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BACKGROUND/AIM: Gastrointestinal stromal tumours (GISTs) harbour genetic aberrations in receptor tyrosine kinase KIT (KIT) or platelet-derived growth factor receptor A (PDGFRA) in 85-90% of the patients. Circulating tumour DNA (ctDNA) is a potential biomarker in patients with GIST. Previous studies investigating ctDNA around surgery in patients with GIST presented divergent results regarding the proportion of patients with detectable ctDNA. This study aimed to 1) investigate the feasibility of detecting and monitoring ctDNA pre-and postoperative, 2) compare two different circulating free DNA (cfDNA) extraction methods, and validate results obtained by next-generation sequencing (NGS) using Real-Time PCR technology. PATIENTS AND METHODS: Eight patients planned for immediate surgery or surgery after neoadjuvant oncological treatment were included in the study, from whom blood collection was performed pre- and postoperatively for ctDNA analysis. Furthermore, blood samples from six patients with GIST harbouring a point mutation in KIT or PDGFRA in tissues from primary tumours were used for comparison and validation sub-study. RESULTS: In this explorative study, none of the patients with very low to intermediate risk GIST harboured KIT, or PDGFRA mutated ctDNA in pre-or postoperative blood samples. The methods used for cfDNA extraction gave similar output, and the two methods for ctDNA analysis gave identical results. CONCLUSION: There is no benefit in analysing ctDNA around surgery in very low to intermediate-risk GIST patients. Larger studies investigating ctDNA in patients with high-risk GIST around surgery are warranted.

The abnormal neurodevelopment secondary to in utero adversities, such as hypoxia, malnutrition and maternal infections, underlies schizophrenia (SZ) etiology. As the genes of MBL-associated serine proteases (MASP) of the complement lectin pathway, MASP1 and MASP2, are expressed in the developing cortex and are functionally important for neuronal migration, we hypothesize that the malfunction of L-ficolin-MASP arm may also be involved in schizophrenia pathophysiology as it was shown for MBL-MASP complexes. We investigated serum L-ficolin and plasma MASP-2 levels, the activity of L-ficolin-bound MASP-2, as well as an array of the complement-related variables in chronic schizophrenic patients in the acute phase of the disease and controls without physical or mental diagnoses. The median concentration of L-ficolin in Armenian controls was 3.66 μg/ml and similar to those reported for other Caucasian populations. SZ-cases had ∼40 % increase in serum L-ficolin (median 5.08 μg/ml; P < 0.0024). In the pooled sample, L-ficolin level was higher in males than in females (P < 0.0031), but this gender dichotomy was not affecting the variable association with schizophrenia (P < 0.016). Remarkably, MASP-2 plasma concentration showed gender-dependent significant variability in the group of patients but not in controls. When adjusted for gender and gender*diagnosis interaction, a significantly high MASP-2 level in female patients versus female controls was observed (median: 362 ng/ml versus 260 ng/ml, respectively; P < 0.0020). A significant increase in L-ficolin-bound MASP-2 activity was also observed in schizophrenia (on the median, cases vs controls: 7.60 vs 6.50 RU; P < 0.021). Correlation analyses of the levels of L-ficolin and MASP-2, L-ficolin-(MASP-2) activity and the demographic data did not show any significant association with the age of individuals, family history, age at onset and duration of the illness, and smoking. Noteworthy, the levels of L-ficolin and MASP-2 in circulation were significantly associated with the type of schizophrenia (paranoid SZ-cases had much higher L-ficolin (P < 0.0035) and lower MASP-2 levels than the other types combined (P < 0.049)). Correlations were also found between: (i) the classical pathway functional activity and L-ficolin level (rs = 0.19, P < 0.010); (ii) the alternative pathway functional activity and MASP-2 level (rs = 0.26, P < 0.00035); (iii) the activity of L-ficolin-bound MASP2 and the downstream C2 component haemolytic activity (rs = −0.19, P < 0.017); and (iv) L-ficolin and the upstream C-reactive protein (CRP) serum concentrations (r = 0.28, P < 0.018). Overall, the results showed L-ficolin-related lectin pathway alterations in schizophrenia pathophysiology. It is likely that in addition to the MBL-MASP component over-activity reported previously, the alterations of the lectin pathway in schizophrenia also involve variations of L-ficolin-(MASP-2) on protein concentration and activity levels.

Gastrointestinal stromal tumour (GIST) is the most common sarcoma and can be seen in any part of the gastrointestinal tract. The effect of tyrosine kinase inhibitors varies with mutation status in receptor tyrosine kinase KIT and in platelet-derived growth factor receptor A (PDGFRA). This case presents a 61-year-old man, diagnosed with an 11-cm GIST located at the stomach with a high risk of recurrence. The patient showed intolerance to imatinib shortly after introduction and subsequently progressed on sunitinib and nilotinib. The patient started fourth-line treatment with sorafenib with an impressive response to a point at which metastases intra-abdominally and in the liver could be resected. After surgery, sorafenib was restarted. Due to toxicity, sorafenib dose was reduced over time. The dose was insufficient to control the disease since a new recurrence was detected. Mutation analyses revealed a GIST harbouring a deletion of codon p.I843_D846del, located at PDGFRA exon 18, right next to the codon D842 where mutations are known leading to imatinib resistance. In this case, the GIST was highly sensitive to sorafenib, and the response was dose related. It is mandatory to perform mutation analyses on primary tumour and at recurrence in the decision-making of the correct treatment for the patient. In March 2021, the patient had been in treatment with sorafenib for 12.5 years and was still without signs of recurrence. A multidisciplinary approach was essential for the long-term survival of the patient in this case.

