Sarcoma http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Endosialin and Associated Protein Expression in Soft Tissue Sarcomas: A Potential Target for Anti-Endosialin Therapeutic Strategies Wed, 27 Jan 2016 09:28:56 +0000 http://www.hindawi.com/journals/sarcoma/2016/5213628/ Endosialin (CD248, TEM-1) is expressed in pericytes, tumor vasculature, tumor fibroblasts, and some tumor cells, including sarcomas, with limited normal tissue expression, and appears to play a key role in tumor-stromal interactions, including angiogenesis. Monoclonal antibodies targeting endosialin have entered clinical trials, including soft tissue sarcomas. We evaluated a cohort of 94 soft tissue sarcoma samples to assess the correlation between gene expression and protein expression by immunohistochemistry for endosialin and PDGFR-β, a reported interacting protein, across available diagnoses. Correlations between the expression of endosialin and 13 other genes of interest were also examined. Within cohorts of soft tissue diagnoses assembled by tissue type (liposarcoma, leiomyosarcoma, undifferentiated sarcoma, and other), endosialin expression was significantly correlated with a better outcome. Endosialin expression was highest in liposarcomas and lowest in leiomyosarcomas. A robust correlation between protein and gene expression data for both endosialin and PDGFR-β was observed. Endosialin expression positively correlated with PDGFR-β and heparin sulphate proteoglycan 2 and negatively correlated with carbonic anhydrase IX. Endosialin likely interacts with a network of extracellular and hypoxia activated proteins in sarcomas and other tumor types. Since expression does vary across histologic groups, endosialin may represent a selective target in soft tissue sarcomas. Daniel J. O’Shannessy, Hongyue Dai, Melissa Mitchell, Shane Huntsman, Stephen Brantley, David Fenstermacher, and Damon R. Reed Copyright © 2016 Daniel J. O’Shannessy et al. All rights reserved. Long-Term Clinical Responses of Neoadjuvant Dendritic Cell Infusions and Radiation in Soft Tissue Sarcoma Thu, 31 Dec 2015 17:18:29 +0000 http://www.hindawi.com/journals/sarcoma/2015/614736/ Purpose. Patients with large >5 cm, high-grade resectable soft tissue sarcomas (STS) have the highest risk of distant metastases. Previously we have shown that dendritic cell (DC) based vaccines show consistent immune responses. Methods. This was a Phase I single institution study of neoadjuvant radiation with DC injections on 18 newly diagnosed high-risk STS patients. Neoadjuvant treatment consisted of 50 Gy of external beam radiation (EBRT), given in 25 fractions delivered five days/week, combined with four intratumoral injections of DCs followed by complete resection. The primary endpoint was to establish the immunological response to neoadjuvant therapy and obtain data on its clinical safety and outcomes. Results. There were no unexpected toxicities or serious adverse events. Twelve out of 18 (67%) patients were alive, of which an encouraging 11/18 (61%) were alive with no systemic recurrence over a period of 2–8 years. Favorable immunological responses correlated with clinical responses in some cases. Conclusions. This study provides clinical support to using dendritic cell injections along with radiation in sarcomas, which when used optimally in combination can help clinical outcomes in soft tissue sarcoma. Study registration number is NCT00365872. Shailaja Raj, Marilyn M. Bui, Gregory Springett, Anthony Conley, Sergio Lavilla-Alonso, Xiuhua Zhao, Dungsa Chen, Randy Haysek, Ricardo Gonzalez, G. Douglas Letson, Steven Eric Finkelstein, Alberto A. Chiappori, Dmitry I. Gabrilovitch, and Scott J. Antonia Copyright © 2015 Shailaja Raj et al. All rights reserved. Characteristics and Patterns of Metastatic Disease from Chordoma Wed, 30 Dec 2015 12:03:00 +0000 http://www.hindawi.com/journals/sarcoma/2015/517657/ Chordoma is a rare, slow-growing malignant tumor arising from notochordal remnants. A retrospective review of patient records at two major referral centers was undertaken to assess the incidence, location, and prognostic factors of metastatic disease from chordoma. 219 patients with chordoma (1962–2009) were identified. 39 patients (17.8%) developed metastatic disease, most frequently to lung (>50%). Median survival from the time of initial diagnosis was 130.4 months for patients who developed metastatic disease and 159.3 months for those who did not (). Metastatic disease was most common in the youngest patients (), and it was 2.5 times more frequent among patients with local recurrence (26.3%) than in those without (10.8%) (). Patient survival with metastatic disease was highly variable, and it was dependent on both the location of the tumor primary and the site of metastasis. Metastasis to distal bone was the most rapid to develop and had the worst prognosis. Victoria A. Young, Kevin M. Curtis, H. Thomas Temple, Frank J. Eismont, Thomas F. DeLaney, and Francis J. Hornicek Copyright © 2015 Victoria A. Young et al. All rights reserved. A Clinicopathological Analysis of Soft Tissue Sarcoma with Telangiectatic Changes Tue, 29 Dec 2015 13:21:08 +0000 http://www.hindawi.com/journals/sarcoma/2015/740571/ Background. Soft tissue sarcoma with a hemorrhagic component that cannot be easily diagnosed by needle biopsy is defined here as soft tissue sarcoma with telangiectatic changes (STST). Methods. We retrospectively reviewed clinicopathological data of STST from 14 out of 784 patients (prevalence: 1.8%) with soft tissue sarcoma. Results. Tumors were found mostly in the lower leg. Histological diagnoses were undifferentiated pleomorphic sarcoma (), synovial sarcoma (), epithelioid sarcoma (), and malignant peripheral nerve sheath tumor and fibrosarcoma (). No history of trauma to the tumor site was recorded in any patient. Needle aspiration transiently reduced the tumor volume, but subsequent recovery of tumor size was observed in all cases. Out of 14 patients, 9 presented with a painful mass. MRI