Rhabdomyosarcoma (RMS) is the most common pediatric head and neck soft-tissue sarcoma. Intergroup Rhabdomyosarcoma Study I-IV demonstrated that patients with alveolar RMS (ARMS), Group III disease, or clinically involved regional lymph nodes had a worse prognosis. The outcomes and prognostic features of patients with nonorbital, nonparameningeal head and neck (NONPHN) RMS treated in subsequent Children's Oncology Group (COG) trials have not been reported.

Patients enrolled in COG low-risk (D9602 or ARST0331), intermediate-risk (D9803 or ARST0531), and high-risk (D9802, ARST0431, or ARST08P1) trials were included. All patients received chemotherapy. Those with Group I (completely resected) ARMS and those with Group II (microscopic residual) or Group III (macroscopic residual) RMS received 36-50.4 Gy adjuvant radiotherapy (RT).

One hundred seventy-two patients with NONPHN RMS were treated across the seven trials. Most patients had cheek primaries (30%), Group II (38%) or Group III (34%) disease, no clinical or radiological evidence of nodal involvement (N0, 80%), and received RT (70%). The median follow-up was 7.7 years. Five-year event-free survival and overall survival were 70.8% and 83.7%, respectively. The regional failure rate for patients with N0 disease was 2%.

Outcomes for patients with NONPHN RMS were similar to contemporary studies. Despite lower RT target volumes on the ARST-series versus the D-series protocols, patients with Group III tumors maintained comparable outcomes. Low regional failure rates suggested that sentinel lymph node sampling in patients with N0 disease and elective nodal RT in patients with ARMS and N0 disease are not necessary.

Soft tissue sarcomas (STS) are rare mesenchymal tumors representing up to 7% of all cancers in children. In the pediatric population, rhabdomyosarcoma (RMS) is the most common histology while the remainder is composed of several distinct histotypes collectively known as nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). RMS and NRSTS have individualized staging and treatment paradigms. Through cooperative group clinical trials, our understanding of STS and outcomes have improved. However, patients with distant metastases and who relapse continue to fare poorly. Global collaborations are necessary to make greater progress for this highest risk population.

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm that is characterized by a proliferation of myofibroblastic and fibroblastic spindle cells, accompanied by an inflammatory infiltrate that is abundant in plasma cells, lymphocytes, and eosinophils. IMT can arise in various anatomical locations but most commonly occurs in the abdominal cavity, retroperitoneum, and lung, particularly in children and young adults. IMT typically demonstrates local invasion or recurrence, whereas metastasis is rare. IMTs pose a diagnostic challenge because of their overlapping morphological characteristics with a heterogeneous group of nonneoplastic and neoplastic lesions. Precise diagnosis is crucial for optimal management and accurate prognostication. Despite recent advancements in IMT diagnosis and treatment, its biological complexity and clinical management remain challenging due to significant histological heterogeneity and molecular genetic diversity. This review provides comprehensive updates on the clinical, molecular, and pathological characteristics of IMT, highlighting the diagnostic approaches and key differential diagnoses.

Primary pulmonary rhabdomyosarcoma (RMS), a rare soft tissue sarcoma, is characterized by a high recurrence rate and a poor prognosis. This systematic review aims to summarize the clinical characteristics, pathological features, treatment, and clinical outcomes of primary pulmonary RMS, and to analyze prognostic-related risk factors to provide robust evidence for future treatment strategies.

Five databases (MEDLINE, Scopus, the Cochrane Central Register of Controlled Trials, EMBASE, and Web of Science) were searched using the relevant terms including "pulmonary", "lung", "alveolar", "ERMS", "ARMS", "RMS" and "rhabdomyosarcoma". Cases with a definitive pathological diagnosis of RMS, complete treatment information, a minimum follow-up period of at least three months, and detailed follow-up records were included. The primary study endpoints were cancer-specific survival (CSS) and progression-free survival (PFS).

22 articles spanning from 1955 to 2023 met the inclusion criteria for the systematic review. The median patient age was 10.5 (2.0, 52.5) years. 22 cases (78.6%) presented with respiratory symptoms due to pulmonary masses at the initial diagnosis. 10 cases were diagnosed with the embryonal type, and the majority (n = 20, 71.4%) underwent surgical treatment. The average PFS time was 60.9 ± 14.8 months. Patients at TNM stage IV were more prone to progression, and CSS was associated with factors including age ≥ 18 years, primary tumor size ≥ 10 cm, and non-surgical treatment. Surgery was identified as an independent factor that could shorten progression time (HR = 4.58 (1.32-15.90), P = 0.017) and improve tumor-related survival (HR = 8.11 (1.45-45.50), P = 0.017).

Patients with higher TNM stages who did not undergo surgery tended to have more aggressive tumors, whereas primary tumors ≥ 10 cm and ages ≥ 18 years were associated with increased tumor-related mortality. Surgery, the primary treatment modality, independently improved CSS rates. Exploring optimal comprehensive treatment strategies that combine surgery, radiotherapy, and chemotherapy represents the principal direction for future research.

Patients with relapsed rhabdomyosarcoma (RMS) are treated with varying approaches and have a poor overall survival (OS). We performed an observational comparison of salvage regimens exploring whether high-dose alkylator combinations were associated with longer OS.

