Pediatric Sarcoma Patients Research Articles

Abstract 6375: Genetic testing station increases access to germline genetic testing

Abstract Despite evidence of clear benefit, genetic testing of pediatric oncology patients for germline variants remains rare due to a variety of factors, including insurance/financial barriers, limited knowledge about genetic testing, and competing interests for time and resources. Limited access to genetic testing, pre-test counseling and multidisciplinary care have been shown to disproportionately affect patients with limited resources. This represents a critical unmet need in pediatric oncology. Genetic testing station (GTS) is a pre-test counseling video tool that reviews what genetic testing is, why it might be indicated, and explains potential results. Similar video tools have been successfully used in other settings to increase rates of genetic testing, but there are no published reports on the effectiveness of a video education intervention to increase genetic testing in pediatric oncology patients. To test the effectiveness of GTS on genetic testing knowledge and feelings about genetic testing compared to in-person counseling, we use 5 previously validated tools pre- and post-intervention. The initial surveys measure genetic testing knowledge, decisional conflict, healthy literacy, evaluation of GTS and demographics. If participants complete genetic testing, we use the MICRA to assess the impact on their cancer risk assessment. Our GTS arm is recruited from UCLA Pediatric Sarcoma patients, and the in-person counseling arm is recruited from the UCLA Cancer Predisposition clinic. We have recruited 28 participants in the GTS arm and seven in the in-person counseling arm, of which 10 are patients over 18 years old, two are patients between 12-17 years old, and 23 are parents. In our GTS arm, there are 20 female and eight male participants. A majority identify as white or Latino. For the in-person counseling arm, there are four male and three female participants who identify as white, Middle Eastern, or Latino. A similar percentage score with high health literacy, 68% in the GTS arm and 71% for the in-person counseling arm. The majority of patients have no decisional conflict pre- or post-intervention for the GTS group, while the in-person counseling arm shows high initial decision conflict that is fully resolved with counseling. There is a statistically significant increase in genetic testing knowledge for five out of 10 questions comparing pre- and post-GTS. For GTS participants who have completed genetic testing and the MICRA, there is overall low distress and uncertainty, but higher scores for parents than adult or minor patients. In conclusion, there has been high interest in germline genetic testing in pediatric oncology patients with all families deciding to pursue genetic testing after viewing GTS. GTS is an effective tool in increasing genetic testing knowledge in participants. Therefore, GTS is a promising approach to increase access to genetic testing, while providing adequate pre-test counseling and no decisional conflict. Citation Format: Camille Hamilton, Mariana Niell Swiller, Franceska Bhansali, Alyssa Hoover, Stephanie Bottomley, Marisa Lewis, Bianca Russell, Julian A. Martinez, Beth Karlan, Noah Federman, Vivian Y. Chang. Genetic testing station increases access to germline genetic testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6375.

Discussion.

Discussion.

Detection of early prognostic biomarkers for metastasis of Ewing's sarcoma in pediatric patients

AimsEwing's Sarcoma is an extremely aggressive tumor in children. The disease is associated with highly metastatic rate, especially at the time of diagnosis, contributing to a lower survival rate and poor prognosis. The study aimed to identify predictive biomarkers for metastatic Ewing's sarcoma through in-depth analysis of the plasma proteome profile of pediatric Ewing's sarcoma patients. Main methodsPlasma samples from Ewing's sarcoma patients and control individuals were profiled using both shotgun and dimethyl-labeled proteomics analysis. Subsequently, Ewing's sarcoma patients were further stratified according to their metastatic state and chemotherapy response. Western blot was used for validation. Univariate and multivariate analyses were performed to determine proteome metastasis predictors. Receiver operating characteristic (ROC) analysis was done to assess the diagnostic significance of the potential plasma Ewing's sarcoma biomarkers. Key findingsOur results revealed a set of proteins significantly associated with the metastatic Ewing's sarcoma disease profile. These proteins include ceruloplasmin and several immunoglobulins. Additionally, our study disclosed significant differentially expressed proteins in pediatric Ewing's sarcoma, including CD5 antigen-like, clusterin, and dermcidin. Stable isotope dimethyl labeling and western blot further confirmed our results, strengthening the impact of such proteins in disease development. Furthermore, an unbiased ROC curve evaluated and confirmed the predictive power of these biomarker candidates. SignificanceThis study presented potential empirical predictive circulating biomarkers for determining the disease status of pediatric Ewing's sarcoma, which is vital for early prediction.

