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We present the case of a patient with Myxofibrosarcoma (MFS), a mesenchymal type of soft tissue sarcoma (STS) and the response to combination immunotherapy with anti PD-1 and anti-CTLA-4 therapy, following disease progression after Standard chemotherapy (SACT) and Radiotherapy (RT). We have shown a timeline of treatment and responses, as well as the overall safety profile and the management of immunotherapy related adverse events. This study demonstrates the potential of checkpoint inhibitors as therapeutic agents in the treatment of MFS.

Abstract 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.

Abstract 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.

Abstract Background Desmoid‐type fibromatosis (DTF) has a highly variable clinical course with varying intensity of symptoms. The objectives of this study were to identify subgroups of DTF patients based on physical symptom burden and to compare symptom burden subgroups on health‐related quality of life (HRQoL) and healthcare use (univariate and multivariate). Methods Desmoid‐type fibromatosis patients from the United Kingdom and the Netherlands received cross‐sectional questionnaires on HRQoL (EORTC QLQ‐C30), DTF‐specific HRQoL (DTF‐QoL) and healthcare utilisation. Latent class cluster analysis was performed to identify subgroups based on patients' symptom burden using EORTC QLQ‐C30 and DTF‐QoL physical symptom items. Multivariate linear and logistic regression analyses were conducted to examine associations of symptom burden with HRQoL and healthcare utilisation, respectively. Results Among 235 DTF patients, four symptom burden clusters were identified, with low symptom burden (24%), intermediate symptom burden‐low pain (20%), intermediate symptom burden‐high pain (25%) and high symptom burden (31%). DTF patients with high symptom burden had clinically relevant lower HRQoL scores compared to patients with low and intermediate symptom burden (p

Abstract 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.

BackgroundEpithelioid hemangioendothelioma (EHE) is an ultra-rare, vascular sarcoma with clinical presentation ranging from an indolent to an aggressive form. Over 50% of patients present with metastatic disease, requiring systemic therapy, although no systemic therapies are specifically approved for EHE. Retrospective evidence supports the activity of mTOR inhibitors (e.g. sirolimus), although available only off-label. EHE patients and advocates are therefore working to support approval of effective treatments by collecting data on patient perspectives and experiences.Materials and methodsIn February 2023, the EHE Rare Cancer Charity (UK) and The EHE Foundation (US), with other advocates, conducted a survey of perspectives and experiences of EHE patients regarding the use and accessibility of sirolimus. The survey consisted of 20 questions designed for individuals undergoing treatment, those who had been treated, or had never been treated with the drug. Widely promoted within the patient community, the online survey categorized patients into three cohorts for the analysis: liver transplant patients, non-transplant patients who had ever taken sirolimus and sirolimus-naïve non-transplant patients.ResultsThe survey evaluated data from 129 patient responses from 21 countries, mostly from USA, UK, Australia, and Canada (70%). The liver transplant, sirolimus and non-sirolimus cohorts were 16%, 25% and 59%, respectively. In the sirolimus group 66% reported treatment durations exceeding one year, with 16% exceeding five years, indicating the drug’s efficacy. In the non-sirolimus group, the drug was not available for 42% and for 11% sirolimus was available but not selected for treatment because of its off-label status. Overall, 87% of all patients across all cohorts expressed the importance of the drug’s availability as hugely or very important.ConclusionThe survey responses highlight the activity of sirolimus for EHE and the importance of securing a label extension for the drug delivering equitable access to this treatment for patients.

Abstract Background Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. Methods In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. Results Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P

Sarcomas comprise a heterogenous group of malignancies, of more than 100 different entities, arising from mesenchymal tissue, and accounting for 1% of adult malignancies. Surgery, radiotherapy and systemic therapy constitute the therapeutic armamentarium against sarcomas, with surgical excision and conventional chemotherapy, remaining the mainstay of treatment for local and advanced disease, respectively. The prognosis for patients with metastatic disease is dismal and novel therapeutic approaches are urgently required to improve survival outcomes. Immunotherapy, is a rapidly evolving field in oncology, which has been successfully applied in multiple cancers to date. Immunomodulating antibodies, adoptive cellular therapy, cancer vaccines, and cytokines have been tested in patients with different types of sarcomas through clinical trials, pilot studies, retrospective and prospective studies. The results of these studies regarding the efficacy of different types of immunotherapies in sarcomas are conflicting, and the application of immunotherapy in daily clinical practice remains limited. Additional clinical studies are ongoing in an effort to delineate the role of immunotherapy in patients with specific sarcoma subtypes.

Abstract Angiosarcomas are rare, aggressive soft tissue sarcomas originating from endothelial cells of lymphatic or vascular origin and associated with a poor prognosis. The clinical and imaging features of angiosarcomas are heterogeneous with a wide spectrum of findings involving any site of the body, but these most commonly present as cutaneous disease in the head and neck of elderly men. MRI and CT are complementary imaging techniques in assessing the extent of disease, focality and involvement of adjacent anatomical structures at the primary site of disease. CT plays an important role in the evaluation of metastatic disease. Given the wide range of imaging findings, correlation with clinical findings, specific risk factors and patterns of metastatic disease can help narrow the differential diagnosis. The final diagnosis should be confirmed with histopathology and immunohistochemistry in combination with clinical and imaging findings in a multidisciplinary setting with specialist sarcoma expertise. The purpose of this review is to describe the clinical and imaging features of primary sites and metastatic patterns of angiosarcomas utilising CT and MRI.

