoses of migraine and risk for cancer in offspring.MethodsWe linked several national registries in Denmark to identify cases from the Cancer Registry among children less than 20years (diagnoses 1996–2016) and controls from the Central Population Register, matched to cases by birth year and sex (25:1 matching rate). Migraine diagnoses were identified from the National Patient Register using International Classification of Diseases, versions 8 and 10 codes and migraine-specific acute or prophylactic treatment recorded in the National Pharmaceutical Register. We used logistic regression to estimate the risk of childhood cancers associated with maternal migraine.ResultsMaternal migraine was positively associated with risk for non-Hodgkin lymphoma (odds ratio [OR]=1.70, 95% confidence interval [CI]: 1.01–2.86), central nervous system tumors ([OR=1.31, 95% CI: 1.02–1.68], particularly glioma [OR=1.64, 95% CI: 1.12–2.40]), neuroblastoma (OR=1.75, 95% CI: 1.00–3.08), and osteosarcoma (OR=2.60, 95% CI: 1.18–5.76).ConclusionsAssociations with maternal migraine were observed for several childhood cancers, including neuronal tumors. Our findings raise questions about the role of lifestyle factors, sex hormones, genetic, and neurochemical factors in the relationship between migraine and childhood cancers.

Background: This Phase 1/2 study is based on the hypothesis that immune checkpoint inhibitors are more effective when given earlier in the course of the disease for advanced soft tissue sarcoma. Methods: Phase I endpoints—maximum tolerated dose in previously treated patients; Phase II endpoints—best response, progression free survival and overall survival and incidence of adverse events in previously untreated patients; Phase I treatments—escalating doses of trabectedin (1.0, 1.2, 1.5 mg/m2) as continuous intravenous infusion over 24 h every 3 weeks, 1 mg/kg of ipilimumab given intravenously every 12 weeks, and 3 mg/kg of nivolumab given intravenously every 2 weeks; Phase II treatments—maximum tolerated dose of trabectedin and defined doses of ipilimumab and nivolumab. Results: Phase I (n = 9)—the maximum tolerated dose of trabectedin was 1.2 mg/m2; Phase II (n = 79)—6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median progression-free survival, 6.7 months (CI 95%: 4.4–7.9), median overall survival, 24.6 months (CI 95%: 17.0–.); Grade 3/4 therapy-related adverse events (n = 92)—increased ALT (25%), fatigue (8.7%), increased AST (8.7%), decreased neutrophil count (5.4%) and anemia (4.6%). Conclusion: SAINT is a safe and effective first-line treatment for advanced soft tissue sarcoma.

Most often, IgM-mediated autoimmune hemolytic anemia (AIHA) presents as cold agglutinin disease in the pediatric population. The IgM warm agglutinins are rare, with few reports in the literature. This case study describes a 5 year old girl with nausea, abdominal pain and jaundice, and a hemoglobin of 5.5 g/dL who was diagnosed with a warm reactive IgM AIHA. The laboratory workup revealed a pan-reactive antibody and a direct antiglobulin test negative for IgG and C3. A thermal amplitude assay revealed reactive IgM antibodies at 37°C, 30°C, 25°C, and 4°C and an antibody titer of 1:8. An adsorption for IgM-specific autoantibodies exposed underlying anti-E and anti-Cw alloantibodies. Transfusion of phenotypically matched red blood cell units supported ongoing hemolysis. The AIHA treatment included steroids followed by rituximab with complete resolution. A literature review shows variable outcomes for warm AIHA in the pediatric population and often describes the presence of warm reactive IgM-mediated AIHA as an indicator for poor prognosis.

Childhood cancer may be related to maternal health in pregnancy. Maternal anemia is a common condition in pregnancy, especially in low-income countries, but the association between maternal anemia and childhood cancer has not been widely studied.To examine the potential relation between maternal anemia during pregnancy and childhood cancers in a population-based cohort study in Taiwan.We examined the relationship between maternal anemia and childhood cancer in Taiwan (N = 2160 cancer cases, 2,076,877 noncases). Cases were taken from the National Cancer Registry, and noncases were selected from birth records. Using national health registries, we obtained maternal anemia diagnoses. We estimated the risks for childhood cancers using Cox proportional hazard analysis.There was an increased risk of cancers in children born to mothers with nutritional anemia (hazard ratio (HR): 1.32, 95% CI 0.99, 1.76). Iron deficiency anemia (HR: 1.30, 95% CI 0.97-1.75) carried an increased risk, while non-nutritional anemias were not associated with childhood cancer risk.Our results provide additional support for screening for anemia during pregnancy. Adequate nutrition and vitamin supplementation may help to prevent some childhood cancer.

T‐lymphokine‐activated killer (T‐LAK) cell‐originated protein kinase (TOPK) is an emerging target with critical roles in various cancers; however, its expression and function in osteosarcoma remain unexplored. We evaluated TOPK expression using RNA sequencing and gene expression data from public databases (TARGET‐OS, CCLE, GTEx, and GENT2) and immunohistochemistry in an osteosarcoma tissue microarray (TMA). TOPK gene expression was significantly higher in osteosarcoma than normal tissues and directly correlated with shorter overall survival. TOPK was overexpressed in 83.3% of the osteosarcoma specimens within our TMA and all osteosarcoma cell lines, whereas normal osteoblast cells had no aberrant expression. High expression of TOPK associated with metastasis, disease status, and shorter overall survival. Silencing of TOPK with small interfering RNA (siRNA) decreased cell viability, and inhibition with the selective inhibitor OTS514 suppressed osteosarcoma cell proliferation, migration, colony‐forming ability, and spheroid growth. Enhanced chemotherapeutic sensitivity and a synergistic effect were also observed with the combination of OTS514 and either doxorubicin or cisplatin in osteosarcoma cell lines. Taken together, our study demonstrated that TOPK is a potential prognostic biomarker and therapeutic target for osteosarcoma treatment., TOPK is aberrantly expressed in osteosarcoma and significantly correlates with shorter overall survival (OS). Therapeutic inhibition of TOPK decreases osteosarcoma cell growth, proliferation, migration, and colony formation. These findings indicate TOPK as a prognostic biomarker for OS and a potential therapeutic target in patients with osteosarcoma.

Childhood cancer risk is associated with maternal health during pregnancy. Anemia in pregnancy is a common condition, especially in low-income countries, but a possible association between maternal anemia and childhood cancer has not been widely studied.We examined the relation in a population-based study in Denmark (N=6420 cancer cases, 160,485 controls). Cases were taken from the Danish Cancer Registry, and controls were selected from national records. We obtained maternal anemia diagnoses from the National Patient and Medical Births registries. In a separate analysis within the years available (births 1995-2014), we examined cancer risks among mothers taking prescribed vitamin supplements, using data from the National Prescription Register. We estimated the risks of childhood cancer using conditional logistic regression.The risks of neuroblastoma [odds ratio (OR= 1.83, 95% confidence interval (CI): 1.04, 3.22] and acute lymphoblastic leukemia (OR= 1.46, 95% CI 1.09, 1.97) were increased in children born to mothers with anemia in pregnancy. There was a two-fold increased risk for bone tumors (OR= 2.59, 95% CI: 1.42, 4.72), particularly osteosarcoma (OR= 3.54, 95% CI 1.60, 7.82). With regards to prescribed supplement use, mothers prescribed supplements for B12 and folate deficiency anemia (OR= 4.03, 95% CI 1.91, 8.50) had an increased risk for cancer in offspring.Our results suggest that screening for anemia in pregnancy and vitamin supplementation may be an actionable strategy to prevent some cases of childhood cancer.