We categorized 110 patients with relapsed RMS from five institutions into two groups, those treated with regimens including a high-dose alkylator (Group A) and those treated without a high-dose alkylator (Group B). We compared OS between the two, adjusting for risk group at diagnosis and institution using Kaplan-Meier and Cox proportional hazards analyses.

Median follow-up in the 32 survivors was 4 years (range: 1.0-16.7 years) with a 28% (95% CI: 19%-37%) 4-year OS. Group A patients had a longer OS compared to Group B (4-year OS 41%, 95% CI: 27%-58%, vs. 14%, 95% CI: 4%-24%, respectively, p = 0.002). Adjustment for risk group at diagnosis abrogated the association (HR 1.4, 95% CI: 0.8-2.3, p = 0.16), while controlling for institution had no effect. In stratified analyses, patients with low risk at diagnosis had the highest effect size, suggesting a benefit after high-dose alkylator regimens (stratified HR 4.4, 95% CI: 0.96-20.3, p = 0.06, reference Group A) compared to intermediate- (stratified HR 1.6, 95% CI: 0.9-3.2, p = 0.13) or high- (stratified HR 0.9, 95% CI: 0.4-1.8, p = 0.7) risk patients.

Patients with relapsed RMS and low-risk group at diagnosis may benefit from high-dose alkylator chemotherapy, while the high-risk group has a dismal outcome regardless of treatment selection. It is inconclusive whether intermediate-risk patients may benefit from such therapy.

Survivors of pediatric head and neck rhabdomyosarcoma (HNRMS) are at risk of developing endocrinopathies following local treatment, resulting from radiation damage to the pituitary gland, hypothalamus, or thyroid gland, often at a young age. Our aim was to determine the prevalence of endocrine dysfunction in long-term HNRMS survivors and compare the prevalence of anterior pituitary insufficiency (API) among different local treatment strategies: external beam radiation with photons, external beam radiation with protons, microscopically radical surgery combined with external irradiation, and macroscopic radical surgery combined with brachytherapy.

Head and neck rhabdomyosarcoma survivors treated between 1993 and 2017, with ≥2 years of follow-up, without recurrent disease or secondary malignancy were eligible for this study. The presence of any endocrine dysfunction was assessed cross-sectionally using Common Terminology Criteria of Adverse Events grading, anthropometrics, and biochemical testing. Retrospective chart review was added to this clinical assessment.

Ninety-six survivors with long follow-up time (median, 9 years) were included. Any endocrinopathy was present in 35% of survivors, with 88% having pituitary, 6% peripheral (thyroid), and 6% combined insufficiencies. None had gonadal insufficiency. Growth hormone deficiency was diagnosed in 31 (32%) survivors, with additional pituitary insufficiencies in 12 (39%). In 8%, central precocious puberty preceded API. None of the survivors given brachytherapy had API.

The prevalence of pituitary dysfunction in HNRMS survivors is high, emphasizing the importance of systematic endocrine assessment during follow-up, including pubertal development and growth. Efforts should be made to further reduce extraneous irradiation to endocrine organs to prevent dysfunction later in life.

Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma, and 5-year overall survival exceeds 70%. With more long-term survivors, it is critical to understand the frequency of late events, including recurrence, second malignant neoplasm, and death, occurring 5 years after diagnosis, and the variables associated with these events. We report late events in patients enrolled on Intergroup Rhabdomyosarcoma Study Group and Children's Oncology Group trials from 1997 to 2013 including D9602, D9803, D9802, ARST0331, ARST0431, ARST0531, and ARST08P1. A late event occurred in 2.9% of 5-year event-free survivors supporting guidelines to limit surveillance for these events to 5 years from diagnosis.

Rhabdomyosarcoma risk stratification is traditionally determined by tumor histology and staging. Recent studies revealed the importance of molecular features in predicting prognosis. We investigated prognosis by age of onset and mutation incidence in rhabdomyosarcoma tumors.

We retrospectively extracted clinical and genomic data from the Clinomics dataset (n = 641). Inclusion criteria was tumors with at least one gene mutation with >5% mutation incidence. Exclusion criteria were unknown risk stratification and age of onset. Statistical analysis was performed using ANOVA (p < 0.05) and Tukey's HSD to compare mutation incidence, EFS, and OS among age groups.

Among 641 patients with rhabdomyosarcoma, 8 of 39 screened genes had >5% mutation incidence: NRAS, BCOR, NF1, TP53, FGFR4, KRAS, HRAS, and CTNNB1. The final cohort consisted of 370 patients: 51 (Age: 0-2 Years), 140 (Age: 2-5 Years), 112 (Age: 5-12 Years) and 67 (Age: 12+). Later age of onset is associated with higher incidence of BCOR and HRAS mutations (p < 0.005, p < 0.001) and poorer EFS and OS (p < 0.05, p < 0.001). In patients with BCOR mutations, later age of onset is associated with poorer EFS and OS (p < 0.005, p < 0.001). NF1 mutations are equally distributed among age groups (p = 0.82), but later age of onset is associated with poorer EFS and OS (p < 0.005, p < 0.001).

