Soft Tissue Sarcoma Subtypes Research Articles

Efficacy of targeted therapy in alveolar soft part sarcoma: A systematic review and meta-analysis.

e23543 Background: Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma, characterized by a specific unbalanced translocation leading to the fusion of the TFE3 gene on chromosome-X to the ASPSCR1 gene on chromosome-17. Despite its indolent course, ASPS presents a challenge in treatment due to its resistance to conventional anthracycline-based chemotherapy and lack of large scale trial data for this rare sarcoma. This review aimed to assess the efficacy of tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) in metastatic alveolar soft part sarcoma. Methods: A systematic search was performed on Embase and Medline databases for studies that assessed best response of patients with unresectable or metastatic ASPS to TKI and ICI therapy, according to the Response Evaluation Criteria in Solid Tumors (RECIST) edition 1.0 or 1.1. This study followed the Preferred Reporting Items for Systematic Reviews (PRISMA) protocol. Four independent reviewers screened abstracts and extracted the data; any discrepancy was resolved by discussion among reviewers. Pooled objective response rate (ORR) and disease control rate (DCR) were obtained using the Freeman-Tukey double-arcsine transformation using random effects model on STATA software (version. 16.1, StataCorp). Results: 27 articles and abstracts published between 2011 and 2020 were included in the review, resulting in 2 randomized clinical trials (104 participants), 14 single arm prospective trials (214 participants), and 11 retrospective studies (120 patients). Among clinical trials, the pooled ORR and DCR were 18% (95% confidence interval [CI] 8 - 30%; I2 = 72.25%; p < 0.01) and 87% (95% CI 97 - 93%; I2 = 43.2%; p = 0.03) respectively. Conclusions: The response rate to targeted therapy in metastatic ASPS is not only clinically meaningful, but also comparable to that of first-line chemotherapy. The majority of patients receiving targeted therapy achieved disease control. Patients who had refractory or progressive disease to one targeted agent demonstrated response to other agents. More randomized trials are warranted to expand treatment options and compare to standard of care regimens.

Pazopanib in the advanced and rare subtypes of soft tissue sarcoma: Russian Sarcoma Group study.

e23528 Background: Sarcoma is a heterogeneous group of tumors that arise from connective tissue. The most frequent localizations of primary tumors are soft tissues and bones of the extremities, and the lungs is the most common localization of metastases. Pazopanib is an antineoplastic agent, multi-kinase inhibitor that retards angiogenesis in tumor tissues and has been shown to be effective in the treatment of patients with advanced sarcoma. Median progression-free survival was 4,6 months (95% CI 3,7–4,8) for pazopanib compared with 1,6 months (0,9–1,8) for placebo in the PALETTE clinical trial. This study designed to detect epidemiology data as well as the pazopanib efficiency for rare sarcoma subtypes. Methods: We collected data from 109 cases with 20 different sarcoma histotypes and 15 localizations, at N.N. Blokhin National Medical Research Center of Oncology from 2018 till 2020. Disease was histologically confirmed by a sarcoma pathologist. The average age of patients was 47.8 years and the women and men ratio was about 2:1. Patients received pazopanib 800 mg once daily and passed control examinations every 2 or 3 months (CT/MRI). Treatment response was assessed by RECIST criteria. Results: The most frequent localizations of primary tumors were the soft tissues of the extremities (39.6%), the uterus (16.9%) and the retroperitoneum (13.2%). The main histological subtypes were leiomyosarcoma (33.6%) and synovial sarcoma (14.9%). There were also included such types like a embryonal rhabdomyosarcoma, chondrosarcoma, Ewing tumors, EHE, alveolar soft part sarcoma, PEComa, clear cell sarcoma, adamantinoma, solitary fibrous tumor, epithelioid sarcoma and myxoid liposarcoma. The majority of patients (61%) received more than 2 of therapy. The average duration of therapy was 7.5 months. Best tumor response by RECIST was as follows: complete response 0 (0%), partial response 2 (2%), stable disease 81 (88,3%), progression disease 25 (27,3%) cases. Median progression-free survival was 8 months (95% CI 6,7-9,2) for pazopanib. Median overall survival was not reached. Overall pazopanib was well tolerated, except one case with SAE. Conclusions: In this study we observed pazopanib efficiency in a rare for pazopanib sarcoma subtypes such as myxoid liposarcoma (1 PR), PEComa, adamantinoma, embryonal rhabdomyosarcoma, malignant peripheral nerve sheath tumor and Ewing tumors. Also our study confirms pazopanib long-term disease control in alveolar soft part sarcoma, clear cell sarcoma, leiomyosarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma which explains median PFS 8 months.

