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Objective: Malignant peripheral nerve sheath tumors (MPNST) are a rare subtype of sarcoma, with a poor outcome. MPNST are regarded as being sporadic or associated with neurofibromatosis type 1 (NF1). Few comparative overall-survival (OS) data in these 2 subsets of MPNST patients exist. The aim of this retrospective study was to assess OS in sporadic and NF1-associated MPNST patients. Methods: Fourteen consecutive patients with initial localized as well as initial metastatic MPNST were diagnosed and treated in our department. Patients with sporadic MPNST were assigned to group A and those with NF1-associated MPNST to group B. Results: Eight versus 6 patients were allocated to groups A and B. Primary tumors were located on the extremities in all but 1 patient. Two patients in group A and 4 patients in group B experienced a relapse. Four patients died in each of the 2 groups. Median follow-up was 66.2 and 57.2 months in group A and group B, respectively. Median OS in group A was 46.9 months versus 12.7 months in group B. Conclusions: In this small, single-center study, sporadic-MPNST patients had a longer median OS than those with NF1-associated MPNST. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background Pulmonary metastasectomy when possible has become therapeutic standard in soft tissue sarcoma patients. However, published reports frequently describe mixed series of patients with bone or soft tissue sarcoma. We report the outcome of 46 soft tissue sarcoma (STS) patients who underwent pulmonary metastasectomy (PM). Methods This current analysis includes retrospective survival data from 46 consecutive STS patients with pulmonary metastases who underwent PM at the Medical University of Vienna between January 2003 and December 2013. Results In total 72 pulmonary metastasectomies were performed. 322 metastatic nodules were resected with a median number of four nodules per intervention and the R0 resection rate was 97.2%. The postoperative complication rate as documented was low. Median follow-up (mFU) was 31.8months (range 3.7-127.4). Median overall survival as calculated from first detection of metastatic disease was 47.1months (95% confidence interval (CI)=36.2-58.1months) and 45.3months (95% CI=33.3-57.4months) when calculated from first PM until death or last follow-up (n=46). Five-year overall survival calculated from primary diagnosis was 62% and 32% when estimated from first PM. Previous disease free interval (DFI) as calculated from date of surgery of the primary tumour until the date of diagnosis of lung metastasis was 12.2months (range 0-140.1months). Median relapse-free survival (mRFS) after first PM to the date of recurrence of lung metastasis, death or last follow-up was 13.4months (95% CI=3-23.8months). Conclusion Median overall survival in this selected patient cohort is 45.3months. Despite the lack of prospective randomised controlled trials, PM is a reasonable treatment strategy in selected patients. [ABSTRACT FROM AUTHOR]

