Soft Tissue Sarcoma Metastasis Research Articles

Abdominal metastases of primary extremity soft tissue sarcoma: A systematic review.

BACKGROUNDDespite the fact that about one third of patients with primary localized extremity soft tissue sarcoma (eSTS) will develop metastatic disease, abdominal metastases (AM) and retroperitoneal metastases (RM) constitute rare events. There is no clear consensus on how to achieve follow-up on patients with primary localized eSTS following curative resection, especially regarding the surveillance of potential AM/RM.AIMTo systematically analyse incidence, diagnosis, treatment and outcome of AM/RM in eSTS patients.METHODSIn this systematic review, 899 studies available in PubMed and published between 2000 and 2018 were screened, identifying 17 original articles focused on AM or RM in eSTS. Article selection was based on the PRISMA guidelines, using the search terms (abdominal metastasis AND soft tissue sarcoma) and (soft tissue sarcoma metastasis abdomen). All studies published between January 1, 2000 and December 31, 2018 were screened. Further articles were identified by cross-searching article references, with the final search date being February 18, 2019. Due to limited data and the different reporting techniques used, the present review focused on descriptive analysis of the included studies.RESULTSOf the 17 studies included, six original articles reported on incidence ± diagnosis, therapy and outcome in AM and RM, whilst three original and eight case reports focused on diagnostic pathway, therapeutic procedures or outcomes without allowing conclusions regarding incidence of AM and RM. According to the former six studies, incidence of AM ranged from 0.9%-5.6% in patients with miscellaneous histological subtypes, and up to 12.1% in patients with myxoid liposarcoma. The most common histological subtypes that developed AM or RM were (myxoid) liposarcoma and leiomyosarcoma, but also rare subtypes such as epithelioid sarcoma, myxofibrosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumour had been reported to develop AM/RM. Surgery for AM/RM was performed in five of eight case-reports (62.5%) and in 20.8%-100.0% of original articles. In particular, patients with hepatic metastases undergoing metastasectomy had a survival benefit compared to patients treated with chemotherapy or best supportive care (> 3 years vs < 6 mo).CONCLUSIONPatients with eSTS should undergo surveillance with abdominal ultrasonography/computed tomography, or even whole-body-magnetic resonance imaging to detect AM/RM at an early stage.

Prognostic Significance of Histological Subtype in Soft Tissue Sarcoma With Distant Metastasis.

Few studies have examined the prognostic significance of histological subtypes in patients with soft tissue sarcoma (STS) and distant metastasis, and we evaluated the relationship between the histological subtypes and clinical outcomes. This retrospective study evaluated the histological subtypes of 105 patients with STS and distant metastasis. The STS histological subtypes were compared based on the clinical information. The Kaplan-Meier curves for overall survival revealed that myxoid liposarcoma had a significantly better prognosis compared to Malignant Peripheral Nerve Sheath Tumor (MPNST) (p=0.0221). In the multivariate logistic regression analyses, the independent predictors of a poor prognosis were: i) large size, ii) advanced stage, and iii) non-surgical treatment for metastasis (p<0.05). The presence or absence of lung metastasis was not significantly associated with prognosis (p=0.4452). Myxoid liposarcoma had a better prognosis compared to MPNST in STS patients with distant metastasis. The surgical removal of distant metastatic lesions may improve the patient's prognosis.

Nodal metastases of soft tissue sarcomas: risk factors, imaging findings, and implications.

Soft tissue sarcomas (STS) are malignancies derived from connective tissue, and regional lymph node metastasis (RLNM), while not common, is an important aspect of prognosis and treatment. Various risk factors, in particular the histological subtype, affect the likelihood of nodal involvement, which can be characterized by imaging features such as nodal dimension and morphology. Currently, surveillance and management vary by institution, as concrete societal guidelines have not been established. Common nodal status assessment strategies include physical exam, US CT, MRI, sentinel lymph node biopsy (SLNB) and radical lymphadenectomy. This article summarizes data regarding relevant risk factors of RLNM, imaging features, and any available data regarding surveillance recommendations.