ENVASARC: A pivotal trial of envafolimab, and envafolimab in combination with ipilimumab, in patients with advanced or metastatic undifferentiated pleomorphic sarcoma or myxofibrosarcoma who have progressed on prior chemotherapy.

TPS11581 Background: Metastatic undifferentiated Pleomorphic Sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, efficacy remains limited in the 2nd line setting and beyond. Pazopanib, the only approved treatment in the refractory setting, has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: microsatellite instability-high (MSI-H) cancer and biliary tract cancer. The activity of envafolimab appears to be similar to other PD-1 antibodies administered i.v. Envafolimab demonstrated a 32% objective response rate (ORR) in MSI-H colorectal cancer patients who failed three approved chemotherapeutics, similar to the ORR of 28% and 33% with nivolumab and pembrolizumab in these patient populations, respectively. The rationale for the ENVASARC trial is based on the previously reported activity of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ̃25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n = 80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks i.v. for four doses (cohort B; n = 80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Clinical trial information: NCT 04480502.

Results of the phase 1b soft-tissue sarcoma (STS) portion of the global randomized, double-blind, placebo-controlled study of tazemetostat (TAZ) plus doxorubicin (DOX) as frontline therapy for advanced epithelioid sarcoma (ES).

11563 Background: ES is a rare, aggressive subtype of STS for which cytotoxic chemotherapy has limited effectiveness. TAZ, an FDA-approved EZH2 inhibitor, has shown single-agent clinical activity and a favorable safety profile in patients with metastatic or locally advanced ES. In preclinical studies, TAZ has shown synergistic antitumor activity with DOX, which is often used as frontline treatment for STS. Here, we present results of the phase 1b study (NCT04204941), designed to assess the recommended phase 3 dose (RP3D), safety, and efficacy of TAZ + DOX in patients with advanced STS. Methods: The open-label, phase 1b portion of this study enrolled adult patients with previously untreated advanced STS. A standard 3 + 3 design was used to assess TAZ 400 mg, 600 mg, and 800 mg orally twice daily in combination with DOX (75 mg/m2 intravenously on day 1 of each cycle, for up to 6 cycles) as frontline therapy. Dose-limiting toxicities (DLTs) were predefined in the protocol. The RP3D of TAZ was determined by Scientific Review Committee review of the safety and pharmacokinetic data from the phase 1b trial, with a target DLT rate of < 33%. Results: As of February 1, 2021, 16 patients are enrolled, including 2 with ES; 10 are still receiving TAZ + DOX and 6 have discontinued (5 due to disease progression, 1 due to patient withdrawal). The median age was 49.5 years (range, 29–82) and all had unresectable STS. Median (range) time on treatment was 13 (0.1–51.1+) weeks across all dose levels evaluated. Two DLTs, both of febrile neutropenia, were observed, one in the TAZ 600 mg + DOX cohort (n = 1/6, 17%), and one in the TAZ 800 mg + DOX cohort (n = 1/3, 33%). When used in combination with DOX, the RP3D of TAZ was 800 mg. Grade 3 or 4 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 13/16 (81.3%) patients. The most common (≥ 20%) TR-TEAEs were neutropenia (n = 11, 69%), anemia (n = 10, 63%), fatigue (n = 10, 63%), stomatitis (n = 9, 56%), nausea (n = 8, 50%), febrile neutropenia (n = 7, 44%), constipation (n = 6, 38%), vomiting (n = 6, 38%), and decreased appetite (n = 5, 31%). TR-TEAEs were defined as attributable to either study agent. Conclusions: The combination of TAZ + DOX was generally well tolerated in this dose finding study in patients with advanced STS. The RP3D to be tested in the phase 3 randomized, double blind, placebo controlled study is TAZ 800 mg twice daily + DOX. The safety profile of this combination is consistent with the respective safety information for TAZ and for DOX. The TR-TEAEs include known toxicities of DOX or TAZ. Further comparison with DOX + placebo in the phase 3 trial will aid in assessing efficacy and safety of the combination of TAZ + DOX. The global phase 3 confirmatory trial will enroll patients with ES who have unresectable disease and have had no prior systemic therapy. Clinical trial information: NCT04204941.

