Publications by authors named "Raphael E Pollock"

203 Publications

Modern multimodality management of patients with caval leiomyosarcoma: New treatment paradigms and potential molecular insights.

J Surg Oncol 2021 Mar 2. Epub 2021 Mar 2.

Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio, USA.

Background And Objectives: Caval leiomyosarcomas (cLMS) are rare soft tissue sarcomas historically associated with high recurrence rates and poor prognosis. While radical resection remains the mainstay of therapy for cLMS, new systemic therapies have presented opportunities for multimodality treatment. We examined the clinical outcomes of patients with cLMS treated with modern, multimodality approaches, and compared their outcomes to those of patients with noncaval retroperitoneal LMS (ncLMS).

Methods: A retrospective, single-institution review identified all patients diagnosed with primary retroperitoneal LMS from 2012 to 2018. Radiographic and pathologic review distinguished patients with cLMS and ncLMS. Standard clinicopathologic variables and response to chemotherapy (when applicable) were analyzed. Primary endpoints were overall (OS) and progression-free survival (PFS).

Results: Eleven patients with cLMS were identified. Median tumor size was 7.5 cm (IQR, 5.0-14.3 cm); all patients had Stage II/III disease. Seven patients received neoadjuvant chemotherapy. Nine cLMS patients underwent R0/R1 resection; two did not complete resection. Six patients received adjuvant systemic therapy. Twenty patients with ncLMS were treated during the same period. No statistical intergroup differences were noted in tumor size, pathologic grade, stage, or resection margin status. Patients with ncLMS were less likely to receive neoadjuvant (10% vs. 64%) and adjuvant chemotherapy (30% vs. 55%). Two-year OS (81% vs. 78%; p = NS) and PFS (55% vs. 46%; p = NS) were comparable between cLMS and ncLMS patients.

Conclusions: Multimodality treatment with systemic therapy and aggressive surgical resection may achieve equivalent survival outcomes for patients with cLMS versus similar ncLMS. We recommend that all patients with cLMS be evaluated for multidisciplinary treatment. Genomic and proteomic expression profiling may identify novel or targetable mutations.
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http://dx.doi.org/10.1002/jso.26442DOI Listing
March 2021

β-catenin S45F mutation results in apoptotic resistance.

Oncogene 2020 08 10;39(34):5589-5600. Epub 2020 Jul 10.

Program in Translational Therapeutics, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.

Wnt/β-catenin signaling is one of the key cascades regulating embryogenesis and tissue homeostasis; it has also been intimately associated with carcinogenesis. This pathway is deregulated in several tumors, including colorectal cancer, breast cancer, and desmoid tumors. It has been shown that CTNNB1 exon 3 mutations are associated with an aggressive phenotype in several of these tumor types and may be associated with therapeutic tolerance. Desmoid tumors typically have a stable genome with β-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of β-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in β-catenin S45F mutants, resulting in decreased induction of apoptosis in these cells. Our findings also demonstrate that RUNX3 plays a pivotal role in the inhibition of apoptosis found in the β-catenin S45F mutants. Restoration of RUNX3 overcomes this inhibition in the S45F mutants, highlighting it as a potential therapeutic target for malignancies harboring this specific CTNNB1 mutation. While the regulatory effect of RUNX3 in β-catenin is already known, our results suggest the possibility of a feedback loop involving these two genes, with the CTNNB1 S45F mutation downregulating expression of RUNX3, thus providing additional possible novel therapeutic targets for tumors having deregulated Wnt/β-catenin signaling induced by this mutation.
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http://dx.doi.org/10.1038/s41388-020-1382-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441052PMC
August 2020

An Fusion Gene in Extraskeletal Undifferentiated Round Cell Sarcoma Expands the Spectrum of Genetic Landscape in the "Ewing-Like" Undifferentiated Round Cell Sarcomas.

Int J Surg Pathol 2021 Feb 7;29(1):109-116. Epub 2020 Jun 7.

Department of Pathology & Laboratory Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

The molecular findings in Ewing sarcoma have greatly expanded in recent years. Furthermore, this is particularly true for the subset termed "Ewing-like" undifferentiated round cell sarcomas in which new translocations have been reported since the fourth edition of the . Amid this expanding genetic landscape, we report a case of extraskeletal undifferentiated round cell "Ewing-like" sarcoma in a 27-year-old female. The patient presented with a large lung mass accompanied on staging imaging by deposits suspicious for metastatic disease in the humerus, calvarium, and lymph nodes of the neck and chest. Biopsy of the lung mass revealed a densely packed monotonous proliferation of round, uniform neoplastic cells with scant cytoplasm. By immunohistochemistry, the tumor cells were diffusely positive for CD99, synaptophysin, TLE1, EMA, and MUC4 and negative for FLI1, PAX7, AE1/3, S100, SOX10, WT1, p63, desmin, and HMB45. Fluorescence in situ hybridization demonstrated rearrangement of the gene. Next-generation sequencing based assay revealed an fusion. Taken together, the histomorphologic and molecular findings were considered consistent with an undifferentiated round cell sarcoma with an fusion. Although described in entities such as sclerosing epithelioid fibrosarcoma, low-grade fibromyxoid sarcoma, and small cell osteosarcoma, this has not been previously described in undifferentiated round cell ("Ewing-like") sarcoma. This finding adds to the growing list of undifferentiated round cell sarcomas with Ewing-like morphologic phenotype-associated fusion genes and may contribute to further defining and characterizing the different subset of tumors in the Ewing family of tumors.
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http://dx.doi.org/10.1177/1066896920929081DOI Listing
February 2021

Extracellular vesicle cross-talk in the liposarcoma microenvironment.