BACKGROUND/AIM: For patients with local gastrointestinal stromal tumor (GIST), risk stratification is used to assess the prognosis and identify patients to offer adjuvant treatment. For patients with advanced or metastatic GIST, no such risk stratification exists. This study aimed to investigate the prognostic value of 31 different plasma small extracellular vesicles' (SEVs) surface proteins in GIST patients. MATERIALS AND METHODS: GIST patients from the two sarcoma centers in Denmark were included. Patients were divided into three groups; group 1: patients undergoing radical surgery; group 2: patients with local, locally advanced, or metastatic GIST; and group 3: patients without evidence of disease after radical surgery. Protein microarray technology was used for the analysis of plasma SEVs. The median plasma SEV marker level was used when comparing groups of patients. The primary endpoint was the progression of GIST. Iterative statistical modeling was used to identify a SEV marker profile/model with a prognostic value. RESULTS: A total of 157 patients were included, with a median follow-up time of 2.05 years. In group 2, a high level of carcinoembryonic antigen (CEA) and a low level of glucose transporter 1 (GLUT-1) were found to be poor prognostic factors [univariate analysis; GLUT-1: hazard ratio (HR)=0.47, 95% confidence interval (CI)=0.22-0.98; CEA: HR=2.12, 95%CI=1.02-4.44]. Composing a model consisting of CEA and GLUT-1 adjusted for age at inclusion was found to have a prognostic value (HR=4.93, 95%CI=2.30-10.57, p

Lactic acid bacteria (LAB) have long been used to extend the shelf life and improve the taste and texture of fermented milk. In this study, we investigated the texturing potential of LAB in plant-based fermentation by high-throughput screening of 1232 Lactococcus lactis strains for texture in milk and liquid soybean matrices. We found that most strains with texturing abilities in fermented milk were also capable of enhancing the texture in fermented soybean, despite the large differences in composition of the two matrices. Exocellular polysaccharide production is believed to contribute positively to fermented milk and plant-base texture. It appeared as if it was the properties of the polysaccharides rather than their protein interaction partners that were responsible for the enhanced texture in both matrices. We mined whole genome sequences of texturing strains for polysaccharide biosynthesis (eps) gene clusters. The comparative genomics approach revealed 10 texturing strains with novel eps gene clusters. Currently, the relationship between the novel genes and their functionality in milk and plant matrices is unknown.

Background: This study investigates the prognostic value of plasma Programmed Death Protein-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) concentrations in patients with Gastrointestinal Stromal Tumor (GIST). Methods: Patients with GIST were included (n = 157) from the two Danish sarcoma centers, independent of disease- and treatment status. The patients were divided into three subgroups; 1: patients with localized disease who underwent radical surgery; 2: patients with local, locally advanced, or metastatic disease; and 3: patients without measurable disease who had undergone radical surgery. Sensitive electrochemiluminescence immune-assays were used to determine PD-1 and PD-L1 concentration in plasma samples. The primary endpoint was the PFS. Results: No patients progressed in group 1 (n = 15), 34 progressed in group 2 (n = 122), and three progressed in group 3 (n = 20). Significantly higher plasma concentrations of PD-1 (p = 0.0023) and PD-L1 (0.012) were found in patients in group 2 compared to PD-1/PD-L1 levels in postoperative plasma samples from patient group 1. Patients with active GIST having a plasma concentration of PD-L1 above the cutoff (225 pg/mL) had a significantly poorer prognosis compared to patients with plasma PD-L1 concentration below the cutoff. Conclusions: Plasma PD-L1 shows potential as a prognostic biomarker in patients with GIST and should be further evaluated.

Anthracycline induced cardiotoxicity is well recognized but only few data exist in sarcoma patients. This study retrospectively aimed to analyze sequential Cadmium Zinc Telluride (CZT)-multigated equilibrium radionuclide angiography (ERNA) for monitoring left ventricular ejection fraction (LVEF) and to assess the real-life incidence of cardiotoxicity in sarcoma patients receiving doxorubicin based chemotherapy.A retrospective analysis was performed on all sarcoma patients referred to Herlev University Hospital between 2012 and 2015. Cardiotoxicity was defined as a decline in LVEF of10% percentage point to a LVEF50% as compared to baseline. Early cardiotoxicity was defined as1 year and late cardiotoxicity as ≥ 1 year. Recovery of cardiotoxicity was defined as a LVEF ≥ 50%.A total of 149 patients were referred, 75 (50%) sarcoma patients were included. The main reason for exclusion was that only one CZT-ERNA had been performed in 50 (68%) of the patients. Twenty-three (31%) of the patients experienced cardiotoxicity, 11 (48%) were female, mean age was 56.9 years. Early cardiotoxicity was observed in 16 (70%) of the patients and 11 (48%) experienced clinical symptoms of cardiotoxicity at diagnosis. Recovery of LVEF was seen in 12 (55%) of the patients and persistent recovery in 10 (45%). The diastolic blood pressure at baseline was positively and significantly associated with a higher risk of developing cardiotoxicity (Relative Risk (RR): 1.039 (95% CI= 1.001 - 1.079;Cardiotoxicity is a relative frequent complication in sarcoma patients treated with doxorubicin based chemotherapy and the diastolic blood pressure at baseline was significantly associated with a higher risk of developing cardiotoxicity.

