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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma among children and adolescents. The management of RMS involves risk stratification of the patients based on various clinicopathological characteristics. The multimodality treatment approach requires chemotherapy, surgery, and/or radiation. The treatment of RMS necessitates the involvement of multiple disciplines, such as pathology, pediatric oncology, surgery, and radiation oncology. The disease heterogeneity, molecular testing, evolving treatment regimens, and limited resources are some of the challenges faced by clinicians while treating a patient with RMS in low- and middle-income countries (LMICs). In this review, we endeavor to bring experts from varying fields to address clinicians' common questions while managing a child or adolescent with RMS in LMICs. This review is most applicable to level 2 centers in LMICs as per the levels of services described by the Adapted Treatment Regimens Working Group of the Pediatric Oncology in Developing Countries committee of the International Society of Pediatric Oncology., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Primitive myxoid mesenchymal tumor of infancy (PMMTI), a rare soft tissue tumor with distinct characteristics. PMMTI tends to have an aggressive local course, with multiple relapses and poor response to treatment. Rare cases of distant metastases have been described before. We described the second case of PMMTI with brain metastasis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim of the study is to describe the factors that influence outcome in adults with head and neck osteosarcoma (HNO) with a specific focus on the margin status., Methods: Patients with a diagnosis of HNO between the years 1996-2021 were reviewed from the Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) Database. Baseline characteristics, pathology, treatment, and outcomes were analyzed. Univariable (UVA) and multivariable (MVA) Cox regression models were performed. 5-year locoregional control rate and overall survival (OS) were estimated using Kaplan-Meier method and Log-Rank test., Results: Of 50 patients with a median age of 40 years (range 16-80), 27 (54%) were male. HNO commonly involved the mandible (n = 21, 42%) followed by maxilla (n = 15, 30%). Thirteen (33.3%) had low-intermediate grade and 26 (66.6%) had high grade tumors. Three patients (6%) had negative resection margins (>5 mm), 24 (48%) had close margins (1-5 mm), 15 (30%) had positive margins (<1mm) and 7 (16%) had unknown margin status. In total, 39 (78%) received chemotherapy - 22 (44%) received neoadjuvant chemotherapy while 17 (34%) received adjuvant chemotherapy. A total of 12 (24%) patients received radiotherapy, of whom 8 (16%) had adjuvant and 3 (6%) had neo-adjuvant. Median follow-up time was 6.3 years (range 0.26-24.9). Disease recurred in 21 patients (42%), of whom 15 (30%) had local recurrence only, 4 (8%) had distant metastasis, and 2 (4%) had both local and distant recurrence. 5-year locoregional control rate and OS was 62% and 79.2% respectively. Resection margins <3 mm was associated with lower 5 years OS and locoregional control rate (Log-Rank p = 0.02, p = 0.01 respectively)., Conclusion: Osteosarcomas of the head and neck are rare and local recurrence remains a concern. Surgical resection with negative resection margins may improve survival, and a 3 mm resection margin threshold may optimize survival. Radiotherapy and/or chemotherapy should be considered in a multidisciplinary setting based on risk-features., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Objectives: We conducted a retrospective multi-centre study to assess the real-world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra-skeletal mesenchymal CS (ESMC)., Methods: After regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method., Results: From July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12-76); median starting dose was 60 mg for CABO (n = 37, range 40-60) and 120 mg for REGO (n = 29, range 40-160). Twenty-eight (42.4%) patients required dose reduction: hand-foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7-13.1); 13.4 months (n = 18, 95% CI 3.4-27.2), 8.1 (n = 4, 95% CI 4.1-9.3) and 18.2 (n = 5, 95% CI (10.4-na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8-5), 3.9 (n = 18, 95% CI 2.1-5.9), 5.53 (n = 4. 95% CI 2.13-NA) and 11.4 (n = 5, 95% CI 1.83-14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis., Conclusion: Our real-world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Radiation-induced sarcoma (RIS) is a late toxicity of radiation therapy (RT) usually associated with poor prognosis. Due to ongoing improvements in childhood cancer treatment and patient outcomes, RIS may become more prevalent notwithstanding evolving indications for RT. Due to limited reported studies, we sought to review our experience with RIS in survivors of pediatric cancer., Methodology: Data were collected on RIS patients following treatment for childhood cancer (initial diagnosis <18 years) identified in the CanSaRCC database. Additionally, details on the protocol guidance at time of treatment were compared with current guidelines for the same disease., Results: Among 12 RIS identified, median age at initial diagnosis was 3.5 years (range 0.16-14) and the latency from RT to RIS diagnosis was 24.5 (range 5.4-46.2) years. Initial diagnoses included neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, Wilms tumor, retinoblastoma and Hodgkin's Lymphoma. RIS histologies included osteosarcoma and soft tissue sarcomas. In comparison to protocols followed at time of diagnosis to current ones (2022), 7/12 (58%) patients would have required RT. RIS treatment included chemotherapy, radiation and surgery in 3/11 (27%), 10/11 (90%), and 7/11 (63%) patients, respectively. With a median follow-up time of 4.7 years from diagnosis of RIS, 8 (66%) patients were alive and 4 (33%) had died of progressive RIS., Conclusion: RIS is a serious late effect of radiotherapy in childhood cancer; however, radiation remains an integral component of primary tumor management and requires participation from a specialized multi-disciplinary team, aiming to mitigate RIS and other potential late effects., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS., Methods: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021)., Results: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice., Conclusions: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Sarcoma can present as locally advanced disease involving pleura for which extra-pleural pneumonectomy (EPP) may be the only surgical option to ensure adequate local control. Data were collected on patients who underwent EPP between January 2009 and August 2021 at Princess Margret Hospital and SickKids (Toronto) using the CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration). Ten patients with locally advanced sarcoma involving the pleura, aged 4 to 59 years (median 19.5 years) underwent EPP. Nine (90%) received pre-operative chemotherapy and eight (80%) achieved an R0 resection. Hemithoracic radiation was administered preoperatively ( n = 6, 60%) or postoperatively ( n = 4, 40%). Five (50%) patients were alive without disease at last follow-up (median 34.2 months) and time from EPP to last FU was median 29.2 months (range 2.2-87.5). Two patients (20%) had local recurrence, 4.3 and 5.8 months from EPP, and both died from progressive disease, 13.1 and 8.2 months from EPP, respectively. One patient died from brain metastasis (17 months), one died from radiation associated osteosarcoma (66 months), and one died from surgical complications (heart failure from constrictive pericarditis). EPP offers a feasible and life-prolonging surgical consideration for patients with locally advanced sarcoma involving the pleura in combination with chemotherapy and radiation. Consequently, EPP should be considered during multi-disciplinary tumor board discussions at high-volume centers.

