Sarcoma The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies Tue, 16 May 2017 00:00:00 +0000 Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST. AeRang Kim, Douglas R. Stewart, Karlyne M. Reilly, David Viskochil, Markku M. Miettinen, and Brigitte C. Widemann Copyright © 2017 AeRang Kim et al. All rights reserved. Results of a Qualitative Study to Develop a Patient Reported Outcome Measure for Patients with 4 Subtypes of Soft Tissue Sarcoma Sun, 14 May 2017 08:45:57 +0000 Objective. The objective of this research was to develop a disease-specific symptom inventory for soft tissue sarcoma. Methods. Literature review and clinical expert and patient interviews were conducted to determine disease-specific symptoms important to patients with one of the four STS subtypes. Clinical experts identified the most relevant STS symptom items from the item pool developed from literature review. Concept elicitation interviews were conducted with patients to elicit their STS symptom experiences followed by a completion of the draft symptom list via web survey. A cognitive interview was conducted on the comprehension and importance of the symptom items. Results. Eighty-three symptom items were compiled and discussed with three clinical experts who identified 26 symptoms specific to the four STS subtypes. A total sample of 27 STS participants with self-reported leiomyosarcoma (74%), undifferentiated sarcoma (15%), synovial sarcoma (7%), or liposarcoma (4%) diagnosis completed the web survey and 10 were interviewed. The draft 12-item STS-specific symptom inventory includes abdominal pain, pressure in abdomen, early satiety, bloating, gastrointestinal pain, muscle pain, bone pain, heavy menstrual flow, shortness of breath, chest pain, cough, and painful menstruation. Conclusion. A number of symptoms are common across STS subtypes and may form a single STS symptom inventory. Anne M. Skalicky, Sameer R. Ghate, Jose Ricardo Perez, and Anne M. Rentz Copyright © 2017 Anne M. Skalicky et al. All rights reserved. Neoadjuvant Ifosfamide and Epirubicin in the Treatment of Malignant Peripheral Nerve Sheath Tumors Thu, 04 May 2017 08:30:24 +0000 Background and Objectives. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with poor overall survival. Response to chemotherapy has been debated for these tumors. Methods. We performed a retrospective analysis of the patients at our institution with a biopsy-proven diagnosis of MPNST that underwent neoadjuvant chemotherapy prior to surgery. Results. We retrospectively identified five patients who received neoadjuvant chemotherapy with epirubicin and ifosfamide that demonstrated a 30% reduction in tumor growth and a 60% response rate by RECIST criteria. Additionally, a metabolic response was observed in all three patients who received serial PET scans during neoadjuvant treatment. The clinical benefit rate, which includes stable disease, was 100%. Conclusions. Our data suggest that MPNSTs do respond to epirubicin and ifosfamide based chemotherapy and prospective studies are warranted to further define the clinical benefit. Angela C. Hirbe, Pippa F. Cosper, Sonika Dahiya, and Brian A. Van Tine Copyright © 2017 Angela C. Hirbe et al. All rights reserved. Evaluation of Quality of Life at Progression in Patients with Soft Tissue Sarcoma Sun, 23 Apr 2017 00:00:00 +0000 Introduction. Soft Tissue Sarcoma (STS) is a rare malignancy of mesodermal tissue, with international incidence estimates between 1.8 and 5 per 100,000 per year. Understanding quality of life (QoL) and the detrimental impact of disease progression is critical for long-term care and survival. Objectives. The primary objective was to explore the relationship between disease progression and health-related quality of life (HRQoL) using data from Eisai’s study (E7389-G000-309). Methods. This was a 1 : 1 randomized, open-label, multicenter, Phase 3 study comparing the efficacy and safety of eribulin versus dacarbazine in patients with advanced STS. The QoL analysis was conducted for the baseline and progression populations using the European Organization for Research and Treatment of Cancer 30-item core QoL questionnaire (EORTC QLQ-C30). Results. There were no statistical differences between the two treatment arms at baseline for any domain (; ). Of the 399 patients who experienced disease progression (unadjusted and adjusting for histology), dacarbazine patients had significantly lower Global Health Status, Physical Functioning scores, and significantly worse Nausea and Vomiting, Insomnia, and Appetite Loss (). Conclusions. These results indicate differences in HRQoL overall and at progression between dacarbazine and eribulin patients, with increases in symptom severity observed among dacarbazine patients. Stacie Hudgens, Anna Forsythe, Ilias Kontoudis, David D’Adamo, Ashley Bird, and Hans Gelderblom Copyright © 2017 Stacie Hudgens et al. All rights reserved. Variations of Surveillance Practice for Patients with Bone Sarcoma: A Survey of Australian Sarcoma Clinicians Tue, 28 Feb 2017 09:34:06 +0000 Introduction. After treatment, bone sarcoma patients carry a high chance of relapse and late effects from multimodal therapy. We hypothesize that significant variation in surveillance practice exists between pediatric medical oncology (PO) and nonpediatric medical oncology (NP) sarcoma disciplines. Methods. Australian sarcoma clinicians were approached to do a web based survey that assessed radiologic surveillance (RS) strategies, late toxicity assessment, and posttreatment psychosocial interventions. Results. In total, 51 clinicians responded. No differences were identified in local disease RS. In metastatic disease response assessment, 100% of POs (23/23) and 93% of NPs (24/26) conducted CT chest. However, this was more likely to