Cancer Lett 2020 09 26;487:27-33. Epub 2020 May 26.

The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Liposarcoma (LPS) is the most prevalent soft tissue sarcoma; among the four different LPS subtypes, dedifferentiated liposarcoma (DDLPS) is especially worrisome given its propensity for local and distant recurrence, with an overall survival rate of only 10% at 10 years. Our understanding of the molecular drivers of this disease is rudimentary at best; knowledge about how DDLPS interacts with cells in the tumor microenvironment (TME) is also lacking. Extracellular vesicle (EVs) have been studied in a number of different systems concerning their ability to influence the TME transferring bioactive molecules. In this review, we outline the role of the TME in the DDLPS progression and recurrence, focusing on the interplay between EVs released from the tumor and their target recipient cells in the TME. Success in the understanding of this process will be critical to an enhanced understanding of the underlying biologic drivers at play, potentially leading to new therapeutic strategies of benefit to patients with this disease.
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http://dx.doi.org/10.1016/j.canlet.2020.04.026DOI Listing
September 2020

Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell Activation.

Cancers (Basel) 2020 Apr 23;12(4). Epub 2020 Apr 23.

Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including Imlygic, an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors. To our knowledge, the effects of combining oncolytic HSV with angiogenesis inhibition on endothelial cell activation has not been previously described. Here, we tested the effects of Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO), an oHSV which expresses a potent anti-angiogenic gene on endothelial cell activation in heavily vascularized solid tumors. oHSV treatment induces endothelial cell activation, which inhibits virus propagation and oncolysis in adjacent tumor cells in vitro. Consistently, this was also observed in intravital imaging of intracranial tumor-bearing mice in vivo where infected tumor endothelial cells could efficiently clear the virus without cell lysis. Quantitative real-time PCR (Q-PCR), leukocyte adhesion assay, and fluorescent microscopy imaging data, however, revealed that RAMBO virus significantly decreased expression of endothelial cell activation markers and leukocyte adhesion, which in turn increased virus replication and cytotoxicity in endothelial cells. In vivo RAMBO treatment of subcutaneously implanted sarcoma tumors significantly reduced tumor growth in mice bearing sarcoma compared to rHSVQ. In addition, histological analysis of RAMBO-treated tumor tissues revealed large areas of necrosis and a statistically significant reduction in microvessel density (MVD). This study provides strong preclinical evidence of the therapeutic benefit for the use of RAMBO virus as a treatment option for highly vascularized tumors.
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http://dx.doi.org/10.3390/cancers12041040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225935PMC
April 2020

Cracking the riddle of dedifferentiated liposarcoma: is EV-MDM2 a key?

Oncoscience 2020 Jan 1;7(1-2):10-13. Epub 2020 Feb 1.

The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.

Dedifferentiated liposarcoma (DDLPS) is molecularly characterized by wt p53 and MDM2 gene amplification causing MDM2 protein over-production, the key oncogenic process in DDLPS. Commonly located in fat-bearing retroperitoneal areas, almost 60% of DDLPS patients undergo multifocal recurrence, typically amenable to palliative treatment only, and occasionally develop distant metastasis. These factors lead to an abysmal 10% 10 year overall survival rate. Tumor cell-derived extracellular vesicles (EVs) can facilitate loco-regional malignancy dissemination by depositing molecular factors that participate in the development of pre-metastatic niches for tumor cell implantation and growth. High number of MDM2 DNA molecules was identified within EVs from DDLPS patient serum (ROC vs normal; 0.95) as well as from DDLPS cell lines. This MDM2 DNA could be transferred to preadipocytes (P-a), a major and ubiquitous cellular component of the DDLPS tumor microenvironment (TME), with subsequent P-a production of matrix metalloproteinase 2 (MMP2), a critical component in the metastatic cascade. From here the hypothesis that the DDLPS microenvironment (specifically P-a cells) may participate in DDLPS recurrence events. Since multifocal loco-regional DDLPS spreading is the main cause of the remarkably high lethality of this disease, a better understanding of the underlying oncogenic processes and their regulatory mechanisms is essential to improve the outcome of this devastating disease.
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http://dx.doi.org/10.18632/oncoscience.497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105156PMC
January 2020

Neoadjuvant radiation improves margin-negative resection rates in extremity sarcoma but not survival.

J Surg Oncol 2020 Jun 30;121(8):1249-1258. Epub 2020 Mar 30.

Department of Surgery, The Ohio State University, Columbus, Ohio.

Background And Objectives: Radiation improves limb salvage in extremity sarcomas. Timing of radiation therapy remains under investigation. We sought to evaluate the effects of neoadjuvant radiation (NAR) on surgery and survival of patients with extremity sarcomas.

Materials And Methods: A multi-institutional database was used to identify patients with extremity sarcomas undergoing surgical resection from 2000-2016. Patients were categorized by treatment strategy: surgery alone, adjuvant radiation (AR), or NAR. Survival, recurrence, limb salvage, and surgical margin status was analyzed.

Results: A total of 1483 patients were identified. Most patients receiving radiotherapy had high-grade tumors (82% NAR vs 81% AR vs 60% surgery; P < .001). The radiotherapy groups had more limb-sparing operations (98% AR vs 94% NAR vs 87% surgery; P < .001). NAR resulted in negative margin resections (90% NAR vs 79% surgery vs 75% AR; P < .0001). There were fewer local recurrences in the radiation groups (14% NAR vs 17% AR vs 27% surgery; P = .001). There was no difference in overall or recurrence-free survival between the three groups (OS, P = .132; RFS, P = .227).