Tumor-specific tumor-infiltrating lymphocytes (TILs) can be in vitro expanded and have the ability to induce complete and durable tumor regression in some patients with melanoma following adoptive cell therapy (ACT). In this preclinical study, we investigated the feasibility of expanding TIL from sarcomas, as well as performing functional in vitro analyses on these. TILs were expanded in vitro by the use of IL2 stimulation with or without the addition of 4-1BB and CD3 antibodies. Phenotypical and functional analyses were mainly performed by flow cytometry. TILs were expanded from 25 of 28 (89%) tumor samples from patients with 9 different sarcoma subtypes. TILs were predominantly αβ T-cells of effector memory subtype with CD4+ dominance. In particular, CD8+ TIL highly expressed LAG3 and to a lesser degree PD-1 and BTLA. In total, 10 of 20 TIL cultures demonstrated in vitro recognition of autologous tumor. In some cases, the fraction of tumor-reactive T cells was more than 20%. 4-1BB stimulation augmented expansion kinetics and favored CD8+ occurrence. In conclusion, TIL expansion from sarcoma is feasible and expanded TILs highly express LAG3 and comprise multifunctional tumor-reactive T-cells.

Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin cancer associated with a high mortality rate in advanced stages [1,2]. For patients with non-resectable advanced/meta...

BACKGROUND: Chemotherapy is ineffective in treating patients with Gastrointestinal Stromal Tumour (GIST). However, several types of tyrosine kinase inhibitors have been investigated since the approval of imatinib in 2001. The purpose of this report was to systematically review studies on the efficacy of neoadjuvant, adjuvant, and lifelong medical oncological treatment of GIST.METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed throughout the review process. The protocol was submitted to the International prospective register of systematic reviews database (ID 251724). A systematic literature search was performed, including phase II- and III studies of biological treatment, reporting on treatment effect in patients with GIST.RESULTS: Of 308 identified publications, 42 studies were included in this review.CONCLUSION: This review gives an overview of the existing evidence for approved lines of oncological treatments and potential alternatives for patients with GIST in the neoadjuvant-, adjuvant- and life-long setting.

Background Patients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib. Patients and methods Since all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were ≥18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission + partial remission + stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks. Results Seventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome. Conclusion Pazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting., Highlights • Pazopanib given in metastatic or locally advanced GIST in third line is beneficial for about half of the patients. • The results indicate a similar progression-free survival as regorafenib in third line with a favourable tolerance. • Plasma concentration of pazopanib correlates weakly with disease control rate.

IMPORTANCE: Patients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone. OBJECTIVE: To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS. DESIGN, SETTING, AND PARTICIPANTS: ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater. INTERVENTIONS: Patients were randomized 1:1 to receive doxorubicin, 75 mg/m2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/placebo monotherapy. MAIN OUTCOMES AND MEASURES: Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations. RESULTS: Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%). CONCLUSIONS AND RELEVANCE: In this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02451943. ispartof: JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION vol:323 issue:13 pages:1266-1276 ispartof: location:IL, Chicago status: published

Purpose We conducted a randomized phase III trial to determine whether adjuvant chemotherapy improves survival in women with uterine leiomyosarcoma. Methods Women with uterus-confined, high-grade leiomyosarcoma who were confirmed disease free by imaging were randomly assigned to four cycles of gemcitabine plus docetaxel, followed by four cycles of doxorubicin, or to observation. All were followed for evidence of recurrence. The primary end point was overall survival (OS). Results With international collaboration, 38 of the targeted accrual of 216 patients were enrolled, after which the study was closed by the National Cancer Institute for accrual futility. Twenty patients were assigned to chemotherapy, 18 to observation. Among the 17 patients treated with at least one cycle of chemotherapy, grade 3 or 4 toxicities were observed in 47%; among the 18 patients assigned to observation, one had grade 3 hypertension. There were six deaths (chemotherapy, n = 5; observation, n = 1), all due to disease. The restricted mean survival time for OS was estimated as 34.3 months (95% CI, 25.3 to 43.3 months) in the chemotherapy arm and as 46.4 months (95% CI, 43.6 to 49.1 months) in the observation arm. There were eight recurrences in each arm. The restricted mean survival time for recurrence-free survival was estimated as 18.1 (95% CI, 14.2 to 22.0) months in the chemotherapy arm and as 14.6 months (95% CI, 10.3 to 19.0 months) in the observation arm. Neither survival outcome comparison was considered statistically robust, due to the small sample size. Conclusion Despite international collaboration to test the role of adjuvant chemotherapy in uterine-confined leiomyosarcoma, this study was closed for accrual futility. Although the sample size precludes robust statistical comparison, observed OS and recurrence-free survival data do not show superior outcomes with adjuvant chemotherapy.

Aggressive fibromatosis also known as desmoid tumors constitute 3% of soft tissue tumors and 0.03% of all cancers [1]. They most commonly occur in women after childbirth and the gender ratio is 1.5...

Survival of patients with high-grade osteosarcoma (HOS), the most common primary bone cancer, has not improved significantly the last 30 years and the disease remains a major challenge. The purpose of this study is to evaluate survival in relation to prognostic factors at time of diagnosis among patients diagnosed with primary appendicular HOS in East Denmark between 1990 and 2010.101 patients (median age = 20 years, female/male ratio = 56/45) diagnosed with primary appendicular high-grade osteosarcoma between 1990 and 2010 were included in this study. Initially, 156 patients diagnosed with osteosarcoma between 1990 and 2010 were identified through the population based Regional Database of Pathology, which covers a population of approximately 2.7 million (east Denmark). 55 patients were excluded due to (A) tumor was low grade (n = 22), (B) located in axial skeleton (n = 18), (C) incorrect diagnosis (n = 11) or (D) biopsy represented a tumor relapse from a former primary osteosarcoma (n = 4). Overall survival was evaluated using the Kaplan-Meier survival analysis and log-rank test. Prognostic factors were analyzed using uni- and multivariate cox-regression method with variables scored equally in the model. p Values.05 were considered statistically significant.The probability of 5- and 10-year survival was 51% (95% CI: 41-61) and 46% (95% CI: 36-56), respectively. Metastatic stage at diagnosis and tumor size ≥10 cm measured radiologically at the largest diameter were independent prognostic factors for decreased survival with significant increased hazard-risks of 3.5 (95% CI: 1.9-6.5) and 1.97 (95% CI: 1.1-3.6), respectively.In this single institution evaluation of primary appendicular HOS we found 5-and 10-year survival rates consistent with international standards for this patient group. Distant metastases and tumor size ≥10 cm at the time of diagnosis were independent prognostic factors for decreased survival in our cohort. These results underline the importance of awareness and early referral from the primary sector.