occur for NPs in the context of a CT chest/abdomen/pelvis (NP: 10/26; PO: 1/23; ). POs were more likely to use CXR for RS (). POs showed more prescriptive intensity in assessment of heart function (), hearing (), and fertility (). POs were more likely to deliver written information for health maintenance/treatment summary (). The majority of respondents described enquiring about psychosocial aspects of health (/37, 89%), but a routine formal psychosocial screen was only used by 23% (/26). Conclusion. There is high variability in bone sarcoma surveillance between PO and NP clinicians. Efforts to harmonize approaches would allow early and late effects recognition/intervention and facilitate improved patient care/transition and research. Jeremy Lewin, Kate Thompson, Susie Bae, Jayesh Desai, Robyn Strong, Denise Caruso, Deborah Howell, Alan Herschtal, Michael Sullivan, and Lisa Orme Copyright © 2017 Jeremy Lewin et al. All rights reserved. Correlation of Ezrin Expression Pattern and Clinical Outcomes in Ewing Sarcoma Thu, 26 Jan 2017 00:00:00 +0000 Background. Ezrin is a membrane-cytoskeleton linker protein that has been associated with metastasis and poor outcomes in osteosarcoma and high-grade soft tissue sarcomas. The prognostic value of ezrin expression in Ewing sarcoma is unknown. Methods. The relationship between ezrin expression and outcome was analyzed in a cohort of 53 newly diagnosed Ewing sarcoma patients treated between 2000 and 2011. The intensity and proportion of cells with ezrin immunoreactivity were assessed in diagnostic tumor tissue using a semiquantitative scoring system to yield intensity and positivity scores for each tumor. Results. Ezrin expression was detected in 72% (38/53) of tumor samples. The proportion of patients with metastatic disease was equal in the positive and negative ezrin expression groups. There was no significant difference in the 5-year event-free survival (EFS) between patients with positive versus negative ezrin expression. Patients whose tumor sample showed high ezrin intensity had significantly better 5-year EFS when compared to patients with low/no ezrin intensity (78% versus 55%; ). Conclusions. Ezrin expression can be detected in the majority of Ewing sarcoma tumor samples. Intense ezrin expression may be correlated with a favorable outcome; however further investigation with a larger cohort is needed to validate this finding. Thomas Cash, Hong Yin, Courtney McCracken, Zhi Geng, Steven G. DuBois, Bahig M. Shehata, Thomas A. Olson, Howard M. Katzenstein, and Cynthia Wetmore Copyright © 2017 Thomas Cash et al. All rights reserved. Routes to Diagnosis for Suspected Sarcoma: The Impact of Symptoms and Clinical Findings on the Diagnostic Process Mon, 26 Dec 2016 12:04:11 +0000 Background and Objectives. Sarcoma patients often experience delay before diagnosis. We examined the association between presenting symptoms/signs and time intervals for suspected sarcoma patients. Methods. 545 consecutive patients suspected for sarcoma referred over a one-year period were included. Median time intervals in routes to diagnosis were collected from medical records and questionnaires. Results. 102 patients (18.7%) had a sarcoma; 68 (12.5%) had other malignancies. Median interval for the patient (time from first symptom to first doctor visit), primary care, local hospital, sarcoma center, diagnostic, and total interval for sarcoma patients were 77, 17, 29, 17, 65, and 176 days, respectively. Sarcoma patients visited more hospital departments and had longer median primary care (+10 days) and diagnostic intervals (+19 days) than patients with benign conditions. Median primary care (−19 days) and sarcoma center (−4 days) intervals were shorter for patients with a lump versus no lump. Median patient (+40 days), primary care (+12 days), diagnostic (+17 days), and total intervals (+78 days) were longer for patients presenting with pain versus no pain. GP suspicion of malignancy shortened local hospital (−20 days) and total intervals (−104 days). Conclusions. The main part of delay could be attributed to the patient and local hospitals. Length of time intervals was associated with presenting symptoms/signs and GP suspicion. Heidi Buvarp Dyrop, Peter Vedsted, Mathias Rædkjær, Akmal Safwat, and Johnny Keller Copyright © 2016 Heidi Buvarp Dyrop et al. All rights reserved. Cryosurgery as Additional Treatment in Tenosynovial Giant Cell Tumors Mon, 26 Dec 2016 08:39:21 +0000 Introduction. Tenosynovial giant cell tumors (TGCT) emerge from the synovium and can behave aggressively. Surgical resection is the standard treatment. However, up to half of the patients with diffuse type show recurrences. Several additional treatments have been applied to reduce recurrences; none of these treatments was proven to be superior to surgical resection solely. This article describes the results of additional cryosurgery to surgical resection. Materials and Methods. We retrospectively evaluated 141 TGCT patients, between 1999 and 2007. Twelve patients had additional cryosurgery. The knee (), hip (), ankle (), and elbow () were affected. Primary outcome variables were treatment indications, recurrences, and complications. Results. Indications for additional cryosurgery were extended disease, bone involvement, and locations that are difficult to surgically get disease-free such as cruciate ligaments. Five patients had recurrent disease, all of which had prior treatments. None of the primary treated patients had recurrent disease. One patient had a deep infection. Discussion. Cryosurgery may serve as an additional treatment for diffuse TCGT in selected cases. However, because of the small number of patients and the heterogeneous group we could not prove an advantage of additional cryosurgery over surgical resection