Soft Tissue Sarcoma Group Research Articles

Outcomes for patients with perineal and perianal rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

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 10years of age, 76% were alveolar histology, 76% were more than 5cm, 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 6.13years, 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 10years 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.

Radiotherapy leads to improved overall survival in patients undergoing resection for Undifferentiated pleomorphic sarcoma

Background and objectivesUndifferentiated pleomorphic sarcoma (UPS) is a frequent subtype within the heterogeneous group of soft tissue sarcomas (STS). The use of radiotherapy (RT) has become an important component of a multimodal approach to treating STS. Key studies have demonstrated that the addition of RT improves rates of local control in STS, though the effect on overall survival (OS) is less clear. Furthermore, there is very limited and conflicting evidence regarding effect of RT on overall survival in UPS. The purposes of this investigation were to examine the association between RT and OS in UPS patients undergoing surgical resection and to determine independent prognostic indicators of OS in this patient population. MethodsThis was a retrospective review of patients who underwent surgical treatment for primary UPS from 1993 to 2021. Associations between RT and OS were analyzed with Kaplan-Meier curves and log-rank testing. Cox proportional hazards regression analysis was used to determine independent prognostic factors of OS. ResultsOne hundred and fourteen patients who underwent surgical resection of primary UPS were included in the study. Ninety-six (84.2 %) patients received RT perioperatively. Use of RT was associated with improved OS on log-rank testing (hazard ratio (HR) 0.20; 95 % confidence interval (CI) 0.11–0.36; p < 0.001). On multivariate analysis, RT was an independent predictor of improved OS (HR 0.18; 95 % CI 0.09–0.39; p < 0.001) while metastasis at presentation (HR 4.82; 95 % CI 2.26–10.27; p < 0.001) and older age (HR 1.92; 95 % CI 1.20–3.36; p = 0.02) were predictive of decreased OS. Use of RT was not significantly associated with a lower rate of local recurrence in our cohort (p = 0.49). ConclusionsUse of RT in combination with surgery was an independent prognostic indicator of improved overall survival in UPS patients. Older age and metastasis at presentation were associated with worse overall survival. Based on this and other available studies, treatment for UPS should involve limb-sparing resection when feasible with RT to ensure optimal survival.

Roadmap for the next generation of Children's Oncology Group rhabdomyosarcoma trials.

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.

ATRX and Its Prognostic Significance in Soft Tissue Sarcoma.

Recently, the association between ATRX and a more aggressive sarcoma phenotype has been shown. We performed a retrospective study of sarcomas from an individual institution to evaluate ATRX as a prognosticator in soft tissue sarcoma. Experimental Design. 128 sarcomas were collected from a single institution and stained for ATRX. The prognostic significance of these markers was evaluated in a smaller cohort of primary soft tissue sarcomas (n = 68). Kaplan-Meier curves were created for univariate analysis, and Cox regression was utilized for multivariate analysis. High expression of ATRX was found to be a positive prognostic indicator for overall survival and metastasis-free survival in our group of soft tissue sarcomas both in univariate analysis and multivariate analysis (HR: 0.38 (0.17-0.85), P=0.02 and HR: 0.49 (0.24-0.99), P=0.05, respectively). High expression of ATRX is a positive prognostic indicator of overall survival and metastasis-free survival in patients with STS. This is consistent with studies in osteosarcoma, which indicate possible mechanisms through which loss of ATRX leads to more aggressive phenotypes. Future prospective clinical studies are required to validate the prognostic significance of these findings.

Cardiac safety of pegylated liposomal doxorubicin after conventional doxorubicin exposure in patients with sarcoma and breast cancer.

