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Background Patients with resected colorectal liver metastasis (CRLM) who display only the desmoplastic histopathological growth pattern (dHGP) exhibit superior survival compared to patients with any non-desmoplastic growth (non-dHGP). The aim of this study was to compare the tumour microenvironment between dHGP and non-dHGP. Methods The tumour microenvironment was investigated in three cohorts of chemo-naive patients surgically treated for CRLM. In cohort A semi-quantitative immunohistochemistry was performed, in cohort B intratumoural and peritumoural T cells were counted using immunohistochemistry and digital image analysis, and in cohort C the relative proportions of individual T cell subsets were determined by flow cytometry. Results One hundred and seventeen, 34, and 79 patients were included in cohorts A, B, and C, with dHGP being observed in 27%, 29%, and 15% of patients, respectively. Cohorts A and B independently demonstrated peritumoural and intratumoural enrichment of cytotoxic CD8+ T cells in dHGP, as well as a higher CD8+/CD4+ ratio (cohort A). Flow cytometric analysis of fresh tumour tissues in cohort C confirmed these results; dHGP was associated with higher CD8+ and lower CD4+ T cell subsets, resulting in a higher CD8+/CD4+ ratio. Conclusion The tumour microenvironment of patients with dHGP is characterised by an increased and distinctly cytotoxic immune infiltrate, providing a potential explanation for their superior survival.

Background: The aim of this study was to identify more accurate variables to improve prognostication of individual patients with colorectal liver metastases (CRLM). Clinicopathological characteristics only partly explain the large range in survival rates. Methods: MessengerRNA expression profiles of resected CRLM of two patient groups were analysed by mRNA sequencing: poor survivors (death from recurrent disease 60 months after surgery). Tumour and adjacent liver parenchyma samples were analysed. Results: MessengerRNA expression profiling of the tumour samples identified 77 genes that were differentially expressed between the two survival groups at a False Discovery Rate (FDR)

While intratumour genetic heterogeneity of primary clear cell renal cell carcinoma (ccRCC) is well characterized, the genomic profiles of metastatic ccRCCs are seldom studied. We profiled the genomes and transcriptomes of a primary tumour and matched metastases to better understand the evolutionary processes that lead to metastasis. In one ccRCC patient, four regions of the primary tumour, one region of the thrombus in the inferior vena cava, and four lung metastases (including one taken after pegylated (PEG)-interferon therapy) were analysed separately. Each sample was analysed for copy number alterations and somatic mutations by whole exome sequencing. We also evaluated gene expression profiles for this patient and 15 primary tumour and 15 metastasis samples from four additional patients. Copy number profiles of the index patient showed two distinct subgroups: one consisted of three primary tumours with relatively minor copy number changes, the other of a primary tumour, the thrombus, and the lung metastases, all with a similar copy number pattern and tetraploid-like characteristics. Somatic mutation profiles indicated parallel clonal evolution with similar numbers of private mutations in each primary tumour and metastatic sample. Expression profiling of the five patients revealed significantly changed expression levels of 57 genes between primary tumours and metastases, with enrichment in the extracellular matrix cluster. The copy number profiles suggest a punctuated evolution from a subregion of the primary tumour. This process, which differentiated the metastases from the primary tumours, most likely occurred rapidly, possibly even before metastasis formation. The evolutionary patterns we deduced from the genomic alterations were also reflected in the gene expression profiles.

Background: The current prognostication of patient survival after surgery for colorectal liver metastases is based on clinical characteristics, but low accuracy makes it difficult to guide treatment for the individual patient. Rapidly evolving technologies have led to the expectation that biomarkers will be able to outperform the current clinical scoring systems and provide more effective personalised treatment. Two main topics prevail in cancer treatment, namely the role of the immune system and the prediction and prognostication by application of high-throughput methodology. The aim of this review is to examine the evidence for prognostic immunological and molecular markers studied in tumour tissue obtained at surgical resection for colorectal liver metastases. Methods: First we analysed immunophenotypical protein markers, that are mainly studied by immunohistochemistry. Second, we review molecular markers by analysing high-throughput studies on tumour mRNA and microRNA expression. Results: CD3, CD4, and CD8 are the most frequently studied protein markers. High intra-tumoural CD3+ T cell infiltration and low CXCR4 expression have the best association with favourable patient survival. Studies that analysed microRNA or mRNA expression data showed very little overlap in prognostic genes. Conclusions: Patient prognostication after surgery for colorectal liver metastases by analysing the immune system remains difficult. Current data are based on diverse and heterogeneous patient populations which prohibits drawing firm conclusions.

Background Repeat liver resection for colorectal liver metastases (CRLMs) is possible in a limited number of patients, with radiofrequency ablation (RFA) as an alternative for unresectable CRLMs. The aim of this study was to analyse survival rates with these interventions. Methods This was a database analysis of patients who underwent first and repeat interventions for synchronous and metachronous CRLMs between 2000 and 2013. Descriptive and survival statistics were calculated. Results Among 431 patients who underwent resection or RFA for CRLMs, 305 patients developed recurrences for which 160 repeat interventions (resection and/or RFA or ablative radiotherapy) were performed. In total, after 707 first or repeat interventions, 516 recurrences (73·0 per cent) developed, of which 276 were retreated curatively. At the time of first intervention, independent risk factors for death were lymph node-positive primary tumour (hazard ratio (HR) 1·40; P = 0·030), more than one CRLM (HR 1·53; P = 0·007), carcinoembryonic antigen level exceeding 200 ng/ml (HR 1·89; P = 0·020) and size of largest CRLM greater than 5 cm (HR 1·54; P = 0·014). The 5-year overall survival rates for liver resection and percutaneous RFA as first intervention were 51·9 and 53 per cent, with a median overall survival of 65·0 (95 per cent c.i. 47·3 to 82·6) and 62·1 (52·2 to 72·1) months, respectively. Conclusion RFA had good oncological outcomes in patients with unresectable CRLMs. Radiofrequency ablation is progressively more applied with each additional intervention.

BACKGROUND: In patients with resectable synchronous colorectal liver metastases (CRLM), either two-staged or simultaneous resections of the primary tumor and liver metastases are performed. Data on radiofrequency ablation (RFA) for the treatment of CRLM during a simultaneous procedure is lacking. The primary aim was to analyze short-term and long-term outcome of RFA in simultaneous treatment. A secondary aim was to compare simultaneous resection with the colorectal-first approach.METHODS: Retrospective analysis of 241 patients with colorectal cancer and synchronous CRLM between 2000-2016. Median follow-up was 36.1 months (IQR 18.2-58.8 months). A multivariable analysis was performed to analyze the postoperative morbidity, using the comprehensive complication index. A propensity matched analysis was performed to compare survival rates.RESULTS: In multivariable analysis, the best predictor of lower complication severity was treatment with RFA (p = 0.040). Higher complication rates were encountered in patients who underwent an abdominoperineal resection (p = 0.027) or age > 60 years (p = 0.022). The matched analysis showed comparable overall survival in RFA treated patients versus patients undergoing a liver resection with a five year overall survival of 39.4% and 37.5%, respectively (p = 0.782). In a second matched analysis, 5-year overall survival rates in simultaneously treated patients (43.8%) was comparable to patients undergoing the colorectal first approach (43.0%, p = 0.223).CONCLUSIONS: RFA treatment of CRLM in simultaneous procedures is associated with a lower complication severity and non-inferior oncological outcome as compared to partial liver resection. RFA should be considered a useful alternative to liver resection.