ESMO Magnitude of Clinical Benefit Scale (MCBS): An evaluation of systemic treatment trials for soft tissue sarcomas (STS).

11553 Background: Patients with STS have poor prognosis in the metastatic setting. Although some treatment options are associated with improved outcomes, such as progression-free (PFS) or overall survival (OS), the overall magnitude of clinical benefit can be unclear. The ESMO MCBS is a validated and reproducible tool developed to quantify the clinical benefit of treatments evaluated in trials ( www.esmo.org/guidelines/esmo-mcbs ). Herein, we report the application of ESMO MCBS to systemic treatment trials involving metastatic STS patients. Methods: A systematic search of Medline, Embase and Cochrane databases for adult phase II and III trials in advanced STS (01/1998 to 12/2020) was carried out. Gastrointestinal stromal tumor trials were excluded. Outcomes, including but not limited to OS, PFS, objective response rate (ORR), toxicity and quality of life (QoL) data were extracted and analyzed. Studies with outcomes that met the criteria for ESMO MCBS v1.1 were evaluated to generate a score of 1 to 5 (score of ≥ 4: substantial benefit). MCBS scoring of each study was performed by at least 2 co-authors for consensus. Results: Among 3454 abstracts screened, a total of 140 Phase II and 28 phase IIII trials were identified. A total of 41 studies fulfilled the criteria for ESMO MCBS scoring. These include 5 phase III studies, as well as 9 randomized and 27 single-arm phase II trials. Fifteen studies involved specific histology, while remaining 26 studies were of all STS subtypes. Chemotherapy, alone or in combination was evaluated in 29 trials, while molecular-targeted agents (MTA) and immune checkpoint inhibitors (IO) were evaluated in 11 and 3 studies, respectively (Table). The median MCBS score was 2 (range 1-4), regardless of drug class or combination. Only 3 studies, all randomized in design, had a MCBS score of 4. All three trials were in the 2nd line setting or beyond, where there is no standard control treatment. None of the trials, irrespective of drug class had a score of 5 and no study showed evidence of significant improvement in QoL. The observed MCBS scores were low, partly because the trials evaluated mainly comprise single-arm studies without QoL assessments, restricting to a maximum MCBS score of 3. Conclusions: Most systemic therapy trials in advanced STS did not confer substantial clinical benefit when evaluated using MCBS. Although randomized phase 3 trials remain the gold standard of treatment evaluation, clinical benefit evaluation of STS trials using tools such as MCBS may be useful. Incorporation of QoL evaluation, even in single-arm studies should be prioritized in metastatic STS trials.[Table: see text]

Re-evaluating tumors of purported specialized prostatic stromal origin reveals molecular heterogeneity, including non-recurring gene fusions characteristic of uterine and soft tissue sarcoma subtypes.

Tumors of purported specialized prostatic stromal origin comprise prostatic stromal sarcomas (PSS) and stromal tumors of uncertain malignant potential (STUMP). Prior studies have described their clinicopathologic characteristics, but the molecular features remain incompletely understood. Moreover, these neoplasms are morphologically heterogeneous and the lack of specific adjunctive markers of prostatic stromal lineage make precise definition more difficult, leading some to question whether they represent a specific tumor type. In this study, we used next-generation DNA and RNA sequencing to profile 25 primary prostatic mesenchymal neoplasms of possible specialized prostatic stromal origin, including cases originally diagnosed as PSS (11) and STUMP (14). Morphologically, the series comprised 20 cases with solid architecture (11 PSS and 9 STUMP) and 5 cases with phyllodes-like growth pattern (all STUMP). Combined DNA and RNA sequencing results demonstrated that 19/22 (86%) cases that underwent successful sequencing (either DNA or RNA) harbored pathogenic somatic variants. Except for TP53 alterations (6 cases), ATRX mutations (2 cases), and a few copy number variants (-13q, -14q, -16q and +8/8p), the findings were largely nonrecurrent. Eight gene rearrangements were found, and 4 (NAB2-STAT6, JAZF1-SUZ12, TPM3-NTRK1 and BCOR-MAML3) were useful for reclassification of the cases as specific entities. The present study shows that mesenchymal neoplasms of the prostate are morphologically and molecularly heterogeneous and include neoplasms that harbor genetic aberrations seen in specific mesenchymal tumors arising in other anatomic sites, including soft tissue and the uterus. These data suggest that tumors of purported specialized prostatic stromal origin may perhaps not represent a single diagnostic entity or specific disease group and that alternative diagnoses should be carefully considered.

