Sarcoma The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Molecular Analysis of a Recurrent Sarcoma Identifies a Mutation in FAF1 Tue, 10 Mar 2015 10:53:25 +0000 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 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. Fluorescence In Situ Hybridization for MDM2 Amplification as a Routine Ancillary Diagnostic Tool for Suspected Well-Differentiated and Dedifferentiated Liposarcomas: Experience at a Tertiary Center Wed, 25 Feb 2015 13:25:50 +0000 Background. The assessment of MDM2 gene amplification by fluorescence in situ hybridization (FISH) has become a routine ancillary tool for diagnosing atypical lipomatous tumor (ALT)/well-differentiated liposarcoma and dedifferentiated liposarcoma (WDL/DDL) in specialist sarcoma units. We describe our experience of its utility at our tertiary institute. Methods. All routine histology samples in which MDM2 amplification was assessed with FISH over a 2-year period were included, and FISH results were correlated with clinical and histologic findings. Results. 365 samples from 347 patients had FISH for MDM2 gene amplification. 170 were positive (i.e., showed MDM2 gene amplification), 192 were negative, and 3 were technically unsatisfactory. There were 122 histologically benign cases showing a histology:FISH concordance rate of 92.6%, 142 WDL/DDL (concordance 96.5%), and 34 cases histologically equivocal for WDL (concordance 50%). Of 64 spindle cell/pleomorphic neoplasms (in which DDL was a differential diagnosis), 21.9% showed MDM2 amplification. Of the cases with discrepant histology and FISH, all but 3 had diagnoses amended following FISH results. For discrepancies of benign histology but positive FISH, lesions were on average larger, more frequently in “classical” (intra-abdominal or inguinal) sites for WDL/DDL and more frequently core biopsies. Discrepancies of malignant histology but negative FISH were smaller, less frequently in “classical” sites but again more frequently core biopsies. Conclusions. FISH has a high correlation rate with histology for cases with firm histologic diagnoses of lipoma or WDL/DDL. It is a useful ancillary diagnostic tool in histologically equivocal cases, particularly in WDL lacking significant histologic atypia or DDL without corresponding WDL component, especially in larger tumors, those from intra-abdominal or inguinal sites or core biopsies. There is a significant group of well-differentiated adipocytic neoplasms which are difficult to diagnose on morphology alone, in which FISH for MDM2 amplification is diagnostically contributory. Khin Thway, Jayson Wang, John Swansbury, Toon Min, and Cyril Fisher Copyright © 2015 Khin Thway et al. All rights reserved. Prognostic Factors and Treatment Results of High-Grade Osteosarcoma in Norway: A Scope Beyond the “Classical” Patient Tue, 17 Feb 2015 11:32:14 +0000 Purpose. A retrospective study of prognostic factors and treatment outcome of osteosarcoma (OS) during modern chemotherapy era with focus on patients with primary metastatic disease, nonextremity localisation, or age >40 years (nonclassical OS). Methods. A nationwide cohort, comprising 424 high-grade Norwegian bone OS patients, was based on registry sources supplemented with clinical records from hospitals involved in sarcoma management between 1975 and 2009. Results. Only 48% were younger patients with tumour in the extremities and without metastasis at diagnosis (classical OS). A considerable discrepancy in survival between classical and nonclassical OS was observed: 61% versus 26% 10-year sarcoma specific survival. Twice as many of the former received both adequate surgery and chemotherapy compared to the latter. This could only partly explain the differences in survival due to inherent chemoresistance in primary metastatic disease and a higher rate of local relapse among patients with axial tumours. Metastasis at diagnosis, increased lactate dehydrogenase, age > 40 years, and tumour size above median value were all adverse prognostic factors for overall survival. Conclusion. We confirm a dramatic difference in outcome between classical and nonclassical high-grade OS patients, but treatment variables could only partly explain the dismal outcome of the latter. Kjetil Berner, Kirsten Sundby Hall, Odd R. Monge, Harald Weedon-Fekjær, Olga Zaikova, and Øyvind S. Bruland Copyright © 2015 Kjetil Berner et al. All rights reserved. Intercalary Reconstruction after Wide Resection of Malignant Bone Tumors of the Lower Extremity Using a Composite Graft with a Devitalized Autograft and a Vascularized Fibula Mon, 16 Feb 2015 11:31:11 +0000 Introduction. Although several intercalary reconstructions after resection of a lower extremity malignant bone tumor are reported, there are no optimal methods which can provide a long-term reconstruction with fewest complications. We present the outcome of reconstruction using a devitalized autograft and a vascularized fibula graft composite. Materials and Methods. We conducted a retrospective review of 11 patients (7 males, 4 females; median age 27 years) undergoing reconstruction using a devitalized autograft (pasteurization (), deep freezing ()) and a vascularized fibula graft composite for lower extremity malignant bone tumors (femur (), tibia ()). Results. The mean period required for callus formation and bone union was 4.4 months and 9.9 months, respectively. Four postoperative complications occurred in 3 patients: 2 infections (1 pasteurized autograft, 1 frozen autograft) and 1 fracture and 1 implant failure (both in pasteurized autografts). Graft removal was required in 2 patients with infections. The mean MSTS score was 81% at last follow-up. Conclusions. Although some complications were noted in early cases involving a pasteurized autograft, our novel method involving a combination of a frozen autograft with a vascularized fibula graft and rigid fixation with a locking plate may offer better outcomes than previously reported allografts or devitalized autografts. Koichi Ogura, Shimpei Miyamoto, Minoru Sakuraba, Tomohiro Fujiwara, Hirokazu Chuman, and Akira Kawai Copyright © 2015 Koichi Ogura et al. All rights reserved. Wiki-Based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma: A New Paradigm in Sarcoma Evidence Mon, 16 Feb 2015 08:46:09 +0000 In 2013 Australia introduced Wiki-based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma. These guidelines utilized a customized MediaWiki software application for guideline development and are the first evidence-based guidelines for clinical management of sarcoma. This paper presents our experience with developing and implementing web-based interactive guidelines and reviews some of the challenges and lessons from adopting an evidence-based (rather than consensus-based) approach to clinical sarcoma guidelines. Digital guidelines can be easily updated with new evidence, continuously reviewed and widely disseminated. They provide an accessible method of enabling clinicians and consumers to access evidence-based clinical practice recommendations and, as evidenced by over 2000 views in the first four months after release, with 49% of those visits being from countries outside of Australia. The lessons learned have relevance to other rare cancers in addition to the international sarcoma community. S. J. Neuhaus, D. Thomas, J. Desai, C. Vuletich, J. von Dincklage, and I. Olver Copyright © 2015 S. J. Neuhaus et al. All rights reserved. Identifying the Prevalence, Trajectory, and Determinants of Psychological Distress in Extremity Sarcoma Thu, 12 Feb 2015 11:48:52 +0000 Objective. Extremity sarcoma (ES) is a rare cancer that presents with unique challenges. This study was performed to identify the prevalence, trajectory, and determinants of distress and characterise sources of stress in this cohort. Methods. Consecutive patients with ES were prospectively recruited between May 2011 and December 2012. Questionnaires were administered during initial diagnosis and then six months and one year after surgery. Results. Distress was reported by about a third of our cohort and associated with poorer physical function, poorer quality of life, and pain. In addition to fears regarding mortality and life role changes, the most common sources of stress were centered on dissatisfaction with the healthcare system, such as frustrations with a lack of communication with the hospital regarding appointments and lack of education regarding management and outcomes. Conclusions. Psychological distress presents early in the cancer journey and persists up to one year after surgery. Distress is associated with negative outcomes. Active screening and effective interventions are necessary to improve outcomes. Sources of stress have been identified that may be amenable to targeted interventions. Melissa H. Tang, David J. Castle, and Peter F. M. Choong Copyright © 2015 Melissa H. Tang et al. All rights reserved. Analysis of the Intratumoral Adaptive Immune Response in Well Differentiated and Dedifferentiated Retroperitoneal Liposarcoma Thu, 29 Jan 2015 13:05:56 +0000 Treatment options are limited in well differentiated (WD) and dedifferentiated (DD) retroperitoneal liposarcoma. We sought to study the intratumoral adaptive immune response and explore the potential feasibility of immunotherapy in this disease. Tumor-infiltrating lymphocytes (TILs) were isolated from fresh surgical specimens and analyzed by flow cytometry for surface marker expression. Previously reported immune cell aggregates known as tertiary lymphoid structures (TLS) were further characterized by immunohistochemistry. In all fresh tumors, TILs were found. The majority of TILs were CD4 T cells; however cytotoxic CD8 T cells were also seen (average: 20% of CD3 T cells). Among CD8 T cells, 65% expressed the immune checkpoint molecule PD-1. Intratumoral TLS may be sites of antigen presentation as DC-LAMP positive, mature dendritic cells were found juxtaposed next to CD4 T cells. Clinicopathologic correlation, however, demonstrated that presence of TLS was associated with worse recurrence-free survival in WD disease and worse overall survival in DD disease. Our data suggest that an adaptive immune response is present in WD/DD retroperitoneal liposarcoma but may be hindered by TLS, among other possible microenvironmental factors; further investigation is needed. Immunotherapy, including immune checkpoint blockade, should be evaluated as a treatment option in this disease. William W. Tseng, Shruti Malu, Minying Zhang, Jieqing Chen, Geok Choo Sim, Wei Wei, Davis Ingram, Neeta Somaiah, Dina C. Lev, Raphael E. Pollock, Gregory Lizée, Laszlo Radvanyi, and Patrick Hwu Copyright © 2015 William W. Tseng et al. All rights reserved. Assessment of Objective Ambulation in Lower Extremity Sarcoma Patients with a Continuous Activity Monitor: Rationale and Validation Thu, 25 Dec 2014 00:10:06 +0000 In addition to patient reported outcome measures, accelerometers may provide useful information on the outcome of sarcoma patients treated with limb salvage. The StepWatch (SW) Activity Monitor (SAM) is a two-dimensional