High-dose chemotherapy for Ewing sarcoma and Rhabdomyosarcoma: A systematic review by the Australia and New Zealand sarcoma association clinical practice guidelines working party.

INTRODUCTION: Patients with high-risk or metastatic Ewing sarcoma (ES) and rhabdomyosarcoma (RMS) have a guarded prognosis. High-dose chemotherapy (HDT) with autologous stem cell transplant (ASCT) has been evaluated as a treatment option to improve outcomes. However, survival benefits remain unclear, and treatment is associated with severe toxicities. METHODS: A systematic review was conducted, using the population, intervention, comparison outcome (PICO) model, to evaluate whether utilization of HDT/ASCT impacts the outcome of patients with ES and RMS compared to standard chemotherapy alone, as part of first line treatment or in the relapse setting. Medline, Embase and Cochrane Central were queried for publications from 1990 to October 2022 that evaluated event-free survival (EFS), overall survival (OS), and toxicities. Each study was screened by two independent reviewers for suitability. A qualitative synthesis of the results was performed. RESULTS: Of 1,172 unique studies screened, 41 studies were eligible for inclusion with 29 studies considering ES, 10 studies considering RMS and 2 studies considering both. In ES patients with high-risk localised disease who received HDT/ASCT after VIDE chemotherapy, consolidation with melphalan-based HDT/ASCT as first line therapy conveyed an EFS and OS benefit over standard chemotherapy consolidation. Efficacy of HDT/ASCT using a VDC/IE backbone, which is now standard care, has not been established. Survival benefits are not confirmed for ES patients with metastatic disease at initial diagnosis. For relapsed/refractory ES, four retrospective studies report improvement in outcomes with HDT/ASCT with the greatest evidence in patients who demonstrate a treatment response before HDT, and in patients under the age of 14. In RMS, there is no proven survival benefit of HDT/ASCT in primary localised, metastatic or relapsed disease. CONCLUSION: Prospective randomised trials are required to determine the utility of HDT/ASCT in ES and RMS. Selected patients with relapsed ES could be considered for HDT/ASCT.

Potential Mechanisms of Melatonin in Osteosarcoma and Bone-Related Neoplasms: Updated Review.

Melatonin (N-acetyl-5-methoxytryptamine) is a secretory product of the pineal gland. A great number of studies have been investigating the functions of this indoleamine in various diseases. Excessive proliferation, reduction in apoptosis, increased angiogenesis, invasion, and metastasis are all processes associated with cancerous tissues. In several cancer types, melatonin is reported to significantly impact these processes. Although bone cancer is relatively rare, it is a serious disease that often becomes metastatic, leading to an unsatisfactory prognosis. In recent decades, significant advances have been made in the therapeutic strategies for bone cancer. Nevertheless, few changes have occurred to patients' outcomes or therapeutic methods. Currently used therapeutic strategies including chemotherapy and radiotherapy often show serious side effects. Moreover, therapeutic options are not sufficient in certain cases, such as metastatic forms of the disease. Therefore, there is a need for a more precise definition of the molecular pathways and cellular functions associated with bone cancer to find novel therapeutic approaches. With such advances, the development of new effective therapies for patients with advanced stage or metastatic forms of the disease will be achieved, resulting in an improved prognosis. This review summarizes what is known about the functions of melatonin in osteosarcoma and Ewing's sarcoma. We explain the underlying mechanisms of action by which melatonin serves as an antitumor agent in bone cancer as well as provide an insight into its synergistic effects with other chemotherapeutic drugs.

Long-term Outcome of Acral Ewing Sarcoma.

BACKGROUND/AIM: Ewing sarcoma is a common primary bone tumor, often located in the distal femur or pelvis. Acral Ewing sarcoma of the upper extremity is exceedingly rare. The aim of this study was to review our institution's experience with the management of rare acral Ewing sarcomas. PATIENTS AND METHODS: We retrospectively reviewed the records of 10 patients with bony Ewing sarcomas located distal to the elbow joint. The group included 9 male and 1 female patient with a mean age at diagnosis of 20±12 years and a mean follow-up of 19 years. RESULTS: All patients presented with a primary complaint of a painful mass. The most common location was the metacarpal (n=4). Patients were treated with chemotherapy and either surgery (n=7) or definitive radiotherapy (n=3). The mean tumor size and necrosis on the resected specimens were 4±1 cm and 87% (range=30-100%), respectively. There was one case of local progression in a patient treated with definitive radiotherapy, which led to an amputation. Four patients developed metastatic disease, most commonly to the lungs. The 5-year survival free of metastatic disease or death due to disease was 55% and 60%, respectively. CONCLUSION: Acral Ewing sarcoma is rare. Combined chemotherapy and surgery lead to definitive local control in all patients, with an acceptable functional outcome.