Retrospective Analysis of the Clinical Presentation, Treatment and Outcome of Angiosarcoma in a Sarcoma Referral Center

Introduction: Angiosarcoma (AS) is a rare subtype of soft tissue sarcoma. We performed a retrospective analysis of patient characteristics, treatments and prognostic factors in patients treated in a single sarcoma center. Methods: We reviewed records of patients treated between 1987 and 2018, categorized in 7 different subtypes according to tissue of origin and underlying risk factors. The Kaplan-Meier method was used to estimate overall survival (OS); the Cox proportional hazards model was used to study prognostic variables. Results: Among 134 patients, 30% had radiation-induced, 31% primary soft tissue, 24% cutaneous, 5% breast, 4% bone, 2% lymphedema-associated and 4% unknown primary AS. Key patient/disease characteristics varied between subgroups. The median OS was 22.0 months for the entire cohort, with 28.9% with a 5-year survival. Metastasis at diagnosis was seen in 23% of patients; 38% developed metachronous metastasis. Sixty-six (49%) patients received systemic therapy; common first-line treatments were doxorubicin (48%) and paclitaxel (39%), without a significant difference in OS between agents. Younger age, breast/radiation-induced AS, primary surgery and palliative chemotherapy were associated with better OS. Synchronous metastasis, soft tissue/unknown primary location correlated with poor survival. Conclusion: AS is a very heterogeneous sarcoma subtype, with substantial variability in clinical presentation and survival among patient subsets. Prognosis is poor, and there is no difference in outcome comparing the 2 most frequently used chemotherapy agents in the first line, paclitaxel and doxorubicin.

Bispecific NKG2D-CD3 and NKG2D-CD16 Fusion Proteins as Novel Treatment Option in Advanced Soft Tissue Sarcomas.

Soft tissue sarcoma (STS) constitutes a rare group of heterogeneous malignancies. Effective treatment options for most subtypes of STS are still limited. As a result, especially in metastatic disease, prognosis is still dismal. The ligands for the activating immunoreceptor NKG2D (NKG2DL) are commonly expressed in STS, but generally absent in healthy tissues. This provides the rationale for utilization of NKG2DL as targets for immunotherapeutic approaches. We here report on the preclinical characterization of bispecific fusion proteins (BFP) consisting of the extracellular domain of the NKG2D receptor fused to Fab-fragments directed against CD3 (NKG2D-CD3) or CD16 (NKG2D-CD16) for treatment of STS. After characterization of NKG2DL expression patterns on various STS cell lines, we demonstrated that both NKG2D-CD16 and NKG2D-CD3 induce profound T and NK cell reactivity as revealed by analysis of activation, degranulation and secretion of IFNγ as well as granule associated proteins, resulting in potent target cell lysis. In addition, the stimulatory capacity of the constructs to induce T and NK cell activation was analyzed in heavily pretreated STS patients and found to be comparable to healthy donors. Our results emphasize the potential of NKG2D-CD3 and NKG2D-CD16 BFP to target STS even in an advanced disease.