nab-Sirolimus is a novel albumin-bound mTOR inhibitor (mTORi) approved in the US for adult patients with malignant PEComa. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC1 and TSC2, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with a broad variety of cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with long-term treatment of nab-sirolimus. PRECISION I (NCT05103358) will evaluate efficacy and safety of nab-sirolimus in patients with TSC1 (Arm A) and TSC2 (Arm B) alterations. Eligible patients are ≥12 years old and mTORi-naïve, possess malignant solid tumors with TSC1 or TSC2 inactivating alterations (confirmed by central review of sequencing reports), and have received appropriate standard treatments, as determined by the investigator. nab-Sirolimus 100 mg/m2 will be given weekly intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began March 2022. Collaboration with leading next-generation sequencing vendors will expedite the identification of patients with qualifying TSC1 or TSC2 mutations; study access will be facilitated through a “just-in-time” approach to trial location activation. Based on the prevalence of TSC1 or TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric (Table). Est incidence of patients with TSC1 or TSC2 alterations available for 1L therapy in 2030 Tumor Type TSC1 Mutations, %a TSC2 Mutations, %a Eligible TSC1 or TSC2 Combined, % Bladder 6.33 1.70 8.03 Hepatobiliary 1.27 3.31 4.58 Endometrial 2.10 1.22 3.32 Soft tissue sarcoma 1.28 1.71 2.99 Ovarian 1.85 0.92 2.77 Esophagogastric 0.65 1.46 2.11 Colorectal carcinoma 0.99 0.39 1.38 Pancreatic 0.57 — 0.57 Note: Estimated incidence of patients in the United States with definite impact TSC1 or TSC2 alterations available for 1L therapy in 2030. All gastrointestinal tumors (bolded) with known incidence of TSC1 or TSC2 and tumor types with combined incidence of TSC1 or TSC2 alterations of >2% are listed. aThe proportion of patients with definite impact mutations (ie, mutations known to have a biological impact, including frameshift, nonsense, and splice-site mutations and deep deletions) was derived from the NIH NCI Genomic Data Commons Data Portal (NIH NCI Genomic Data Commons). 1L, first-line. Citation Format: Jordi Rodon Ahnert, Brian Schulte, Michael J. Demeure, Dustin Deming, Noah Federman, Meredith A. McKean, Elizabeth Lee, Alexander Spira, David J. Kwiatkowski, Maen Hussein, Erlinda Gordon, David Crockett, Kristen Ganjoo, Lee D. Cranmer, Anita N. Schmid, Willis H. Navarro, Loretta M. Itri, Gopa Iyer. Phase 2, multicenter open-label basket trial of nab-sirolimus for patients with inactivating alterations in TSC1 or TSC2 (PRECISION I) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT057.

Desmoid tumor (DT) is a rare, soft tissue neoplasm associated with an unpredictable clinical course. Although lacking metastatic potential, DT is often locally aggressive and invasive, causing significant morbidity. Both sporadic DT and familial adenomatous polyposis (FAP)-associated DT are linked to constitutive activation of the Wnt signaling pathway with mutations in the β-catenin oncogene CTNNB1 or the tumor suppressor gene APC, respectively. Cross-talk between the Notch and Wnt pathways, as well as activation of the Notch pathway resulting from dysregulation of the Wnt pathway, suggest a possible therapeutic target for DT. Due to the role γ-secretase plays in Notch signaling through cleavage of the Notch intracellular domain (with subsequent translocation to the nucleus to activate gene transcription), γ-secretase inhibitors (GSIs) have emerged as a potential treatment for DT. Two GSIs, nirogacestat (PF-03084014) and AL102 are in later-stage clinical development; nirogacestat is being evaluated in a phase 3, randomized, placebo-controlled trial while AL102 is being evaluated in a phase 2/3, dose-finding (part A) and placebo-controlled (part B) trial. This review summarizes current understanding of the molecular pathogenesis of DT focusing on dysregulation of the Wnt signaling pathway, crosstalk with the Notch pathway, and the potential therapeutic role for GSIs in DT.

Background Pediatric Orthopaedic Oncology is a developing subspecialty within the field of Pediatric Orthopaedics. Traditionally, the field of Orthopaedic Oncology has been focused on the skeletally mature individual, and the research tends to be all encompassing rather than truly evaluating isolated populations. The purpose of this review is to summarize the most clinically relevant literature in the field of Pediatric Orthopaedic Oncology over the last 6 years. Methods We evaluated the PubMed database utilizing keywords for pediatric orthopaedic oncology: sarcoma, osteosarcoma, Ewing sarcoma, bone cyst. In additionally, we further broadened our search by searching for relevant articles in the contents sections of major orthopaedic surgery journals that routinely publish both pediatric and orthopaedic oncology literature. In keeping with "What's New," we selected the most clinically relevant articles published in the last 6 years from January 1, 2014 through February 2020. Basic science and systemic therapies literature was widely reviewed and the research and clinical trials most relevant to pediatric sarcoma and neoplastic processes found in the pediatric population were included. Results Our search yielded 60 articles that met general criteria, from which 14 were determined to be most relevant to the goals of this paper. Of the papers presented in this review, there were papers related to management of benign tumors/tumor-like conditions, bone cysts, limb salvage procedures, and amputation procedures. Ultimately included in the review were 5 studies related to limb salvage, 4 related to bone cysts, 1 related to multiple hereditary exostoses, 2 related to osteofibrous dysplasia, 1 related to chondroblastoma, and 1 discussing cementation in skeletally immature patients. They were level III, IV, and V studies. Basic science and systemic therapies literature was widely reviewed and the research and clinical trials most relevant to pediatric sarcoma and neoplastic processes found in the pediatric population were included. Our search of the basic science and systemic therapies literature yielded 19 sources were found to be pertinent to our aims and 18 of those sources were published between 2015 and 2020. Conclusions There are many, varied, and creative procedures in the realm of limb salvage, though there remains a lack of high-level evidence to support some of the more novel procedures. In regards to benign bone tumors, despite a more solid base of literature, there still does not seem to be consensus as to the best treatment. In particular, there continue to be many schools of thought on the treatment of benign bone cysts. Research in the basic science arena and systemic therapies are advancing in exciting ways in regards to pediatric sarcoma. Orthopaedic oncologic research specific to the pediatric population overall continues to be impeded by low sample sizes and inadequate levels of evidence, which limits the ability of surgeons to draw definitive conclusions from the literature.

The Ewing sarcoma family of tumors (ESFT) are high-grade small round blue cell malignancies traditionally presenting in children and adolescents. The most common site of primary disease is bone, though extraskeletal primary sites are well-recognized.() We present six cases of primary ESFT of the kidney and one case of the adrenal gland. Patients were 11–18 years of age at diagnosis. Metastases at diagnosis were present in most cases (n=6). All patients underwent surgery, and most received radiation (n=5). Five patients relapsed after initial remission. Comprehensive review of the primary renal ESFT literature was used to analyze various factors, including age, gender, disease metrics, metastases at diagnoses, and overall survival in a total of 362 cases. Notably, while the general ESFT population has reported rates of metastasis at diagnosis of 20–25%,(2) this rate in the renal ESFT population was 53% with a rate of 59% in adolescent and young-adult (AYA) patients (11–24 years). Nodal disease at diagnosis was present in 24% of renal ESFT cases compared with 3.2% in patients with primary skeletal ESFT.(3) While this malignant process may share histologic and molecular features with its bone and soft tissue counterparts, primary renal ESFT presentations appear to be more aggressive and have worse outcomes.