characteristics included intratumoral nodules (64.3%). The local recurrence rate was 14.3%, and the 2-year event-free survival rate was poorer (50%) than that of most sarcomas. Conclusions. STST is unique in its clinicopathological presentation. Painful hematomas without a trauma history, intratumoral nodules within a large hemorrhagic component, and subsequent recovery of tumor size after aspiration are indicative of the presence of STST. Hiroshi Kobayashi, Keisuke Ae, Taisuke Tanizawa, Tabu Gokita, Noriko Motoi, and Seiichi Matsumoto Copyright © 2015 Hiroshi Kobayashi et al. All rights reserved. Genomic, Epigenomic, and Transcriptomic Profiling towards Identifying Omics Features and Specific Biomarkers That Distinguish Uterine Leiomyosarcoma and Leiomyoma at Molecular Levels Mon, 28 Dec 2015 11:45:01 +0000 http://www.hindawi.com/journals/sarcoma/2015/412068/ Uterine leiomyosarcoma (LMS) is the worst malignancy among the gynecologic cancers. Uterine leiomyoma (LM), a benign tumor of myometrial origin, is the most common among women of childbearing age. Because of their similar symptoms, it is difficult to preoperatively distinguish the two conditions only by ultrasound and pelvic MRI. While histopathological diagnosis is currently the main approach used to distinguish them postoperatively, unusual histologic variants of LM tend to be misdiagnosed as LMS. Therefore, development of molecular diagnosis as an alternative or confirmatory means will help to diagnose LMS more accurately. We adopted omics-based technologies to identify genome-wide features to distinguish LMS from LM and revealed that copy number, gene expression, and DNA methylation profiles successfully distinguished these tumors. LMS was found to possess features typically observed in malignant solid tumors, such as extensive chromosomal abnormalities, overexpression of cell cycle-related genes, hypomethylation spreading through large genomic regions, and frequent hypermethylation at the polycomb group target genes and protocadherin genes. We also identified candidate expression and DNA methylation markers, which will facilitate establishing postoperative molecular diagnostic tests based on conventional quantitative assays. Our results demonstrate the feasibility of establishing such tests and the possibility of developing preoperative and noninvasive methods. Tomoko Miyata, Kenzo Sonoda, Junko Tomikawa, Chiharu Tayama, Kohji Okamura, Kayoko Maehara, Hiroaki Kobayashi, Norio Wake, Kiyoko Kato, Kenichiro Hata, and Kazuhiko Nakabayashi Copyright © 2015 Tomoko Miyata et al. All rights reserved. Intra-Articular Synovial Sarcomas: Incidence and Differentiating Features from Localized Pigmented Villonodular Synovitis Thu, 24 Dec 2015 12:36:06 +0000 http://www.hindawi.com/journals/sarcoma/2015/903873/ Purpose. To determine the incidence of intra-articular synovial sarcomas and investigate if any radiological variables can differentiate them from localized (unifocal) pigmented villonodular synovitis (PVNS) and if multivariate data analysis could be used as a complementary clinical tool. Methods. Magnetic resonance images and radiographs of 7 cases of intra-articular synovial sarcomas and 14 cases of localized PVNS were blindedly reviewed. Variables analyzed were size, extra-articular growth, tumor border, blooming, calcification, contrast media enhancement, effusion, bowl of grapes sign, triple signal intensity sign, synovial low signal intensity, synovitis, age, and gender. Univariate and multivariate data analysis, the method of partial least squares-discriminant analysis (PLS-DA), were used. Register data on all synovial sarcomas were extracted for comparison. Results. The incidence of intra-articular synovial sarcomas was 3%. PLS-DA showed that age, effusion, size, and gender were the most important factors for discrimination between sarcomas and localized PVNS. No sarcomas were misclassified as PVNS with PLS-DA, while some PVNS were misclassified as sarcomas. Conclusions. The most important variables in differentiating intra-articular sarcomas from localized PVNS were age, effusion, size, and gender. Multivariate data analysis can be helpful as additive information to avoid a biopsy, if the tumor is classified as most likely being PVNS. D. Nordemar, J. Öberg, O. Brosjö, and M. Skorpil Copyright © 2015 D. Nordemar et al. All rights reserved. Retinal Targets ALDH Positive Cancer Stem Cell and Alters the Phenotype of Highly Metastatic Osteosarcoma Cells Thu, 24 Dec 2015 08:42:58 +0000 http://www.hindawi.com/journals/sarcoma/2015/784954/ Aldehyde dehydrogenase (ALDH) is a cancer stem cell marker. Retinoic acid has antitumor properties, including the induction of apoptosis and inhibition of proliferation. Retinal, the precursor of retinoic acid, can be oxidized to retinoic acid by dehydrogenases, including ALDH. We hypothesized that retinal could potentially be transformed to retinoic acid with higher efficiency by cancer stem cells, due to the higher ALDH activity. We previously observed that ALDH activity is greater in highly metastatic K7M2 osteosarcoma (OS) cells than in nonmetastatic K12 OS cells. We also demonstrated that ALDH activity correlates with clinical metastases in bone sarcoma patients, suggesting that ALDH may be a therapeutic target specific to cells with high metastatic potential. Our current results demonstrated that retinal preferentially affected the phenotypes of ALDH-high K7M2 cells in contrast to ALDH-low K12 cells, which could be mediated by the more efficient transformation of retinal to retinoic acid by ALDH in K7M2 cells. Retinal treatment of highly metastatic K7M2 cells decreased their proliferation, invasion capacity, and resistance to oxidative stress. Retinal altered the expression of metastasis-related genes. These observations indicate that retinal may be used to specifically target metastatic cancer stem cells in OS. Xiaodong Mu, Stuti Patel, Damel Mektepbayeva, Adel Mahjoub, Johnny Huard, and Kurt Weiss Copyright © 2015 