Assessment of the Interval to Diagnosis in Pediatric Bone Sarcoma.

The timely diagnosis of primary bone malignancies in pediatric patients is critical to clinical outcomes. The purpose of this study is to investigate the initial presentation of pediatric bone sarcoma patients to an academic health care system and assess the current interval to diagnosis. We conducted a retrospective review of pediatric patients (aged 1-18) with biopsy-proven diagnosis of osteosarcoma or Ewing sarcoma presenting between 2004 and 2020. All living patients had 1 year or more of follow-up. Primary outcomes were interval to diagnosis, clinical features on initial presentation, percent of patients with negative radiographic workup at initial presentation, and number of health care encounters before diagnosis. Seventy-one patients (osteosarcoma, 51; Ewing sarcoma, 20) were included. Average age at presentation was 13.1 ± 3.3 years (range, 4.4-18.3). Average symptom duration was 5.4 ± 13.9 months (range, 0.1-84). Clinical features at initial presentation included limb/back pain (91.5% of patients), activity modification/pain medication use (78.9%), palpable mass (40.8%), night pain (35.2%), limp (25.4%), limb disuse (18.3%), and recent fever history (2.8%). Fourteen of 71 patients (19.7%) had negative radiographs at initial presentation. Average number of health care encounters before diagnosis was 1.9 ± 0.6 (range, 1.0-4.0), with most in the outpatient pediatrician clinics (81.2%) and emergency department (18.3%). Average time to diagnosis from initial presentation was 19.5 ± 65 days (range, 0-493); the 14 patients with initial negative radiographs had a statistically significant prolonged interval to diagnosis of 54 ± 134 days (range, 0-493; P = 0.018). We found pediatric patients with primary bone sarcoma present with an average interval to diagnosis of 20 days. Twenty percent of patients had a significantly prolonged interval to diagnosis of 54 days. Clinical features suggest night pain is not a sensitive indicator. In patients of appropriate age with persistent unilateral pain in suspicious locations, early advanced imaging with magnetic resonance imaging should be considered.

Intracranial Relapse in Pediatric Sarcoma.

Advances in local control techniques, chemotherapy regimens, and imaging modalities have led to improvements in both morbidity and mortality in pediatric sarcoma patients. However, approximately one-third of patients develop disease relapse and intracranial metastasis was considered rare. The incidence of sarcoma brain metastasis is thought to have increased and is associated with grim outcomes. This was a retrospective study of 3 deidentified patient charts illustrating the possibility of the central nervous system as a potential site for pediatric sarcoma relapse and investigate the patterns of such relapses. We note this is the first report of infantile fibrosarcoma brain metastasis and a rare report of sarcoma lymph node metastasis. In addition, each patient was treated with targeted therapies, including entrectinib, Ruxolitnib, and pazopanib. Caregivers in cases 2 and 3 reported new-onset neurological manifestations before identification of new brain metastasis, indicating a lag in detection of new intracranial relapse in asymptomatic sarcoma patients. We suggest implementing a brief review of systems screening tool focused on concerning neurological manifestations to screen for new brain metastasis.

Longitudinal strain analysis for assessment of early cardiotoxicity during anthracycline treatment in childhood sarcoma: A single center experience.