only. Cryosurgery should be considered for further evaluation in a prospective study. If there is any effect it would be helpful, especially in patients with multiple TGCT recurrences. F. G. M. Verspoor, A. Scholte, I. C. M. van der Geest, G. Hannink, and H. W. B. Schreuder Copyright © 2016 F. G. M. Verspoor et al. All rights reserved. Giant Cell Tumor: A Rare Condition in the Immature Skeleton—A Retrospective Study of Symptoms, Treatment, and Outcome in 16 Children Wed, 23 Nov 2016 05:56:27 +0000 Background. Pediatric giant cell tumor (GCT) of bone is rare and the course of the disease in the immature skeleton is sparsely described. We performed a retrospective study addressing symptoms, treatment, and outcome in children with GCT. Methods. Review of medical records and images of patients with GCT. Patients were detected from our hospital prospective database and those with open epiphyseal cartilages were included. Results. 16 children (75% girls) from 6 to 15 years old were identified. Eight lesions (50%) were in long bones and 4 (25%) in flat bones. One lesion appeared to be purely epiphyseal. All patients had pain as the initial symptom. Local recurrence developed in 2 patients. 14 of 16 patients returned to normal activity with no sequelae. One patient developed anisomelia after surgery. Conclusions. The biological tumor behavior in children does not seem to differ from what is reported in adults. Lesions in flat bones are very unusual, but our data alone do not provide enough evidence to conclude that this is more common in the immature skeleton. Literature review showed only one previous case report describing a purely epiphyseal GCT. Intralesional curettage is appropriate treatment and gives good functional results with acceptable recurrence rates. Thale M. Asp Strøm, Anette Torød Skeie, Ingvild Koren Lobmaier, and Olga Zaikova Copyright © 2016 Thale M. Asp Strøm et al. All rights reserved. miR-125b and miR-100 Are Predictive Biomarkers of Response to Induction Chemotherapy in Osteosarcoma Mon, 21 Nov 2016 08:11:03 +0000 Osteosarcoma is the most common primary malignancy in bone. Patients who respond poorly to induction chemotherapy are at higher risk of adverse prognosis. The molecular basis for such poor prognosis remains unclear. We investigated miRNA expression in eight open biopsy samples to identify miRNAs predictive of response to induction chemotherapy and thus maybe used for risk stratification therapy. The samples were obtained from four patients with inferior necrosis (Huvos I/II) and four patients with superior necrosis (Huvos III/IV) following induction chemotherapy. We found six miRNAs, including miR-125b and miR-100, that were differentially expressed > 2-fold () in patients who respond poorly to treatment. The association between poor prognosis and the abundance of miR-125b and miR-100 was confirmed by quantitative reverse transcriptase-polymerase chain reaction in 20 additional osteosarcoma patients. Accordingly, overexpression of miR-125b and miR-100 in three osteosarcoma cell lines enhanced cell proliferation, invasiveness, and resistance to chemotherapeutic drugs such as methotrexate, doxorubicin, and cisplatin. In addition, overexpression of miR-125b blocked the ability of these chemotherapy agents to induce apoptosis. As open biopsy is routinely performed to diagnose osteosarcoma, levels of miR-125b and miR-100 in these samples may be used as basis for risk stratification therapy. Daisuke Kubota, Nobuyoshi Kosaka, Tomohiro Fujiwara, Akihiko Yoshida, Yasuhito Arai, Zhiwei Qiao, Fumitaka Takeshita, Takahiro Ochiya, Akira Kawai, and Tadashi Kondo Copyright © 2016 Daisuke Kubota et al. All rights reserved. Phase II Trial of Angiotensin-(1-7) for the Treatment of Patients with Metastatic Sarcoma Tue, 08 Nov 2016 09:13:03 +0000 Background. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous antiangiogenic hormone with anticancer activity. In a phase I study of Ang-(1-7), two of three patients with metastatic sarcoma experienced disease stabilization. This phase II study examined clinical and biomarker outcomes for patients with metastatic sarcoma. Methods. Ang-(1-7) was administered by subcutaneous injection at a dose of 20 mg daily. If excessive toxicities occurred in the first cohort, a dose deescalation cohort was allowed. Blood samples were obtained to measure changes in biomarkers. Results. Treatment was well-tolerated and the dose deescalation cohort was not required. Plasma PlGF concentrations following treatment were not statistically significantly changed. A significant increase in plasma Ang-(1-7) was observed at 4 hours after injection. The median progression-free survival was 2.7 months (95% CI; 1.4 to 4.1 months), and the median overall survival was 10.2 months (95% CI; 5.3 to 18.3 months). Two patients with vascular sarcomas demonstrated prolonged disease stabilization of 10 months (hemangiopericytoma) and 19 months (epithelioid hemangioendothelioma). Conclusions. Ang-(1-7) at a dose of 20 mg daily was well-tolerated. This prospective phase II study failed to confirm the PlGF biomarker effect identified in the prior phase I study. Prolonged disease stabilization in hemangiopericytoma and epithelioid hemangioendothelioma may warrant further investigation. Paul D. Savage, James Lovato, K. Bridget Brosnihan, Antonius A. Miller, and W. Jeffrey Petty Copyright © 2016 Paul D. Savage et al. All rights reserved. Trabectedin Followed by Irinotecan Can Stabilize Disease in Advanced Translocation-Positive Sarcomas with Acceptable Toxicity Mon, 24 Oct 2016 13:15:08 +0000 Background. Preclinical data indicate that trabectedin followed by irinotecan has strong synergistic effects on Ewing sarcoma. This is presumably due to hypersensitization of the tumor cells to the camptothecin as an