bims-myxlip 2022-06-19 papers

Surg Oncol Clin N Am. 2022 Jul;pii: S1055-3207(22)00025-4. [Epub ahead of print]31(3): 547-558

Management of Synovial Sarcoma and Myxoid Liposarcoma.

Synovial sarcoma and myxoid liposarcoma are translocation-related sarcomas, with a high risk of developing distant metastasis, which often affect young patients and which are sensitive to chemo and radiotherapy. Surgery is the mainstay of therapy in localized disease. In these entities, perioperative radiotherapy is frequently administered, and chemotherapy is evaluated in patients with high-risk limb/trunk wall tumors in which an advantage in overall survival has been shown in the latest clinical trials. In the advanced setting, new strategies, such as cellular therapy are being developed in these histologic types, with promising, although still preliminary, results.

Keywords: Advanced soft tissue sarcoma; Cellular therapy; Chemotherapy; Myxoid liposarcoma; Radiotherapy; Synovial sarcoma; Targeted therapy

DOI: https://doi.org/10.1016/j.soc.2022.03.012

Surg Oncol Clin N Am. 2022 Jul;pii: S1055-3207(22)00017-5. [Epub ahead of print]31(3): 381-397

Immunotherapy in Sarcoma: Where Do Things Stand?

Cristiam Moreno Tellez, Yan Leyfman, Sandra P D'Angelo, Breelyn A Wilky, Armelle Dufresne.

Early experiences with modern immunotherapy have been disappointing in trials of unselected sarcoma subtypes. However, remarkable efficacy has been observed with immune checkpoint inhibitors (ICIs) in a subset of patients, with the most promising outcomes to date in alveolar soft part sarcoma, cutaneous angiosarcoma, undifferentiated pleomorphic sarcoma (UPS), and dedifferentiated liposarcoma (dLPS). Adoptive cellular therapies targeting cancer testis antigens have shown promising activity, but only synovial sarcoma (SS) and myxoid/round cell liposarcomas reliably express these targets. The majority of sarcomas are immunologically "cold" with sparse immune infiltration, which may explain the poor response to immunotherapy. Current immunotherapy trials for sarcomas explore combination therapies with checkpoint inhibitors to overcome immune evasion and novel targets in adoptive cellular therapies. The role of tertiary lymphoid structures, PD-L1 expression, tumor mutational burden, microsatellite instability, and tumor lymphocytes as biomarkers for response are areas of active investigation. In this review, we highlight prior and ongoing clinical efforts to improve outcomes with immunotherapy and discuss the current state of understanding for biomarkers to select patients most likely to benefit from this approach.

Keywords: Adoptive cellular therapy; Immune checkpoint inhibitors; Immunotherapy; Soft tissue sarcoma; Tertiary lymphoid structure; Tumor microenvironment

DOI: https://doi.org/10.1016/j.soc.2022.03.004

Surg Oncol Clin N Am. 2022 Jul;pii: S1055-3207(22)00026-6. [Epub ahead of print]31(3): 559-568

The Cancer Genome Atlas: Impact and Future Directions in Sarcoma.

Jessica Burns, Jeffrey M Brown, Kevin B Jones, Paul H Huang.

Sarcomas are rare and heterogeneous malignancies. Owing to their low prevalence and limited capacity to conduct large-scale clinical trials, understanding the molecular mechanisms of sarcomagenesis has become important in determining appropriate treatment. The Cancer Genome Atlas soft tissue sarcoma (STS) project (TCGA-SARC) was the largest and most comprehensive attempt to profile the genomics of multiple STS subtypes. TCGA-SARC made huge contributions to disease understanding. Since the publication of TCGA-SARC, numerous studies have used molecular profiling to assess STS biology. Herein molecular profiling studies in STS are reviewed and future directions with regard to omics profiling in STS research are discussed.

Keywords: Multiomics; Profiling; Sarcoma; TCGA

DOI: https://doi.org/10.1016/j.soc.2022.03.013

Am J Transl Res. 2022 ;14(5): 2894-2909

A novel method for potentiation of chemotherapy in soft tissue sarcomas with BromAc.

Lillian Dong, Kevin Ke, Samina Badar, Ahmed H Mekkawy, Javed Akhter, Krishna Pillai, Carly J Carter, David L Morris.

Single-agent doxorubicin currently forms part of standard care for patients with sarcomas. However, efficacy is limited by the presence of dose-dependent cardiotoxicity and toxicity to renal, hepatic, and neurological systems. Therefore, there is a pressing need for novel drug regimens which can provide increased efficacy and safety. BromAc is a novel drug combination developed as a mucolytic agent which has demonstrated anticancer activity both in vitro and in vivo in several cancers. Here, we investigated the efficacy of BromAc in combination with doxorubicin for four subtypes of sarcoma. Cell proliferation, alongside western blot for a variety of cell cycle, apoptosis, and autophagy biomarkers assays was performed following treatment of cell lines in vitro at various concentrations of BromAc and doxorubicin. The impact of drug treatment on MUC1 and MUC4 levels was assessed through immune-cytological methods. Drug agent synergy was assessed through the Chou-Talalay framework. BromAc treatment in combination with doxorubicin was more efficacious than single-agent doxorubicin, with synergistic effects observed. The immuno-cytological analysis demonstrated significant mucin depletion following treatment with BromAc and doxorubicin used in combination, providing a potential mechanistic underpinning for the observed anticancer effects.

Keywords: Bromelain; acetylcysteine; cancer; chemo-resistance; chemo-sensitisation; epithelioid sarcoma; fibrosarcoma; soft tissue sarcoma; synovial sarcoma

Surg Oncol Clin N Am. 2022 Jul;pii: S1055-3207(22)00014-X. [Epub ahead of print]31(3): 321-340

WHO Pathology: Highlights of the 2020 Sarcoma Update.

Inga-Marie Schaefer, Alessandro Gronchi.

Keywords: Leiomyosarcoma; Liposarcoma; Marker; Rearrangement; Risk stratification; Round cell sarcoma; Sarcoma; WHO classification

DOI: https://doi.org/10.1016/j.soc.2022.03.001

Nat Commun. 2022 Jun 15. 13(1): 3406

Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma.

There are more than 70 distinct sarcomas, and this diversity complicates the development of precision-based therapeutics for these cancers. Prospective comprehensive genomic profiling could overcome this challenge by providing insight into sarcomas' molecular drivers. Through targeted panel sequencing of 7494 sarcomas representing 44 histologies, we identify highly recurrent and type-specific alterations that aid in diagnosis and treatment decisions. Sequencing could lead to refinement or reassignment of 10.5% of diagnoses. Nearly one-third of patients (31.7%) harbor potentially actionable alterations, including a significant proportion (2.6%) with kinase gene rearrangements; 3.9% have a tumor mutational burden ≥10 mut/Mb. We describe low frequencies of microsatellite instability (<0.3%) and a high degree of genome-wide loss of heterozygosity (15%) across sarcomas, which are not readily explained by homologous recombination deficiency (observed in 2.5% of cases). In a clinically annotated subset of 118 patients, we validate actionable genetic events as therapeutic targets. Collectively, our findings reveal the genetic landscape of human sarcomas, which may inform future development of therapeutics and improve clinical outcomes for patients with these rare cancers.

DOI: https://doi.org/10.1038/s41467-022-30496-0