Pelvic Ewing sarcoma: Should all patients receive pre-operative radiotherapy, or should it be delivered selectively?

BACKGROUND: Locally recurrent disease following surgical resection of Ewing sarcoma (ES) confers a poor prognosis. Limited evidence is available evaluating non-selective use of pre-operative radiotherapy (RT) for patients with pelvic ES and its effect on local control and survival. PATIENTS AND METHODS: 49 consecutive patients with pelvic ES were identified retrospectively from a prospectively collated database. Patients either received non-selective pre-operative RT and surgery (n = 27), or selective post-operative RT (n = 22) (surgery alone (n = 11) or surgery and post-operative RT (n = 11)). RESULTS: Patients who had non-selective pre-operative radiotherapy appeared to have a higher LRFS, 88.0% compared to 66.5% in the selective RT group (p = 0.096, Kaplan Meier; p = 0.028, Chi-squared). Administration of non-selective, pre-operative RT to all patients with pelvic ES elevates the LFRS to that of the good responder group (≥90% tumour necrosis and margins, p = 0.880). There was no difference in metastasis-free survival, 60.0% and 54.5% (p = 0.728) and overall survival (OS), 57.7% and 63.6% (p = 0.893). The majority of pre-operative RT patients had both good necrosis (≥90%) (p = 0.003) and widely excised tumours, 81.5% vs 59.1% (p = 0.080). Tumour volume ≥250 ml was associated with worse LRFS (p = 0.045) and post-operative complications (p = 0.017). There may be improved LRFS (p = 0.057) with pre-operative proton-beam RT compared to surgery and selective post-operative RT. CONCLUSION: Pre-operative photon or proton-beam RT to all pelvic ES may improve LRFS compared to the selective delivery of post-operative RT. Radiotherapy delivered to all patients results in a greater percentage of highly necrotic tumours at surgical excision, enabling a greater proportion of patients with wide resection margins.

Inactivation of ICAM1 inhibits metastasis and improves the prognosis of Ewing's sarcoma.

BACKGROUND: Ewing's sarcoma (ES) is a kind of malignant tumor, which often occurs in the long bone, pelvis, and other bone tissues, as well as some soft tissues. It often occurs in children and adolescents, second only to osteosarcoma and rhabdomyosarcoma. In the past 30 years, little progress has been made on the genomic mechanism of ES metastasis. METHODS: The gene expression sequence of ES metastasis samples was compared with that of primary tumor samples to obtain differentially expressed genes (DEGs). Subsequently, we annotated the gene functions and enriched pathways of DEGs. Additionally, the protein and protein interaction network were constructed to screen key genes that can lead to the metastasis in ES. Then, cell and molecular biology experiments were conducted to verify the results obtained from the bioinformatics analysis. Finally, we assessed the correlation of expression between the key genes EWSR and FLI1, and conducted a survival analysis of ICAM1. RESULTS: Our study revealed 153 DEGs. Of these, 82 (53.59%) were upregulated and the remaining 71 (46.41%) were downregulated. The bioinformatics analysis showed that ICAM1 was the key gene leading to the invasion and metastasis of ES. Through cell biology and molecular biology experiments, inactivation of ICAM1 inhibited the metastasis of ES cells. The survival and correlation analyses showed that ICAM1 was a risk factor in patients with ES, and that ICAM1 expression was correlated with EWSR and FLI1 expression. CONCLUSION: Our study shows that inactivation of ICAM1 inhibits metastasis and improves the prognosis of ES. Additionally, our findings provide a better understanding of the underlying mechanisms of metastatic ES, a basis for an accurate diagnosis, and therapeutic targets for ES patients.

Exosomes in Bone Sarcomas: Key Players in Metastasis.

Bone sarcomas are rare cancers which often present with metastatic disease and are still associated with poor survival rates. Studies in the last decade have identified that exosomes, a type of extracellular vesicle released by cells, play an important role in tumour progression and dissemination. Through the transfer of their cargo (RNAs, proteins, and lipids) across cells, they are involved in cellular cross-talk and can induce changes in cellular behaviour. Exosomes have been shown to be important in metastasis organotropism, induction of angiogenesis and vascular permeability, the education of cells towards a pro-metastatic phenotype or the interaction between stromal and tumour cells. Due to the importance exosomes have in disease progression and the high incidence of metastasis in bone sarcomas, recent studies have evaluated the implications of these extracellular vesicles in bone sarcomas. In this review, we discuss the studies that evaluate the role of exosomes in osteosarcoma, Ewing sarcoma, and preliminary data on chondrosarcoma.