Kaposi Sarcoma (KS) is driven by human herpes virus 8 causing vascular proliferation which is induced by loss of immune function most often due to HIV or immunosuppressants. KS occurs with increased incidence in kidney transplant recipients, but rarely is disseminated. We report a 64-year-old male who developed severely disseminated KS 5 months after ABO-incompatible kidney-transplantation. No guidelines for chemotherapy exist in this case and reduced kidney function and impaired immune system complicates the use of systemic chemotherapy in kidney transplant recipients. A combination of paclitaxel and gemcitabine followed by two days of hemodialysis treatment was chosen since paclitaxel can be given in full dose independently of kidney function and gemcitabine is metabolised to 2′,2′-difluorodeoxyuridine which is found to be highly dialysable. The present treatment was well tolerated by the patient with one episode of leukopenia and elevated alanine transaminase during treatment which resolved. There were no serious adverse events and the patient obtained a complete remission verified by Positron Emission Tomography CT after ending chemotherapy and at one-year follow up.

AIM The aim of this study was to estimate nationally the survival of children, adolescents, and young adults with head and neck soft tissue sarcomas. MATERIALS AND METHODS The authors included patients 0 to 21 years of age and diagnosed with rhabdomyosarcoma (RMS) or nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) located in the head and neck between 1980 and 2014. Survival probabilities were estimated using the Kaplan-Meier method. The authors estimated the effect of covariates with univariate and multivariate Cox regression analyses. The cumulative recurrence in RMS was estimated when considering death as a competing risk. RESULTS We identified 72 patients (50% male individuals, whereas 72% had RMS). Elder patients (older than 15 y) did worse compared with younger patients (log-rank test P=0.001). Patients diagnosed from 1980 to 1999 did worse than patients diagnosed from 2000 to 2014 (log-rank test P=0.02). Similarly, younger (younger than 15 y) patients did significantly better when diagnosed from 2000 to 2014 with reference to those diagnosed from 1980 to 1999 (log-rank test P=0.026). The multivariate hazard ratio was 0.46 (95% confidence interval, 0.23-0.92) for patients diagnosed from 2000 to 2014 with reference to patients diagnosed from 1980 to 1999. The 1-year cumulative recurrence for RMS was 21.2% (95% confidence interval, 12.3%-35.0%). CONCLUSION Overall survival has improved throughout the study period, which is attributable to advancement in diagnostics, treatment, and the application of standardized guidelines from international protocols.

Background. Head and neck soft tissue sarcomas (HNSTS) constitute a rare and heterogeneous cancer entity. Management remains a challenge due to the rarity and varied biological behaviour among various subtypes. This systematic review examines the characteristics of tumours and patients with HNSTS. Materials and Methods. A systematic literature review and meta-analysis were performed using the electronic databases PubMed and Embase. Eight eligible studies were identified, and 13 variables were extracted from each study including 5-year overall survival (OS) rate and 5-year disease-free survival (DFS) rate. Results. We identified eight studies (n = 1,120 patients; 739 males (66%)) from six different countries). In total, 24 histological subtypes were found, and 20% of the sarcomas (n = 215) could not be subclassified. 607 sarcomas (57%) were Conclusion. HNSTS holds a relative poor prognosis possibly explained by the heterogeneity of the disease. Treatment of HNSTS has shown to be highly diverse, underlining the importance of uniformed treatment guidelines in order to achieve improved survival outcomes.

BACKGROUND: This subgroup analysis of a phase 3 study compares outcomes for eribulin versus dacarbazine in patients with leiomyosarcoma. METHODS: Patients ≥18 years old with advanced liposarcoma or leiomyosarcoma, ECOG PS ≤2, and ≥2 prior treatment regimens were randomly assigned (1:1) to eribulin mesylate (1.4 mg/m² intravenously on day 1 and day 8) or dacarbazine (either 850, 1000, or 1200 mg/m² intravenously) every 21 days until disease progression. The primary end point was OS; additional end points were progression-free survival (PFS) and objective response rate (ORR). RESULTS: 309 Patients with leiomyosarcoma were included (eribulin, n = 157; dacarbazine, n = 152). Median age was 57 years; 42% of patients had uterine disease and 57% had nonuterine disease. Median OS was 12.7 versus 13.0 months for eribulin versus dacarbazine, respectively (hazard ratio [HR] = 0.93 [95% CI 0.71-1.20]; P = 0.57). Median PFS (2.2 vs 2.6 months, HR = 1.07 [95% CI 0.84-1.38]; P = 0.58) and ORR (5% vs 7%) were similar between eribulin- and dacarbazine-treated patients. Grade ≥3 TEAEs occurred in 69% of patients receiving eribulin and 59% of patients receiving dacarbazine. CONCLUSIONS: Efficacy of eribulin in patients with leiomyosarcoma was comparable to that of dacarbazine. Both agents had manageable safety profiles. ispartof: BRITISH JOURNAL OF CANCER vol:120 issue:11 pages:1026-1032 ispartof: location:England status: published