effect of trabectedin in addition to synergistic suppression of EWS-FLI1 downstream targets. A strong effect was also reported in a human rhabdomyosarcoma xenograft. Procedure. Twelve patients with end-stage refractory translocation-positive sarcomas were treated with trabectedin followed by irinotecan within a compassionate use program. Eight patients had Ewing sarcoma and four patients had other translocation-positive sarcomas. Results. Three-month survival rate was 0.75 after the start of this therapy. One patient achieved a partial response according to RECIST criteria, five had stable disease, and the remaining six progressed through therapy. The majority of patients experienced significant hematological toxicity (grades 3 and 4). Reversible liver toxicity and diarrhea also occurred. Conclusions. Our experience with the combination of trabectedin followed with irinotecan in patients with advanced sarcomas showed promising results in controlling refractory solid tumors. While the hematological toxicity was significant, it was reversible. Quality of life during therapy was maintained. These observations encourage a larger clinical trial. J. Herzog, F. von Klot-Heydenfeldt, S. Jabar, A. Ranft, C. Rossig, U. Dirksen, J. Van den Brande, M. D’Incalci, I. von Luettichau, P. J. Grohar, W. E. Berdel, and St. Burdach Copyright © 2016 J. Herzog et al. All rights reserved. Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma Sun, 16 Oct 2016 15:15:42 +0000 Myxoid liposarcoma is a rare form of soft-tissue sarcoma. Although most patients initially respond well to treatment, approximately 21% relapse, highlighting the need for alternative treatments. To identify novel treatment regimens and gain a better understanding of myxoid liposarcoma tumor biology, we screened various candidate and approved targeted therapeutics and chemotherapeutics against myxoid liposarcoma cell lines. Therapeutics that target angiogenesis showed antitumor activity. The small molecule inhibitor axitinib, which targets angiogenesis by inhibiting the VEGFR and PDGFR families and c-Kit, inhibited cell cycle progression and induced apoptosis in vitro, as well as having significant antitumor activity against MLS 1765 myxoid liposarcoma xenografts in mice. Axitinib also displayed synergistic antitumor activity in vitro when combined with the potassium channel ionophore salinomycin or the BH3 mimetic ABT-737. Another angiogenesis-targeting therapeutic, 4EGI-1, which targets the oncoprotein eIF4E, significantly decreased angiogenic ligand expression by myxoid liposarcoma cells and reduced tumor cell growth. To verify this oncogenic addiction to angiogenic pathways, we utilized VEGFR-derived ligand traps and found that autocrine VEGFR signaling was crucial to myxoid liposarcoma cell survival. Overall, these findings suggest that autocrine angiogenic signaling through the VEGFR family is critical to myxoid liposarcoma cell survival and that further study of axitinib as a potential anticancer therapy is warranted. Lauren T. Kerr, Jacqueline F. Donoghue, Alexander L. Wilding, and Terrance G. Johns Copyright © 2016 Lauren T. Kerr et al. All rights reserved. The Discrepancy between Patient and Clinician Reported Function in Extremity Bone Metastases Tue, 20 Sep 2016 07:34:10 +0000 Background. The Musculoskeletal Tumor Society (MSTS) scoring system measures function and is commonly used but criticized because it was developed to be completed by the clinician and not by the patient. We therefore evaluated if there is a difference between patient and clinician reported function using the MSTS score. Methods. 128 patients with bone metastasis of the lower () and upper () extremity completed the MSTS score. The MSTS score consists of six domains, scored on a 0 to 5 scale and transformed into an overall score ranging from 0 to 100% with a higher score indicating better function. The MSTS score was also derived from clinicians’ reports in the medical record. Results. The median age was 63 years (interquartile range [IQR]: 55–71) and the study included 74 (58%) women. We found that the clinicians’ MSTS score (median: 65, IQR: 49–83) overestimated the function as compared to the patient perceived score (median: 57, IQR: 40–70) by 8 points (). Conclusion. Clinician reports overestimate function as compared to the patient perceived score. This is important for acknowledging when informing patients about the expected outcome of treatment and for understanding patients’ perceptions. Stein J. Janssen, Eva A. J. van Rein, Nuno Rui Paulino Pereira, Kevin A. Raskin, Marco L. Ferrone, Francis J. Hornicek, Santiago A. Lozano-Calderon, and Joseph H. Schwab Copyright © 2016 Stein J. Janssen et al. All rights reserved. Molecular Targets and Emerging Therapeutic Options for Uterine Leiomyosarcoma Mon, 19 Sep 2016 14:18:00 +0000 Uterine leiomyosarcoma (uLMS) is an aggressive malignancy characterized by its early metastasis, high rates of recurrence, and poor prognosis. Multiple obstacles complicate the clinical management of uLMS. These include the fact that most uLMS are typically identified only after a woman has undergone hysterectomy or myomectomy, the limited efficacy of adjuvant therapy for early stage disease, and the poor response of metastatic disease to current treatments. Here, we discuss recent insights into the molecular basis of uLMS and discuss emerging options for its clinical management. Particular attention is given to the biologic basis of these strategies with the goal of understanding the rationale motivating their use. Heather Miller, Chiemeka Ike, Jennifer Parma, Ramya P. Masand, Claire M. Mach, and Matthew L. Anderson Copyright © 2016 Heather Miller et al. All rights reserved. Current Immunotherapies for Sarcoma: Clinical Trials and Rationale Wed, 14 Sep 