Abstract LB-306: Long non-coding RNA NEAT1 promotes lung metastasis of soft tissue sarcoma by regulating RNA splicing pathways

Abstract Soft tissue sarcomas (STS) are malignant tumors from diverse mesenchymal tissues. About 40% STS patients develop fatal lung metastasis with a median survival of 15 months. The mechanisms driving the development of lung metastasis in sarcoma patients are poorly understood. Therefore, our lab has developed a genetically engineered mouse model (GEMM) of high-grade primary STS with conditional mutations in Kras and Trp53 (KP) where 40% of mice tumors develop lung metastasis. This KP model recapitulates human patients with Undifferentiated Pleomorphic Sarcoma (UPS), one of the most common subtypes of STS diagnosed in adults. RNA sequencing (RNA-Seq) was performed on paired primary and lung metastases in KP mouse sarcomas and determined that the expression of the long non-coding RNA (lncRNA) Neat1 is increased in lung metastases compared to paired primary tumors. Real time PCR (qPCR) in 22 paired KP mouse primary sarcomas and lung metastases further confirmed that Neat1 is significantly upregulated in some lung metastases. In addition, RNA-Seq and qPCR data from 10 pairs of human primary sarcomas and matched lung metastases also showed that NEAT1 levels are increased in lung metastases. Furthermore, NEAT1 RNA in situ hybridization (ISH) on tissue microarrays (TMAs) of human primary UPS and lung metastases determined that the expression of NEAT1 is upregulated in lung metastases. Next, CRISPR/Cas9 technology was applied to delete Neat1 in primary mouse sarcoma cells and loss of expression of Neat1 was confirmed by qPCR and northern blot in knockout (KO) clones. In addition, loss of Neat1 significantly reduced lung metastasis in vivo following tail vein injection of these modified cells into nude mice. Furthermore, RNA pull down assay with mass spectrometry analysis determined Neat1 interacting proteins, such as Khsrp, were mainly involved in RNA splicing pathways which was also shown to be dysregulated in lung metastases and Neat1 KO cells. Finally, CRISPR/Cas9 mediated knockout of Khsrp significantly reduced lung metastasis in vivo following tail vein injection of these modified cells into nude mice. Overall, these results suggest that upregulation of Neat1 promotes lung metastasis of soft tissue sarcoma through regulating RNA splicing pathways and NEAT1 is a potential target to prevent or treat lung metastasis in sarcoma patients. Citation Format: Jianguo Huang, Eric Xu, Mohit Sachdeva, Timothy Robinson, Xiaodi Qin, Dadong Zhang, Kouros Owzar, Nalan Gokgoz, Andrew Seto, Irene Andrulis, Jay Wunder, Tomoyo Okada, Simuel Singer, Alexander Lazar, Brian Rubin, David G. Kirsch. Long non-coding RNA NEAT1 promotes lung metastasis of soft tissue sarcoma by regulating RNA splicing pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-306.

Multi-Constrained Joint Non-Negative Matrix Factorization With Application to Imaging Genomic Study of Lung Metastasis in Soft Tissue Sarcomas.

The study of pathogenic mechanism at the genetic level by imaging genetics methods enables to effectively reveal the association of histopathology and genetics. However, there is a lack of effective and accurate tools to establish association models from macroscopic to microscopic. The multi-constrained joint non-negative matrix factorization (MCJNMF) was developed for simultaneous integration of genomic data and image data to identify common modules related to disease. Two types of data matrices were projected onto a common feature space, in which heterogeneous variables with large coefficients in the same projected direction form a common module. Meanwhile, the correlation between original data features was integrated by using regularization constraints to improve the biological relevance. Sparsity constraints and orthogonal constraints were performed on decomposition factors to minimize the redundancy between different bases and to reduce algorithm complexity. This algorithm was successfully performed on the module identification of lung metastasis in soft tissue sarcomas (STSs) by integrating FDG-PET image and DNA methylation data features. Multilevel analysis on the top extracted modules revealed that these modules were closely related to the lung metastasis. Particularly, several genes with diagnostic potential for lung metastasis can be discovered from high score modules. This method not only can be applied for the accurate identification of patterns related to pathogenic mechanism of diseases, but also has a significant implication for discovering protein biomarkers. This method provides avenues for further studies of identifying complex association patterns of diseases according to different types of biological data.