Real-World Outcomes of Advanced Soft Tissue Sarcoma Patients Treated with Pazopanib

Background: Pazopanib is an oral multitarget tyrosine kinase inhibitor that is currently approved for the treatment of select subtypes of advanced Soft Tissue Sarcoma (STS) in patients who have progressed on prior anthracyclinebased chemotherapy regimens. In this study, we examine data from multiple centers to assess the efficacy of pazopanib in practice outside of a clinical trial setting. Methods: A retrospective chart analysis was conducted for pre-treated, advanced soft tissue sarcoma patients who began treatment with pazopanib in Alberta, Canada and Cairo, Egypt (2012-2018). Results: In total, 39 predominantly male (56.4%) patients received pazopanib. The median age was 51, 67% of whom had an ECOG of one or less. The predominant sarcoma subtype was leiomyosarcoma (30.8%), and all patients had received at least one prior line of systemic therapy. Thirtytwo of the 39 patients (82%) were initially given the full dose of 800mg with a median time on treatment of 116 days. Seven of the 39 (18%) patients required a dose reduction while on treatment. A majority (94.9%) of patients ultimately discontinued pazopanib treatment for reasons including death (21.6%), disease progression (62.2%), and toxicity (16.4%). The median progression-free and overall survival for these patients was 4.1 months (95%CI, 3.6-4.5) and 8.4 months (95% CI, 4.3-12.5), respectively. Conclusion: Pazopanib is an efficient and generally well-tolerated oral systemic therapy for the treatment of advanced, pre-treated, non-adipocytic soft tissue sarcoma. These results show the efficacy of pazoponib outside of a clinical trial setting.

The Feasibility Study of Hypofractionated Radiotherapy with Regional Hyperthermia in Soft Tissue Sarcomas

Simple SummaryThe recommended management of marginally resectable or unresectable soft tissue sarcomas is an attempt of neoadjuvant therapy. The use of neoadjuvant chemotherapy is limited in low-grade tumors, sarcomas with chemoresistant pathology or in unfit patients. There is a growing evidence on hypofractionated radiotherapy in soft tissue sarcomas, but its efficacy may be limited by radioresistance that is frequently associated with chemoresistance. Regional hyperthermia is a potent and minimally invasive radiosensitizer. We aimed to investigate the feasibility of moderately hypofractionated radiotherapy combined with regional hyperthermia in aforementioned clinical situations. Our findings indicate that proposed combination is feasible while maintaining good short-term local efficacy and tolerance. It could serve as a basis for further studies on radiotherapy with hyperthermia in soft tissue sarcomas. Introduction: Management of marginally resectable or unresectable soft tissue sarcomas (STS) in patients who are not candidates for neoadjuvant chemotherapy due to chemoresistant pathology or contraindications remains a challenge. Therefore, in these indications, we aimed to investigate a feasibility of 10x 3.25 Gy radiotherapy combined with regional hyperthermia (HT) that could be followed by surgery or 4x 4 Gy radiotherapy with HT. Materials and methods: We recruited patients with locally advanced marginally resectable or unresectable STS who (1) presented chemoresistant STS subtype, or (2) progressed after neoadjuvant chemotherapy, or (3) were unfit for chemotherapy. The primary endpoint was the feasibility of the proposed regimen. Results: Thirty patients were enrolled. All patients received the first part of the treatment, namely radiotherapy with HT. Among them, 14 received the second part of radiotherapy with HT whereas 13 patients underwent surgery. Three patients did not complete the treatment protocol. The feasibility criteria were fulfilled in 90% of patients. Two patients developed distant metastases. One patient died due to distant progression. One patient developed rapid local recurrence after surgery. Conclusions: Hypofractionated radiotherapy with HT is a feasible treatment for marginally resectable or unresectable STS in patients who are not candidates for chemotherapy. Results of this clinical trial support the further validation of RT and HT combinations in STS.

Establishment of an Academic Tissue Microarray Platform as a Tool for Soft Tissue Sarcoma Research.

