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PURPOSE: To assess immunogenic effects in unembolized contralateral tumor after single lobar Y90-radioembolization (SIRT) of colorectal liver metastases(CRLM). MATERIAL AND METHODS: The analysis comprised 10 patients with microsatellite stable (MSS) CRLM scheduled for staged treatment in the prospective BLINDED trial. Eligibility criteria included bilobar metastatic disease with >5 lesions without any treatment within 3 weeks. Baseline biopsy was followed by initial SIRT treatment of one liver lobe, followed by a second biopsy of yet untreated tumors in the other liver lobe at a median of 13 (4-49) days immediately prior to second treatment. Tumor biopsies and peripheral blood mononuclear cells (PBMC) were collected before treatments for immune cell analysis. Patients were stratified into "responders" and "non-responders" based on tumor control or progression during follow up. RESULTS: At baseline, responders (n=4) displayed lower concentrations of FoxP3+ cells and co-location of CD4+FoxP3+ cells than non-responders (both p=0.02) in tumor tissues. At second biopsy, non-responders showed a higher CD68+ macrophage density (p=0.0014) than responders. Responders displayed fewer CD4+FoxP3+ T cells than CD8+ T cells at all timepoints (p=0.02 and p=0.0428). Non-responders demonstrated a trending increase of CD68+ macrophages (p=0.062), as well as a higher CD8+PD1+/CD8+ ratio (p=0.062). PBMC of non-responders displayed lower CD8+PD1+ T cells and CD8+PD1+/CD8+ ratio at both timepoints. CONCLUSION: SIRT induces local immunogenic effects in non-exposed MCC CRLM, as well as systemic exhaustion of immune cells in non-responders. Clinical implications such as a prognostic role or synergism of SIRT and checkpoint inhibition in MSS CRLM warrant further investigation.
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BACKGROUND: Molecular changes in HCC development are largely unknown. As the liver plays a fundamental role in the body's metabolism, metabolic changes are to be expected. AIMS: We aimed to identify metabolomic changes in HCC in comparison to liver cirrhosis (LC) patients, which could potentially serve as novel biomarkers for HCC diagnosis and prognosis. METHODS: Metabolite expression from 38 HCC from the SORAMIC trial and 32 LC patients were analyzed by mass spectrometry. Metabolites with significant differences between LC and HCC at baseline were analyzed regarding expression over follow-up. In addition, association with overall survival was tested using univariate Cox proportional-hazard analysis. RESULTS: 41 metabolites showed differential expression between LC and HCC patients. 14 metabolites demonstrated significant changes in HCC patients during follow-up. Campesterol, lysophosphatidylcholine, octadecenoic and octadecadienoic acid, and furoylglycine showed a differential expression in the local ablation vs. palliative care group. High expression of eight metabolites (octadecenoic acid, 2-hydroxybutyrate, myo-inositol, isocitrate, erythronic acid, creatinine, pseudouridine, and erythrol) were associated with poor overall survival. The association between poor OS and octadecenoic acid and creatinine remained statistically significant even after adjusting for tumor burden and LC severity. CONCLUSION: Our findings give promising insides into the metabolic changes during HCC carcinogenesis and provide candidate biomarkers for future studies. Campesterol and furoylglycine in particular were identified as possible biomarkers for HCC progression. Moreover, eight metabolites were detected as predictors for poor overall survival.