Background: Some sarcomas respond to immune checkpoint inhibition, but predictive biomarkers are unknown. We analyzed tumor DNA methylation profiles in relation to immunological parameters and response to anti-programmed cell death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy in patients with sarcoma., Patients and Methods: We retrospectively identified adult patients who had received anti-PD-1 ICI therapy for recurrent sarcoma in two independent centers. We performed (1) blinded radiological response evaluation according to immune response evaluation criteria in solid tumors (iRECIST) ; (2) tumor DNA methylation profiling of >850,000 probes using Infinium MethylationEPIC microarrays; (3) analysis of tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and intratumoral expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) using immunohistochemistry; and (4) evaluation of blood-based systemic inflammation scores (neutrophil-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio). Response to anti-PD-1 ICI therapy was bioinformatically and statistically correlated with DNA methylation profiles and immunological data., Results: 35 patients (median age of 50 (23-81) years; 18 females, 17 males; 27 soft tissue sarcomas; 8 osteosarcomas) were included in this study. The objective response rate to anti-PD-1 ICI therapy was 22.9% with complete responses in 3 out of 35 and partial responses in 5 out of 35 patients. Adjustment of DNA methylation data for tumor-infiltrating immune cells resulted in identification of methylation differences between responders and non-responders to anti-PD-1 ICI. 2453 differentially methylated CpG sites (DMPs; 2043 with decreased and 410 with increased methylation) were identified. Clustering of sarcoma samples based on these DMPs revealed two main clusters: methylation cluster 1 (MC1) consisted of 73% responders and methylation cluster 2 (MC2) contained only non-responders to anti-PD-1 ICI. Median progression-free survival from anti-PD-1 therapy start of MC1 and MC2 patients was 16.5 and 1.9 months, respectively (p=0.001). Median overall survival of these patients was 34.4 and 8.0 months, respectively (p=0.029). The most prominent DNA methylation differences were found in pathways implicated in Rap1 signaling, focal adhesion, adherens junction Phosphoinositide 3-kinase (PI3K)-Akt signaling and extracellular matrix (ECM)-receptor interaction., Conclusions: Our data demonstrate that tumor DNA methylation profiles may serve as a predictive marker for response to anti-PD-1 ICI therapy in sarcoma., Competing Interests: Competing interests: AS has received travel support from PharmaMar. AB has research support from Daiichi Sankyo and Roche; honoraria for lectures, consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo; as well as travel support from Roche, Amgen, Daiichi Sankyo and AbbVie. MP has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen. The following for-profit companies have supported clinical trials and contracted research conducted by MP with payments made to his institution: Böhringer-Ingelheim, Bristol-Myers Squibb, Roche, Daiichi Sankyo, Merck Sharp & Dome, Novocure, GlaxoSmithKline, AbbVie. TB reports personal fees from Roche (lecture fee), personal fees from Amgen (lecture fee, advisory board), personal fees from Bayer (lecture fee, advisory board), personal fees from Novartis (lecture fee, advisory board), personal fees from PharmaMar (lecture fee, advisory board), personal fees from Eisai (lecture fee, advisory board), personal fees from Eli Lilly (lecture fee, advisory board), outside the submitted work. RH is supported by Clinician Scientist Program of the University Medicine Essen Clinician Scientist Academy (UMEA) sponsored by faculty of medicine and Deutsche Forschungsgemeinschaft (DFG). RH has received travel grants from Lilly, Novartis and PharmaMar, as well as fees from Lilly outside of the submitted work. SB reports personal fees from Deciphera, grants from Incyte, grants and personal fees from Blueprint Medicines, personal fees from Lilly, grants and personal fees from Novartis, personal fees from Daichii-Sankyo, personal fees from Plexxikon, personal fees from Exelixis, personal fees from Bayer, other from Pfizer, during the conduct of the study; personal fees from Pharmamar, personal fees from Lilly, personal fees from Roche, personal fees from GSK, outside the submitted work. All other authors report no conflicts of interest concerning this specific publication., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Olaratumab is a humanized monoclonal antiplatelet-derived growth factor receptor alpha antibody that has been approved in combination with doxorubicin for the treatment of patients with metastatic soft tissue sarcoma (STS). The purpose of this retrospective study was to assess the clinical efficacy in STS patients treated with olaratumab in a real-world setting in Austria., Methods: Retrospectively collected longitudinal data from patients treated between November 2016 and September 2018 at 9 Austrian centers were obtained from the respective medical charts. All patients who received at least one dose of olaratumab were eligible. Parameters of most interest were response rates, progression-free survival (PFS) and overall survival (OS)., Results: Altogether 55 patients were included in the analysis. The median age was 58 years. In total, 65.5% (n = 36), 21.8% (n = 12) and 12.7% (n = 7) received olaratumab as first, second or ≥third line treatment, respectively. Olaratumab was administered either in combination with doxorubicin (81.8%, n = 45) or liposomal doxorubicin (16.4%, n = 9); one patient received olaratumab as upfront monotherapy. The median PFS and OS were 2.6 and 11.4 months, respectively. The objective response rate was 11.4% and the disease control rate was 40.9%., Conclusion: In this real-world analysis the outcome was less pronounced compared to the results of both the phase Ib/II approval trial and the confirmatory phase III trial. The latter failed to show an improvement in OS and PFS for the doxorubicin/olaratumab combination. As such, olaratumab should not be used anymore in patients with STS.

Objectives: Osteosarcoma of the jaw (OSAJ) is fundamentally different in clinical practice from its peripheral counterparts. Studies are difficult to conduct due to low incidence rates. The primary aim of this study was to provide for the first time a comprehensive retrospective analysis of the treatment concepts and outcome data of OSAJ patients treated at the University Hospital Vienna and to compare these with two recently published studies on OSAJ. The clinical study was accompanied by a biomarker study investigating the prognostic relevance of melanoma-associated antigen-A (MAGE-A) in OSAJ specimens., Method: Eighteen patients were included, and their outcomes were compared to published data. Immunohistochemistry was performed with mouse monoclonal antibodies against MAGE-A. Survival rates were estimated by the Kaplan-Meyer method. The log-rank test was used to analyze potential prognostic parameters. Fisher's exact test was performed to define the significant differences between the survival rates of the current study and the DOESAK registry., Results: Disease-specific survival was 93.8% after five and 56.3% after ten years. The development of metastases (p=0.033) or relapse (p=0.037) was associated with worsened outcomes in our group as well as in the comparative group. Despite the different treatment concepts of the study groups, survival rates were comparable. MAGE-A failed to show prognostic relevance for OSAJ patients., Conclusions: Uncertainties about the optimal treatment strategies of OSAJ patients will currently remain. Thus, prospective studies of OSAJ are needed but are only feasible in a multicenter study setting, conducted over a prolonged time period.