In patients with at least one mutation in BCOR, NF1, TP53, KRAS, HRAS, or CTNNB1, later age of onset is associated with poorer prognosis. In patients with mutations only in tumor suppressor genes BCOR or NF1, later age of onset is associated with poorer prognosis.

Retrospective Cohort Study.

II.

Clinical trials conducted by the Intergroup Rhabdomyosarcoma (RMS) Study Group and the Children's Oncology Group have been pivotal to establishing current standards for diagnosis and therapy for RMS. Recent advancements in understanding the biology and clinical behavior of RMS have led to more nuanced approaches to diagnosis, risk stratification, and treatment. The complexities introduced by these advancements, coupled with the rarity of RMS, pose challenges to conducting large-scale phase 3 clinical trials to evaluate new treatment strategies for RMS. Given these challenges, systematic planning of future clinical trials in RMS is paramount to address pertinent questions regarding the therapeutic efficacy of drugs, biomarkers of response, treatment-related toxicity, and patient quality of life. Herein, the authors outline the proposed strategic approach of the Children's Oncology Group Soft Tissue Sarcoma Committee to the next generation of RMS clinical trials, focusing on five themes: improved novel agent identification and preclinical to clinical translation, more efficient trial development and implementation, expanded opportunities for knowledge generation during trials, therapeutic toxicity reduction and quality of life, and patient engagement.

Failure-free survival (FFS) rates of low-risk patients with rhabdomyosarcoma improved in Intergroup Rhabdomyosarcoma Study IV after the escalation of cyclophosphamide total dose to 26.4 g/m2. However, this dose may increase the risk of adverse events, including infertility, in some patients. The JRS-I LRA0401 and LRB0402 protocols aimed to reduce the cyclophosphamide dose to 9.6 g/m2 and 17.6 g/m2, respectively, without decreasing the FFS rates.

Subgroup-A patients received eight cycles (24 weeks) of vincristine, actinomycin D, and 1.2 g/m2/cycle cyclophosphamide. Subgroup-B patients received eight cycles (24 weeks) of vincristine, actinomycin D, and 2.2 g/m2/cycle cyclophosphamide, followed by six cycles (24 weeks) of vincristine and actinomycin D. Group II/III patients in both subgroups received radiotherapy.

In subgroup A (n = 12), the 3-year FFS rate was 83% (95% confidence interval [CI], 48-96), and the 3-year overall survival (OS) rate was 100%. Only one isolated local recurrence was observed (8.3%). There were no unexpected grade-4 toxicities and no deaths. In subgroup B (n = 16), the 3-year FFS and OS rates were 88% (95% CI, 59-97) and 94% (95% CI, 63-99), respectively. There were no unexpected grade 4 toxicities and no deaths.

Shorter duration therapy using vincristine, actinomycin D, and lower dose cyclophosphamide with or without radiotherapy for patients with low-risk subgroup A rhabdomyosarcoma (JRS-I LRA0401 protocol) and moderate reduction of cyclophosphamide dose for patients with low-risk subgroup B rhabdomyosarcoma (JRS-I LRB0402 protocol) did not compromise FFS.

To describe clinical features, risk factors, and outcomes of patients with perineal and perianal rhabdomyosarcoma.

The records of 51 patients (38 perineal and 13 perianal) enrolled on Children's Oncology Group clinical trials between 1997 and 2012 were reviewed.

At presentation, 53% were female, 65% were older than 10 years of age, 76% were alveolar histology, 76% were more than 5 cm, 84% were invasive, 65% were regional node positive by imaging, 49% were metastatic, only 16% were grossly resected upfront, and 25% of patients had a delayed excision. At a median follow-up of 6.13 years, estimated 5-year event-free survival (EFS) was 38% [22.17%-53.38%], and overall survival (OS) was 42% [26.66%-58.21%]. The rates of local, regional, and distant failure were 15.6%, 13.7%, 43.1%, respectively; all failures ultimately died. By univariate analysis, only age more than 10 years negatively impacted 5-year EFS (p = .023) and OS (p = .09), and IRS Group also impacted OS (p = .043). In Cox proportional hazards model, neither of these variables were significant after adjusting for other factors.

Patients with perineal and perianal rhabdomyosarcoma have a poor overall prognosis, probably related to poor patient and disease characteristics at presentation.

The impact of established prognostic factors on survival outcomes for childhood rhabdomyosarcoma (RMS) have not been well described in the adolescent and young adult (AYA) RMS patient population.

This is a retrospective analysis of patients with newly diagnosed RMS enrolled between 1997 and 2016 on seven previously reported Children's Oncology Group (COG) clinical trials. Demographics, clinical features, treatment details, and outcome data were collected. Five-year event-free survival (EFS) and overall survival (OS) were estimated for patients diagnosed at age 15-39 years and those diagnosed under age 15 years using the Kaplan-Meier method. Log-rank test was used to compare prognostic factors for EFS and OS. Factors significant in the univariable analysis were included in a Cox proportional hazards regression model. Nonsignificant covariates were removed from the multiple regression model.