accelerometer worn on the ankle that records an objective measure of walking performance. The purpose of this study was to validate the SW in a cross-sectional population of adult patients with lower extremity sarcoma treated with limb salvage. The main outcome was correlation of total steps with the Toronto Extremity Salvage Score (TESS). In a sample of 29 patients, a mean of 12 days of SW data was collected per patient (range 6–16), with 2767 average total steps (S.D. 1867; range 406–7437). There was a moderate positive correlation between total steps and TESS . Patients with osseous tumors walked significantly less than those with soft tissue sarcoma (1882 versus 3715, ). This study supports the validity of the SAM as an activity monitor for the objective assessment of real world physical function in sarcoma patients. Kenneth R. Gundle, Stephanie E. Punt, and Ernest U. Conrad III Copyright © 2014 Kenneth R. Gundle et al. All rights reserved. Stereotactic Body Radiotherapy for Metastatic and Recurrent Ewing Sarcoma and Osteosarcoma Tue, 09 Dec 2014 00:10:13 +0000 Background. Radiotherapy has been utilized for metastatic and recurrent osteosarcoma and Ewing sarcoma (ES), in order to provide palliation and possibly prolong overall or progression-free survival. Stereotactic body radiotherapy (SBRT) is convenient for patients and offers the possibility of increased efficacy. We report our early institutional experience using SBRT for recurrent and metastatic osteosarcoma and Ewing sarcoma. Methods. We reviewed all cases of osteosarcoma or ES treated with SBRT between 2008 and 2012. Results. We identified 14 patients with a total of 27 lesions from osteosarcoma or ES . The median total curative/definitive SBRT dose delivered was 40 Gy in 5 fractions (range, 30–60 Gy in 3–10 fractions). The median total palliative SBRT dose delivered was 40 Gy in 5 fractions (range, 16–50 Gy in 1–10 fractions). Two grade 2 and 1 grade 3 late toxicities occurred, consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy. Toxicity was seen in the settings of concurrent chemotherapy and reirradiation. Conclusions. This descriptive report suggests that SBRT may be a feasible local treatment option for patients with osteosarcoma and ES. However, significant toxicity can result, and thus systematic study is warranted to clarify efficacy and characterize long-term toxicity. Lindsay C. Brown, Rachael A. Lester, Michael P. Grams, Michael G. Haddock, Kenneth R. Olivier, Carola A. S. Arndt, Peter S. Rose, and Nadia N. Laack Copyright © 2014 Lindsay C. Brown et al. All rights reserved. Can Orthopedic Oncologists Predict Functional Outcome in Patients with Sarcoma after Limb Salvage Surgery in the Lower Limb? A Nationwide Study Tue, 18 Nov 2014 00:00:00 +0000 Accurate predictions of functional outcome after limb salvage surgery (LSS) in the lower limb are important for several reasons, including informing the patient preoperatively and, in some cases, deciding between amputation and LSS. This study aimed to elucidate the correlation between surgeon-predicted and patient-reported functional outcome of LSS in the Netherlands. Twenty-three patients (between six months and ten years after surgery) and five independent orthopedic oncologists completed the Toronto Extremity Salvage Score (TESS) and the RAND-36 physical functioning subscale (RAND-36 PFS). The orthopedic oncologists made their predictions based on case descriptions (including MRI scans) that reflected the preoperative status. The correlation between patient-reported and surgeon-predicted functional outcome was “very poor” to “poor” on both scores ( values ranged from 0.014 to 0.354). Patient-reported functional outcome was generally underestimated, by 8.7% on the TESS and 8.3% on the RAND-36 PFS. The most difficult and least difficult tasks on the RAND-36 PFS were also the most difficult and least difficult to predict, respectively. Most questions had a “poor” intersurgeon agreement. It was difficult to accurately predict the patient-reported functional outcome of LSS. Surgeons’ ability to predict functional scores can be improved the most by focusing on accurately predicting more demanding tasks. Sjoerd Kolk, Kevin Cox, Vivian Weerdesteyn, Gerjon Hannink, Jos Bramer, Sander Dijkstra, Paul Jutte, Joris Ploegmakers, Michiel van de Sande, Hendrik Schreuder, Nico Verdonschot, and Ingrid van der Geest Copyright © 2014 Sjoerd Kolk et al. All rights reserved. Preoperative Diagnosis of Usual Leiomyoma, Atypical Leiomyoma, and Leiomyosarcoma Tue, 21 Oct 2014 10:07:43 +0000 Uterine smooth muscle tumors (SMTs) are common pelvic tumors in women, and most of them are diagnosed as usual leiomyoma (UL). Exclusion of malignant disease is important in the management of SMTs. However, differentiation of SMTs remains difficult. In this study, we aimed to improve the preoperative diagnosis of SMTs. We examined 21 ULs, 7 atypical leiomyomas (ALs), and 6 leiomyosarcomas (LMSs), all of which were diagnosed by uterine tumor biopsy. Immunohistochemical findings (low-molecular-mass polypeptide 2 (LMP2) and Ki-67) and clinical features (serum lactate dehydrogenase level and menopause) were evaluated. Statistically significant differences in the expression of LMP2 and Ki-67 were observed between UL and AL and between UL and LMS. The combined LMP2 and Ki-67 score was significantly different between UL and AL, between UL and LMS, and between AL and LMS. The combined immunohistochemistry and clinical findings score (total score) was also significantly different between