Conclusion: In this large study, radiotherapy improved limb salvage rates and decreased local recurrences. Receipt of NAR achieves more margin-negative resections however this did not improve local recurrence or survival rates over.
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http://dx.doi.org/10.1002/jso.25905DOI Listing
June 2020

A sommelier to guide wine selection and a specialist to manage the sarcoma patient: Barriers to referral and definition of a sarcoma specialist.

J Surg Oncol 2020 05 11;121(6):925-926. Epub 2020 Feb 11.

Division of Surgical Oncology, The James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.

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http://dx.doi.org/10.1002/jso.25863DOI Listing
May 2020

Adipose Tumor Microenvironment.

Adv Exp Med Biol 2020 ;1226:73-86

Program in Translational Therapeutics, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

The term "adipose tissue" represents a multicellular and multifunctional organ involved in lipid storage, in hormone and temperature regulation, and in the protection of bones and vital organs from impact-based damage. Emerging evidence now suggests a more malignant role of adipose tissue in promoting cancer onset and progression via the release of secreted factors such as interleukin-6 (IL6) and extracellular vesicles (EVs). These adipose-source factors subsequently affect various aspects of tumorigenesis and/or cancer progression by either directly enhancing the tumor cell oncogenic phenotype or indirectly by the stimulating adjacent normal cells to adopt a more pro-cancer phenotype. Due to the recent growing interest in the role of IL6 and EVs released by adipose tissue in cancer promotion and progression, we are focusing on the protumorigenic impact of fat tissue via IL6 and EV secretion.
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http://dx.doi.org/10.1007/978-3-030-36214-0_6DOI Listing
February 2020

Trends in the Use of Adjuvant Chemotherapy for High-Grade Truncal and Extremity Soft Tissue Sarcomas.

J Surg Res 2020 01 5;245:577-586. Epub 2019 Sep 5.

Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio. Electronic address:

Background: In the randomized controlled trial (RCT) EORTC 62931, adjuvant chemotherapy failed to show improvement in relapse-free survival (RFS) or overall survival (OS) for patients with resected high-grade soft tissue sarcoma (STS). We evaluated whether the negative results of this 2012 RCT have influenced multidisciplinary treatment patterns for patients with high-grade STS undergoing resection at seven academic referral centers.

Methods: The U.S. Sarcoma Collaborative database was queried to identify patients who underwent curative-intent resection of primary high-grade truncal or extremity STS from 2000 to 2016. Patients with recurrent tumors, metastatic disease, and those receiving neoadjuvant chemotherapy were excluded. Patients were divided by treatment era into early (2000-2011, pre-European Organisation for Research and Treatment of Cancer [EORTC] trial) and late (2012-2016, post-EORTC trial) cohorts for analysis. Rates of adjuvant chemotherapy and clinicopathologic variables were compared between the two cohorts. Univariate and multivariate regression analyses were used to determine factors associated with OS and RFS.

Results: 949 patients who met inclusion criteria were identified, with 730 patients in the early cohort and 219 in the late cohort. Adjuvant chemotherapy rates were similar between the early and late cohorts (15.6% versus 14.6%; P = 0.73). Patients within the early and late cohorts demonstrated similar median OS (128 months versus median not reached, P = 0.84) and RFS (107 months versus median not reached, P = 0.94). Receipt of adjuvant chemotherapy was associated with larger tumor size (13.6 versus 8.9 cm, P < 0.001), younger age (53.3 versus 63.7 years, P < 0.001), and receipt of adjuvant radiation (P < 0.001). On multivariate regression analysis, risk factors associated with decreased OS were increasing American Society of Anesthesiologists class (P = 0.02), increasing tumor size (P < 0.001), and margin-positive resection (P = 0.01). Adjuvant chemotherapy was not associated with OS (P = 0.88). Risk factors associated with decreased RFS included increasing tumor size (P < 0.001) and margin-positive resection (P = 0.03); adjuvant chemotherapy was not associated with RFS (P = 0.23).

Conclusions: Rates of adjuvant chemotherapy for resected high-grade truncal or extremity STS have not decreased over time within the U.S. Sarcoma Collaborative, despite RCT data suggesting a lack of efficacy. In this retrospective multi-institutional analysis, adjuvant chemotherapy was not associated with RFS or OS on multivariate analysis, consistent with the results from EORTC 62931. Rates of adjuvant chemotherapy for high-grade STS were low in both cohorts but may be influenced more by selection bias based on clinicopathologic variables such as tumor size, margin status, and patient age than by prospective, randomized data.
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http://dx.doi.org/10.1016/j.jss.2019.08.002DOI Listing
January 2020

Derived from Dedifferentiated Liposarcoma Extracellular Vesicles Induces MMP2 Production from Preadipocytes.

Cancer Res 2019 10 6;79(19):4911-4922. Epub 2019 Aug 6.

Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio.