Xiaodong Mu et al. All rights reserved. Epiphyseal Sparing and Reconstruction by Frozen Bone Autograft after Malignant Bone Tumor Resection in Children Mon, 21 Dec 2015 11:11:32 +0000 http://www.hindawi.com/journals/sarcoma/2015/892141/ Limb salvage surgery has become the standard treatment for malignant primary bone tumors in the extremities. Limb salvage represents a challenge in skeletally immature patients. Several treatment options are available for limb reconstruction after tumor resection in children. We report our results using the technique of epiphyseal sparing and reconstruction with frozen autograft bone in 18 children. The mean follow-up period for the all patients included in this study is 72 ± 26 m. Eight patients remained disease-free, seven patients lived with no evidence of disease, two were alive but with disease, and one patient died of the disease. Five- and ten-year rates of survival were 94.4%. Graft survival at 5 and 10 years was 94.4%. Functional outcome using the Enneking scale was excellent in 17 patients (94.4%) and poor in one patient (5.5%). Complications include 2 nonunions, 2 fractures, 2 deep infections, 1 soft tissue recurrence, and leg length discrepancy in 7 cases. This technique is a good reconstructive choice in a child with a nonosteolytic primary or secondary bone tumor, responsive to chemotherapy, without involvement of the articular cartilage. It is a straight forward, effective, and biological technique, which affords immediate mobilization of joints and possible cryoimmune effects, with excellent long term functional outcome and less complication. Ahmed Hamed Kassem Abdelaal, Norio Yamamoto, Katsuhiro Hayashi, Akihiko Takeuchi, Shinji Miwa, and Hiroyuki Tsuchiya Copyright © 2015 Ahmed Hamed Kassem Abdelaal et al. All rights reserved. Sarcopenia Does Not Affect Survival or Outcomes in Soft-Tissue Sarcoma Tue, 01 Dec 2015 15:02:43 +0000 http://www.hindawi.com/journals/sarcoma/2015/146481/ Background and Objective. Sarcopenia is associated with decreased survival and increased complications in carcinoma patients. We hypothesized that sarcopenic soft-tissue sarcoma (STS) patients would have decreased survival, increased incidence of wound complications, and increased length of postresection hospital stay (LOS). Methods. A retrospective, single-center review of 137 patients treated surgically for STS was conducted. Sarcopenia was assessed by measuring the cross-sectional area of bilateral psoas muscles (total psoas muscle area, TPA) at the level of the third lumbar vertebrae on a pretreatment axial computed tomography scan. TPA was then adjusted for height (cm2/m2). The association between height-adjusted TPA and survival was assessed using Cox proportional hazard model. A logistical model was used to assess the association between height-adjusted TPA and wound complications. A linear model was used to assess the association between height-adjusted TPA and LOS. Results. Height-adjusted TPA was not an independent predictor of overall survival (). Patient age () and tumor size () and grade () were independent predictors of overall survival. Height-adjusted TPA was not a predictor of increased hospital LOS (), greater incidence of postoperative infection (), or other wound complications (). Conclusions. Sarcopenia does not appear to impact overall survival, LOS, or wound complications in patients with STS. Robert J. Wilson, Vignesh K. Alamanda, Katherine G. Hartley, Nathan W. Mesko, Jennifer L. Halpern, Herbert S. Schwartz, and Ginger E. Holt Copyright © 2015 Robert J. Wilson et al. All rights reserved. A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies Mon, 30 Nov 2015 06:45:57 +0000 http://www.hindawi.com/journals/sarcoma/2015/826124/ Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study. Jody E. Hooper, Emma L. Cantor, Macgregor S. Ehlen, Avirup Banerjee, Suman Malempati, Peter Stenzel, Randy L. Woltjer, Regina Gandour-Edwards, Neal C. Goodwin, Yan Yang, Pali Kaur, Carol J. Bult, Susan D. Airhart, and Charles Keller Copyright © 2015 Jody E. Hooper et al. All rights reserved. Homogenous Good Outcome in a Heterogeneous Group of Tumors: An Institutional Series of Outcomes of Superficial Soft Tissue Sarcomas Sun, 08 Nov 2015 09:21:40 +0000 http://www.hindawi.com/journals/sarcoma/2015/325049/ Introduction. Superficial soft tissue sarcomas (S-STS) are generally amenable to wide excision. We hypothesized that local recurrence (LR) should be low, even without radiation therapy (RT), and sought to examine the contribution of depth to LR and OS. Methods. Patients with S-STS were retrospectively reviewed. Demographics, tumor features, treatment received, and outcomes were analyzed. Results. 103 patients were identified. Median age was 55 years; 53% of patients were female. Tumor site was 39% in trunk, 38% in the lower extremity, 14% in the upper extremity, and 9% in other locations. The most common histology was 36% leiomyosarcoma. Median tumor size was 2.8 cm (range 0.2–14 cm). Sixty-six percent of tumors were of intermediate/high grade. RT was administered preoperatively in 6% of patients and postoperatively in 15% of patients. An R0 resection was accomplished in 92%. At a median follow-up of 34.2 months (range 2.3–176), 9 patients had a LR (8.7%). Tumor size and grade were not associated with LR. OS was not associated with any tumor or patient variables on univariate analysis. Conclusions. LR was low for S-STS, even with large or high grade tumors and selective use of RT. Surgical resection alone may be adequate therapy for most patients. Superficial location seems to supersede other factors imparting a good prognosis for this group of tumors. Valerie Francescutti, Sartaj S. Sanghera, Richard T. Cheney, Austin Miller, Kilian Salerno, Rachel Burke, Joseph J. Skitzki, and John M. Kane III Copyright © 2015 Valerie Francescutti et al. All rights reserved. The Identification of Prognostic Factors and Survival Statistics of Conventional Central Chondrosarcoma Sun, 08 Nov 2015 