Soft tissue sarcoma (STS) is a heterogeneous family of rare mesenchymal tumors, characterized by histopathological and molecular diversity. Tissue microarray (TMA) is a tool that allows performing research in orphan diseases in a more efficient and cost-effective way. TMAs are paraffin blocks consisting of multiple small representative tissue cores from biological samples, for example, from multiple donors, diverse sites of disease, or multiple different diseases. In 2015, we began constructing TMAs using archival tumor material from STS patients. Specimens were well annotated in terms of histopathological diagnosis, treatment, and clinical follow-up of the tissue donors. Each TMA block contains duplicate or triplicate 1.0–1.5 mm tissue cores from representative tumor areas selected by sarcoma pathologists. The construction of TMAs was performed with TMA Grand Master (3DHistech). So far, we have established disease-specific TMAs from 7 STS subtypes: gastrointestinal stromal tumor (72 cases included in the array), alveolar soft part sarcoma (n = 12 + 47), clear cell sarcoma (n = 22 + 32), leiomyosarcoma (n = 55), liposarcoma (n = 42), inflammatory myofibroblastic tumor (n = 12 + 21), and alveolar rhabdomyosarcoma (n = 24). We also constructed a multisarcoma TMA covering a representative number of important histopathological subtypes on arrays for screening purposes, namely, angiosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxoid liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, myxofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma, with 7–11 individual cases per subtype. We are currently expanding the list of TMAs with additional sarcoma entities, considering the heterogeneity of this family of tumors. Our extensive STS TMA platform is suitable for rapid and cost-effective morphological, immunohistochemical, and molecular characterization of the tumor as well as for the identification of potential novel diagnostic markers and drug targets. It is readily available for collaborative projects with research partners.

Impact of Multimodality Imaging to Improve Radiation Therapy (RT) Target Volume Definition for Malignant Peripheral Nerve Sheath Tumor (MPNST)

Malignant peripheral nerve sheath tumor (MPNST) is a rare subtype of soft tissue sarcoma originating from the cells of peripheral nerve sheaths, and a relatively poor prognosis may be associated with MPNST due to the risk of recurrence and metastasis...

Integrated case-control and somatic-germline interaction analyses of soft-tissue sarcoma

PurposeThe contribution of rare genetic variation in the development of soft-tissue sarcoma (STS) remains underexplored. To address this gap, we conducted a whole-exome case-control and somatic-germline interaction study to identify...

Clinical implications of systemic and local immune responses in human angiosarcoma

Angiosarcomas are a rare subtype of soft-tissue sarcomas which exhibit aggressive clinical phenotypes with limited treatment options and poor outcomes. In this study, we investigated the clinical relevance of the peripheral blood neutrophil-to-lymphocyte ratio (NLR) as a marker of systemic immune response, as well as its correlation with intra-tumoral immune profiles in a subgroup of cases (n = 35) using the NanoString PanCancer IO360 panel and multiplex immunohistochemistry. In the overall cohort (n = 150), angiosarcomas of the head and neck (AS-HN) comprised most cases (58.7%) and median overall survival (OS) was 1.1 year. NLR, classified as high in 78 of 112 (70%) evaluable patients, was independently correlated with worse OS (HR 1.84, 95%CI 1.18–2.87, p = 0.0073). Peripheral blood NLR was positively correlated with intra-tumoral NLR (tNLR) (Spearman’s rho 0.450, p = 0.0067). Visualization of tumor-infiltrating immune cells confirmed that tNLR scores correlated directly with both neutrophil (CD15+ cells, rho 0.398, p = 0.0198) and macrophage (CD68+ cells, rho 0.515, p = 0.0018) cell counts. Interestingly, tNLR correlated positively with oncogenic pathway scores including angiogenesis, matrix remodeling and metastasis, and cytokine and chemokine signaling, as well as myeloid compartment scores (all p < 0.001). In patients with documented response assessment to first-line chemotherapy, these pathway scores were all significantly higher in non-responders (47%) compared to responders. In conclusion, systemic and local immune responses may inform chemotherapy response and clinical outcomes in angiosarcomas.

Extraskeletal osteosarcomas: current update.

Extraskeletal osteosarcoma is a very infrequently diagnosed soft-tissue sarcoma subtype which has identical histological features to bone osteosarcoma. However, itsdemographics, presentation, radiology and treatment strategy differ from those ofosteosarcoma. Its diagnosis can be at times challenging due to radiological and pathological mimics which have more common incidence. A multimodality approach is essential for optimizing the outcomes in extraskeletal osteosarcoma. Although there are certain caveats on inclusion of adjuvant therapies (radiotherapy and chemotherapy), in all cases surgical resection with wide local margins is considered the gold standard for adequate local control. The outcome in advanced disease remains dismal and there is ahuge unmet need for prospective studies addressing the optimal treatment strategy. In this article, we review the evidence available for the management of extraskeletal osteosarcoma.