The growing population of long-term childhood cancer survivors encounter a substantial burden of cardiovascular complications. The highest risk of cardiovascular complications is associated with exposure to anthracyclines and chest radiation. Longitudinal cardiovascular surveillance is recommended for childhood cancer patients; however, the optimal methods and timing are yet to be elucidated. We aimed to investigate the feasibility of different echocardiographic methods to evaluate left ventricular systolic function in retrospective datasets, including left ventricular ejection fraction (LVEF), fractional shortening (FS), global longitudinal strain (GLS) and longitudinal strain (LS) as well as the incidence and timing of subclinical left ventricular dysfunction detected by these methods. A retrospective longitudinal study was performed with re-analysis of longitudinal echocardiographic data, acquired during treatment and early follow-up, including 41 pediatric sarcoma patients, aged 2.1-17.8 years at diagnosis, treated at Astrid Lindgren Children's Hospital, Stockholm, Sweden, during the period 2010-2021. All patients had received treatment according to protocols including high cumulative doxorubicin equivalent doses (≥250 mg/m2 ). In 68% of all 366 echocardiograms, LS analysis was feasible. Impaired LS values (<17%) was demonstrated in >40%, with concomitant impairment of either LVEF or FS in 20% and combined impairment of both LVEF and FS in <10%. Importantly, there were no cases of abnormal LVEF and FS without concomitant LS impairment. Our findings demonstrate feasibility of LS in a majority of echocardiograms and a high incidence of impaired LS during anthracycline treatment for childhood sarcoma. We propose inclusion of LS in pediatric echocardiographic surveillance protocols.

Detection of circulating tumor-derived material in peripheral blood of pediatric sarcoma patients: A systematic review

BackgroundDetection of circulating tumor-derived material (cTM) in the peripheral blood (PB) of cancer patients has been shown to be useful in early diagnosis, prediction of prognosis, and disease monitoring. However, it has not yet been thoroughly evaluated for pediatric sarcoma patients. MethodsWe searched the PubMed and EMBASE databases for studies reporting the detection of circulating tumor cells, circulating tumor DNA, and circulating RNA in PB of pediatric sarcoma patients. Data on performance in identifying cTM and its applicability in diagnosis, and evaluation of tumor characteristics, prognostic factors, and treatment response was extracted from publications. ResultsA total of 79 studies were assigned for the present systematic review, including detection of circulating tumor cells (116 patients), circulating tumor DNA (716 patients), and circulating RNA (2887 patients). Circulating tumor cells were detected in 76% of patients. Circulating DNA was detected in 63% by targeted NGS, 66% by shallow WGS, and 79% by digital droplet PCR. Circulating RNA was detected in 37% of patients. ConclusionOf the cTM from Ewing's sarcoma and rhabdomyosarcoma ctDNA proved to be the best target for clinical application including diagnosis, tumor characterization, prognosis, and monitoring of disease progression and treatment response. For osteosarcoma the most promising targets are copy number alterations or patient specific micro RNAs, however, further investigations are needed to obtain consensus on clinical utility.

Abstract 3251: The immunostimulatory effect of 9-ING-41, a small molecule GSK-3 inhibitor, in sarcomas

Abstract Due to the rarity and genomic disparity of soft tissue and bone sarcomas, actionable therapeutic targets have been elusive. However, inhibition of GSK-3β has emerged as a potentially promising therapy that could be of great benefit to pediatric and adult sarcoma patients. Saos-2 osteosarcoma and 93T449 liposarcoma cell lines were pretreated at IC5072 with small molecule GSK-3β inhibitor 9-ING-41 (elraglusib). The cells were harvested for western blot analysis after 48 hours of treatment. Additionally, both cancer cell lines as well as TALL-104 T-cells and NK-92 NK cells were treated with 0.5 μM 9-ING-41 for 24 hours and harvested for Luminex cytokine profiling. The western blots demonstrated an increase in cPARP, an apoptotic marker, in both cancer cell lines after 9-ING-41 treatment. Additionally, an increase in PD-L1 expression was observed. The cytokine analysis revealed stimulation of immune cell activity in response to 9-ING-41. Treated T-cells had an increase in CXCL11, which is associated with T-cell recruitment, as well as an increased level of IL-18, which is shown to induce increased IFN-γ in Th1 cells. Additionally, NK-92 cells demonstrated an increase in IL-8 chemokine and an increase in soluble TRAIL (TRAIL/TNFSF10). The cancer cell lines showed a homogenous increase in growth factor TGF-ɑ, however, only the Saos-2 osteosarcoma cell line demonstrated an increase of IL-6. We are further validating the data with follow-up cytokine profiling. The increase in immunostimulatory cytokines as well as the increased expression of PD-L1 suggest a rationale for combining 9-ING-41 with immune checkpoint blockade therapy. The potential synergistic effect of these two therapies is currently under investigation with co-culture experiments of sarcoma and immune cells. The treatment cohorts for these experiments include 9-ING-41 combined with either anti-PD-L1, anti-PD-1, or anti-CTLA-4 immune checkpoint inhibitors. Our results suggest a promising combination therapeutic strategy for patients with soft tissue and bone sarcomas and future work will strive to better elucidate the mechanisms of efficacy. Citation Format: William J. MacDonald, Samuel Lew, Kelsey E. Huntington, Rishi R. Lulla, Bradley D. DeNardo, Wafik S. El-Deiry. The immunostimulatory effect of 9-ING-41, a small molecule GSK-3 inhibitor, in sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3251.

