Non-rhabdomyosarcoma Soft Tissue Sarcomas Research Articles

CINSARC score use in pediatric non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) in the Children’s Oncology Group (COG) studies ARST0332 and ARST1321.

10013 Background: Despite genomic and histologic heterogeneity, limited risk stratification is used in the treatment of NRSTS (grade, size, presence of metastases, and extent of surgical resection). Genomic signatures including CINSARC score and Genomic Index (GI), both measures of genomic instability, have been shown to be prognostic in retrospective studies, but are not routinely used clinically. Here we evaluated the association of these scores with EFS and OS on two consecutive, prospective COG NRSTS studies, ARST0332 and ARST1321. Methods: All patients enrolled to ARST0332 or ARST1321 with sufficient banked tumor in the COG biospecimen repository were included in this analysis. Whole exome and transcriptome sequencing was performed on DNA and RNA from banked FFPE and flash frozen specimens. Raw WES reads were mapped to hg38 using BWA. The base qualities of the aligned reads were recalibrated and realigned by GATK. RNAseq data was aligned to hg38 by STAR. Differential expression analysis was performed by DESeq2. Stratified log rank and proportional hazards models were used to evaluate the association of CINSARC score and GI above or below the median with EFS and OS. Results: Tumors from 197 patients yielded sufficient DNA and 166 sufficient RNA, of which 177 and 142, respectively, passed sequencing quality metrics and were included. Demographics of these patients were generally representative of overall trial enrollment with most patients between ages 10-17 years (53%) with localized disease (77-80%). The most common histologic diagnoses were synovial sarcoma (35-37%) and MPNST (9-12%). Median follow-up was 6 years. CINSARC high vs low was associated with worse EFS (5-year 52.1% vs 74.6%, p < 0.01) and OS (5-year 66.2% vs 83.6%, p < 0.01). Accounting for sex and presence of metastatic disease, the hazard ratio for CINSARC high was 2.4 for EFS and 2.7 for OS (p < 0.01). CINSARC maintained the association with EFS among patients with non-metastatic disease (p = 0.017), and with OS among patients with metastatic disease (p = 0.031). GI analysis is ongoing and will be reported. Conclusions: In this analysis from the largest prospective North American pediatric NRSTS studies to date, CINSARC score was prognostic for EFS and OS. Further analysis including additional clinical prognostic factors (tumor size, grade, and extent of resection) is ongoing and will be reported. Use of CINSARC score for risk stratification should be considered on future NRSTS clinical trials. Clinical trial information: NCT00346164 , NCT02180867 .

Myofibroblastic sarcoma: A study of demographic and socioeconomic factors.

e23545 Background: Myofibroblastic sarcoma is a type of non-rhabdomyosarcoma soft tissue sarcoma originating from spindle cells of mesenchymal origin with myofibroblastic differentiation. First described in 1998, there is little known about the prognostic factors of this rare and relatively new cancer. This typically non-metastasizing tumor is primarily found in the head, neck, or extremities. Treatment focuses on tumor excision, and the 5-year overall survival of low-grade myofibroblastic sarcoma cancer is 72%. This study analyzed data from the National Cancer Database (NCDB) to understand how demographic factors contribute to the treatment and prognosis of myofibroblastic sarcoma. Methods: A retrospective cohort analysis was conducted on demographic factors of patients with confirmed myofibroblastic sarcoma (ICD-8825-3) using the NCDB from 2004-2020. Regression analysis was used to study trends of patient age, sex, race, education, insurance status, distance from facility, and Charles/Deyo score within this population. Results: A total of 111 patients (N = 111) were identified in the database with a confirmed diagnosis of myofibroblastic sarcoma from 2004 to 2020 with an increasing frequency of diagnoses per year (R^2 = 0.6283). The average age of diagnosis was 47.3 (SD = 24.17, range = 0 - 90 years). Although Myofibroblastic sarcoma appeared throughout the body, the most prominent sites were the long bones of the lower limb and associative joints (6%) followed by the uterus (5%). The majority of patients were white (83%), non-Hispanic (86%), and female (63%). A higher percentage of patients lived in metropolitan areas with a population greater than 1 million (58%) compared to smaller metropolitan, urban, or rural counties (42%). Most of the patients were treated at an academic/research program (30%) followed by a comprehensive community cancer program (21%). More facility locations were based in the Pacific (15%) and the Middle Atlantic (11%) regions. The primary payer at diagnosis was private insurance/managed care (44%) followed by Medicare (32%) and Medicaid (19%). Few patients (5%) received palliative care. Conclusions: To the best of our knowledge, this is the first NCDB analysis on Myofibroblastic sarcoma. Based on our dataset, Myofibroblastic sarcoma tends to occur in the long bones of the lower limb and associative joints which differed slightly from what we found in previous reports, which described the head and neck as the two areas of highest prevalence. This is the first time the socioeconomic factors have been described in the literature: these patients are more likely to be non-Hispanic, female individuals, living in smaller towns. This study offers insight on how much further investigation is required to better understand the impact of demographic and socioeconomic factors on early diagnosis and treatments.

