Sarcoma The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . 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. High Dose Thiotepa in Patients with Relapsed or Refractory Osteosarcomas: Experience of the SFCE Group Tue, 04 Feb 2014 09:09:42 +0000 Introduction. Osteosarcoma relapse has a poor prognosis, with less than 25% survival at 5 years. We describe the experience of the French Society of Paediatric Oncology (SFCE) with high dose (HD) thiotepa and autologous stem cell transplantation (ASCT) in 45 children with relapsed osteosarcoma. Patients and Methods. Between 1992 and 2004, 53 patients received HD thiotepa (900 mg/m2) followed by ASCT in 6 centres. Eight patients were excluded from analysis, and we retrospectively reviewed the clinical radiological and anatomopathological patterns of the 45 remaining patients. Results. Sixteen girls and 29 boys (median age, 15.9 years) received HD thiotepa after initial progression of metastatic disease (2), first relapse (26), and second or third relapse (17). We report 12 radiological partial responses and 9 of 31 histological complete responses. Thirty-two patients experienced further relapses, and 13 continued in complete remission after surgical resection of the residual disease. Three-year overall survival was 40%, and 3-year progression-free survival was 24%. Delay of relapse (+/− 2 years from diagnosis) was a prognostic factor (). No acute toxic serious adverse event occurred. Conclusion. The use of HD thiotepa and ASCT is feasible in patients with relapsed osteosarcoma. A randomized study for recurrent osteosarcoma between standard salvage chemotherapy and high dose thiotepa with stem cell rescue is ongoing. Perrine Marec-Berard, Céline Segura-Ferlay, Marie-Dominique Tabone, Helene Pacquement, Cyril Lervat, Jean-Claude Gentet, Claudine Schmitt, Nathalie Gaspar, and Laurence Brugières Copyright © 2014 Perrine Marec-Berard et al. All rights reserved. Epidemiology, Treatment Patterns, and Outcomes of Metastatic Soft Tissue Sarcoma in a Community-Based Oncology Network Sun, 12 Jan 2014 00:00:00 +0000 Purpose. To assess epidemiology, treatment patterns, and outcomes of metastatic soft tissue sarcoma (mSTS) patients in USA community oncology practices. Methods. This retrospective, descriptive study used US Oncology’s iKnowMed electronic health records database. Adults (≥18 years) with mSTS and at least two visits between July 2007 and June 2010 were included. Key outcomes were practice patterns, overall survival (OS), and progression-free survival (PFS). Results. 363 mSTS patients (174 treated and 189 untreated) met the prespecified exclusion/inclusion criteria. The most common subtypes were leiomyosarcoma (; 29%), liposarcoma (; 11%), and synovial sarcoma (; 3%); the remainder (; 57%) comprised 27 histologic subtypes. Treated patients were younger and had lower ECOG scores; 75% and 25% received first-line combination or monotherapy, respectively. Median OS of treated and untreated patients was 22 and 17 months, respectively, and 29 months in patients with the three most common subtypes. Before controlling for effects of covariates, younger age and lower ECOG scores were associated with better OS and PFS. Conclusion. This study provides insights into mSTS epidemiology, treatment patterns, and outcomes in a large community-based oncology network. These results warrant further studies with larger cohorts. Clara Chen, Rohit Borker, James Ewing, Wan-Yu Tseng, Michelle D. Hackshaw, Shanmugapriya Saravanan, Rahul Dhanda, and Eric Nadler Copyright © 2014 Clara Chen et al. All rights reserved. Analysis of Surgical Site Infection after Musculoskeletal Tumor Surgery: Risk Assessment Using a New Scoring System Wed, 08 Jan 2014 08:20:18 +0000 Surgical site infection (SSI) has not been extensively studied in musculoskeletal tumors (MST) owing to the rarity of the disease. We analyzed incidence and risk factors of SSI in MST. SSI incidence was evaluated in consecutive 457 MST cases (benign, 310 cases and malignant, 147 cases) treated at our institution. A detailed analysis of the clinical background of the patients, pre- and postoperative hematological data, and other factors that might be associated with SSI incidence was performed for malignant MST cases. SSI occurred in 0.32% and 12.2% of benign and malignant MST cases, respectively. The