Surgical treatment of pediatric thoracic Ewing tumors.

This study aims to determine the thoracic surgery techniques, surgical indications, the role and effectiveness of surgical treatment in multimodal treatment applied to pediatric Ewing sarcoma patients. Between A pril 2004 a nd November 2020, a total of 15 pediatric patients ( 9 males, 6 females; mean age: 10.1±4.5 years; range, 3 to 18 years) who were diagnosed with primary thoracic Ewing sarcoma and operated were retrospectively analyzed. Tumor-related factors and treatment modalities for Ewing sarcoma originating from the chest wall and mediastinum were examined. The most common complaint was pain in nine patients. While the tumor originated from the ribs in nine patients, it originated from the soft tissue (n=2), mediastinum (n=2), and extra-thoracic tissue (n=2) in six patients. Complete resection was achieved in 10 patients. While neoadjuvant chemotherapy was applied to eight patients, chemotherapy and radiotherapy was applied to 14 and five patients, respectively. Bone marrow transplantation was performed in one patient. The mean follow-up was 54.2±44.9 months. Recurrence was seen in six patients in a mean duration of 17.8±7.4 months. The most effective treatment for thoracic Ewing sarcoma is complete resection. Multimodal therapy in the form of surgical resection, chemotherapy and/or radiotherapy provides optimal efficacy and the most favorable survival. The follow-up period should be kept short, since recurrences are common.

59P Introducing liquid biopsy for paediatric sarcoma patients into the clinical routine

59P Introducing liquid biopsy for paediatric sarcoma patients into the clinical routine

Identification of germline cancer predisposition variants in pediatric sarcoma patients from somatic tumor testing

Genetic predisposition is an important risk factor for cancer in children and adolescents but detailed associations of individual genetic mutations to childhood cancer are still under intense investigation. Among pediatric cancers, sarcomas can arise in the setting of cancer predisposition syndromes. The association of sarcomas with these syndromes is often missed, due to the rarity and heterogeneity of sarcomas and the limited search of cancer genetic syndromes. This study included 43 pediatric and young adult patients with different sarcoma subtypes. Tumor profiling was undertaken using the Oncomine Childhood Cancer Research Assay (Thermo Fisher Scientific). Sequencing results were reviewed for potential germline alterations in clinically relevant genes associated with cancer predisposition syndromes. Jongmans´ criteria were taken into consideration for the patient selection. Fifteen patients were selected as having potential pathogenic germline variants due to tumor sequencing that identified variants in the following genes: CDKN2A, NF1, NF2, RB1, SMARCA4, SMARCB1 and TP53. The variants found in NF1 and CDKN2A in two different patients were detected in the germline, confirming the diagnosis of a cancer predisposition syndrome. We have shown that the results of somatic testing can be used to identify those at risk of an underlying cancer predisposition syndrome.