Aleutian Mink Disease Virus (AMDV) is a frequently encountered pathogen associated with commercial mink breeding. AMDV infection leads to increased mortality and compromised animal health and welfare. Currently little is known about the molecular evolution of the virus, and the few existing studies have focused on limited regions of the viral genome.This paper describes a robust, reliable, and fast protocol for amplification of the full AMDV genome using long-range PCR. The method was used to generate next generation sequencing data for the non-virulent cell-culture adapted AMDV-G strain as well as for the virulent AMDV-Utah strain. Comparisons at nucleotide- and amino acid level showed that, in agreement with existing literature, the highest variability between the two virus strains was found in the left open reading frame, which encodes the non-structural (NS1–3) genes. This paper also reports a number of differences that potentially can be linked to virulence and host range.To the authors’ knowledge, this is the first study to apply next generation sequencing on the entire AMDV genome. The results from the study will facilitate the development of new diagnostic tools and can form the basis for more detailed molecular epidemiological analyses of the virus.

In Denmark, 4500 hysterectomies are performed each year for benign gynecological diseases. The decision making process regarding the route of hysterectomy depends primarily upon the technical possi...

Summary Background Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. Methods We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m 2 via bolus injection administered over 5–20 min or continuous intravenous infusion for 6–96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m 2 intravenously for 30–60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. Findings Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1·06, 95% CI 0·88–1·29; p=0·527), with a median overall survival of 18·4 months (95% CI 15·6–22·1) with doxorubicin plus evofosfamide versus 19·0 months (16·2–22·4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3–4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3–4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one ( Interpretation The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting. Funding Threshold Pharmaceuticals.

BACKGROUND: Limb-sparing surgery for sarcomas has become possible in most cases. However, the impact of the procedure on the functional outcome has only been investigated in a few studies. The aim of this study has been to identify tumor- and patient-related factors associated with reduced functional outcome and quality of life after limb-sparing surgery in soft tissue sarcoma patients. MATERIAL AND METHODS: In total, 128 patients (mean age = 58, female/male = 54/74) who were treated with limb-sparing surgery without bone resection for soft tissue sarcomas in Denmark during the period 1 January 2009 to 31 December 2011 were included. Patients were asked to participate at least one year after surgery, and patients who had experienced local recurrence or metastatic disease were excluded. The Toronto Extremity Salvage Score (TESS) measured functional disability, while the Musculoskeletal Tumor Society Score (MSTS) measured functional impairment. European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 measured quality of life. Tumor- and patient-related factors (age, gender, tumor depth, tumor size, malignancy, comorbidity, location, and radiotherapy) were extracted from the Danish National Sarcoma Database. Wilcoxon rank-sum test and Kruskal-Wallis were used for univariable analysis. Adjusted odds ratios were estimated by using multiple logistic regression models. RESULTS: In the multiple regression analysis, it was found that female gender (p = 0.03), lower extremity tumors (p

Item does not contain fulltext BACKGROUND: Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide-which have been used to treat soft-tissue sarcoma for more than 30 years-still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone. METHODS: We did this phase 3 randomised controlled trial (EORTC 62012) at 38 hospitals in ten countries. We included patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, age 18-60 years with a WHO performance status of 0 or 1. They were randomly assigned (1:1) by the minimisation method to either doxorubicin (75 mg/m(2) by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m(2); 25 mg/m(2) per day, days 1-3) plus ifosfamide (10 g/m(2) over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by centre, performance status (0 vs 1), age (/=50 years), presence of liver metastases, and histopathological grade (2 vs 3). Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to six cycles. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00061984. FINDINGS: Between April 30, 2003, and May 25, 2010, 228 patients were randomly assigned to receive doxorubicin and 227 to receive doxorubicin and ifosfamide. Median follow-up was 56 months (IQR 31-77) in the doxorubicin only group and 59 months (36-72) in the combination group. There was no significant difference in overall survival between groups (median overall survival 12.8 months [95.5% CI 10.5-14.3] in the doxorubicin group vs 14.3 months [12.5-16.5] in the doxorubicin and ifosfamide group; hazard ratio [HR] 0.83 [95.5% CI 0.67-1.03]; stratified log-rank test p=0.076). Median progression-free survival was significantly higher for the doxorubicin and ifosfamide group (7.4 months [95% CI 6.6-8.3]) than for the doxorubicin group (4.6 months [2.9-5.6]; HR 0.74 [95% CI 0.60-0.90], stratified log-rank test p=0.003). More patients in the doxorubicin and ifosfamide group than in the doxorubicin group had an overall response (60 [26%] of 227 patients vs 31 [14%] of 228; p