BackgroundThe selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.MethodsPatients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).FindingsBetween May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [

The tropomyosin receptor kinase (TRK) family of proteins is encoded by neurotrophic tyrosine receptor kinase (NTRK) genes and has a role in the development and normal functioning of the nervous system. NTRK gene fusions have been identified as oncogenic drivers in a wide range of tumors in both adult and pediatric patients. There has recently been a paradigm shift in cancer treatment toward biomarker-based targeted therapies, as an increasing number of actionable targets are being identified across different tumors and/or tumor histologies. These targeted agents offer greater comparative effectiveness and safety vs historical nontargeted standard therapies. The development of drugs that specifically target oncogenic drivers of cancer has led to the emergence of screening technologies to identify the patients most likely to benefit from targeted therapy. This review describes the role of NTRK gene fusions in cancer and outlines the epidemiology of NTRK gene fusions, the therapeutic benefits of targeting TRK fusions with small molecule inhibitors, and recommendations for NTRK gene fusion testing in adult and pediatric patients with cancer, in order to guide treatment decisions.

Larotrectinib and entrectinib are tumor-agnostic tropomyosin receptor kinase (TRK) inhibitors that are indicated for the treatment of advanced or metastatic solid tumor cancers with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Regulatory approval of both agents was based on data from single-arm phase 1/2 studies, including tumor-agnostic basket trials. In the absence of randomized controlled trials, there remains a paucity of data to demonstrate the comparative effectiveness of larotrectinib and entrectinib vs established standard-of-care treatments in cancers with NTRK gene fusions. Furthermore, no studies have directly compared the 2 agents. This article reviews what is known about the comparative effectiveness of larotrectinib and entrectinib vs standard therapies in TRK fusion cancer and examines the comparative effectiveness of the 2 TRK inhibitors. Historical and intrapatient comparisons suggest that TRK inhibitors improve disease response compared with preexisting treatments across most tumor histologies; indirect and limited comparisons of phase 1/2 data and preliminary simulation modeling suggest a potential advantage for larotrectinib over entrectinib in terms of clinical response and survival. Although limited, these data provide some insight into the position of these treatments in established treatment paradigms for TRK fusion cancer, a setting where real-world evidence will be slow to accrue due to the rare nature of these tumors but may be the only way in the future to answer the outstanding questions regarding these 2 agents. Meanwhile, we need to try to obtain the maximum benefit that can be achieved for our patients using the currently available knowledge.

Chordomas are rare tumors of notochordal origin, most commonly arising in the sacrum or skull base. Primary treatment of chordoma is surgery, however complete resection is not always feasible due to their anatomic location, and recurrence rates remain high. Chordomas are considered insensitive to conventional chemotherapy, and their rarity complicates running timely and adequately powered trials to identify effective regimens. Therefore, there is a need for discovery of novel therapeutic approaches. Drug discovery efforts in chordoma have been mostly limited to cell line models. Patient-derived organoids can accelerate drug discovery studies and predict patient responses to therapy. In this proof-of-concept study, we successfully established organoids from seven chordoma tumor samples obtained from five patients presenting with tumors in different sites and stages of disease. The organoids recapitulated features of the original parent tumors and inter-as well as intra-patient heterogeneity. High-throughput screenings performed on the organoids highlighted targeted agents such as PI3K/mTOR, EGFR, and JAK2/STAT3 inhibitors among the most effective molecules. Pathway analysis underscored how the NF-kB and IGF-1R pathways are sensitive to perturbations and potential targets to pursue for combination therapy of chordoma.

Well-preserved molecular cargo in circulating extracellular vesicles (EVs) offers an ideal material for detecting oncogenic gene alterations in cancer patients, providing a noninvasive diagnostic solution for detection of disease status and monitoring treatment response. Therefore, technologies that conveniently isolate EVs with sufficient efficiency are desperately needed. Here, a lipid labeling and click chemistry-based EV capture platform ("Click Beads"), which is ideal for EV message ribonucleic acid (mRNA) assays due to its efficient, convenient, and rapid purification of EVs, enabling downstream molecular quantification using reverse transcription digital polymerase chain reaction (RT-dPCR) is described and demonstrated. Ewing sarcoma protein (EWS) gene rearrangements and kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutation status are detected and quantified using EVs isolated by Click Beads and matched with those identified in biopsy specimens from Ewing sarcoma or pancreatic cancer patients. Moreover, the quantification of gene alterations can be used for monitoring treatment responses and disease progression.

TPS818 Background: Albumin-bound ( nab)-sirolimus, a novel mTOR inhibitor (mTORi) that utilizes nanoparticle technology to preferentially target tumors, is approved in the US for the treatment of adults with malignant PEComa. In an exploratory analysis of the AMPECT registrational trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with TSC1 and TSC2 inactivating alterations, respectively, had confirmed response (Wagner, J Clin Oncol. 2021). Importantly, both TSC1 and TSC2 alterations have been observed in patients with various gastrointestinal cancers (Table). Overall, most treatment-related adverse events (TRAEs) in AMPECT were grade 1/2 and manageable for long-term treatment; no grade ≥4 TRAEs occurred. Methods: PRECISION I (NCT05103358) is a phase 2, open-label, multi-institutional basket trial evaluating efficacy and safety of nab-sirolimus in patients with alterations in TSC1 (Arm A) and TSC2 (Arm B). Patients ≥12 years old with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 (confirmed by central review of next generation sequencing reports) who have progressed on standard therapies and are mTORi-naïve are eligible. nab-Sirolimus 100 mg/m2 will be administered weekly as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate determined by independent review using RECIST v1.1; other endpoints include duration of response, disease control rate, time to response, progression-free survival by independent radiographic review, overall survival, patient-reported quality of life, and safety. Enrollment is ongoing. The most frequent tumor types expected in this tissue-agnostic trial are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric based on the prevalence of TSC1 or TSC2 alterations (Table). Clinical trial information: NCT05103358 . [Table: see text]

BackgroundAlthough viral hepatitis causes paediatric hepatocellular carcinoma and hepatic and extrahepatic cancers in adults, there are few epidemiologic studies on paediatric-cancer risks from parental viral hepatitis. In a nationwide study in a viral hepatitis endemic region and with confirmation in another population-based sample, we examined associations between parental hepatitis B (HBV) and C (HCV) infections and risks of cancers in offspring.MethodsWe included all children born in Taiwan in 2004–2014 (N = 2 079 037) with 2160 cancer cases ascertained from the Cancer Registry. We estimated risks for paediatric cancers using Cox proportional-hazard regressions. We checked these associations in a nationwide case–control study in Denmark (6422 cases, 160 522 controls).ResultsIn Taiwan, paternal HBV was related to child’s hepatoblastoma [hazard ratio (HR) = 1.77, 95% confidence interval (CI) = 1.05, 2.97] when identified at any time in the medical record, and when analyses were limited to hepatitis diagnoses occurring before the child’s birth, risks increased (HR = 2.08, 95% CI = 1.13–3.80). Paternal HCV was related to child’s non-Hodgkin lymphoma (HR = 2.06, 95% CI = 1.13–3.74). Maternal HCV was weakly related to increased risks of all childhood cancers [all types combined; HR = 1.45, 95% CI = 0.95–2.22]. The population-attributable fraction of hepatoblastoma for maternal, paternal and child HBV was 2.6%, 6.8% and 2.8%, respectively.ConclusionsParental HBV and HCV may be risk factors for hepatic and non-hepatic cancers in children. If associations are causal, then parental screening and treatment with antivirals may prevent some paediatric cancers.