Dedifferentiated liposarcoma (DDLPS) is frequently diagnosed late, and patients typically respond poorly to treatments. DDLPS is molecularly characterized by wild-type p53 and amplification of the gene, which results in overexpression of MDM2 protein, a key oncogenic process in DDLPS. In this study, we demonstrate that extracellular vesicles derived from patients with DDLPS or from DDLPS cell lines are carriers of MDM2 DNA that can be transferred to preadipocytes, a major and ubiquitous cellular component of the DDLPS tumor microenvironment, leading to impaired p53 activity in preadipocytes and increased proliferation, migration, and production of matrix metalloproteinase 2; treatment with MDM2 inhibitors repressed these effects. Overall, these findings indicate that MDM2 plays a crucial role in DDLPS by enabling cross-talk between tumor cells and the surrounding microenvironment and that targeting vesicular MDM2 could represent a therapeutic option for treating DDLPS. SIGNIFICANCE: Extracellular vesicles derived from dedifferentiated liposarcoma cells induce oncogenic properties in preadipocytes.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774856PMC
October 2019

Synchronous recurrence of concurrent colon adenocarcinoma and dedifferentiated liposarcoma.

BMJ Case Rep 2019 May 13;12(5). Epub 2019 May 13.

Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.

A 62-year-old man presented with concurrent sigmoid colon adenocarcinoma and small bowel mesenteric dedifferentiated liposarcoma. Following surgical resection of the colon cancer, complete excision of the mesenteric sarcoma and adjuvant folinic acid, fluorouracil and oxaliplatin (FOLFOX) chemotherapy, the patient demonstrated no radiological evidence of disease for more than 2 years. The patient then developed synchronous recurrence of both cancers: the colon cancer metastasised to the liver and a pelvic lymph node, and the liposarcoma recurred in the original location. The patient underwent additional chemotherapy with complete response of the metastatic colon cancer and stable disease for the liposarcoma. The recurrent mesenteric tumour was subsequently resected. Although concurrent cancers have been reported, this unique case of synchronous recurrence raises interesting hypotheses regarding host-tumour interaction and immune surveillance.
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http://dx.doi.org/10.1136/bcr-2018-228868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536183PMC
May 2019

Degree of Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma.

Oncologist 2019 07 24;24(7):989-996. Epub 2019 Apr 24.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA

Background: Dedifferentiated liposarcomas (DDLPS) are mesenchymal tumors associated with universally poor response to treatment. Genomic amplification of murine double minute 2 () is used as a diagnostic biomarker; however, no established biomarkers exist to guide DDLPS treatment. In the largest study of its kind, we report that the extent of amplification, not simply the presence of amplification, may be biologically important to the actions of DDLPS.

Patients And Methods: The distribution of amplification in DDLPS was assessed using data from a commercial sequencing laboratory ( = 642) and The Cancer Genome Atlas ( = 57). Data from two retrospective clinical trials ( = 15, = 16) and one prospective clinical trial ( = 25) were used to test 's utility as a clinical biomarker. in vitro and in vivo assessments were conducted in DDLPS cell lines.

Results: Genomic amplification follows a highly reproducible log-normal distribution. In patients with DDLPS treated with complete tumor resection, elevated was associated with shortened time to recurrence as measured by genomic amplification ( = .003) and mRNA expression ( = .04). In patients requiring systemic therapy, higher amplification was associated with reduced overall survival ( = .04). Doxorubicin treatment of DDLPS cells in vitro demonstrated variable sensitivity based on baseline levels, and doxorubicin treatment elevated MDM2 expression. In vivo, treatment with doxorubicin followed by an MDM2 inhibitor improved doxorubicin sensitivity.

Conclusion: amplification levels in DDLPS follow a reproducible distribution and are associated with clinical outcomes and drug sensitivity. These results suggest that a prospective study of as a predictive biomarker in DDLPS is warranted.

Implications For Practice: No validated biomarkers exist for treatment selection in dedifferentiated liposarcoma (DDLPS). Although murine double minute 2 () is currently used for diagnosis, the clinical relevance of amplification has yet to be fully assessed. This study found that amplification follows a predictable distribution in DDLPS and correlates with clinical and biological outcomes. These data suggests that amplification may be a useful biomarker in DDLPS.
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http://dx.doi.org/10.1634/theoncologist.2019-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656442PMC
July 2019

Autophagy inhibition overcomes sorafenib resistance in S45F-mutated desmoid tumors.

Cancer 2019 08 12;125(15):2693-2703. Epub 2019 Apr 12.

Program in Translational Therapeutics, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Background: Desmoid tumors (DTs) are rare and understudied fibroblastic lesions that are frequently recurrent and locally invasive. DT patients often experience chronic pain, organ dysfunction, decrease in quality of life, and even death.

Methods: Sorafenib has emerged as a promising therapeutic strategy, which has led to the first randomized phase 3 clinical trial devoted to DTs. Concurrently, we conducted a comprehensive analysis of sorafenib efficacy in a large panel of desmoid cell strains to probe for response mechanism.

Results: We found distinctive groups of higher- and lower-responder cells. Clustering the lower-responder group, we observed that CTNNB1 mutation was determinant of outcome. Our results revealed that a lower dose of sorafenib was able to inhibit cell viability, migration, and invasion of wild-type and T41A-mutated DTs. Apoptosis induction was observed in those cells after treatment with sorafenib. On the other hand, the lower dose of sorafenib was not able to inhibit cell viability, migration, or invasion or to induce apoptosis in the S45F-mutated DTs. The investigation of autophagy showed the dependency of S45F-mutated DTs on this pathway as a part of cell survival mechanism. Significantly, when autophagy was inhibited genetically or pharmacologically in the S45F mutant cell strains, sensitivity to sorafenib was restored.

Conclusions: Our findings suggest that the response to sorafenib differs when comparing S45F-mutated DTs and T41A-mutated or wild-type DTs. Furthermore, the combination of hydroxychloroquine and sorafenib enhances the antiproliferative and proapoptotic effects in S45F-mutated DT cells, suggesting that profiling β-catenin status could guide clinical management of desmoid patients who are considering sorafenib treatment.
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http://dx.doi.org/10.1002/cncr.32120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625904PMC
August 2019

Perioperative chemotherapy is not associated with improved survival in high-grade truncal sarcoma.