Tumor Infiltrating Lymphocytes May Predict for Distant Metastasis in Soft Tissue Sarcomas

The presence of tumor infiltrating lymphocytes (TILs) has been shown to be prognostic in malignancies such as breast, ovarian and colorectal cancer. Moreover, hypofractionated radiation therapy (RT) has been shown to improve tumor control and lead to an increased number of TILs in tumors. However, the significance of TILs in soft tissue sarcoma (STS) remains to be determined. In this study, we aim to determine if TILs are prognostic in patients undergoing pre-operative RT for STS of the extremity and chest-wall, and to evaluate if hypofractionated RT is associated with increased TILs when compared to standard fractionation. H&E slides from resected specimens of extremity and trunk STS patients who underwent pre-operative standard fractionation at 2 Gy/fx or hypofractionation at 7 Gy/fx were reviewed by a blinded pathologist to quantify TILs. All hypofractionated patients were enrolled on an institutional clinical trial. TILs were defined as lymphocytes infiltrating in areas of viable tumor cells. TILs were quantified utilizing 40x and 10x objectives lens (Olympus BX40 microscope) at the tumor hot spots (areas of tumors with highest concentration of TILs) and expressed as a percentage; TILs%/ 40x and TILs%/ 10x. Receiver-operating curve (ROC) analysis was performed to assess the best cut-off that predicted for distant metastasis (DM) in patients undergoing pre-operative RT. Distant metastasis-free survival (DMFS) was calculated using Kaplan-Meier survival analysis. A t-test was performed to assess the difference in means between the 2 groups. Seventy-nine patients with stage I-III STS of the extremity and chest-wall were analyzed, 61 who underwent standard and 18 who underwent hypofractionated RT. Median overall age was 56. Median overall tumor size was 9.8 cm. Median dose of the standard and hypofractionated groups were 50 Gy and 35 Gy, respectively. 30% of patients developed DM in the standard fractionated group vs 11% in the hypofractionated group (p=0.07). The median overall % TILs at 10x and 40x was 20% and 25%, respectively. The mean % TILs at 10x and 40x for the standard and hypofractionated RT was 19.68% vs 31% (p=0.06) and 26.2% vs 42.8% (p=0.03), respectively. ROC analysis revealed that % TILs (10x and 40x) ≤10 was associated with increased risk of distant metastasis (p<0.0001). Median DMFS for patients with % TILs ≤10 was 44.3 months vs >54 months for % TILs > 10% (p=0.0009). In localized STS of the extremity and chest-wall, increasing % TILs was associated improved DMFS. Hypofractionated RT appears to be protective with these patients demonstrating higher % TILs and a decreased rate of developing DM. A cut-off ≤10 % TILs of was shown to be associated with poorer DMFS in this study for all patients treated with pre-operative RT. Further validation of the clinical utility of TILs in this context is warranted.