Clinical features and outcomes of young patients with low-grade non-rhabdomyosarcoma soft tissue sarcomas treated with a risk-based strategy: A report from Children's Oncology Group study ARST0332.

In retrospective analyses, the Pediatric Oncology Group [POG) and the Federation National des Centres de Lutte Contre le Cancer (FNCLCC) histologic grade predict outcome in pediatric non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), but prospective data on grading, clinical features, and outcomes of low-grade NRSTS are limited. We analyzed patients less than 30years of age enrolled on Children's Oncology Group (COG) study ARST0332 (NCT00346164) with POG grade 1 or 2 NRSTS. Low-risk patients were treated with surgery alone. Intermediate-/high-risk patients received ifosfamide/doxorubicin and radiotherapy, with definitive resection either before or after 12weeks of chemoradiotherapy. Estimated 5-year event-free and overall survival were 90% and 100% low risk (n=80), 55% and 78% intermediate risk (n=15), and 25% and 25% high risk (n=4). In low-risk patients, only local recurrence was seen in 10%; none with margins greater than 1mm recurred locally. Sixteen of 17 intermediate-/high-risk patients who completed neoadjuvant chemoradiotherapy underwent gross total tumor resection, 80% with negative margins. Intermediate-/high-risk group events included one local and seven metastatic recurrences. Had the FNCLCC grading system been used to direct treatment, 29% of low-risk (surgery alone) patients would have received radiotherapy ± chemotherapy. Most low-risk patients with completely resected POG low-grade NRSTS are successfully treated with surgery alone, and surgical margins greater than 1mm may be sufficient to prevent local recurrence. Patients with intermediate- and high-risk low-grade NRSTS have outcomes similar to patients with high-grade histology, and require more effective therapies. Use of the current FNCLCC grading system may result in overtreatment of low-risk NRSTS curable with surgery alone.

Proton Therapy in Non-Rhabdomyosarcoma Soft Tissue Sarcomas of Children and Adolescents.

This paper provides insights into the use of Proton Beam Therapy (PBT) in pediatric patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). NRSTS are a heterogeneous group of rare and aggressive mesenchymal extraskeletal tumors, presenting complex and challenging clinical management scenarios. The overall survival rate for patients with NRSTS is around 70%, but the outcome is strictly related to the presence of various variables, such as the histological subtype, grade of malignancy and tumor stage at diagnosis. Multimodal therapy is typically considered the preferred treatment for high-grade NRSTS. Radiotherapy plays a key role in the treatment of children and adolescents with NRSTS. However, the potential for radiation-induced side effects partially limits its use. Therefore, PBT represents a very suitable therapeutic option for these patients. The unique depth-dose characteristics of protons can be leveraged to minimize doses to healthy tissue significantly, potentially allowing for increased tumor doses and enhanced preservation of surrounding tissues. These benefits suggest that PBT may improve local control while reducing toxicity and improving quality of life. While clear evidence of therapeutic superiority of PBT over other modern photon techniques in NRSTS is still lacking-partly due to the limited data available-PBT can be an excellent treatment option for young patients with these tumors. A dedicated international comprehensive collaborative approach is essential to better define its role within the multidisciplinary management of NRSTS. Shared guidelines for PBT indications-based on the patient's age, estimated outcome, and tumor location-and centralization in high-level referral centers are needed to optimize the use of resources, since access to PBT remains a challenge due to the limited number of available proton therapy facilities.