PURPOSEIn Scotland, approximately 350 sarcoma cases are diagnosed per year and treated in one of the five specialist centers. Many patients are required to travel long distances to access specialist care. The COVID-19 pandemic brought a number of rapid changes into the care for patients with cancer, with increasing utilization of telemedicine. We aimed to evaluate how the utilization of telemedicine affects professionals and patients across Scotland and care delivery, at the Beatson West of Scotland Cancer Centre Sarcoma Unit.METHODSBetween June 8 and August 25, 2020, we invited patients and professional sarcoma multidisciplinary team members to participate in separate online anonymous survey questionnaires, to assess their attitudes toward telemedicine. Data were extracted, and descriptive statistics were performed.RESULTSPatient satisfaction (n = 64) with telemedicine was high (mean = 9.4/10) and comparable with traditional face-to-face appointments (mean = 9.5/10). Patients were receptive to the use of telemedicine in certain situations, with patients strongly opposed to being told bad news via telemedicine (88%). Providers recommended the use of telemedicine in certain patient populations and reported largely equivalent workloads when compared with traditional consultations. Providers reported that telemedicine should be integrated into regular practice (66%), with patients echoing this indicating a preference for a majority of telemedicine appointments (57%).CONCLUSIONTelemedicine in sarcoma care is favorable from both clinician and patient perspectives. Utilization of telemedicine for patients with rare cancers such as sarcomas is an innovative approach to the delivery of care, especially considering the time and financial pressures on patients who often live a distance away from specialist centers. Patients and providers are keen to move toward a more flexible, mixed system of care.

Abstract Background As with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment. Methods Patient data for multiple cardiac‐related treatment‐emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231). Results Multivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24‐2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12‐2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75‐4.17]; p

A shift in radiology to a data-driven specialty has been unlocked by synergistic developments in imaging biomarkers (IB) and computational science. This is advancing the capability to deliver “virtual biopsies” within oncology. The ability to non-invasively probe tumour biology both spatially and temporally would fulfil the potential of imaging to inform management of complex tumours; improving diagnostic accuracy, providing new insights into inter- and intra-tumoral heterogeneity and individualised treatment planning and monitoring. Soft tissue sarcomas (STS) are rare tumours of mesenchymal origin with over 150 histological subtypes and notorious heterogeneity. The combination of inter- and intra-tumoural heterogeneity and the rarity of the disease remain major barriers to effective treatments. We provide an overview of the process of successful IB development, the key imaging and computational advancements in STS including quantitative magnetic resonance imaging, radiomics and artificial intelligence, and the studies to date that have explored the potential biological surrogates to imaging metrics. We discuss the promising future directions of IBs in STS and illustrate how the routine clinical implementation of a virtual biopsy has the potential to revolutionise the management of this group of complex cancers and improve clinical outcomes.

Abstract Background Metastatic epithelioid sarcoma (EPS) remains a largely unmet clinical need in children, adolescents and young adults despite the advent of EZH2 inhibitor tazemetostat. Methods In order to realise consistently effective drug therapies, a functional genomics approach was used to identify key signalling pathway vulnerabilities in a spectrum of EPS patient samples. EPS biopsies/surgical resections and cell lines were studied by next‐generation DNA exome and RNA deep sequencing, then EPS cell cultures were tested against a panel of chemical probes to discover signalling pathway targets with the most significant contributions to EPS tumour cell maintenance. Results Other biologically inspired functional interrogations of EPS cultures using gene knockdown or chemical probes demonstrated only limited to modest efficacy in vitro. However, our molecular studies uncovered distinguishing features (including retained dysfunctional SMARCB1 expression and elevated GLI3, FYN and CXCL12 expression) of distal, paediatric/young adult‐associated EPS versus proximal, adult‐associated EPS. Conclusions Overall results highlight the complexity of the disease and a limited chemical space for therapeutic advancement. However, subtle differences between the two EPS subtypes highlight the biological disparities between younger and older EPS patients and emphasise the need to approach the two subtypes as molecularly and clinically distinct diseases.

Abstract Background This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra‐rare sarcoma, marked by WWTR1‐CAMTA1 or YAP1‐TFE3 fusions. Methods Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan‐Meier method. Results Overall, 73 patients were included; 21 had more than one treatment. Thirty‐three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m‐) PFS and m‐OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m‐PFS and m‐OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m‐PFS and m‐OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF‐α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m‐PFS and m‐OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported. Conclusion Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.

Abstract Soft tissue sarcomas (STS) are rare and heterogeneous tumours comprising over 80 different histological subtypes. Treatment options remain limited in advanced STS with high rates of recurrence following resection of localised disease. Prognostication in clinical practice relies predominantly on histological grading systems as well as sarcoma nomograms. Rapid developments in gene expression profiling technologies presented opportunities for applications in sarcoma. Molecular profiling of sarcomas has improved our understanding of the cancer biology of these rare cancers and identified potential novel therapeutic targets. In particular, transcriptomic signatures could play a role in risk classification in sarcoma to aid prognostication. Unlike other solid and haematological malignancies, transcriptomic signatures have not yet reached routine clinical use in sarcomas. Herein, we evaluate early developments in gene expression profiling in sarcomas that laid the foundations for transcriptomic signature development. We discuss the development and clinical evaluation of key transcriptomic biomarker signatures in sarcomas, including Complexity INdex in SARComas (CINSARC), Genomic Grade Index, and hypoxia-associated signatures. Prospective validation of these transcriptomic signatures is required, and prospective trials are in progress to evaluate reliability for clinical application. We anticipate that integration of these gene expression signatures alongside existing prognosticators and other Omics methodologies, including proteomics and DNA methylation analysis, could improve the identification of ‘high-risk’ patients who would benefit from more aggressive or selective treatment strategies. Moving forward, the incorporation of these transcriptomic prognostication signatures in clinical practice will undoubtedly advance precision medicine in the routine clinical management of sarcoma patients.

