Sarcoma The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Multimodality Treatment in Ewing’s Sarcoma Family Tumors of the Maxilla and Maxillary Sinus: Review of the Literature Thu, 16 Jun 2016 07:35:34 +0000 The Ewing sarcoma family of tumors (ESFT) encompasses a group of highly aggressive, morphologically similar, malignant neoplasms sharing a common spontaneous genetic translocation that affect mostly children and young adults. These predominantly characteristic, small round-cell tumors include Ewing’s sarcoma of the bone and soft tissue, as well as primitive neuroectodermal tumors (PNETs) involving the bone, soft tissue, and thoracopulmonary region (Askin’s tumor). Extraosseous ESFTs are extremely rare, especially in the head and neck region, where literature to date consists of sporadic case reports and very small series. We hereby present a review of the literature published on ESFTs reported in the maxilla and maxillary sinus region from 1968 to 2016. David Thorn, Christoph Mamot, Fatime Krasniqi, Frank Metternich, and Sven Prestin Copyright © 2016 David Thorn et al. All rights reserved. A Phase I/II Clinical Trial of Belinostat (PXD101) in Combination with Doxorubicin in Patients with Soft Tissue Sarcomas Tue, 14 Jun 2016 10:44:51 +0000 Background. Belinostat is a novel histone deacetylase inhibitor. Primary Objectives. Maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of belinostat (Bel) in combination with doxorubicin (Dox) in solid tumours (phase I) and response rate (RR) in soft tissue sarcomas (phase II). Methods. Bel was administered as a 30-minute IV infusion on days 1–5 and on day 5 with Dox. The dose escalation schedule was as follows: cohort 1: Bel 600 mg/m2 and 50 mg/m2 Dox, cohort 2: Bel 600 mg/m2 and 75 mg/m2 Dox, cohort 3: Bel 800 mg/m2 and 75 mg/m2 Dox, and cohort 4: Bel 1000 mg/m2 and 75 mg/m2 Dox. Results. 41 patients were included (25 in phase I, 16 in phase II). Adverse events were fatigue (95%), nausea (76%), and alopecia (63%). There was one DLT, grade 3 rash/hand and foot syndrome. MTD was Bel 1000 mg/m2/d and Dox 75 mg/m2. Four responses were seen: 2 PR in phase I, RR of 8%; in phase II, 1 PR/1 CR, RR of 13%, and 9 patients (56%) with SD. Conclusion. The combination was well tolerated. Response rate was moderate but median time to progression was 6.0 months (95% CI, 1.6–9.7 months) which is superior to some reports of single-agent Dox. Joanna Vitfell-Rasmussen, Ian Judson, Akmal Safwat, Robin L. Jones, Philip Blach Rossen, Maja Lind-Hansen, Poul Knoblauch, and Anders Krarup-Hansen Copyright © 2016 Joanna Vitfell-Rasmussen et al. All rights reserved. Notch Signaling Mediates Skeletal Muscle Atrophy in Cancer Cachexia Caused by Osteosarcoma Thu, 09 Jun 2016 06:06:42 +0000 Skeletal muscle atrophy in cancer cachexia is mediated by the interaction between muscle stem cells and various tumor factors. Although Notch signaling has been known as a key regulator of both cancer development and muscle stem cell activity, the potential involvement of Notch signaling in cancer cachexia and concomitant muscle atrophy has yet to be elucidated. The murine K7M2 osteosarcoma cell line was used to generate an orthotopic model of sarcoma-associated cachexia, and the role of Notch signaling was evaluated. Skeletal muscle atrophy was observed in the sarcoma-bearing mice, and Notch signaling was highly active in both tumor tissues and the atrophic skeletal muscles. Systemic inhibition of Notch signaling reduced muscle atrophy. In vitro coculture of osteosarcoma cells with muscle-derived stem cells (MDSCs) isolated from normal mice resulted in decreased myogenic potential of MDSCs, while the application of Notch inhibitor was able to rescue this repressed myogenic potential. We further observed that Notch-activating factors reside in the exosomes of osteosarcoma cells, which activate Notch signaling in MDSCs and subsequently repress myogenesis. Our results revealed that signaling between tumor and muscle via the Notch pathway may play an important role in mediating the skeletal muscle atrophy seen in cancer cachexia. Xiaodong Mu, Rashmi Agarwal, Daniel March, Adam Rothenberg, Clifford Voigt, Jessica Tebbets, Johnny Huard, and Kurt Weiss Copyright © 2016 Xiaodong Mu et al. All rights reserved. A Comprehensive Single Institutional