Outcome of patients with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcomas enrolled in phase 2 cooperative group clinical trials: A report from the Children's Oncology Group.

The aim of this study was to estimate the event-free survival (EFS) of children and young adults with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) treated in nonrandomized phase 2 studies conducted by the Children's Oncology Group (COG) and predecessor groups to establish a benchmark EFS for future phase 2 NRSTS trials evaluating the activity of novel agents. A retrospective analysis of patients with recurrent or refractory NRSTS prospectively enrolled in nonrandomized phase 2 COG and predecessor group trials between 1994 and 2015 was conducted. EFS was defined as disease progression/relapse or death and calculated via the Kaplan-Meier method. The log-rank test and relative risk regression were used to compare EFS distribution by age at enrollment, sex, race, NRSTS histology, prior lines of therapy, calendar year of trial, and type of radiographic response. In total, 137 patients were enrolled in 13 phase 2 trials. All trials used radiographic response rate as a primary outcome, and none of the agents used were considered active on the basis of trial-specified thresholds. The estimated median EFS and 6-month EFS of the entire study cohort was 1.5 months (95% confidence interval [CI], 1.3-1.8 months) and 19.4% (95% CI, 12.7%-26%), respectively. No difference in EFS was observed by age at enrollment, sex, race, NRSTS histology subtype, prior lines of therapies, and trial initiation year. EFS significantly differed by radiographic response. The EFS for children and young adults with relapsed or refractory NRSTS remains suboptimal. Established EFS can be referenced as a benchmark for future single-agent phase 2 trials incorporating potentially active novel agents in this population.

Local treatment in initially unresected non-rhabdomyosarcoma soft-tissue sarcomas of children and adolescents: A retrospective single-center experience.

Pediatric non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) are a heterogeneous group of aggressive tumors. Patients with locally advanced/initially unresected disease represent a subset of patients with unsatisfactory outcome: limited data are available on the best treatment approach, in particular regarding local therapy. This retrospective analysis concerned 71 patients<21 years old with nonmetastatic, initially unresected adult-type NRSTS, treated at a referral center for pediatric sarcomas from 1990 to 2021. Patients were treated using a multimodal approach, based on the protocols adopted at the time of their diagnosis. The series included a selected group of patients with unfavorable clinical characteristics, i.e., most cases had high-grade and large tumors, arising from axial sites in 61% of cases. All patients received neoadjuvant chemotherapy, 58 (82%) had delayed surgery (R0 in 45 cases), and 50 (70%) had radiotherapy. Partial response to chemotherapy was observed in 46% of cases. With a median follow-up of 152 months (range, 18-233), 5-year event-free survival (EFS) and overall survival (OS) were 39.9% and 56.5%, respectively. Survival was significantly better for patients who responded to chemotherapy, and those who had a delayed R0 resection. Local relapse at 5 years was 7.7% for patients who did not undergo delayed surgery. Our series underscores the unsatisfactory outcome of initially unresected NRSTS patients. Improving the outcome of this patient category requires therapeutic strategies able to combine novel effective systemic therapies with a better-defined local treatment approach to offer patients the best chances to have R0 surgery.

Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers.