Background: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies., Methods: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan., Results: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types., Conclusions: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients., (© 2021 American Cancer Society.)

Objective: Disease spectrum in pediatric sarcoma differs substantially from adults. We report a cohort of very young children with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) detailing their molecular features, treatment, and outcome., Methods: We report features of consecutive children (age <2 years) with NRSTS (2000-2017). Archival pathological material was re-reviewed, with additional molecular techniques applied where indicated., Results: Twenty-nine patients (16 females, 55%) were identified (median age 6 months; range 0-23). Most common diagnoses included infantile fibrosarcoma (IFS, n = 14, 48%), malignant rhabdoid tumor (MRT, n = 4, 14%), and undifferentiated sarcoma (n = 4, 14%). Twenty-seven of 29 (93%) had tumor molecular characterization to confirm diagnosis. Clinical presentation included a swelling/mass (n = 23, 79%). Disease extent was localized (n = 20, 69%), locoregional (n = 6, 21%), or metastatic (n = 3, 10%). Seventeen of 29 (59%) who underwent surgery achieved complete resection (R0). Other treatments included conventional chemotherapy (n = 26, 90%), molecularly targeted therapies (n = 3, 10%), and radiation (n = 5, 17%). At last follow-up (median 3 years; range 0.3-16.4), 23 (79%) were alive, disease-free and six (21%) had died of disease. All patients with IFS were alive and all those with MRT died. A cancer predisposition syndrome (CPS) was confirmed in three of 10 (30%) genetically tested patients., Conclusion: We recommend tumor molecular characterization in all young patients including evaluation for CPS to optimize treatment options and prognostication., (© 2021 Wiley Periodicals LLC.)