388 Background: Lifetime cumulative doses of conventional doxorubicin (&gt;450 mg/m2) are associated with dose-dependent cardiotoxicity. In soft tissue sarcoma (STS) and breast cancer, conventional doxorubicin is often utilized in earlier lines of therapy, whereas pegylated liposomal doxorubicin (PLD) is typically reserved for recurrent and metastatic disease. PLD is associated with less cardiotoxicity than conventional doxorubicin and high doses of PLD can be administered without increased risk of cardiotoxicity in patients without prior exposure to conventional doxorubicin. Limited data exists evaluating cardiotoxicity associated with PLD treatment after conventional doxorubicin, especially when doxorubicin lifetime doses approach the established cumulative total lifetime dose of 450-550 mg/m2. This study aims to evaluate the cardiac safety of PLD use in patients who had prior exposure to conventional doxorubicin. Methods: This was a single-center, observational, retrospective cohort study conducted in patients ≥18 years with STS or breast cancer, who were exposed to conventional doxorubicin from an earlier line of treatment prior to PLD between January 2010 – May 2022. Patients participating in clinical trials were excluded. The primary outcome of the study was cardiac safety. Cardiac toxicity was defined as ≥ 10% decrease in left ventricle ejection fraction (LVEF) or new diagnosis of heart failure within 6 months after PLD cessation. Results: 494 patients were screened and 50 patients met inclusion criteria, 8 STS and 42 breast cancer patients. Median lifetime cumulative conventional doxorubicin dose in patients with STS was 450 mg/m2 with a max dose of 825 mg/m2, and 240 mg/m2 with a max dose of 300 mg/m2 in breast cancer patients. Median lifetime cumulative PLD dose was 105 mg/m2 (range: 35-150 mg/m2) in the STS group and 105 mg/m2 (range: 35-510 mg/m2) in the breast cancer group. A decrease of ≥ 10% in LVEF was not observed in the STS group. 22 breast cancer patients had available LVEF data on PLD; 3 of these patients experienced ≥ 10% in LVEF drop and one of three patients was diagnosed heart failure. The average cumulative dose of PLD administered in patients with &gt; 10% decrease in LVEF was 177 mg/m2 and had an average of 3.5 cycles. Most of STS patients initiated PLD treatment within 2 years after conventional doxorubicin while most breast patients initiated PLD treatment at least 10 years following conventional doxorubicin exposure. Conclusions: PLD administration in patients with prior exposure to conventional doxorubicin appears to be safe with limited cardiotoxicity in patients with STS and breast cancer. Future research is needed to determine if and how often routine cardiac monitoring is needed for patients on PLD without existing cardiac risk.

Management and outcomes of chest wall rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

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.

Abstract 2586: OncogenicPIK3CA promotes hematopoietic reprogramming and cell transdifferentiation developing hematopoietic malignancy