The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes in 576 children, adolescents and young adults with recurrent/refractory solid tumors from the MOSCATO-01 and MAPPYACTS trials, using normal and tumor whole exome and RNA sequencing data and benchmarked algorithms. There was no evidence for narrowed HLA allelic diversity but discordant homozygosity and allele frequencies across tumor types and subtypes, such as in embryonal and alveolar rhabdomyosarcoma, neuroblastoma MYCN and 11q subtypes, and high-grade glioma, and several alleles may represent protective or susceptibility factors to specific pediatric solid cancers. There was a paucity of somatic mutations in HLA and antigen processing and presentation (APP) genes in most tumors, except in cases with mismatch repair deficiency or genetic instability. The prevalence of loss-of-heterozygosity (LOH) ranged from 5.9 to 7.7% in HLA class I and 8.0 to 16.7% in HLA class II genes, but was widely increased in osteosarcoma and glioblastoma (~15-25%), and for DRB1-DQA1-DQB1 in Ewing sarcoma (~23-28%) and low-grade glioma (~33-50%). HLA class I and HLA-DR antigen expression was assessed in 194 tumors and 44 patient-derived xenografts (PDXs) by immunochemistry, and class I and APP transcript levels quantified in PDXs by RT-qPCR. We confirmed that HLA class I antigen expression is heterogeneous in advanced pediatric solid tumors, with class I loss commonly associated with the transcriptional downregulation of HLA-B and transporter associated with antigen processing (TAP) genes, whereas class II antigen expression is scarce on tumor cells and occurs on immune infiltrating cells. Patients with tumors expressing sufficient HLA class I and TAP levels such as some glioma, osteosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft-tissue sarcoma cases may more likely benefit from T cell-based approaches, whereas strategies to upregulate HLA expression, to expand the immunopeptidome, and to target TAP-independent epitopes or possibly LOH might provide novel therapeutic opportunities in others. The consequences of HLA class II expression by immune cells remain to be established. Immunogenetic profiling should be implemented in routine to inform immunotherapy trials for precision medicine of pediatric cancers.

Angiosarcoma in children: the experience of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology and literature review

Angiosarcoma is a rare and highly malignant endothelial tumor, which occurs mainly in adults and is extremely rare in children and adolescents. The German guidelines for the treatment of soft tissue sarcomas provided by the Cooperative Weichteilsarkom Studiengruppe in 2012 included a separate therapeutic regimen for pediatric angiosarcoma consisting of a combination of vincristine/doxorubicin/cyclophosphamide (VDC) and paclitaxel. The aim of this article was to describe the epidemiological, clinical, and morphological characteristics of angiosarcoma, to review treatment approaches, and to present the experience of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation in the treatment of children with angiosarcoma. Our study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. The study included 5 patients diagnosed with angiosarcoma who had received treatment between 2012 and 2022. The patients’ parents gave consent to the use of their child's data, including photographs, for research purposes and in publications. Data on the patients’ age, gender, tumor location and extension, performed treatment and outcomes of the disease were analyzed. The male:female ratio was 0.66:1 and the median age was 5.2 years. Tumors were located in the soft tissues (n = 3) and in the bones (n = 2). In all the cases, invasion of the surrounding tissues was observed. There were no distant metastases at the time of diagnosis. Two (40%) patients underwent primary resection (R1) and 3 (60%) patients had tumor biopsy. Four patients received therapy according to the German guidelines for the treatment of angiosarcoma (VDC/paclitaxel courses), and 1 patient received treatment according to the guidelines for the management of non-rhabdomyosarcoma soft-tissue sarcomas (courses with vincristine, ifosfamide, doxorubicin/ vincristine, ifosfamide, actinomycin D). Objective response to treatment was achieved in 3 (60%) cases. Local control treatment of these 3 patients consisted of radiation therapy with a total dose of 50.4 Gy after R1 resection in 2 cases and biopsy in 1 case. After a median follow-up of 32 months, 2 patients who had received VDC/paclitaxel were alive without events (with complete and partial response), 3 patients died of progressive disease. Our data confirm the aggressive behavior of angiosarcoma in children. Protocol therapy that includes multiagent chemotherapy based on paclitaxel and doxorubicin along with local control treatment makes it possible to achieve a long-term control of the disease in some patients. However, further research on molecular and genetic characteristics of angiosarcoma is required to find potential novel targets for molecular targeted therapy. Further studies investigating the effectiveness of checkpoint inhibitors in angiosarcoma are also needed.

Soft Tissue Sarcomas in Adolescents and Young Adults.