Human mesenchymal stromal cells do not promote recurrence of soft tissue sarcomas in mouse xenografts after radiation and surgery

Background. Mesenchymal stromal cells (MSCs) promote wound healing, including after radiotherapy (RT) and surgery. The use of MSCs in regenerative medicine in the context of malignancy, such as to enhance wound healing post-RT/surgery in patients with soft tissue sarcomas (STSs), requires safety validation. The aim of this study was to determine the effects of human MSCs on STS growth in vitro and local recurrence and metastasis in vivo. Methods. Human primary STS and HT-1080 fibrosarcoma lines were transduced to express luciferase/eGFP (enhanced green fluorescent protein). Sarcoma cells were co-cultured or co-injected with bone marrow–derived MSCs for growth studies. Xenograft tumor models were established with STS lines in NOD/SCID/γcnull mice. To emulate a clinical scenario, subcutaneous tumors were treated with RT/surgery prior to MSC injection into the tumor bed. Local and distant tumor recurrence was studied using histology and bioluminescence imaging. Results. MSCs did not promote STS proliferation upon co-culture in vitro, which was consistent among MSCs from different donors. Co-injection of MSCs with sarcoma cells in mice exhibited no significant tumor-stimulating effect, compared with control mice injected with sarcoma cells alone. MSC administration after RT/surgery had no effect on local recurrence or metastasis of STS. Discussion. These studies are important for the establishment of a safety profile for MSC administration in patients with STS. Our data suggest that MSCs are safe in STS management after standard of care RT/surgery, which can be further investigated in early-phase clinical trials to also determine the efficacy of MSCs in reducing morbidity and to mitigate wound complications in these patients.

Surgery for metachronous metastasis of soft tissue sarcoma – A magnitude of benefit analysis using propensity score methods

IntroductionMetastasectomy is hypothesised to improve OS in metastatic STS, but evidence in favour of this approach derives from non-controlled single-arm cohorts affected by selection bias. The objective was to quantify the effect of metastasectomy vs. non-surgical management on overall survival (OS) in patients with metachronous metastases from extremity- and trunk soft tissue sarcoma (STS). Materials and methodsFrom a population of 1578 STS patients, 135 patients who underwent surgery for localised STS at two European centres between 1998 and 2015 and developed metachronous STS metastases were included. Propensity score analyses with inverse-probability-of-treatment-weights (IPTW) and landmark analyses were performed to control for selection and immortal time bias, respectively. ResultsOS was significantly longer in the 68 patients undergoing metastasectomy than in the 67 patients who were treated non-invasively for their metastasis (10-year OS: 23% vs. 4%; hazard ratio (HR) = 0.34, 95% CI: 0.22–0.53, p < 0.0001). This association prevailed after IPTW-weighting of the data to control for the higher prevalence of favourable prognostic factors in the surgery group (adjusted 10-year OS: 17% vs. 3%, log-rank p < 0.0001; HR = 0.33, 95% CI: 0.20–0.52, p < 0.0001). Five-year OS estimates were 27.8% in patients who had and 14.5% in patients who had not undergone metastasectomy within the first 3 months after diagnosis of a metastasis (p < 0.0001). ConclusionIn this observational bi-centre study, metastasectomy was associated with prolonged survival in patients with metachronous STS metastases. In the absence of randomized studies, our results indicate that metastasectomy should be considered as an important treatment option for metachronous STS metastases.

Abstract 516: Long noncoding RNA NEAT1 promotes lung metastasis of soft tissue sarcoma