Abstract PIK3CA mutation is one of the most common, recurrent genetic abbrations identified across multiple types of cancers. Such mutations sustain activation of PI3K/AKT/mTOR pathway, being considered reliable therapeutic targets; yet, the functional consequences still remain unclear. Angiosarcomas are a heterogenous group of soft-tissue sarcomas that form malignant endothelium with disorganized, irregular blood-filled vascular spaces, and a subset of the vascular tumors harbor PIK3CA mutations. In this study, we found that one of 11 canine angiosarcoma cells gave rise to vascular tumors in 3 of 3 mice in a series of xenograft experiments using a total of 86 immunodeficient BNX mice. Intriguingly, we also observed that xenografts developed lymphoproliferative tumors indicating a mouse B-cell origin in 3 of 4 mice from one case of canine patient-derived tumor xenografts: four tumor cases surgically implanted in a total of 16 BNX mice. Additionally, canine angiosarcoma cells induced splenomegaly with expansion of Ter-119+ erythroid progenitors in NSG mice. Canine angiosarcoma cells (two cell lines; DHSA-1426 and EFB) were capable of hematopoietic expansion and cell lineage differentiaton in vitro. Since PIK3CA mutations appear to promote cellular stemness and impairment of cell lineage differentiation, we determined if the mutations play a role in hematopoietic regulations of angiosarcoma cells. DHSA-1426 angiosarcoma cells were used to induce PIK3CA H1047R mutations using CRISPR/Cas9. We found that PIK3CA mutant angiosarcoma cells dysregulated AKT, ERK, and mTOR pathway with enrichement of inflammatory cytokines such as IL-6, IL-8, and MCP-1. Single cell RNA-seq data showed that PIK3CA mutant angiosarcoma cells established distinct single cell clusters representing immune reactions, cellular stemness, and lineage differentiation. Furthermore, PIK3CA mutant angiosarcoma cells developed malignant hematopoietic tumor in one of five BNX mice, while no evidence of hematopoietic tumor formation was found in mice transplanted with non-mutant cells. Altogether, our data suggest that angiosarcoma cells have the capacity to promote hematopoietic imbalance impacting on cellular ontogeny and lineage differentiation, potentially mediated by oncogenic PIK3CA. Our ongoing work is determining the mechanism of the cell fate decisions using bi-potential hematoendothelial progenitors derived from induced pluripotent stem cells harboring oncogenic PIK3CA. Citation Format: Emma Kozurek, Erin B. Dickerson, Jong Hyuk Kim. OncogenicPIK3CA promotes hematopoietic reprogramming and cell transdifferentiation developing hematopoietic malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2586.

Development and validation of a nomogram for predicting survival in patients with malignant myofibroblastic tumor.

Malignant myofibroblastic tumors are a rare group of soft tissue sarcomas, for which a prognosis prediction model is lacking. Based on the Surveillance, Epidemiology, and End Results (SEER) database and cases from Nanjing Drum Tower Hospital, the current study constructed and validated a nomogram to assess overall survival of patients with malignant myofibroblastic tumors. Data of patients with myofibroblastic tumors diagnosed between 2000 and 2018 were extracted from the SEER database. Similarly, data of patients with myofibroblastic tumor in Nanjing Drum Tower Hospital between May 2016 and March 2022 were collected. Then, we conducted univariate and multivariate Cox analyses to identify independent prognostic parameters to develop the nomogram. The model was evaluated by concordance index (C-index), calibration curve, the area under the curve (AUC), decision curve analysis (DCA), Kaplan-Meier analysis, and subgroup analyses. Seven variables were selected to construct the nomogram. The results of the C-index (0.783), calibration curve, the AUCs, and subgroup analyses demonstrated the accurate predictive capacity and excellent discriminative ability of the nomogram. The DCA of the model indicated its better clinical net benefit than that of the traditional system. Evaluation of the predictive performance of the nomogram revealed the superior sensitivity and specificity of the model and the higher prediction accuracy of the outcomes compared with those of the traditional system. The established nomogram may assist patients in consultation and help physicians in clinical decision-making.

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

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

Incarcerated metastasis as the first manifestation of a rare sarcoma.

Desmoplastic small round cell tumor belongs to a group of soft tissue sarcomas. It is a rare disease, since its discovery in 1989, only hundreds of cases have been described in the literature. Due to the rare incidence of the tumor, this disease remains unknown in common medical practice. It occurs most often in men at young age. Its prognosis is serious and the average survival of patients ranges from 1.5 to 2.5 years. Treatment options include surgical resection, chemo-, radio- and targeted therapy. Our work presents a case report of a 40 year-old patient sufferred from this sarcoma. The first manifestation of the disease was an incarcerated epigastric hernia with omentum and sarcoma metastasis. A resection of the incarcerated part of the omentum was performed with a biopsy from another intra-abdominal lesion. Biopsy specimens were sent for histopathological evaluation. For the generalization of the disease, further surgery was not indicated and systemic palliative chemotherapy in the VDC-IE regimen was chosen. At the time of submitting the manuscript, the patient has survived 6 months since the surgical procedure.

Using Evidence-Based Medicine to Support Clinical Decision-Making in RMS.