Soft tissue sarcomas (STS) represent a heterogeneous group of extraskeletal mesenchymal tumors that affect individuals throughout the entire age continuum. Despite this pervasive influence, key differences exist in the presentation of these sarcomas across varying age groups that have prevented a more uniform approach to management. Notably, rhabdomyosarcoma (RMS) is more common in children, while most nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) subtypes are more prevalent in adults. Older patients with NRSTS appear to have more molecularly complex biology and often present with more advanced disease compared with children. Poorer outcome disparities are observed in older patients with RMS despite receiving similar treatment as younger patients. In this review, we highlight differences in epidemiology, biology, and management paradigms for pediatric and adult patients with STS and explore opportunities for a unified approach to enhance the care and outcomes within the AYA population.

Indeterminate pulmonary nodules in non-rhabdomyosarcoma soft tissue sarcoma: A study of the European paediatric Soft Tissue Sarcoma Study Group.

The aim of this study was to assess the clinical impact of indeterminate pulmonary nodules (no more than four pulmonary nodules of less than 5mm or one nodule measuring between 5 and less than 10mm by computed tomography [CT]) in children and adolescents with adult-type non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) at diagnosis. Patients with NRSTS treated in 11 centers as part of the European paediatric Soft Tissue Sarcoma Study Group (EpSSG) were retrospectively assessed. Local radiologists, blinded to clinical information except for patients' age and tumor histotype, reviewed the chest CT at diagnosis and filled out a case report form. Because patients with or without indeterminate nodules in the EpSSG NRSTS 2005 study received the same type of treatment, event-free survival (EFS) and overall survival (OS) between groups by log-rank test were compared. Overall, 206 patients were examined: 109 (52.9%) were without any nodules, 78 (38%) had at least one indeterminate nodule, and 19 (9.2%) had nodules meeting the definition of metastases, which were then considered to be misclassified and were excluded from further analyses. Five-year EFS was 78.5% (95% CI, 69.4%-85.1%) for patients without nodules and 69.6% (95% CI, 57.9%-78.7%) for patients with indeterminate nodules (p=.135); 5-year OS was 87.4% (95% CI, 79.3%-92.5%) and 79.0% (95% CI, 67.5%-86.8%), respectively (p=.086). This study suggests that survival does not differ in otherwise nonmetastatic patients with indeterminate pulmonary nodules compared to nonmetastatic patients without pulmonary nodules. Radiologists should be aware of the classification of indeterminate pulmonary nodules in non-rhabdomyosarcoma soft tissue sarcomas and use it in their reports. More than a third of patients with non-rhabdomyosarcoma soft tissue sarcoma can be affected by indeterminate pulmonary nodules. Indeterminate pulmonary nodules do not significantly affect the overall survival of pediatric patients with non-rhabdomyosarcoma soft tissue sarcoma.

Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody

Phosphatase of regenerating liver 3 (PRL3) is a specific tumor antigen overexpressed in a broad range of adult cancer types. However, its physiological expression in pediatric embryonal and mesenchymal tumors and its association with clinical outcomes in children is unknown. We sought to profile the expression of PRL3 in pediatric tumors in relation to survival outcomes, expression of angiogenesis markers, and G-protein-coupled receptor (GPCR)-mitogen-activated protein kinase (MAPK) signaling targets. PRL3-zumab, a first-in-class humanized antibody, was administered in a dose escalation schedule in a first-in-child clinical trial to study toxicity, pharmacokinetics, and clinical outcomes. Among 64 pediatric tumors, PRL3 was most frequently expressed in neuroblastoma (100%), rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas (71%), and renal sarcomas (60%) but absent in paired normal tissues. PRL3 was expressed in 75% of relapsed tumors and associated with shorter median event-free survival. Microarray profiling of PRL3-positive tumors showed elevation of angiogenin, TIMP1 and TIMP2, and GPCR-MAPK signaling proteins that commonly interacted with PRL3. The first use of PRL3-zumab in a pediatric patient saw no adverse events. A 28.6% reduction in maximum target lesion diameter was achieved when PRL3-zumab was administered concurrently with hypofractionated radiation. These findings support wider exploration of PRL3 expression in embryonal and mesenchymal tumors and further clinical application of PRL3-zumab in pediatric patients.