09:10:27 +0000 http://www.hindawi.com/journals/sarcoma/2015/623746/ Introduction. Chondrosarcomas are malignant bone tumors that are characterized by the production of chondroid tissue. Since radiation therapy and chemotherapy have limited effect on chondrosarcoma, treatment of most patients depends on surgical resection. We conducted this study to identify independent predictive factors and survival characteristics for conventional central chondrosarcoma and dedifferentiated central chondrosarcoma. Methods. A systematic literature review was performed in September 2014 using the Pubmed, Embase, and Cochrane databases. Subsequent to a beforehand-composed selection procedure we included 13 studies, comprising a total of 1114 patients. Results. The prognosis of central chondrosarcoma is generally good for the histologically low-grade tumors. Prognosis for the high-grade chondrosarcoma and the dedifferentiated chondrosarcoma is poor with lower survival rates. Poor prognostic factors in conventional chondrosarcoma for overall survival are high-grade tumors and axial/pelvic tumor location. In dedifferentiated chondrosarcoma the percentage of dedifferentiated component has significant influence on disease-free survival. Conclusion. Despite the fact that there are multiple prognostic factors identified, as shown in this study, there is a need for prospective and comparative studies. The resulting knowledge about prognostic factors and survival can give direction in the development of better therapies. This could eventually lead to an evidence-based foundation for treating chondrosarcoma patients. Sjoerd P. F. T. Nota, Yvonne Braun, Joseph H. Schwab, C. Niek van Dijk, and Jos A. M. Bramer Copyright © 2015 Sjoerd P. F. T. Nota et al. All rights reserved. Potential Therapeutic Targets in Uterine Sarcomas Wed, 21 Oct 2015 13:51:47 +0000 http://www.hindawi.com/journals/sarcoma/2015/243298/ Uterine sarcomas are rare tumors accounting for 3,4% of all uterine cancers. Even after radical hysterectomy, most patients relapse or present with distant metastases. The very limited clinical benefit of adjuvant cytotoxic treatments is reflected by high mortality rates, emphasizing the need for new treatment strategies. This review summarizes rising potential targets in four distinct subtypes of uterine sarcomas: leiomyosarcoma, low-grade and high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma. Based on clinical reports, promising approaches for uterine leiomyosarcoma patients include inhibition of VEGF and mTOR signaling, preferably in combination with other targeted or cytotoxic compounds. Currently, the only targeted therapy approved in leiomyosarcoma patients is pazopanib, a multitargeted inhibitor blocking VEGFR, PDGFR, FGFR, and c-KIT. Additionally, preclinical evidence suggests effect of the inhibition of histone deacetylases, tyrosine kinase receptors, and the mitotic checkpoint protein aurora kinase A. In low-grade endometrial stromal sarcomas, antihormonal therapies including aromatase inhibitors and progestins have proven activity. Other potential targets are PDGFR, VEGFR, and histone deacetylases. In high-grade ESS that carry the YWHAE/FAM22A/B fusion gene, the generated 14-3-3 oncoprotein is a putative target, next to c-KIT and the Wnt pathway. The observation of heterogeneity within uterine sarcoma subtypes warrants a personalized treatment approach. Tine Cuppens, Sandra Tuyaerts, and Frédéric Amant Copyright © 2015 Tine Cuppens et al. All rights reserved. Age, Tumor Characteristics, and Treatment Regimen as Event Predictors in Ewing: A Children’s Oncology Group Report Mon, 05 Oct 2015 09:56:58 +0000 http://www.hindawi.com/journals/sarcoma/2015/927123/ Purpose. To associate baseline patient characteristics and relapse across consecutive COG studies. Methods. We analyzed risk factors for LESFT patients in three randomized COG trials. We evaluated age at enrollment, primary site, gender, tumor size, and treatment (as randomized). We estimated event-free survival (EFS, Kaplan-Meier) and compared risk across groups (log-rank test). Characteristics were assessed by proportional hazards regression with the characteristic of interest as the only component. Confidence intervals (CI) for RR were derived. Factors related to outcome at level 0.05 were included in a multivariate regression model. Results. Between 12/1988 and 8/2005, 1444 patients were enrolled and data current to 2001, 2004, or 2008 were used. Patients were with a median age of 12 years (0–45), 55% male and 88% Caucasian. The 5-year EFS was 68.3% ± 1.3%. In univariate analysis age, treatment, and tumor location were identified for inclusion in the multivariate model, and all remained significant (p < 0.01). Since tumor size was not collected in the last study, the other two were reanalyzed. This model identified age, treatment, tumor location, and tumor size as significant predictors. Conclusion. Age > 18 years, pelvic tumor, size > 8 cms, and chemotherapy without ifosfamide/etoposide significantly predict worse outcome. AEWS0031 is NCT00006734, INT0091 and INT0054 designed before 1993 (unregistered). Neyssa Marina, Linda Granowetter, Holcombe E. Grier, Richard B. Womer, R. Lor Randall, Karen J. Marcus, Elizabeth McIlvaine, and Mark Krailo Copyright © 2015 Neyssa Marina et al. All rights reserved. Corrigendum to “Outcome of Rhabdomyosarcoma in First Year of Life: Children’s Cancer Hospital 57357 Egypt” Wed, 30 Sep 2015 14:35:47 +0000 http://www.hindawi.com/journals/sarcoma/2015/721253/ Enas El Nadi, Emad A. H. Moussa, Wael Zekri, Hala Taha, Alaa Yones, Mohamed Saad Zaghloul, Madeeha El Wakeel, and Rania M. Labib Copyright © 2015 Enas El Nadi et al. All rights reserved. Clinical Outcomes of Surgical Treatments for Primary Malignant Bone Tumors Arising in the Acetabulum Wed, 16 Sep 2015 12:46:53 +0000 http://www.hindawi.com/journals/sarcoma/2015/430576/ The functional and oncologic results of eighteen patients with primary malignant periacetabular tumors were reviewed