Review of 2 Years in a Designated Fast-Track Sarcoma Diagnostic Clinic Linked with a Sarcoma Specialist Advisory Group: Meeting the Target but Failing the Task? Thu, 02 Jun 2016 12:05:41 +0000 Background. National guidelines prompted the implementation of a designated two-week wait referral pathway to facilitate the early diagnosis of sarcomas, to improve treatment outcomes. Methods. Patients referred to the Cambridge Sarcoma Diagnostic Clinic between January 2013 and December 2014 were identified through the electronic appointments system. Information was retrospectively retrieved about patient characteristics and details of the diagnostic pathway. Results. 17.3% of patients referred (69/397) were diagnosed with a malignancy. Of these, 59.3% (41/69) had primary sarcomas, 17.4% (12/69) had metastatic cancer, and 23.2% (16/69) had a different primary malignancy. 15% of the 41 sarcomas were <5 cm, 34% in the 5–10 cm range, and 51% >10 cm. Sarcomas diagnosed through this clinic represented 13% (41/315) of sarcomas managed at the centre during the same 2 years. Conclusion. While we achieved the target of 10% (41/397) sarcoma diagnosis rate in the rapid access clinic, only 15% of these were <5 cm better prognosis lesions. This calls into question the “real world” impact of such diagnostic clinics on early diagnosis of sarcomas. In order to enhance generic cancer diagnostic skills, training in these diagnostic clinics could be usefully integrated into national training curricula for both surgical and nonsurgical oncologists. Zoltan Szucs, Dochka Davidson, Han Hsi Wong, Gail Horan, Philip W. P. Bearcroft, Ian Grant, Robert Grimer, Melanie A. Hopper, Helen Hatcher, and Helena Earl Copyright © 2016 Zoltan Szucs et al. All rights reserved. Biomechanical Analysis of a Novel Acetabulum Reconstruction Technique with Acetabulum Reconstruction Cage and Threaded Rods after Type II Pelvic Resections Tue, 31 May 2016 14:15:59 +0000 Background. Periacetabular resections with reconstruction has high rates of complications due to the complexity of the reconstruction. We have improvised a novel technique of reconstruction for type II and type II + III pelvic resections with the use of a commercially available acetabulum reconstruction cage (gap II, Stryker) and threaded rods. Objectives. The aim of our study is to determine the biomechanical strength of our reconstruction compared to the traditional cemented total hip replacement (THR) designs in normal acetabulum and establish its mode of failure. Methods. Five sets of hemipelvises were biomechanically tested (Instron® 3848, MA, USA). These constructs were subjected to cyclic loading and load to failure. Results. The reconstructed acetabulum was stiffer and required a higher load to failure compared to the intact pelvis with a standard THR. The mean stiffness of the reconstructed pelvis was  Nmm−1 compared to the intact pelvis, which was  Nmm−1 ( value = 0.01). The mean load to failure for the standard acetabular cup construct was  N while that of the reconstructed pelvis with the acetabulum cage and threaded rods was  N. Conclusion. Reconstruction of the pelvis with an acetabular reconstruction cage and threaded rods is a biomechanical viable option. Vivek Ajit Singh, Hassan Elbahri, and Rukmanikanthan Shanmugam Copyright © 2016 Vivek Ajit Singh et al. All rights reserved. Overall Survival and Response to Systemic Therapy in Metastatic Extrauterine Leiomyosarcoma Sun, 29 May 2016 09:47:53 +0000 Background. Leiomyosarcomas (LMS) represent a heterogeneous subset of soft tissue sarcomas. Factors influencing prognosis for patients with metastatic extrauterine LMS (euLMS) are not well described. Limited data are available regarding responses to systemic therapy. Methods. We collected clinical and pathologic information for all patients with metastatic euLMS seen at Memorial Sloan Kettering Cancer Center between 1989 and 2012. Objective responses to first-line therapy were analyzed for a subset of patients with available baseline and on-treatment imaging using RECIST 1.1. Results. 