Dedifferentiated chondrosarcoma is a rare primary bone malignancy with a very poor prognosis. The aim of the study was to identify pretreatment serum markers as prognostic factors for the overall survival (OS) of patients with dedifferentiated chondrosarcoma. We retrospectively reviewed 33 patients with histologically confirmed dedifferentiated chondrosarcoma treated at our department from 1977 to 2015. Kaplan-Meier estimation, uni- and multivariable Cox proportional hazard model were performed to evaluate the association between serum markers such as the C-reactive protein and OS. In univariable analysis, CRP was strongly associated with OS (HR 1.35; 95%CI 1.13-1.61; p = 0.001). This association prevailed after adjustment for AJCC tumor stage (HR 1.31; 95%CI 1.02-1.57; p = 0.031) in multivariable analysis. In conclusion, our data gave evidence that baseline CRP is an independent predictor for OS in patients with dedifferentiated chondrosarcoma. CRP could be exploited for the clinical prediction of this disease in the future. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:2797-2801, 2018., (© 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society.)

Recent evidence suggests that common prognostic factors predicting disease progression and survival in soft tissue sarcomas (STS) are not applicable to all STS entities, indicating the need for histotype specific evaluation of new prognosticators. This study aimed at evaluating preoperative serum creatinine, albumin, and the albumin-creatinine ratio (ACR) as markers for survival in patients with malignant fibroblastic and myofibroblastic sarcomas. One hundred and thirty-two patients who underwent sarcoma resection have been included. Statistical analysis comprised uni- and multivariable Cox proportional hazard models, competing risk analysis and Kaplan-Meier estimates. The 5-year overall survival (OS) was estimated at 64.1% (95%CI: 53.7-72.8) and the 5-year sarcoma-specific mortality was 19.9% (95%CI: 12.8-28.1). Elevated serum creatinine levels were significantly associated with an impaired sarcoma-specific survival (SSS) adjusted for tumor stage (subdistribution hazard ratio (SHR) per 1 mg/dl increase: 3.27; 95%CI: 1.87-5.73; p < 0.0001). Low serum albumin levels were associated with a shorter recurrence-free survival (RFS) experience (HR per 10 g/L increase: 0.62; 95%CI: 0.41-0.94; p = 0.024). The ACR emerged as an AJCC-stage-independent prognosticator of SSS (SHR per 1 unit increase: 0.94; 95%CI: 0.90-0.98; p = 0.003). In conclusion, serum albumin and creatinine have been confirmed as predictive biomarkers for disease-specific outcomes in myofibroblastic and fibroblastic sarcomas. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2815-2824, 2017., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Low serum albumin levels and impaired kidney function have been associated with decreased survival in patients with a variety of cancer types. In a retrospective cohort study, we analyzed 84 patients with liposarcoma treated at from May 1994 to October 2011. Uni- and multivariable Cox proportional hazard models and competing risk analyses were performed to evaluate the association between putative biomarkers with disease-specific and overall survival. The median age of the study population was 51.7 (range 19.6-83.8) years. In multivariable analysis adjusted for AJCC tumor stage, serum creatinine was highly associated with disease-specific survival (Subdistribution Hazard ratio (SHR) per 1 mg/dl increase = 2.94; 95%CI 1.39-6.23; p = 0.005). High albumin was associated with improved overall and disease-specific survival (Hazard Ratio (HR) per 10 units increase = 0.50; 95%CI 0.26-0.95; p = 0.033 and SHR = 0.64; 95%CI 0.42-1.00; p = 0.049). The serum albumin-creatinine-ratio emerged to be associated with both overall and disease-specific survival after adjusting for AJCC tumor stage (HR = 0.95; 95%CI 0.92-0.99; p = 0.011 and SHR = 0.96; 95%CI 0.93-0.99; p = 0.08). Our study provides evidence for a tumor-stage-independent association between higher creatinine and lower albumin with worse disease-specific survival. Low albumin and a high albumin-creatinine-ratio independently predict poor overall survival. Our work identified novel prognostic biomarkers for prognosis of patients with liposarcoma., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Data on prognostic biomarkers in soft tissue sarcomas are scarce. The aim of the study was to define prognostic markers in patients with a liposarcoma, a subtype of sarcoma derived from adipose tissue. We restrospectively reviewed 85 