Total 2151 patients including 402 AYAs were analyzed. AYAs were more likely to present with primary tumors ≥5 cm in size, metastatic disease, alveolar histology, and have FOXO1 fusions compared to children. Five-year EFS for the AYA cohort was 44.2% versus 67% for children (p < .001), and 5-year OS was 52% for the AYA cohort versus 78% for children (p < .001). Multivariable analysis revealed tumor site, size and invasiveness, clinical group, and histology were prognostic in AYAs.

AYAs with RMS have a poorer prognosis compared to younger children due to multiple factors. Further research focused on AYAs to better understand RMS biology and improve treatments is critical to improve survival.

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.

Small round cell neoplasms are diagnostically challenging owing to their clinical and pathologic overlap, necessitating use of large immunopanels and molecular analysis. Ewing sarcomas (ES) are the most common, but EWSR1 is translocated in several diverse neoplasms, some with round cell morphology. Molecular advances enable classification of many tumors previously termed 'atypical ES'. The current WHO Classification includes two new undifferentiated round cell sarcomas (with CIC or BCOR alterations), and a group of sarcomas in which EWSR1 partners with non-Ewing family transcription factor genes. This article reviews the spectrum of small round cell sarcomas within the gastrointestinal tract and abdomen.

In the United States, approximately 850-900 children and adolescents each year are diagnosed with soft tissue sarcomas (STS). STS are divided into rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma STS (NRSTS). RMS and NRSTS are risk stratified into low-, intermediate-, and high-risk categories, with 5-year survival rates of approximately 90%, 50%-70%, and 20%, respectively. Recent key achievements from the Children's Oncology Group (COG) STS Committee include the identification of new molecular prognostic factors for RMS, development and validation of a novel risk stratification system for NRSTS, successful completion of a collaborative NRSTS clinical trial with adult oncology consortia, and collaborative development of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT). Current COG trials for RMS are prospectively evaluating a new risk stratification system that incorporates molecular findings, de-intensification of therapy for a very low-risk subgroup, and augmented therapy approaches for intermediate- and high-risk RMS. Trials for NRSTS exploring novel targets and local control modalities are in development.

Despite the low incidence of soft tissue sarcomas (STSs), hundreds of thousands of new STS cases are diagnosed annually worldwide, and approximately half of them eventually progress to advanced stages. Currently, chemotherapy is the first-line treatment for advanced STSs. There are difficulties in selecting appropriate drugs for multiline chemotherapy, or for combination treatment of different STS histological subtypes. In this study, we first comprehensively reviewed the efficacy of various chemotherapeutic drugs in the treatment of STSs, and then described the current status of sensitive drugs for different STS subtypes. anthracyclines are the most important systemic treatment for advanced STSs. Ifosfamide, trabectedin, gemcitabine, taxanes, dacarbazine, and eribulin exhibit certain activities in STSs. Vinca alkaloid agents (vindesine, vinblastine, vinorelbine, vincristine) have important therapeutic effects in specific STS subtypes, such as rhabdomyosarcoma and Ewing sarcoma family tumors, whereas their activity in other subtypes is weak. Other chemotherapeutic drugs (methotrexate, cisplatin, etoposide, pemetrexed) have weak efficacy in STSs and are rarely used. It is necessary to select specific second- or above-line chemotherapeutic drugs depending on the histological subtype. This review aims to provide a reference for the selection of chemotherapeutic drugs for multi-line therapy for patients with advanced STSs who have an increasingly long survival.

Rhabdomyosarcoma (RMS) of the chest wall presents unique management challenges and local control considerations. The benefit of complete excision is uncertain and must be weighed against potential surgical morbidity. Our aim was to assess factors, including local control modality, associated with clinical outcomes in children with chest wall RMS.

Forty-four children with RMS of the chest wall from low-, intermediate-, and high-risk Children's Oncology Group studies were reviewed. Predictors of local failure-free survival (FFS), event-free survival (EFS), and overall survival (OS) were assessed, including clinical characteristics and staging, primary tumor anatomic locations, and local control modalities. Survival was assessed by Kaplan-Meier analysis and the log-rank test.

Tumors were localized in 25 (57%) and metastatic in 19 (43%), and they involved the intercostal region (52%) or superficial muscle alone (36%). Clinical group was I (18%), II (14%), III (25%), and IV (43%), and ultimately 19 (43%) patients had surgical resection (upfront or delayed), including 10 R0 resections. Five-year local FFS, EFS, and OS were 72.1%, 49.3%, and 58.5%, respectively. Univariate factors associated with local FFS included age, International Rhabdomyosarcoma Study (IRS) group, extent of surgical excision, tumor size, superficial tumor location, and presence of regional or metastatic disease. Other than tumor size, the same factors were associated with EFS and OS.

Chest wall RMS has variable presentation and outcome. Local control is a significant contributor to EFS and OS. Complete surgical excision, whether upfront or after induction chemotherapy, is usually only possible for smaller tumors confined to the superficial musculature but is associated with improved outcomes. While overall outcomes remain poor for patients with initially metastatic tumors, regardless of local control modality, complete excision may be beneficial for patients with localized tumors if it can be achieved without excess morbidity.

Extremity rhabdomyosarcoma (RMS) is associated with a very poor outcome compared with other sites, mainly because of its high incidence of alveolar histology and regional lymph node involvement. To better define prognostic markers in this clinical subset, we investigated our experience of 61 patients with extremity RMS treated at our tertiary cancer center for the past 2 decades.

