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Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice.In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls).The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29-58), 170 (15%) of 1162 probands had multiple primary cancers, and 155 (17%) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55%) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1·43, 95% CI 1·24-1·64, p0·0001), with 227 known or expected pathogenic variants occurring in 217 individuals. All classes of pathogenic variants (known, expected, or predicted) were associated with earlier age of cancer onset. In addition to TP53, ATM, ATR, and BRCA2, an unexpected excess of functionally pathogenic variants was seen in ERCC2. Probands were more likely than controls to have multiple pathogenic variants compared with the combined control cohort group and the LifePool control cohort (OR 2·22, 95% CI 1·57-3·14, p=1·2 × 10(-6)) and the cumulative burden of multiple variants correlated with earlier age at cancer diagnosis (Mantel-Cox log-rank test for trend, p=0·0032). 66 of 1162 probands carried notifiable variants following expert clinical review (those recognised to be clinically significant to health and about which patients should be advised), whereas 293 (25%) probands carried variants with potential therapeutic significance.About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment.Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, National Cancer Institute, Liddy Shriver Sarcoma Initiative.

Sarcomas and Gastrointestinal Stromal Tumors: Presentations From the 2008 European Society for Medical Oncology International Symposium.-- et al., Despite complex genetics, aneuploid tumors like dedifferentiated liposarcoma have specific and reproducible chromosomal changes such as amplification of HDM2 and CDK4 that represent potential targets for systemic therapy. In addition, there are cancer cell survival pathways that may not be the target of chromosomal translocations or mutations that are still estimable targets for new systemic therapeutics, be it pathways involved in angiogenesis or apoptosis. In this review, we examine target selection for specific sarcoma subtypes, and demonstrate with a few examples new techniques being used to delineate novel therapeutic inroads for patients with sarcoma. © 2009 Elsevier Inc. All rights reserved., Enrique de Alava is supported by the European Commission (NoE EuroBoNet), Ministry of Science and Innovation of Spain-FEDER (PI052524, RD06/0020/0059). Silvana Pilotti is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC). Robert G. Maki is supported by Program Project Grant No. P01-CA47179; Cycle for Survival. David M. Thomas is supported by the Victorian Cancer Agency Clinician Researcher fellowship, and Cancer Australia.

Summary Background Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. Methods We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. Findings Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21–43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24–47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28–51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3–4. The most common grade 3–4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). Interpretation The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. Funding National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.

BACKGROUND: Data regarding the role of systemic therapy in patients with advanced well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS) are limited. METHODS: From 2000 to 2010, 208 patients with advanced WDLPS/DDLPS received chemotherapy in 11 participating institutions. Clinical and pathological data were collected by reviewing medical records. RESULTS: Median age was 63 years (range 32-84). Combination chemotherapy was delivered in 85 cases (41%) and single agent in 123 cases (59%), respectively. One hundred and seventy-one patients (82%) received an anthracycline-containing regimen. Using RECIST, objective response was observed in 21 patients (12%), all treated with anthracyclines. Median progression-free survival (PFS) was 4.6 months [95% confidence interval (CI) 3.3-5.9]. On multivariate analysis, age and performance status (PS) were the sole factors significantly associated with poor PFS. Median overall survival (OS) was 15.2 months (95% CI 11.8 -18.7). On multivariate analysis, grade and PS were the sole factors significantly associated with OS. CONCLUSIONS: Chemotherapy was associated with clinical benefit in 46% of patients with advanced WDLPS/DDLPS. OS remains poor, even though visceral metastatic disease is less frequent than in other sarcomas.

In the days before the term "high-grade undifferentiated pleomorphic sarcoma" came into use, one of the most common sarcoma diagnoses was "malignant fibrous histiocytoma," and before that, in an era before immunohistochemistry, "fibrosarcoma" was used to describe most sarcomas. "Spindle cell" is a descriptive phrase that denotes the cellular shape of many of the sarcomas encountered in the adult population. As a result, they are usually treated differently from small round cell sarcomas, and have different biological characteristics than those tumors and sarcomas with epithelioid morphology. As a very broad generalization, sarcomas with a spindle cell microscopic morphology occur in adults and are treated primarily with surgery and often adjuvant or neoadjuvant radiation as primary therapy. In comparison to small round cell sarcomas such as Ewing sarcoma, the use of adjuvant chemotherapy remains controversial, and the sensitivity of these tumors to chemotherapy in the metastatic setting is highly variable. In this article, we describe some of the clinical and biological characteristics of this group of sarcomas.

