Opportunities and Challenges in Soft Tissue Sarcoma Risk Stratification in the Era of Personalised Medicine.

OPINION STATEMENT: Soft tissue sarcomas (STS) are a rare and heterogeneous group of cancers. Treatment options have changed little in the past thirty years, and the role of neoadjuvant chemotherapy is controversial. Accurate risk stratification is crucial in STS in order to facilitate clinical discussions around peri-operative treatment. Current risk stratification tools used in clinic, such as Sarculator, use clinicopathological characteristics and may be specific to anatomical site or to histology. More recently, risk stratification tools have been developed using molecular or immunological data. Combining Sarculator with other risk stratification tools may identify novel patient groups with differential clinical outcomes. There are several considerations when translating risk stratification tools into widespread clinical use, including establishing clinical utility, health economic value, being applicable to existing clinical pathways, having strong real-world performance, and being supported by investment into infrastructure. Future work may include incorporation of novel modalities and data integration techniques.

Proteomic profiling improves prognostic risk stratification of the Sarculator nomogram in soft tissue sarcomas of the extremities and trunk wall.

BACKGROUND: High-risk soft tissue sarcomas of the extremities and trunk wall (eSTS), as defined by the Sarculator nomogram, are more likely to benefit from (neo)adjuvant anthracycline-based therapy compared to low/intermediate-risk patients. The biology underpinning these differential treatment outcomes remain unknown. METHODS: We analysed proteomic profiles and clinical outcomes of 123 eSTS patients. A Cox model for overall survival including the Sarculator was fitted to individual data to define four risk groups. A DNA replication protein signature-Sarcoma Proteomic Module 6 (SPM6) was evaluated for association with clinicopathological factors and risk groups. SPM6 was added as a covariate together with Sarculator in a multivariable Cox model to assess improvement in prognostic risk stratification. RESULTS: DNA replication and cell cycle proteins were upregulated in high-risk versus very low-risk patients. Evaluation of the functional effects of CRISPR-Cas9 gene knockdown of proteins enriched in high-risk patients using the cancer cell line encyclopaedia database identified candidate drug targets. SPM6 was significantly associated with tumour malignancy grade (p = 1.6e-06), histology (p = 1.4e-05) and risk groups (p = 2.6e-06). Cox model analysis showed that SPM6 substantially contributed to a better calibration of the Sarculator nomogram (Index of Prediction Accuracy = 0.109 for Sarculator alone versus 0.165 for Sarculator + SPM6). CONCLUSIONS: Risk stratification of patient with STS is defined by distinct biological pathways across a range of cancer hallmarks. Incorporation of SPM6 protein signature improves prognostic risk stratification of the Sarculator nomogram. This study highlights the utility of integrating protein signatures for the development of next-generation nomograms.

Clinical Implications and Molecular Features of Extracellular Matrix Networks in Soft Tissue Sarcomas.

PURPOSE: The landscape of extracellular matrix (ECM) alterations in soft tissue sarcomas (STS) remains poorly characterized. We aimed to investigate the tumor ECM and adhesion signaling networks present in STS and their clinical implications. EXPERIMENTAL DESIGN: Proteomic and clinical data from 321 patients across 11 histological subtypes were analyzed to define ECM and integrin adhesion networks. Subgroup analysis was performed in leiomyosarcomas (LMS), dedifferentiated liposarcomas (DDLPS), and undifferentiated pleomorphic sarcomas (UPS). RESULTS: This analysis defined subtype-specific ECM profiles including enrichment of basement membrane proteins in LMS and ECM proteases in UPS. Across the cohort, we identified three distinct coregulated ECM networks which are associated with tumor malignancy grade and histological subtype. Comparative analysis of LMS cell line and patient proteomic data identified the lymphocyte cytosolic protein 1 cytoskeletal protein as a prognostic factor in LMS. Characterization of ECM network events in DDLPS revealed three subtypes with distinct oncogenic signaling pathways and survival outcomes. Evaluation of the DDLPS subtype with the poorest prognosis nominates ECM remodeling proteins as candidate antistromal therapeutic targets. Finally, we define a proteoglycan signature that is an independent prognostic factor for overall survival in DDLPS and UPS. CONCLUSIONS: STS comprise heterogeneous ECM signaling networks and matrix-specific features that have utility for risk stratification and therapy selection, which could in future guide precision medicine in these rare cancers.