J Surg Res 2018 11 23;231:248-256. Epub 2018 Jun 23.

Department of Surgery, The Ohio State University, Columbus, Ohio. Electronic address:

Background: The treatment benefit of perioperative chemotherapy (CTX) for truncal soft tissue sarcoma (STS) is not well established. This study evaluates the association of CTX with survival for patients with resected primary high-grade truncal STS.

Materials And Methods: Adult patients with high-grade truncal STS who had curative-intent resection from 2000 to 2016 at seven U.S. institutions were evaluated retrospectively. Patients were stratified by receipt of CTX. Kaplan-Meier curves with log-rank tests were used to compare overall survival (OS) and recurrence-free survival. Logistic regression models were used to evaluate characteristics associated with OS.

Results: Of patients with primary high-grade truncal STS, 235 underwent curative-intent resections. The most common histology was undifferentiated pleomorphic sarcoma and mean tumor size was 7.8 cm. Thirty percent of the patients received CTX (n = 70). Among patients receiving CTX, 34% (n = 24) had neoadjuvant CTX, 44% (n = 31) adjuvant CTX, and 21% (n = 15) had neoadjuvant and adjuvant CTX. Patients receiving CTX were more likely to receive radiation (51% versus 34%, P = 0.01), have deep tumors (86% versus 73%, P = 0.037) and solid organ invasion (14% versus 3%, P = 0.001). On univariate analysis, patients who received CTX had worse OS (P < 0.01) and a trend toward worse recurrence-free survival (P = 0.08). Margin status was the only variable associated with improved OS on multivariate analysis (odds ratio 4.36, 95% confidence interval 1.56, 12.13, P < 0.01).

Conclusions: In this multi-institutional retrospective analysis of resected high-grade truncal STS, receipt of perioperative CTX was not associated with improved OS, which may be related to selection bias. Microscopically negative margin status was the only independent factor associated with OS.
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http://dx.doi.org/10.1016/j.jss.2018.05.030DOI Listing
November 2018

The TLR7/8/9 Antagonist IMO-8503 Inhibits Cancer-Induced Cachexia.

Cancer Res 2018 12 12;78(23):6680-6690. Epub 2018 Sep 12.

Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

: Muscle wasting is a feature of the cachexia syndrome, which contributes significantly to the mortality of patients with cancer. We have previously demonstrated that miR-21 is secreted through extracellular vesicles (EV) by lung and pancreatic cancer cells and promotes JNK-dependent cell death through its binding to the TLR7 receptor in murine myoblasts. Here, we evaluate the ability of IMO-8503, a TLR7, 8, and 9 antagonist, to inhibit cancer-induced cachexia. Using EVs isolated from lung and pancreatic cancer cells and from patient plasma samples, we demonstrate that IMO-8503 inhibits cell death induced by circulating miRNAs with no significant toxicity. Intraperitoneal administration of the antagonist in a murine model for Lewis lung carcinoma (LLC-induced cachexia) strongly impaired several cachexia-related features, such as the expression of Pax7 as well as caspase-3 and PARP cleavage in skeletal muscles, and significantly prevented the loss of lean mass in tumor-bearing mice. IMO-8503 also impaired circulating miRNA-induced cell death in human primary myoblasts. Taken together, our findings strongly indicate that IMO-8503 serves as a potential therapy for the treatment of cancer cachexia. SIGNIFICANCE: Cancer-associated cachexia is a significant problem for patients with cancer that remain poorly understood, understudied, and inadequately treated; these findings report a potential new therapeutic for the treatment of TLR7-mediated cancer cachexia.
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541227PMC
December 2018

Surgical management of retroperitoneal sarcoma and opportunities for global collaboration.

Chin Clin Oncol 2018 Aug;7(4):39

Department of Surgery, Section of Surgical Oncology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.

Retroperitoneal sarcomas (RPS) are rare cancers that often reach massive size before detection. The mainstay of treatment for RPS is surgical resection, and complete resection is the only chance for potential cure. The management of RPS can be challenging and in individual cases, radiation and systemic therapy may be beneficial in both primary and recurrent disease. Further research through multi-institutional collaboration, ideally on a global level, is needed to better understand RPS and optimize management of this disease.
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http://dx.doi.org/10.21037/cco.2018.07.05DOI Listing
August 2018

Multidisciplinary management of soft tissue sarcoma.

Chin Clin Oncol 2018 Aug;7(4):34

Ohio State University, Columbus, OH, USA.

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http://dx.doi.org/10.21037/cco.2018.08.09DOI Listing
August 2018

miR-133a function in the pathogenesis of dedifferentiated liposarcoma.

Cancer Cell Int 2018 26;18:89. Epub 2018 Jun 26.

1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.

Background: Sarcomas are malignant heterogeneous tumors of mesenchymal derivation. Dedifferentiated liposarcoma (DDLPS) is aggressive with recurrence in 80% and metastasis in 20% of patients. We previously found that miR-133a was significantly underexpressed in liposarcoma tissues. As this miRNA has recently been shown to be a tumor suppressor in many cancers, the objective of this study was to characterize the biological and molecular consequences of miR-133a underexpression in DDLPS.