Abstract Soft tissue sarcomas (STS) are malignant tumors from diverse mesenchymal tissues. About 40% STS patients develop fatal lung metastasis with a median survival of 15 months. The mechanisms driving the development of lung metastasis in sarcoma patients are poorly understood. Therefore, our lab has developed a genetically engineered mouse model (GEMM) of high-grade primary STS with conditional mutations in Kras and Trp53 (KP) where 40% of mice tumors develop lung metastasis. This KP model recapitulates human patients with Undifferentiated Pleomorphic Sarcoma (UPS), one of the most common subtypes of STS diagnosed in adults. RNA sequencing (RNA-Seq) was performed on paired primary and lung metastases in KP mouse sarcomas and determined that the expression of the long non-coding RNA (lncRNA) Neat1 is increased in lung metastases compared to paired primary tumors. Real time PCR (qPCR) in 22 paired KP mouse primary sarcomas and lung metastases further confirmed that Neat1 is significantly upregulated in lung metastases. In addition, RNA-Seq data from 5 pairs of human primary sarcomas and matched lung metastases also showed that NEAT1 levels are increased in lung metastases. Furthermore, NEAT1 RNA in situ hybridization (ISH) on tissue microarrays (TMAs) of human primary UPS and lung metastases determined that the expression of NEAT1 is upregulated in lung metastases. Next, CRISPR/Cas9 technology was applied to delete Neat1 in primary mouse sarcoma cells and loss of expression of Neat1 was confirmed by qPCR and northern blot in knockout (KO) clones. In addition, loss of Neat1 significantly reduced lung metastasis in vivo following tail vein injection of these modified cells into nude mice. To further test that loss of Neat1 reduces lung metastasis in primary sarcoma mouse model, primary tumors with Neat1 deletion are generated in GEMMs using in vivo CRISPR/Cas9 technology and KrasLSL-G12D/+; Trp53Flox/Flox; Neat1-/- (KPN) mouse model. Finally, RNA-Seq and capture hybridization analysis of RNA targets (CHART) are performed to determine mechanisms by which Neat1 regulates lung metastasis. Overall, these results suggest that upregulation of Neat1 promotes lung metastasis of soft tissue sarcoma and NEAT1 is a potential target to prevent or treat lung metastasis in sarcoma patients. Citation Format: Jianguo Huang, Eric Xu, Mohit Sachdeva, Timothy Robinson, Xiaodi Qin, Dadong Zhang, Kouros Owzar, Nalan Gokgoz, Andrew Seto, Irene Andrulis, Jay Wunder, Tomoyo Okada, Samuel Singer, Alexander Lazar, Brian Rubin, David G. Kirsch. Long noncoding RNA NEAT1 promotes lung metastasis of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 516.

112 - Human mesenchymal stromal cells administered after radiotherapy and surgery in a soft tissue sarcoma mouse xenograft model do not promote local recurrence or metastasis

Mesenchymal stromal cells (MSCs) are promising candidates for tissue regeneration. We are investigating the potential of MSCs to overcome the morbidity of delayed wound healing after standard of care surgery and involved field irradiation for soft tissue sarcomas (STS). We previously showed that MSCs facilitate the healing of irradiated deep and superficial wounds in a rat model. We next assessed the safety of MSCs in the setting of residual cancer. We studied the effect of MSCs on proliferation, recurrence and metastasis of human STS in vitro and in vivo in a NOD/SCID/γc null mouse xenograft model. We isolated primary human STS cells and gene marked available permanent STS lines that we co-cultured or co-injected with or without MSCs. Tumor cell proliferation and growth were evaluated by flow cytometry and bioluminescence imaging, respectively. We demonstrated that MSCs do not affect the proliferation of STS lines in vitro and in vivo. In vitro proliferation assayed by CFSE showed that doubling times of fibrosarcoma and primary undifferentiated sarcoma (PUS) lines were comparable with and without MSCs (22 hr vs. 23 hr, p = 0.7 and 25 hr vs. 26 hr, p = 0.5, resp). No difference in bioluminescence emission was observed for fibrosarcoma or PUS co-cultured with and without MSCs for 7 days (4.8 × 107 p/s/cm2/sr vs. 5.9 × 107 p/s/cm2/sr p = 0.7 and 5.3 × 105 p/s/cm2/sr vs. 5.9 × 105 p/s/cm2/sr p = 0.6, resp.), and the in vivo co-injection model also confirmed no direct proliferative potential of MSCs on either fibrosarcoma or PUS (1.2 × 109 p/s/cm2/sr vs. 9.7 × 108 p/s/cm2/sr p = 0.4, and 3.6 × 108 p/s/cm2/sr vs. 3.9 × 108 p/s/cm2/sr p = 0.9, respectively). Administration of MSCs after radiotherapy and surgical removal in the pre-established fibrosarcoma xenograft model had no effect on local recurrence (4.1 × 108 p/s/cm2/sr vs. 5.9 × 108 p/s/cm2/sr, p = 0.4) or metastasis (2.0 × 1011 p/s vs. 2.7 × 1011 p/s, p = 0.36) of the tumor compared with control animals. Both MSC treated and control groups showed metastatic tumor nodules in axillary lymph nodes, liver and kidney to the same extent 3 weeks after surgery. Our preclinical data showed that MSCs did not stimulate tumor cells and suggest that an early phase clinical trial to assess safety and determine preliminary evidence of efficacy with MSCs after standard of care therapy for STS is warranted.