Use of 3-Dimensional Printing Technology in Complex Spine Surgeries.

BACKGROUND: Medical implications of 3-dimensional (3D) printing technology have evolved and are increasingly used. Surgical spine oncology involves at times complex resection using various surgical approaches and unique spinal reconstruction. As high general complication rates, including hardware failure, are reported, careful preoperative planning and optimized fixation techniques should be performed. 3D printing technology allows the improvement of preoperative planning, practice and exploration of various surgical approaches, and designing customized surgical tools and patient specific implants. OBJECTIVE: To investigate the use of 3D printing technology in complex spine surgeries. METHODS: Between 2015 and 2018, all complex spine oncological cases were evaluated and assessed for the possible benefit of use of 3D printing technology. Following high-quality imaging, a computerized integrated 3D model was created. Based on the planned procedure considering the various surgical steps, a customized 3D model was planned and printed, and in select cases a 3D custom-made implant was designed and printed in various sizes with matching trials. RESULTS: A total of 7 cases were selected for the use of a 3D printing technology. For all, a custom-made model was created. In 3 of these cases, a customized 3D-printed implant was used. Special customized intraoperative instruments were made for 2 cases, and a simulated surgical approach was performed in 5 cases. In 2 cases, pre-bent rods were made based on the model created and were used in surgery later on. CONCLUSIONS: For complex spine oncology cases, the use of 3D printing allowed better preoperative planning, simplified the operative procedure, and enabled improved reconstruction.

Focal adhesion kinase confers pro-migratory and antiapoptotic properties and is a potential therapeutic target in Ewing sarcoma.

Oncogenesis of Ewing sarcoma (EwS), the second most common malignant bone tumor of childhood and adolescence, is dependent on the expression of chimeric EWSR1-ETS fusion oncogenes, most often EWSR1-FLI1 (E/F). E/F expression leads to dysregulation of focal adhesions (FAs) enhancing the migratory capacity of EwS cells. Here, we show that, in EwS cell lines and tissue samples, focal adhesion kinase (FAK) is expressed and phosphorylated at Y397 in an E/F-dependent way involving Ezrin. Employing different EwS cell lines as in vitro models, we found that key malignant properties of E/F are mediated via substrate-independent autophosphorylation of FAK on Y397. This phosphorylation results in enhanced FA formation, Rho-dependent cell migration, and impaired caspase-3-mediated apoptosis in vitro. Conversely, treatment with the FAK inhibitor 15 (1,2,4,5-benzenetetraamine tetrahydrochloride (Y15) enhanced caspase-mediated apoptosis and EwS cell migration, independent from the respective EWSR1-ETS fusion type, mimicking an anoikis-like phenotype and paralleling the effects of FAK siRNA knockdown. Our findings were confirmed in vivo using an avian chorioallantoic membrane model and provide a first rationale for the therapeutic use of FAK inhibitors to impair metastatic dissemination of EwS.

High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008.

PURPOSE: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Individual risk evaluation for local recurrence and distant metastasis in Ewing sarcoma: A multistate model: A multistate model for Ewing sarcoma.

BACKGROUND: We investigated the effects of surgical margins, histological response, and radiotherapy on local recurrence (LR), distant metastasis (DM), and survival in Ewing sarcoma. PROCEDURE: Disease evolution was retrospectively studied in 982 patients with Ewing sarcoma undergoing surgery after chemotherapy using a multistate model with initial state surgery, intermediate states LR, pulmonary metastasis (DMpulm), other DM ± LR (DMother), and final state death. Effect of risk factors was estimated using Cox proportional hazard models. RESULTS: The median follow-up was 7.6 years (95% CI, 7.2-8.0). Risk factors for LR are pelvic location, HR 2.04 (1.10-3.80), marginal/intralesional resection, HR 2.28 (1.25-4.16), and radiotherapy, HR 0.52 (0.28-0.95); for DMpulm the risk factors are <90% necrosis, HR 2.13 (1.13-4.00), and previous pulmonary metastasis, HR 4.90 (2.28-8.52); for DMother are 90% to 99% necrosis, HR 1.56 (1.09-2.23), <90% necrosis, HR 2.66 (1.87-3.79), previous bone/other metastasis, HR 3.08 (2.03-4.70); and risk factors for death without LR/DM are pulmonary metastasis, HR 8.08 (4.01-16.29), bone/other metastasis, HR 10.23 (4.90-21.36), and <90% necrosis, HR 6.35 (3.18-12.69). Early LR (0-24 months) negatively influences survival, HR 3.79 (1.34-10.76). Once DMpulm/DMother arise only previous bone/other metastasis remain prognostic for death, HR 1.74 (1.10-2.75). CONCLUSION: Disease extent and histological response are risk factors for progression to DM or death. Tumor site and surgical margins are risk factors for LR. If disease progression occurs, previous risk factors lose their relevance. In case of isolated LR, time to recurrence is important for decision-making. Radiotherapy seems protective for LR especially in pelvic/axial. Low percentages of LR in extremity tumors and associated toxicity question the need for radiotherapy in extremity Ewing sarcoma.