The foundations of evidence-based practice are the triad of patient values and preferences, healthcare professional experience, and best available evidence, used together to inform clinical decision-making. Within the field of rhabdomyosarcoma, collaborative groups such as the European Paediatric Soft Tissue Sarcoma Group (EpSSG) have worked to develop evidence to support this process. We have explored many of the key research developments within this review, including patient and public involvement, decision-making research, research into areas other than drug development, core outcome sets, reporting and dissemination of research, evidence synthesis, guideline development and clinical decision rules, research of research methodologies, and supporting research in RMS.

1491MO New benchmarks for designing clinical trials in advanced or metastatic liposarcoma (LPS) or synovial sarcoma (SS): An EORTC soft tissue and bone sarcoma group meta-analysis

1491MO New benchmarks for designing clinical trials in advanced or metastatic liposarcoma (LPS) or synovial sarcoma (SS): An EORTC soft tissue and bone sarcoma group meta-analysis

Abstract LB140: The genomic landscape of primary and secondary angiosarcomas, a rare heterogenous group of soft tissue sarcomas

Abstract Background: Angiosarcomas (AS) are a rare heterogenous group of soft tissue sarcomas (STS) that form in the lining of blood vessels or lymphatic vessels. They comprise of primary (de novo) AS and secondary AS. The etiology of primary AS is unknown. Secondary AS arise due to DNA damaging factors like prior radiotherapy (RT), ultraviolet (UV) light exposure or chronic lymphedema (Stewart Treves syndrome). Treatment options are limited and their prognosis is poor. Development of new treatment strategies is difficult due to the rarity of these subgroups of STS. Genomic profiling of primary and secondary AS may provide a rationale for targeted treatment strategies. Method: Tumor samples were retrospectively collected from patients diagnosed with AS in the Netherlands. Patients were categorized as primary/secondary AS. Genomic profiles were analyzed using “TruSight Oncology 500”, a Next Generation Sequencing panel that analyzes variants in 523 cancer relevant genes. Results: Tumor DNA from 51 treatment naive AS patients was analyzed. The cohort comprised of 26 patients with a primary AS, divided in 5 subgroups: Heart (n=5, 10%), primary breast (n=5, 10%), skin not UV associated (n=4, 8%), soft tissue (n=5, 10%) and visceral (n=7, 14%) AS. The other 25 patients had a secondary AS, subdivided in RT-associated (n=13, 25%), Stewart Treves (n=5, 10%) and UV-associated (n=7, 14%) AS. Mean Tumor Mutational Burden (TMB) was 7.1 mutations per Mb for all patients (4.2 mut/Mb in primary AS vs 10.1 in secondary AS, p = 0.91). High TMB (≥10 mut/Mb) was found in 6 patients (12%) divided over 3 subgroups: UV associated AS (n=3/7 (43%)), visceral AS (n=2/7 (28%)) and skin not UV associated AS (n=1/4 (25%)). No patients were microsatellite instable. A pathogenic mutation, amplification or deletion was identified in 82% of all patients (n=42, 70% of primary AS vs 100% of secondary AS (p=&amp;lt;0.01)). In 36 patients (71%) at least one (likely) pathogenic mutation was detected (54% primary vs 88% secondary AS, (p=0,013)). In 20 patients (39%) a mutation in the DNA damage response (DDR) pathway was detected (12% primary vs 68% secondary AS (p=&amp;lt;0.01)). The most frequently found mutations were TP53 (10%), BRAF (6%), ERCC4 (6%), PTPRD (6%), WETD2 (6%), SETD2 (6%) and PIK3CA (4%). Amplifications were found in 49% (n=25) of all patients (15% primary vs 84% secondary AS, (p=&amp;lt;0,01)). MYC amplifications were detected in 41% of all patients (15% of primary vs 68% of secondary AS), including 100% of Stewart Treves AS, 92% of RT associated AS and 75% of skin not UV associated AS. FLT4 (20%) and CRKL (12%) amplifications occurred only in secondary AS. FLT4 was seen in 31% of RT-associated AS. Conclusion: We showed a clear distinction in genomic profiles of AS subgroups with specific pathogenic alterations. Especially secondary AS may benefit from treatment with ICI based on frequent MYC amplifications, DDR mutations, and high TMB. These data show clear evidence for the development of future treatment strategies with targeted therapy and ICI for this rare heterogeneous group of STS. Citation Format: Stefan G. van Ravensteijn, Yvonne M. Versleijen-Jonkers, Melissa H. Hillebrandt-Roeffen, Maikel Nederkoorn, Mark A. Gorris, Kiek Verrijp, Leonie I. Kroeze, Tessa J. de Bitter, Richarda M. de Voer, Uta E. Flucke, Ingrid M. Desar. The genomic landscape of primary and secondary angiosarcomas, a rare heterogenous group of soft tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB140.