Candidate Biomarkers for Specific Intraoperative Near-Infrared Imaging of Soft Tissue Sarcomas: A Systematic Review.

Simple SummaryNear-infrared imaging of tumors during surgery facilitates the oncologic surgeon to distinguish malignant from healthy tissue. The technique is based on fluorescent tracers binding to tumor biomarkers on malignant cells. Currently, there are no clinically available fluorescent tracers that specifically target soft tissue sarcomas. This review searched the literature to find candidate biomarkers for soft tissue sarcomas, based on clinically used therapeutic antibodies. The search revealed 7 biomarkers: TEM1, VEGFR-1, EGFR, VEGFR-2, IGF-1R, PDGFRα, and CD40. These biomarkers are abundantly present on soft tissue sarcoma tumor cells and are already being targeted with humanized monoclonal antibodies. The conjugation of these antibodies with a fluorescent dye will yield in specific tracers for image-guided surgery of soft tissue sarcomas to improve the success rates of tumor resections.Surgery is the mainstay of treatment for localized soft tissue sarcomas (STS). The curative treatment highly depends on complete tumor resection, as positive margins are associated with local recurrence (LR) and prognosis. However, determining the tumor margin during surgery is challenging. Real-time tumor-specific imaging can facilitate complete resection by visualizing tumor tissue during surgery. Unfortunately, STS specific tracers are presently not clinically available. In this review, STS-associated cell surface-expressed biomarkers, which are currently already clinically targeted with monoclonal antibodies for therapeutic purposes, are evaluated for their use in near-infrared fluorescence (NIRF) imaging of STS. Clinically targeted biomarkers in STS were extracted from clinical trial registers and a PubMed search was performed. Data on biomarker characteristics, sample size, percentage of biomarker-positive STS samples, pattern of biomarker expression, biomarker internalization features, and previous applications of the biomarker in imaging were extracted. The biomarkers were ranked utilizing a previously described scoring system. Eleven cell surface-expressed biomarkers were identified from which 7 were selected as potential biomarkers for NIRF imaging: TEM1, VEGFR-1, EGFR, VEGFR-2, IGF-1R, PDGFRα, and CD40. Promising biomarkers in common and aggressive STS subtypes are TEM1 for myxofibrosarcoma, TEM1, and PDGFRα for undifferentiated soft tissue sarcoma and EGFR for synovial sarcoma.

European society for medical oncology virtual congress: Molecular analysis for precision oncology, October 9th - October 10th, 2020.

European society for medical oncology virtual congress: Molecular analysis for precision oncology, October 9th - October 10th, 2020.

Sarcoma classification by DNA methylation profiling

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.

Comprehensive miRNA expression analysis for histological subtypes of soft tissue sarcoma

Comprehensive miRNA expression analysis for histological subtypes of soft tissue sarcoma

Molecular targeted therapy for advanced or metastatic soft tissue sarcoma.

Soft tissue sarcomas are a form of rare and heterogeneous neoplasms with high recurrence rate and mortality. Over the past decades, less progress has been achieved. Surgical management with or without adjuvant/neoadjuvant radiotherapy is still the first-line treatment for localized soft tissue sarcomas, and chemotherapy is the additional option for those with high-risk. However, not all patients with advanced or metastatic soft tissue sarcomas benefit from conventional chemotherapy, targeted therapy takes the most relevant role in the management of those resistant to or failed to conventional chemotherapy. Heterogeneous soft tissue sarcomas vary from biological behavior, genetic mutations, and clinical presentation with a low incidence, indicating the future direction of histotype-based even molecule-based personalized therapy. Furthermore, increasing preclinical studies were carried out to investigate the pathogenesis and potential therapeutic targets of soft tissue sarcomas and increasing new drugs have been developed in recent years, which had started opening new doors for clinical treatment for patients with advanced/metastatic soft tissue sarcomas. Here we sought to summarize the concise characteristics and advance in the targeted therapy for the most common subtypes of soft tissue sarcomas.