Retrospective Analysis of Outcomes of Patients with Relapsed, Refractory and Metastatic Sarcomas who have received Metronomic Chemotherapy.

INTRODUCTION: Paediatric soft tissue sarcoma treatments and outcomes have improved significantly in the last few decades. However, a significant number of patients still succumb to the disease. In low-middle income countries there are dual problems of advanced disease at presentation and financial burden leading to poor compliance to therapy. Hence, we designed a low-cost oral metronomic chemotherapy protocol for these patients and studied the responses and toxicities to therapy in a tertiary referral hospital. PATIENTS AND METHODS: This is retrospective, single institutional, observational study. We retrospectively reviewed data of patients with relapsed, refractory or metastatic soft tissue sarcoma (STS) [ Ewing Sarcoma (ES); Rhabdomyosarcoma (RMS) or other STS] who were treated with the metronomic protocol of oral Tamoxifen, Etoposide and Cyclophosphamide (TEC) during the period April 1998 to September 2013, at the Tata Memorial Hospital, Parel, Mumbai. Patients with ES and RMS were primarily treated on our Institutional protocols. The patients included in the analysis were those who had relapsed after the primary protocols and then treated with metronomic TEC protocol; or those with primary refractory or metastatic disease (RMS, ES) and received metronomic TEC therapy. RESULTS: 49 patients were enrolled. Among the 49 patients, 32 were diagnosed ES, 13 RMS and 4 other STS. For the whole cohort response rates (RR) were 59% and clinical benefit rate (CBR) was 79%. Patients in the study were grouped into the following subgroups. Systemic recurrent/relapsed disease (N=24), metastatic disease at presentation (N=15) and local disease (refractory/recurrent) (N=10). None of the patients required blood or platelet support or admission for supportive care. The PFS for the above groups were 16.8 months, 12.5 months and 126.68 months respectively. This compares favorably with other historical cohorts in a similar setting. CONCLUSIONS: This study provides a preliminary evidence efficacy and tolerability of metronomic chemotherapy in poor risk ES and RMS. It also demonstrates that with this low-cost low risk treatment few patients could go into long term remissions despite high disease burden.

Surgical management of primary malignant proximal fibular tumors: Functional and clinical outcomes of 23 patients.

OBJECTIVES: This study aims to evaluate the clinical characteristics and treatment outcomes of patients with primary malignant tumors located in the proximal fibula. PATIENTS AND METHODS: This retrospective study included 23 patients (15 males, 8 females; mean age 22.1 years; range, 9 to 63 years) with primary malignant tumors located in the proximal fibula between May 2007 and May 2017. The anamnesis or medical history, physical examination, plain chest radiography, lung computed tomography, direct radiograph, and magnetic resonance imaging of the affected extremity and routine laboratory tests of all patients were evaluated. RESULTS: Of the patients, 11 were diagnosed with osteosarcoma (47.8%), nine with Ewing's sarcoma (39.1%), two with chondrosarcoma (8.7%), and one was diagnosed with synovial sarcoma (4.3%). Pain and palpable mass were the most common symptoms. Six patients had lung metastases at the time of diagnosis. Of the patients, eight were performed Malawer type 1 resection (34.8%), nine type 2 resection (39.1%), four above knee amputation (17.4%), and two proximal tibia tumor resection prosthesis (8.6%). Mean follow-up duration was 36 months (range, 12 to 119 months). Local recurrence developed in three patients. Mean Musculoskeletal Tumor Society (MSTS) score of all patients was 62. CONCLUSION: Surgical treatment of primary malignant tumors of the proximal fibula is problematic. In appropriate indications, Malawer type 1 resection should be the treatment of choice due to lower local recurrence rates and higher MSTS scores.