pathological types. The findings of this study suggest that the accuracy of the preoperative diagnosis of SMTs may be improved by using a combination of immunohistochemical and clinical findings. M. Matsuda, T. Ichimura, M. Kasai, M. Murakami, N. Kawamura, T. Hayashi, and T. Sumi Copyright © 2014 M. Matsuda et al. All rights reserved. Clinical Features and Outcomes Differ between Skeletal and Extraskeletal Osteosarcoma Tue, 09 Sep 2014 08:16:03 +0000 Background. Extraskeletal osteosarcoma (ESOS) is a rare subtype of osteosarcoma. We investigated patient characteristics, overall survival, and prognostic factors in ESOS. Methods. We identified cases of high-grade osteosarcoma with known tissue of origin in the Surveillance, Epidemiology, and End Results database from 1973 to 2009. Demographics were compared using univariate tests. Overall survival was compared with log-rank tests and multivariate analysis using Cox proportional hazards methods. Results. 256/4,173 (6%) patients with high-grade osteosarcoma had ESOS. Patients with ESOS were older, were more likely to have an axial tumor and regional lymph node involvement, and were female. Multivariate analysis showed ESOS to be favorable after controlling for stage, age, tumor site, gender, and year of diagnosis [hazard ratio 0.75 (95% CI 0.62 to 0.90); ]. There was an interaction between age and tissue of origin such that older patients with ESOS had superior outcomes compared to older patients with skeletal osteosarcoma. Adverse prognostic factors in ESOS included metastatic disease, larger tumor size, older age, and axial tumor site. Conclusion. Patients with ESOS have distinct clinical features but similar prognostic factors compared to skeletal osteosarcoma. Older patients with ESOS have superior outcomes compared to older patients with skeletal osteosarcoma. Sheila Thampi, Katherine K. Matthay, W. John Boscardin, Robert Goldsby, and Steven G. DuBois Copyright © 2014 Sheila Thampi et al. All rights reserved. Histopathological Diagnostic Discrepancies in Soft Tissue Tumours Referred to a Specialist Centre: Reassessment in the Era of Ancillary Molecular Diagnosis Tue, 05 Aug 2014 00:00:00 +0000 Introduction. Soft tissue tumour pathology is a highly specialised area of surgical pathology, but soft tissue neoplasms can occur at virtually all sites and are therefore encountered by a wide population of surgical pathologists. Potential sarcomas require referral to specialist centres for review by pathologists who see a large number of soft tissue lesions and where appropriate ancillary investigations can be performed. We have previously assessed the types of diagnostic discrepancies between referring and final diagnosis for soft tissue lesions referred to our tertiary centre. We now reaudit this 6 years later, assessing changes in discrepancy patterns, particularly in relation to the now widespread use of ancillary molecular diagnostic techniques which were not prevalent in our original study. Materials and Methods. We compared the sarcoma unit's histopathology reports with referring reports on 348 specimens from 286 patients with suspected or proven soft tissue tumours in a one-year period. Results. Diagnostic agreement was seen in 250 cases (71.8%), with 57 (16.4%) major and 41 (11.8%) minor discrepancies. There were 23 cases of benign/malignant discrepancies (23.5% of all discrepancies). 50 ancillary molecular tests were performed, 33 for aiding diagnosis and 17 mutational analyses for gastrointestinal stromal tumour to guide therapy. Findings from ancillary techniques contributed to 3 major and 4 minor discrepancies. While the results were broadly similar to those of the previous study, there was an increase in frequency of major discrepancies. Conclusion. Six years following our previous study and notably now in an era of widespread ancillary molecular diagnosis, the overall discrepancy rate between referral and tertiary centre diagnosis remains similar, but there is an increase in frequency of major discrepancies likely to alter patient management. A possible reason for the increase in major discrepancies is the increasing lack of exposure to soft tissue cases in nonspecialist centres in a time of subspecialisation. The findings support the national guidelines in which all suspected soft tissue tumour pathology specimens should be referred to a specialist sarcoma unit. Khin Thway, Jayson Wang, Taka Mubako, and Cyril Fisher Copyright © 2014 Khin Thway et al. All rights reserved. Computer-Assisted Planning and Patient-Specific Instruments for Bone Tumor Resection within the Pelvis: A Series of 11 Patients Wed, 02 Jul 2014 11:31:20 +0000 Pelvic bone tumor resection is challenging due to complex geometry, limited visibility, and restricted workspace. Accurate resection including a safe margin is required to decrease the risk of local recurrence. This clinical study reports 11 cases of pelvic bone tumor resected by using patient-specific instruments. Magnetic resonance imaging was used to delineate the tumor and computerized tomography to localize it in 3D. Resection planning consisted in desired cutting planes around the tumor including a safe margin. The instruments were designed to fit into unique position on the bony structure and to indicate the desired resection planes. Intraoperatively, instruments were positioned freehand by the surgeon and bone cutting was performed with an oscillating saw. Histopathological analysis of resected specimens showed tumor-free bone resection margins for all cases. Available postoperative