2016 13:14:35 +0000 Sarcoma tumors are rare and heterogeneous, yet they possess many characteristics that may facilitate immunotherapeutic responses. Both active strategies including vaccines and passive strategies involving cellular adoptive immunotherapy have been applied clinically. Results of these clinical trials indicate a distinct benefit for select patients. The recent breakthrough of immunologic checkpoint inhibition is being rapidly introduced to a variety of tumor types including sarcoma. It is anticipated that these emerging immunotherapies will exhibit clinical efficacy for a variety of sarcomas. The increasing ability to tailor immunologic therapies to sarcoma patients will undoubtedly generate further enthusiasm and clinical research for this treatment modality. Demytra Mitsis, Valerie Francescutti, and Joseph Skitzki Copyright © 2016 Demytra Mitsis et al. All rights reserved. HIV-1 Evolutionary Patterns Associated with Metastatic Kaposi’s Sarcoma during AIDS Mon, 29 Aug 2016 08:47:09 +0000 Kaposi’s sarcoma (KS) in HIV-infected individuals can have a wide range of clinical outcomes, from indolent skin tumors to a life-threatening visceral cancer. KS tumors contain endothelial-related cells and inflammatory cells that may be HIV-infected. In this study we tested if HIV evolutionary patterns distinguish KS tumor relatedness and progression. Multisite autopsies from participants who died from HIV-AIDS with KS prior to the availability of antiretroviral therapy were identified at the AIDS and Cancer Specimen Resource (ACSR). Two patients (KS1 and KS2) died predominantly from non-KS-associated disease and KS3 died due to aggressive and metastatic KS within one month of diagnosis. Skin and visceral tumor and nontumor autopsy tissues were obtained (). Single genome sequencing was used to amplify HIV RNA and DNA, which was present in all tumors. Independent HIV tumor clades in phylogenies differentiated KS1 and KS2 from KS3, whose sequences were interrelated by both phylogeny and selection. HIV compartmentalization was confirmed in KS1 and KS2 tumors; however, in KS3, no compartmentalization was observed among sampled tissues. While the sample size is small, the HIV evolutionary patterns observed in all patients suggest an interplay between tumor cells and HIV-infected cells which provides a selective advantage and could promote KS progression. Susanna L. Lamers, Rebecca Rose, David J. Nolan, Gary B. Fogel, Andrew E. Barbier, Marco Salemi, and Michael S. McGrath Copyright © 2016 Susanna L. Lamers et al. All rights reserved. Ewing’s Sarcoma as a Second Malignancy in Long-Term Survivors of Childhood Hematologic Malignancies Mon, 25 Jul 2016 07:11:22 +0000 Modern multimodal treatment has significantly increased survival for patients affected by hematologic malignancies, especially in childhood. Following remission, however, the risk of developing a further malignancy is an important issue. The long-term estimated risk of developing a sarcoma as a secondary malignancy is increased severalfold in comparison to the general population. Ewing’s sarcoma family encompasses a group of highly aggressive, undifferentiated, intra- and extraosseous, mesenchymal tumors, caused by several types of translocations usually involving the EWSR1 gene. Translocation associated sarcomas, such as Ewing sarcoma, are only rarely encountered as therapy associated secondary tumors. We describe the clinical course and management of three patients from a single institution with Ewing’s sarcoma that followed successfully treated lymphoblastic T-cell leukemia or non-Hodgkin lymphoma. The literature on secondary Ewing’s sarcoma is summarized and possible pathogenic mechanisms are critically discussed. Fabian Wolpert, Michael A. Grotzer, Felix Niggli, Dieter Zimmermann, Elisabeth Rushing, and Beata Bode-Lesniewska Copyright © 2016 Fabian Wolpert et al. All rights reserved. A Systematic Literature Review of Adverse Events Associated with Systemic Treatments Used in Advanced Soft Tissue Sarcoma Tue, 19 Jul 2016 13:25:06 +0000 This systematic literature review describes adverse events (AEs) among patients with soft tissue sarcoma (STS) who received second-line or later anticancer therapies. Searches were conducted in PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for studies of adults with advanced or metastatic STS who received systemic anticancer therapy before enrollment in a randomized-controlled trial of pazopanib, another targeted cancer agent, or cytotoxic chemotherapy. Of 204 publications identified, seven articles representing six unique studies met inclusion criteria. Additional safety results for pazopanib were identified on Hematologic toxicities were common with all therapies evaluated (pazopanib, trabectedin, dacarbazine ± gemcitabine, gemcitabine ± docetaxel, cyclophosphamide, and ifosfamide). Studies differed in AE type, timing of assessment, and outcomes reported, although patient populations and AE assessment timing were relatively similar for pazopanib and trabectedin. AEs that were more common with trabectedin than pazopanib were anemia, neutropenia, nausea/vomiting, and elevations in aspartate aminotransferase and alanine aminotransferase. An AE that was more common with pazopanib than trabectedin was anorexia. Only the pazopanib study reported AE frequencies versus placebo. A planned meta-analysis was not feasible, as there was no common comparator. More well-designed studies that include common comparators are needed for comparison of safety effects among treatments for STS. Ann Colosia, Shahnaz Khan, Michelle D. Hackshaw, Alan Oglesby, James A. Kaye, and Jeffrey M. Skolnik Copyright © 2016 Ann Colosia et al. All rights reserved. Immediate versus Delayed Sarcoma Reconstruction: Impact on Outcomes Wed, 13 Jul 