Hepatitis B virus (HBV) causes self-limited infections in the majority of adult patients; however, in less than 5% of infected adults and in a larger proportion of children, HBV infection evolves into a chronic liver disease, which may lead to severe sequelae. Available data indicate a vigorous and broad T-cell response in patients with acute self-limited hepatitis B, which is in contrast with the much weaker and often barely detectable T-cell response observed during chronic HBV infections, in which HBV-specific T-lymphocytes have been described to be deeply dysfunctional.¹ x 1 Bertoletti, A. and Ferrari, C. Kinetics of the immune response during HBV and HCV infection. Hepatology. 2003; 38: 4–13 Google Scholar See all References ^{, 2} x 2 Rehermann, B. and Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005; 5: 215–229 Google Scholar See all References ^{, 3} x 3 Das, A., Hoare, M., Davies, N. et al. Functional skewing of the global CD8 T-cell population in chronic hepatitis B virus infection. J Exp Med. 2008; 205: 2111–2124 Google Scholar See all References Among the different mechanisms proposed to explain such a functional T-cell impairment, exhaustion by persistent exposure to high antigen concentrations represents a possible cause,⁴ x 4 Chang, J.J., Thompson, A.J.V., Visvanathan, K. et al. The phenotype of hepatitis B virus-specific T cells differs in the liver and blood in chronic hepatitis B virus infection. Hepatology. 2007; 46: 1332–1340 Google Scholar See all References ^{, 5} x 5 Zhang, Z., Zhang, J.-Y., Wherry, E.J. et al. Dynamic programmed death 1 expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B. Gastroenterology. 2008; 134: 1938–1949 Abstract | Full Text | Full Text PDF | Scopus (94) | Google Scholar See all References ^{, 6} x 6 Boni, C., Fisicaro, P., Valdatta, C. et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol. 2007; 81: 4215–4225 Google Scholar See all References and T-cell attrition through Bcl2 signalling⁷ x 7 Lopes, A.R., Kellam, P., Das, A. et al. Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection. J Clin Invest. 2008; 118: 1835–1845 Google Scholar See all References as well as impaired T-cell receptor signaling through the ζ-chain³ x 3 Das, A., Hoare, M., Davies, N. et al. Functional skewing of the global CD8 T-cell population in chronic hepatitis B virus infection. J Exp Med. 2008; 205: 2111–2124 Google Scholar See all References have been shown to be involved.

Fourteen heart transplant recipients were monitored for human cytomegalovirus (HCMV) infection based on determination of antigenemia, viremia, and DNAemia (by polymerase chain reaction [PCR]) in peripheral blood polymorphonuclear leukocytes (PMNL). Three patients had symptomatic primary, 10 had recurrent (3 asymptomatic), and 1 (seronegative) had no HCMV infection. Severe clinical symptoms appeared when levels of viremia/antigenemia were >50 infected PMNL/2 × 10⁵ cells examined. Of200 blood samples examined, 93 (46.5%) were positive for viremia/antigenemia and DNAemia, whereas 48 (24.0%) were positive for DNAemia only; 59 (29.5%) were negative in all assays. Follow-up ofHCMV infections in heart transplant recipients showed that PCR can detect viral appearance in blood 7–10 days earlier than assays for antigenemia/ viremia. On the other hand, viral disappearance from blood, as assessed by PCR, occurred weeks or months later than revealed by other assays. Detection of virus by PCR only was never associated with overt HCMV-related clinical symptoms. Of the 8 symptomatic patients treated with ganciclovir, 2 became PCR-negative at the end of treatment and 1 cleared virus from blood in the following weeks, whereas 5 showed persistent or recurrent infection.