Colonic Ewing Sarcoma/PNET associated with liver metastases: A systematic review and case report.

Ewing Sarcoma is a highly lethal undifferentiated tumor of bone. ES is a small round cell tumor with etiological and characteristic chromosomal translocations between TET/FET (TLS/FUS, EWSR1, and TAF15) and ETS (E26 transformation-specific) family genes. Generally, therapeutic approach for metastatic Ewing Sarcoma includes both local (surgery and radiotherapy) and systemic (chemotherapy) disease control with an overall cure rate of 20%. For extra-osseous tumors, the most common primary sites of disease are trunk, extremities, head and neck, retroperitoneum. Among other sites, Ewing Sarcoma/PNET may also rarely arise in colon and rectum. Even if colonic Ewing Sarcoma/PNET have been previously reported in 5 cases, none of those reports came from right side of the colon. In this article, we report the first case of right-sided Ewing Sarcoma with synchronous liver metastases completely responding to first line chemotherapy. Furthermore, we provide a systematic qualitative review of the current literature on adult colorectal Ewing Sarcoma using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Spinal Ewing Sarcoma Metastatic to Bilateral Orbits.

A 39-year-old woman with primary spinal Ewing sarcoma and known lung metastases presented with painless bilateral decreased visual acuity over a 1-month period. Examination revealed bilateral disc edema. MRI of the brain/orbits showed metastatic lesions to the dura and bilateral orbits. Venous sinus thrombosis extending to the jugular vein was also noted. To the authors' knowledge, this is the first case of bilateral orbital metastasis and papilledema secondary to Ewing sarcoma and related hypercoagulability.

Metastasis of Ewing's sarcoma to the thyroid gland: A case report.

Ewing's sarcoma (ES) is an aggressive pediatric malignancy. We present a case of ES with thyroid metastasis. The patient was diagnosed with ES at age 8. Despite aggressive treatment, she suffered disease progression. Surveillance demonstrated a left thyroid lesion. This grew rapidly within 2 months, causing tracheal compression. She underwent hemi-thyroidectomy to prevent airway compromise. Due to her refractory ES, she was enrolled in the Vigil immunotherapy vaccine trial; thus, the specimen was used for vaccine development. This is the first reported case of skeletal ES with metastasis to the thyroid, requiring hemithyroidectomy to prevent airway compromise.

Age dependency of primary tumor sites and metastases in patients with Ewing sarcoma.

BACKGROUND: The median age of patients with Ewing sarcoma (EwS) at diagnosis is around 14-15 years. Older age is associated with a worse outcome. The correlation of age at diagnosis on sites of disease has not been fully described. OBJECTIVE: The goal of this study was to evaluate the differences in sites of primary tumor and metastatic tumor involvement according to age groups. DESIGN/METHOD: EwS data from the Gesellschaft für Pädiatrische Onkologie und Hämatology (GPOH) database of the Cooperative Ewing Sarcoma Study (CESS) 81/86 and the European Intergroup Cooperative Ewing's Sarcoma Study EICESS 92 and the EUROpean Ewing tumor Working Initiative of National Groups-99-Protocol (EURO-E.W.I.N.G.-99) study were analyzed. Patient and tumor characteristics were evaluated statistically using chi square tests. RESULTS: The study population included 2,635 patients with bone EwS. Sites of primary and metastatic tumors differed according to the age groups of young children (0-9 years), early adolescence (10-14 years), late adolescence (15-19 years), young adults (20-24 years), and adults (more than 24 years). Young children demonstrated the most striking differences in site of disease with a lower proportion of pelvic primary and axial tumors. They presented less often with metastatic disease at diagnosis. CONCLUSIONS: Site of primary and metastatic tumor involvement in EwS differs according to patient age. The biological and developmental etiology for these differences requires further investigations.

The Successful Treatment of Metastatic Extraosseous Ewing Sarcoma with Pazopanib.

The clinical efficacy and outcomes of pazopanib treatment for metastatic extraosseous Ewing sarcoma remain unclear. We herein report a case of heavily pre-treated metastatic extraosseous Ewing sarcoma in which pazopanib treatment achieved a significant improvement. A 17-year-old girl was referred to our hospital due to metastatic extraosseous Ewing sarcoma. The initial cytotoxic chemotherapy was temporarily effective, however, her disease eventually progressed, and she was subsequently treated with pazopanib. The recurrent tumor showed a marked response to pazopanib therapy; the therapeutic effect has lasted for more than 26 months. The present case suggests that pazopanib may be a therapeutic option for extraosseous Ewing sarcoma.