Background: Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound with single-agent activity in soft tissue sarcoma (STS). The study's aim was to determine the safety and efficacy of selinexor in combination with doxorubicin in patients with locally advanced/metastatic STS., Methods: This phase 1b study used a mTPI design. Patients received selinexor at either 60 or 80 mg weekly PO plus doxorubicin (75 mg/m 2 IV q21 days). Patients with clinical benefit (defined as ≥stable disease via RECIST 1.1) after six cycles of combination treatment received maintenance selinexor until disease progression or unacceptable toxicity. Disease assessments were conducted every two cycles. Pharmacokinetic data were collected on the first three patients per dose level., Results: Twenty-five patients were enrolled (20 female, ECOG 0/1: 13/12, median age 57 years [range 21-74]). Disease subtypes included leiomyosarcoma (n = 6), malignant peripheral nerve sheath tumour (n = 3) and other sarcomas (n = 16). Three (12%) and 22 (88%) patients were treated at 60 mg and 80 mg of selinexor, respectively. The most common ≥G3 drug-related adverse events (AEs) were haematological, including neutropenia (56%), febrile neutropenia (28%) and anaemia (24%). There were four dose-limiting toxicities (febrile neutropenia (x2), vomiting, fatigue) all at the 80 mg dose level. There was one death secondary to heart failure. Of the 24 evaluable patients, 5 (21%) had a partial response and 15 (63%) had SD as best response. The estimated median progression-free survival (PFS) and overall survival (OS) were 5.5 (95% CI:4.1-5.7) and 10.5 (95% CI:7.5-14) months., Conclusion: In a heterogeneous group of patients with locally advanced/metastatic STS, the combination of selinexor and doxorubicin fulfilled the prespecified boundary for tolerability., Competing Interests: Conflict of interest statement ARA: Honoraria: Boehringer Ingelheim; Consulting/advisory: Lilly; Merck; Boehringer Ingelheim; Adaptimmune; Research funding: CASI Pharmaceuticals; Boehringer Ingelheim; Lilly; Novartis; Deciphera; Karyopharm Therapeutics; Pfizer; Roche/Genentech; Boston Biomedical; Bristol-Myers Squibb; MedImmune; Amgen; GlaxoSmithKline; Blueprint Medicines; Merck; Abbvie; Adaptimmune; Iterion. JL: Consulting/advisory: Bayer. The rest of the authors have no disclosures or conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma., Methods: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0-2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing., Findings: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7-26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8-19·0), median duration of response was not reached (95% CI 9·2-not estimable). 16 (26% [95% CI 16-39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9-7·4). Median progression-free survival was 5·5 months (95% CI 3·4-5·9), and median overall survival was 19·0 months (11·0-not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths., Interpretation: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941)., Funding: Epizyme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Clinical experience suggests a high prevalence of emotional distress in patients with desmoid tumor (DT). We examine longitudinal Distress Assessment and Response Tool (DART) scores to estimate prevalence and persistence of distress, and compare cross-sectional data between DT and malignant sarcoma cohorts, to identify predictors of distress., Methods: Patients with DT completed DART at: T1-diagnosis, T2-during, T3-<6 months, and T4-≥6 months, post-treatment. DART includes patient-reported outcome measures of physical symptoms (ESAS-r), depression (PHQ-9), anxiety (GAD-7), and social difficulties (SDI-21). Descriptive prevalence and persistence of anxiety, depression, and wellbeing are reported, and mixed model regression analyses determine predictors of distress., Results: Between 2012 and 2018, a total of 152 DART screens from 94 patients with DT were completed (T1: n = 44, T2: n = 31, T3: n = 22, T4: n = 55). Patients had a mean age 40 years, 78% were female and DT locations were abdominal wall (48%), extremity (30%), and mesentery (22%). Moderate to severe ESAS-r scores (≥4) persisted at T4 for anxiety (20%), depression (13%), and poor wellbeing (31%). Compared to 402 patients with malignant sarcoma, patients with abdominal wall sited DT reported severe PHQ-9 and GAD-7 scores twice as frequently. Abdominal wall location, female sex, history of mood problems, and psychosocial concerns were significant predictors of anxiety, depression, and poor wellbeing in DT., Conclusions: Adults with DT experience persistently high emotional distress compared to patients with malignant sarcoma. Women with abdominal wall DT, prior mood, and current psychosocial concerns need early attention within multidisciplinary treatment settings to reduce persistent distress., (© 2019 John Wiley & Sons, Ltd.)