Abstract Background [68 Ga]Ga-DOTATATE PET/CT is now recognised as the most sensitive functional imaging modality for the diagnosis of well-differentiated neuroendocrine tumours (NET) and can inform treatment with peptide receptor radionuclide therapy with [177Lu]Lu-DOTATATE. However, somatostatin receptor (SSTR) expression is not unique to NET, and therefore, [68 Ga]Ga-DOTATATE PET/CT may have oncological application in other tumours. Molecular profiling of gastrointestinal stromal tumours that lack activating somatic mutations in KIT or PDGFRA or so-called ‘wild-type’ GIST (wtGIST) has demonstrated that wtGIST and NET have overlapping molecular features and has encouraged exploration of shared therapeutic targets, due to a lack of effective therapies currently available for metastatic wtGIST. Aims To investigate (i) the diagnostic role of [68 Ga]Ga-DOTATATE PET/CT; and, (ii) to investigate the potential of this imaging modality to guide treatment with [177Lu]Lu-DOTATATE in patients with wtGIST. Methods [68 Ga]Ga-DOTATATE PET/CT was performed on 11 patients with confirmed or metastatic wtGIST and one patient with a history of wtGIST and a mediastinal mass suspicious for metastatic wtGIST, who was subsequently diagnosed with a metachronous mediastinal paraganglioma. Tumour expression of somatostatin receptor subtype 2 (SSTR2) using immunohistochemistry was performed on 54 tumour samples including samples from 8/12 (66.6%) patients who took part in the imaging study and 46 tumour samples from individuals not included in the imaging study. Results [68 Ga]Ga-DOTATATE PET/CT imaging was negative, demonstrating that liver metastases had lower uptake than background liver for nine cases (9/12 cases, 75%) and heterogeneous uptake of somatostatin tracer was noted for two cases (16.6%) of wtGIST. However, [68 Ga]Ga-DOTATATE PET/CT demonstrated intense tracer uptake in a synchronous paraganglioma in one case and a metachronous paraganglioma in another case with wtGIST. Conclusions Our data suggest that SSTR2 is not a diagnostic or therapeutic target in wtGIST. [68 Ga]Ga-DOTATATE PET/CT may have specific diagnostic utility in differentiating wtGIST from other primary tumours such as paraganglioma in patients with sporadic and hereditary forms of wtGIST.

Soft tissue sarcomas are a highly heterogenous group of tumors with limited systemic therapy options. Eribulin, a synthetic analogue of halichondrin B, is a potent mitotic inhibitor. A phase 3 trial of previously treated advanced Liposarcoma and Leiomyosarcoma demonstrated superiority of eribulin to dacarbazine. Eribulin appears to be particularly effective for liposarcomas. It has also been shown to be a safe and effective treatment alternative to doxorubicin in patients where doxorubicin is contraindicated. From retrospective studies, eribulin has demonstrated efficacy in patients with angiosarcoma, pleomorphic sarcomas, synovial sarcomas, rhabdomyosarcomas, angiosarcomas, and myxofibrosarcomas. Future areas of development include liposomal eribulin, which may provide increased efficacy and lower toxicity, and delineation of biomarkers of response and resistance, allowing better selection of patients for treatment.

PURPOSEMany patients with cancer, often those with rare cancers such as sarcomas, travel long distances to access expert care. The COVID-19 pandemic necessitated widespread changes in delivery of cancer care, including rapid adoption of telemedicine-based care. We aimed to evaluate the impact of telemedicine on patients, clinicians, and care delivery at the Royal Marsden Hospital (RMH) Sarcoma Unit during the pandemic.METHODSData were extracted from patient records for all planned outpatient appointments at the RMH Sarcoma Unit from March 23 to April 24, 2020. Patients and clinicians completed separate questionnaires to understand their experiences.RESULTSOf 379 planned face-to-face appointments, 283 (75%) were converted to telemedicine. Face-to-face appointments remained for patients who needed urgent start of therapy or performance status assessment. Patients lived on average > 1.5 hours from RMH. Patient satisfaction (n = 108) with telemedicine was high (mean, 9/10), and only 48% (n = 52/108) would not want to hear bad news using telemedicine. Clinicians found telemedicine efficient, with no associated increased workload, compared with face-to-face appointments. Clinicians indicated lack of physical examination did not often affect care provision when using telemedicine. Most clinicians (n = 17; 94%) believed telemedicine use was practice changing; congruently, 80% (n = 86/108) of patients desired some telemedicine as part of their future care, citing reduced cost and travel time.CONCLUSIONTelemedicine can revolutionize delivery of cancer care, particularly for patients with rare cancers who often live far away from expert centers. Our study demonstrates important patient and clinician benefits; assessment of longer-term impact on patient outcomes and health care systems is needed.