patients with liposarcoma treated at our department from May 1994 to October 2011. Kaplan-Meier curves, uni-, and multivariable Cox proportional hazard models and competing risk analysis were performed to evaluate the association between putative biomarkers with disease-specific and overall survival. We observed a significant association between both alkalic phosphatase (ALP; subhazard ratio [SHR] per 1 unit increase: 1.35; 95%CI 1.10-1.65; p = 0.005) and C-reactive protein (CRP; SHR per 1 mg/dl increase: 2,57; 95%CI 1.36-4,86; p = 0.004) with disease-specific survival. Hemoglobin (Hb) (HR per 1 g/dl increase: 065; 95%CI 0.48-0.87; p = 0.003) was associated with overall survival. These associations prevailed after multivariable adjustment for AJCC tumor stage. This study identifies CRP and ALP as novel independent predictors of disease-specific survival in patients with liposarcoma., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Angiogenesis, among other signaling pathways, plays a key-role in sarcoma biology. Regorafenib (RE) has recently been shown to be effective in imatinib and sunitinib-refractory GIST in a phase III trial., Methods/design: We are conducting an international trial (France, Austria and Germany) consisting in 4 parallel double-blind placebo-controlled randomized (1/1) phase II trials to assess the activity and safety of RE in doxorubicin-refractory STS (ClinicalTrials.gov: NCT01900743). Each phase II trial is dedicated to one of the 4 following histological subgroups: liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcoma. Within each randomized trial the following stratification factors will be applied: countries and prior exposure to pazopanib. Key-eligibility criteria are: measurable disease, age ≥18, not > 3 previous systemic treatment lines for metastatic disease, metastatic disease not amenable to surgical resection. The primary endpoint is progression-free survival (PFS) according to central radiological review. Secondary endpoints are: Toxicity (NCI-CTC AE V4.0); time to progression; Growth modulation index in pts receiving RE after randomization; 3 and 6 months PFS-Rates, best response rate and overall survival. Each phase II trial will be separately analyzed. In 3 trials, statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; β = 0.05 with a total sample size of 192 pts. To take into account the rarity of synovial sarcoma, the statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; β = 0.2 Tumor assessment is done monthly during the 4 first months, and every 3 months thereafter. After central radiological confirmation of tumor progression, an optional open-label option is offered to eligible patients., Discussion: The design of this trial allows an assessment of regorafenib activity over placebo in four sarcoma strata and might provide evidence for launching a phase III trial. This study includes both integrative and exploratory translational research program. The study is enrolling since June 2013 (TRIAL REGISTRATION NUMBER: EudraCT N°: 2012-005743-24, on the 15(th) February 2012).

Purpose: This phase I study was performed to evaluate coagulation alterations during extracorporeal circulation (ECC) induced whole body hyperthermia (WBHT) in 12 patients with advanced soft tissue sarcomas., Methods: To distinguish between effects of normothermic ECC and ECC-WBHT, blood samples were drawn at different time points: at baseline, after 30 min on normothermic ECC, at the end of the heating period, and 24 h and 7 days thereafter. Standard coagulation tests, coagulation factors, thrombelastography,platelets and reticulated platelets, liver enzymes, and scintigraphic platelet imaging were performed., Results: Normothermic ECC resulted in coagulation alterations most likely due to systemic anticoagulation. Induction of hyperthermia caused thrombocytopenia, increased fibrin degradation products,prolonged clotting times, alteration in coagulation factors, and increased liver enzymes. The majority of these effects was most pronounced 24 h after ECC-WBHT. In addition, late liver sequestration of platelets was demonstrated in scintigraphic imaging at that time point., Conclusions: Temporal correlation between hemostatic alterations and elevation in liver enzymes leads to the assumption that liver impairment might play a crucial role in coagulation disturbances observed during ECC-WBHT and thereafter, thus strongly supported by liver sequestration of platelets.Therefore a close monitoring of hepatic derived coagulation alterations in patients undergoing extracorporeal whole body hypothermia is warranted.

