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Background: Increased time to diagnosis in sarcoma is associated with poor prognosis and patient outcomes. Research is needed to identify whether opportunities to expedite the diagnosis of sarcoma in general practice exist., Aim: To examine pre-diagnostic GP clinical activity before sarcoma diagnosis., Design and Setting: An Australian retrospective cohort study using hospital registry data (Australian Comprehensive Cancer Outcomes and Research Database [ACCORD]) linked to two primary care datasets (Patron and MedicineInsight)., Method: The frequency of general practice healthcare utilisation events (general practice attendances, prescriptions, blood test, and imaging requests) were compared in 377 patients with soft tissue sarcoma (STS) and 64 patients with bone sarcoma (BS) in the year pre-diagnosis. Poisson regression models were used to calculate monthly incidence rate ratios (IRR) for the 24 months pre-diagnosis and estimate inflection points for when healthcare use started to increase from baseline., Results: In the 6 months pre-diagnosis, patients with sarcoma had a median of 3-4 general practice attendances, around one-third had a GP imaging request (33% [ n = 21] BS and 36% [ n = 134] STS), and approximately one in five had multiple imaging requests (19% [ n = 12] BS and 21% [ n = 80] STS). GP imaging requests progressively increased up to eight-fold from 6 months before sarcoma diagnosis (IRR 8.43, 95% confidence interval [CI] = 3.92 to 18.15, P <0.001) and general practice attendances increased from 3 months pre-diagnosis., Conclusion: Patients with sarcoma have increased GP clinical activity from 6 months pre-diagnosis, indicating a diagnostic window where potential opportunities exist for earlier diagnosis. Interventions to help identify patients and promote appropriate use of imaging and direct specialist centre referrals could improve earlier diagnosis and patient outcomes., (© The Authors.)

Background: Mesenchymal chondrosarcoma (MCS) is an ultra-rare sarcoma that follows a more aggressive course than conventional chondrosarcoma. This study evaluates prognostic factors, treatments (surgery, chemotherapy, and radiation), and outcomes in an Australian setting., Methods: We collected demographics, clinicopathological variables, treatment characteristics, and survival status from patients with MCS registered on the national ACCORD sarcoma database. Outcomes include overall survival (OS) and progression-free survival (PFS)., Results: We identified 22 patients with MCS between 2001-2022. Median age was 28 (range 10-59) years, 19 (86%) had localised disease at diagnosis of whom 16 had surgery (84%), 11 received radiation (58%), and 10 chemotherapy (53%). Ten (52%) developed recurrence and/or metastases on follow-up and three patients with initial metastatic disease received surgery, radiation, and chemotherapy. At a median follow-up of 50.9  (range 0.4-210) months nine patients had died. The median OS was 104.1 months (95% CI 25.8-182.3). There was improved OS for patients with localised disease who had surgical resection of the primary (p = 0.003) and those with ECOG 0-1 compared to 2-3 (p = 0.023) on univariate analysis., Conclusions: This study demonstrates contemporary Australian treatment patterns of MCS. The role of chemotherapy for localised disease remains uncertain. Understanding treatment patterns and outcomes help support treatment decisions and design of trials for novel therapeutic strategies., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aim: Despite lack of advances in the first-line systemic therapy, the overall survival (OS) has continued to improve in patients with advanced soft tissue sarcoma (STS) with the recent estimation of median OS at 20 months. Several systemic therapy options are available now for the second-line and beyond, with more treatment tailored to histology and molecular subtype. The aim of this retrospective study was to characterize current patterns of care in managing patients with advanced STS (aSTS) in Australia., Methods: Sarcoma databases from 7 Australian sarcoma services were accessed to identify patients diagnosed with locally advanced inoperable and/or metastatic STS between January 1, 2010 and December 31, 2015. Baseline clinicopathological factors and initial treatment patterns were descriptively analyzed. For the Victorian cohort where treatment of aSTS and follow-up details were available, further exploratory analysis was conducted to determine the impact of patient and tumor characteristics and the use of palliative-intent treatment OS., Results: Of 2261 cases of STS, 671 were deemed as aSTS. Two thirds were relapsed disease with a mean 1.9 years from initial diagnosis. Median age at diagnosis of aSTS was 59 years (18-95 years) and 56.3% was male. Histology classification revealed four main subtypes: undifferentiated pleomorphic sarcoma (UPS) (23.1%), leiomyosarcoma (18.2%), liposarcoma (12.8%), synovial sarcoma (8.2%), and other comprising 14 STS subtypes. For the Victorian cohort (N = 361), approximately 80% of patients accessed palliative-intent treatment of various modalities. Nearly 40% of patients underwent tumor-debulking surgery or metastasectomy, of which lung wedge resection was the most common (N = 83, 47.7%). A total of 438 palliative-intent radiotherapy treatments were delivered to 259 patients (71.7%), with the majority in the form of external beam radiotherapy. Palliative-intent systemic therapy was delivered to 51.5% of patients (N = 186), mostly (73%). Anthracycline-based therapy was the most commonly delivered therapy (N = 135, 72.6%). Approximately half of the patients in each line of therapy failed to proceed to the subsequent line of systemic therapy with 29.4% receiving three or more lines of therapy (N = 55). A total of 18.3% of patient (N = 34) participated in clinical trials or accessed off-label drugs. The median OS for the Victoria cohort was 15.4 months (95% confidence interval: 12.1, 18.2). The UPS histology subtype was associated with poorer OS, whereas receiving any modality of palliative-intent treatment conferred survival benefit., Conclusion: In Australia, aSTS is managed with diverse treatment approaches comprising various therapy modalities. Further work is planned in describing healthcare resource utilization and estimating costs by this patient cohort., (© 2022 John Wiley & Sons Australia, Ltd.)