Soft tissue sarcomas are rare cancers of mesenchymal origin or differentiation comprising over 70 different histological subtypes. Due to their mesenchymal differentiation, sarcomas are thought to produce and deposit large quantities of extracellular matrix (ECM) components. Interactions between ECM ligands and their corresponding adhesion receptors such as the integrins and the discoidin domain receptors play key roles in driving many fundamental oncogenic processes including uncontrolled proliferation, cellular invasion and altered metabolism. In this review, we focus on emerging studies that describe the key ECM components commonly found in soft tissue sarcomas and discuss preclinical and clinical evidence outlining the important role that these proteins and their cognate adhesion receptors play in sarcomagenesis. We conclude by providing a perspective on the need for more comprehensive in-depth analyses of both the ECM and adhesion receptor biology in multiple histological subtypes in order to identify new drug targets and prognostic biomarkers for this group of rare diseases of unmet need.

Osteosarcoma is a rare, primary tumour of bone. Curative treatment consists of multi-agent chemotherapy and complete surgical resection. Despite the use of multi-agent chemotherapy, the risk of recurrence is high. Survival outcomes for patients with osteosarcoma have not changed since the 1980′s. Based on biologic rationale, there has been interest in adding immunotherapies to upfront curative intent chemotherapy, including mifamurtide (a macrophage activator) and interferon. However, results to date have been disappointing. In the metastatic setting, checkpoint inhibitors alone have not proven effective. Ongoing translational work is needed to further understand which patients may benefit from immune-oncology approaches with standard cytotoxic chemotherapy.

Abstract Background Cancer patients with advanced disease routinely exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates molecular sequencing data with functional assay data to develop patient-specific combination cancer treatments. Methods Tissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach identified a synergistic personalized two-drug combination. Cells derived from the primary murine tumor were allografted into mouse models and used to validate the personalized two-drug combination. Computational modeling of single agent drug screening and RNA sequencing of multiple heterogenous sites from a single patient’s epithelioid sarcoma identified a personalized two-drug combination effective across all tumor regions. The heterogeneity-consensus combination was validated in a xenograft model derived from the patient’s primary tumor. Cell cultures derived from human and canine undifferentiated pleomorphic sarcoma were assayed by drug screen; computational modeling identified a resistance-abrogating two-drug combination common to both cell cultures. This combination was validated in vitro via a cell regrowth assay. Results Our computational modeling approach addresses three major challenges in personalized cancer therapy: synergistic drug combination predictions (validated in vitro and in vivo in a genetically engineered murine cancer model), identification of unifying therapeutic targets to overcome intra-tumor heterogeneity (validated in vivo in a human cancer xenograft), and mitigation of cancer cell resistance and rewiring mechanisms (validated in vitro in a human and canine cancer model). Conclusions These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.

The tumor, node, metastases (TNM) anatomic staging system plays a pivotal role in cancer care, research, and cancer control activities. Since the first edition of the American Joint Committee on Cancer TNM staging classification published in 1977, soft tissue sarcomas have been staged in an anatomic site agnostic fashion whereby the primary tumor size (T) was categorized as T1 if 5 cm; this remained unchanged through the 7th edition of the TNM. However, soft tissue sarcomas of the head and neck (STSHN) usually present smaller than sarcomas of other sites, but carry a disproportionate risk of local recurrence. Up to 70% of tumors are less than 5 cm at presentation, and therefore classified together as T1. Given the rarity of STSHN, there is a paucity of data to guide progress in their classification. Moreover, the majority of publications only report tumor size as less than or greater than 5 cm, presumably based on conventions of the TNM system that remained unchanged for 40 years, thereby affecting progress of STSHN classification. This formed the impetus for change in the 8th edition in 2 key ways: 1) several soft tissue sarcoma site based changes occurred including STSHN now having its own system, and 2) primary tumor size cut-offs of 2 cm and 4 cm used in STSHN now reflect sizes that head and neck specialists commonly encounter in their practice. This update was pragmatic in modifying the TNM from a system with a T category not serving STSHN and which was originally based on sarcoma data from non-head and neck anatomic sites. The background to this change is outlined which provides a framework in which data can be reported to generate evidence for future staging modifications. Keywords: Head and neck cancer, Soft tissue sarcoma, Cancer staging, TNM staging

Synovial sarcoma is a rare translocation-driven cancer with poor survival outcomes, particularly in the advanced setting. Previous synovial sarcoma preclinical studies have relied on a small panel of cell lines which suffer from the limitation of genomic and phenotypic drift as a result of being grown in culture for decades. Patient-derived xenografts (PDX) are a valuable tool for preclinical research as they retain many histopathological features of their originating human tumour; however, this approach is expensive, slow, and resource intensive, which hinders their utility in large-scale functional genomic and drug screens. To address some of these limitations, in this study, we have established and characterised a novel synovial sarcoma cell line, ICR-SS-1, which is derived from a PDX model and is amenable to high-throughput drug screens. We show that ICR-SS-1 grows readily in culture, retains the pathognomonic SS18::SSX1 fusion gene, and recapitulates the molecular features of human synovial sarcoma tumours as shown by proteomic profiling. Comparative analysis of drug response profiles with two other established synovial sarcoma cell lines (SYO-1 and HS-SY-II) finds that ICR-SS-1 harbours intrinsic resistance to doxorubicin and is sensitive to targeted inhibition of several oncogenic pathways including the PI3K-mTOR pathway. Collectively, our studies show that the ICR-SS-1 cell line model may be a valuable preclinical tool for studying the biology of anthracycline-resistant synovial sarcoma and identifying new salvage therapies following failure of doxorubicin.