LBA3 Background: Dox is standard therapy in STS. In a Ph 2 trial, olaratumab (a human IgG1 antibody targeting PDGFRα) + dox improved overall survival (OS) and progression-free survival (PFS) vs dox. ANNOUNCE aimed to confirm the OS benefit in advanced STS. Methods: Adult pts with unresectable locally advanced or metastatic STS, anthracycline-naïve, and ECOG PS 0-1 were eligible. Pts were randomized 1:1 to olaratumab (20mg/kg Cycle 1, 15mg/kg subsequent cycles) or PBO on Days 1 and 8 of each 21-day cycle combined with dox (75mg/m2) on Day 1 for up to 8 cycles. After 8 cycles, pts with disease control continued olaratumab or PBO until progression or toxicity. Randomization was stratified by histology, prior systemic therapy, ECOG PS, and geographic region. Dexrazoxane use was allowed to mitigate dox-related cardiotoxicity. Primary endpoints were OS in the intent-to-treat (ITT) population and/or leiomyosarcoma (LMS) subset of the ITT population; the study was designed to be positive if either primary endpoint was met. Secondary endpoints included PFS, response/disease control rates, safety, and pharmacokinetics. Results: 509 pts were randomized: 258 in the investigational and 251 in the control arm. Baseline pt characteristics were well balanced. Dexrazoxane was received by 63.0% vs 65.1% of pts (investigational vs control arm, respectively, for all data). In the ITT population, median OS was 20.4 vs 19.8 months (m) (HR=1.05, 95% CI: 0.84-1.30; p = 0.69) and was 21.6 vs 21.9 m in LMS pts (HR=0.95, 95% CI: 0.69-1.31; p = 0.76). Median PFS was lower in the investigational arm in the ITT population (5.4 vs 6.8 m; HR=1.23, 95% CI: 1.01-1.50; p = 0.04) and in LMS pts (4.3 vs 6.9 m, HR=1.22, 95% CI: 0.92-1.63; p = 0.17). Median dox exposure was 6 vs 7 cycles. Safety was similar between arms. Olaratumab serum concentrations reached levels expected from prior trials. Additional subgroup/biomarker results will be presented. Conclusions: ANNOUNCE did not confirm that olaratumab + dox, followed by olaratumab monotherapy, improves OS over dox in pts with advanced STS. Further analyses are warranted to explore the inconsistent outcomes between the Ph 3 and Ph 2 studies. Clinical trial information: NCT02451943.

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/m2and 50 mg/m2Dox, cohort 2: Bel 600 mg/m2and 75 mg/m2Dox, cohort 3: Bel 800 mg/m2and 75 mg/m2Dox, and cohort 4: Bel 1000 mg/m2and 75 mg/m2Dox.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.

Anthracycline treatments are hampered by dose-related cardiotoxicity, frequently leading to heart failure (HF) with a very poor prognosis. The authors report a case of a 19-year-old man developing HF after anthracycline treatment for Ewing sarcoma. Despite medical treatment, his condition deteriorated to terminal HF, leading to implantation of a mechanical left ventricular assist device (LVAD). His heart function recovered, allowing explantation of the device 14 months after implantation. Heart transplantation is often contraindicated in the first years after treatment for cancers, and LVAD as "bridge to recovery" may be warranted in similar patients.

Approximately 10% of the pheochromocytomas and 20% of the paragangliomas are malignant with poor survival. As the biological behaviour of these tumours cannot be predicted with certainty from pathology the diagnosis of malignancy is difficult. Genetic testing is gaining impact as mutations in the tumour suppressor gene Von Hippel-Lindau and the mitochondrial succinate dehydrogenase enzyme complex subunit B (SDHB) are associated with malignancy. Excess release of catecholamines is characteristic for pheochromocytomas. High levels of chromogranin A, that is co-stored and co-secreted with catecholamines, may indicate tumour mass and malignancy and can be used to monitor response and relapse. The secretory and non-secretory tumours can be visualised with functional (specific and non-specific) imaging as SPECT and PET using ¹²³I-MIBG, somatostatin analogues, ¹⁸F-DOPA, and ¹⁸F-FDG. These modalities are recommended in patients with extra-adrenal and suspected metastatic/malignant disease, in case of distorted post-operative anatomy, and when suspected recurrence. The sensitivities of ¹²³I-MIBG scintigraphy or ¹⁸F-DOPA PET are relatively low in SDHB mutated tumours, but high using ¹⁸F-FDG. Specific PET imaging with somatostatin analogues generally has high sensitivity in malignant disease. There are no curative therapeutic options for malignant, metastatic pheochromocytomas/paragangliomas, wherefore consolidation of quality of life is essential. Adjuvant radionuclide treatment with beta-emitting isotopes coupled to MIBG or somatostatin analogues have shown response in approximately 30%. Chemotherapy is restricted to patients not accessible for surgery and resistant to radionuclide therapy. Novel targeted therapies, which mainly through a cytostatic effect interfere with specific targeted molecules needed for carcinogenesis and tumour growth show encouraging results.

Antibody-mediated gp120 shedding and HIV neutralization exhibit similar kinetics and thermodynamic requirements., Interference with virus entry is known to be the principle mechanism of HIV neutralization by antibodies, including 2F5 and 4E10, which bind to the membrane-proximal external region (MPER) of the gp41 envelope protein. However, to date, the precise molecular events underlying neutralization by MPER-specific antibodies remain incompletely understood. In this study, we investigated the capacity of these antibodies to irrevocably sterilize HIV virions. Long-term effects of antibodies on virions can differ, rendering neutralization either reversible or irreversible. MPER-specific antibodies irreversibly neutralize virions, and this capacity is associated with induction of gp120 shedding. Both processes have similar thermodynamic properties and slow kinetics requiring several hours. Antibodies directed to the CD4 binding site, V3 loop, and the MPER can induce gp120 shedding, and shedding activity is detected with high frequency in plasma from patients infected with divergent genetic HIV-1 subtypes. Importantly, as we show in this study, induction of gp120 shedding is closely associated with MPER antibody inhibition, constituting either a primary event leading to virion neutralization or representing an immediate consequence thereof, and thus needs to be factored into the mechanistic processes underlying their activity.

5505Background: We conducted a phase III trial to determine whether adjuvant chemotherapy with gemcitabine-docetaxel followed by doxorubicin improves survival compared to observation in women with ...