Clinical features and outcomes of infantile soft-tissue sarcoma: A multicenter retrospective study in Beijing.

Soft-tissue sarcomas during infancy are rare and understudied. With no data on this specific condition, we performed a retrospective study of infant-onset sarcomas based on a multi-institutional cohort in Beijing, China, collected over the past decade. We reviewed infantile soft-tissue sarcomas' clinical characteristics, treatments, and outcomes. The patients with soft-tissue sarcoma diagnosed from 0 to 12 months in four primary children's hospitals in Beijing from January 2010 to December 2019 were evaluated. Fifty-one patients were enrolled, including 31 males and 20 females. The median age at the diagnosis was five months (range, 0-12), and seven (13.7%) patients were diagnosed in the first month of their life. Histologically, twenty-five patients were diagnosed with rhabdomyosarcoma (RMS), six were diagnosed with extraosseous Ewing sarcoma (EES), and twenty were diagnosed with nonrhabdomyosarcoma soft-tissue sarcoma (NRSTS). The treatment principles and details of RMS focused on reference to the Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols. For EES and NRSTS, chemotherapy was prescribed according to children's oncology group protocols. The five-year EFS/OS rates of RMS were 26.4% ± 19.5%/56.2 ± 17.8%, the five-year EFS/OS rate of EES was 50% ± 20.4%, and the five-year EFS/OS of NRSTS was 85.2% ± 9.8%/100%. Infant-onset soft-tissue sarcoma is heterogeneous. The primary location of the abdominal or pelvic cavity of RMS and EWS was at a later stage and had a poorer prognosis. Multimodal therapy resulted in successful disease control for the majority of patients. Standardization of treatment protocols will facilitate care for such challenging conditions.

Outcomes After Preoperative Chemoradiation With or Without Pazopanib in Non-Rhabdomyosarcoma Soft Tissue Sarcoma: A Report From Children's Oncology Group and NRG Oncology.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.ARST1321 was a phase II study designed to compare the near complete pathologic response rate after preoperative chemoradiation with/without pazopanib in children and adults with intermediate-/high-risk chemotherapy-sensitive body wall/extremity non-Rhabdomyosarcoma Soft Tissue Sarcoma (ClinicalTrials.gov identifier: NCT02180867). Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary aim of the study, the outcome data for this cohort were analyzed. Eight-five eligible patients were randomly assigned to receive (regimen A) or not receive (regimen B) pazopanib in combination with ifosfamide and doxorubicin + preoperative radiotherapy followed by primary resection at week 13 and then further chemotherapy at week 25. As of December 31, 2021, at a median survivor follow-up of 3.3 years (range, 0.1-5.8 years), the 3-year event-free survival for all patients in the intent-to-treat analysis was 52.5% (95% CI, 34.8 to 70.2) for regimen A and 50.6% (95% CI, 32 to 69.2) for regimen B (P = .8677, log-rank test); the 3-year overall survival was 75.7% (95% CI, 59.7 to 91.7) for regimen A and 65.4% (95% CI, 48.1 to 82.7) for regimen B (P = .1919, log-rank test). Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib, outcomes were not statistically significantly different between the two regimens.

Marginal resection as a potential curative treatment option of infantile fibrosarcoma with good response after chemotherapy: A case report of an ETV6-NTRK3 positive infantile fibrosacroma of the distal tibia.

The infantile fibrosarcoma (IFS) is a non-rhabdomyosarcoma soft tissue sarcoma with locally aggressive properties. State of the art therapy consists of neoadjuvant chemotherapy followed by wide resection according to the criteria of the musculoskeletal tumor society. An ETV6-NTRK3 positive IFS of the distal tibia in a 21-months old child showed good response to chemotherapy. Due to refusal of amputation marginal resection completing the margins with a high speed drill and filling the space with bone cement was performed. At latest follow-up 10 years after surgery, no recurrence was observed. An individual therapy for surgical treatment of IIFS is recommended. This comprises marginal resection in instead of the golden standard "wide resection" in selected cases.