to determine the impact of surgical treatment. The reconstruction procedures were endoprosthesis (11), hip transposition (4), iliofemoral arthrodesis (2), and frozen bone autograft (1). After a mean follow-up of 62 months, 13 patients were alive and 5 had died of their disease; the 5-year overall survival rate was 67.2%. The corresponding mean MSTS scores of patients with endoprosthesis (11) and other reconstructions (7) were 42% and 55% (49%, 68%, and 50%), respectively. Overall, postoperative complications including deep infection or dislocation markedly worsened the functional outcome. Iliofemoral arthrodesis provided better function than the other procedures, whereas endoprosthetic reconstruction demonstrated poor functional outcome except for patients who were reconstructed with the adequate soft tissue coverage. Avoiding postoperative complications is highly important for achieving better function, suggesting that surgical procedures with adequate soft tissue coverage or without the massive use of nonbiological materials are preferable. Appropriate selection of the reconstructive procedures for individual patients, considering the amount of remaining bone and soft tissues, would lead to better clinical outcomes. Tomohiro Fujiwara, Koichi Ogura, Eisuke Kobayashi, Yoshikazu Tanzawa, Fumihiko Nakatani, Hirokazu Chuman, and Akira Kawai Copyright © 2015 Tomohiro Fujiwara et al. All rights reserved. Rhabdomyosarcoma: Advances in Molecular and Cellular Biology Tue, 01 Sep 2015 13:55:37 +0000 http://www.hindawi.com/journals/sarcoma/2015/232010/ Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. The two major histological subtypes of RMS are alveolar RMS, driven by the fusion protein PAX3-FKHR or PAX7-FKHR, and embryonic RMS, which is usually genetically heterogeneous. The prognosis of RMS has improved in the past several decades due to multidisciplinary care. However, in recent years, the treatment of patients with metastatic or refractory RMS has reached a plateau. Thus, to improve the survival rate of RMS patients and their overall well-being, further understanding of the molecular and cellular biology of RMS and identification of novel therapeutic targets are imperative. In this review, we describe the most recent discoveries in the molecular and cellular biology of RMS, including alterations in oncogenic pathways, miRNA (miR), in vivo models, stem cells, and important signal transduction cascades implicated in the development and progression of RMS. Furthermore, we discuss novel potential targeted therapies that may improve the current treatment of RMS. Xin Sun, Wei Guo, Jacson K. Shen, Henry J. Mankin, Francis J. Hornicek, and Zhenfeng Duan Copyright © 2015 Xin Sun et al. All rights reserved. Clinical Epidemiology of Low-Grade and Dedifferentiated Osteosarcoma in Norway during 1975 and 2009 Sun, 30 Aug 2015 08:07:58 +0000 http://www.hindawi.com/journals/sarcoma/2015/917679/ Purpose. To describe epidemiological, clinical characteristics and treatment outcomes of low-grade osteosarcoma (LGOS), including dedifferentiated osteosarcoma (DLGOS). Method. We analysed a nationwide cohort comprised of patients with histologically verified LGOS and DLGOS between 1975 and 2009, based on registry sources supplemented with clinical records from hospitals involved in sarcoma management. Results. Fifty-four patients were identified, 12 of whom had DLGOS. The annual incidence for all patients was 0.3 per million, with the peak incidence in the third decade of the life. Fifteen patients experienced local relapses during follow-up and ten developed metastatic diseases, including three at primary diagnosis. Patients with DLGOS dominated the metastatic relapse group. The five-year sarcoma-specific survival rate was 91%, with no documented improvement over time. Free margin following surgical resection of the primary tumour had a positive impact on survival. As expected, both local relapse and metastasis during follow-up were associated with an unfavourable outcome. Radiotherapy predicted poor survival due to the selection of high-risk patients in need of such treatment. Neither higher age nor axial tumour localisation was adverse prognostic factors. Conclusion. LGOS has an excellent prognosis when surgically resected with a free margin; however, LGOS has the potential to dedifferentiate and metastasize with a poor outcome. Kjetil Berner, Tom Børge Johannesen, and Øyvind S. Bruland Copyright © 2015 Kjetil Berner et al. All rights reserved. Intraoperative Radiotherapy in the Management of Locally Recurrent Extremity Soft Tissue Sarcoma Sun, 09 Aug 2015 09:41:20 +0000 http://www.hindawi.com/journals/sarcoma/2015/913565/ Purpose. To investigate the efficacy and morbidity of limb-sparing surgery with intraoperative radiotherapy (IORT) for patients with locally recurrent extremity soft tissue sarcoma (ESTS). Methods and Materials. Twenty-six consecutively treated patients were identified in a single institution retrospective analysis of patients with locally recurrent ESTS treated with IORT following salvage limb-sparing resection from May 2000 to July 2011. Fifteen (58%) patients received external beam radiotherapy (EBRT) prior to recurrence (median dose 63 Gy), while 11 (42%) patients received EBRT following IORT (median dose 52 Gy). The Kaplan-Meier product limit method was used to estimate disease control and survival and subsets were compared using a log rank statistic, Cox’s regression model was used to determine independent predictors of disease outcome, and toxicity was reported according to CTCAE v4.0 guidelines. Results. With a median duration of follow-up from surgery and IORT of 34.9 months (range: 4 to 139 mos.), 10 patients developed a local recurrence with 4 subsequently undergoing amputation. The 5-year estimate for local control (LC) was 58% (95% CI: 36–75%), for amputation-free was 81% (95% CI: 57–93%), for metastasis-free control (MFC) was 56% (95% CI: 31–75%), for disease-free survival (DFS) was 35% (95% CI: 