Proteomic features of soft tissue tumours in adolescents and young adults.

BACKGROUND: Adolescents and young adult (AYA) patients with soft tissue tumours including sarcomas are an underserved group with disparities in treatment outcomes. METHODS: To define the molecular features between AYA and older adult (OA) patients, we analysed the proteomic profiles of a large cohort of soft tissue tumours across 10 histological subtypes (AYA n = 66, OA n = 243), and also analysed publicly available functional genomic data from soft tissue tumour cell lines (AYA n = 5, OA n = 8). RESULTS: Biological hallmarks analysis demonstrates that OA tumours are significantly enriched in MYC targets compared to AYA tumours. By comparing the patient-level proteomic data with functional genomic profiles from sarcoma cell lines, we show that the mRNA splicing pathway is an intrinsic vulnerability in cell lines from OA patients and that components of the spliceosome complex are independent prognostic factors for metastasis free survival in AYA patients. CONCLUSIONS: Our study highlights the importance of performing age-specific molecular profiling studies to identify risk stratification tools and targeted agents tailored for the clinical management of AYA patients.

Soft tissue tumours are cancers that develop in the connective and supporting tissues of the body, such as muscle or fat. These tumours arise in patients across the entire age range. However, improvements in survival outcomes in adolescent and young adult (AYA) patients have lagged behind outcomes in older adults (OA) and children. To better understand the biology of AYA patients with soft tissue tumours, we analysed protein profiles across 10 different types. We identified biological differences between AYA and OA patients and report an age-specific signature that can potentially be used to help predict which AYA patients are more likely to have aggressive cancers that will spread to other parts of the body. Our study highlights the importance of performing age-specific studies to identify new tools to predict patient outcomes and potentially find more suitable treatments.

Molecular Heterogeneity in Leiomyosarcoma and Implications for Personalised Medicine.

OPINION STATEMENT: Leiomyosarcoma (LMS) is one of the more common subtypes of soft tissue sarcomas (STS), accounting for about 20% of cases. Differences in anatomical location, risk of recurrence and histomorphological variants contribute to the substantial clinical heterogeneity in survival outcomes and therapy responses observed in patients. There is therefore a need to move away from the current one-size-fits-all treatment approach towards a personalised strategy tailored for individual patients. Over the past decade, tissue profiling studies have revealed key genomic features and an additional layer of molecular heterogeneity among patients, with potential utility for optimal risk stratification and biomarker-matched therapies. Furthermore, recent studies investigating intratumour heterogeneity and tumour evolution patterns in LMS suggest some key features that may need to be taken into consideration when designing treatment strategies and clinical trials. Moving forward, national and international collaborative efforts to aggregate expertise, data, resources and tools are needed to achieve a step change in improving patient survival outcomes in this disease of unmet need.

Efficacy and Safety of Ripretinib in Advanced Gastrointestinal Stromal Tumors within an Expanded Access Program: A Cohort Study.

Ripretinib, a novel tyrosine kinase inhibitor used in advanced gastrointestinal stromal tumors (GIST) resistant to standard therapies, was assessed in the United Kingdom (UK) within an Expanded Access Program (EAP). A retrospective review of patients treated between January 2020 and October 2021 within the ripretinib EAP in our Institution was conducted. Clinician-documented and mRECIST 1.1 assessments were collected. The primary endpoints were progression-free survival (PFS) and time to treatment discontinuation (TTD). Treatment beyond progression (TBP), overall survival (OS), objective response rates and safety data were also analyzed. Survival curves were constructed using the Kaplan-Meier method, and univariate and multivariate Cox regression analyses were performed. All analyses were performed with R software. Overall, forty-five patients were included. After a median follow-up of 24.2 (95% CI 19.7-29.7) months, the median PFS of the group receiving 150 mg ripretinib once daily (OD) was 7.9 (95% CI 5.6-19.3) months. In the cohort of 22 patients with dose escalation upon tumor progression to 150 mg ripretinib twice daily (BD), the median PFS from BD was 5.4 (95% CI 2.8-9.3) months. Overall, median PFS and OS values for patients on ripretinib were 9.7 (95% CI 8.3-18.1) and 14.0 (95% CI 9.9-NA) months, respectively. TTD was similar to PFS. TBP was observed in about one third of all patients. Objective responses to ripretinib OD and BD treatments were observed in 16.7% and 10.0% of the patients, respectively. No new safety signals were identified. In conclusion, patients with advanced GIST receiving ripretinib in the UK within the EAP reported prolonged benefits, in line with the recent phase III clinical trials.

Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation.

BACKGROUNDPhase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.METHODSThe primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20-240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle).RESULTSIntermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40-240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage-response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding.CONCLUSIONCeralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity.TRIAL REGISTRATIONClinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84.FUNDINGCancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.

A CT-based radiomics classification model for the prediction of histological type and tumour grade in retroperitoneal sarcoma (RADSARC-R): a retrospective multicohort analysis.

BACKGROUND: Retroperitoneal sarcomas are tumours with a poor prognosis. Upfront characterisation of the tumour is difficult, and under-grading is common. Radiomics has the potential to non-invasively characterise the so-called radiological phenotype of tumours. We aimed to develop and independently validate a CT-based radiomics classification model for the prediction of histological type and grade in retroperitoneal leiomyosarcoma and liposarcoma. METHODS: A retrospective discovery cohort was collated at our centre (Royal Marsden Hospital, London, UK) and an independent validation cohort comprising patients recruited in the phase 3 STRASS study of neoadjuvant radiotherapy in retroperitoneal sarcoma. Patients aged older than 18 years with confirmed primary leiomyosarcoma or liposarcoma proceeding to surgical resection with available contrast-enhanced CT scans were included. Using the discovery dataset, a CT-based radiomics workflow was developed, including manual delineation, sub-segmentation, feature extraction, and predictive model building. Separate probabilistic classifiers for the prediction of histological type and low versus intermediate or high grade tumour types were built and tested. Independent validation was then performed. The primary objective of the study was to develop radiomic classification models for the prediction of retroperitoneal leiomyosarcoma and liposarcoma type and histological grade. FINDINGS: 170 patients recruited between Oct 30, 2016, and Dec 23, 2020, were eligible in the discovery cohort and 89 patients recruited between Jan 18, 2012, and April 10, 2017, were eligible in the validation cohort. In the discovery cohort, the median age was 63 years (range 27-89), with 83 (49%) female and 87 (51%) male patients. In the validation cohort, median age was 59 years (range 33-77), with 46 (52%) female and 43 (48%) male patients. The highest performing model for the prediction of histological type had an area under the receiver operator curve (AUROC) of 0·928 on validation, based on a feature set of radiomics and approximate radiomic volume fraction. The highest performing model for the prediction of histological grade had an AUROC of 0·882 on validation, based on a radiomics feature set. INTERPRETATION: Our validated radiomics model can predict the histological type and grade of retroperitoneal sarcomas with excellent performance. This could have important implications for improving diagnosis and risk stratification in retroperitoneal sarcomas. FUNDING: Wellcome Trust, European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group, the National Institutes for Health, and the National Institute for Health and Care Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.

Pharmacological EZH2 inhibition combined with retinoic acid treatment promotes differentiation and apoptosis in rhabdomyosarcoma cells.