computed tomography was registered to preoperative computed tomography to measure location accuracy (minimal distance between an achieved and desired cut planes) and errors on safe margin (minimal distance between the achieved cut planes and the tumor boundary). The location accuracy averaged 2.5 mm. Errors in safe margin averaged −0.8 mm. Instruments described in this study may improve bone tumor surgery within the pelvis by providing good cutting accuracy and clinically acceptable margins. François Gouin, Laurent Paul, Guillaume Anthony Odri, and Olivier Cartiaux Copyright © 2014 François Gouin et al. All rights reserved. Cell Senescence in Myxoid/Round Cell Liposarcoma Tue, 24 Jun 2014 06:54:41 +0000 Myxoid/round cell liposarcoma (MLS/RCLS) is the second most common liposarcoma type and characterized by the fusion oncogenes FUS-DDIT3 or EWSR1-DDIT3. Previous analysis of cell cycle regulatory proteins revealed a prominent expression of G1-cyclins, cyclin dependent kinases, and their inhibitors but very few cells progressing through the G1/S boundary. Here, we extend the investigation to proteins involved in cell senescence in an immunohistochemistry based study of 17 MLS/RCLS cases. Large subpopulations of tumor cells expressed the RBL2 pocket protein and senescence associated heterochromatin 1γ and IL8 receptor β. We conclude that MLS/RCLS tissues contain major populations of senescent tumor cells and this may explain the slow growth rate of this tumor type. Christina Kåbjörn Gustafsson, Anders Ståhlberg, Katarina Engtröm, Anna Danielsson, Ingela Turesson, and Pierre Åman Copyright © 2014 Christina Kåbjörn Gustafsson et al. All rights reserved. Adult versus Pediatric Neuroblastoma: The M.D. Anderson Cancer Center Experience Thu, 12 Jun 2014 07:41:08 +0000 Background. Staging and treatment of adult neuroblastoma has yet to be formalized. We sought to determine the utility of the pediatric classification system in adults and determine the efficacy of different treatment modalities. Methods. Medical records of 118 adults (patients >17 years old) and 112 pediatric patients (ages 2–17), who were treated for neuroblastoma at M.D. Anderson Cancer Center from January 1994 to September 2012, were reviewed. International neuroblastoma risk group (INRG) variables were abstracted. The primary outcome of interest was actuarial progression-free survival. Results. Median age of pediatric patients was 5 years (range 3–16) and 47 years (range 18–82) for adult patients. There were no differences in PFS or OS between stage-matched risk categories between pediatric and adult patients (L1-, L2-, and M-). In the treatment of L1 disease, median PFS for adults treated with surgery and radiation was 11.1 months compared with single modality local treatment ± chemotherapy (6.4 and 5.1 months, resp.; ). Median PFS in L2 adult patients was 5.2 months with local therapy and 4 months with the addition of chemotherapy (). Conclusions. Adult and pediatric patients with neuroblastoma achieve similar survival outcomes. INRG classification should be employed to stratify adult neuroblastoma patients and help select treatment. Henry J. Conter, Vancheswaran Gopalakrishnan, Vinod Ravi, Joann L. Ater, Shreyaskumar Patel, and Dejka M. Araujo Copyright © 2014 Henry J. Conter et al. All rights reserved. Cost-Effectiveness of Pazopanib in Advanced Soft Tissue Sarcoma in the United Kingdom Thu, 12 Jun 2014 07:32:45 +0000 In the phase III PALETTE trial, pazopanib improved progression-free survival (PFS) compared with placebo in patients with advanced/metastatic soft tissue sarcomas (mSTS) who had received prior chemotherapy. We used a multistate model to estimate expected PFS, overall survival (OS), lifetime STS treatment costs, and quality-adjusted life-years (QALYs) for patients receiving pazopanib, placebo, trabectedin, ifosfamide, or gemcitabine plus docetaxel as second-line mSTS therapies. The cost-effectiveness of pazopanib was expressed as the incremental costs per QALY gained. Estimates of PFS/OS, adverse events, and utilities for pazopanib and placebo were from the PALETTE trial. Estimates of relative effectiveness of the other comparators were from an unadjusted indirect comparison versus pazopanib. Costs were from published sources. Pazopanib is estimated to increase QALYs by 0.128 and costs by £7,976 versus placebo; cost per QALY gained with pazopanib versus placebo is estimated to be £62,000. Compared with the other chemotherapies, pazopanib provides similar QALYs at a lower cost. Pazopanib may not be cost-effective versus placebo but may be cost-effective versus the most commonly used active treatments, although this conclusion is uncertain. Given the unmet need for effective treatments for mSTS, pazopanib may be an appropriate alternative to some currently used medications in the United Kingdom. Jordan Amdahl, Stephanie C. Manson, Robert Isbell, Ayman Chit, Jose Diaz, Lily Lewis, and Thomas E. Delea Copyright © 2014 Jordan Amdahl et al. All rights reserved. MRI Evaluation of Resection Margins in Bone Tumour Surgery Mon, 26 May 2014 06:44:38 +0000 In 12 patients operated on for bone sarcoma resection, a postoperative magnetic resonance imaging of the resection specimens was obtained in order to assess the surgical margins. Margins were classified according to MRI in R0, R1, and R2 by three independent observers: a radiologist and two orthopaedic surgeons. Final margin evaluation (R0, R1, and R2) was assessed by a confirmed pathologist. Agreement for margin evaluation between the pathologist and