Background: The purpose of this study was to retrospectively analyze the relationship between neo-adjuvant chemotherapy (NAC) and outcome in patients with high-grade extremity sarcomas. Patients and methods: Inclusion criteria were high-grade, deep, >5 cm extremity soft tissue sarcomas. Patients diagnosed between 1990 and 2001 were treated with surgery only (n = 282) or NAC containing doxorubicin/ifosfamide/mesna (AIM) (n = 74). The stratified Cox proportional hazards model was used to test the effect of NAC on disease-specific survival and recurrence while adjusting for known prognostic factors. Results: NAC was associated with improved disease-specific survival for this cohort of patients (P = 0.02). This overall improvement appears to be driven by the benefit of NAC on disease-specific survival for patient with tumors >10 cm. The 3-year disease-specific survival for tumors >10 cm was 0.62 (95% CI: 0.53 ‐ 0.71) for patients not receiving NAC and 0.83 (95% CI: 0.72 ‐ 0.95) for patients receiving NAC. Conclusion: NAC with AIM was associated with a significant improvement in disease-specific survival in patients with high-grade extremity soft tissue sarcomas >10 cm. These data emphasize the need for further prospective clinical studies of neo-adjuvant or adjuvant chemotherapy for patients

Follicular dendritic cell tumors are rare cancers of the lymph nodes of the head and neck. Despite a relatively high rate of recurrence, these neoplasms have a limited impact on the airways because they can be potentially cured by surgical resection. We present the case of a young woman with an unresectable follicular dendritic cell tumor involving the paratracheal region causing upper airway obstruction and respiratory failure. This malignant tumor created numerous management dilemmas and therapeutic challenges related to the unstable airway and the need for tracheal stenting to bypass the airway obstruction.

Background: Data regarding the role of systemic therapy in patients with advanced pleomorphic liposarcomas (PLPS) are very limited.

Introduction Data related to management and outcome of BM of sarcoma are scarce. Methods From 1991 to 2010, from over 4500 sarcoma pts treated at MSKCC, 107 developed BM. Results Highest relative frequency came from ASPS (26%,7/27 pts), with an absolute number highest for LMS(37%). BM metachronous in 96 cases (90%). Median time between diagnosis of metastatic sarcoma and the diagnosis of BM was 9 months (range 5.5–12.5). Locoregional treatment (surgery ± RT) in 83 pts (78%). Systemic CT in 18 pts (17%) after diagnosis of BM. One PR (EWS) in 15 evaluable pts. One hundred-one pts died (94%), 6 still alive. Two living pts with follow-up >24 months had complete surgery of BM. Deaths related to BM progression were 54 (54%), related exclusively to systemic PD were 47 (46%). Median OS was 3.6 months (95% CI: 2.9-4.3). One-year OS rate was 16% (95% CI 9–23). On univariate analysis, histology, delay between the diagnosis of sarcoma and BM relapse, number of lesions, disease status and PS were significantly associated with OS. Surgery was significantly related to improved OS while RT was not. On multivariate analysis, time between diagnosis of sarcoma and BM relapse and disease status were pre-therapeutic prognostic factors associated with OS. Conclusions SARCOMA pts with BM have poor outcome. RT was not associated with improved survival. Long-term survival is achieved in small proportion of pts managed by surgery. CT had little activity after BM, consistent with the advanced nature of the pts' sarcomas. Disclosure All authors have declared no conflicts of interest.

It is been known for many years that the insulin-like growth factor (IGF) signalling pathway is important in human cancer. The IGF-1 receptor (IGF-1R) is upregulated in colorectal, breast, prostate and lung cancers. It was also known to be a potential target in Ewing's sarcoma. The advent of specific monoclonal antibodies and small molecule tyrosine kinase inhibitors of IGF-1R led to many clinical trials. A combination of figitumumab with platinum doublet chemotherapy resulted in a higher response rate and improved progression-free survival (PFS) in phase II, but a phase III trial was negative. In Ewing's sarcoma activity was seen with R-1507, figitumumab and other agents. However, response rates in phase II studies were generally low, 14.2% with figitumumab, and duration generally short, e.g. with figitumumab median PFS 1.9 months, median survival 8.9 months. Occasionally, durable responses have been seen lasting for several years. Could better selection by the use of circulating biomarkers, e.g. IGF-1, or IGF binding proteins, be useful or does the answer lie with combinations? Laboratory studies suggest that combining IGF-1R inhibitors with inhibitors of AKT/mTOR, EGFR or MEK, could help to overcome resistance. Given the dearth of new agents for Ewing's sarcoma it is to be hoped that continued access to these agents will enable further work on mechanisms of resistance and appropriate combination phase I/II studies to be performed. The book is not yet closed on IGF-1R as a target. Disclosure The author has declared no conflicts of interest.