BACKGROUND: Rhabdomyosarcomas (RMS) are predominantly paediatric sarcomas thought to originate from muscle precursor cells due to impaired myogenic differentiation. Despite intensive treatment, 5-year survival for patients with advanced disease remains low (< 30%), highlighting a need for novel therapies to improve outcomes. Differentiation therapeutics are agents that induce differentiation of cancer cells from malignant to benign. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2) suppresses normal skeletal muscle differentiation and is highly expressed in RMS tumours. RESULTS: We demonstrate combining inhibition of the epigenetic modulator EZH2 with the differentiating agent retinoic acid (RA) is more effective at reducing cell proliferation in RMS cell lines than single agents alone. In PAX3-FOXO1 positive RMS cells this is due to an RA-driven induction of the interferon pathway resulting in apoptosis. In fusion negative RMS, combination therapy led to an EZH2i-driven upregulation of myogenic signalling resulting in differentiation. In both subtypes, EZH2 is significantly associated with enrichment of trimethylated lysine 27 on histone 3 (H3K27me3) in genes that are downregulated in untreated RMS cells and upregulated with EZH2 inhibitor treatment. These results provide insight into the mechanism that drives the anti-cancer effect of the EZH2/RA single agent and combination treatment and indicate that the reduction of EZH2 activity combined with the induction of RA signalling represents a potential novel therapeutic strategy to treat both subtypes of RMS. CONCLUSIONS: The results of this study demonstrate the potential utility of combining EZH2 inhibitors with differentiation agents for the treatment of paediatric rhabdomyosarcomas. As EZH2 inhibitors are currently undergoing clinical trials for adult and paediatric solid tumours and retinoic acid differentiation agents are already in clinical use this presents a readily translatable potential therapeutic strategy. Moreover, as inhibition of EZH2 in the poor prognosis FPRMS subtype results in an inflammatory response, it is conceivable that this strategy may also synergise with immunotherapies for a more effective treatment in these patients.

A Practical Approach to Small Round Cell Tumors Involving the Gastrointestinal Tract and Abdomen.

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.

Pharmacotherapeutic strategies for epithelioid sarcoma: are we any closer to a non-surgical cure?

INTRODUCTION: Epithelioid sarcoma (ES) is a rare soft tissue sarcoma subtype, predominantly occurring in children and young adults. Despite optimal management of localized disease, approximately 50% of patients develop advanced disease. The management of advanced ES remains challenging due to limited response to conventional chemotherapy and despite novel oral EZH2 inhibitors that have better tolerability but similar efficacy to chemotherapy. AREAS COVERED: We performed a literature review using the PubMed (MEDLINE) and Web of Science databases. We have focused on the role of chemotherapy, targeted agents such as EZH2 inhibitors, potential new targets and immune checkpoint inhibitors and combinations of therapies currently undergoing clinical investigation. EXPERT OPINION: ES is a soft tissue sarcoma with a heterogeneous pathological, clinical, and molecular presentation. In the current era of precision medicine, more trials with targeted therapies and a combination of chemotherapy or immunotherapy with targeted therapies are required to establish optimal treatment for ES.

The proteomic landscape of soft tissue sarcomas.

Soft tissue sarcomas (STS) are rare and diverse mesenchymal cancers with limited treatment options. Here we undertake comprehensive proteomic profiling of tumour specimens from 321 STS patients representing 11 histological subtypes. Within leiomyosarcomas, we identify three proteomic subtypes with distinct myogenesis and immune features, anatomical site distribution and survival outcomes. Characterisation of undifferentiated pleomorphic sarcomas and dedifferentiated liposarcomas with low infiltrating CD3 + T-lymphocyte levels nominates the complement cascade as a candidate immunotherapeutic target. Comparative analysis of proteomic and transcriptomic profiles highlights the proteomic-specific features for optimal risk stratification in angiosarcomas. Finally, we define functional signatures termed Sarcoma Proteomic Modules which transcend histological subtype classification and show that a vesicle transport protein signature is an independent prognostic factor for distant metastasis. Our study highlights the utility of proteomics for identifying molecular subgroups with implications for risk stratification and therapy selection and provides a rich resource for future sarcoma research.

The biology and treatment of leiomyosarcomas.

Leiomyosarcoma (LMS) is a soft tissue sarcoma of smooth muscle origin that can arise in multiple anatomical sites and is broadly classified as extra-uterine LMS or uterine LMS. There is substantial interpatient heterogeneity within this histological subtype, and despite multi-modal therapy, clinical management remains challenging with poor patient prognosis and few new therapies available. Here we discuss the current treatment landscape of LMS in both the localised and advanced disease setting. We further describe the latest advances in our evolving understanding of the genetics and biology of this group of heterogeneous diseases and summarise the key studies delineating the mechanisms of acquired and intrinsic chemotherapy resistance in this histological subtype. We conclude by providing a perspective on how novel targeted agents such as PARP inhibitors may usher in a new paradigm of biomarker-driven therapies that will ultimately impact the outcomes of patients with LMS.