A quantification method of somatic mutations in normal tissues and their accumulation in pediatric patients with chemotherapy

Somatic mutations are accumulated in normal human tissues with aging and exposure to carcinogens. If we can accurately count any passenger mutations in any single DNA molecule, since their quantity is much larger than driver mutations, we can sensitively detect mutation accumulation in polyclonal normal tissues. Duplex sequencing, which tags both DNA strands in one DNA molecule, enables accurate count of such mutations, but requires a very large number of sequencing reads for each single sample of human-genome size. Here, we reduced the genome size to 1/90 using the BamHI restriction enzyme and established a cost-effective pipeline. The enzymatically cleaved and optimal sequencing (EcoSeq) method was able to count somatic mutations in a single DNA molecule with a sensitivity of as low as 3 × 10-8 per base pair (bp), as assessed by measuring artificially prepared mutations. Taking advantages of EcoSeq, we analyzed normal peripheral blood cells of pediatric sarcoma patients who received chemotherapy (n = 10) and those who did not (n = 10). The former had a mutation frequency of 31.2 ± 13.4 × 10-8 per base pair while the latter had 9.0 ± 4.5 × 10-8 per base pair (P < 0.001). The increase in mutation frequency was confirmed by analysis of the same patients before and after chemotherapy, and increased mutation frequencies persisted 46 to 64 mo after chemotherapy, indicating that the mutation accumulation constitutes a risk of secondary leukemia. EcoSeq has the potential to reveal accumulation of somatic mutations and exposure to environmental factors in any DNA samples and will contribute to cancer risk estimation.

Precision Medicine Highlights Dysregulation of the CDK4/6 Cell Cycle Regulatory Pathway in Pediatric, Adolescents and Young Adult Sarcomas.

Simple SummaryThis review provides an overview of clinical features and current therapies in children, adolescents, and young adults (AYA) with sarcoma. It highlights the basic and clinical findings on the cyclin-dependent kinases 4 and 6 (CDK4/6) cell cycle regulatory pathway in the context of the precision medicine-based molecular profiles of the three most common types of pediatric and AYA sarcomas—osteosarcoma (OS), rhabdomyosarcoma (RMS), and Ewing sarcoma (EWS).Despite improved therapeutic and clinical outcomes for patients with localized diseases, outcomes for pediatric and AYA sarcoma patients with high-grade or aggressive disease are still relatively poor. With advancements in next generation sequencing (NGS), precision medicine now provides a strategy to improve outcomes in patients with aggressive disease by identifying biomarkers of therapeutic sensitivity or resistance. The integration of NGS into clinical decision making not only increases the accuracy of diagnosis and prognosis, but also has the potential to identify effective and less toxic therapies for pediatric and AYA sarcomas. Genome and transcriptome profiling have detected dysregulation of the CDK4/6 cell cycle regulatory pathway in subpopulations of pediatric and AYA OS, RMS, and EWS. In these patients, the inhibition of CDK4/6 represents a promising precision medicine-guided therapy. There is a critical need, however, to identify novel and promising combination therapies to fight the development of resistance to CDK4/6 inhibition. In this review, we offer rationale and perspective on the promise and challenges of this therapeutic approach.

Free Vascularized Fibula Salvage of Failed CPH in Pediatric Sarcoma Patients.

Background Due to extended life expectancy and recent improvements in surgical techniques, limb salvage has replaced amputation as the gold standard and is now performed in 90–95% of upper extremity malignancies. However, many of these salvage procedures are associated with significant postsurgical complications. In particular, the clavicula pro humero (CPH) procedure is associated with high rates of nonunion. We present our experience with upper extremity salvage using the free vascularized fibular flap (VFF) after failure or nonunion of the original CPH procedure in the pediatric population. Methods Five patients under the age of 18 diagnosed with upper extremity sarcoma who underwent tumor resection with immediate CPH reconstruction complicated with nonunion, and subsequent revision with free VFF were included. Data on patient demographics, oncologic characteristics, surgical procedures, intraoperative details, postoperative complications, and time to graft union were recorded. Results Five patients (average age = 8.4 years; range = 5–10 years at surgery date) underwent secondary limb salvage procedure with free VFF reconstruction following failed CPH reconstruction for proximal humeral osteosarcoma (n = 4) or Ewing sarcoma (n = 1). The mean follow-up was 3.7 years. Complications occurred in five patients (100%), with three patients requiring reoperation (60%). Four patients achieved graft union (average union time = 3.7 months) and successful limb reconstruction. Four patients were alive with no local recurrence of the disease. One patient did not achieve union and was lost to follow-up. Conclusion Primary bone tumors in the pediatric population require wide surgical resection, and reconstruction often has high complication rates that can warrant further procedures. A free VFF is a viable option for upper extremity salvage after previously failed reconstructions because it provides vascularized tissue to a scarred tissue bed and allows for the replacement or augmentation of large bony defects.