215 patients with metastatic euLMS had a median overall survival (OS) of 2.6 years from the time of metastasis. Older age, male sex, and ≥3 initial sites of metastasis were associated with worse OS on multivariate analysis. Objective response rate (ORR) in was 19% overall and 25%, 26%, and 25% for gemcitabine, gemcitabine plus docetaxel, and anthracycline-alkylator combinations. Patients whose tumors objectively responded to first-line therapy had a lower risk of death versus those who did not (Hazard Ratio 0.46; 95% CI: 0.26–0.79, ). Conclusions. Anthracycline- and gemcitabine-based regimens have similar activity in this cohort of euLMS. Prognostic factors for OS include older age, male sex, and ≥3 initial sites. A. N. Shoushtari, J. Landa, D. Kuk, A. Sanchez, B. Lala, N. Schmidt, C. Okoli, P. Chi, M. A. Dickson, M. M. Gounder, M. L. Keohan, A. M. Crago, W. D. Tap, and S. P. D’Angelo Copyright © 2016 A. N. Shoushtari et al. All rights reserved. An Uncemented Spreading Stem for the Fixation in the Metaphyseal Femur: A Preliminary Report Sun, 15 May 2016 09:21:24 +0000 Surgical treatment to restore full range of motion and full weight bearing after extensive femoral bone resection in patients with primary or metastatic femoral tumours is individually challenging. Especially when the remaining distal or proximal bone is very short, a rigid fixation of an implant is difficult to achieve due to the reverse funnel shape of the metaphysis. Herein, we present a novel implant design using a spreading mechanism in the distal part of the prosthesis for rigid, uncemented fixation in the remaining femoral bone after extensive tumour resection of the femur. We present the outcome of 5 female patients who underwent implantation of this spreading stem after extensive proximal or distal femoral bone resection. There was no radiological or clinical loosening or implant-related revision surgery in our follow-up (mean 21.46 months, range 3.5–46 months). This uncemented spreading stem may therefore represent an alternative option for fixation of a prosthetic device in the remaining metaphyseal femur. Daniel Burger, Matthias Pumberger, and Bruno Fuchs Copyright © 2016 Daniel Burger et al. All rights reserved. Extracorporeal Irradiation and Reimplantation with Total Hip Arthroplasty for Periacetabular Pelvic Resections: A Review of 9 Cases Wed, 20 Apr 2016 14:23:37 +0000 We report the early results of nine patients with periacetabular malignancies treated with Enneking and Dunham type 2 resection and reconstruction using extracorporeally irradiated (ECI) tumour bone combined with total hip arthroplasty (THA). Diagnosis was chondrosarcoma in six patients, osteosarcoma in two patients, and metastatic renal cell carcinoma in one patient. All patients underwent surgical resection and the resected specimen was irradiated with 50 Gy in a single fraction before being prepared for reimplantation as a composite autograft. The mean follow-up was 21 months (range, 3–59). All patients were alive at latest follow-up. No local recurrence was observed. One patient serially developed three pulmonary metastases, all of which were resected. One experienced hip dislocation due to incorrect seating of an acetabular liner. This was successfully treated with revision of the liner with no further episodes of instability. There were no cases of deep infection or loss of graft. The average Musculoskeletal Tumor Society (MSTS) score was 75% (range, 57–87%). Type 2 pelvic reconstruction with ECI and THA has shown excellent early oncological and functional results in our series. Preservation of the gluteus maximus and hip abductors is important for joint stability and prevention of infection. Lester Wai Mon Chan, Jungo Imanishi, Samuel Y. Ngan, Sarat Chander, Julie Chu, Renae Thorson, Grant Pang, and Peter Choong Copyright © 2016 Lester Wai Mon Chan et al. All rights reserved. A Therapeutic Role for Survivin in Mitigating the Harmful Effects of Ionizing Radiation Sun, 17 Apr 2016 10:39:48 +0000 Background. Radiation therapy is a form of adjuvant care used in many oncological treatment protocols. However, nonmalignant neighboring tissues are harmed as a result of this treatment. Therefore, the goal of this study was to induce the production of survivin, an antiapoptotic protein, to determine if this protein could provide protection to noncancerous cells during radiation exposure. Methods. Using a murine model, a recombinant adenoassociated virus (rAAV) was used to deliver survivin to the treatment group and yellow fluorescence protein (YFP) to