Biphenotypic Sinonasal Sarcoma: Case Reports of Diagnostic Findings and Clinical Management of 3 Cases.

BACKGROUND: Biphenotypic sinonasal sarcoma (BSNS) is a rare spindle cell sarcoma distinctly arising in the sinonasal area, with dual myogenic and neural differentiation, and characterised by the presence of PAX3 gene fusion, typically with MAML3. Although the majority may be indolent, up to 25% of cases reported in the literature are locally aggressive, with invasion of adjacent critical structures in the head and neck region. CASE REPORT: We report 3 cases of BSNS reviewed at our institution between 2016-2020 in addition to the current literature. Patient 1 underwent surgery followed by adjuvant radiotherapy but relapsed 24 months later and was not fit for systemic anticancer therapy and managed with palliative care. Due to comorbidities, patient 2 was recommended for active surveillance, with a view to intervening with radiotherapy should there be evidence of clinical progression. At 60 months, the nasal cavity mass remained stable on serial imaging. Patient 3 underwent primary surgical R0 resection and was offered adjuvant post operative radiotherapy 60 Gy/30 fractions/6 weeks but opted for active surveillance and has no clinical or radiological evidence of recurrence 22 months after surgery. CONCLUSION: The primary management for BSNS is surgical resection. We recommend discussing the role of postoperative adjuvant radiotherapy 60 Gy/30 fractions/6 weeks in patients who are fit for treatment. In clinical practice, dose levels will be constrained by surrounding normal tissues. At present, the role of systemic anticancer therapy is undefined. A prospective registry of ultra-rare cases may provide an evidence base with which to select optimal treatment strategies for BSNS in the future.

Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma.

BACKGROUND: Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults. METHODS: To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first approach encompassed DNA exome and RNA deep sequencing of the largest human CCS cohort yet reported consisting of 47 patient tumor samples and 8 cell lines. RESULTS: Sequencing revealed recurrent mutations in cell cycle checkpoint, DNA double-strand break repair or DNA mismatch repair genes, with a correspondingly low to intermediate tumor mutational burden. DNA multi-copy gains with corresponding high RNA expression were observed in CCS tumor subsets. CCS cell lines responded to the HER3 ADC patritumab deruxtecan in a dose-dependent manner in vitro, with impaired long term cell viability. CONCLUSION: These studies of the genomic, transcriptomic and chemical biology landscape represent a resource 'atlas' for the field of CCS investigation and drug development. CHK inhibitors are identified as having potential relevance, CREB1 inhibitors non-dependence of CCS on CREB1 activity was established, and the potential utility of HER3 ADC being used in CCS is found.

PARP inhibition utilized in combination therapy with Olaparib-Temozolomide to achieve disease stabilization in a rare case of BRCA1-mutant, metastatic myxopapillary ependymoma.

Myxopapillary ependymoma (MPE) is a primary tumor of the central nervous system (CNS), characteristically an indolent malignancy involving the spinal conus medullaris, Filum terminale or cauda equina. We present a rare case of MPE, recurrent in the pelvic soft tissue with eventual pleural and intra-pulmonary metastasis. Refractory to repeated gross resection, adjuvant radiotherapy, platinum-based chemotherapy and temozolomide exploitation of mutant somatic BRCA1 status with the addition of a poly (ADP-ribose); polymerase inhibitor (PARPi) in a novel combination regimen with olaparib-temozolomide (OT) has achieved stable radiological disease after 10 cycles.

Evidence of Chemoresponsiveness in Unresectable Metastatic Angiomatoid Fibrous Histiocytoma.