Patients with sarcoma are best managed at specialised sarcoma centres as supported by published literature. Optimal management requires multidisciplinary team input to formulate the diagnosis and treatment sequencing taking into consideration multiple clinical and pathologic factors. This systematic review aimed to evaluate the impact on outcomes of radiotherapy at specialised sarcoma centres. A systematic review was conducted using the population, intervention, comparison and outcome model. A literature search was performed using Medline, Embase, Cochrane Central databases for publications from 1990 to February 2022 that evaluated the local control, survival and toxicity of radiotherapy at specialised sarcoma centres. A total of 21 studies were included (17 cancer registry studies, four retrospective comparative studies). Four studies reported the local recurrence endpoint when radiotherapy was part of limb conservation treatment and showed better conformity to clinical practice guidelines and an improved local recurrence free rate when radiotherapy treatment is supported through, but may not be necessarily delivered at a specialised sarcoma centres. Only one retrospective study analysed toxicity specifically and demonstrated that patients who received preoperative radiotherapy at community centres compared to radiotherapy at a specialised sarcoma centre were more likely to develop a major wound complication. Fourteen studies reported overall survival, and 12 of these showed significantly better 5-year overall survival for patients managed at specialised sarcoma centres, however the specific impact of radiotherapy delivered at sarcoma centres could not be determined. In conclusion, patients with sarcoma should be managed through specialised sarcoma centres for better oncological outcomes. Radiotherapy in specialised sarcoma centre is associated with a lower rate of wound complications and may contribute to improved oncological outcomes as part of the limb conservation treatment at a specialised sarcoma centre., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS., Methods: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021)., Results: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice., Conclusions: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies., Methods: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan., Results: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types., Conclusions: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients., (© 2021 American Cancer Society.)

The identification of rearrangements driving expression of neurotrophic receptor tyrosine kinase ( NTRK ) family kinases in tumors has become critically important because of the availability of effective, specific inhibitor drugs. Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) can identify novel and recurrent expressed fusions. Here we describe three SPECC1L-NTRK fusions identified in two pediatric central nervous system cancers and an extracranial solid tumor using WGS and RNA-seq. These fusions arose either through a simple balanced rearrangement or in the context of a complex chromoplexy event. We cloned the SPECC1L-NTRK2 fusion directly from a patient sample and showed that enforced expression of this fusion is sufficient to promote cytokine-independent survival and proliferation. Cells transformed by SPECC1L-NTRK2 expression are sensitive to a TRK inhibitor drug. We report here that SPECC1L-NTRK fusions can arise in a range of pediatric cancers. Although WGS and RNA-seq are not required to detect NTRK fusions, these techniques may be of benefit when NTRK fusions are not suspected on clinical grounds or not identified by other methods., (© 2020 Khuong-Quang et al.; Published by Cold Spring Harbor Laboratory Press.)