Methods: Real-time PCR was used to evaluate expression levels of miR-133a in human DDLPS tissue, normal fat tissue, and human DDLPS cell lines. DDLPS cells were stably transduced with miR-133a vector to assess the effects in vitro on proliferation, cell cycle, cell death, migration, and metabolism. A Seahorse Bioanalyzer system was also used to assess metabolism in vivo by measuring glycolysis and oxidative phosphorylation (OXPHOS) in subcutaneous xenograft tumors from immunocompromised mice.

Results: miR-133a expression was significantly decreased in human DDLPS tissue and cell lines. Enforced expression of miR-133a decreased cell proliferation, impacted cell cycle progression kinetics, decreased glycolysis, and increased OXPHOS. There was no significant effect on cell death or migration. Using an in vivo xenograft mouse study, we showed that tumors with increased miR-133a expression had no difference in tumor growth compared to control, but did exhibit an increase in OXPHOS metabolic respiration.

Conclusions: Based on our collective findings, we propose that in DDPLS, loss of miR-133a induces a metabolic shift due to a reduction in oxidative metabolism favoring a Warburg effect in DDLPS tumors, but this regulation on metabolism was not sufficient to affect DDPLS.
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http://dx.doi.org/10.1186/s12935-018-0583-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019219PMC
June 2018

Multimodality Treatment of Desmoplastic Small Round Cell Tumor: Chemotherapy and Complete Cytoreductive Surgery Improve Patient Survival.

Clin Cancer Res 2018 10 5;24(19):4865-4873. Epub 2018 Jun 5.

Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Desmoplastic small round cell tumor (DSRCT), which harbors EWSR1-WT1 t(11;22)(p13:q12) chromosomal translocation, is an aggressive malignancy that typically presents as intra-abdominal sarcomatosis in young males. Given its rarity, optimal treatment has not been defined. We conducted a retrospective study of 187 patients with DSRCT treated at MD Anderson Cancer Center over 2 decades. Univariate and multivariate regression analyses were performed. We determined whether chemotherapy, complete cytoreductive surgery (CCS), hyperthermic intraperitoneal cisplatin (HIPEC), and/or whole abdominal radiation (WART) improve overall survival (OS) in patients with DSRCT. Critically, because our institutional practice limits HIPEC and WART to patients with less extensive, potentially resectable disease that had benefited from neoadjuvant chemotherapy, a time-variant analysis was performed to evaluate those adjunct treatment modalities. The pre-2003 5-year OS rate of 5% has substantially improved to 25% with the advent of newer chemotherapies and better surgical and radiotherapy techniques (HR, 0.47; 95% CI, 0.29-0.75). Chemotherapy response (log rank = 0.004) and CCS (log rank < 0.0001) were associated with improved survival. Although WART and HIPEC lacked statistical significance, our study was not powered to detect their potential impact upon OS. Improved 3- and 5-year OS were observed following multidisciplinary treatment that includes Ewing sarcoma (ES)-based chemotherapy and complete tumor cytoreductive surgery, but few if any patients are cured. Prospective randomized studies will be required to prove whether HIPEC or WART are important. In the meantime, chemotherapy and CCS remain the cornerstone of treatment and provide a solid foundation to evaluate new biologically targeted therapies. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168359PMC
October 2018

Second Primary Malignancies in Patients with Well-differentiated/Dedifferentiated Liposarcoma.

Anticancer Res 2018 Jun;38(6):3535-3542

Department of Surgery, University of Southern California, Keck School of Medicine, Los Angeles, CA, U.S.A.

Background: Well-differentiated/dedifferentiated (WD/DD) liposarcoma is a rare malignancy of putative adipocyte origin. To our knowledge, there have only been isolated case reports describing second primary cancer in patients with this disease. We report on a combined case series of such patients and explore the frequency of this occurrence using a national cancer database.

Materials And Methods: Demographics and clinicopathological data were collected from patients with WD/DD liposarcoma who were found to have a concurrent or subsequent second primary cancer, at one of three sarcoma referral centers from 2014-2016. The Surveillance, Epidemiology and End Results (SEER) database was also queried to identify adult patients diagnosed with WD/DD liposarcoma between 1973-2012. Observed/expected (O/E) ratios of second primary malignancies among these cases were calculated by comparison to the age-adjusted cancer incidence in the general population using SEER*stat software.

Results: In total, 26 out of 312 consecutive patients (8.3%) with WD/DD liposarcoma at our centers had a second primary cancer identified within 2 years of liposarcoma diagnosis. In the SEER database, among 1,845 patients with WD/DD liposarcoma, 75 (4.1%) had a second cancer within 2 years after liposarcoma diagnosis (O/E ratio=1.81, 99% confidence interval(CI)=1.33-2.40). Patients less than 50 years old at the time of liposarcoma diagnosis had a higher O/E ratio for second primary malignancy compared to older patients. A total of 269 patients (14.6%) developed a second cancer (O/E=1.33, 99% CI=1.15-1.54).

Conclusion: In some patients with WD/DD liposarcoma, there appears to be an increased risk of having a second primary cancer. Further validation and investigation is needed, as this finding may have implications (e.g. closer screening) for patients with this disease.
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http://dx.doi.org/10.21873/anticanres.12625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492098PMC
June 2018

Surgery for Abdominal Well-Differentiated Liposarcoma.

Curr Treat Options Oncol 2018 01 16;19(1). Epub 2018 Jan 16.

Division of Surgical Oncology, Department of Surgery, The Ohio State University, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH, 43210, USA.