Background: Adult patients with advanced soft tissue sarcomas (STS) are generally treated similarly, regardless of great differences between STS subtypes, disease presentation and patients' characteristics. As ifosfamide is frequently applied in first line systemic therapy, we aimed to establish prognostic and predictive factors for outcome to ifosfamide-based therapy. Methods: A retrospective, exploratory analysis was performed on data from 1337 advanced STS patients who received first-line ifosfamide-containing chemotherapy. For predictive factor analysis, 660 patients treated with doxorubicin monotherapy served as comparators. Results: Independent favourable prognostic factors for overall survival (OS) were good performance status, female gender, low histological grade, extremity primary tumour site and locally advanced disease; for progression-free survival (PFS), the combination of doxorubicin and ifosfamide, locally advanced disease, and tumour entity with a lower risk to progress for synovial sarcoma patients compared to leiomyosarcoma. For response, independent favourable prognostic factors were doxorubicin combined with ifosfamide, higher histological grade, and histology with synovial sarcoma patients having the highest chance to respond. Predictive factor analysis showed that compared to doxorubicin monotherapy, patients who benefited less from ifosfamide-based therapies were leiomyosarcoma patients in terms of OS, and patients with liposarcoma for response. No predictive factors were found for PFS. Conclusion: In this study, we established an independent set of prognostic and predictive factors for outcome to ifosfamide-based chemotherapy in advanced STS patients. This study provides important information for the interpretation and design of clinical trials for specific STS entities and may contribute to further treatment individualisation of advanced STS patients.

The lectin pathway of complement is activated upon binding of mannan-binding lectin (MBL) or ficolins (FCNs) to their targets. Upon recognition of targets, the MBL-and FCN-associated serine proteases (MASPs) are activated, allowing them to generate the C3 convertase C4b2a. Recent findings indicate that the MASPs also activate components of the coagulation system. We have previously shown that MASP-1 has thrombin-like activity whereby it cleaves and activates fibrinogen and factor XIII. MASP-2 has factor Xa-like activity and activates prothrombin through cleavage to form thrombin. We now report that purified L-FCN-MASPs complexes, bound from serum to N-acetylcysteine-Sepharose, or MBL-MASPs complexes, bound to mannan-agarose, generate clots when incubated with calcified plasma or purified fibrinogen and factor XIII. Plasmin digestion of the clot and analysis using anti-D-dimer antibodies revealed that the clot was made up of fibrin and was similar to that generated by thrombin in normal human plasma. Fibrinopeptides A and B (FPA and FPB, respectively) were released after fibrinogen cleavage by L-FCN-MASPs complexes captured on N-acetylcysteine-Sepharose. Studies of inhibition of fibrinopeptide release indicated that the dominant pathway for clotting catalysed by the MASPs is via MASP-2 and prothrombin activation, as hirudin, a thrombin inhibitor that does not inhibit MASP-1 and MASP-2, substantially inhibits fibrinopeptide release. In the light of their potent chemoattractant effects on neutrophil and fibroblast recruitment, the MASP-mediated release of FPA and FPB may play a role in early immune activation. Additionally, MASP-catalysed deposition and polymerization of fibrin on the surface of micro-organisms may be protective by limiting the dissemination of infection.

Mycobacterium tuberculosis is the leading cause of infectious disease in humans in the world. It evades the host immune system by being phagocytosed by macrophages and residing intracellularly. Complement-dependent opsonisation of extracellular mycobacteria may assist them to enter macrophages. This work examines in detail the mechanisms of complement activation by whole mycobacteria using Mycobacterium bovis BCG as a model organism. M. bovis BCG directly activates the classical, lectin and alternative pathways, resulting in fixation of C3b onto macromolecules of the mycobacterial surface. Investigation into the classical pathway has shown direct binding of human C1q to whole mycobacteria in the absence of antibodies. Most human sera contain IgG and IgM-anti-(M. bovis BCG), and pre-incubation with human immunoglobulin enhances C1q binding to the bacteria. Therefore classical pathway activation is both antibody-independent and dependent. The bacteria also activate the alternative pathway in an antibody-independent manner, but Factor H also binds, suggesting some regulation of amplification by this pathway. For the lectin pathway we have demonstrated direct binding of both MBL and L-ficolin from human serum to whole mycobacteria and subsequent MASP2 activation. H-ficolin binding was not observed. No M. bovis BCG cell surface or secreted protease appears likely to influence complement activation. Together, these data provide a more detailed analysis of the mechanisms by which M. bovis BCG interacts with the complement system.

The complement system is an important recognition and effector mechanism of the innate immune system that upon activation leads to the elimination of foreign bodies. It can be activated through three pathways of which the lectin pathway is one. The lectin pathway relies on the binding of mannan-binding lectin (MBL) or the ficolins and the subsequent activation of the MBL-associated serine proteases (MASPs), namely, MASP1, 2 and 3 which all form complexes with both MBL and the ficolins. Major substrates have only been identified for MASP2 i.e. C4 and C2. For MASP1 only a few protein substrates which are cleaved at a low rate have been identified while none are known for MASP3. Since chromogenic substrate screenings have shown that MASP1 has thrombin-like activity, we wanted to investigate the catalytic potential of MASP1 towards two major proteins involved in the clotting process, fibrinogen and factor XIII, and compare the activity directly with that of thrombin. We found that rMASP1 and thrombin cleave factor XIII A-chain and the fibrinogen beta-chain at identical sites, but differ in cleavage of the fibrinogen alpha-chain. The thrombin turnover rate of factor XIII is approximately 650 times faster than that of rMASP1 at 37 degrees C, pH 7.4. rMASP1 cleavage of fibrinogen leads to the release of the proinflammatory peptide fibrinopeptide B. Thus rMASP1 has similar, but not identical specificity to thrombin and its catalytic activity for factor XIII and fibrinogen cleavage is much lower than that of thrombin. Nevertheless, rMASP1 can drive the formation of cross-linked fibrinogen. Since MASP1 is activated on contact of MBL or the ficolins with microorganisms, fibrinogen and factor XIII may be involved in the elimination of invading pathogens.