Purpose: The aims of the current study were to better understand, from the perspective of adolescents and young adults (AYAs) with sarcoma, parents, and providers, the friendship support needs of AYAs with bone and soft tissue sarcoma and the role of social media in facilitating social support for AYAs with sarcoma. Methods: Semistructured interviews were conducted with 21 participants. AYA (n = 10) ranged in age from 14 to 23 years (mean 19.3, standard deviation 3.4 years; 50% female). All AYAs reported a current or past diagnosis of sarcoma, except for one patient who had another cancer diagnosis but was receiving treatment through the sarcoma clinic. Five parents of the adolescent participants were interviewed, as well as six health care providers. Data analysis was conducted using theory-driven immersion/crystallization, incorporating the Resilience in Illness Model as a framework to guide interpretation of the data. Results: Four main themes associated with social support from friends and social media were identified: (1) Social media provides a way to feel normal and connected to friends; (2) Social media accentuates the frustration of being left behind; (3) Social media facilitates the need to be understood by peers who have experienced sarcoma, and (4) Social media can lead to despair, and also provide hope for the future. Conclusions: Connecting with peers through social media can play an important role in providing support for AYAs with sarcoma, but it may also amplify feelings of frustration and anxiety. Future work is needed to determine intervention components that can maximize the benefits of social media for social support of AYAs with sarcoma. Clinical Trial Registration number: NCT03130751.

Background The effect of maternal diabetes on childhood cancer has not been widely studied. Methods We examined this in two population-based studies in Denmark (N = 6420 cancer cases, 160,484 controls) and Taiwan (N = 2160 cancer cases, 2,076,877 non-cases) using logistic regression and Cox proportional hazard regression adjusted for birth year, child’s sex, maternal age and birth order. Results Gestational diabetes in Denmark [odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.71–1.35] or type II and gestational diabetes in Taiwan (type II: hazard ratio (HR) = 0.81, 95% CI: 0.63–1.05; gestational diabetes: HR = 1.06, 95% CI: 0.92–1.22) were not associated with cancer (all types combined). In Denmark, maternal type I diabetes was associated with the risk of glioma (OR = 2.33, 95% CI: 1.04–5.22), while in Taiwan, the risks of glioma (HR = 1.59, 95% CI: 1.01–2.50) were elevated among children whose mothers had gestational diabetes. There was a twofold increased risk for hepatoblastoma with maternal type II diabetes (HR = 2.02, 95% CI: 1.02–4.00). Conclusions Our results suggest that maternal diabetes is an important risk factor for certain types of childhood cancers, emphasising the need for effective interventions targeting maternal diabetes to prevent serious health effects in offspring.

Tumor-derived extracellular vesicles (EVs) play essential roles in intercellular communication during tumor growth and metastatic evolution. Currently, little is known about the possible roles of tumor-derived EVs in sarcoma because the lack of specific surface markers makes it technically challenging to purify sarcoma-derived EVs. In this study, a specific purification system is developed for Ewing sarcoma (ES)-derived EVs by coupling covalent chemistry-mediated EV capture/ release within a nanostructure-embedded microchip. The purification platform-ES-EV Click Chip-takes advantage of specific anti-LINGO-1 recognition and sensitive click chemistry-mediated EV capture, followed by disulfide cleavage-driven EV release. Since the device is capable of specific and efficient purification of intact ES EVs with high purity, ES-EV Click Chip is ideal for conducting downstream functional studies of ES EVs. Absolute quantification of the molecular hallmark of ES (i.e., EWS rearrangements) using reverse transcription Droplet Digital PCR enables specific quantification of ES EVs. The purified ES EVs can be internalized by recipient cells and transfer their mRNA cargoes, exhibiting their biological intactness and potential role as biological shuttles in intercellular communication.

Introduction: Detecting oncogenic drivers across multiple cancers has brought about a shift toward a more targeted therapeutic approach. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are genomic rearrangements containing the kinase domain of one of three tropomyosin receptor kinases (TRK) and a dimerization domain contributed by another gene, generating fusion proteins, which are oncogenic drivers, targetable with TRK inhibitors. Larotrectinib is a first-in-class TRK inhibitor, granted accelerated FDA approval for treating TRK fusion cancer. This breakthrough indication across cancer subtypes and ages, from infancy through adulthood, highlights the need to understand the heterogeneous patient population and cancer types studied in larotrectinib clinical trials. Areas covered: We provide a narrative review of preclinical, pharmacokinetic, efficacy, and safety data for larotrectinib from three clinical trials that led to regulatory approval. Expert opinion: Larotrectinib elicits impressive responses in most patients with TRK fusion cancer, regardless of tumor type and age. Treatment is well tolerated with a low rate of treatment-emergent grade 3-4 adverse events, dose reductions and discontinuations due to adverse events, and recent findings indicate patient-reported improvement in quality of life. This highlights the importance of early testing for NTRK gene fusions in cancers that may harbor them, even if rare.

Malignant peripheral nerve sheath tumors (MPNSTs) comprise a rare, aggressive subtype of soft tissue sarcoma. While surgery is the mainstay of therapy for this disease, the role of neoadjuvant therapy remains undefined.This study reviewed patients 16 years of age and older who underwent surgical treatment for MPNST between 1974 and 2012 at the authors' institution. Univariate and multivariate analyses were performed of clinicopathologic and treatment variables predictive of disease-specific survival (DSS) and disease-free survival.Eighty-eight patients with primary localized MPNST underwent surgical treatment between 1974 and 2012 at our institution. Of these, 38 (43%) underwent neoadjuvant chemotherapy and had tissue available for analysis. Neoadjuvant radiation was given to 25 patients (68%). The median follow-up time for survivors was 12.5 years (range, 4 to 27 y). Nine patients (23%) had underlying MPNST. With a cutoff of ≥90% pathologic necrosis and/or fibrosis defining response, we identified 14 responders (36%). On univariate analysis, patient age, tumor size, and pathologic response were significantly associated with DSS (P=0.015, 0.011, and 0.030, respectively).Although the impact of neoadjuvant chemotherapy on the outcome of primary localized MPNST patients continues to be debated, this study shows that a pathologic response to therapy is associated with a significant improvement in DSS. The challenge moving forward is to determine upfront which patients will be "responders" to standard systemic therapy and which patients should be considered for newer investigational agents as part of a clinical trial.

Patient-derived xenografts (PDXs) have provided the research community with dynamic and robust translational model systems to study cancer biology and accelerate drug development. To advance translational oncology, we have developed a library of PDXs and provide next-generation sequencing characterization of these models. Here, we provide mutation and transcriptomic profiles of our PDX collection along with comparisons against matched normal and cancer patient profiles. Lastly, we provide a web portal providing comprehensive genomic profiles for every PDX model to identify mutation, copy number, fusions, microsatellite status, gene expression, and enriched pathways to facilitate identification of clinically relevant models. Citation Format: Jonathan Nakashima, Long Do, Warren Andrews, Yuan-Hung Chien, Jantzen Sperry, Bianca Carapia, Deborah Yan, Giovanni Rivera, Noah Federman, Arun Singh, Fritz C. Eilber, Brian Datnow. Next-generation characterization of patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3117.