the radiologist was perfect (). Agreement between the pathologist and an experienced orthopaedic surgeon was very good while it was fair between the pathologist and a junior orthopaedic surgeon. MRI should be considered as a tool to give quick information about the adequacy of margins and to help the pathologist to focus on doubtful areas and to spare time in specimen analysis. But it may not replace the pathological evaluation that gives additional information about tumor necrosis. This study shows that MRI extemporaneous analysis of a resection specimen may be efficient in bone tumor oncologic surgery, if made by an experienced radiologist with perfect agreement with the pathologist. Simon Vandergugten, Sidi Yaya Traore, Olivier Cartiaux, Frédéric Lecouvet, Christine Galant, and Pierre-Louis Docquier Copyright © 2014 Simon Vandergugten et al. All rights reserved. Role of Intraoperative Pathology Consultation in Skeletal Tumors and Tumor-Like Lesions Mon, 19 May 2014 00:00:00 +0000 Early and accurate detection of bone tumors and their staging are important since some of them are highly malignant. Intraoperative pathological consultation in bone tumors and tumor-like conditions is quite complex; however, it allows improvement in prognosis and limb salvage. Present study was conducted on 52 patients who underwent surgical procedure after clinical and radiological diagnosis of bone tumors/tumor-like conditions. Fresh unfixed tissue was quickly inspected grossly, followed by preparation of imprint smears and frozen section which were evaluated by two pathologists separately and compared subsequently with reports of paraffin-embedded sections. Clinical reasons for intraoperative consultation were to make diagnosis in 65.4% of cases and to determine resection margin status in 21.1% while in 13.5% of cases, it was for both indications. Diagnostic yield of imprint smears was 87.8% (13 malignant, 22 benign, and 1 tumor-like) and of frozen section was 90.2% (16 malignant, 19 benign, and 2 nonneoplastic) while paraffin sections could diagnose specific tumors in 95.1% (18 malignant, 18 benign, and 3 nonneoplastic). Although frozen section had better sensitivity (88.2%), it had less specificity (94.7%) as compared to imprint smears (76.5% and 100%, resp.). Imprint cytology and frozen section together provide a quick, safe, and reliable intraoperative provisional tissue diagnosis in skeletal tumors and tumor-like conditions. Poonam Bhaker, Harsh Mohan, Uma Handa, and Sudhir Kumar Copyright © 2014 Poonam Bhaker et al. All rights reserved. Osteosarcoma in Pediatric Patients and Young Adults: A Single Institution Retrospective Review of Presentation, Therapy, and Outcome Wed, 30 Apr 2014 13:45:00 +0000 Background. Little is known about how cumulative chemotherapy delivery influences the poorer outcome observed in young adult (YA, 18–40 years) versus pediatric (<18 years) osteosarcoma patients. Here, we retrospectively examined differences in presentation, therapy, including cumulative chemotherapy dose, and outcome in YA and pediatric patients. Methods. We reviewed 111 cases of high-grade osteosarcoma at Moffitt Cancer Center between 1988 and 2012. Presentation factors, therapies, and survival were compared between YA and pediatric cohorts. Results. The cohorts were equivalent with respect to metastatic status, gender, tumor size, tumor site, and histological subtype. We found that the YA patients tended to have poorer histologic response to neoadjuvant chemotherapy measured by necrosis with 55% and 35% of pediatric versus YA patients responding favorably (). Only 39% of YA patients achieved the typical pediatric dose of methotrexate, doxorubicin, and cisplatin. These patients had a 3-year EFS of 76% (CI 53–100%) versus 47% (CI 26–69%; ) in those who received less chemotherapy. Conclusion. Age continues to be a prognostic factor in osteosarcoma. Our study suggests that presentation factors are not associated with prognosis, while poorer response to chemotherapy and lower cumulative dose of chemotherapy delivered to YA patients may contribute to poorer outcomes. Candace L. Haddox, Gang Han, Leon Anijar, Odion Binitie, G. Douglas Letson, Marilyn M. Bui, and Damon R. Reed Copyright © 2014 Candace L. Haddox et al. All rights reserved. Aberrant Hedgehog Signaling and Clinical Outcome in Osteosarcoma Sun, 30 Mar 2014 12:20:52 +0000 Despite the importance of Hedgehog signaling in bone development, the relationship between Hedgehog pathway expression and osteosarcoma clinical characteristics and outcome has not been investigated. In this study of 43 high-grade human osteosarcoma samples, we detected high expression levels of the Hedgehog ligand gene, IHH, and target genes, PTCH1 and GLI1, in most samples. Further analysis in tumors of patients with localized disease at diagnosis identified coexpression of IHH and PTCH1 exclusively in large tumors. Higher levels of IHH were observed more frequently in males and patients with higher levels of GLI1 were more responsive to chemotherapy. Subgroup analysis by tumor size and IHH expression indicated that the well-known association between survival and tumor size was further refined when IHH levels were taken into consideration. Winnie W. Lo, Dushanthi Pinnaduwage, Nalan Gokgoz, Jay S. Wunder, and Irene L. Andrulis Copyright © 2014 Winnie W. Lo et al. All rights reserved. DDIT3 Expression in Liposarcoma Development Tue, 25 Mar 2014 09:46:42 +0000 Liposarcomas are mesenchymal tumors containing variable numbers of lipoblasts or adipocytes. The most