Presentation of congenital soft-tissue sarcomas: A single institution experience.

e23551 Background: Pediatric sarcomas make up 10% of pediatric tumors and involve a varied range of histological patterns with different prognosis which creates therapeutic challenges. Neonatal presentation is rare among sarcomas and poses further challenges in therapy. Methods: We present 5 cases of congenital sarcomas reporting pathology, genetics, treatment, and outcomes. We retrospectively identified 5 patients with sarcomas diagnosed in the neonatal period from a single institution in Miami from 2017 – 2022 in order to identify similarities between neonatal sarcomas. Our sarcomas included an embryonal rhabdomyosarcoma (RMS), infantile fibrosarcoma (IFS), rhabdoid tumor, and two undifferentiated sarcomas. Results: The presentation occurred between birth and four days old. Location at presentation was varied. Four of our patients were Nonrhabdomyosarcoma Soft Tissue Sarcomas (NRSTS). Only one patient was diagnosed prenatally, while three were diagnosed at birth, and one at 4 days of life. Three patients presented spindle cell pathology. One of our undifferentiated sarcomas was classified as IFS-like, Archer FusionPlex was negative for mutation. Our other undifferentiated sarcoma showed a COL1A1 gene rearrangement on chromosome 17q.21 with immunostains positive for BCOR, SMARCB1, SMARCA4. Congenital fibrosarcoma showed ETV6 fusion with NTRK and immunostains positive for FLI-1, SMA, CD34, INI-1. The RMS showed focal loss of PTCH1 and FANCC and had immunostains positive for desmin and myogenin. The metastatic rhabdoid tumor showed SMARCB1 whole gene deletion as well as a 570kB deletion in chromosome 22q11.23. Three patients were treated on ARST 0331 with vincristine, doxorubicin, and cyclophosphamide (VAC), with the undifferentiated sarcoma requiring advancement to ARST 0332. The patient with metastatic rhabdoid tumor was treated with AREN 0321. Four patients required surgery. We had 1-year-survival in three patients, all treated on ARST 0331 or ARST 0332. The patient with metastatic rhabdoid tumor died at 4 months of age while on AREN 0321, and our patient with IFS-like sarcoma decompensate and died at ten days old, prior to starting therapy. Conclusions: We show multiple genetic mutations with SMARCB1 alteration in both an undifferentiated sarcoma and a malignant rhabdoid tumor but otherwise found no significant pattern among individual sarcomas. Our cases show good outcomes for patients qualifying for ARST 0331. We highlight the need for improved methods of detection of pediatric tumors in utero.

Metastatic adult-type non-rhabdomyosarcoma soft tissue sarcomas in children and adolescents: A cohort study from the European paediatric Soft tissue sarcoma Study Group.

Limited data exist on the clinical behavior of pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with distant metastases at onset, and a clear standard of care has not yet been defined. This cohort study reports on pediatric adult-type metastatic NRSTS enrolled in two concurrent prospective European studies, i.e., the randomized BERNIE study and the single-arm MTS 2008 study developed by the European paediatric Soft tissue sarcoma Study Group. Treatment programs were originally designed for patients with metastatic rhabdomyosarcoma, i.e., nine courses of multidrug chemotherapy (with or without bevacizumab in the BERNIE study), followed by 12 cycles of maintenance therapy, whereas radiotherapy and/or surgery (on primary tumor and/or metastases) were delayed until after seven courses of chemotherapy had been administered. The study included 61 patients <21years old treated from July 2008 to December 2016. The lung was the site of metastases in 75% of the cases. All patients received multi-agent chemotherapy, 44% had local therapy to primary tumor, and 18% had treatment of metastases. Median time to progression/relapse was 6months. A high rate of tumor progression was observed during the initial part of the chemotherapy program. With a median follow-up of 41.5months (range, 2-111months), 3-year event-free survival and overall survival were 15.4% (95% confidence interval [CI], 7.6-25.7) and 34.9% (95% CI, 22.7-47.5), respectively. There were no statistically significant differences in outcome depending on the type of treatment administered. The study confirmed the overall poor outcome for patients with metastatic NRSTS, whose treatment remains a challenge. Pediatric non-rhabdomyosarcoma soft tissue sarcomas form a heterogeneous group of rare tumors. Although recent international studies have defined the standard of care for patients with localized disease, limited data are available on the clinical behavior of patients with distant metastases. This study on 61 metastatic cases treated on two prospective European protocols confirms that the chances of survival of such patients are often dismal and a standard treatment is still lacking.