Bone and soft tissue sarcomas span a spectrum of over one hundred histologic subtypes. Developing clinical trials and identifying effective therapies remains a challenge given the rarity of these tumors and scarcity of available tumor models. Patient-derived tumor organoids (PDTOs) are representative of the native physiology of tumors across an array of malignancies (Phan et al, 2019; Al Shihabi et al, 2021). For rare tumors such as bone and soft tissue sarcomas, PDTOs could constitute an important tool to better understand the biology of the disease and identify treatment options. Here, we present the pipeline we have established at UCLA to systematically procure tissue, develop and characterize individualized sarcoma PDTOs, and identify tumor sensitivities using high-throughput drug screening. We have collected tumor specimens from 114 patients diagnosed with sarcomas, representing more than 30 distinct subtypes of soft tissue and bone tumors. We have established suitable conditions to generate organoids from over 100 samples collected from needle biopsies, tumor resections, and metastasectomies, including soft tissue sarcomas (liposarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma, etc.) and bone sarcomas (chondrosarcoma, osteosarcoma, Ewing sarcoma, etc.). We take advantage of our mini-ring technology to generate PDTOs in a format compatible with high-throughput drug screening (Phan et al, 2019; Nguyen et al, 2020). Our results highlight tumor-specific drug susceptibilities to chemotherapeutics, targeted agents, and combination therapies, generating results within a week from surgery. We will show how several of the organoid response patterns we identified transcend cancer subtype and patient characteristics. Our findings support the feasibility of rapidly generating individualized organoid models from bone and soft tissue sarcomas to facilitate biological interrogations and investigate response to treatment. Direct testing of PDTOs derived from clinical specimens can provide timely, actionable information for functional precision medicine approaches with the potential to improve patient outcomes. Citation Format: Ahmad Al Shihabi, Peyton J. Tebon, Jomjit Chantharasamee, Huyen T. Nguyen, Sara Sartini, Ardalan Davarifar, Nasrin Tavanaie, Scott D. Nelson, Noah Federman, Jane Yanagawa, Alice Soragni. A pipeline for functional precision medicine in bone and soft tissue sarcoma organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3078.

Metastatic osteosarcoma is a rare and highly lethal cancer that affects children and young adults. The rarity of osteosarcoma and its highly heterogeneous genetic composition have resulted in a lack of curative treatments for recurrent and metastatic disease. In this study, we present the functional and molecular characterization of a case of a pediatric patient with left distal femur osteosarcoma and pulmonary metastases at presentation. Through longitudinal sampling over the course of the patient’s illness, we have procured tissue from the initial treatment-naïve diagnostic biopsy, primary tumor resection and multiple subsequent lung metastasectomies, and have developed patient-derived tumor organoids (PDTOs) from the viable samples. PDTOs are useful pre-clinical models that are representative of the source tissue and allow further interrogations of the biology of tumors. These models can also help with the identification of effective personalized therapies (Al Shihabi et al, 2021). We applied our mini-ring organoid screening technology (Phan et al, 2019; Nguyen et al, 2020) to perform high-throughput drug screening with different pharmacologic agents. We also performed deep whole-genome sequencing on all collected samples and corresponding organoids to reconstruct their evolutionary history, identify driver mutations and quantify heterogeneity in mutational processes across time and space. Our preliminary data show that the subclonal content of the tumor and derivative organoids as well as the PDTO drug responses vary with the patient’s treatment history. We identify the genomic makeup of the subclones and posit changes that may be responsible for chemoresistance. Furthermore, our data shows correlations between the subclonal genomic composition of the PDTOs and source tissue, thereby reinforcing that PDTOs are capable of accurately recapitulating the subclonal heterogeneity of the parental tumor. Citation Format: Ardy Davarifar, Jane Yanagawa, Ahmad Al Shihabi, Huyen T. Nguyen, Lydia Y. Liu, Adriana Salcedo, Alfredo Gonzalez, Takafumi N. Yamaguchi, Nicholas Bernthal, Scott D. Nelson, Noah Federman, Paul C. Boutros, Alice Soragni. A reconstruction of evolutionary trajectories in primary tissue and PDTOs in a patient with metastatic osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3071.

Metastatic disease continues to be a significant cause of mortality among cancer patients. Despite advancements in patient-derived xenografts (PDXs), translational models of metastasis are lacking. To overcome this challenge, we have developed luciferase tagged PDX cultures and utilized optical imaging to create robust translational in vivo models of metastasis. Here, we show that these models can be implanted orthotopically into common metastatic sites, or injected intravenously or intracardiacally to study spontaneous metastasis. Furthermore, we apply these models in humanized NOG-EXL mice to demonstrate immunophenotypic differences among tumors in different anatomical sites. Citation Format: Jonathan Nakashima, Jantzen Sperry, Christophe Pedros, Bianca Carapia, Deborah Yan, Giovanni Rivera, Noah Federman, Arun Singh, Fritz C. Eilber, Brian Datnow. Development of bioluminescent PDX models to study metastasis and evaluate therapeutic interventions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3116.

e15048 Background: Defects in cell cycle control are fundamental oncogenic drivers and targeting deregulated cell cycling is under intensive study. Cell cycle cyclin G1 (CCNG1) inhibitor therapy, exemplified by DeltaRex-G, a tumor-targeted retro vector encoding a cytocidal CCNG1 inhibitor gene, has been tested in over 280 cancer patients worldwide in early studies, inducing long term (10-13 years) survival in certain patients with intractable metastatic pancreatic adenocarcinoma, sarcoma, and breast cancer. Hence, further clinical development of DeltaRex-G for cancer patients who have few or no therapeutic options is apropos. Methods: Primary objective: To determine overall survival. Secondary objective: To evaluate disease control, best overall response, and incidence of treatment-related adverse events. Patient and Methods: Study 1 is entitled “Blessed: Expanded Access for DeltaRex-G for Advanced Pancreatic Cancer and Sarcoma (NCT04091295)”. Study 2 is entitled “Compassionate Use of DeltaRex-G for Advanced Cancers. In both studies, patients will receive DeltaRex-G at 1-3 x 10e11 cfu i.v. over 15-30 minutes, 3 x a week until significant disease progression or unacceptable toxicity occurs. Results: Seventeen patients were enrolled, 9 sarcomas, 2 pancreatic adenocarcinomas, 1 non-small cell lung cancer, 2 breast carcinoma, 1 prostate cancer, 1 cholangiocarcinoma, and 1 basal cell carcinoma and actinic keratosis. Three patients were enrolled in Study 1 and 14 patients were enrolled in Study 2. Two patients were initially enrolled in Study 1 and later enrolled in Study 2. Twelve of 17 enrolled patients were treated with DeltaRex-G monotherapy or in combination with FDA-approved cancer therapies. Of the 12 treated patients, 5 are alive 10 to 30 months from DeltaRex-G treatment initiation. Two patients with early-stage triple receptor-positive and triple receptor-negative breast cancer who received DeltaRex-G as adjuvant/first-line therapy are alive one year in complete remission; 2 patients with chemo-resistant Stage 4 sarcoma are alive 2 1/2 years, and one patient with advanced basal cell carcinoma is alive 10 months from treatment initiation. There were no treatment-related adverse events reported. Conclusions: Taken together,the data suggest that (1) Adjuvant/first-line therapy with DeltaRex-G may reduce the incidence of recurrence of early-stage invasive carcinoma of the breast and (2) DeltaRex-G may evoke tumor growth stabilization after failing standard chemotherapy. Phase 2 studies are planned to evaluate if DeltaRex-G (1) will reduce the incidence of recurrence in early-stage invasive carcinoma of breast, (2) improve survival in pancreatic cancer, and (3) prolong progression-free survival and overall survival in advanced sarcoma. Clinical trial information: NCT04091295.