Single metastasis of myxoid liposarcoma from the thigh to thyroid gland: a case report

BackgroundThyroid metastasis of soft tissue sarcoma is very rare, and the diagnosis is especially difficult when only a single lesion is present.Case presentationA 50-year-old man was diagnosed with myxoid liposarcoma of the right thigh and treated with wide resection. Two and a half years after the surgery, a growing low-density area was incidentally observed in the right lobe of his thyroid gland on follow-up chest computed tomography. Fine needle aspiration biopsy was performed twice, and the thyroid mass was suspected of being a sarcoma metastasis. He was treated by hemithyroidectomy, and the lesion was pathologically confirmed as a metastasis of myxoid liposarcoma.ConclusionWe experienced single thyroid gland metastasis in patients with myxoid liposarcoma in whom a growing mass is observed in the thyroid gland after radical surgery of the primary site.

The rupture of common iliac artery due to the para-aortic lymph node metastasis of soft tissue sarcoma at the thigh

The rupture of common iliac artery due to the para-aortic lymph node metastasis of soft tissue sarcoma at the thigh

Aquaporin-1 and -5 are involved in the invasion and proliferation of soft tissue sarcomas

Background and aimRecent studies of several carcinomas have reported that aquaporin possesses novel oncogenic properties. The aim of this study was to clarify the involvement of aquaporin-1 and −5 in the proliferation, invasion and metastasis of soft tissue sarcomas. Materials and methodsThe expression of aquaporin-1 and -5 was immunohistochemically examined in 73 soft tissue sarcomas as well as in benign, locally aggressive soft tissue tumors, and in soft tissues of adult humans and human fetuses. The mRNA and protein expression of aquaporin-1 and -5 genes were quantified in 19 sarcoma tissues. ResultsAquaporin-1 was expressed in the tumor cells of 37 (51%) and aquaporin-5 in 29 (40%) of 73 soft tissue sarcomas. Two expression patterns were identified: a differentiation-dependent pattern, similar to their expression in adult human soft tissue and in benign soft tissue tumors, and an aggressiveness-related pattern, that is similar to their expression in the mesenchymal cells of the developing fetal limb. The latter expression pattern proved to be an independent prognostic factor for patients with soft tissue sarcoma, in which aquaporin-1 was related to the invasiveness, and aquaporin-5 to the proliferation of soft tissue sarcoma cells. ConclusionThese results indicate pivotal roles for aquaporin-1 and -5 in the aggressive growth and metastatic potential of soft tissue sarcomas, suggesting that they are promising targets for the treatment of patients with intractable soft tissue sarcoma.