Opinion Statement: Retroperitoneal sarcomas are rare tumors of which liposarcoma is the most common histology. Surgical resection remains the mainstay of therapy, particularly for the well-differentiated subtype. They can grow to massive size before causing symptoms or detection. Well-differentiated liposarcoma, while having a negligible metastatic rate, is fraught with a high local recurrence rate, despite a complete surgical resection. Reasons for this are not completely known but may be related to a field defect of the retroperitoneal fat creating a niche for recurrence. These tumors are classically chemo- and radio-resistant. Surgical therapy of recurrences can be challenging, but remains the treatment of choice for well-differentiated liposarcoma. In an attempt to improve on survival and recurrence rates for retroperitoneal liposarcoma, an extended resection approach has been promoted by a few groups. This involves the en bloc resection of contiguous organs that are not macroscopically involved. While this has improved local recurrence rates, benefit for overall survival has not been demonstrated. Interestingly, the improvement in local recurrence rate appeared to be driven by histology and was most improved in the well-differentiated subtype compared to historical data. However, for well-differentiated liposarcomas that are multifocal, this approach may be less useful. The application of this approach still requires further study in terms of balancing increased morbidity of extended resection against the potential for multiple surgeries for recurrence.
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http://dx.doi.org/10.1007/s11864-018-0520-6DOI Listing
January 2018

Historical perspectives and future directions in the surgical management of retroperitoneal sarcoma.

J Surg Oncol 2018 Jan 11;117(1):7-11. Epub 2017 Nov 11.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Retroperitoneal sarcomas (RPS) have fascinated and intrigued physicians both past and present. Operative mortality rates were historically very high and complete resection was not possible for the majority of patients until only the last 2 decades. More recently, changes to the surgical approach and clinical decision-making in RPS have improved patient outcomes. With select integration of nonsurgical therapies, continued RPS-specific research, and ongoing collaborative efforts among major referral centers, the future appears promising.
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http://dx.doi.org/10.1002/jso.24888DOI Listing
January 2018

Retroperitoneal sarcomas: Big tumors that involve more than just "Getting it Out".

J Surg Oncol 2018 Jan 11;117(1):5-6. Epub 2017 Nov 11.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

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http://dx.doi.org/10.1002/jso.24886DOI Listing
January 2018

Clinicopathological variables of sporadic schwannomas of peripheral nerve in 291 patients and expression of biologically relevant markers.

J Neurosurg 2018 09 8;129(3):805-814. Epub 2017 Sep 8.

5Neurosurgery and.

OBJECTIVE While sporadic peripheral schwannomas (SPSs) are generally well treated with surgery, their biology is not well understood. Consequently, treatment options are limited. The aim of this study was to provide a comprehensive description of SPS. The authors describe clinicopathological features and treatment outcomes of patients harboring these tumors, and they assess expression of biomarkers using a clinically annotated tissue microarray. Together, these data give new insight into the biology and management of SPS. METHODS Patients presenting with a primary SPS between 1993 and 2011 (n = 291) were selected from an institutional registry to construct a clinical database. All patients underwent follow-up, and short- and long-term outcomes were assessed. Expression of relevant biomarkers was assessed using a new tissue microarray (n = 121). RESULTS SPSs were generally large (mean 5.5 cm) and frequently painful at presentation (55%). Most patients were treated with surgery (80%), the majority of whom experienced complete resolution (52%) or improvement (18%) of their symptoms. Tumors that were completely resected (85%) did not recur. Some patients experienced short-term (16%) and long-term (4%) complications postoperatively. Schwannomas expressed higher levels of platelet-derived growth factor receptor-β (2.1) than malignant peripheral nerve sheath tumors (MPNSTs) (1.5, p = 0.004) and neurofibromas (1.33, p = 0.007). Expression of human epidermal growth factor receptor-2 was greater in SPSs (0.91) than in MPNSTs (0.33, p = 0.002) and neurofibromas (0.33, p = 0.026). Epidermal growth factor receptor was expressed in far fewer SPS cells (10%) than in MPNSTs (58%, p < 0.0001) or neurofibromas (37%, p = 0.007). SPSs more frequently expressed cytoplasmic survivin (66% of tumor cells) than normal nerve (46% of cells), but SPS expressed nuclear survivin in fewer tumor cells than in MPNSTs (24% and 50%, respectively; p = 0.018). CONCLUSIONS Complete resection is curative for SPS. Left untreated, however, these tumors can cause significant morbidity, and not all patients are candidates for resection. SPSs express a pattern of biomarkers consistent with the dysregulation of the tumor suppressor merlin observed in neurofibromatosis Type 2-associated schwannomas, suggesting a shared etiology. This SPS pattern is distinct from that of other tumors of the peripheral nerve sheath.
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http://dx.doi.org/10.3171/2017.2.JNS153004DOI Listing
September 2018

Pulmonary tumor embolism secondary to soft tissue and bone sarcomas: a case report and literature review.

World J Surg Oncol 2017 Aug 30;15(1):168. Epub 2017 Aug 30.

Department of Surgical Oncology, University of Toronto, Toronto, ON, Canada.

Background: Tumor embolisms (TE) are an underappreciated source of pulmonary embolisms in sarcoma. Most evidence in the literature is limited to case reports and none have described the presence of TE secondary to myxofibrosarcoma. We report the first case of myxofibrosarcoma TE and perform a review of the literature for TE secondary to bone and soft tissue sarcomas (STS).