duration of the surgery () and intraoperative blood loss () was significantly more in the SSI group than in the non-SSI group. We established the musculoskeletal oncological surgery invasiveness (MOSI) index by combining 4 risk factors (blood loss, operation duration, preoperative chemotherapy, and the use of artificial materials). The MOSI index (0–4 points) score significantly correlated with the risk of SSI, as demonstrated by an SSI incidence of 38.5% in the group with a high score (3-4 points). The MOSI index score and laboratory data at 1 week after surgery could facilitate risk evaluation and prompt diagnosis of SSI. Satoshi Nagano, Masahiro Yokouchi, Takao Setoguchi, Hiromi Sasaki, Hirofumi Shimada, Ichiro Kawamura, Yasuhiro Ishidou, Junichi Kamizono, Takuya Yamamoto, Hideki Kawamura, and Setsuro Komiya Copyright © 2014 Satoshi Nagano et al. All rights reserved. Costs Associated with Intravenous Cancer Therapy Administration in Patients with Metastatic Soft Tissue Sarcoma in a US Population Mon, 23 Dec 2013 15:25:27 +0000 Background. The most common chemotherapies in metastatic soft tissue sarcoma (mSTS) require intravenous (IV) administration. This often requires patients to make multiple outpatient visits per chemotherapy cycle, possibly impeding patients’ daily activities and increasing caregiver burden and medical costs. This study investigated costs associated with IV cancer therapy administration in mSTS from the payer perspective of the health care system. Patients and Methods. From the Experian Healthcare database, 1,228 mSTS patients were selected. Data were analyzed on outpatient visits during 2005–2012 involving IV cancer therapy administration. Costs were estimated on a per patient per visit (PPPV) and per patient per month (PPPM) basis. Results. The mean (median) cost of IV therapy was $2,427 ($1,532) PPPV and $5,468 ($4,310) PPPM, of which approximately 60% was IV drug costs. IV administration costs averaged $399 PPPV and $900 PPPM, representing 16.5% of total visit costs. Anthracycline and alkylating-agents-based therapies had the highest PPPV and PPPM IV administration costs, respectively (mean $479 and $1,336, resp.). Patients with managed care insurance had the highest IV administration costs (mean $504 PPPV; $1,120 PPPM). Conclusions. IV administration costs constitute a considerable proportion of the total costs of receiving an IV cancer therapy to treat mSTS. Mei Sheng Duh, Michelle D. Hackshaw, Jasmina I. Ivanova, Gregory Kruse, Lesley-Ann N. Miller, Patrick Lefebvre, Paul Karner, and Bruce Wong Copyright © 2013 Mei Sheng Duh et al. All rights reserved. Can Experienced Observers Differentiate between Lipoma and Well-Differentiated Liposarcoma Using Only MRI? Mon, 09 Dec 2013 10:21:07 +0000 Well-differentiated liposarcoma represents a radiographic diagnostic dilemma. To determine the accuracy, interrater reliability, and relationship of stranding, nodularity, and size in the MRI differentiation of lipoma and well-differentiated liposarcoma, MRI scans of 60 patients with large (>5 cm), deep, pathologically proven lipomas or well-differentiated liposarcomas were examined by 10 observers with subspecialty training blinded to diagnosis. Observers indicated whether the amount of stranding, nodularity, and size of each tumor suggested a benign or malignant diagnosis and rendered a diagnosis of lipoma or well-differentiated liposarcoma. The accuracy, reliability, and relationship of stranding, nodularity, and size to diagnosis were calculated for all samples. 69% of reader MRI diagnoses agreed with final pathology diagnosis (95% CI 65–73%). Readers tended to err choosing a diagnosis of liposarcoma, correctly identifying lipomas in 63% of cases (95% CI 58–69%) and liposarcomas in 75% of cases (95% CI 69–80%). Assessment of the relationship of stranding, nodularity, and size to correct diagnosis showed that the presence of each was associated with a decreased likelihood of a lipoma pathological diagnosis (). While the radiographic diagnosis of lipoma or well-differentiated liposarcoma cannot be made with 100% certainty, experienced observers have a 69% chance of rendering a correct diagnosis. Patrick W. O'Donnell, Anthony M. Griffin, William C. Eward, Amir Sternheim, Lawrence M. White, Jay S. Wunder, and Peter C. Ferguson Copyright © 2013 