Background: Soft-tissue sarcomas in children are a histologically heterogenous group of malignant tumors accounting for approximately 7% of childhood cancers. There is a paucity of data on the value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for initial staging and whether PET influenced management of these patients., Objective: The aim of this analysis is to assess the use of 18 F-FDG PET exclusively, and as a supplement to cross-sectional imaging in comparison to typical imaging protocols (CT and magnetic resonance imaging [MRI]) for initial staging as well as therapy planning in pediatric soft-tissue sarcoma patients., Materials and Methods: The list of 18 F-FDG PET/CT performed for soft-tissue sarcoma between March 2007 and October 2017 was obtained from the Hospital Information System database. Twenty-six patients who had received 18 F-FDG PET, MRI and/or CT at initial diagnosis were included in the study. 18 F-FDG PET and concurrent diagnostic CT and MRI at initial staging were independently reviewed to note the number of primary and metastatic lesions detected by each modality. A chart review was conducted to collect information on final diagnosis, staging and treatment plan., Results: During the study period, 26 patients (15 females) ages 1.3-17.9 years (median age: 6 years) had received 18 F-FDG PET/CT at initial diagnosis of soft-tissue sarcoma. Diagnostic CT was available for comparison in all 26 patients and MRI was available in 18 patients. The mean interval between cross-sectional imaging and 18 F-FDG PET was 5.9 days (range: 0-30 days). All 26 primary lesions were equally detected by 18 F-FDG PET compared to CT and MRI. From 84 metastatic lesions, 16 were detected by PET as well as CT and MRI, 12 by 18 F-FDG PET only (included mainly lymph node metastases) and 56 by CT and MRI only (included mainly lung metastases). 18 F-FDG PET changed therapy planning in 5 patients out of 26 (19%) by showing additional lesions not detected by CT and MRI., Conclusion: 18 F-FDG PET proved to be a valuable tool for precise initial staging of pediatric soft-tissue sarcoma patients, especially in detecting lymph node metastasis, and could be included in their initial work-up. Given the relative rarity and heterogeneity of this group of tumors, additional investigations are required to definitely establish a role for 18 F-FDG PET in the initial staging and therapy planning of soft-tissue sarcoma in the pediatric population.

Background: The physical function of children with sarcoma after surgery has not been studied explicitly. This paucity of research is partly because of the lack of a sufficiently sensitive pediatric functional measure. The goal of this study was to establish and validate a standardized measure of physical function in pediatric patients with extremity tumors., Questions/purposes: (1) What is the best format and content for new upper- and lower-extremity measures of physical function in the pediatric population? (2) Do the new measures exhibit floor and/or ceiling effects, internal consistency, and test-retest reliability? (3) Are the new measures valid?, Methods: In Phase 1, interviews with 17 consecutive children and adolescents with bone tumors were conducted to modify the format and content of draft versions of the pediatric Toronto Extremity Salvage Score (pTESS). In Phase 2, the pTESS was formally translated into French. In Phase 3, 122 participants between 7 and 17.9 years old with malignant or benign-aggressive bone tumors completed the limb-specific measure on two occasions. Older adolescents also completed the adult TESS. Floor and ceiling effects, internal consistency, test-retest reliability, and validity were evaluated., Results: Feedback from interviews resulted in the removal, addition, and modification of draft items, and the pTESS-Leg and pTESS-Arm questionnaires were finalized. Both versions exhibited no floor or ceiling effects and high internal consistency (α > 0.92). The test-retest reliability was excellent for the pTESS-Leg (intraclass correlation coefficient [ICC] = 0.94; 95% CI, 0.90-0.97) and good for the pTESS-Arm (ICC = 0.86; 95% CI, 0.61-0.96). Known-group validity (ability to discriminate between groups) was demonstrated by lower mean pTESS-Leg scores for participants using gait aids or braces (mean = 68; SD = 21) than for those who did not (mean = 87; SD = 11; p < 0.001). There was no significant difference between pTESS arm scores among respondents using a brace (n = 5; mean = 73; SD = 11) and those without (n = 22; mean = 83; SD = 19; p = 0.13). To evaluate construct validity, we tested a priori hypotheses. The duration since chemotherapy correlated moderately with higher pTESS-Leg scores (r = 0.4; p < 0.001) but not with pTESS-Arm scores (r = 0.1; p = 0.80), and the duration since tumor resection correlated moderately with higher pTESS-Leg scores (r = 0.4; p < 0.001) but not pTESS-Arm scores (r = 0.2; p = 0.4). Higher VAS scores (that is, it was harder to do things) antecorrelated with both pTESS versions (pTESS-Leg: r = -0.7; p < 0.001; pTESS-Arm: r = -0.8; p < 0.001). To assess criterion validity, we compared the pTESS with the current "gold standard" (adult TESS). Among adolescents, strong correlations were observed between the TESS and pTESS-Leg (r = 0.97, p < 0.001) and pTESS-Arm (r = 0.9, p = 0.007)., Conclusions: Both pTESS versions exhibited no floor or ceiling effects and had high internal consistency. The pTESS-Leg demonstrated excellent reliability and validity, and the pTESS-Arm demonstrated good reliability and reasonable validity. The pTESS is recommended for cross-sectional evaluation of self-reported physical function in pediatric patients with bone tumors., Level of Evidence: Level II, outcome measurement development.