The complement system is a protein cascade capable of neutralizing invading pathogens. One of its activation pathways is the lectin pathway which is dependent on the binding of MBL or the ficolins. The specificity of L-ficolin binding has been investigated previously and it was observed that binding is dependent on acetyl groups. If this was the only requirement this would enable L-ficolin to bind to most mammalian glycosylations since they contain acetylated monosaccharides. To investigate this further L-ficolin was subjected to glycan-array analysis in which L-ficolin binding to 279 different glycans was investigated. Few of these bound L-ficolin above background level but clear structural requirements were discovered.

Background and purpose Magnetic resonance (MR) imaging is superior to computed tomography (CT) in radiotherapy of brain tumours. In this study an open low-field MR-simulator is evaluated in order to eliminate the cost of and time spent on additional CT scanning. Materials and methods Eleven patients with brain tumours are both CT and MR scanned and the defined tumour volumes are compared. Image distortions and dose calculations based on CT density correction, MR unit density and MR bulk density, bone segmentation are performed. Monte Carlo simulations using 4 and 8 MV beams on homogeneous and bone segmented mediums are performed. Results Mean MR and CT tumour volumes of approximately the same size ( V MR ¯ = 55 ± 34 cm 3 and V CT ¯ = 51 ± 32 cm 3 ) are observed, but for individual patients, small intersection volumes are observed. The MR images show negligible distortion within radial distances below 12 cm ( 2%) just behind the skull if bone is not segmented. Conclusions It is feasible to use an MR-simulator for radiotherapy planning of brain tumours if bone is segmented or a careful choice of beam energy (>4 MV) is selected.

The diagnosis of gastrointestinal stromal tumor (GIST) relies on a combination of the following criteria: anatomic location, typical histopathology, and the presence of CD 117-antigen (the tyrosine kinase receptor, c-kit) or CD 34-antigen. Imatinib mesylate, a specific tyrosine kinase inhibitor, is highly efficient against locally advanced or metastatic GIST. We report a case of unresectable duodenal GIST, which we were able to resect with curative intent after down-staging treatment with a dosage of imatinib 400 mg daily for 8 months. We performed Whipple's procedure combined with en bloc resection of the right kidney and adrenal gland. The patient was recurrence free at his 24-month follow-up examination. Down-staging treatment may be worthwhile in selected patients, but further prospective studies of imatinib in this setting are necessary. We think that imatinib should be continued postoperatively, as the risk of recurrence in these patients may be high.

Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations. Recently, a promising vaccine antigen based on the RSV fusion protein (RSV F) stabilized in the native prefusion conformation has been described. Here we report alternative strategies to arrest RSV F in the prefusion conformation based on the prevention of hinge movements in the first refolding region and the elimination of proteolytic exposure of the fusion peptide. A limited number of unique mutations are identified that stabilize the prefusion conformation of RSV F and dramatically increase expression levels. This highly stable prefusion RSV F elicits neutralizing antibodies in cotton rats and induces complete protection against viral challenge. Moreover, the structural and biochemical analysis of the prefusion variants suggests a function for p27, the excised segment that precedes the fusion peptide in the polypeptide chain., Respiratory syncytial virus (RSV) is a highly contagious childhood pathogen of the respiratory tract for which no vaccine is currently available. Here the authors present a strategy to stabilize the RSV F protein in a prefusion conformation that can elicit a strong protective immune response in animal models.

The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of time-to-event end points in cancer randomized controlled trials. We relied on a consensus method based on a multidisciplinary panel of experts to develop these guidelines for trials on sarcomas and gastrointestinal stromal tumors. Background The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). Methods We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. Results Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. Conclusion Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.

Background. Trabectedin was in Europe approved for treatment of metastatic soft tissue sarcoma (STS) in 2007 based on results of a phase II study with relatively few patients. The purpose of this nationwide retrospective study was to assess efficacy and safety of using trabectedin in the entire unselected cohort of patients with metastatic sarcoma and to test known, as well as new prognostic factors that may affect overall survival (OS). Patients and methods. Between January 2008 and April 2013, 117 patients were treated with trabectedin for metastatic sarcoma in the three specialized sarcoma centers in Denmark. Known prognostic factors such as age, gender and performance status, the histopathology as well as other new factors such as response to previous chemotherapy and hyponatremia were tested. Results. Median age was 59 years. Lipo- and leiomysosarcomas (L-sarcomas) represented 43% of the cases and 18% had hyponatremia before the start of trabectedin. The median number of previous lines of chemotherapy was two (range 0-6) and the median number of chemotherapy cycles given before trabectedin was nine (range 0-85). The median number of trabectedin cycles was three (range 1-17). The median OS for the whole cohort was seven months. Poor performance status, non-L-sarcomas, and hyponatremia were statistically significant adverse prognostic factors with median survival of: 4, 5, and 2 months compared to 9, 12 and 13 months, respectively. Moreover, having achieved clinical benefit [complete response (CR), partial response (PR) or stable disease (SD)] from previous chemotherapy was a favorable prognostic factor for response to trabectedin. In multivariate analysis hyponatremia was the only independent significant poor prognostic factor affecting OS. Conclusions. This retrospective study confirmed the previously published safety and efficacy of trabectedin in patients with metastatic sarcoma and showed hyponatremia to be a strong independent statistically significant poor prognostic factor.