Patrick W. O'Donnell et al. All rights reserved. Clinical Activity and Tolerability of a 14-Day Infusional Ifosfamide Schedule in Soft-Tissue Sarcoma Wed, 04 Dec 2013 15:43:16 +0000 Background. Soft-tissue sarcomas (STS) are a heterogeneous group of diseases with lack of effective treatments in most cases. Previous data suggest that continuous infusional ifosfamide regimens might improve cytotoxicity and tolerability compared to standard schedules. Methods. We retrospectively report the outcome of 35 patients affected by STS treated with a 14-day infusional ifosfamide regimen (1000 mg/m2/day) in our institution. Predictive factors for toxicity were also explored. Results. Median age was 53 years. There were 16 males and 19 females. Classification by histology was dedifferentiated liposarcoma (DDLPS): 22 (62.8%), synovial sarcoma: 7 (20%), myxoid/round-cell liposarcoma: 3 (8.5%), and others: 3 (8.5%). Overall, 7 patients (20%) achieved partial response (PR) and 10 patients (29%) achieved stable disease (SD). DDLPS showed special sensitivity: 5 patients (22.7%) had PR, 7 patients (31.8%) had SD, and disease control rate was 54.5%. Median progression-free survival and overall survival were 4.2 and 11.2 months, respectively. The most common toxicities were fatigue, nausea, and vomiting (all grades: 85.7%, 83%, and 54.3%, resp.). Neither hypoalbuminaemia nor gender was found to predict toxicity, although encephalopathy predominantly affected females. Conclusion. Ifosfamide administered as a 14-day continuous infusion is a safe regimen in STS with notable activity in DDLPS. Juan Martin-Liberal, Salma Alam, Anastasia Constantinidou, Cyril Fisher, Komel Khabra, Christina Messiou, David Olmos, Scott Mitchell, Omar Al-Muderis, Aisha Miah, Mark Linch, Robin L. Jones, Michelle Scurr, Ian Judson, and Charlotte Benson Copyright © 2013 Juan Martin-Liberal et al. All rights reserved. Reduced Latency in the Metastatic Niche Contributes to the More Aggressive Phenotype of LM8 Compared to Dunn Osteosarcoma Cells Wed, 04 Dec 2013 13:36:24 +0000 Metastasis is the major cause of death of osteosarcoma patients and its diagnosis remains difficult. In preclinical studies, however, forced expression of reporter genes in osteosarcoma cells has remarkably improved the detection of micrometastases and, consequently, the quality of the studies. We recently showed that Dunn cells equipped with a lacZ reporter gene disseminated from subcutaneous primary tumors as frequently as their highly metastatic subline LM8, but only LM8 cells grew to macrometastases. In the present time-course study, tail-vein-injected Dunn and LM8 cells settled within 24 h at the same frequency in the lung, liver, and kidney of mice. Furthermore, Dunn cells also grew to macrometastases, but, compared to LM8, with a delay of two weeks in lung and one week in liver and kidney tissue, consistent with prolonged survival of the mice. Dunn- and LM8-cell-derived ovary and spine metastases occurred less frequently. In vitro, Dunn cells showed less invasiveness and stronger contact inhibition and intercellular adhesion than LM8 cells and several cancer- and dormancy-related genes were differentially expressed. In conclusion, Dunn cells, compared to LM8, have a similar capability but a longer latency to form macrometastases and provide an interesting new experimental system to study tumor cell dormancy. Matthias J. E. Arlt, Ingo J. Banke, Josefine Bertz, Ram Mohan Ram Kumar, Roman Muff, Walter Born, and Bruno Fuchs Copyright © 2013 Matthias J. E. Arlt et al. All rights reserved. Cost Effectiveness of First-Line Treatment with Doxorubicin/Ifosfamide Compared to Trabectedin Monotherapy in the Management of Advanced Soft Tissue Sarcoma in Italy, Spain, and Sweden Sun, 03 Nov 2013 08:12:17 +0000 Background. Doxorubicin/ifosfamide is a first-line systemic chemotherapy for the majority of advanced soft tissue sarcoma (ASTS) subtypes. Trabectedin is indicated for the treatment of ASTS after failure of anthracyclines and/or ifosfamide; however it is being increasingly used off-label as a first-line treatment. This study estimated the cost effectiveness of these two treatments in the first-line management of ASTS in Italy, Spain, and Sweden. Methods. A Markov model was constructed to estimate the cost effectiveness of doxorubicin/ifosfamide