Prognostic value of fluorodeoxyglucose positron emission tomography derived metabolic parameters and textural features in pediatric sarcoma.

The aim of this study was to evaluate the prognostic value of PET-derived metabolic features and textural parameters of primary tumors in pediatric sarcoma patients. The imaging findings of 43 patients (14 girls and 29 boys; age 11.4 ± 4.4 years) who underwent 18-fluorodeoxyglucose positron emission tomography (PET)/computed tomography for primary staging prior to therapy between 2005 and 2020 were retrospectively evaluated. The diagnoses were osteosarcoma in 10, rhabdomyosarcoma in 10, and Ewing sarcoma in 23 patients. PET metabolic data and textural features of primary tumors were obtained. Cox proportional hazards regression models were used to identify predictors for progression-free survival and overall survival. Survival curves were estimated by using the Kaplan-Meier method. Distant metastases were detected in primary staging in 13 patients (30.2%). The median follow-up duration after diagnosis was 28 months (range: 10-171 months). In multivariate Cox regression analysis, the presence of distant metastasis and neighborhood grey-level difference matrix_Contrast (ngldm_Contrast) were found as independent predictors for both progression-free survival and overall survival. Grey-level zone length matrix_Zone-length nonuniformity (glzlm_ZLNU) was also found as an independent predictor for overall survival. The Kaplan-Meier survival analysis showed that higher ngldm_Contrast and glzlm_ZLNU values of primary tumors were significantly associated with shorter progression-free survival and overall survival. In addition to the presence of distant metastasis at initial diagnosis, textural features of primary tumors may be used as prognostic biomarkers to identify patients with worse prognosis in pediatric sarcoma. Higher tumor heterogeneity is significantly associated with shorter progression-free survival and OS.

Feasibility and safety of outpatient administration of ifosfamide and etoposide for pediatric patients with Ewing sarcoma in a resource-limited setting amid the COVID-19 pandemic.

BackgroundTo assess feasibility and safety of outpatient administration of ifosfamide and etoposide (IE) for pediatric Ewing sarcoma (EWS) patients in a resource‐limited setting amid the COVID‐19 pandemic.Materials and MethodsRetrospective study of patients with EWS who received outpatient IE from January 2020 until January 2021 at our institution. Ifosfamide 1800 mg/m2 was given for 5 days with MESNA (2‐mercaptoethane sulfonate sodium) infusion and additional boluses before and after 9 hours of hydration. Patients >10 years of age with the ability to drink orally at home, no pre‐existing renal dysfunction or history of hematuria were included. They were monitored for hemorrhagic cystitis with a urine dipstick before, midway, and at end of infusion. A urine analysis was done 24 hours after the last dose of ifosfamide.ResultsForty‐seven (100%) cycles were given as outpatient during the study period. Thirty‐five (74%) cycles were given on time, two (4%) cycles were delayed due to mucositis, two (4%) due to delayed count recovery, and eight (18%) due to unavailability of outpatient appointments. The median interval between these cycles was 15 days (range 14–44 days). No episode of hemorrhagic cystitis was reported. Urine analysis was not done at 24 hours for 27 (58%) cycles, so microscopic hematuria may have been missed. This outpatient protocol saved 32% (USD 299) per cycle in cost and 282 days of hospitalization.ConclusionOutpatient administration of IE for pediatric patients with EWS is feasible, safe, and cost‐effective during the COVID‐19 pandemic.

Clinical Value of NGS Genomic Studies for Clinical Management of Pediatric and Young Adult Bone Sarcomas.