2016 09:58:58 +0000 Background. Sarcoma is a rare malignancy, and more recent management algorithms emphasize a multidisciplinary approach and limb salvage, which has resulted in an increase in overall survival and limb preservation. However, limb salvage has resulted in a higher rate of wound complications. Objective. To compare the complications between immediate and delayed (>three weeks) reconstruction in the multidisciplinary limb salvage sarcoma patient population. Methods. A ten-year retrospective review of patients who underwent sarcoma resection was performed. The outcome of interest was wound complication in the postoperative period based on timing of reconstruction. We defined infection as any infection requiring intravenous antibiotics, partial flap failure as any flap requiring a debridement or revision, hematoma/seroma as any hematoma/seroma requiring drainage, and wound dehiscence as a wound that was not completely intact by three weeks postoperatively. Results. 70 (17 delayed, 53 immediate) patients who underwent sarcoma resection and reconstruction met the inclusion criteria. Delayed reconstruction significantly increased the incidence of postoperative wound infection and wound dehiscence. There was no difference in partial or total flap loss, hematoma, or seroma between the two groups. Discussion and Conclusion. Immediate reconstruction results in decreased wound complications may reduce the morbidity associated with multidisciplinary treatment in the limb salvage sarcoma patient. Kyle J. Sanniec, Cristine S. Velazco, Lyndsey A. Bryant, Nan Zhang, William J. Casey III, Raman C. Mahabir, and Alanna M. Rebecca Copyright © 2016 Kyle J. Sanniec et al. All rights reserved. Surveillance Strategies for Sarcoma: Results of a Survey of Members of the Musculoskeletal Tumor Society Wed, 13 Jul 2016 08:55:13 +0000 Background. Surveillance is crucial to oncology, yet there is scant evidence to guide strategies. Purpose. This survey identified sarcoma surveillance strategies for Musculoskeletal Tumor Society (MSTS) members and rationales behind them. Understanding current practice should facilitate studies to generate evidence-based surveillance protocols. Methods. Permission was granted by the Research and Executive Committee of the MSTS to survey members on surveillance strategies. First, the questionnaire requested demographic and clinical practice information. Second, the survey focused on clinicians’ specific surveillance soft tissue and bone sarcoma protocols. Results. 20 percent of MSTS members completed the survey. The primary rationale for protocols was training continuation, followed by published guidelines, and finally personal interpretation of the literature. 95% of the respondents believe that additional studies regarding appropriate surveillance protocols are needed. 87% reported patient concerns regarding radiation exposure from surveillance imaging. For soft tissue and bone sarcoma local recurrence, responders identified surgical margin, histologic grade, and tumor size as the most important factors. For metastases, important risk factors identified included histologic grade, tumor size, and histologic type. Protocols demonstrated wide variation. Conclusion. This survey demonstrates that surveillance strategies utilized by MSTS members are not evidence-based, providing rationale for multi-institutional studies. It also confirms the public health issue of excessive radiation exposure. David D. Greenberg and Brooke Crawford Copyright © 2016 David D. Greenberg and Brooke Crawford. All rights reserved. Multimodality Treatment in Ewing’s Sarcoma Family Tumors of the Maxilla and Maxillary Sinus: Review of the Literature Thu, 16 Jun 2016 07:35:34 +0000 The Ewing sarcoma family of tumors (ESFT) encompasses a group of highly aggressive, morphologically similar, malignant neoplasms sharing a common spontaneous genetic translocation that affect mostly children and young adults. These predominantly characteristic, small round-cell tumors include Ewing’s sarcoma of the bone and soft tissue, as well as primitive neuroectodermal tumors (PNETs) involving the bone, soft tissue, and thoracopulmonary region (Askin’s tumor). Extraosseous ESFTs are extremely rare, especially in the head and neck region, where literature to date consists of sporadic case reports and very small series. We hereby present a review of the literature published on ESFTs reported in the maxilla and maxillary sinus region from 1968 to 2016. David Thorn, Christoph Mamot, Fatime Krasniqi, Frank Metternich, and Sven Prestin Copyright © 2016 David Thorn et al. All rights reserved. A Phase I/II Clinical Trial of Belinostat (PXD101) in Combination with Doxorubicin in Patients with Soft Tissue Sarcomas Tue, 14 Jun 2016 10:44:51 +0000 Background. Belinostat is a novel histone deacetylase inhibitor. Primary Objectives. Maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of belinostat (Bel) in combination with doxorubicin (Dox) in solid tumours (phase I) and response rate (RR) in soft tissue sarcomas (phase II). Methods. Bel was administered as a 30-minute IV infusion on days 1–5 and on day 5 with Dox. The dose escalation schedule was as follows: cohort 1: Bel 600 mg/m2 and 50 mg/m2 Dox, cohort 2: Bel 600 mg/m2 and 75 mg/m2 Dox, cohort 3: Bel 800 mg/m2 and 75 mg/m2 Dox, and cohort 4: Bel 1000 mg/m2 and 75 mg/m2 Dox. Results. 