ENMD-2076, an aurora-A kinase inhibitor with anti-angiogenic properties, has shown activity in solid and hematologic malignancies. We investigated oral ENMD-2076 in an open-label, single-arm phase II study using 275 mg daily on a 28-day cycle in patients with advanced soft-tissue sarcomas (STS) receiving ≤1 line of prior therapy. Primary endpoint was 6-month progression-free survival (PFS) with ≤15% indicating no interest, and ≥40% indicating further interest in ENMD-2076. Secondary/exploratory endpoints included clinical benefit (CBR ≥6-months) and objective response (ORR) rates, PFS, OS, safety, and whole-exome sequencing (WES) for potentially associated biomarkers. Overall, 23/25 (92%) patients receiving ENMD-2076 were efficacy evaluable with median follow-up of 14 months (range 2.2-39.5). Common subtypes were leiomyosarcoma (n = 10), undifferentiated pleomorphic sarcoma (n = 3), angiosarcoma (n = 3), and alveolar soft-part sarcoma (n = 3). The 6-month PFS was 20.8% (95% CI:3.2-38.4) with a CBR of 17% (95% CI:1.55-33.23) and ORR of 9% (95% CI:3.08-20.46). Median PFS was 2.5 months (95% CI:2.20-4.47) and OS was 14.1 months (95% CI:6.07-20.07). The most common high-grade treatment-related adverse event was hypertension (60%). WES identified PTPRB mutations in 3/4 patients (p = 0.018) benefiting from ENMD-2076. Although this study failed to meet its primary endpoint, occasional responses and prolonged stable disease was noted. ENMD-2076 evaluation in PTPRB mutated tumors and/or angiosarcoma is warranted.

Soft tissue sarcoma (STS) is a family of malignancies for which individual management decisions can be complex. There is a paucity of level 1 evidence, as the rarity and heterogeneity of STS pose challenges to the design and execution of randomized controlled trials. Radiotherapy (RT) is routinely used to facilitate function-preserving surgery and to improve local control. Delivery of RT in the preoperative setting can decrease chronic toxicities at the cost of increased wound complications in the short-term. The role of adjuvant systemic therapies remains controversial in adult STS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

After diagnosis of retroperitoneal sarcoma (RPS), detailed imaging and multidisciplinary discussion should guide treatment including surgical resection and in select cases, neoadjuvant therapy. Local recurrence is common in RPS and is associated with grade, histologic subtype, completeness of resection, and size. As guidelines to standardize RPS patient management emerge, expert pathologic assessment and management in centers of excellence are benchmarks of quality of care. The efficacy of current chemotherapy is limited and there is a critical need to understand the molecular basis of sarcoma so that new drug therapies are developed. Multicenter clinical trials are needed to limit opinion and controversy in this complex and challenging disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease., Patients and Methods: Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m(2), 50 mg/m(2), or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was performed under fasting and fed states (low v high fat content) and using various formulations of selinexor (tablet, capsule, or suspension). Tumor biopsies before and during treatment were evaluated for pharmacodynamic changes., Results: The most commonly reported drug-related adverse events (grade 1 or 2) were nausea, vomiting, anorexia, and fatigue, which were well managed with supportive care. Commonly reported grade 3 or 4 toxicities were fatigue, thrombocytopenia, anemia, lymphopenia, and leukopenia. Selinexor was significantly better tolerated when administered as a flat dose on an intermittent schedule. PK analysis of selinexor revealed a clinically insignificant increase (approximately 15% to 20%) in drug exposure when taken with food. Immunohistochemical analysis of paired tumor biopsies revealed increased nuclear accumulation of tumor suppressor proteins, decreased cell proliferation, increased apoptosis, and stromal deposition. Of the 52 patients evaluable for response, none experienced an objective response by RECIST (version 1.1); however, 17 (33%) showed durable (≥ 4 months) stable disease, including seven (47%) of 15 evaluable patients with dedifferentiated liposarcoma., Conclusion: Selinexor was well tolerated at a 60-mg flat dose on a 3-weeks-on, 1-week-off schedule. There was no clinically meaningful impact of food on PKs. Preliminary evidence of anticancer activity in sarcoma was demonstrated., (© 2016 by American Society of Clinical Oncology.)