11553 Background: Rhabdomyosarcoma(RMS) is the most common soft tissue sarcoma in children. Relapsed/refractory(R/R) RMS has a poor outcome and remains an area of unmet need. Histone deacetylase (HDAC) inhibitors have been shown to have activity in preclinical models of RMS. Mocetinostat (Mirati Pharmaceuticals) is an investigational oral HDAC inhibitor, that targets HDACs 1, 2, 3 and 11. Mocetinostat displayed high activity in in vitro RMS cell lines, RMS xenograft models and exerted synergistic activity in combination with vinorelbine. We report early interim results of the Phase 1 trial of mocetinostat with vinorelbine in R/R RMS. Methods: An investigator initiated Phase 1,open-label, dose escalation/expansion clinical trial. A modified intent to treat approach is used for efficacy analysis for a target accrual of 20 subjects in the dose expansion cohort. Subjects with R/R RMS were age ≥ 18 years old(yo) for the phase 1 dose escalation cohort and ≥12 yo for the phase 1 dose expansion. Mocetinostat 40mg, 70mg or 90mg was taken orally 3 times weekly with vinorelbine 25mg/m2 IV on day 1,8, and 15 in 21 day cycles. Maximum tolerated dose of mocetinostat in the dose escalation phase was 40mg, which was selected for dose expansion. Subjects were treated until disease progression by RECIST 1.1 or unacceptable toxicity. Results: A total of 8(6 FOXO translocation(+), 1 (FOXO-), and 1 unknown) have been enrolled at time of submission. 5 in dose escalation cohort, and 3 in dose expansion. Median age was 19 yo(range 16-63), Median prior treatment regimens were 2(range 1-4). All patients had measurable metastatic disease. 6 of 8 subjects had prior exposure to vinorelbine in prior salvage chemotherapy or maintenance chemotherapy. As of 20JAN2022 safety cutoff, most common AEs (all grades) observed in 7 evaluable treated patients include neutropenia (n = 5), anemia(n = 5), and nausea(n = 4). The only grade 3 or 4 treatment related AEs were neutropenia, lymphopenia and anemia. Myelosuppression was transient, reversible and responsive to growth factors. No SAEs related to mocetinostat and/or vinorelbine have been reported. As of efficacy cutoff 20JAN2022, 7 of 8 patients are evaluable for response. 4 subjects had a partial response (PR), 2 subjects had stable disease (SD) and 1 subject had progressive disease for a clinical benefit rate of 86% (CR+PR+SD). Rapid responses were seen in the majority of patients at median of 1.5 months(mos). Of the 6 responders, 4 had duration of responses (DOR) > 6 mo with a median DOR of 8 mos (range 4-16mo). Conclusions: In this interim analysis, Mocetinostat plus vinorelbine shows high efficacy and acceptable safety profile in this heavily pretreated group of R/R RMS patients. This study is open to accrual and enrollment is ongoing. Clinical trial information: NCT04299113.

10030 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in various tumor types across all ages. Larotrectinib is a first-in-class, central nervous system (CNS)-active, highly selective tropomyosin receptor kinase (TRK) inhibitor approved for pediatric and adult patients (pts) with TRK fusion-positive cancer, demonstrating an objective response rate (ORR) of 88% across 78 pediatric pts with non-CNS cancers (van Tilburg et al, SIOP 2021). We report an analysis of the efficacy and safety of larotrectinib in an expanded dataset of pediatric pts with TRK fusion-positive cancer. Methods: Pediatric pts (< 18 years) with non-CNS TRK fusion-positive cancer in larotrectinib clinical trials (NCT02637687, NCT02576431) were included and ORR (RECIST v1.1) was investigator (INV)-assessed. Data cut-off was July 20, 2021. Results: A total of 94 pts were included in this analysis. Tumor types included infantile fibrosarcoma (52%), other soft tissue sarcoma (40%), congenital mesoblastic nephroma (2%), thyroid cancer (2%), bone sarcoma (1%), breast cancer (1%), and melanoma (1%). Pts had gene fusions involving NTRK1 (43%), NTRK2 (3%), or NTRK3 (54%). Median age was 2.2 years (range 0–18 years). Of the 62 (66%) pts who received prior systemic therapy, 32 (52%) received ≥2 lines. The INV-assessed best ORR for the 93 evaluable pts was 84% (95% confidence interval [CI] 75–91): 35 (38%) complete response (CR; including two pending confirmation and 10 pathological CR), 43 (46%) partial response (two pending confirmation), 11 (12%) stable disease, two (2%) progressive disease, and two (2%) not determined. The median time to response was 1.8 months. Overall, median duration of response was 43.3 months (95% CI 23.4–NE); median follow-up was 26.0 months. Median progression-free survival and overall survival (OS) were 37.4 months (95% CI 22–NE) and not reached, respectively; median follow-up was 21.2 and 30.3 months, respectively. The 36-month OS rate was 93% (95% CI 86–99). Treatment duration ranged from 1+ to 63+ months. At data cut-off, 31 pts had progressed; 18 continued treatment post-progression for ≥4 weeks. There were no treatment-related deaths. Treatment-related adverse events (TRAEs) occurred in 81% of pts (23% were Grade [G] 1, 28% G2, 25% G3, and 5% G4). The most common TRAE was increased aspartate aminotransferase (31 pts [33%]). Four pts (4%) discontinued treatment due to TRAEs. Neurological TRAEs occurred in 12% of pts (5% were G1, 4% G2, and 2% G3). The most common neurological TRAE was headache (5 pts [5%]). Conclusions: In this expanded dataset, larotrectinib continues to demonstrate rapid and durable tumor-agnostic efficacy, extended survival, and a favorable safety profile in pediatric pts with TRK fusion-positive cancer. These results highlight the importance of identifying NTRK gene fusions in pediatric solid tumors. Clinical trial information: NCT02576431, NCT02637687.