Simple SummaryClinical management of sarcomas is complex because they are rare and heterogeneous tumors. Management requires a coordinated multidisciplinary approach, especially in children. Genomic characterization of this complex group of tumors contributes to the identification of prognostic biomarkers and to the continued expansion of therapeutic options. In this article, we present the positive experience of two Spanish hospitals in the use of genomic analysis in the overall clinical management of sarcomas in children and young adults. We describe on a case-by-case basis how genomic analysis has contributed to both diagnosis and treatment.Genomic techniques enable diagnosis and management of children and young adults with sarcomas by identifying high-risk patients and those who may benefit from targeted therapy or participation in clinical trials. Objective: to analyze the performance of an NGS gene panel for the clinical management of pediatric sarcoma patients. We studied 53 pediatric and young adult patients diagnosed with sarcoma, from two Spanish centers. Genomic data were obtained using the Oncomine Childhood Cancer Research Assay, and categorized according to their diagnostic, predictive, or prognostic value. In 44 (83%) of the 53 patients, at least one genetic alteration was identified. In 80% of these patients, the diagnosis was obtained (n = 11) or changed (n = 9), and thus genomic data affected therapy. The most frequent initial misdiagnosis was Ewing’s sarcoma, instead of myxoid liposarcoma (FUS-DDDIT3), rhabdoid soft tissue tumor (SMARCB1), or angiomatoid fibrous histiocytoma (EWSR1-CREB1). In our series, two patients had a genetic alteration with an FDA-approved targeted therapy, and 30% had at least one potentially actionable alteration. NGS-based genomic studies are useful and feasible in diagnosis and clinical management of pediatric sarcomas. Genomic characterization of these rare and heterogeneous tumors also helps in the search for prognostic biomarkers and therapeutic opportunities.

Association Between Neutrophil to Lymphocyte Ratio and Outcomes for Metastatic Pediatric Sarcoma Patients Treated With Stereotactic Body Radiotherapy

<h3>Purpose/Objective(s)</h3> The relationship between immune parameters and oncologic outcomes after stereotactic body radiotherapy (SBRT) is an area of active investigation. The neutrophil to lymphocyte ratio (NTLR) has been observed to be a prognostic marker in cancer survival across many cancers. We hypothesized that the NLTR is prognostic for patients undergoing SBRT for metastatic sarcoma. <h3>Materials/Methods</h3> From our IRB-approved single-institution registry, all patients treated with SBRT for metastatic sarcoma between 2014 and 2020 were identified. We evaluated treatment variables, complete blood count (CBC) data to calculate NLTR values, local control for each lesion, and survival. Wilcox Signed Rank Test and Friedman Test were used to compare intragroup NTLR changes between lesions experiencing local failure vs. local control. Overall survival was estimated using the Kaplan-Meier (KM) method, and univariate (UVA) and multivariable (MVA) Cox models were calculated. A receiver operating characteristic (ROC) curve was generated to determine a cut point for NTLR values to stratify low and high-risk groups. KM Curves were drawn to compare the two groups, and log rank statistics were calculated. <h3>Results</h3> Forty-two patients with 138 total lesions met inclusion criteria. Median follow up time of all patients was 9.7 months (range, 0.5-34.5). The median SBRT dose was 30 Gy (range, 15-60) given in 4 fractions (range, 1-5). Patients were heavily pre-treated with systemic therapy. Local control for all lesions was 66.7% (95% CI, 56.6-78.5%) at 1 year, and 50.2% (95% CI, 38.2-66.1) at 2-years. Median NTLR for controlled lesions before and after SBRT were 5.05 (IQR: 2.70 - 13.4) and 4.79 (IQR: 2.32 - 9.44), respectively. Median NTLR for failed lesions before and after SBRT were 3.31 (IQR: 2.24-4.98) and 3.51 (IQR: 3-6.13), respectively, and at local failure were 5.62 (IQR: 3.83 - 5.89). The change in median NTLR within the controlled group was not significant (<i>P</i> = .30) but was significant within the failed group (<i>P</i> = .027). Higher NLTR before SBRT was associated with poorer survival in both the univariate (HR = 1.11, 95% CI: 1.04-1.19) and multivariable (HR: 1.12, 95% CI: 1.03-1.21). The optimal NTLR cut point by survival ROC analysis was 5 (Youden index: .418). 1 year survival in the entire cohort was 47.6% (34.3%-66.1%). Patients with an NTLR above 5 at time of treatment had a 1-year survival of 37.7% (21.44%-66.3%), while patients with an NTLR below 5 had a significantly improved 1 year survival of 63% (43.3%-91.6%, <i>P</i> = .014). <h3>Conclusion</h3> Neutrophil to lymphocyte ratio at the time of treatment was prognostic for survival in patients undergoing stereotactic body radiotherapy for metastatic pediatric sarcoma. Change in the NTLR over time was a significant predictor of local failure. Further investigation into the interactions between immune parameters and sarcoma SBRT is warranted.