The patients had a median age of 8 years at diagnosis, equal gender distribution, and two-thirds occurred in the lower extremity. Most (85%) patients had FOXO1 fusion-positive alveolar RMS (ARMS), with 70% having a PAX3::FOXO1 transcript. Remaining were seven patients with fusion-negative embryonal RMS (ERMS) and two with MYOD1-mutant spindle cell/sclerosing RMS (SRMS). In 40% of the patients, material was available for DNA-based targeted sequencing using MSK-IMPACT cancer gene panel.

One-third of patients presented with localized disease at diagnosis while the remaining had regional nodal (18%) or distant metastases (51%). Metastatic disease, high-risk group, and age 10 years or older significantly affected the overall survival (OS; hazard ratio [HR], 2.68 [P = .004], 2.78 [P = .010] and 2.26 [P = .034], respectively). Although the presence of metastatic disease had a dismal impact on 5-year EFS and OS (19% and 29%, respectively), nodal involvement had a comparatively lower impact on 5-year EFS and 5-year OS (43% and 66%, respectively). PAX3::FOXO1 ARMS had worse prognosis and afflicted older children compared with PAX7::FOXO1 (HR = 3.45, P = .016). The most common events in the ARMS group included MED12 alterations, CDK4 amplifications, and CDKN2A deletions (8%-17%). The latter two abnormalities were mutually exclusive, enriched for acral and high-risk lesions, and correlated with poor outcome on OS (P = .02).

Our data provide rationale for considering the integration of molecular abnormalities to refine risk stratification in extremity RMS.

To determine outcomes of children with rhabdomyosarcoma (RMS) with isolated lung metastases.

Data were analyzed for 428 patients with metastatic RMS treated on COG protocols. Categorical variables were compared using Chi-square or Fisher's exact tests. Event-free survival (EFS) and overall survival (OS) were estimated using Kaplan-Meier method and compared using the log-rank test.

Compared with patients with other metastatic sites (n = 373), patients with lung-only metastases (n = 55) were more likely to be <10 years of age, have embryonal histology (embryonal rhabdomyosarcoma), have N0 disease, and less likely to have primary extremity tumors. Lung-only patients had significantly better survival outcomes than patients with all other sites of metastatic disease (p < .0001) with 5-year EFS of 48.1 versus 18.8% and 5-year OS of 64.1 versus 26.9%. Patients with lung-only metastases, and those with a single extrapulmonary site of metastasis, had better survival compared with patients with two or more sites of metastatic disease (p < .0001). In patients with ERMS and lung-only metastases, there was no significant difference in survival between patients ≥10 years and 1-9 years (5-year EFS: 58.3 vs. 68.2%, 5-year OS: 66.7 vs. 67.7%).

With aggressive treatment, patients with ERMS and lung-only metastatic disease have superior EFS and OS compared with patients with other sites of metastatic disease, even when older than 10 years of age. Consideration should be given to including patients ≥10 years with ERMS and lung-only metastases in the same group as those <10 years in future risk stratification algorithms.

Racial and ethnic disparities have been demonstrated in pediatric and adult cancers. However, there is no consensus on whether such disparities exist in the presentation, treatment, and outcome of patients with rhabdomyosarcoma (RMS).

Patient information from the seven most recent RMS clinical trials was obtained from the Children's Oncology Group (COG). Chi-squared analyses were used to compare patient, tumor, and treatment characteristics across racial and ethnic groups. Pairwise analyses comparing Non-Hispanic Black (NHB) versus Non-Hispanic White (NHW) racial groups and Hispanic versus NHW ethnic groups were conducted for significant characteristics. Kaplan-Meier method and Wilcoxon signed-rank tests were performed to analyze outcomes.

In the overall cohort (n = 2157), patients' self-identified race/ethnicity was: 0.4% American Indian/Alaska Native, 2.6% Asian, 12.6% Hispanic, 0.2% Native American/other Pacific Islander, 12.8% NHB, 61.9% NHW, and 9.6% unknown. Six characteristics differed by race/ethnicity: age, histology, IRS group, invasiveness, metastatic disease, and FOXO1 fusion partner. Five were significant in pairwise comparisons: NHB patients were more likely to present at age ≥ 10 years and with invasive tumors than NHW patients; Hispanic patients were more likely to present with alveolar histology, metastatic disease, and IRS group IV disease than NHW patients. No differences were found in event free or overall survival of the entire cohort, in risk group-based subset analyses, or among patients with high-risk characteristics significant on pairwise analysis.

While NHB and Hispanic patients enrolled in COG trials presented with higher risk features than NHW patients, there were no outcome differences by racial or ethnic group.

Orbital rhabdomyosarcoma (ORMS) commonly presents as low-risk disease (stage 1, group I-III, embryonal RMS) with excellent outcome. Long-term follow-up of patients with low-risk ORMS and outcomes of less common subgroups of ORMS treated on recent Children's Oncology Group (COG) trials have not been reported.