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions., Competing Interests: Disclosure KB has received consultant fees from Bayer and Merck, and research support from Bayer, Merck, and Eli Lilly. GDD discloses scientific consultancy with sponsored research to Dana-Farber from Bayer, Pfizer, Novartis, Roche/Genentech, Epizyme, LOXO Oncology, AbbVie, GSK, Janssen, PharmaMar, ZioPharm, Daiichi Sankyo, Adaptimmune, and Mirati; scientific consultancy for GSK, EMD Serono, Sanofi, ICON plc, WCG/Arsenal Capital, Polaris Pharmaceuticals, MJ Hennessy/OncLive, C4 Therapeutics, Synlogic, and MEDSCAPE; consultant/SAB member with minor equity holding for G1 Therapeutics, Caris Life Sciences, Champions Biotechnology, Bessor Pharma, Erasca Pharmaceuticals, RELAY Therapeutics, and Caprion/HistoGeneX; board of directors member and scientific advisory board consultant with minor equity for Blueprint Medicines, Merrimack Pharmaceuticals (ended Oct 2019), and Translate BIO; royalties from Novartis to Dana-Farber for use of patent of imatinib in GIST; non-financial interests with McCann Health, Alexandria Real Estate Equities, and AACR Science Policy and Government Affairs Committee (Chair). JD discloses advisory/consultancy roles for Amgen, Novartis, Lilly, GSK, Pierre Fabre, and Eisai; institutional research funding from Novartis, Lilly, GSK, Roche/Genentech, BMS, AstraZeneca, and BeiGene. PH discloses consultancy fees from Roche and Pfizer, and research support from Novartis. HJ has a co-appointment at Orion Pharma, has received fees from Neutron Therapeutics, and owns stocks of Orion Pharma and Sartar Therapeutics. YKK discloses consultancy for Taiho, Ono, Merck, Daehwa, BMS, Astellas, Zymeworks, ALX ONCOLOGY, Amgen, Novartis, MacroGenics, and Surface Oncology. SP discloses grant support from Blueprint Medicines and Hutchison MediPharma; consultancy for Daiichi Sankyo, Epizyme, Dova, Decimera, Bayer, and Immune Design. FPL discloses advisory/consultancy roles for Bayer and Roche, and institutional research grants from Bayer. PR has received honoraria for lectures and advisory boards from Novartis, MSD, Roche, BMS, Sanofi, Merck, Amgen, Pfizer, Pierre Fabre, and Blueprint Medicines, outside the scope of this report. WDT discloses advisory/consultancy roles for Lilly, EMD Serono, Eisai, Janssen, Immune Design, Daiichi Sankyo, Blueprint Medicines, LOXO Oncology, GSK, Agios Pharmaceuticals, NanoCarrier, Deciphera, Certis Oncology Solutions, and Atropos Therapeutics; patent for CDK4 inhibitor companion diagnostic (14/854 329) pending to MSKCC/SKI; stock ownership in Certis Oncology Solutions and Atropos Therapeutics; participation in FDA ODAC meeting for pexidartinib. DT is the CEO of a non-profit company, Omico, which undertakes precision oncology activities across Australia. He has received honoraria or consultant fees from Roche, Pfizer, Bayer, AstraZeneca, Merck, and the Maine Cancer Genome Initiative. He has received research support from Roche, Pfizer, Bayer, AstraZeneca, Amgen, Eisai, Illumina, and Sun Pharma. JZ discloses honoraria from Pfizer, Merck Serono, Specialized Therapeutics, Targovax, Halozyme, Gilead Sciences, and Bayer; advisory/consultancy roles for Pfizer, Merck Serono, Targovax, MSD, Sirtex Medical, Halozyme, Lipotek, Novella, and Khloris Biosciences; institutional research funding from Bayer, Merck Serono, Roche, BMS, Pfizer, AstraZeneca, Specialized Therapeutics, Baxalta/Shire, Lilly, Boehringer-Ingelheim, and MSD; travel/accommodation/expenses from Merck Serono, AstraZeneca, MSD, Deciphera, and Sirtex; shareholder/stockholder/stock options in GW Pharmaceuticals, Aimmune, Vertex, Bluebird Bio, Alnylam, BioMarin, Sage Therapeutics, Dova Pharmaceuticals, Therapeutics MD, Juno Therapeutics, Kite Pharma, Kiadis Pharma, CSL Ltd, Cochlear, Amarin, Freq Therapeutics, Global Blood Therapeutics, Gilead, uniQure, Sangamo, Acceleron, Zogenix, Myovant Science, and Khloris Biosciences; board of directors for Praxis Australia; non-remunerated activities for Australian Clinical Trials Alliance (Chair), National Oncology Alliance (co-Chair), and All.Can Australia (co-Chair). All other authors have declared no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Several unanswered questions surround the management of retroperitoneal sarcoma (RPS). Guidelines recommend treatment by a multidisciplinary team at a specialized referral centre. The objective of this study was to describe the management of RPS at an Australian specialist sarcoma centre, comparing outcomes to international standards and analysing for predictors of local failure., Methods: A retrospective review of a prospectively maintained database was performed on patients with RPS treated between 2008 and 2016. A 5-year outcome analyses focussed on patients undergoing curative-intent surgery for primary, non-metastatic RPS., Results: Eighty-eight patients underwent surgery for primary RPS. Five-year overall survival was 66%, 5-year freedom from local recurrence was 65% and 5-year freedom from distant metastasis was 71%. Overall survival was associated with tumour grade (hazard ratio (HR) 6.1, P < 0.001) and histologic organ invasion (HR 5.7, P < 0.001). Variables associated with improved freedom from local recurrence were macroscopically complete resection (HR 0.14, P < 0.001) and neoadjuvant radiotherapy (HR 0.33, P = 0.014). Treatment at a specialist sarcoma centre was associated with a higher rate of preoperative biopsy and neoadjuvant radiotherapy (both with P < 0.001). There was a trend towards improved local control for patients undergoing surgery at a specialist centre (P = 0.055)., Conclusion: This is the largest Australian series of RPS and outcomes are comparable to major international sarcoma centres. Patients treated at a specialist centre had higher rates of preoperative diagnosis and tailored therapy which was associated with improved outcomes. Patients with suspected RPS should be referred to a specialist centre for optimal preoperative evaluation and multidisciplinary management., (© 2018 Royal Australasian College of Surgeons.)