Background: The objective of this study was to assess patient, tumor, and treatment factors that affected overall survival in a group of patients who underwent surgery for soft tissue sarcoma (STS) and presented with American Joint Commission on Cancer stage IV disease., Methods: A retrospective review was undertaken of a single institution's database from the years 1986 to 2006 in all patients who met the following inclusion criteria: 1) surgical management of the primary tumor was undertaken, and 2) metastatic disease was present at the time of initial presentation. In total, 112 patients were identified who met the inclusion criteria., Results: The 5-year survival rate for the entire group was 17%. In univariate analysis, the variables that were identified as statistically significant for predicting improved overall survival were resection of metastatic disease (P = .003), <4 pulmonary metastases (P = .05), and the presence of lymph node metastases versus pulmonary metastases (P = .0002). In multivariate analysis, only the presence of lymph node metastases versus pulmonary metastases retained statistical significance (P = .05). The 5-year survival rate for patients who had lymph nodes metastases at diagnosis was 59%, whereas it was only 8% for patients who presented with pulmonary metastases., Conclusions: Patients who presented with metastatic STS had a very poor prognosis despite aggressive surgical management of their primary tumor. The current results indicated that, although patients with isolated lymph node metastases may be cured by surgical resection, patients with pulmonary metastases are unlikely to be cured even with aggressive surgical management and should be treated with palliation of symptoms as the main objective., (Copyright © 2010 American Cancer Society.)

Children with relapsed, recurrent or metastatic sarcomas represent a therapeutic challenge for the pediatric oncologist. Strategies for the development of newer therapies for children with these sarcomas have, in the past, been histology-specific. For example, drug development in rhabdomyosarcoma has relied upon the preclinical xenograft model, whereas therapies for pediatric nonrhabdomyosarcomatous soft tissue sarcomas have mostly been derived from adult trials. The progress to date and the tools used in the treatment of advanced pediatric sarcomas will be summarized in this review.

Pediatric undifferentiated soft tissue sarcomas represent a major challenge for pathologists and clinicians. The goal of this study was to identify cases that warranted this diagnosis by current standards of analysis and then determine if there are clinicopathological commonalities that may be useful for diagnosis, management, and prognosis. Eighteen potential patients were identified using the institutional pathology database. Three cases were reclassified as specific sarcomas, and 2 cases had insufficient material for molecular analysis, leaving 13 cases for pathological review and 12 patients for radiological and clinical review. There were 7 males and 6 females. The median age at diagnosis was 11 years (1 month to 16 years). Tumors commonly involved the trunk (7 of 13; 54%) and ranged in size from 1.7 to 14.5 cm (mean, 6.7 cm). Eleven patients received ifosfamide/etoposide chemotherapy and 4 received irradiation. Five-year event-free and overall survival (EFS and OS) rates were 54% and 74%, respectively. The predominant histological pattern was round to plump spindled cells forming sheets (9 of 13; 69%) and severe atypia was associated with decreased survival (P = 0.048). Immunohistochemistry showed positivity for vimentin (92%), CD117 (92%), and vascular endothelial growth factor (69%), and 8% to 23% showed focal positivity for epithelial, neural, or myogenic markers. Tumors were uniformly negative for translocations associated with pediatric sarcomas. The presence of certain common morphological and immunohistochemical features in the absence of specific molecular genetic abnormalities allows for a diagnosis of pediatric undifferentiated soft tissue sarcoma; however, whether this group of neoplasms forms a unique category of tumors or a common precursor pathway for a number of different sarcomas awaits further study.