Ovarian sarcomas account for 1% of all ovarian malignancies and amongst these, primary ovarian leiomyosarcoma is the rarest subtype. Primary ovarian leiomyosarcoma has a very poor prognosis, with less than 20% of patients being alive at 5 years. Only a few cases have been published in the literature and there is very limited knowledge on the clinical behaviour and optimal management of these tumours. We have performed a retrospective analysis of a prospectively maintained database to identify all primary ovarian leiomyosarcoma diagnosed and treated at the Royal Marsden NHS Foundation Trust between 1998 and 2020. Sixteen patients were identified from our database and fifteen were eligible for the analysis. Twelve patients presented with localized disease and underwent initial surgery and three patients had metastatic disease at presentation. Recurrence-free survival post-surgery was 16 months. Eight patients received first-line chemotherapy and four patients received second-line chemotherapy. Two patients had indolent metastatic disease and benefited from local therapies only. The median overall survival in the metastatic setting in our cohort was 51 months, which is consistent with previously published cases. Primary ovarian leiomyosarcoma is an extremely rare malignancy with a poor prognosis. This study is the largest case series of primary ovarian leiomyosarcoma published to date, providing clinically important information regarding survival and metastatic rate as well as treatment outcomes in the metastatic setting.

Accumulating evidence suggests that platelets play a key role in cancer metastatic dissemination through their multilevel interaction with tumor cells. Most crucial is the contribution of platelets to the formation and expansion of the early metastatic niche, a protective microenvironment that nurtures the first metastatic cells and is necessary for the establishment of overt metastatic disease. A multitude of mechanisms have been proposed toward this effect. The current review examines the implication of platelets in the three most well-studied mechanisms: (a) the initial preparation of the metastatic microenvironment by the formation of the extracellular matrix (ECM) and the recruitment of granulocytes, (b) the creation of the neovasculature (important for providing the developing tumor with oxygen and nutrients and clearing away the metabolic waste), and (c) the evasion of the immune response by the creation of an immune-suppressive environment around the developing metastases. Finally, the review provides current perspectives on the potential clinical relevance of platelets in cancer progression and their consequent role in cancer therapeutics.

Purpose. Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. Patients and Methods. Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles. Results. Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (p=0.47). Median OS was not reached in either arm. Conclusions. Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.

Soft tissue tumors are diagnostically challenging, and it is recommended that these are reported or reviewed by specialist soft tissue pathologists. We present our experience with second-opinion (consultation) cases in a specialist tertiary sarcoma center. The aim of this study was to determine areas of diagnostic difficulty in soft tissue pathology. We assessed 581 second-opinion cases which were reviewed by two experienced pathologists in a period of one year. There was 62% concordance between the original and the second-opinion diagnosis, with diagnostic discrepancy in 38%. The largest group of soft tissue neoplasms received for second opinion was fibroblastic/myofibroblastic tumors, and most major diagnostic problems were encountered in adipocytic and so-called “fibrohistiocytic” tumors. Major diagnostic errors impacting management were found in 148 cases (25%). Morphologic assessment of tumors, judicious use of molecular techniques, newer immunostains and their interpretation, along with importance of knowledge of rarer entities were found to be most useful in avoiding errors.

Gastrointestinal stromal tumor (GIST) is a devastating disease, especially in the setting of metastasis. The natural progression of GIST has been significantly altered by the development of small molecule tyrosine kinase inhibitors (TKIs), including imatinib, sunitinib, and regorafenib, all of which are FDA approved. However, TKIs are not always well-tolerated, and the refractory disease continues to be a problem. For these reasons, alternative treatments are needed. In this report, we discuss a patient with metastatic wild-type (WT) GIST refractory to multiple TKIs, but with a durable clinical response to the anti-programmed cell death protein 1 (PD-1) antibody, nivolumab. This report suggests that continued research evaluating checkpoint inhibitors in GIST is warranted.

Preclinical data suggest that a “prime-boost” vaccine regimen using a target-expressing lentiviral vector for priming, followed by a recombinant protein boost, may be effective against cancer; however, this strategy has not been evaluated in a clinical setting. CMB305 is a prime-boost vaccine designed to induce a broad anti-NY-ESO-1 immune response. It is composed of LV305, which is an NY-ESO-1 expressing lentiviral vector, and G305, a recombinant adjuvanted NY-ESO-1 protein. This multicenter phase 1b, first-in-human trial evaluated CMB305 in patients with NY-ESO-1 expressing solid tumors. Safety was examined in a 3 + 3 dose-escalation design, followed by an expansion with CMB305 alone or in a combination with either oral metronomic cyclophosphamide or intratumoral injections of a toll-like receptor agonist (glucopyranosyl lipid A). Of the 79 patients who enrolled, 81.0% had sarcomas, 86.1% had metastatic disease, and 57.0% had progressive disease at study entry. The most common adverse events were fatigue (34.2%), nausea (26.6%), and injection-site pain (24.1%). In patients with soft tissue sarcomas, a disease control rate of 61.9% and an overall survival of 26.2 months (95% CI, 22.1–NA) were observed. CMB305 induced anti-NY-ESO-1 antibody and T-cell responses in 62.9% and 47.4% of patients, respectively. This is the first trial to test a prime-boost vaccine regimen in patients with advanced cancer. This approach is feasible, can be delivered safely, and with evidence of immune response as well as suggestion of clinical benefit.