17–54%), and for overall survival (OS) was 50% (95% CI: 24–71%). Prior EBRT did not appear to influence disease control (LC, ; MFC, ) or survival (DFS, ; OS, ). Grade 3 or higher acute and late toxicities were reported for 6 (23%) and 8 (31%) patients, respectively. The frequency of both acute and late grade 3 or higher toxicities occurred equally between patients who received EBRT prior to or after IORT. Conclusions. IORT in combination with oncologic resection of recurrent ESTS yields good rates of local control and limb-salvage with acceptable morbidity. Within the limitations of small subsets, these data suggest that prior EBRT does not significantly influence disease control or toxicity. Christopher L. Tinkle, Vivian Weinberg, Steve E. Braunstein, Rosanna Wustrack, Andrew Horvai, Thierry Jahan, Richard J. O’Donnell, and Alexander R. Gottschalk Copyright © 2015 Christopher L. Tinkle et al. All rights reserved. Whole Lung Irradiation in Adults with Metastatic Ewing Sarcoma: Practice Patterns and Implications for Treatment Thu, 25 Jun 2015 09:22:53 +0000 http://www.hindawi.com/journals/sarcoma/2015/591698/ Background. Whole lung irradiation (WLI) is a standard treatment component for children with metastatic Ewing Sarcoma (ES), but data on WLI for adults are sparse. Design. An email survey was sent to expert sarcoma-dedicated oncologists worldwide: An adult with excellent performance status presents with primary ES in the leg and multiple pulmonary metastases. The patient achieves complete radiographic response after chemotherapy and resection of the primary. Would you give bilateral WLI to (1) this adult patient?, (2) this patient if 20 years old (yo)?, (3) this patient if 45 yo?, or (4) this patient if 60 yo? Results. 38 experts responded, including 24 adult, 1 adolescent young adult, and 13 pediatric oncologists. 63%, 63%, 62%, and 50% of respondents offered WLI to the adult, 20-year-old, 45-year-old, and 60-year-old, respectively. Pediatric oncologists more likely endorsed WLI across all ages including the adult (), 20-year-old (), 45-year-old (), and 60-year-old (). There were no significant differences between medical and radiation oncologists or between European/Australian and American providers. Conclusions. Almost two-thirds of experts surveyed supported WLI for adults with metastatic ES up to age 45 and half supported WLI for a 60-year-old. Continued collaboration across adult and pediatric oncology is needed to define evidence-based strategies across the age spectrum. Shyam K. Tanguturi, Suzanne George, Karen J. Marcus, George D. Demetri, and Elizabeth H. Baldini Copyright © 2015 Shyam K. Tanguturi et al. All rights reserved. Corrigendum to “Sarcoma Immunotherapy: Past Approaches and Future Directions” Tue, 09 Jun 2015 07:19:24 +0000 http://www.hindawi.com/journals/sarcoma/2015/259817/ S. P. D’Angelo, W. D. Tap, G. K. Schwartz, and R. D. Carvajal Copyright © 2015 S. P. D’Angelo et al. All rights reserved. Mesenchymal Chondrosarcoma in Children and Young Adults: A Single Institution Retrospective Review Wed, 03 Jun 2015 13:03:11 +0000 http://www.hindawi.com/journals/sarcoma/2015/608279/ Background. Mesenchymal chondrosarcoma is an aggressive, uncommon histologic entity arising in bone and soft tissues. We reviewed our institutional experience with this rare diagnosis. Methods. We conducted a retrospective chart review on patients with mesenchymal chondrosarcoma over a 24-year period. Clinicopathologic and radiographic features were reviewed. Results. Twelve patients were identified. Nine were females; median age was 14.5 years (1.2–19.7 years). The most common site was the head/neck (7/12). Disease was localized in 11/12 patients (one with lung nodules). Six with available tissue demonstrated NCOA2 rearrangement by FISH. Six underwent upfront surgical resection, and six received neoadjuvant therapy (2 chemotherapy alone and 4 chemotherapy and radiation). All patients received adjuvant chemotherapy (most commonly ifosfamide/doxorubicin) and/or radiation (median dose 59.4 Gy). At a median follow-up of 4.8 years, 5-year disease-free survival and overall survival were 68.2% (95% CI 39.8%, 96.6%) and 88.9% (95% CI 66.9%, 100%). Two patients had distant recurrences at 15 and 42 months, respectively. Conclusion. Aggressive surgical resection of mesenchymal chondrosarcoma with chemoradiotherapy yields excellent local control and may reduce likelihood of late recurrence. Characterization of downstream targets of the HEY1-NCOA2 fusion protein, xenograft models, and drug screening are needed to identify novel therapeutic strategies. Michael W. Bishop, Jessica M. Somerville, Armita Bahrami, Sue C. Kaste, Rodrigo B. Interiano, Jianrong Wu, Shenghua Mao, Frederick A. Boop, Regan F. Williams, Alberto S. Pappo, and Sandeep Samant Copyright © 2015 Michael W. Bishop et al. All rights reserved. Management Strategies in Advanced Uterine Leiomyosarcoma: Focus on Trabectedin Mon, 18 May 2015 14:18:36 +0000 http://www.hindawi.com/journals/sarcoma/2015/704124/ The treatment of advanced uterine leiomyosarcomas (U-LMS) represents a considerable challenge. Radiological diagnosis prior to hysterectomy is difficult, with the diagnosis frequently made postoperatively. Whilst a total abdominal hysterectomy is the cornerstone of management of early disease, the role of routine adjuvant pelvic radiotherapy and adjuvant chemotherapy is less clear, since they may improve local tumor control in high risk patients but are not associated with an overall survival benefit. For recurrent or disseminated U-LMS, cytotoxic chemotherapy remains the mainstay of treatment. There have been few active chemotherapy drugs approved for advanced disease, although newer drugs such as trabectedin with its pleiotropic mechanism of actions represent an important addition to the standard front-line systemic therapy with doxorubicin and ifosfamide. In this review, we outline the therapeutic potential and in particular the emerging evidence-based strategy of therapy