41 patients were included (25 in phase I, 16 in phase II). Adverse events were fatigue (95%), nausea (76%), and alopecia (63%). There was one DLT, grade 3 rash/hand and foot syndrome. MTD was Bel 1000 mg/m2/d and Dox 75 mg/m2. Four responses were seen: 2 PR in phase I, RR of 8%; in phase II, 1 PR/1 CR, RR of 13%, and 9 patients (56%) with SD. Conclusion. The combination was well tolerated. Response rate was moderate but median time to progression was 6.0 months (95% CI, 1.6–9.7 months) which is superior to some reports of single-agent Dox. Joanna Vitfell-Rasmussen, Ian Judson, Akmal Safwat, Robin L. Jones, Philip Blach Rossen, Maja Lind-Hansen, Poul Knoblauch, and Anders Krarup-Hansen Copyright © 2016 Joanna Vitfell-Rasmussen et al. All rights reserved. Notch Signaling Mediates Skeletal Muscle Atrophy in Cancer Cachexia Caused by Osteosarcoma Thu, 09 Jun 2016 06:06:42 +0000 Skeletal muscle atrophy in cancer cachexia is mediated by the interaction between muscle stem cells and various tumor factors. Although Notch signaling has been known as a key regulator of both cancer development and muscle stem cell activity, the potential involvement of Notch signaling in cancer cachexia and concomitant muscle atrophy has yet to be elucidated. The murine K7M2 osteosarcoma cell line was used to generate an orthotopic model of sarcoma-associated cachexia, and the role of Notch signaling was evaluated. Skeletal muscle atrophy was observed in the sarcoma-bearing mice, and Notch signaling was highly active in both tumor tissues and the atrophic skeletal muscles. Systemic inhibition of Notch signaling reduced muscle atrophy. In vitro coculture of osteosarcoma cells with muscle-derived stem cells (MDSCs) isolated from normal mice resulted in decreased myogenic potential of MDSCs, while the application of Notch inhibitor was able to rescue this repressed myogenic potential. We further observed that Notch-activating factors reside in the exosomes of osteosarcoma cells, which activate Notch signaling in MDSCs and subsequently repress myogenesis. Our results revealed that signaling between tumor and muscle via the Notch pathway may play an important role in mediating the skeletal muscle atrophy seen in cancer cachexia. Xiaodong Mu, Rashmi Agarwal, Daniel March, Adam Rothenberg, Clifford Voigt, Jessica Tebbets, Johnny Huard, and Kurt Weiss Copyright © 2016 Xiaodong Mu et al. All rights reserved. A Comprehensive Single Institutional Review of 2 Years in a Designated Fast-Track Sarcoma Diagnostic Clinic Linked with a Sarcoma Specialist Advisory Group: Meeting the Target but Failing the Task? Thu, 02 Jun 2016 12:05:41 +0000 Background. National guidelines prompted the implementation of a designated two-week wait referral pathway to facilitate the early diagnosis of sarcomas, to improve treatment outcomes. Methods. Patients referred to the Cambridge Sarcoma Diagnostic Clinic between January 2013 and December 2014 were identified through the electronic appointments system. Information was retrospectively retrieved about patient characteristics and details of the diagnostic pathway. Results. 17.3% of patients referred (69/397) were diagnosed with a malignancy. Of these, 59.3% (41/69) had primary sarcomas, 17.4% (12/69) had metastatic cancer, and 23.2% (16/69) had a different primary malignancy. 15% of the 41 sarcomas were <5 cm, 34% in the 5–10 cm range, and 51% >10 cm. Sarcomas diagnosed through this clinic represented 13% (41/315) of sarcomas managed at the centre during the same 2 years. Conclusion. While we achieved the target of 10% (41/397) sarcoma diagnosis rate in the rapid access clinic, only 15% of these were <5 cm better prognosis lesions. This calls into question the “real world” impact of such diagnostic clinics on early diagnosis of sarcomas. In order to enhance generic cancer diagnostic skills, training in these diagnostic clinics could be usefully integrated into national training curricula for both surgical and nonsurgical oncologists. Zoltan Szucs, Dochka Davidson, Han Hsi Wong, Gail Horan, Philip W. P. Bearcroft, Ian Grant, Robert Grimer, Melanie A. Hopper, Helen Hatcher, and Helena Earl Copyright © 2016 Zoltan Szucs et al. All rights reserved. Biomechanical Analysis of a Novel Acetabulum Reconstruction Technique with Acetabulum Reconstruction Cage and Threaded Rods after Type II Pelvic Resections Tue, 31 May 2016 14:15:59 +0000 Background. Periacetabular resections with reconstruction has high rates of complications due to the complexity of the reconstruction. We have improvised a novel technique of reconstruction for type II and type II + III pelvic resections with the use of a commercially available acetabulum reconstruction cage (gap II, Stryker) and threaded rods. Objectives. The aim of our study is to determine the biomechanical strength of our reconstruction compared to the traditional cemented total hip replacement (THR) designs in normal acetabulum and establish its mode of failure. Methods. Five sets of hemipelvises were biomechanically tested (Instron® 3848, MA, USA). These constructs were subjected to cyclic loading and load to failure. Results. The reconstructed acetabulum was stiffer and required a higher load to failure compared to the intact pelvis with a standard THR. The mean stiffness of the reconstructed pelvis was  Nmm−1 compared to the intact pelvis, which was  Nmm−1 ( value = 0.01). The mean load to failure for the standard acetabular cup construct was  N while that of the reconstructed pelvis with the acetabulum cage and threaded rods was  N. Conclusion. Reconstruction of the pelvis with an acetabular reconstruction cage and threaded rods is a biomechanical viable option. Vivek Ajit Singh, Hassan Elbahri, and Rukmanikanthan Shanmugam Copyright © 2016 Vivek Ajit Singh et al. All rights reserved. Overall Survival and Response to Systemic Therapy in Metastatic Extrauterine Leiomyosarcoma Sun, 29 May 2016 09:47:53 +0000 Background. Leiomyosarcomas (LMS) represent a heterogeneous subset of soft tissue sarcomas. Factors influencing prognosis for patients with metastatic extrauterine LMS (euLMS) are not well described. Limited data are available regarding responses to systemic therapy. Methods. We collected clinical and pathologic information for all patients with metastatic euLMS seen at Memorial Sloan Kettering Cancer Center between 1989 and 2012. Objective responses to first-line therapy were analyzed for a subset of patients with available baseline and on-treatment imaging using RECIST 1.1. Results. 