Immunotherapy in soft tissue sarcoma (STS) has experienced a surge of interest in the past decade, contributing to an expanding number of therapeutic options for this extremely heterogenous group of rare malignancies. Immune checkpoint inhibitors (CPIs) targeting the PD-1 and CTLA-4 axes have demonstrated promising responses in a select number of STS subtypes, including rarer subtypes, such as alveolar soft part sarcoma, SWI/SNF-deficient sarcomas, clear cell sarcoma, and angiosarcoma. Multiple pan-subtype sarcoma trials have facilitated the study of possible predictive biomarkers of the CPI response. It has also become apparent that certain therapies, when combined with CPIs, can enhance response rates, although the specific mechanisms of this possible synergy remain unconfirmed in STS. In addition to CPIs, several other immune targeting agents, including anti-tumour-associated macrophage and antigen-directed therapies, are now under assessment in STS with promising efficacy in some subtypes. In this article, we review the state of the art in immunotherapy in STS, highlighting the pre-clinical and clinical data available for this promising therapeutic strategy.

Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal tumors, rhabdomyosarcomas, and liposarcomas. These alterations include genetic events such as translocations, mutations, and amplifications as well as transcriptional overexpression. Targeting FGFR has therefore been proposed as a novel potential therapeutic approach, also in light of the clinical activity shown by multi-target tyrosine kinase inhibitors in specific subtypes of sarcomas. Despite promising preclinical evidence, thus far, clinical trials have enrolled very few sarcoma patients and the efficacy of selective FGFR inhibitors appears relatively low. Here, we review the known alterations of the FGFR pathway in sarcoma patients as well as the preclinical and clinical evidence for the use of FGFR inhibitors in these diseases. Finally, we discuss the possible reasons behind the current clinical data and highlight the need for biomarker stratification to select patients more likely to benefit from FGFR targeted therapies.

Osteosarcoma is the most common primary bone sarcoma and is often diagnosed in the 2nd–3rd decades of life. Response to the aggressive and highly toxic neoadjuvant methotrexate-doxorubicin-cisplatin (MAP) chemotherapy schedule is strongly predictive of outcome. Outcomes for patients with osteosarcoma have not significantly changed for over thirty years. There is a need for more effective treatment for patients with high risk features but also reduced treatment-related toxicity for all patients. Predictive biomarkers are needed to help inform clinicians to de-escalate or add therapy, including immune therapies, and to contribute to future clinical trial designs. Here, we review a variety of approaches to improve outcomes and quality of life for patients with osteosarcoma with a focus on incorporating toxicity reduction, immune therapy and molecular analysis to provide the most effective and least toxic osteosarcoma therapy.

Dermatofibrosarcoma protuberans (DFSP), the most common dermal sarcoma, is a low-grade, slow growing fibroblastic malignant neoplasm that most frequently affects middle aged adults and is characterized by a high local recurrence rate and a low propensity for metastasis. Wide surgical resection or Mohs micrographic surgery (MMS) are the preferred approaches for localized disease, while radiation therapy is warranted for inoperable disease or for cases with positive margins where re-excision is not possible. DFSP is generally regarded as refractory to conventional chemotherapy. Treatment options for systemic disease were limited until the discovery of a unique translocation, t(17;22)(q22;q13) (COL1A1;PDGFB) found in a majority of cases. In recent years, imatinib, a PDGFβR, ABL and KIT inhibitor, has revolutionized systemic therapy in DFSP. In this review, we summarize the epidemiological, clinical, histological and genetic characteristics of DFSP and update the readers on its current management.

Soft tissue sarcomas are a group of rare tumors derived from mesenchymal tissue, accounting for about 1% of adult cancers. There are over 60 different histological subtypes, each with their own unique biological behavior and response to systemic therapy. The outcome for patients with metastatic soft tissue sarcoma is poor with few available systemic treatment options. For decades, the mainstay of management has consisted of doxorubicin with or without ifosfamide. Trabectedin is a synthetic agent derived from the Caribbean tunicate, Ecteinascidia turbinata. This drug has a number of potential mechanisms of action, including binding the DNA minor groove, interfering with DNA repair pathways and the cell cycle, as well as interacting with transcription factors. Several phase II trials have shown that trabectedin has activity in anthracycline and alkylating agent-resistant soft tissue sarcoma and suggest use in the second- and third-line setting. More recently, trabectedin has shown similar progression-free survival to doxorubicin in the first-line setting and significant activity in liposarcoma and leiomyosarcoma subtypes. Trabectedin has shown a favorable toxicity profile and has been approved in over 70 countries for the treatment of metastatic soft tissue sarcoma. This manuscript will review the development of trabectedin in soft tissue sarcomas.

Liposarcoma is one of the most common subtypes of soft-tissue sarcoma and consists of three main subtypes, of which well-differentiated liposarcoma and dedifferentiated liposarcoma account for 40–45%. The current mainstay of systemic treatment for patients with metastatic or unresectable disease remains doxorubicin with or without ifosfamide in the first-line setting. Recently, eribulin and trabectedin have been approved by the US Food and Drug Administration for recurrent liposarcomas and progress in molecular characterization of these tumors has opened up new and potential novel treatment targets. This review will focus on the evidence base for current treatment strategies and will also discuss potential future options.