Insulin-like growth factor 1 and its binding protein-2 in tumor and peritumoral tissues as important factors involved in recurrence of soft tissue sarcomas in older men.

e23556 Background: The system of insulin-like growth factors (IGF) is involved in the pathogenesis of many malignant tumors. At the same time, the specificity of this system in recurrent soft tissue sarcomas is unknown. The purpose of this study was to analyze the IGF system in tumors and their peritumoral areas in men with recurrent soft tissue sarcomas. Methods: The study included 26 men aged 57.8±6.2 years with primary (n = 12, group 1, controls) and recurrent (n = 14, group 2, main group) soft tissue sarcoma of the extremities, T2bN0M0. Grade 1 tumors were diagnosed in 6 patients of group 1 and in 7 patients of group 2, while the other patients had G3 or G4 tumors. 95% of tumors were liposarcomas. All patients of group 2 had previously underwent surgical and radiation treatment for primary sarcomas and their relapses (up to 2 episodes), with the last surgery more than 1 year ago. Levels of the IGF system components were determined in tumor (T) and peritumoral (PT) tissues by ELISA, and ratios of IGF(T)/IGF(PT) were calculated. Results: Levels of the IGF system components in patients of group 1 were similar in T and PT. In group 2, levels of IGF1 and IGFВР2 in T were respectively 2.2 and 1.6 times (p &lt; 0.05) lower than in PT, but did not differ significantly from the levels in group 1. The IGF1(T)/IGF1(PT) ratio in patients of group 2 was 1.8 times (p &lt; 0.05) lower than in group 1. PT levels of IGF2 in group 2 depended on the tumor grade: they were 1.5 times (p &lt; 0.05) higher in G1 than in G3-G4, while no such dependence was observed in T. Conclusions: The levels of the IGF system components in recurrent soft tissue sarcomas in older men had some peculiarities. Unlike primary sarcomas with similar levels of the studied components of the IGF system in tumors and in peritumoral tissues, recurrent tumors contained less IGF1 and IGFBP2 than the corresponding peritumoral areas. The levels of IGF2 in the peritumoral tissues of recurrent tumors depended on the tumor grade.

First-line chemotherapy in advanced intra-abdominal well-differentiated/dedifferentiated liposarcoma: An EORTC Soft Tissue and Bone Sarcoma Group retrospective analysis.