Patients with ORMS enrolled on COG trials from 1997 to 2013 were identified. Demographic information and disease characteristics were collected. Outcomes were determined for the following subgroups: 1) low-risk ORMS, 2) resected (group I/II) low-risk ORMS, 3) non-low-risk ORMS, and 4) recurrent ORMS. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method. ResultsThe authors identified 218 patients with ORMS. Most tumors were embryonal/botryoid (n = 169; 77.5%), <5 cm (n = 213; 97.7%), group III (n = 170; 78.0%), and without lymph node involvement (N0; n = 215; 98.6%). For 192 patients with low-risk ORMS, the 10-year EFS and OS rates were 85.5% (95% confidence interval [CI], 77.0%-94.0%) and 95.6% (95% CI, 90.8%-100.0%), respectively. Those with group I/II low-risk ORMS (n = 5 in group I; n = 39 in group IIA) had 10-year EFS and OS rates of 88.0% (95% CI, 72.6%-100.0%) and 97.6% (95% CI, 90.0%-100.0%), respectively. Twenty-six patients with non-low-risk ORMS had 5-year EFS and OS rates of 88.5% (95% CI, 75.6%-100.0%) and 95.8% (95% CI, 87.7%-100.0%), respectively. For patients with recurrent ORMS, the 10-year OS rate from the time of recurrence was 69.4% (95% CI, 50.0%-88.8%).

Patients with ORMS had favorable long-term survival outcomes on COG studies from 1997 to 2013, including those who had both low-risk and non-low-risk disease. A significant proportion of patients with recurrent ORMS may achieve long-term survival.

The International Soft-Tissue Sarcoma Consortium (INSTRuCT) was founded as an international collaboration between different pediatric soft-tissue sarcoma cooperative groups (Children's Oncology Group, European Pediatric Soft-Tissue Sarcoma Group, and Cooperative Weichteilsarkom Studiengruppe). Besides other tasks, a major goal of INSTRuCT is to develop consensus expert opinions for best clinical treatment. This consensus paper for patients with rhabdomyosarcoma of the female genital tract (FGU-RMS) provides treatment recommendations for local treatment, long-term follow-up, and fertility preservation. Therefore, a review of the current literature was combined with recommendations of the treatment protocols of the appropriate clinical trials. Additionally, opinions of international FGU-RMS experts were incorporated into recommendations. Results were that the prognosis of FGU-RMS is favorable with an excellent response to chemotherapy. Initial complete surgical resection is not indicated, but diagnosis should be established properly. In patients with tumors localized at the vagina or cervix demonstrating incomplete response after induction chemotherapy, local radiotherapy (brachytherapy) should be carried out. In patients with persistent tumors at the corpus uteri, hysterectomy should be performed. Fertility preservation should be considered in all patients. In conclusion, for the first time, an international consensus for the treatment of FGU-RMS patients could be achieved, which will help to harmonize the treatment of these patients in different study groups.

Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide.

The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination.

Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose oral cyclophosphamide, and one study evaluated vinorelbine and intravenous cyclophosphamide in combination with temsirolimus or bevacizumab. All RMS patients had relapsed or refractory disease and had received at least one prior therapy. Response was reported according to RECIST1.1 and was defined as a complete or partial response. Response data was obtained from published results or from trial principal investigator. RMS NOS patients were grouped with ERMS patients for this analysis. Summary estimates comparing differences between ARMS and ERMS response rates were generated using a random-effects model to account for heterogeneity among the studies.

One hundred fifty-six enrolled patients evaluable for response were included in the meta-analysis, 85 ARMS, 64 ERMS and 7 RMS-NOS. The combined effect generated from the random-effects model demonstrated a 41% increase (p = 0.001, 95% CI; 0.21-0.60) in response to vinorelbine as a single agent or in combination in patients with ARMS compared to patients with ERMS. There was no significant difference in the rate of progressive disease between patients with ARMS compared to ERMS (p = 0.1, 95%CI; -0.26-0.02).

Vinorelbine is an active agent for the treatment of relapsed or refractory RMS and a meta-analysis of Phase 2 studies shows that radiographic responses in patients with ARMS were significantly higher than ERMS or RMS-NOS.

These data support further investigation of vinorelbine in newly diagnosed patients with RMS particularly those with alveolar histology.