Myoepithelial tumors of the soft tissues represent a rare group of neoplasms that vary in their clinical behavior, pathologic features and genetics. They are histopathologically typified by a myoepithelial immunohistochemical phenotype, of expression of one or more epithelial markers, S100 protein and smooth muscle actin. Because of their rarity and occurrence over a wide age range and at a variety of anatomic sites, they can be difficult to diagnose due to the lack of familiarity by physicians, which is compounded by their spectrum of histologic features and morphologic overlap with several other neoplasms. Recent genetic insights have aided classification, and it is increasingly understood that soft tissue myoepithelial neoplasms can be stratified into two distinct morphologic and genetic subgroups. We describe a case of a 44-year-old man who was diagnosed with a primary myoepithelial neoplasm of the paracecal mesentery, which showed aggressive local recurrence after four years. The tumor was composed of cords of ovoid cells within chondromyxoid stroma, and displayed a characteristic pancytokeratin, S100 protein and smooth muscle actin-positive myoepithelial immunoprofile. Primary myoepithelioma has not been previously described at this site, and this case highlights this varied family of tumors, emphasizes the need to consider myoepithelial tumor in the differential diagnoses of carcinoma variants occurring in the bowel or mesentery, and also adds to the number of reported myoepithelial neoplasms showing markedly aggressive behavior.

Background. Worse chemotherapy response for neurofibromatosis type 1- (NF1-) associated compared to sporadic malignant peripheral nerve sheath tumors (MPNST) has been reported. Methods. We evaluated the objective response (OR) rate of patients with AJCC Stage III/IV chemotherapy-naive NF1 MPNST versus sporadic MPNST after 4 cycles of neoadjuvant chemotherapy, 2 cycles of ifosfamide/doxorubicin, and 2 cycles of ifosfamide/etoposide. A Simon optimal two-stage design was used (target response rate 40%). Results. 34 NF1 (median age 33 years) and 14 sporadic (median age 40 years) MPNST patients enrolled. Five of 28 (17.9%) evaluable NF1 MPNST patients had a partial response (PR), as did 4 of 9 (44.4%) patients with sporadic MPNST. Stable disease (SD) was achieved in 22 NF1 and 4 sporadic MPNST patients. In both strata, results in the initial stages met criteria for expansion of enrollment. Only 1 additional PR was observed in the expanded NF1 stratum. Enrollment was slower than expected and the trial closed before full accrual. Conclusions. This trial was not powered to detect differences in response rates between NF1 and sporadic MPNST. While the OR rate was lower in NF1 compared to sporadic MPNST, qualitative responses were similar, and disease stabilization was achieved in most patients.

PM00104 (Zalypsis®) is a synthethic tetrahydroisoquinolone alkaloid, which is structurally similar to many marine organisms. The compound has been proposed as a potential chemotherapeutic agent in the treatment of solid human tumors and hematological malignancies. PM00104 is a DNA binding agent, causing inhibition of the cell cycle and transcription, which can lead to double stranded DNA breaks. After rigorous pre-clinical testing, the drug has been evaluated in a number of phase II clinical trials. This manuscript provides a review of current trials and appraises the efficacy of PM00104 as a future cancer treatment.

Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and posttreatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.

Uterine leiomyosarcoma is a rare and aggressive malignancy with poor overall prognosis. There have been few reports of metastatic leiomyosarcoma in the gallbladder. We report a case of a 41-year-old female who underwent total abdominal hysterectomy due to presumed uterine fibroids. The postoperative pathology revealed high-grade pleomorphic leiomyosarcoma, with involvement of the uterine serosal surface. She subsequently underwent exploratory laparotomy, followed by pelvic radiation and chemotherapy. Since initial management she has developed metastatic disease and has been under treatment and surveillance for 11 years. She has undergone multiple surgical procedures and numerous lines of systemic therapy for metastatic leiomyosarcoma, including cholecystectomy for a metastatic lesion in the gallbladder. There have been no previous reports of metastatic leiomyosarcoma in the gallbladder. Despite extensive metastatic disease this patient has had prolonged survival with multi-modality management.

Dedifferentiated liposarcoma (DDL) is a histologically pleomorphic sarcoma, traditionally defined as well-differentiated liposarcoma with abrupt transition to high grade, nonlipogenic sarcoma. It can occur as part of recurrent well-differentiated liposarcoma, or may arise de novo. DDL most frequently occurs within the retroperitoneum, and while it is prone to local recurrence, it usually has a lower rate of metastasis than other pleomorphic sarcomas. We describe a case of retroperitoneal dedifferentiated liposarcoma in a 63-year-old male, who showed MDM2 amplification with fluorescence in situ hybridization, which displayed unusually aggressive behavior, with brain, lung and subcutaneous soft tissue metastases. As previous reports of metastatic liposarcoma have largely grouped DDL in with other (genetically and clinically distinct) liposarcoma subtypes, we highlight and discuss the rare occurrence of brain metastasis in MDM2-amplified retroperitoneal liposarcoma.

Myoepithelial neoplasms of the soft tissues are a rare, heterogeneous group of tumors for which classification continues to evolve. While well defined within salivary glands, they can also arise in viscera and soft tissues, where diagnosis is challenging due to the lack of clinical and pathological familiarity. We present the case of a 36 year old man with myoepithelial carcinoma arising as a primary tumor within the soft tissues of the neck, which metastasized to the cecum, causing intussusception. This spindle cell neoplasm showed the classic S100 protein, smooth muscle actin and pancytokeratin-positive immunoprofile. Metastasis of myoepithelial carcinoma to the cecum has not been previously described, and coupled with the spindle cell morphology, may cause significant diagnostic difficulty in the absence of clinical familiarity, particularly as there is morphologic overlap with spindle cell neoplasms arising more commonly in gastrointestinal sites, including gastrointestinal stromal tumor, leiomyosarcoma and sarcomatoid carcinoma.