No prospective trial with anthracycline-based chemotherapy has individually assessed response in a well-differentiated (WD)/dedifferentiated (DD) liposarcoma patient cohort. We conducted a retrospective analysis of first-line chemotherapy in liposarcoma of intra-abdominal origin (IA-LPS) in patients who had entered the European Organisation for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG) trials. We searched for all adult patients treated with first-line chemotherapy for advanced IA-LPS in the EORTC STBSG phase 2 and 3 trials from 1978. Treatment was aggregated into 5 groups: anthracycline alone, ifosfamide alone, doxorubicin plus ifosfamide (D+IFO), doxorubicin/cyclophosphamide/vincristine/dacarbazine, and "other" (brostallicin, trabectedin). Response was assessed prospectively by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. A total of 109 patients with IA-LPS from 13 trials were identified (104 evaluable for response). Overall, there were 10/109 (9.2%) responders: 3/48 (6.3%) in the anthracycline alone group, 2/15 (13%) in the ifosfamide alone group, and 4/18 (22%) in the D+IFO group. At the 10-month median follow-up (interquartile range, 6-24), the median OS was 19 months (95% CI, 15-21) and median PFS 4 months (95% CI, 3-6). D+IFO achieved a not statistically significant longer median PFS (12 months) and median OS (31 months) than observed with other regimens. Univariate/multivariate analysis did not identify prognostic factors. Cytotoxic chemotherapy, in particular anthracycline alone, had marginal activity in advanced IA-LPS. Ifosfamide-containing regimens showed higher activity, although it was not statistically significant and in a small number of cases, with the combination of doxorubicin and ifosfamide appearing to be the more active regimen available in fit patients. This series provides a benchmark for future trials on new drugs in WD/DD liposarcoma.

Local control of parameningeal rhabdomyosarcoma: An expert consensus guideline from the International Soft Tissue Sarcoma Consortium (INSTRuCT).

The International Soft Tissue Sarcoma Database Consortium (INSTRuCT) consists of a collaboration between the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, the European pediatric Soft Tissue Sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). As part of the larger initiative of INSTRuCT to provide consensus expert opinions for clinical treatment of pediatric soft tissue sarcoma, we sought to provide updated, evidenced-based consensus guidelines for local treatment of parameningeal rhabdomyosarcoma using both existing literature as well as recommendations from the relevant cooperative group clinical trials. Overall, parameningeal rhabdomyosarcoma represents a distinctly challenging disease to treat, given its location near many critical structures in the head and neck, frequently advanced local presentation, and predilection for local failure. Definitive chemoradiation remains the standard treatment approach for parameningeal rhabdomyosarcoma, with surgery often limited to biopsy or salvage therapy for recurrent disease. In this consensus paper, we specifically discuss consensus guidelines and evidence for definitive local management with radiotherapy, with a focus on imaging for radiotherapy planning, dose and timing of radiation, approach for nodal irradiation, various radiation techniques, including proton therapy, and the limited role of surgical resection.

Marginal excision of cutaneous mast cell tumors in dogs was not associated with a higher rate of complications or prolonged wound healing than marginal excision of soft tissue sarcomas.

To compare wound healing following planned marginal excision of cutaneous mast cell tumors (MCTs) with that of soft tissue sarcomas (STSs) and to identify risk factors for wound healing complications and delay in healing. 126 dogs that underwent intentional marginal excision of cutaneous MCTs (n = 77) or subcutaneous STSs (49). Medical records of included dogs were reviewed and signalment, tumor size, tumor location, skin closure type, time to healing, reported complications, histopathological grade, and surgical margins were recorded. These variables and outcomes (complication rate and time to complete healing) were compared between dogs in the MCT and STS groups. Potential risk factors for complications and delayed healing were analyzed. No significant difference between the groups was found in any of the variables. Wound healing complication rates were 29% (22/77) for the MCT group and 31% (15/49) for the STS group. The mean ± SD time to complete healing was 16.5 ± 7.5 days for the MCT group and 17.7 ± 9.3 days for the STS group. These outcomes did not differ significantly between groups. For both groups, the use of subdermal plexus flap reconstruction was associated with the development of complications and increased time to complete healing. Marginal excision of cutaneous MCTs was not associated with a higher rate of complication or prolonged wound healing, compared with marginal excision of STSs. The use of flap reconstruction in skin closure may delay healing and planned adjuvant therapy. Owners should be counseled regarding these risks and where appropriate and feasible, surgery without reconstruction should be considered.