The surgeon will see you now: selecting soft-tissue sarcoma patients for pulmonary metastasectomy

Soft-tissue sarcoma (STS) is a heterogeneous disease comprised by a number of histologic subtypes. Patterns of metastases, however, are common amongst these tumors. In particular, the lung is the primary site of metastases in STS and pulmonary metastases develop in up to 50% of STS patients (1-4). In the relative absence of effective systemic therapy, metastatic STS presents significant challenges in oncology, and pulmonary metastasectomy (PM) has become a common therapeutic modality for patients with metastatic pulmonary disease (3,5). The data underlying the rationale for PM for STS, however, are comprised predominantly by low level evidence, and it has been argued that the favorable outcomes of PM studies are resultant from selection biases towards tumors with favorable tumor biology. Whereas to some extent this may be true, an opposing argument supports the viewpoint that a thorough understanding of patient characteristics associated with favorable clinical outcomes could be utilized to intentionally select individuals in whom PM is beneficial. Such data would be clinically useful and could contribute to a decision-making framework for patients with STS.

Metastasis of soft tissue sarcomas in lymph node: A cytomorphological study.

Soft-tissue sarcoma (STS) rarely metastasizes to lymph node compared to carcinoma. Fine-needle aspiration cytology (FNAC) carries a pivotal role in diagnosis of metastatic tumor to lymph node. This study highlights the role of FNAC in diagnosis of STS metastasis to lymph node. A retrospective study over a period by 4 years carried out. FNAC of enlarged lymph node was performed in patients with STS. Cytology smears were examined in conjunction with clinical details. Histopathology and Immunohistochemistry (IHC) were correlated in synchronous cases. Out of 326 patients, 21 with STS had enlarged lymph nodes, of which 19 cases showed involvement (5.8%). Sixteen cases were metachronous and 3 cases showed synchronous involvement. Fifteen cases had regional lymph nodes while 4 cases had distal lymph node involvement. Head and neck and lower extremities were the most common primary sites of STS. Rhabdomyosarcoma was the most common sarcoma metastasing to the lymph nodes followed by synovial sarcoma, malignant peripheral nerve sheath tumor, and clear cell sarcoma. Other rare tumors included leiomyosarcoma, epitheloid sarcoma, liposarcoma, malignant fibrous histiocytoma, and Ewing's sarcoma/peripheral neuroectodermal tumor. We had a case of dermatofibrosarcoma protuberance (DFSP) of scalp with cervical lymph node metastasis. Very unusual about this case was its rare primary site and the rarer lymph node metastasis. FNAC plays an important role in the diagnosis of lymph node metastasis in cases of STS.

MiR-429 inhibits metastasis by targeting KIAA0101 in Soft Tissue Sarcoma

Soft tissue sarcomas (STS) are a heterogeneous group of rare tumors with high metastatic potential. There being only a handful of publication on metastasis of STS, we investigated the miRNA mediated target gene regulations in modulating the metastatic processes in this cancer. In this study, we amalgamated gene and miRNA expression profiles of high-grade STS samples with miRNA target predictions and identified miR-429 targeting KIAA0101 as a novel pair, which remain unexplored in STS metastasis. We validated their expression in metastatic fibrosarcoma cell line, HT1080 and performed several functional assays using miRNA mimics and KIAA0101 over-expression vector to confirm their role in metastasis. We observed miR-429 is downregulated in HT1080 cells and acting as an anti-metastatic miRNA that inhibited proliferation, migration, anchorage independent growth and invasion by de-repressing KIAA0101. Moreover, the renilla luciferase reporter assay confirmed that miR-429 targets KIAA0101 by binding to its 3/UTR and influence its expression. Taken together, our work demonstrated miR-429 mediates deregulation of KIAA0101 by acting as an anti-metastatic miRNA that targets KIAA0101 pro-metastatic gene during metastasis of STS.