215 patients with metastatic euLMS had a median overall survival (OS) of 2.6 years from the time of metastasis. Older age, male sex, and ≥3 initial sites of metastasis were associated with worse OS on multivariate analysis. Objective response rate (ORR) in was 19% overall and 25%, 26%, and 25% for gemcitabine, gemcitabine plus docetaxel, and anthracycline-alkylator combinations. Patients whose tumors objectively responded to first-line therapy had a lower risk of death versus those who did not (Hazard Ratio 0.46; 95% CI: 0.26–0.79, ). Conclusions. Anthracycline- and gemcitabine-based regimens have similar activity in this cohort of euLMS. Prognostic factors for OS include older age, male sex, and ≥3 initial sites. A. N. Shoushtari, J. Landa, D. Kuk, A. Sanchez, B. Lala, N. Schmidt, C. Okoli, P. Chi, M. A. Dickson, M. M. Gounder, M. L. Keohan, A. M. Crago, W. D. Tap, and S. P. D’Angelo Copyright © 2016 A. N. Shoushtari et al. All rights reserved. An Uncemented Spreading Stem for the Fixation in the Metaphyseal Femur: A Preliminary Report Sun, 15 May 2016 09:21:24 +0000 Surgical treatment to restore full range of motion and full weight bearing after extensive femoral bone resection in patients with primary or metastatic femoral tumours is individually challenging. Especially when the remaining distal or proximal bone is very short, a rigid fixation of an implant is difficult to achieve due to the reverse funnel shape of the metaphysis. Herein, we present a novel implant design using a spreading mechanism in the distal part of the prosthesis for rigid, uncemented fixation in the remaining femoral bone after extensive tumour resection of the femur. We present the outcome of 5 female patients who underwent implantation of this spreading stem after extensive proximal or distal femoral bone resection. There was no radiological or clinical loosening or implant-related revision surgery in our follow-up (mean 21.46 months, range 3.5–46 months). This uncemented spreading stem may therefore represent an alternative option for fixation of a prosthetic device in the remaining metaphyseal femur. Daniel Burger, Matthias Pumberger, and Bruno Fuchs Copyright © 2016 Daniel Burger et al. All rights reserved. Extracorporeal Irradiation and Reimplantation with Total Hip Arthroplasty for Periacetabular Pelvic Resections: A Review of 9 Cases Wed, 20 Apr 2016 14:23:37 +0000 We report the early results of nine patients with periacetabular malignancies treated with Enneking and Dunham type 2 resection and reconstruction using extracorporeally irradiated (ECI) tumour bone combined with total hip arthroplasty (THA). Diagnosis was chondrosarcoma in six patients, osteosarcoma in two patients, and metastatic renal cell carcinoma in one patient. All patients underwent surgical resection and the resected specimen was irradiated with 50 Gy in a single fraction before being prepared for reimplantation as a composite autograft. The mean follow-up was 21 months (range, 3–59). All patients were alive at latest follow-up. No local recurrence was observed. One patient serially developed three pulmonary metastases, all of which were resected. One experienced hip dislocation due to incorrect seating of an acetabular liner. This was successfully treated with revision of the liner with no further episodes of instability. There were no cases of deep infection or loss of graft. The average Musculoskeletal Tumor Society (MSTS) score was 75% (range, 57–87%). Type 2 pelvic reconstruction with ECI and THA has shown excellent early oncological and functional results in our series. Preservation of the gluteus maximus and hip abductors is important for joint stability and prevention of infection. Lester Wai Mon Chan, Jungo Imanishi, Samuel Y. Ngan, Sarat Chander, Julie Chu, Renae Thorson, Grant Pang, and Peter Choong Copyright © 2016 Lester Wai Mon Chan et al. All rights reserved. A Therapeutic Role for Survivin in Mitigating the Harmful Effects of Ionizing Radiation Sun, 17 Apr 2016 10:39:48 +0000 Background. Radiation therapy is a form of adjuvant care used in many oncological treatment protocols. However, nonmalignant neighboring tissues are harmed as a result of this treatment. Therefore, the goal of this study was to induce the production of survivin, an antiapoptotic protein, to determine if this protein could provide protection to noncancerous cells during radiation exposure. Methods. Using a murine model, a recombinant adenoassociated virus (rAAV) was used to deliver survivin to the treatment group and yellow fluorescence protein (YFP) to the control group. Both groups received targeted radiation. Visual inspection, gait analysis, and tissue histology were used to determine the extent of damage caused by the radiation. Results. The YFP group demonstrated ulceration of the irradiated area while the survivin treated mice exhibited only hair loss. Histology showed that the YFP treated mice experienced dermal thickening, as well as an increase in collagen that was not present in the survivin treated mice. Gait analysis demonstrated a difference between the two groups, with the YFP mice averaging a lower speed. Conclusions. The use of gene-modification to induce survivin expression in normal tissues allows for the protection of nontarget areas from the negative side effects normally associated with ionizing radiation. Katherine H. Carruthers, Gregory Metzger, Eugene Choi, Matthew J. During, and Ergun Kocak Copyright © 2016 Katherine H. Carruthers et al. All rights reserved.