Case Presentation: A 36-year-old female presented with debilitating pain of the right upper extremity secondary to a recurrent soft tissue sarcoma. She had distant metastasis to the lung. An MRI revealed a 25-cm shoulder mass involving the proximal arm muscles with encasement of the axillary artery, vein, and brachial plexus. A palliative forequarter amputation was performed and tumor thrombus was evident within the axillary artery and vein. Postoperatively, she developed an acute onset of dyspnea and hypoxia. A computed tomography scan revealed a pulmonary saddle embolism. A bilateral lower extremity venous duplex was negative. She became hemodynamically unstable despite resuscitation and was placed on vasopressor support. A transthoracic echocardiogram revealed elevated pulmonary artery pressure, tricuspid regurgitation, right heart dilation, and reduced right heart systolic function consistent with acute cor pulmonale. The patient did not want to pursue a median sternotomy with pulmonary artery embolectomy and expired from cardiopulmonary arrest within 24 h of the operation. The final pathology revealed a 25 × 16 × 13 cm high-grade myxofibrosarcoma with invasion into the bone, skin, and neurovascular bundle as well as evidence of tumor thrombus.

Conclusion: TE is a rare but deadly cause of pulmonary embolism in sarcoma. A high index of suspicion is necessary in individuals who present with respiratory-related symptoms, especially dyspnea. Diagnostic confirmation with a computed tomography scan of the chest and echocardiogram should be rapid. Unlike venous thromboembolism, pulmonary embolectomy remains the preferred therapeutic approach.
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http://dx.doi.org/10.1186/s12957-017-1223-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577830PMC
August 2017

Exosome-Derived miR-25-3p and miR-92a-3p Stimulate Liposarcoma Progression.

Cancer Res 2017 07 6;77(14):3846-3856. Epub 2017 Jun 6.

The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Despite the development of combined modality treatments against liposarcoma in recent years, a significant proportion of patients respond only modestly to such approaches, possibly contributing to local or distant recurrence. Early detection of recurrent or metastatic disease could improve patient prognosis by triggering earlier clinical intervention. However, useful biomarkers for such purposes are lacking. Using both patient plasma samples and cell lines, we demonstrate here that miR-25-3p and miR-92a-3p are secreted by liposarcoma cells through extracellular vesicles and may be useful as potential biomarkers of disease. Both miR-25-3p and miR-92a-3p stimulated secretion of proinflammatory cytokine IL6 from tumor-associated macrophages in a TLR7/8-dependent manner, which in turn promoted liposarcoma cell proliferation, invasion, and metastasis via this interaction with the surrounding microenvironment. Our findings provide novel and previously unreported insight into liposarcoma progression, identifying communication between liposarcoma cells and their microenvironment as a process critically involved in liposarcoma progression. This study establishes the possibility that the pattern of circulating miRNAs may identify recurrence prior to radiological detectability while providing insight into disease outcome and as a possible approach to monitor treatment efficacy. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033276PMC
July 2017

Postoperative Morbidity After Radical Resection of Primary Retroperitoneal Sarcoma: A Report From the Transatlantic RPS Working Group.

Ann Surg 2018 05;267(5):959-964

Department of Surgery, Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom.

Objective: To investigate the safety of radical resection for retroperitoneal sarcoma (RPS).

Background: The surgical management of RPS frequently involves complex multivisceral resection. Improved oncologic outcomes have been demonstrated with this approach compared to marginal excision, but the safety of radical resection has not been shown in a large study population.

Methods: The Transatlantic Retroperitoneal Sarcoma Working Group (TARPSWG) is an international collaborative of sarcoma centers. A combined experience of 1007 consecutive resections for primary RPS from January 2002 to December 2011 was studied retrospectively with respect to adverse events. A weighted organ score was devised to account for differences in surgical complexity. Univariate and multivariate logistic regression analyses were performed to investigate associations between adverse events and number and patterns of organs resected. Associations between adverse events and overall survival, local recurrence, and distant metastases were investigated.

Results: Severe postoperative adverse events (Clavien-Dindo ≥3) occurred in 165 patients (16.4%) and 18 patients (1.8%) died within 30 days. Significant predictors of severe adverse events were age (P = 0.003), transfusion requirements (P < 0.001), and resected organ score (P = 0.042). Resections involving pancreaticoduodenectomy, major vascular resection, and splenectomy/pancreatectomy were found to entail higher operative risk (odds ratio >1.5). There was no impact of postoperative adverse events on overall survival, local recurrence, or distant metastases.

Conclusions: A radical surgical approach to RPS is safe when carried out at a specialist sarcoma center. High-risk resections should be carefully considered on an individual basis and weighed against anticipated disease biology. There appears to be no association between surgical morbidity and long-term oncologic outcomes.
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http://dx.doi.org/10.1097/SLA.0000000000002250DOI Listing
May 2018

Autophagy as a potential target for sarcoma treatment.

Biochim Biophys Acta Rev Cancer 2017 Aug 24;1868(1):40-50. Epub 2017 Feb 24.

Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, USA.. Electronic address:

Autophagy is a constitutively active, evolutionary conserved, catabolic process for maintaining homeostasis in cellular stress responses and cell survival. Although its mechanism has not been fully illustrated, recent work on autophagy in various types of sarcomas has demonstrated that autophagy exerts an important role in sarcoma cell growth and proliferation, in pro-survival response to therapies and stresses, and in therapeutic resistance of sarcoma. Thus, the autophagic process is being seen as a possibly novel therapeutic target of sarcoma. Additionally, some co-regulators of autophagy have also been investigated as promising biomarkers for the diagnosis and prognosis of sarcoma. In this review, we summarize contemporary advances in the role of autophagy in sarcoma and discuss the potential of autophagy as a new target for sarcoma treatment.
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http://dx.doi.org/10.1016/j.bbcan.2017.02.004DOI Listing
August 2017