Abstract 1634: The RALA pathway drives invasion and metastasis of soft tissue sarcomas by regulating MMP14 localization and activity

Abstract Soft tissue sarcomas (STS) are a heterogeneous group of tumors originating from mesodermal tissues such as skeletal muscle, adipose, and fibrous tissue. The propensity of STS to metastasize, particularly to the lung which occurs in approximately 20% of all cases, is the major source of mortality associated with this disease. Currently, themolecular mechanisms that drive STS metastasis are poorly understood greatly limiting our ability to determine which STS will metastasize and impeding the development of targeted therapies for the treatment of STS metastases. In this study we utilized analysis of publicly available gene expression data to identify loss of PPP2R1B expression as a strong prognosticator of STS metastasis. In vitro analyses using SW872 liposarcoma (LPS) and HT1080 fibrosarcoma cell lines determined that PPP2R1B plays an essential role in the dephosphorylation and inactivation of RALA, a major downstream effector of the Ras pathway. RALA was found to be essential for invasion of STS cells in modified Boyden chamber assays as knockdown of RALA by either siRNA or shRNA significantly decreased invasion through matrigel. Analysis of publicly available gene expression data revealed that RALA expression correlated with more aggressive LPS subtypes and was prognostic of LPS metastasis. Furthermore, we identify the transmembrane matrix metalloprotease MMP14 (MT1-MMP) as a key downstream effector of RALA mediated invasion in STS. Stable knockdown of RALA in SW872 and HT1080 cells resulted in significant mislocalization of MMP14 and reduced MMP14 enzymatic activity. MMP14 expression was also significantly prognostic of metastasis in a publically available LPS cohort. Finally, we demonstrate that a three gene signature comprised of PPP2R1B, RALA, and MMP14 can retrospectively stratify LPS patients into groups of low, moderate, or high risk for metastatic recurrence. To the best of our knowledge this is the first demonstration of a vital role for PPP2R1A and RALA in STS invasion and metastasis and these data demonstrate a novel role for RALA in the localization and activity of MMP14. In conclusion, we have identified the PPP2R1B-RALA-MMP14 axis as driver of STS metastasis with potential clinical value as both a prognostic marker and therapeutic target. Citation Format: Steven T. Sizemore, Fen Xia, Arnab Chakravarti. The RALA pathway drives invasion and metastasis of soft tissue sarcomas by regulating MMP14 localization and activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1634.

Left ventricular metastasis of soft tissue sarcoma causing heart failure: Presentation of two cases

Left ventricular metastasis of soft tissue sarcoma causing heart failure: Presentation of two cases

Izolirana ekstremitetna perfuzija

Isolated limb perfusion is a surgical procedure that can be used to treat an advanced malignant melanoma and soft tissue sarcomas, it is also effective in treating in-transit metastases of melanoma and local metastases of soft tissue sarcomas. With perfusion of the affected limb with cytostatic agents it is possible to avoid amputation and mutilating operations that significantly reduced the function of the limb. Since the procedure is isolated on a limb, it can be perfused with much higher doses of cytotoxic drugs, systemic toxicity is thus reduced or prevented. The most common side effects are erythema and edema.Cytotoxic drugs, that are manly used, are melphalan and tumor necrosis factor alpha. Efficient also proved to be simultaneous hyperthermia of the affected limb.

Epigenetic re-expression of HIF-2α suppresses soft tissue sarcoma growth.

In soft tissue sarcomas (STS), low intratumoural O2 (hypoxia) is a poor prognostic indicator. HIF-1α mediates key transcriptional responses to hypoxia, and promotes STS metastasis; however, the role of the related HIF-2α protein is unknown. Surprisingly, here we show that HIF-2α inhibits high-grade STS cell growth in vivo, as loss of HIF-2α promotes sarcoma proliferation and increases calcium and mTORC1 signalling in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. We find that most human STS have lower levels of EPAS1 (the gene encoding HIF-2α) expression relative to normal tissue. Many cancers, including STS, contain altered epigenetics, and our findings define an epigenetic mechanism whereby EPAS1 is silenced during sarcoma progression. The clinically approved HDAC inhibitor Vorinostat specifically increases HIF-2α, but not HIF-1α, accumulation in multiple STS subtypes. Vorinostat inhibits STS tumour growth, an effect ameliorated by HIF-2α deletion, implicating HIF-2α as a biomarker for Vorinostat efficacy in STS.