compared to trabectedin monotherapy, defined as the cost per QALY gained, in each country. Results. First-line treatment with doxorubicin/ifosfamide resulted in lower two-year healthcare costs and more QALYs than first-line treatment with trabectedin monotherapy in all three countries. Probabilistic sensitivity analysis showed that at a cost per QALY threshold of €35,000, >90% of a cohort would be cost effectively treated with doxorubicin/ifosfamide compared to trabectedin monotherapy in all three countries. Conclusion. Within the model’s limitations, first-line treatment of patients with ASTS with doxorubicin/ifosfamide instead of trabectedin monotherapy affords a cost-effective use of publicly funded healthcare resources in Italy, Spain, and Sweden and is therefore the preferred treatment in all three countries. These findings support the recommendation that trabectedin should remain a second-line treatment. Julian F. Guest, Monica Panca, Erikas Sladkevicius, Nicholas Gough, and Mark Linch Copyright © 2013 Julian F. Guest et al. All rights reserved. Rapid Screening of Novel Agents for Combination Therapy in Sarcomas Thu, 24 Oct 2013 11:06:34 +0000 For patients with sarcoma, metastatic disease remains very difficult to cure, and outcomes remain less than optimal. Treatment options have not largely changed, although some promising gains have been made with single agents in specific subtypes with the use of targeted agents. Here, we developed a system to investigate synergy of combinations of targeted and cytotoxic agents in a panel of sarcoma cell lines. Agents were investigated alone and in combination with varying dose ratios. Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984). A promising combination, dasatinib and triciribine, was explored in a murine model using the A673 cell line, and tumors were evaluated by MRI and histology for therapy effect. We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines. Sorafenib and topotecan demonstrated a mixed response. Our systematic drug screening method allowed us to screen a large number of combinations of sarcoma agents. This method can be easily modified to accommodate other cell line models, and confirmatory assays, such as animal experiments, can provide excellent preclinical data to inform clinical trials for these rare malignancies. Christopher L. Cubitt, Jiliana Menth, Jana Dawson, Gary V. Martinez, Parastou Foroutan, David L. Morse, Marilyn M. Bui, G. Douglas Letson, Daniel M. Sullivan, and Damon R. Reed Copyright © 2013 Christopher L. Cubitt et al. All rights reserved. The Vascularized Fibular Graft in the Pediatric Upper Extremity: A Durable, Biological Solution to Large Oncologic Defects Mon, 07 Oct 2013 18:30:59 +0000 Skeletal reconstruction after large tumor resection is challenging. The free vascularized fibular graft (FVFG) offers the potential for rapid autograft incorporation as well as growing physeal transfer in pediatric patients. We retrospectively reviewed eleven pediatric patients treated with FVFG reconstructions of the upper extremity after tumor resection. Eight male and three female patients were identified, including four who underwent epiphyseal transfer. All eleven patients retained a functional salvaged limb. Nonunion and graft fracture were the most common complications relating to graft site (27%). Peroneal nerve palsy occurred in 4/11 patients, all of whom received epiphyseal transfer. Patients receiving epiphyseal transplant had a mean annual growth of 1.7 cm/year. Mean graft hypertrophy index increased by more than 10% in all cases. Although a high complication rate may be anticipated, the free vascularized fibula may be used to reconstruct large skeletal defects in the pediatric upper extremity after oncologic resection. Transferring the vascularized physis is a viable option when longitudinal growth is desired. Nicki Zelenski, Brian E. Brigman, L. Scott Levin, Detlev Erdmann, and William C. Eward Copyright © 2013 Nicki Zelenski et al. All rights reserved. Safety and Efficacy of Stereotactic Body Radiation Therapy in the Treatment of Pulmonary Metastases from High Grade Sarcoma Tue, 01 Oct 2013 16:16:33 +0000 Introduction. Patients with high-grade sarcoma (HGS) frequently develop metastatic disease thus limiting their long-term survival. Lung metastases (LM) have historically