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BACKGROUND: The risk of recurrence of gastrointestinal stromal tumour (GIST) after surgery needs to be estimated when considering adjuvant systemic therapy. We assessed prognostic factors of patients with operable GIST, to compare widely used risk-stratification schemes and to develop a new method for risk estimation. METHODS: Population-based cohorts of patients diagnosed with operable GIST, who were not given adjuvant therapy, were identified from the literature. Data from ten series and 2560 patients were pooled. Risk of tumour recurrence was stratified using the National Institute of Health (NIH) consensus criteria, the modified consensus criteria, and the Armed Forces Institute of Pathology (AFIP) criteria. Prognostic factors were examined using proportional hazards and non-linear models. The results were validated in an independent centre-based cohort consisting of 920 patients with GIST. FINDINGS: Estimated 15-year recurrence-free survival (RFS) after surgery was 59·9% (95% CI 56·2-63·6); few recurrences occurred after the first 10 years of follow-up. Large tumour size, high mitosis count, non-gastric location, presence of rupture, and male sex were independent adverse prognostic factors. In receiver operating characteristics curve analysis of 10-year RFS, the NIH consensus criteria, modified consensus criteria, and AFIP criteria resulted in an area under the curve (AUC) of 0·79 (95% CI 0·76-0·81), 0·78 (0·75-0·80), and 0·82 (0·80-0·85), respectively. The modified consensus criteria identified a single high-risk group. Since tumour size and mitosis count had a non-linear association with the risk of GIST recurrence, novel prognostic contour maps were generated using non-linear modelling of tumour size and mitosis count, and taking into account tumour site and rupture. The non-linear model accurately predicted the risk of recurrence (AUC 0·88, 0·86-0·90). INTERPRETATION: The risk-stratification schemes assessed identify patients who are likely to be cured by surgery alone. Although the modified NIH classification is the best criteria to identify a single high-risk group for consideration of adjuvant therapy, the prognostic contour maps resulting from non-linear modelling are appropriate for estimation of individualised outcomes. FUNDING: Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation and Helsinki University Research Funds. [ABSTRACT FROM AUTHOR]

Background FOLFIRINOX-regime is a combination-chemotherapy that provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients, but is associated with severe toxicity. Aim of this study is to explore the role of miRNAs as modulators of chemosensitivity and their potential as biomarkers of sensitivity to FOLFIRINOX-therapy. Methods HTS of 997 LNA-MIR-inhibitors was performed in PDAC cell lines treated with a combination of Fluorouracil (F), Oxaliplatin (O) and Irinotecan (I) that mimics FOLFIRINOX-regime. Validation experiments were performed with miRvana probes. Apoptosis was measured by flow-cytometry and western-blotting. Knock-out of microRNA was achieved by CRISPR-CAS9 in MiaPaca2 cells. HITS-CLIP assay was used to identify MIR1307 target site. Drug sensitivity was tested in xenograft models. Plasma MIR1307 was assessed by ddPCR. Results 41 and 84 miRNA-inhibitors enhanced FOI activity by > 30% (p < 0.001) in Capan1 and MiaPaCa2. These included MIR1307-inhibitor that was validated in 6 PDAC cell lines. The effect of FOI in comparison to DMSO was greater in cells transfected with MIR1307 inhibitor vs control, making the effect of this MIR specific for chemotherapy. MIR1307 was over-expressed in tumours of 40/60 human PC cases, confirming clinical relevance. DNA damage markers were upregulated (pH2AX2, 8OHdG, DNA breaks) in KO cells treated with FOI and therapy-induced apoptosis was higher in KO cells. Re-expression of MIR1307 in KO cells increased resistance to FOI chemotherapy and protected from FOI-induced DNA damage. HITS-CLIP assay identified binding of MIR1307 to CLIC5, whose expression was increased in KO cells and reduced by rescued expression of MIR1307. Both WT and KO xenografts responded to FOI chemotherapy but response was transient in WT mice, while we noticed a prolonged response in KO tumours. Baseline plasma level of MIR1307 correlated with overall survival in patients receiving FOLFIRINOX chemotherapy. Conclusions We identified MIR1307 as a potential modulator of sensitivity to FOI-chemotherapy in PC. MIR1307 inhibition impairs the ability of the cells to recover from chemotherapy damage and therefore enhances its activity. Legal entity responsible for the study The authors. Funding Pancreatic Cancer UK Research Innovation Fund, Cancer Research UK. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]