Introduction This is a prospective, single-center trial in pediatric patients with sarcoma aiming to evaluate [18F]FDG PET/CT as a tool for early response assessment to neoadjuvant chemotherapy (neo-CTX). Methods Bone or soft tissue sarcoma patients with (1) baseline [18F]FDG PET/CT within 4 weeks prior to the start of neo-CTX (PET1), (2) early interim [18F]FDG PET/CT (6 weeks after the start of neo-CTX (PET2), (3) evaluation of neo-CTX response by histology or MRI, and (4) definitive therapy after neo-CTX (surgery or radiation) were included. Semiquantitative PET parameters (SUVmax, SUVmean, SUVpeak, MTV and TLG) and their changes from PET1 to PET2 (ΔPET) were obtained. The primary endpoint was to evaluate the predictive value of PET1, PET2 and ΔPET parameters for overall survival (OS) and time to progression (TTP). The secondary outcome was to evaluate if [18F]FDG PET/CT can predict the response to neo-CTX assessed by histopathology or MRI. Primary and secondary outcomes were also evaluated in a subpopulation of patients with bone involvement only. Results Thirty-four consecutive patients were enrolled (10 females; 24 males; median age 15.1 years). 17/34 patients (50%) had osteosarcoma, 13/34 (38%) Ewing's sarcoma, 2/34 (6%) synovial sarcoma and 2/34 (6%) embryonal liver sarcoma. Median follow-up was 39 months (range 16–84). Eight of 34 patients (24%) died, 9/34 (27%) were alive with disease, and 17/34 (50%) had no evidence of residual/recurrent disease. Fifteen of 34 (44%) and 19/34 (56%) were responders and non-responders, respectively. PET2-parameters were associated with longer TTP (p p = 0.047). None of the PET1, PET2 or ΔPET parameters were associated with OS. Conclusion [18F]FDG PET/CT performed 6 weeks after the start of neo-CTX can serve as an early interim biomarker for TTP and pathologic response but not for OS in pediatric patients with sarcoma.

Introduction: This is a prospective, single-center trial in pediatric patients with sarcoma aiming to evaluate [18F]FDG PET/CT as a tool for early response assessment to neoadjuvant chemotherapy (neo-CTX).Methods: Bone or soft tissue sarcoma patients with i) baseline [18F]FDG PET/CT within four weeks prior to the start of neo-CTX (PET1), ii) early interim [18F]FDG PET/CT (six weeks after the start of neo-CTX (PET2), iii) evaluation of neo-CTX response by histology or MRI, and iv) definitive therapy after neo-CTX (surgery or radiation) were included. Semi-quantitative PET parameters (SUVmax, SUVmean, SUVpeak, MTV and TLG) and their changes from PET1 to PET2 (ΔPET) were obtained. The primary endpoint was to evaluate the predictive value of PET1, PET2 and ΔPET parameters for overall survival (OS) and time to progression (TTP). The secondary outcome was to evaluate if [18F]FDG PET/CT can predict the response to neo-CTX assessed by histopathology or MRI. Primary and secondary outcomes were also evaluated in a sub-population of patients with bone involvement only.Results: Thirty-four consecutive patients were enrolled (10 females; 24 males; median age 15.1 years). 17/34 patients (50%) had Osteosarcoma, 13/34 (38%) Ewing Sarcoma, 2/34 (6%) synovial sarcoma and 2/34 (6%) embryonal liver sarcoma. Median follow-up was 39 months (range 16-84). Eight of 34 patients (24%) died, 9/34 (27%) were alive with disease and 17/34 (50%) had no evidence of residual/recurrent disease. Fifteen of 34 (44%) and 19/34 (56%) were responders and non-responders, respectively. PET2-parameters were associated with longer TTP (p Conclusion: [18F]FDG PET/CT performed six weeks after the start of neo-CTX can serve as an early interim biomarker for TTP and pathologic response but not for OS in pediatric patients with sarcoma.

Spina bifida has been reported to co-occur with pediatric cancer, but comprehensive evaluations remained elusive. We investigated this co-occurrence in two large, population-based studies in Taiwan (N = 1900 cancer cases, 2,077,137 controls) and Denmark (N = 5508 cases, 137,700 controls). Analyses in Denmark were restricted to the period before prenatal diagnostics became available (2004) and pregnancy terminations of fetuses with birth defects became more common. Using national patient and cancer registries, we linked spina bifida and cancer diagnoses among cases and non-cases. The risk of spina bifida among all cancer cases was increased and similar in Denmark [odds ratio (OR)=8.4, 95% confidence interval (CI) 5.1-13.8] and Taiwan (OR = 8.5, 95% CI 4.0-17.8), particularly for central nervous system (CNS) tumors (Denmark: OR = 16.3, 95% CI 8.1-33.0; Taiwan: OR = 26.6, 95% CI 8.5, 83.1), including benign CNS tumors (Denmark: OR = 41.5, 95% CI 21.2, 81.4). These findings suggest the need for comprehensive investigation of shared risk factors in the link between spina bifida and pediatric cancer.

This is the case of a previously healthy 15-month-old girl who initially presented to her primary pediatrician with a 2-week history of intermittent periorbital edema. The edema had improved by the time of the visit, and a urine specimen was unable to be obtained in the clinic. A routine fingerstick demonstrated anemia to 8.8 mg/dL, so the patient was started on ferrous sulfate. She then returned to the emergency department 1 month later with severe periorbital edema and pallor but no other significant symptoms. On physical examination, she was tachycardic with striking periorbital edema and an otherwise normal physical examination. She was noted to have a severe microcytic anemia (hemoglobin of 3.9 mg/dL and mean corpuscular volume of 53.1 fL) and hypoalbuminemia (albumin of 1.9 g/dL and total protein of 3.3 g/dL). The remainder of her electrolytes and liver function test results were within normal limits. A urinalysis was sent, which was negative for protein. Our panel of experts reviews her case to determine a unifying diagnosis for both her severe anemia and her hypoalbuminemia.

Author(s): Momcilovic, M; Lee, JT; Braas, D; Graeber, TG; Parlati, F; Demo, S; Li, R; Gricowski, M; Shuman, R; Ibarra, J; Fridman, D; St.John, M; Bernthal, N; Federman, N; Yanagawa, J; Dubinett, SM; Sadeghi, S; Christofk, HR; Shackelford, DB

Purpose. Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. Patients and Methods. Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles. Results. Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (p=0.47). Median OS was not reached in either arm. Conclusions. Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.

Background The highly selective oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib has demonstrated significant activity in adult and pediatric TRK fusion cancers. In the current study, the authors describe the clinical course of children with locally advanced TRK fusion sarcoma who were treated preoperatively with larotrectinib and underwent subsequent surgical resection. Methods A total of 24 children were treated on a pediatric phase 1 trial of larotrectinib (ClinicalTrials.gov identifier NCT02637687). Five children who had a documented TRK fusion sarcoma and underwent surgical resection were included in the current analysis. Tumor response (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1) and surgical outcomes were collected prospectively. Results A total of 5 patients (median age, 2 years; range, 0.4-12 years) had locally advanced infantile fibrosarcoma (3 patients) or soft-tissue sarcoma (2 patients). Four patients had disease that was refractory to standard therapy. All 5 patients achieved a partial response to larotrectinib by version 1.1 of RECIST and underwent surgical resection after a median of 6 cycles (range, 4-9 cycles) of treatment. Surgical resections were R0 (negative resection margins with no tumor at the inked resection margin) in 3 patients, R1 (microscopic residual tumor at the resection margin) in 1 patient, and R2 (macroscopic residual tumor at the resection margin) in 1 patient. Three patients achieved complete (2 patients) or near-complete (>98% treatment effect; 1 patient) pathologic responses. These patients remained in follow-up and were no longer receiving larotrectinib for a minimum of 7 to 15 months postoperatively. Two patients had viable tumor at the time of surgical resection and positive resection margins and continued to receive adjuvant larotrectinib. No patients experienced postoperative complications or wound healing issues. Conclusions Children with locally advanced TRK fusion sarcomas may proceed to surgical resection after treatment with the selective TRK inhibitor larotrectinib, thereby sparing them the potentially significant morbidity noted with current approaches. These results support the evaluation of larotrectinib as presurgical therapy in children with newly diagnosed TRK fusion sarcomas.