Non‐osteogenic, non‐Ewing soft‐tissue sarcoma (NONE‐STS) of bone is a rare presentation of primary bone cancers. Optimal treatments and outcomes for this heterogenous group are poorly described. We evaluated the factors associated with long‐term outcomes in patients with this disease. Patients with localized NONE‐STS of bone treated at the Toronto Sarcoma Program from 1987 to 2017 were identified. Clinical characteristics, treatment, and survival information were collected. Kaplan‐Meier (log‐rank) survival estimates from the time of definitive surgery, with uni‐/multivariate analyses (Cox) of sarcoma‐specific survival were performed. A total of 106 patients (60.4% male; median age 46 years) with NONE‐STS of bone were identified. Common histologies included undifferentiated pleomorphic sarcoma [UPS]/malignant fibrous histiocytoma [MFH] (UPS/MFH, 41.5%), leiomyosarcoma (LMS, 20.8%), and fibrosarcoma (FS, 11.3%). Tumors were often high grade (59.4%) and involved the extremities (88.7%), with most receiving chemotherapy (67.9%) with cisplatin/doxorubicin‐based regimens (73.6%). In the full cohort, 10‐year DFS (45.7%, [95%CI: 35.7‐55.8%]), OS (53.4%, [95%CI: 41.7‐62.2%]), and SSS (63.9%, [95%CI: 53.9‐72.5%]) were moderate. Histology specific, 10‐year SSS was 70.7% [95%CI: 56.1‐85.5%] for UPS/MFH, 51.8% [95%CI: 29.8‐73.8%] for LMS, and 72.2% [95%CI: 45.1‐99.2%] for FS. Only UPS/MFH (n = 4) showed sarcoma‐related death >10 years. Multivariate analysis identified axial location (HR = 35.5, [95%CI: 3.4‐369.6]), high grade (HR = 16.9, [95%CI: 1.6‐185.1]), and disease relapse (HR = 485.1, [95%CI: 36.3‐6482.6]) as risk factors for death (p < 0.05). Treatment with chemotherapy (HR = 0.1, [95%CI: 0.01‐0.86]) and necrosis ≥85% (HR = 0.2, [95%CI: 0.04‐0.99]) showed improved survival (p < 0.05). NONE‐STS of bone has favorable long‐term survival similar to osteosarcoma. Patients receiving chemotherapy derive benefit in retrospective analyses. UPS/MFH histologies show sarcoma‐related death beyond 10 years. Further data on histologic subgroups are needed. [ABSTRACT FROM AUTHOR]

Background: Soft-tissue sarcomas in children are a histologically heterogenous group of malignant tumors accounting for approximately 7% of childhood cancers. There is a paucity of data on the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for initial staging and whether PET influenced management of these patients.Objective: The aim of this analysis is to assess the use of 18F-FDG PET exclusively, and as a supplement to cross-sectional imaging in comparison to typical imaging protocols (CT and magnetic resonance imaging [MRI]) for initial staging as well as therapy planning in pediatric soft-tissue sarcoma patients.Materials and Methods: The list of 18F-FDG PET/CT performed for soft-tissue sarcoma between March 2007 and October 2017 was obtained from the Hospital Information System database. Twenty-six patients who had received 18F-FDG PET, MRI and/or CT at initial diagnosis were included in the study. 18F-FDG PET and concurrent diagnostic CT and MRI at initial staging were independently reviewed to note the number of primary and metastatic lesions detected by each modality. A chart review was conducted to collect information on final diagnosis, staging and treatment plan.Results: During the study period, 26 patients (15 females) ages 1.3-17.9 years (median age: 6 years) had received 18F-FDG PET/CT at initial diagnosis of soft-tissue sarcoma. Diagnostic CT was available for comparison in all 26 patients and MRI was available in 18 patients. The mean interval between cross-sectional imaging and 18F-FDG PET was 5.9 days (range: 0-30 days). All 26 primary lesions were equally detected by 18F-FDG PET compared to CT and MRI. From 84 metastatic lesions, 16 were detected by PET as well as CT and MRI, 12 by 18F-FDG PET only (included mainly lymph node metastases) and 56 by CT and MRI only (included mainly lung metastases). 18F-FDG PET changed therapy planning in 5 patients out of 26 (19%) by showing additional lesions not detected by CT and MRI.Conclusion: 18F-FDG PET proved to be a valuable tool for precise initial staging of pediatric soft-tissue sarcoma patients, especially in detecting lymph node metastasis, and could be included in their initial work-up. Given the relative rarity and heterogeneity of this group of tumors, additional investigations are required to definitely establish a role for 18F-FDG PET in the initial staging and therapy planning of soft-tissue sarcoma in the pediatric population. [ABSTRACT FROM AUTHOR]