Background: Preoperative radiotherapy (RT) is commonly used to treat localised soft-tissue sarcomas (STS). Hypoxia is an important determinant of radioresistance. Whether antiangiogenic therapy can 'normalise' tumour vasculature, thereby improving oxygenation, remains unknown., Methods: Two cohorts were prospectively enrolled. Cohort A evaluated the implications of hypoxia in STS, using the hypoxic tracer (18)F-azomycin arabinoside (FAZA-PET). In cohort B, sunitinib was added to preoperative RT in a dose-finding phase 1b/2 design., Results: In cohort A, 13 out of 23 tumours were hypoxic (FAZA-PET), correlating with metabolic activity (r(2)=0.85; P<0.001). Two-year progression-free (PFS) and overall (OS) survival were 61% (95% CI: 0.44-0.84) and 87% (95% CI: 0.74-1.00), respectively. Hypoxia was associated with radioresistance (P=0.012), higher local recurrence (Hazard ratio (HR): 10.2; P=0.02), PFS (HR: 8.4; P=0.02), and OS (HR: 41.4; P<0.04). In Cohort B, seven patients received sunitinib at dose level (DL): 0 (50 mg per day for 2 weeks before RT; 25 mg per day during RT) and two patients received DL: -1 (37.5 mg per day for entire period). Dose-limiting toxicities were observed in 4 out of 7 patients at DL 0 and 2 out of 2 patients at DL -1, resulting in premature study closure. Although there was no difference in PFS or OS, patients receiving sunitinib had higher local failure (HR: 8.1; P=0.004)., Conclusion: In STS, hypoxia is associated with adverse outcomes. The combination of sunitinib with preoperative RT resulted in unacceptable toxicities, and higher local relapse rates.

Each year approximately 800 Australians are diagnosed with sarcoma, accounting for less than 1% of cancer diagnoses overall. A significant proportion of these sarcoma cases are in children and adolescents. The rarity and heterogeneity of this group of tumours, coupled with Australasia's relative geographical isolation, pose significant challenges in developing locoregional basic, translational and clinical research. The Australasian Sarcoma Study Group (ASSG) was established in 2008 as a Cooperative Cancer Clinical Research Group and is now the peak body for sarcoma research in Australasia, providing a mechanism to drive and coordinate collaborative research, promote education and assist with advocating for sarcoma within the region. This paper describes the development of ASSG and examines the current state of play with regard to sarcoma research in Australasia.

Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic amplification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 amplification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists.