been treated with surgical resection (metastasectomy). A potential alternative for controlling LM could be stereotactic body radiation therapy (SBRT). We evaluated the outcomes from our institutional experience utilizing SBRT. Methods. Sixteen consecutive patients with LM from HGS were treated with SBRT between 2009 and 2011. Routine radiographic and clinical follow-up was performed. Local failure was defined as CT progression on 2 consecutive scans or growth after initial shrinkage. Radiation pneumonitis and radiation esophagitis were scored using Common Toxicity Criteria (CTC) version 3.0. Results. All 16 patients received chemotherapy, and a subset (38%) also underwent prior pulmonary metastasectomy. Median patient age was 56 (12–85), and median follow-up time was 20 months (range 3–43). A total of 25 lesions were treated and evaluable for this analysis. Most common histologies were leiomyosarcoma (28%), synovial sarcoma (20%), and osteosarcoma (16%). Median SBRT prescription dose was 54 Gy (36–54) in 3-4 fractions. At 43 months, local control was 94%. No patient experienced G2-4 radiation pneumonitis, and no patient experienced radiation esophagitis. Conclusions. Our retrospective experience suggests that SBRT for LM from HGS provides excellent local control and minimal toxicity. Niraj Mehta, Michael Selch, Pin-Chieh Wang, Noah Federman, Jay M. Lee, Fritz C. Eilber, Bartosz Chmielowski, Nzhde Agazaryan, Michael Steinberg, and Percy Lee Copyright © 2013 Niraj Mehta et al. All rights reserved. Osteosarcoma: Lessons Learned and Future Avenues Wed, 04 Sep 2013 11:55:05 +0000 Ajay Puri, Norman Jaffe, and Hans Gelderblom Copyright © 2013 Ajay Puri et al. All rights reserved. Sporadic versus Radiation-Associated Angiosarcoma: A Comparative Clinicopathologic and Molecular Analysis of 48 Cases Tue, 03 Sep 2013 11:26:09 +0000 Angiosarcomas are aggressive tumors of vascular endothelial origin, occurring sporadically or in association with prior radiotherapy. We compared clinicopathologic and biologic features of sporadic angiosarcomas (SA) and radiation-associated angiosarcomas (RAA). Methods. From a University of Michigan institutional database, 37 SA and 11 RAA were identified. Tissue microarrays were stained for p53, Ki-67, and hTERT. DNA was evaluated for TP53 and ATM mutations. Results. Mean latency between radiotherapy and diagnosis of RAA was 11.9 years: 6.7 years for breast RAA versus 20.9 years for nonbreast RAA (). Survival after diagnosis did not significantly differ between SA and RAA (). Patients with nonbreast RAA had shorter overall survival than patients with breast RAA (). The majority of SA (86.5%) and RAA (77.8%) were classified as high-grade sarcomas (). RAA were more likely to have well-defined vasoformative areas (55.6% versus 27%, ). Most breast SA were parenchymal in origin (80%), while most breast RAA were cutaneous in origin (80%). TMA analysis showed p53 overexpression in 25.7% of SA and 0% RAA, high Ki-67 in 35.3% of SA and 44.4% RAA, and hTERT expression in 100% of SA and RAA. TP53 mutations were detected in 13.5% of SA and 11.1% RAA. ATM mutations were not detected in either SA or RAA. Conclusions. SA and RAA are similar in histology, immunohistochemical markers, and DNA mutation profiles and share similar prognosis. Breast RAA have a shorter latency period compared to nonbreast RAA and a significantly longer survival. Jennifer Hung, Susan M. Hiniker, David R. Lucas, Kent A. Griffith, Jonathan B. McHugh, Amichay Meirovitz, Dafydd G. Thomas, Rashmi Chugh, and Joseph M. Herman Copyright © 2013 Jennifer Hung et al. All rights reserved. Biological Reconstruction for Sarcoma Mon, 05 Aug 2013 09:46:56 +0000 Andreas Leithner, Per-Ulf Tunn, and Pietro Ruggieri Copyright © 2013 Andreas Leithner et al. All rights reserved. Outcome of Rhabdomyosarcoma in First Year of Life: Children’s Cancer Hospital 57357 Egypt Thu, 25 Jul 2013 09:59:26 +0000 Background. Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children. Fifty percent of RMS cases occur in the first 10 years of life and less commonly in infants younger than one-year old. These infants require adapted multimodality treatment approaches. Patients and Methods. We analyzed patients’ characteristics, treatment modalities, and the outcome for RMS infants treated at Children’s Cancer Hospital Egypt (CCHE) between July 2007 and December 2010 and compared them to patients above one year treated on the same protocol. Results. Out of the 126 RMS treated during this period, 18 were below the age of one year. The male: female ratio was 1.25 : 1. The median age at diagnosis was 0.7 ± 0.2 years. Most of the cases (27.8%) were presented in head and neck regions. The estimated 4-years failure-free survival and overall survival for infants were 49 ± 12% and 70 ± 12%, respectively. These failure-free survival rate and overall survival rate did not differ from those for older patients (). Conclusion. Infants with RMS are a unique group of RMS who needs special concerns in tailoring treatment in addition to concerns regarding toxicity and morbidity in infants. Enas El Nadi, Emad A. H. Moussa, Wael Zekri, Hala Taha, Alaa Yones, Mohamed Saad Zaghloul, Madeeha El Wakeel, and Rania M. Labib Copyright © 2013 Enas El Nadi et al. All rights reserved. Osteosarcoma: A Comparison of Jaw versus Nonjaw Localizations and Review of the Literature Mon, 15 Jul 2013 12:24:25 +0000 Purpose. It is assumed that osteosarcomas of the jaws mainly occur at older ages, whereas the most prominent sites, that is, the long bones, are more affected at ages <20. Jaw-localized tumors are less malignant and have lower metastatic spread rates. Patients and Methods. This study analyses the nationwide data of the Dutch Cancer Registry on osteosarcoma during the period from 1991 to 2010. Age-corrected incidence rates were calculated. Results. In 949, 38 patients had tumors in the maxilla and in 58 in the mandible. Median age for maxilla, mandible, and other localizations was 45.5, 49, and 23 years, respectively. Age-corrected incidence for osteosarcomas increased after a steep decline for the age cohorts from 20 to 60 years to nearly the same level as the younger patients. The incidence for maxillary lesions showed a steady increase from 0.46 to 1.60 per million over all age ranges; the highest incidence for mandibular lesions was found in the age cohort from 60 to 79 years. In respect to histology, no shifts for age were found, except for Paget’s disease-related osteosarcoma. In older patients, chemotherapy was omitted more often. Overall survival was similar for all age groups, except for extragnatic tumor patients in the age range of 60–79 years. Conclusions. Osteosarcomas have comparable incidences below the age of 20 as compared with ages >60 years. Poorer outcome in older people is likely due to refraining from chemotherapy. H. van den Berg, W. H. Schreuder, and J. de Lange Copyright © 2013 H. van den Berg et al. All rights reserved. Recent Developments in the Surgical Treatment of Bone Tumors and Their Impact on Quality of Life Sun, 14 Jul 2013 08:59:57 +0000 Andreas F. Mavrogenis, Ulrich Lenze, Hans Rechl, G. Douglas Letson, and Pietro Ruggieri Copyright © 2013 Andreas F. Mavrogenis et al. All rights reserved. Metastatic Pattern, Local Relapse, and Survival of Patients with Myxoid Liposarcoma: A Retrospective Study of 45 Patients Thu, 20 Jun 2013 18:25:15 +0000 Purpose. To assess the metastatic pattern of the histological subtype myxoid liposarcoma (MLS) with no or few round cells. Methods. Forty-five patients (F/M = 27/18, mean age 49 (range 17–85) years) were diagnosed with MLS at two Danish sarcoma centres in the period 1995–2004. A retrospective review of patients' files combined with an extraction of survival data from the Danish Centralised Civil Register was performed. Results. Seven patients had distant metastases during the observation period. Two patients had metastases at the time of diagnosis, while metastases occurred within 2.5 years in four patients, and in one patient 11.9 years after primary diagnosis. All metastases occurred at extrapulmonary sites. The first local relapse occurred within 3 years after surgery in six patients, in one patient after 4.0 years, and in one patient 7.7 years after surgery. The 5- and 10-year overall survival was 80% and 69%, respectively. Both the 5- and 10-year distant metastases-free survival was, respectively, 86%. The 5- and 10-year local relapse-free survival was, respectively, 83% and 80%. Conclusions. Patients with MLS had only extra-pulmonary metastases, and no lung metastases were found. Most local relapses and distant metastases occurred within the first 