Hepatology : official journal of the American Association for the Study of Liver Diseases
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Interleukin-33 (IL-33), a cytokine with pleiotropic functions, is elevated in serum of patients with hepatocellular carcinoma (HCC). This study investigated the effects of local IL-33 expression in resected HCC on patient survival and on the immunological and molecular tumor microenvironment. Tissue of resected HCCs was stained for hematoxylin and eosin, Masson trichrome, alpha-smooth muscle actin, IL-33, CD8, and IL-13 and analyzed by flow cytometry. Besides histomorphologic evaluation, the immunohistochemical stainings were analyzed for the respective cell numbers separately for tumor area, infiltrative margin, and distant liver stroma. These findings were correlated with clinical data and patient outcome. Further, gene expression of different HCC risk groups was compared using microarrays. In multivariable analysis, infiltration of HCCs by IL-33(+) cells (P = 0.032) and CD8(+) cells (P = 0.014) independently was associated with prolonged patient survival. Flow cytometry demonstrated that cytotoxically active subpopulations of CD8(+) cells, in particular CD8(+) CD62L(-) KLRG1(+) CD107a(+) effector-memory cells, are the main producers of IL-33 in these HCC patients. Using infiltration by IL-33(+) and CD8(+) cells as two separate factors, an HCC immune score was designed and evaluated that stratified patient survival (P = 0.0004). This HCC immune score identified high- and low-risk patients who differ in gene expression profiles (P < 0.001). ⋯ Infiltration of HCCs by IL-33(+) and CD8(+) cells is independently associated with prolonged patient survival. We suggest that this is due to an induction of highly effective, cytotoxically active CD8(+) CD62L(-) KLRG1(+) CD107a(+) effector-memory cells producing IL-33. Based on these two independent factors, we established an HCC immune score that provides risk stratification for HCC patients and can be used in the clinical setting.
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Patients who fail to achieve sustained virological response (SVR) after treatment with sofosbuvir (SOF) plus ribavirin (RBV) with or without pegylated interferon (Peg-IFN) do not have established retreatment options. We conducted an open-label trial to assess the efficacy and safety of ledipasvir (LDV)-SOF plus RBV in patients with genotype 1 hepatitis C virus (HCV) who did not achieve SVR after treatment in phase II and III trials of SOF regimens. We enrolled 51 patients at 24 sites in the United States. All patients received the fixed-dose combination tablet of LDV-SOF once-daily plus weight-based RBV (1,000 or 1,200 mg/day) for 12 weeks. The efficacy endpoint was the proportion of patients with SVR 12 weeks after discontinuation of therapy (SVR12). Of the 51 patients enrolled, 25 (49%) had previously received SOF plus Peg-IFN-RBV, 20 (39%) had received SOF-RBV, 5 (10%) had received SOF placebo plus Peg-IFN-RBV, and 1 (2%) received GS-0938 monotherapy. Fourteen (27%) had compensated cirrhosis at baseline, and 47 (92%) had non-CC interleukin-28B genotypes. SVR12 was achieved by 50 of the 51 patients (98%) treated. Among the 45 patients who received SOF in earlier treatment, 44 (98%) achieved SVR12. The only patient who did not achieve SVR12 was a patient with genotype 3a HCV who had been incorrectly genotyped as 1a in the previous study. Given the high rates of SVR12, no differences among patient subgroups were discernible. Of 51 patients, 41 (80%) experienced at least one adverse event (AE), but most events were mild to moderate in severity. The most common AEs were fatigue, headache, and diarrhea. One patient discontinued treatment because of an unrelated AE (bipolar disorder). ⋯ Twelve weeks of LDV-SOF plus RBV was an effective and safe treatment for patients who have not achieved SVR with earlier regimens that included SOF.