IMMUNOHISTOCHEMICAL FEATURES IN SOFT TISSUE SARCOMAS

Sarcomas are relatively rare, accounting for only 1% of all adult malignancies and 15% of childhood malignancies [2]. According to the World Health Organization (WHO), the group of soft tissue sarcomas includes more than 100 different histological subtypes [3]. According to the recommmendations of the WHO to improve the accuracy of diagnosis in soft tissue sarcoma, the traditional histopathological examination should be supplemented with immunohistochemical and molecular methods [1]. It was carried out immunohistochemical research of CD31 receptor of Vascular Endothelial Growth Factor (VEGF) in 129 patients with STS. The age range of patients is on average 14-77 years with a peak in the age of 50-59 years. The most common reason for initial visit to a medical institution was palpable tumor (100%). It was studied the following correlative interdependences: It was determined that histodifferentiation of tumour is in inverse correlation with expression CD31 receptor. Distinctions of expression level of CD31 are shown, depending on the degree of tumor differentiation, presence or absence of its spontaneous necrotization, limphoid infiltration of pathological nidus and amount of vessels in tumor tissue. That is as high the degree of histological differentiation of tumour as low the level of expression CD31 receptor (χ2=35,4; p&lt;0,001; р=-0,322). In FHTof ST is exposed inverse dependence between expression CD31 endotelial cells with spontaneous necrosis and lymphoid infiltration. As more the size and foci of spontaneous necrosis (χ2=67,1; p&lt;0,001; р=-0,473) and lymphoid infiltration (χ2=46,1; p&lt;0,001; р=-0,346), as low the level of expression CD31 receptor. It was found that the high level of espression CD31 receptor is in direct correlation with metastasis (χ2=18,6; р=0,42; p&lt;0,001) and recurrence (χ2=9,43; р=0,30; p&lt;0,01) of the process. Studied modern approaches to the diaqnostics and treatment of malignancies. One such approach is ”Oncology Control”, which means minimizing the risk of recurrence at the local and systemic level. Following treatment, follow-up should include history and physical examination accompanied by imaging (Ultrasound or MRI) every 3 to 6 month for 2 to 3 years, and then every 6 to 12 months thereafter to asses for recurrence. So in high positivity of CD31 receptor is exposed unfavourable prognosis in patients with STS. Summarizing before said we have come to the conclusion that immune-histo-chemical investigation of CD31 receptor of VEGF has important prognostical meaning in patients STS.

Undifferentiated and dedifferentiated soft tissue neoplasms: Immunohistochemical surrogates for differential diagnosis.

Undifferentiated soft tissue sarcomas (USTS) are described in the current World Health Organization Classification of Soft Tissue and Bone Tumours as those showing no identifiable line of differentiation when analyzed by presently available technologies. This is a markedly heterogeneous group, and the diagnosis of USTS remains one of exclusion. USTS can be divided into four morphologic subgroups: pleomorphic, spindle cell, round cell and epithelioid undifferentiated sarcomas, with this combined group accounting for up to 20% of all soft tissue sarcomas. As molecular advances enable the stratification of emerging genetic subsets within USTS, particularly within undifferentiated round cell sarcomas, other groups, particularly the category of undifferentiated pleomorphic sarcomas (UPS), still remain difficult to substratify and represent heterogeneous collections of neoplasms often representing the common morphologic endpoints of a variety of malignant tumors of various (mesenchymal and non-mesenchymal) lineages. However, recent molecular developments have also enabled the identification and correct classification of many tumors from various lines of differentiation that would previously have been bracketed under 'UPS'. This includes pleomorphic neoplasms and dedifferentiated neoplasms (the latter typically manifesting with an undifferentiated pleomorphic morphology) of mesenchymal (e.g. solitary fibrous tumor and gastrointestinal stromal tumor) and non-mesenchymal (e.g. melanoma and carcinoma) origin. The precise categorization of 'pleomorphic' or 'undifferentiated' neoplasms is critical for prognostication, as, for example, dedifferentiated liposarcoma typically behaves less aggressively than other pleomorphic sarcomas, and for management, including the potential for targeted therapies based on underlying recurrent molecular features. In this review we focus on undifferentiated and dedifferentiated pleomorphic and spindle cell neoplasms, summarizing their key genetic, morphologic and immunophenotypic features in the routine diagnostic setting, and the use of immunohistochemistry in their principal differential diagnosis, and highlight new developments and entities in the group of undifferentiated and dedifferentiated soft tissue sarcomas.