Background: Soft-tissue sarcomas require tailored and multidisciplinary treatment and management. However, little is known about how sarcomas are treated and managed throughout the Asia-Pacific region., Materials and Methods: MEDLINE was systematically searched using prespecified criteria. Publications (previous 10 years) that reported tumour characteristics, treatment patterns, survival outcomes, and/or safety outcomes of patients with soft-tissue sarcoma were selected. Exclusion criteria were studies of patients <18 years of age; ≤ 10 patients; countries other than Australia, Hong Kong, Indonesia, Korea, Malaysia, New Zealand, Philippines, Singapore, Taiwan, or Thailand; >20% benign tumours; sarcomas located in bones or joints; gastrointestinal stromal tumour; Kaposi's sarcoma; or not reporting relevant outcomes., Results: Of the 1,822 publications retrieved, 35 (32 studies) were included. Nearly all patients (98%, 1,992/2,024; 31 studies) were treated with surgery, and more studies used adjuvant radiotherapy than chemotherapy (24 vs 17 studies). Survival outcomes and recurrence rates varied among the studies because of the different histotypes, sites, and disease stages assessed. Only 5 studies reported safety findings., Conclusions: These findings highlight the lack of specific data available about soft-tissue sarcomas in the Asia-Pacific region. Better efforts to understand how the sarcoma is managed and treated will help improve patient outcomes in the region.

The individual rarity of the many subtypes of soft tissue sarcomas has historically mandated an empiric approach to systemic therapy. Doxorubicin, first reported to have activity in sarcomas 40 years ago, remains the generalizable first-line treatment of choice for many subtypes, with no other drug or combination having shown an overall-survival advantage. Other cytotoxic agents, such as paclitaxel for angiosarcoma or gemcitabine with docetaxel for leiomyosarcoma, are commonly used for certain histologic subtypes based on relatively small studies. Trabectedin, particularly active against leiomyosarcoma and myxoid liposarcoma, is approved in many countries worldwide but not yet in the United States or Australia. Newer cytotoxic agents, including ifosfamide derivatives, are in current phase III testing. Although advances is systemic therapy of soft-tissue sarcomas have been hampered by their biologic heterogeneity, this diversity also serves as fertile ground for discovery and validation of targetable molecular drivers. The most notable success in this regard has been the development of small molecule therapies for gastrointestinal stromal tumors. Other targets of recent interest include mouse double minute 2 homolog (MDM2) in dedifferentiated liposarcoma and anaplastic lymphoma kinase (ALK) in inflammatory myofibroblastic tumor. Molecular therapies that have shown activity in diverse sarcoma populations include mammalian target of rapamycin (mTOR) inhibitors and vascular endothelial growth factor (VEGF-R) inhibitors. Among the latter, pazopanib demonstrated a progression-free survival over placebo in prior-treated patients with advanced sarcoma, and is now approved for use in the sarcomas in many countries. Efforts to understand the key molecular aberrations in any particular tumor continue towards a goal of individualized sarcoma therapy.

The Royal College of Pathologists of Australasia is developing a series of protocols as an educational tool to assist pathologists in the reporting of relevant information for specific cancer specimens. The protocol for the management of soft tissue tumour resections has recently been released, and this document elaborates the relevant literature on which that protocol drew. Sarcoma is uncommon but is associated with significant morbidity and mortality, and its management is complex. Diagnostic errors are not uncommon and these can have disastrous effects on patient outcome. Sophisticated ancillary testing is often an important adjunct to diagnosis and prognostication. Referral to a specialist sarcoma unit is indicated for both adult and paediatric sarcoma.

Purpose: Reactivation of p53 tumor suppressor activity in diseases such as soft-tissue sarcoma is considered an attractive means of targeted therapy. By systematically assessing alterations affecting the p53 pathway, we aimed to (a) classify sarcoma subtypes, (b) define a potential role in malignancy, and (c) identify potential patient biomarkers in this heterogeneous disease., Experimental Design: We have mapped mutational events in a panel of 192 benign or malignant bone and soft-tissue sarcomas. Analyses included TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 amplification and MDM2 SNP309 status., Results: We found an inverse relationship between MDM2 amplification and TP53 mutations, with a predominantly wild-type CDKN2A background. A high rate of point mutations in TP53 was observed uniquely in leiomyosarcoma, osteosarcoma, and MFH. Both MDM2 and MDM4 were also amplified in a subtype-specific manner, which was frequently seen as a coamplification event. We have also analyzed the risk allele frequencies for MDM2 SNP309, and show that the G allele was strongly associated with both liposarcomas and MDM2 amplification., Conclusions: Our data emphasize the critical role of p53 inactivation in sarcomagenesis, whereby different pathway alterations may be related to the heterogeneity of the disease. Moreover, we observed a strong association of malignancy with TP53 mutation, or MDM2 amplification and the presence of a G allele in SNP309, especially in lipoma versus liposarcoma. We propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists., (©2010 AACR.)