common entities, well differentiated/dedifferentiated liposarcoma (WDLS/DDLS) and myxoid/round cell liposarcoma (MLS/RCLS), are both characterized by genetic rearrangements that affect the expression of the transcription factor DDIT3. DDIT3 induces liposarcoma morphology when ectopically expressed in a human fibrosarcoma. The role of DDIT3 in lipomatous tumors is, however, unclear. We have analyzed the expression of DDIT3 in 37 cases of liposarcoma (WDLS/DDLS n = 10, MLS/RCLS n = 16, and pleomorphic liposarcomas (PLS) n = 11) and 11 cases of common benign lipomas. Major cell subpopulations of WDLS/DDLS and MLS/RCLS tumors were found to express DDIT3 or the derived fusion protein, whereas PLS cases showed only a few positive cells. The lipomas contained large subpopulations expressing DDIT3. No correlation between numbers of DDIT3 expressing cells and numbers of lipoblasts/adipocytes was found. In vitro adipogenic treatment of two DDIT3 expressing cell lines induced lipid accumulation in small subpopulations only. Our results suggest a dual, promoting and limiting, role for DDIT3 in the formation of lipoblasts and liposarcoma morphology. Christina Kåbjörn Gustafsson, Katarina Engström, and Pierre Åman Copyright © 2014 Christina Kåbjörn Gustafsson et al. All rights reserved. Sarcoma Immunotherapy: Past Approaches and Future Directions Thu, 20 Mar 2014 09:29:58 +0000 Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25–50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease. S. P. D'Angelo, W. D. Tap, G. K. Schwartz, and R. D. Carvajal Copyright © 2014 S. P. D'Angelo et al. All rights reserved. Validation of the SF-6D Health State Utilities Measure in Lower Extremity Sarcoma Wed, 19 Mar 2014 09:27:55 +0000 Aim. Health state utilities measures are preference-weighted patient-reported outcome (PRO) instruments that facilitate comparative effectiveness research. One such measure, the SF-6D, is generated from the Short Form 36 (SF-36). This report describes a psychometric evaluation of the SF-6D in a cross-sectional population of lower extremity sarcoma patients. Methods. Patients with lower extremity sarcoma from a prospective database who had completed the SF-36 and Toronto Extremity Salvage Score (TESS) were eligible for inclusion. Computed SF-6D health states were given preference weights based on a prior valuation. The primary outcome was correlation between the SF-6D and TESS. Results. In 63 pairs of surveys in a lower extremity sarcoma population, the mean preference-weighted SF-6D score was 0.59 (95% CI 0.4–0.81). The distribution of SF-6D scores approximated a normal curve (skewness = 0.11). There was a positive correlation between the SF-6D and TESS (, ). Respondents who reported walking aid use had lower SF-6D scores (0.53 versus 0.61, ). Five respondents underwent amputation, with lower SF-6D scores that approached significance (0.48 versus 0.6, ). Conclusions. The SF-6D health state utilities measure demonstrated convergent validity without evidence of ceiling or floor effects. The SF-6D is a health state utilities measure suitable for further research in sarcoma patients. Kenneth R. Gundle, Amy M. Cizik, Stephanie E. W. Punt, Ernest U. Conrad III, and Darin J. Davidson Copyright © 2014 Kenneth R. Gundle et al. All rights reserved. Brain Metastasis in Bone and Soft Tissue Cancers: A Review of Incidence, Interventions, and Outcomes Sun, 16 Mar 2014 00:00:00 +0000 Bone and soft tissue malignancies account for a small portion of brain metastases. In this review, we characterize their incidence, treatments, and prognosis. Most of the data in the literature is based on case reports and small case series. Less than 5% of brain metastases are from bone and soft tissue sarcomas, occurring most commonly in Ewing’s sarcoma, malignant fibrous tumors, and osteosarcoma. Mean interval from initial cancer diagnosis to brain metastasis is in the range of 20–30 months, with most being detected before 24 months (osteosarcoma, Ewing sarcoma, chordoma, angiosarcoma, and rhabdomyosarcoma), some at 24–36 months (malignant fibrous tumors, malignant peripheral nerve sheath tumors, and alveolar soft part sarcoma), and a few after 36 months (chondrosarcoma and liposarcoma). Overall mean survival ranges between 7 and 16 months, with the majority surviving < 12 months (Ewing’s sarcoma, liposarcoma, malignant fibrous tumors, malignant peripheral nerve sheath tumors, angiosarcoma and chordomas). Management is heterogeneous involving surgery, radiosurgery, radiotherapy, and chemotherapy. While a survival advantage may exist for those given aggressive treatment involving surgical resection, such patients tended to have a favorable preoperative performance status and minimal systemic disease. Faris Shweikeh, Laura Bukavina, Kashif Saeed, Reem Sarkis, Aarushi Suneja, Fadi Sweiss, and Doniel Drazin Copyright © 2014 Faris Shweikeh et al. All rights reserved. Synovial Chondrosarcoma Arising in Synovial Chondromatosis Wed, 05 Mar 2014 12:05:27 +0000 Primary synovial chondromatosis (SC) is a rare proliferative disorder that causes pain, swelling, and restriction of movement to the joints it affects. The disease frequently runs a protracted course, often requiring multiple surgical procedures to obtain some control. Few reports exist detailing the natural history of SC, although malignant transformation to synovial chondrosarcoma (CHS) is recognized to be a rare event. The aim of our study was to review a large orthopaedic oncology database in order to evaluate the incidence of CHS arising from SC. We