While factors influencing outcomes of rhabdomyosarcoma (RMS) in developed countries have evolved from clinical characteristics to molecular profiles, similar data from developing countries are scarce. This is a single-centre analysis of outcomes in treated cases of RMS, with emphasis on prevalence, risk-migration and prognostic impact of Forkhead Box O1 (FOXO1) in non-metastatic RMS. All children with histopathologically proven RMS, treated between January 2013 and December 2018 were included. Intergroup Rhabdomyosarcoma Study-4 risk stratification was used, with treatment based on a multimodality-regimen with chemotherapy (Vincristine/Ifosfamide/Etoposide and Vincristine/Actinomycin-D/Cyclophosphamide) and appropriate local therapy. Formalin-fixed paraffin-embedded tissues were tested using Reverse Transcriptase-Polymerase Chain Reaction for FOXO1-fusions (PAX3(P3F); PAX7(P7F)). A total of 221 children (Cohort-1) were included, of which 182 patients had non-metastatic disease (Cohort-2). Thirty-six (16%), 146 (66%), 39 (18%) patients were low-risk (LR), intermediate-risk (IR) and high-risk, respectively. FOXO1-fusion status was available in 140 patients with localised RMS (Cohort 3). P3F and P7F were detected in 25/49 (51%) and 14/85 (16.5%) of alveolar and embryonal variants, respectively. The 5-year-event-free survival (EFS)/overall survival (OS) of Cohorts 1, 2 and 3 was 48.5%/55.5%, 54.6%/62.6% and 55.1%/63.7%, respectively. Amongst the localised RMS, presence of nodal metastases and primary tumour size > 10 cms were adverse prognostic factorvs (p < 0.05). On incorporating fusion-status in risk-stratification, 6/29 (21%) patients migrated from LR (A/B) to IR. All patients who re-categorised as LR (FOXO1 negative) had a 5-year EFS/OS of 80.81%/90.91%. FOXO1-negative tumours had a better 5-year relapse-free survival (58.92% versus 44.63%; p = 0.296) with a near-significant correlation in favourable-site tumours (75.10% versus 45.83%; p = 0.063). While FOXO1-fusions have superior prognostic utility compared to histology alone in localised, favourable-site RMS, traditional prognostic factors (tumour size and nodal metastases) impacted outcome the most in this subset. Strengthening of early referral systems in community and timely local intervention can help in improving outcome in resource-constrained countries.

A 3-year-old boy developed proptosis over 3 weeks. CT and MRI disclosed a 3.2 × 1.9 cm soft-tissue mass of the right extraconal and intraconal orbit with sphenoid bone erosion. After debulking through an upper eyelid crease incision, the tumor was diagnosed as a spindle cell/sclerosing rhabdomyosarcoma. DNA sequencing was negative for an L122R mutation in MyoD1 . Spindle cell/sclerosing rhabdomyosarcoma is an uncommon variant of this neoplasm, and only 2 patients with orbital tumors have been reported in 2 case series. Spindle cell/sclerosing rhabdomyosarcomas confined to the orbit are considered to have an excellent prognosis when treated with chemotherapy and radiation therapy. Diagnosis and treatment planning rely on histology, immunohistochemistry, and molecular analysis.

Introduction: Metronomic maintenance therapy (MMT) has significantly improved the survival of patients with high-risk rhabdomyosarcoma in clinical trials. However, there remains a lack of relevant data on its effectiveness in real-world situations. Methods: We retrospectively retrieved data of 459 patients < 18 years of age diagnosed with rhabdomyosarcoma at Sun Yat-sen University Cancer Center from January 2011 to July 2020 from our database. The MMT regimen was oral vinorelbine 25-40 mg/m² for twelve 4-week cycles on days 1, 8, and 15, and oral cyclophosphamide 25-50 mg/m² daily for 48 consecutive weeks. Results: A total of 57 patients who underwent MMT were included in the analysis. The median follow-up time was 27.8 (range: 2.9-117.5) months. From MMT to the end of follow-up, the 3-year PFS and OS rates were 40.6% ± 6.8% and 58.3% ± 7.2%, respectively. The 3-year PFS was 43.6% ± 11.3% in patients who were initially diagnosed as low- and intermediate-risk but relapsed after comprehensive treatment (20/57), compared with 27.8% ± 10.4% in high-risk patients (20/57) and 52.8% ± 13.3% in intermediate-risk patients who did not relapse (17/57). The corresponding 3-year OS for these three groups was 65.8% ± 11.4%, 50.1% ± 12.9%, and 55.6% ± 13.6%, respectively. Conclusion: We present a novel study of MMT with oral vinorelbine and continuous low doses of cyclophosphamide in real-world pediatric patients with RMS. Our findings showed that the MMT strategy significantly improved patient outcomes and may be an effective treatment for high-risk and relapsed patients.

The survival of patients with localized embryonal rhabdomyosarcoma (RMS) completely resected at diagnosis is greater than 90%. Most patients have paratesticular, uterine, or vaginal RMS, limiting specific analyses of RMS localized in other anatomic regions. This international study was conducted to define the outcome for completely resected embryonal RMS at sites other than paratesticular, uterine, or vaginal primary sites.

A total of 113 patients aged 0-18 years were identified who were enrolled from January 1995 to December 2016 in Children's Oncology Group (COG) (64 patients) and European protocols (49). Genitourinary nonbladder and prostate RMS were excluded. The recommended chemotherapy was vincristine and actinomycin-D (VA) for 24 weeks or ifosfamide plus VA in the European protocols and VA for 48 weeks or VA plus cyclophosphamide in the COG protocols.

The most common primary sites were nonparameningeal head and neck (40.7%), other (23.9%), and extremities (20.4%). In the COG studies, 42% of patients received VA and 58% VA plus cyclophosphamide. In Europe, 53% received VA and 47% ifosfamide plus VA. With a median follow-up of 97.5 months, the 5-year progression-free and overall survival was 80.0% (71.2%-86.4%) and 92.5% (85.6%-96.2%), respectively, without significant differences between chemotherapy regimens. Tumor size (< or >5 cm) significantly influenced overall survival: 96.2% (88.6%-98.8%) vs. 80.6% (59.5%-91.4%), respectively (p = .01).