the control group. Both groups received targeted radiation. Visual inspection, gait analysis, and tissue histology were used to determine the extent of damage caused by the radiation. Results. The YFP group demonstrated ulceration of the irradiated area while the survivin treated mice exhibited only hair loss. Histology showed that the YFP treated mice experienced dermal thickening, as well as an increase in collagen that was not present in the survivin treated mice. Gait analysis demonstrated a difference between the two groups, with the YFP mice averaging a lower speed. Conclusions. The use of gene-modification to induce survivin expression in normal tissues allows for the protection of nontarget areas from the negative side effects normally associated with ionizing radiation. Katherine H. Carruthers, Gregory Metzger, Eugene Choi, Matthew J. During, and Ergun Kocak Copyright © 2016 Katherine H. Carruthers et al. All rights reserved. Confirmed Activity and Tolerability of Weekly Paclitaxel in the Treatment of Advanced Angiosarcoma Thu, 25 Feb 2016 16:47:35 +0000 Background. In several prospective and retrospective studies, weekly paclitaxel showed promising activity in patients with angiosarcoma. Patients and Methods. Our study was originally designed as a prospective, phase II multicenter trial for patients younger than 75, with ECOG performance status 0–2, affected by locally advanced or metastatic angiosarcoma. Patients received paclitaxel 80 mg/m2 intravenously, at days 1, 8, and 15 every 4 weeks, until disease progression or unacceptable toxicity. Primary endpoint was objective response. Results. Eight patients were enrolled but, due to very slow accrual, the trial was prematurely stopped and further 10 patients were retrospectively included in the analysis. Out of 17 evaluable patients, 6 patients obtained an objective response (5 partial, 1 complete), with an objective response rate of 35% (95% confidence interval 17%–59%). Of note, five responses were obtained in pretreated patients. In the paper, details of overall survival, progression-free survival, and tolerability are reported. Conclusions. In this small series of patients with locally advanced or metastatic angiosarcoma, weekly paclitaxel was confirmed to be well tolerated and active even in pretreated patients. Gaetano Apice, Antonio Pizzolorusso, Massimo Di Maio, Giovanni Grignani, Vittorio Gebbia, Angela Buonadonna, Annarosaria De Chiara, Flavio Fazioli, Giampaolo De Palma, Danilo Galizia, Carlo Arcara, Nicola Mozzillo, and Francesco Perrone Copyright © 2016 Gaetano Apice et al. All rights reserved. Total Humeral Endoprosthetic Replacement following Excision of Malignant Bone Tumors Sun, 21 Feb 2016 08:32:43 +0000 Humerus is a common site for malignant tumors. Advances in adjuvant therapies and reconstructive methods provide salvage of the upper limb with improved outcomes. Reports of limb salvage with total humeral replacement in extensive humeral tumors are sparse. We undertook a retrospective study of 20 patients who underwent total humeral endoprosthetic replacement as limb salvage following excision of extensile malignant tumor from 1990 to 2011. With an average followup of 42.9, functional and oncological outcomes were analyzed. Ten patients were still alive at the time of review. Mean estimated blood loss was 1131 mL and duration of surgery was 314 minutes. Deep infection was encountered in one patient requiring debridement while mechanical loosening of ulnar component was identified in one patient. Subluxation of prosthetic humeral head was noted in 3 patients. Mean active shoulder abduction was 12.5° and active flexion was 15°. Incompetence of abduction mechanism was the major determinant of poor active functional outcome. Mean elbow flexion was 103.5° with 30.5° flexion contracture in 10 patients with good and useful hand function. Average MSTS score was 71.5%. Total humeral replacement is a reliable treatment option in restoring mechanical stability and reasonable functional results without compromising patient survival, with low complication rate. Suhel Kotwal, Bryan Moon, Patrick Lin, Robert Satcher Jr., and Valerae Lewis Copyright © 2016 Suhel Kotwal et al. 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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.