Background. Belinostat is a novel histone deacetylase inhibitor. Primary Objectives. Maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of belinostat (Bel) in combination with doxorubicin (Dox) in solid tumours (phase I) and response rate (RR) in soft tissue sarcomas (phase II). Methods. Bel was administered as a 30-minute IV infusion on days 1–5 and on day 5 with Dox. The dose escalation schedule was as follows: cohort 1: Bel 600 mg/m2 and 50 mg/m2 Dox, cohort 2: Bel 600 mg/m2 and 75 mg/m2 Dox, cohort 3: Bel 800 mg/m2 and 75 mg/m2 Dox, and cohort 4: Bel 1000 mg/m2 and 75 mg/m2 Dox. Results. 41 patients were included (25 in phase I, 16 in phase II). Adverse events were fatigue (95%), nausea (76%), and alopecia (63%). There was one DLT, grade 3 rash/hand and foot syndrome. MTD was Bel 1000 mg/m2/d and Dox 75 mg/m2. Four responses were seen: 2 PR in phase I, RR of 8%; in phase II, 1 PR/1 CR, RR of 13%, and 9 patients (56%) with SD. Conclusion. The combination was well tolerated. Response rate was moderate but median time to progression was 6.0 months (95% CI, 1.6–9.7 months) which is superior to some reports of single-agent Dox.

We report a response to pazopanib in a 69-year-old man with heavily pre-treated metastatic extraosseous Ewing sarcoma in addition to molecular profiling of his tumor. To our knowledge, this case is the earliest to demonstrate activity of an oral multi-targeted kinase inhibitor in Ewing sarcoma. This case provides rationale for adding a Ewing sarcoma arm to SARC024, a phase II study of regorafenib, another multi-targeted kinase inhibitor, in patients with liposarcoma, osteosarcoma and Ewing and Ewing-like sarcomas (NCT02048371). This national multi-institutional study is ongoing.

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract. The introduction of a number of small molecule tyrosine kinase inhibitors has revolutionized the management of metastatic disease. Surgery is the mainstay of management for localized disease. Patients with high risk tumors are treated with adjuvant imatinib. We report the rare presentation of a localized primary small bowel gastrointestinal stromal tumor in association with multiple liver abscesses. Cystic liver lesions should be fully evaluated in gastrointestinal tumor patients to exclude an infective cause. Treatment with intravenous antibiotics resulted in clinical and radiological improvement of the liver abscesses. The small bowel tumor was treated with surgical resection.

Primary splenic angiosarcoma is a very rare neoplasm with a high propensity for metastatic disease and poor prognosis. There is a paucity of literature concerning this specific sarcoma subtype and the role of systemic therapy is not well defined. A retrospective review of the prospectively maintained University of Washington/Seattle Cancer Care Alliance Sarcoma Unit database was performed to identify patients with splenic angiosarcoma treated between 2007 and 2012. In total there were 19 patients with angiosarcoma treated at the Seattle Cancer Care Alliance from 2007 to 2012. The number of patients with splenic angiosarcoma was 2 (11%). The first patient was a woman aged 57 years who was referred with metastatic splenic angiosarcoma to the liver, post-splenectomy. She was treated with 4 cycles of weekly paclitaxel prior to metastatic resection and 4 cycles of the same drug in an adjuvant scenario, achieving a pathological complete response to treatment. She is alive and on third-line systemic therapy. The second patient was a male patient aged 30 years who presented with metastatic high-grade splenic angiosarcoma and was treated with 3 lines of systemic therapy, including doxorubicin, paclitaxel and gemcitabine+docetaxel, but developed a gastrointestinal metastasis with subsequent gastrointestinal bleeding. Splenic angiosarcoma is a very rare neoplasm. Surgery remains the mainstay of management for localized disease. Paclitaxel administered weekly proved to be well-tolerated and resulted in a good radiological response in one of our patients, enabling resection of metastatic disease. Durable clinical benefit can be achieved in metastatic splenic angiosarcoma with multi modality management.

Ewing's sarcoma family of tumours comprises a group of very aggressive diseases that are potentially curable with multimodality treatment. Despite the undoubted success of current treatment, approximately 30% of patients will relapse and ultimately die of disease. The insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the genesis, growth, proliferation, and the development of metastatic disease in Ewing's sarcoma. In addition, IGF1-R has been validated, both in vitro and in vivo, as a potential therapeutic target in Ewing's sarcoma. Phase I studies of IGF-1R monoclonal antibodies reported several radiological and clinical responses in Ewing's sarcoma patients, and initial reports of several Phase II studies suggest that about a fourth of the patients would benefit from IGF-1R monoclonal antibodies as single therapy, with approximately 10% of patients achieving objective responses. Furthermore, these therapies are well tolerated, and thus far severe toxicity has been rare. Other studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies are expected. Despite, the initial promising results, not all patients benefit from IGF-1R inhibition, and consequently, there is an urgent need for the identification of predictive markers of response.

Immunotherapy has shown promise in a number of tumor types, but its exact role in sarcoma remains to be defined. Advanced bone and soft tissue sarcomas are challenging diseases to treat with an unmet need for effective systemic therapy. Previous reports have suggested that immune-based treatments may be effective in sarcoma, but such approaches have not yet become part of standard clinical practice. A number of sarcoma subtypes express targets known as cancer testis antigens and hence may be excellent targets for immunotherapy. This paper will focus on the recent advances and understanding of cancer testis antigens in sarcoma and also clinical data of immunotherapeutic approaches in these diseases.