Malignant hepatic tumors in children are rare, comprising 1.3% of all pediatric malignancies. Following hepatoblastoma, hepatocellular carcinoma is the second most common. Other malignant hepatic tumors seen in childhood include those of mesenchymal origin including undifferentiated embryonal sarcoma, angiosarcoma, rhabdomyosarcoma and epithelioid hemangioendothelioma, as well as biliary tumors such as cholangiocarcinoma. Diagnosis can be challenging because of their rarity, and the recognition of distinctive imaging features for certain tumors such as epithelioid hemangioendothelioma and biliary rhabdomyosarcoma can focus the differential diagnosis and expedite the diagnostic process. A complete MRI examination with hepatocyte-specific contrast media and diffusion-weighted imaging helps to focus the differential diagnosis, and, although findings are often nonspecific, in some cases typical features on MRI can be helpful in diagnosis. Histopathological analysis is usually required for definitive diagnosis. Hepatic tumors tend to be aggressive, and full staging is imperative to establish disease extent. Significant proportions are not amenable to upfront surgical resection and often require a multimodality approach including neoadjuvant chemotherapy within a multidisciplinary setting. Facilitating complete surgical resection is usually required for better survival. In this review, we emphasize pathology and imaging features for rare liver tumors that are useful in reaching a prompt diagnosis. We also discuss general clinical findings, prognosis and management of these tumors. [ABSTRACT FROM AUTHOR]

Ewing‐like sarcomas are an emerging subgroup of small round blue cell sarcomas that share various degrees of morphological, immunohistochemical, molecular, and clinical similarity with Ewing sarcoma. Despite these similarities, Ewing‐like sarcomas lack the pathognomonic molecular hallmark of Ewing sarcoma: A translocation between a gene of the RNA‐binding TET family (EWSR1 or FUS) with a gene of the ETS‐transcription family (FLI1, ERG, ETV1, ETV4, or FEV). Recently, increased use of modern molecular methods based on next‐generation sequencing have enabled the identification of distinct subgroups within this previously uncharacterized group of Ewing‐like sarcomas based on the discovery of novel molecular driving events. The focus of this review is to provide an update on the main subcategories of Ewing‐like sarcomas discovered to date: CIC‐rearranged sarcomas, BCOR‐rearranged sarcomas, sarcomas with a rearrangement between EWSR1 and a non‐ETS family gene, and the substantial fraction of tumors which remain uncharacterized by molecular methods. There is increasing evidence that these tumors represent stand‐alone entities with unique characteristics rather than simply a subgroup of Ewing sarcoma; thus, the question of the best therapeutic approach for these often aggressive sarcomas remains of primary importance. Ultimately, large collaborative efforts will be necessary to better determine the characteristics of this rare, heterogeneous family of tumors. Ewing‐like sarcomas are an emerging subtype of round blue cell tumor. Recent molecular analysis have enabled the discovery of multiple subgroups with potential implications on diagnosis, prognosis, and treatment of these rare neoplastic diseases. [ABSTRACT FROM AUTHOR]

Rhabdomyosarcoma (RMS) represents the most common soft tissue sarcoma in the pediatric age group. While RMS has been traditionally classified on the basis of its histological appearance (with embryonal and alveolar being most common), it is now clear that the PAX-FOXO1 fusion product drives prognosis. We report here a case of pelvic embryonal RMS in a 3-month-old male who was subsequently found to have developed brain metastases during the course of chemotherapy. Cytogenetic analysis of the brain metastases at the time of autopsy as well as next-generation sequencing analysis revealed a reciprocal translocation involving the SH3 domain containing ring finger 3 gene (SH3RF3, on chromosome 2q13) and the Lipase C gene (LIPC, on chromosome 15q21.3). Due to the poor quality of the pretreatment and postresection samples, cytogenetics and NGS analysis looking for the presence of this balanced translocation in these specimens could not be performed. To the authors' knowledge, this translocation has never been described in RMS. Further studies are needed to determine the biological and clinical implications of this novel translocation. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined if differences in therapeutic strategy in pediatric and adult specialty sarcoma centers are associated with clinical outcome. The study reviewed the medical data of patients with Ewing sarcoma (EWS), who were treated between 1990 and 2005 at tertiary care pediatric and adult institutions. It discovered that the doses of alkylating agents and timing of local therapy infleunce clinical outcome in patients with EWS.