Background: Synovial sarcoma is a rare subgroup of all soft-tissue sarcomas. The aim of this retrospective single-center analysis was to investigate the outcome of patients with initially localized disease., Patients and Methods: Twenty-six patients were enrolled in this retrospective single-center analysis. Baseline characteristics, treatment and outcome were evaluated., Results: In 13 patients (50%), the tumor was located in the lower extremity and in 4 patients (15%) in the upper extremity. Surgical resection was done in all but 2 patients (92%). Re-resection was done in 7 patients (27%). Fourteen patients (54%) received adjuvant chemotherapy. After a median follow-up of 23.3 months (range: 2.6-150.3), median disease-free survival was not reached at the time of analysis. Eight patients (31%) relapsed after initial therapy. Surgery was done in 2 patients, amputation in 1 patient, palliative chemotherapy was administered in 3 and radiation therapy in 2 patients. Median overall survival (OS) for all patients was not reached at the time of analysis. The estimated 5-year OS rate was 62%., Conclusion: Patients with initially localized synovial sarcoma who were included in this retrospective single-center analysis have an estimated 5-year OS rate of 62%., (© 2014 S. Karger AG, Basel.)

Soft tissue sarcomas are heterogeneous tumours and relatively uncommon. There have been advances over the past years concerning pathology, clinical behaviour, diagnosis strategies and the treatment. To summarize these advances as well as making it public is one of the goals of the following consensus guidelines. But why do we need special guidelines for Austria? There are international guidelines published by the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN). The cause is that we need an explanation of the matrix the ESMO and the NCCN gave according to our clinical practice, the local requirements and facilities in Austria. The following recommendations were drawn up following a consensus meeting of sarcoma specialists from the three high volume centres located at the medical universities in Austria. All fields of involved physicians from diagnosis to therapy worked together to know that soft tissue sarcomas are an interdisciplinary challenge and multimodal treatment is essential. For this reason, these guidelines not only explain but also give the state of the art and clear recommendations. One of the most important guidelines is that any patient with a suspected soft tissue sarcoma should be referred to one of the three university centres and managed by a specialist sarcoma multidisciplinary team. We hope that the consensus is helpful for the clinical practice and improves the quality of care for patients with soft tissue sarcomas in Austria.

Purpose: This phase I study was performed to evaluate the feasibility and toxicity of a new method of extracorporeal perfusion-induced whole body hyperthermia (WBHT) in patients with advanced sarcoma avoiding the need of intubation and general anesthesia., Methods: One double-lumen femoral venous access was inserted by Seldinger's technique to obtain WBHT (41.8°C for 120 minutes) via an extracorporeal circuit. No concomitant chemotherapy was applied. Up to 4 treatments of WBHT were performed under moderate sedation in 6 spontaneously breathing patients. Invasive hemodynamic monitoring was performed by use of a pulmonary artery catheter., Results: After their first WBHT session, 2 patients were excluded from further treatment due to transient liver toxicity or catheter-related complication, so a total of 12 cycles remained for analyses. In all patients, conscious sedation resulted in sufficient spontaneous respiration without the need for mandatory ventilation. Median time to reach the target temperature was 84 minutes (range 60-142). Hemodynamic changes revealed the expected hyperdynamic state: heart rate, cardiac index, and stroke volume index significantly increased (p<0.05), whereas blood pressure and systemic and pulmonary vascular resistance index significantly decreased (p<0.05). A net fluid balance of 5822±1766 mL as well as norepinephrine (mean; 0.062 µg·kg¹·min⁻¹) were necessary to maintain the mean arterial blood pressure >60 mmHg., Conclusion: Our data demonstrate the feasibility of this method of extracorporeal WBHT without mandatory ventilation. Hemodynamic side effects in spontaneously breathing patients during perfusion-induced WBHT seem less severe than those observed in radiant heat WBHT.

Adequate treatment of gastrointestinal stromal tumors (GISTs) is linked to an interdisciplinary treatment approach. Austrian representatives of medical oncology, surgery, pathology, radiology and gastroenterology have issued this consensus manuscript within the context of currently available and published literature. The paper contains guidelines and recommendations for diagnosis, therapy and follow-up of GIST patients in Austria.

Diagnosis and treatment of gastrointestinal stromal tumors (GIST) requires an interdisciplinary treatment approach. This strategy should be reflected by the content of this article. Austrian representatives of 'GIST relevant' specialties authored this publication on a consensual base. This manuscript should be regarded as a guideline for 'GIST involved' colleagues in Austria.