Purpose: The success of immune checkpoint inhibitors strengthens the notion that tumor growth and regression are immune regulated. To determine whether distinct tissue immune microenvironments differentially affect clinical outcome in non–small cell lung cancer (NSCLC), an extended analysis of PD-L1 and tumor-infiltrating lymphocytes (TIL) was performed. Experimental Design: Samples from resected adenocarcinoma (ADC 42), squamous cell carcinoma (SCC 58), and 26 advanced diseases (13 ADC and 13 SCC) treated with nivolumab were analyzed. PD-L1 expression and the incidence of CD3, CD8, CD4, PD-1, CD57, FOXP3, CD25, and Granzyme B TILs were immunohistochemically assessed. Results: PD-L1 levels inversely correlated with N involvement, although they did not show a statistically significant prognostic value in resected patients. The incidence and phenotype of TILs differed in SCC versus ADC, in which EGFR and KRAS mutations conditioned a different frequency and tissue localization of lymphocytes. NSCLC resected patients with high CD8^pos lymphocytes lacking PD-1 inhibitory receptor had a longer overall survival (OS: HR = 2.268; 95% CI, 1.056–4.871, P = 0.03). PD-1-to-CD8 ratio resulted in a prognostic factor both on univariate (HR = 1.952; 95% CI, 1.34–3.12, P = 0.001) and multivariate (HR = 1.943; 95% CI, 1.38–2.86, P = 0.009) analysis. Moreover, low PD-1 incidence among CD8^pos cells was a distinctive feature of nivolumab-treated patients, showing clinical benefit with a prolonged progression-free survival (PFS: HR = 4.51; 95% CI, 1.45–13.94, P = 0.004). Conclusions: In the presence of intrinsic variability in PD-L1 expression, the reservoir of PD-1–negative effector T lymphocytes provides an immune-privileged microenvironment with a positive impact on survival of patients with resected disease and response to immunotherapy in advanced NSCLC. Clin Cancer Res; 1–13. ©2017 AACR.

Hepatocellular carcinoma (HCC) is the most frequent cause of death in patients with hepatitis C virus (HCV)–induced cirrhosis. Despite a number of studies in different populations worldwide suggesting an association between HCV genotype 1 and the risk of HCC, no consensus has emerged yet on this matter, which is still controversial. In an attempt to clarify this issue, a prospective study of 163 consecutive HCV-positive patients with cirrhosis, who were enrolled between January 1989 and December 1990, was carried out. HCC occurrence was detected by ultrasound surveillance every 6 months. Independent predictors of HCC were assessed with a Cox regression analysis. After a median follow-up of 10.7 years, 44 [4.26/100/year, confidence interval (CI) = 3.11–5.68/100/year] of 104 patients infected with genotype 1b developed HCC versus 10 (1.69/100/year, CI = 0.82–3.09/100/year) of 52 patients infected with genotype 2a/c ( P = 0.0001). Multivariate analysis showed that HCV genotype 1b was independently associated with HCC development [hazard ratio (HR) = 3.02, 95% CI = 1.40–6.53]. Other predictors of HCC were esophageal varices (HR = 2.15, 95% CI = 1.03–4.47), male gender (HR = 2.12, 95% CI = 1.10–4.11), and age over 60 years (HR = 5.96, 95% CI = 1.23–28.8). Conclusion: HCV genotype 1b is associated with a statistically significant higher risk of developing HCC. Patients with cirrhosis that are infected with this genotype require more intensive surveillance for the early detection and aggressive management of neoplasia.

In most patients with cirrhosis, successful percutaneous ablation or surgical resection of hepatocellular carcinoma (HCC) is followed by recurrence. Radiofrequency ablation (RFA) has proven effective for treating HCC nodules, but its repeatability in managing recurrences and the impact of this approach on survival has not been evaluated. To this end, we retrospectively analyzed a prospective series of 706 patients with cirrhosis (Child-Pugh class ≤B7) who underwent RFA for 859 HCC ≤35 mm in diameter (1-2 per patient). The results of RFA were classified as complete responses (CRs) or treatment failures. CRs were obtained in 849 nodules (98.8%) and 696 patients (98.5%). During follow-up (median, 29 months), 465 (66.8%) of the 696 patients with CRs experienced a first recurrence at an incidence rate of 41 per 100 person-years (local recurrence 6.2; nonlocal 35). Cumulative incidences of first recurrence at 3 and 5 years were 70.8% and 81.7%, respectively. RFA was repeated in 323 (69.4%) of the 465 patients with first recurrence, restoring disease-free status in 318 (98.4%) cases. Subsequently, RFA was repeated in 147 (65.9%) of the 223 patients who developed a second recurrence after CR of the first, restoring disease-free status in 145 (98.6%) cases. Overall, there were 877 episodes of recurrence (1-8 per patient); 577 (65.8%) of these underwent RFA that achieved CRs in 557 (96.5%) cases. No procedure-related deaths occurred in 1,921 RFA sessions. Estimated 3- and 5-year overall and disease-free (after repeated RFAs) survival rates were 67.0% and 40.1% and 68.0 and 38.0%, respectively. Conclusion: RFA is safe and effective for managing HCC in patients with cirrhosis, and its high repeatability makes it particularly valuable for controlling intrahepatic recurrences. (Hepatology 2011)