Pleuropneumonectomy as Salvage Therapy in Children Suffering from Primary or Metastatic Sarcomas with Pleural Localizations.

Simple SummaryPediatric sarcoma patients with pleuropulmonary lesions have a dismal prognosis because the impossibility to achieve local control. Local therapy with radiotherapy, whether in combination with chemotherapy, appears to be insufficient to eliminate the tumor cells. The aim of this study was to determine if pleuropneumonectomy (PP) could be a therapeutic option. We retrospectively reviewed nine patients who underwent PP for pleuropulmonary localization of primary localized sarcoma or metastatic recurrence. Surgery and complications were analyzed, pulmonary function tests were conducted, and quality of life was determined. Outcome is variable, four patients died within 14 months after PP, one patient suffered from local recurrence, and four patients are in long-lasting remission. This extended operation is quite well tolerated. Lung function seems preserved, and quality of life is generally good. Because it gives improvement of survival in patients with pleural lesions, PP can be considered as effective salvage therapy in selected patients.Pediatric sarcoma patients with pleuropulmonary lesions have a dismal prognosis because the impossibility to obtain local control. The aim of this study was to determine if pleuropneumonectomy (PP) could be a therapeutic option. We retrospectively reviewed nine patients who underwent salvage PP for pleuropulmonary localization of primary localized sarcoma or metastatic recurrence. Surgery and complications were analyzed, pulmonary function tests were conducted, and quality of life was determined with EORTC-QLQ-C30 questionnaire. At the time of PP age was between 9–17 years. Underlying disease included metastatic osteosarcoma (n = 5), Ewing sarcoma (two metastatic, one primary), and one primary undifferentiated sarcoma. Early complications occurred in three patients. Mean postoperative hospitalization stay was 14.5 days. Pulmonary function test showed 19–66% reduction of total lung capacity which led to mild exercise intolerance but did not affect daily life. Four patients died of multi-metastatic relapse <14 months after PP, one patient had a local recurrence, and four patients are in complete remission between 1.5 and 12 years after PP. In conclusion, in this small patient group treated with a pleuropneumonectomy for primary or metastatic lesions, outcome is variable; however, this extended surgical technique was generally quite well tolerated. Postoperative lung function seems well preserved, and it seems to lead to at least an extension of life with good quality and therefor can be considered as salvage therapy.

Cell-surface vimentin positive circulating tumor cells as a diagnostic and prognostic indicator in pediatric sarcoma patients.

e15022 Background: Despite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as &lt; 35%. Currently, there are no biomarkers available to assess disease status in patients with sarcomas and as such, disease surveillance remains only reliant on serial imaging which increases the risk of secondary malignancies and heightens patient anxiety. Methods: Here, we enumerated the cell surface vimentin (CSV+) CTCs in the blood of 92 sarcoma pediatric and adolescent and young adult (AYA) patients. Results: We discovered the CSV+CTC could serve as a possible biomarker of disease with sensitivity of 85.3% and specificity of 75%. Significantly, patients who were deemed to be CSV+ CTC positive were found to have a worse overall survival compared to those who were CSV+ CTC negative (773 days vs 2622 days). Addition of readily available genetic analyses improved the sensitivity in both diagnostic and prognostic tests. Conclusions: Our findings indicate that CSV+ CTCs have both diagnostic and prognostic value and can possibly serve as a measure of disease burden.