Background: Single-agent gemcitabine and vinorelbine have activity in treatment of patients with soft-tissue sarcomas. The combination of gemcitabine plus vinorelbine has activity against several forms of metastatic carcinoma with acceptable toxicity. This study evaluated the efficacy and tolerability of gemcitabine plus vinorelbine in advanced soft-tissue sarcoma., Methods: A single academic center performed this phase II trial. Eligible patients had unresectable or metastatic soft-tissue sarcomas, Eastern Cooperative Group performance status of 0-2, adequate organ function, and 4 months. There has been 1 CR lasting >1 year in a patient with high-grade pleomorphic spindle-cell sarcoma., Conclusions: Gemcitabine given by a fixed-dose rate of infusion combined with vinorelbine was associated with clinically meaningful rates of disease control in patients with advanced soft-tissue sarcoma. Toxicity was acceptable. This study contributed to data that have supported the administration of fixed-dose rate gemcitabine-based drug regimens in soft-tissue sarcomas., (Copyright (c) 2007 American Cancer Society)

Purpose: SU5416 (semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor-2 and KIT receptor tyrosine kinases. This Phase II study was conducted to investigate the safety and efficacy of SU5416 for patients with soft tissue sarcomas., Experimental Design: Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m(2) twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment., Results: The median progression-free survival was 1.8 months. Median overall survival was 22.8 months. No objective tumor responses were observed. There was evidence of shorter survival among patients with high baseline urine VEGF levels (P = 0.04). No grade 4 toxicities were observed. The most common grade 3 toxicities were headache and thrombosis. Other less serious toxicities included fatigue, nausea, and abdominal pain. The median systolic blood pressure increased from 118 mmHg at baseline to 133 after 1 month of treatment (P = 0.01). Post-treatment tumor biopsies showed no significant decreases in VEGF receptor phosphorylation compared with baseline in 3 evaluable patients. One patient with gastrointestinal stromal tumor who had rapid progression during SU5416 treatment was subsequently treated with another KIT inhibitor, imatinib mesylate, and had a partial response lasting >36 months., Conclusions: SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor or KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.

Gastrointestinal stromal tumors (GIST) represent the most common type of mesenchymal malignancy in the gastrointestinal tract. With the discovery of uncontrolled KIT tyrosine kinase signaling as a critical component in the pathogenesis of this disease, the diagnostic and treatment options for patients with GIST have evolved rapidly. Pathology review by an experienced pathologist is critical to the classification of this disease. Expert and definitive surgery remains the mainstay of treatment in patients with localized, resectable disease. Imatinib mesylate has been shown to be the first successful systemic therapy for patients with metastatic or unresectable disease and has revolutionized the treatment of this often rapidly progressive and fatal disease. Ongoing studies are evaluating the role of imatinib in the preoperative and postsurgical adjuvant settings. Although resistance to imatinib will appear over time, there is reason for optimism that the mechanisms of resistance will be identified and eventually overcome. The application of molecular understanding of GIST to the development of a selective, scientifically rational therapy is a classic example of multidisciplinary translational oncology research.

In 2013 Australia introduced Wiki-based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma. These guidelines utilized a customized MediaWiki software application for guideline development and are the first evidence-based guidelines for clinical management of sarcoma. This paper presents our experience with developing and implementing web-based interactive guidelines and reviews some of the challenges and lessons from adopting an evidence-based (rather than consensus-based) approach to clinical sarcoma guidelines. Digital guidelines can be easily updated with new evidence, continuously reviewed and widely disseminated. They provide an accessible method of enabling clinicians and consumers to access evidence-based clinical practice recommendations and, as evidenced by over 2000 views in the first four months after release, with 49% of those visits being from countries outside of Australia. The lessons learned have relevance to other rare cancers in addition to the international sarcoma community. [ABSTRACT FROM AUTHOR]