BackgroundGene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients.MethodsThis multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion status; had a Karnofsky (≥16 years of age) or Lansky (

BackgroundFusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.MethodsWe enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.ResultsA total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.ConclusionsLarotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).

Wilms tumor is the most common childhood kidney cancer. 15% of patients with Wilms tumor have germline pathogenic variants in genes or regions such as WT1 or the 11p15 region. Variants in these regions can include structural or copy number alterations or alterations in methylation. In the majority of cases of Wilms tumor no known pathogenic variant could be found using the state-of-the-art technologies, including comprehensive approaches such as Illumina whole exome sequencing. One explanation for this is that such technologies have difficulties in detecting structural variants (SVs) in areas associated with repeat or low complexity sequence. In addition, Illumina technology does not immediately support direct methylation detection. Therefore, we hypothesized that analysis of bilateral Wilms tumor of unknown etiology using long-read sequencing could reveal molecular events of potential clinical interest. We performed in-depth genomic analysis on a whole blood DNA sample from a patient with a bilateral Wilms tumor. This patient had no significant family history of cancer, and previously tested negative for Beckwith-Wiedemann syndrome by methylation testing of the 11p15 region; clinical exome sequencing of the patient's germline detected no variants associated with Wilms tumors. We sequenced the genome at 40x depth using PromethION Nanopore sequencing. 29180 SVs (deletions or insertions larger than 30 base pairs) were detected using Sniffles and 26480 were detected with SVIM. Only SVs that were detected by both methods were considered for downstream analysis. Variants were annotated and filtered using a short-read catalog of SVs (gnomAD-SV), a long-read catalog, the Database of Genomic Variants catalog, and by comparison to 11 in-house genomes. We focused on SVs, copy number variants, and methylation events affecting genes previously associated with Wilms tumor. Our long-read sequencing approach detected compound heterozygotes using phased variant calls. A heterozygous missense mutation was identified in haplotype one, while a 300 base pair insertion in an ALU element was present in haplotype two. These two compound heterozygous variants overlap an exon of the OVCH2 gene, and the ALU element was not detected by the prior Illumina analysis. Additionally, we determined the frequency of methylation in CpG sites genomewide using nanopolish. Using a normal blood sample from an unrelated individual as a control, we searched for extreme differences across large and gene promoter regions. Hypermethylation in the promoter regions of genes in the 11p15.5 locus was observed in the patient as compared to the control. Hypomethylation in this region is associated with Beckwith-Wiedemann syndrome. In conclusion, nanopore technology is able to detect variants missed by Illumina sequencing, and has the potential to yield new findings of interest in a case of a child with suspected cancer predisposition syndrome. Citation Format: Allison R. Cheney, Jean Monlong, Holly C. Beale, Hugh Olsen, Ellen Towle Kephart, Katrina Learned, Shanna White, Julian A. Martinez-Agosto, Noah Federman, Mark Akeson, Miten Jain, Vivian Y. Chang, Olena M. Vaske. Long-read sequencing characterization of a patient with bilateral Wilms tumor of unknown etiology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 261.

Patient-derived xenografts provide a functional test system in a living organism, making them the leading assay for precision oncology and drug development. In vivo pharmacology studies are widely performed using subcutaneous implantation; however, due to significant changes in the tumor microenvironment, this methodology falls short of modeling the full complexities of human cancer. We use quantitative magnetic resonance imaging (MRI) to report differences in growth kinetics and pharmacological response between orthotopic and subcutaneous implantation of patient-derived xenografts. We demonstrate that O-PDX models can predict effective treatment strategies for individual patients and forecast tumor recurrence after therapy. Furthermore, we use this approach to develop in vivo models of acquired drug resistance to strategize future treatment options and aid in drug development. Citation Format: Jonathan Nakashima, Jantzen Sperry, Bianca Carapia, Deborah Yan, Angelina Chin, Aliakbar Shahsafaei, Joan Chen, Yuan-Hung Chien, Christophe Pedros, Noah Federman, Arun Singh, Fritz C. Eilber, Brian Datnow. Orthotopic patient-derived xenografts (O-PDX) are effective precision oncology models that can predict therapeutic response, recurrence, and acquired drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3013.

Purpose Given the diverse and aggressive nature of soft tissue sarcomas (STSs), a need exists for more-precise therapy. Patient-derived orthotopic xenografts (PDOXs) provide a unique platform for personalized treatment. Thus, identification of patient and treatment factors that predict PDOX establishment is important. This study assessed the feasibility of incorporating PDOXs into the clinical setting and identifying factors associated with PDOX establishment. Patients and Methods From May 2015 to May 2016, 107 patients with biopsy-proven or potential STS were enrolled. Tumor samples were obtained intraoperatively and orthotopically implanted into nude mice in the corresponding anatomic location. PDOXs were considered established after engraftment and serial passage. Factors associated with establishment were analyzed by logistic regression and time to establishment by time-to-event analysis. Results Only high-grade tumors established (32 of 72 [44.4%]). The establishment rate (ER) varied by neoadjuvant therapy and treatment response, with the highest ER among untreated high-grade tumors (26 of 42 [61.9%]). Tumors exposed to radiation preoperatively did not establish (zero of 11 [0%]), and tumors exposed to neoadjuvant chemotherapy had a lower ER (31.9%) than untreated tumors. Only STSs with minimal pathologic response to neoadjuvant treatment (≤ 30%) established a PDOX (six of 18 [33.3%]). Median establishment time was 54 days, which varied by neoadjuvant therapy but was not statistically significant ( P = .180). Conclusion To our knowledge, in the largest STS PDOX study to date, we demonstrate a 62% ER among untreated high-grade tumors with a median establishment time of 54 days. Neoadjuvant therapy, particularly radiation, and pathologic response to treatment were associated with a reduced rate of PDOX establishment.

Sclerostin (SOST) is an extracellular Wnt signaling antagonist which negatively regulates bone mass. Despite this, the expression and function of SOST in skeletal tumors remain poorly described. Here, we first describe the immunohistochemical staining pattern of SOST across benign and malignant skeletal tumors with bone or cartilage matrix (n = 68 primary tumors). Next, relative SOST expression was compared to markers of Wnt signaling activity and osteogenic differentiation across human osteosarcoma (OS) cell lines (n = 7 cell lines examined). Results showed immunohistochemical detection of SOST in most bone-forming tumors (90.2%; 46/51) and all cartilage-forming tumors (100%; 17/17). Among OSs, variable intensity and distribution of SOST expression were observed, which highly correlated with the presence and degree of neoplastic bone. Patchy SOST expression was observed in cartilage-forming tumors, which did not distinguish between benign and malignant tumors or correlate with regional morphologic characteristics. Finally, SOST expression varied widely between OS cell lines, with more than 97-fold variation. Among OS cell lines, SOST expression positively correlated with the marker of osteogenic differentiation alkaline phosphatase and did not correlate well with markers of Wnt/β-catenin signaling activity. In summary, SOST is frequently expressed in skeletal bone- and cartilage-forming tumors. The strong spatial correlation with bone formation and the in vitro expression patterns are in line with the known functions of SOST in nonneoplastic bone, as a feedback inhibitor on osteogenic differentiation. With anti-SOST as a potential therapy for osteoporosis in the near future, its basic biologic and phenotypic consequences in skeletal tumors should not be overlooked.