Angiomatoid fibrous histiocytoma (AFH) is a soft tissue neoplasm of intermediate biological potential. Typically a slow-growing tumor, it can recur locally. Rarely, it manifests as a soft tissue sarcoma capable of metastasis. When metastases are nonamenable to local therapy, it is believed uniformly fatal. We present 3 patients with metastatic AFH who demonstrated a sustained response to chemotherapy; including one who achieved complete remission with cryoablation. These cases reinforce the potential value of chemotherapy in some patients with unresectable metastatic AFH and provide the first case in the literature of cryoablation in AFH.

Datasets for reporting of soft-tissue sarcoma: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: Soft-tissue tumours are rare and both accurate diagnosis and proper treatment represent a global challenge. Current treatment guidelines also recommend review by specialised pathologists. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of soft-tissue sarcomas. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of international pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's guidelines for dataset development, an international expert panel consisting of pathologists, a surgical oncologist, and a medical oncologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were subspecialised soft-tissue sarcoma experts and affiliated with tertiary referral centres. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the documents were finalised and ratified, and the datasets, which included a synoptic reporting guide, were published on the ICCR website. CONCLUSION: These first international datasets for soft-tissue sarcomas are aimed to promote high-quality, standardised pathology reporting. Their adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve patient's management.

Oncologic outcomes of surgically managed primary pelvic soft tissue sarcoma; tumour biology or surgical constraints of the true pelvis?

BACKGROUND: Pelvic soft tissue sarcomas are rare. Potentially curative resection remains challenging due to anatomical constraints of true pelvis and tumour spread through various anatomical hiatus. We sought to review the oncological outcomes of surgically managed cases at our centre and determine whether outcomes differ for patients with localised (limited to pelvis) versus extensive disease (with extra-pelvic extension). METHODS: Sixty-seven patients who underwent surgical resection with curative intent at the centre for primary, non-metastatic, WHO intermediate to high-grade soft tissue sarcoma of the true pelvis from January 2012 through January 2020 were analysed. Establishment of the extent of disease was made by review of pre-treatment imaging and surgical notes. Oncologic endpoints examined were resection margin, recurrence rate, disease-free and overall survival. RESULTS: Rates of complete oncological resection and disease control were similar for tumours with localised or extensive disease. On logistic regression analysis, tumour grade, and a negative resection margin (R0) correlated with the risk of recurrence (p=<0.05). On further multinomial analysis, R0 resection was associated with improved local control, but not metastatic relapse (p = 0.003). 5-year local recurrence-free and distant metastasis-free survival were 61.3% and 67.1%, respectively. Five and 10-year overall survival were 64% and 36%, respectively. Age >50 years and high tumour grade were associated with a worse outcome (p < 0.05). CONCLUSIONS: When potentially curative surgery is performed for pelvic sarcoma, disease-extent does not influence oncologic outcomes. While a complete oncologic resection determines the risk of local recurrence, tumour grade and metastatic relapse remain primary prognostic determinants for overall survival.

Current management of benign retroperitoneal tumors.

Benign retroperitoneal tumors (BRT) represent a rare group of heterogeneous diseases. The literature lacks high-quality evidence about the optimal management of BRT, and most of the information available takes the form of case reports or case series. The aim of this review is to provide an overview of current management strategies for adult patients with BRT. A literature search using PubMed indexed articles was conducted and BRT were classified into five different biological subgroups: 1) lipomatous tumors, 2) smooth muscle tumors, 3) peripheral nerve sheath tumors, 4) myofibroblastic tumors, and 5) others. Tumors that are primarily pelvic in origin were excluded. Despite the significant heterogeneity of the disease, several generic considerations have emerged and can be applied to the management of BRT. Specifically, the risk of misdiagnosing a BRT with another pathology such as retroperitoneal sarcoma is notable. When encountered, suspected BRT should therefore be referred to a specialized sarcoma center. Multidisciplinary tumor boards, present at these centers, have a pivotal role in managing BRT. The decision of whether to offer surgery, nonsurgical treatment or a "watch-and-wait" approach should be made after multidisciplinary discussion, depending on tumor histology. Moving forward, collaborative research efforts dedicated to BRT remain crucial in gathering evidence and knowledge to further optimize patient care.