Efficacy and safety of nivolumab and trabectedin in pretreated patients with advanced soft tissue sarcomas (STS): Preliminary results of a phase II trial of the German Interdisciplinary Sarcoma Group (GISG-15, NitraSarc) for the non-L sarcoma cohort.

11545 Background: Single-agent PD-1 inhibitors have modest activity in the treatment of most STS. Potential strategies to increase efficacy include combination therapies targeting the tumor microenvironment. Considering that apart from direct growth inhibition and death of malignant cells, trabectedin (Tr) also induces macrophage depletion and/or different immunologic effects, suggesting a possible synergistic effect of combined Tr plus anti-PD-1 treatment. We therefore aimed to evaluate the efficacy and safety of combined Tr and nivolumab (Ni) as a second-line treatment in STS. Methods: The prospective, explorative, two group, non-randomized phase II NiTraSarc trial enrolled pretreated patients (pt) with advanced STS (Group A: lipo- or leiomyosarcomas, Group B: non-L-sarcomas). Pt were initially treated with 3 cycles of Tr 1.5 mg/m2, followed by the combination of Tr 1.5 mg/m2 + Ni 240 mg (“late combination cohort” (LCC)) for up to 16 cycles. After positive results of a preplanned interim analysis, pt received the combination therapy starting with cycle 2 (“early combination cohort” (ECC)). 92 pt were recruited to the trial (55 in Group A, 37 in Group B). Primary efficacy endpoint is progression-free survival rate after 6 months (PFSR6) according to RECIST v.1.1. This is a first analysis of the primary efficacy endpoint in Group B based on a modified intention-to-treat (mITT) population of evaluable 36 pt: 23 and 13 pt from the LCC and ECC, respectively. Results: The most common Group B subtypes comprised undifferentiated pleomorphic/not otherwise specified sarcoma (UPS/NOS, 13pt) and fibromyxoid sarcoma (FMS, 6pt). After a median follow-up of 5 months (m) PFSR6 was 13.9% for all pt, 8.7% in LCC and 23.1% in ECC. Median duration of disease stabilization (DoDS) was 4m in all pt, the LCC and the ECC. Two pt had a partial response (PR), 10 had disease stabilization (SD), while 13 pt progressed, and 11 had missing data. By subtype: PR- UPS/NOS=2 (DoDS 12.7m/12.5m). SD: UPS/NOS=3, epithelioid=2, synovial=2, FMS=1, fibrosarcoma=1, other=1. All 36 pt experienced at least one adverse event (AE) reaching a total of 579 AEs, 141 (24.4%) of which were considered to be grade ≥3 treatment-related AEs. The main grade ≥3 AEs were: leukopenia (47.2% of pt), neutropenia (41.7% of pt), thrombocytopenia (33.3% of pt), increased ALT (30.6% of pt), and anemia (27.8% of pt). Conclusions: Tr+Ni was well tolerated and showed activity in at least some patients with non-L-sarcomas (mostly UPS/NOS) especially in the ECC. Analyses of the collected data, including PD-L1 expression profile, with the goal to establish whether Tr+Ni should be further pursued in these patients, are ongoing. ClinicalTrials.gov Identifier: NCT03590210; EudraCT: 2017-001083-38. Clinical trial information: NCT03590210.