Adjuvant therapy for orbital non-rhabdomyosarcoma soft tissue sarcoma: comparison of long-term outcome between radiotherapy and chemotherapy

To illustrate clinicopathological features of orbital non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), and to compare the treatment outcome between postoperative radiotherapy (RT) and chemotherapy in a retrospective analysis nearly 20y. A retrospective cohort study of 56 patients with orbital NRSTS were reviewed, 34 of whom received postoperative RT, and 22 received postoperative chemotherapy. The clinicopathological features, local recurrence, metastases, and survival data were recorded. Survival analysis was performed using the Kaplan-Meier method. During follow-up (111.8mo, ranged 8-233mo) for 56 patients, 19 patients of them developed local recurrence, and 7 patients developed distant metastases. Fifteen patients died during follow-up period. Overall survival rates considering the whole study group was 78.57% at 5y, and 72.16% at 10y after the initial diagnosis. Compared with chemotherapy, RT was associated with lower risk of local recurrence [hazard ratio for RT vs chemotherapy, 0.263, 95% confidence interval (CI), 0.095-0.728, P=0.0015]; with lower risk of distant metastasis (hazard ratio for RT vs chemotherapy, 0.073, 95%CI, 0.015-0.364, P=0.0014); and with lower risk of death from disease (hazard ratio for RT vs chemotherapy, 0.066, 95%CI, 0.022-0.200, P<0.0001). The 5-year survival rate in RT group was 97.06% compared to 50% in chemotherapy group. In patients with orbital NRSTS, postoperative RT provides better control of local recurrence, distant metastasis, and death from disease than chemotherapy. RT is the more preferrable adjuvant therapy compared to chemotherapy possibly.

Neoadjuvant pazopanib in nonrhabdomyosarcoma soft tissue sarcomas (ARST1321): A report of major wound complications from the Children's Oncology Group and NRG Oncology.

The impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/- chemotherapy for soft tissue sarcoma. Wound complications were evaluated on dose-finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/- pazopanib, +/- ifosfamide/doxorubicin (ID) for sarcoma therapy. Of 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites. The addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

The significance of margins in pediatric Non-Rhabdomyosarcoma soft tissue sarcomas: Consensus on surgical margin definition harmonization from the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT).

Margin status following surgery in children, adolescents, and young adults with soft tissue sarcomas is controversial and has been defined differently by various specialties, with definitions changing over time and by cooperative group. The International Soft Tissue Sarcoma Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, European pediatric Soft Tissue sarcoma Study Group (EpSSG), and the European Cooperative Weichteilsarkom Studiengruppe (CWS) devoted to improving patient outcomes by pooling and mining cooperative group clinical trial data. The INSTRuCT non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) working group aimed to develop international harmonized recommendations regarding surgical margin assessment and definitions in children and adolescents with soft tissue tumors. This review addresses accepted principles and areas of controversy, including the perspectives of surgeons, pathologists, radiation oncologists, and pediatric oncologists, to develop a framework for building common guidelines for future research.

Imaging recommendations for the management of pediatric non-rhabdomyosarcoma soft tissue sarcoma (NRSTS): Consensus statement of the International Soft Tissue Sarcoma Consortium (INSTRuCT)

Imaging recommendations for the management of pediatric non-rhabdomyosarcoma soft tissue sarcoma (NRSTS): Consensus statement of the International Soft Tissue Sarcoma Consortium (INSTRuCT)