with trabectedin in patients with advanced U-LMS. Frédéric Amant, Domenica Lorusso, Alexander Mustea, Florence Duffaud, and Patricia Pautier Copyright © 2015 Frédéric Amant et al. All rights reserved. Phase II Trial of Gemcitabine and Docetaxel with Bevacizumab in Soft Tissue Sarcoma Thu, 14 May 2015 12:42:56 +0000 http://www.hindawi.com/journals/sarcoma/2015/532478/ Gemcitabine (G) and docetaxel (D) are commonly used to treat recurrent/metastatic soft tissue sarcoma. This study tested the hypothesis that outcomes would be improved by addition of bevacizumab (B). The initial design was randomized double-blind trial of G + D + B versus G + D + placebo. Due to slow accrual this was modified to single-arm open-label G + D + B. Eligible patients had diagnosis of leiomyosarcoma, pleomorphic undifferentiated sarcoma, pleomorphic liposarcoma, or angiosarcoma. Treatment was B 15 mg/kg on d1, G 900 mg/m2 on d1 and d8, and D 75 mg/m2 on d8, q21d. Primary endpoint was progression-free survival (PFS) at 6 months and would be met if ≥17 patients were progression-free at 6 m. Secondary endpoints are response rate, PFS at 3 m, overall survival, and toxicity. Of 44 patients enrolled, 35 were treated with GDB and evaluable for safety and efficacy. Median age was 55, 50% male, most ECOG 0. Toxicity is mostly myelosuppression with one deep vein thrombosis and one small bowel perforation possibly related to B. There were 17 partial responses (49%) by RECIST 1.1. Among 35 patients, the number who remained on study and progression-free was 24 at 3 m and 15 at 6 m. 9 withdrew prior to 6 m for reasons other than toxicity or progression. PFS at 6 m was 65% (95% CI: 51–85%). The primary endpoint of 6 m PFS was not met due to censoring of patients who withdrew. However PFS at 3 m (76%) was promising and response rate was higher than expected from G + D. Mark A. Dickson, David R. D’Adamo, Mary L. Keohan, Sandra P. D’Angelo, Richard D. Carvajal, Mrinal M. Gounder, Robert G. Maki, Li-Xuan Qin, Robert A. Lefkowitz, Olivia R. McKennon, Catherine M. Hirst, Gary K. Schwartz, and William D. Tap Copyright © 2015 Mark A. Dickson et al. All rights reserved. Medication Exposures and Subsequent Development of Ewing Sarcoma: A Review of FDA Adverse Event Reports Thu, 07 May 2015 16:52:37 +0000 http://www.hindawi.com/journals/sarcoma/2015/948159/ Background. Ewing sarcoma family of tumors (ESFT) are rare but deadly cancers of unknown etiology. Few risk factors have been identified. This study was undertaken to ascertain any possible association between exposure to therapeutic drugs and ESFT. Methods. This is a retrospective, descriptive study. A query of the FDA Adverse Event Reporting System (FAERS) was conducted for all reports of ESFT, January 1, 1998, through December 31, 2013. Report narratives were individually reviewed for patient characteristics, underlying conditions and drug exposures. Results. Over 16 years, 134 ESFT reports were identified, including 25 cases of ESFT following therapeutic drugs and biologics including immunosuppressive agents and hormones. Many cases were confounded by concomitant medications and other therapies. Conclusions. This study provides a closer look at medication use and underlying disorders in patients who later developed ESFT. While this study was not designed to demonstrate any clear causative association between ESFT and prior use of a single product or drug class, many drugs were used to treat immune-related disease and growth or hormonal disturbances. Further studies may be warranted to better understand possible immune or neuroendocrine abnormalities or exposure to specific classes of drugs that may predispose to the later development of ESFT. Judith U. Cope, Gregory H. Reaman, and Joseph M. Tonning Copyright © 2015 Judith U. Cope et al. All rights reserved. The Use of Radiation Therapy in Well-Differentiated Soft Tissue Sarcoma of the Extremities: An NCDB Review Thu, 07 May 2015 12:44:57 +0000 http://www.hindawi.com/journals/sarcoma/2015/186581/ Objective. This study investigated patterns of utilization of radiation therapy (RT) and correlated this with overall survival by assessing patients with well-differentiated soft tissue sarcoma of the extremity (STS-E) in the National Cancer Database (NCDB). Methods. All patients diagnosed with well-differentiated STS-E between 1998 and 2006 were identified in the NCDB. Patients were stratified by use of surgery alone versus use of adjuvant RT after surgery and analyzed using multivariate analysis, Kaplan-Meier analysis, and propensity matching. Results. 2113 patients with well-differentiated STS-E were identified in the NCDB for inclusion with a mean follow-up time of 74 months. 69% of patients were treated with surgery alone, while 26% were treated with surgery followed by adjuvant RT. Patients undergoing amputation were less likely to receive adjuvant RT. There was no difference in overall survival between patients with well-differentiated STS treated with surgery alone and those patients who received adjuvant RT. Conclusions. In the United States, adjuvant RT is being utilized in a quarter of patients being treated for well-differentiated STS-E. While the use of adjuvant RT may be viewed as a means to facilitate limb salvage, this large national database review confirms no survival benefit, regardless of tumor size or margin status. Alexander L. Lazarides, William C. Eward, Paul J. Speicher, Chun-Han Hou, Daniel P. Nussbaum, Cindy Green, Dan G. Blazer III, David G. Kirsch, and Brian E. Brigman Copyright © 2015 Alexander L. Lazarides et al. All rights reserved. Cured of Primary Bone Cancer, But at What Cost: A Qualitative Study of Functional Impairment and Lost Opportunities Thu, 09 Apr 2015 08:36:25 +0000 http://www.hindawi.com/journals/sarcoma/2015/484196/ Purpose. Our study aims to explore how former cancer patients experience physical and psychosocial late effects 3–7 years after they underwent treatment for primary bone sarcoma in the hip/pelvic region. A