2-3 years after surgery. Hanna M. Fuglø, Katja Maretty-Nielsen, Dorrit Hovgaard, Johnny Ø. Keller, Akmal A. Safwat, and Michael M. Petersen Copyright © 2013 Hanna M. Fuglø et al. All rights reserved. Adult Ewing Sarcoma: Survival and Local Control Outcomes in 102 Patients with Localized Disease Tue, 11 Jun 2013 11:29:31 +0000 Objectives. To assess the clinical features and local control (LC) outcomes in adult patients with localized Ewing Sarcoma (ES). Methods. The records of 102 ES patients with localized disease ≥18 years of age seen from 1977 to 2007 were reviewed. Factors relevant to prognosis, survival, and LC were analyzed. Results. The 5-year overall survival (OS) and event-free survival (EFS) were 60% and 52%, respectively, for the entire cohort. Treatment era (1977–1992 versus 1993–2007) remained an independent prognostic factor for OS on multivariate analysis, with improved outcomes observed in the 1993–2007 era (). The 5-year OS and EFS for the 1993–2007 era were 73% and 60%, respectively. Ifosfamide and etoposide based chemotherapy and surgery were more routinely used in the 1993–2007 era (). The 5-year local failure rate (LFR) was 14%, with a 5-year LFR of 18% for surgery, 33% for radiation, and 0% for combined surgery and radiation in the 1993–2007 era (). Conclusion. Modern survival outcomes for adults with localized ES are similar to multi-institutional results in children. This improvement over time is associated with treatment intensification with chemotherapy and increased use of surgery. Aggressive LC (combined surgery and radiation) may improve outcomes in poor prognosis patients. Safia K. Ahmed, Steven I. Robinson, Scott H. Okuno, Peter S. Rose, and Nadia N. Issa Laack Copyright © 2013 Safia K. Ahmed et al. All rights reserved. Biological Extremity Reconstruction after Sarcoma Resection: Past, Present, and Future Thu, 06 Jun 2013 15:50:19 +0000 In sarcoma surgery besides a wide local resection, limb salvage became more and more important. Reconstruction of bone and soft tissue defects after sarcoma resection poses a major challenge for surgeons. Nowadays a broad range of reconstructive methods exist to deal with bony defects. Among these are prostheses, bone autografts, or bone allografts. Furthermore a variety of plastic reconstructive techniques exist that allow soft tissue reconstruction or coverage after sarcoma resection. Here we discuss the historical highlights, the present role, and possible future options for biological reconstruction. Lukas A. Holzer and Andreas Leithner Copyright © 2013 Lukas A. Holzer and Andreas Leithner. All rights reserved. Low-Grade Fibromyxoid Sarcoma: Incidence, Treatment Strategy of Metastases, and Clinical Significance of the FUS Gene Thu, 30 May 2013 09:00:42 +0000 Aim. The aim of this study was to assess the incidence of low-grade fibromyxoid sarcoma (LGFMS), present treatment results of metastatic LGFMS, and investigate the clinical significance of the FUS gene rearrangement. Methods. This study included 14 consecutive LGFMS patients treated at the Aarhus Sarcoma Centre in 1979–2010. Fluorescent in situ hybridization (FISH) analysis for FUS break-apart was performed for all patients. Results. The incidence of LGFMS was 0.18 per million, representing 0.6% of all soft tissue sarcomas. Four patients needed multiple biopsies/resections before the correct diagnosis was made. Four patients experienced local recurrence, and three patients developed metastases. The treatment of metastatic LGFMS varied from multiagent chemotherapy to repeated, selective surgery of operable metastases. The best response to chemotherapy was short-term stabilization of disease progression, seen with Trabectedin. The prevalence of the FUS break-apart was 21.4%. We found no significant difference in clinical characteristics and outcomes in correlation with the FUS break-apart. Conclusion. LGFMS is a rare disease with multiple challenges. The FUS break-apart was not associated with local recurrence or metastases in our study. To date the only treatment resulting in disease-free periods is surgery; however further investigation into the management of metastatic LGFMS is necessary. Katja Maretty-Nielsen, Steen Baerentzen, Johnny Keller, Heidi Buvarp Dyrop, and Akmal Safwat Copyright © 2013 Katja Maretty-Nielsen et al. All rights reserved.