identified 78 patients who have presented to our centre with primary synovial chondromatosis (SC). Of those patients, 5 went on to develop malignant change. This represents a 6.4% incidence of developing synovial chondrosarcoma (CHS) within preexisting primary synovial chondromatosis. The patients had a mean age of 28 years at first diagnosis with synovial chondromatosis with the median time from original diagnosis to malignant transformation being 20 years (range 2.7–39 yrs). Scott Evans, Michele Boffano, Samena Chaudhry, Lee Jeys, and Robert Grimer Copyright © 2014 Scott Evans et al. All rights reserved. Comorbidity in Adult Bone Sarcoma Patients: A Population-Based Cohort Study Thu, 27 Feb 2014 16:13:47 +0000 Background. Comorbidity is an important prognostic factor for survival in different cancers; however, neither the prevalence nor the impact of comorbidity has been investigated in bone sarcoma. Methods. All adult bone sarcoma patients from western Denmark treated at the Aarhus Sarcoma Centre in the period from 1979 to 2008 were identified through a validated population-based database. Charlson Comorbidity Index scores were computed, using discharge diagnoses from the Danish National Patient Registry. Survival was assessed as overall and disease-specific mortality. The impact of comorbidity was examined as rates according to the level of comorbidity as well as uni- and multivariately using proportional hazard models. Results. A total of 453 patients were identified. The overall prevalence of comorbidity was 19%. The prevalence increased with age and over the study period. In patients with Ewing/osteosarcoma, comorbidity was not associated with an increased overall or disease-specific mortality. However, patients with bone sarcomas other than Ewing/osteosarcoma had increased overall mortality. Independent prognostic factors for disease-specific survival were age, tumor size, stage at diagnosis, soft tissue involvement, grade, and surgery. Conclusion. The prevalence of comorbidity in bone sarcoma patients is low. Comorbidity impaired survival in patients with non-Ewing/nonosteosarcoma, histology. This emphasizes the importance of not only treating the sarcoma but also comorbidity. Ninna Aggerholm-Pedersen, Katja Maretty-Nielsen, Johnny Keller, Steen Baerentzen, and Akmal Safwat Copyright © 2014 Ninna Aggerholm-Pedersen et al. All rights reserved. MRI-Based Assessment of Safe Margins in Tumor Surgery Thu, 20 Feb 2014 16:46:51 +0000 Introduction. In surgical oncology, histological analysis of excised tumor specimen is the conventional method to assess the safety of the resection margins. We tested the feasibility of using MRI to assess the resection margins of freshly explanted tumor specimens in rats. Materials and Methods. Fourteen specimen of sarcoma were resected in rats and analysed both with MRI and histologically. Slicing of the specimen was identical for the two methods and corresponding slices were paired. 498 margins were measured in length and classified using the UICC classification (R0, R1, and R2). Results. The mean difference between the 498 margins measured both with histology and MRI was 0.3 mm (SD 1.0 mm). The agreement interval of the two measurement methods was [−1.7 mm; 2.2 mm]. In terms of the UICC classification, a strict correlation was observed between MRI- and histology-based classifications (, ). Discussion. This experimental study showed the feasibility to use MRI images of excised tumor specimen to assess the resection margins with the same degree of accuracy as the conventional histopathological analysis. When completed, MRI acquisition of resected tumors may alert the surgeon in case of inadequate margin and help advantageously the histopathological analysis. Laura Bellanova, Thomas Schubert, Olivier Cartiaux, Frédéric Lecouvet, Christine Galant, Xavier Banse, and Pierre-Louis Docquier Copyright © 2014 Laura Bellanova et al. All rights reserved. Consumptive Coagulopathy in Angiosarcoma: A Recurrent Phenomenon? Thu, 13 Feb 2014 12:36:41 +0000 Objectives. To report the prevalence of consumptive coagulopathy in angiosarcoma patients seen at a single center. Methods. We retrospectively reviewed case records of 42 patients diagnosed with angiosarcoma at Mount Sinai Hospital between 2000 and 2013. Results. Seven patients (17%) met clinical criteria for disseminated intravascular coagulation (DIC) in absence of concomitant clinical states known to cause coagulopathy or myelosuppression. In all patients who received systemic antineoplastic therapy with resultant disease response or stability, DIC resolved in tandem with clinical improvement. DIC recurred at time of disease progression in all cases. Two patients had bulky disease, defined as diameter of largest single or contiguous tumor mass measuring 5 cm or more. All patients demonstrated an aggressive clinical course with short duration of disease control and demise within 1 year. In contrast, evaluation over the same period of 17 epithelioid hemangioendothelioma patients serving as a clinical control group revealed no evidence of DIC. Conclusion. Angiosarcomas can be associated with a consumptive coagulopathy arising in tandem with disease activity. Vigilance for this complication will be needed in the course of often aggressive multimodality therapy. The potential utility of coagulopathy as a prognostic biomarker will need to be explored in future studies. Mohamad Farid, Linda Ahn, Andrew Brohl, Angela Cioffi, and Robert G. Maki Copyright © 2014 Mohamad Farid et al. All rights reserved.