qualitative, phenomenological, and hermeneutic design was applied. Methods. Sarcoma survivors () previously treated at Oslo University Hospital, Norwegian Radium Hospital were selected to participate. In-depth and semistructured interviews were conducted. The interviews were analysed using inductive thematic analysis. Results. The participants reported that the late effects had three core spheres of impact: “their current daily life,” “their future opportunities,” and “their identity.” They expressed negative changes in activity, increased dependence on others, and exclusion from participation in different areas. Their daily life, work, sports activities, and social life were all affected. Several of their experiences are similar to those described by people with functional impairment or disability. Conclusion. Patients cured of bone cancer in the hip/pelvic region pay a significant price in terms of functional impairment, practical challenges, exclusion from important aspects of life, and loss of previous identity. It is important to appreciate this in order to help bone cancer survivors who struggle to reorient their life and build a secure new identity. Lena Fauske, Oyvind S. Bruland, Ellen Karine Grov, and Hilde Bondevik Copyright © 2015 Lena Fauske et al. All rights reserved. Myeloablative Chemotherapy with Autologous Stem Cell Transplant for Desmoplastic Small Round Cell Tumor Tue, 07 Apr 2015 09:19:57 +0000 http://www.hindawi.com/journals/sarcoma/2015/269197/ Desmoplastic small round cell tumor (DSRCT), a rare, aggressive neoplasm, has a poor prognosis. In this prospective study, we evaluated the role of myeloablative chemotherapy, followed by autologous stem cell transplant in improving survival in DSRCT. After high-dose induction chemotherapy and surgery, 19 patients with chemoresponsive DSRCT underwent autologous stem cell transplant. Myeloablative chemotherapy consisted of carboplatin (400–700 mg/m2/day for 3 days) + thiotepa (300 mg/m2/day for 3 days) ± topotecan (2 mg/m2/day for 5 days). All patients were engrafted and there was no treatment-related mortality. Seventeen patients received radiotherapy to sites of prior or residual disease at a median of 12 weeks after transplant. Five-year event-free and overall survival were 11 ± 7% and 16 ± 8%, respectively. Two patients survive disease-free 16 and 19 years after transplant (both in complete remission before transplant). 14 patients had progression and died of disease at a median of 18 months following autologous transplant. These data do not justify the use of myeloablative chemotherapy with carboplatin plus thiotepa in patients with DSRCT. Alternative therapies should be considered for this aggressive neoplasm. Christopher J. Forlenza, Brian H. Kushner, Nancy Kernan, Farid Boulad, Heather Magnan, Leonard Wexler, Suzanne L. Wolden, Michael P. LaQuaglia, and Shakeel Modak Copyright © 2015 Christopher J. Forlenza et al. All rights reserved. Molecular Analysis of a Recurrent Sarcoma Identifies a Mutation in FAF1 Tue, 10 Mar 2015 10:53:25 +0000 http://www.hindawi.com/journals/sarcoma/2015/839182/ A patient presented with a recurrent sarcoma (diagnosed as leiomyosarcoma) 12 years after the removal of an initial cancer (diagnosed as extracompartmental osteosarcoma) distally on the same limb. Following surgery, the sarcoma and unaffected muscle and bone were subjected to measurements of DNA exome sequence, RNA and protein expression, and transcription factor binding. The investigation provided corroboration of the diagnosis leiomyosarcoma, as the major upregulations in this tumor comprise muscle-specific gene products and calcium-regulating molecules (calcium is an important second messenger in smooth muscle cells). A likely culprit for the disease is the point mutation S181G in FAF1, which may cause a loss of apoptotic function consecutive to transforming DNA damage. The RNA levels of genes for drug transport and metabolism were extensively skewed in the tumor tissue as compared to muscle and bone. The results suggest that the tumor represents a recurrence of a dormant metastasis from an originally misdiagnosed neoplasm. A loss of FAF1 function could cause constitutive WNT pathway activity (consistent with the downstream inductions of IGF2BP1 and E2F1 in this cancer). While the study has informed on drug transport and drug metabolism pharmacogenetics, it has fallen short of identifying a suitable target for molecular therapy. Georg F. Weber Copyright © 2015 Georg F. Weber. All rights reserved. Improvement in Overall Survival from Extremity Soft Tissue Sarcoma over Twenty Years Tue, 03 Mar 2015 11:55:56 +0000 http://www.hindawi.com/journals/sarcoma/2015/279601/ Several patient demographic factors, including marital status, have been demonstrated to have prognostic significance for survival in extremity soft tissue sarcoma (ESTS). A study population of 12,546 adult patients diagnosed with ESTS from 1991 to 2010 was identified from the SEER database, a large population-based registry, in order to determine whether overall survival had changed over this recent 20-year period. The study population was divided into three groups by year of diagnosis: 1991–1996, 1997–2003, and 2004–2010. We used the Kaplan-Meier method and Cox proportional hazards regression to assess survival differences between different demographic groups and prognostic clinical characteristics. Over the course of time, the 5-year overall survival rates have increased from 28% in the earliest time period to 62% in the latest . On multivariate analysis, the mortality rate progressively declined from the 1991–1996 group (HR: 3.02, CI: 2.78–3.29) to the 1997–2003 group (HR: 2.21, CI: 2.06–2.37), with the 2004–2010 group having the best overall survival, despite increases in the proportion of patients with tumors greater than 5 cm in size , and those presenting with metastasis . Andrew J. Jacobs, Ryan Michels, Joanna Stein, and Adam S. Levin Copyright © 2015 Andrew J. Jacobs et al. All rights reserved.