Survival of patients with nonalveolar RMS completely resected at diagnosis is excellent among tumors arising from nonparatesticular, uterine, and vaginal sites, and patients may be treated successfully with low-intensity chemotherapy. To reduce the burden of treatment, VA for 24 weeks may be considered in children with tumors <5 cm.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence that includes FP-RMS, harboring the fusion oncoprotein PAX3/7-FOXO1 and FN-RMS, often mutant in the RAS pathway. Risk stratifications of RMS patients determine different prognostic groups and related therapeutic treatment. Current multimodal therapeutic strategies involve surgery, chemotherapy (CHT) and radiotherapy (RT), but despite the deeper knowledge of response mechanisms underpinning CHT treatment and the technological improvements that characterize RT, local failures and recurrence frequently occur. This review sums up the RMS classification and the management of RMS patients, with special attention to RT treatment and possible radiosensitizing strategies for RMS tumors. Indeed, RMS radioresistance is a clinical problem and further studies aimed at dissecting radioresistant molecular mechanisms are needed to identify specific targets to hit, thus improving RT-induced cytotoxicity.

Vincristine is an essential component of rhabdomyosarcoma treatment. However, it can cause motor neurotoxicity, necessitating dose reductions. We retrospectively reviewed the rates and patterns of vincristine-induced motor neuropathy in children treated for rhabdomyosarcoma, and investigated effects on outcome. Fifteen of 43 patients (35%) developed motor neuropathies necessitating dose reductions, which ranged from 1.7% to 58% of planned cumulative dose. Older age was the only significant clinical risk factor. Almost half (47%) recovered during treatment with subsequent dose escalation. Most patients had complete resolution of symptoms upon follow-up. There was no discernible effect of treatment reduction on survival or relapse rates.

There is limited data available on the treatment outcomes of pediatric rhabdomyosarcoma (RMS) in Asian populations. Therefore, we aimed to review the baseline characteristics, clinical outcomes, and prognostic factors in children with RMS from Thailand.

The data of children under 15 years of age diagnosed with RMS between 2003 and 2019 from a large tertiary hospital in Southern Thailand were retrospectively reviewed. Descriptive statistics were utilized to describe the clinical characteristics. The Kaplan-Meier method was utilized to estimate survival. Cox proportional hazards regression analysis was utilized to determine prognostic factors that affect survival.

A total of 42 children RMS were included in this study. The median age at diagnosis was 6.4 years (IQR, 2.4-10.2). Among these patients, 11 (26%) were older than 10 years, and 13 (31%) presented with metastatic disease at diagnosis. The 5-year overall survival (OS) rate was 39% for all children. Age greater than 10 years (hazard ratio (HR): 3.3, 95% CI: 1.2-9.2) and metastatic disease at diagnosis (hazard ratio (HR): 2.8, 95% CI: 1.1-7.5) were independently associated with poorer survival. The 3-year OS for children with metastatic disease (stage IV) was 15% (95% CI: 4.3-55).

The percentage of metastatic disease in our cohort was higher than that in previous reports and may have contributed to a poorer outcome. Age greater than 10 years and metastatic disease at diagnosis were noted as adverse prognostic factors.

The Children's Oncology Group (COG) uses Clinical Group (CG) and modified Tumor Node Metastasis (TNM) stage to classify rhabdomyosarcoma (RMS). CG is based on surgicopathologic findings and is determined after the completion of initial surgical procedure(s) but prior to chemotherapy and/or radiation therapy. The modified TNM stage is based on clinical and radiographic findings and is assigned prior to any treatment. These systems have evolved over several decades. We review the history, evolution, and rationale behind the current CG and modified TNM classification systems used by COG for RMS. Data from the seven most recently completed and reported frontline COG trials (D9602, D9802, D9803, ARST0331, ARST0431, ARST0531, ARST08P1) were analyzed, and confirm that CG and modified TNM stage remain relevant and useful for predicting prognosis in RMS. We propose updates based on recent data and discuss factors warranting future study to further optimize these classification systems.

Pediatric sarcomas constitute one of the largest groups of childhood cancers, following hematopoietic, neural, and renal lesions. Partly because of their diversity, they continue to offer challenges in diagnosis and treatment. In spite of the diagnostic, nosologic, and therapeutic gains made with genetic technology, newer means for investigation are needed. This article reviews emerging technology being used to study human neoplasia and how these methods might be applicable to pediatric sarcomas. Methods reviewed include single cell RNA sequencing (scRNAseq), spatial multi-omics, high-throughput functional genomics, and clustered regularly interspersed short palindromic sequence-Cas9 (CRISPR-Cas9) technology. In spite of these advances, the field continues to be challenged by a dearth of properly annotated materials, particularly from recurrences and metastases and pre- and post-treatment samples.

Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population with variable overall survival rates ranging between approximately 6% and 100% depending on defined risk factors. Although the risk stratification of patients has been refined across five decades of collaborative group studies, molecular prognostic biomarkers beyond FOXO1 fusion status have yet to be incorporated prospectively in upfront risk-based therapy assignments. This review describes the evolution of risk-based therapy and the current risk stratification, defines a new risk stratification incorporating novel biomarkers, and provides the rationale for the current and upcoming Children's Oncology Group RMS studies.