Impact of Nutritional Status on Neutrophil-to-Lymphocyte Ratio as a Predictor of Efficacy and Adverse Events of Immune Check-Point Inhibitors

The neutrophil -to-lymphocyte ratio (NLR) is useful for predicting the effectiveness of treatment with immune checkpoint inhibitors (ICIs) and immune-related adverse events (irAEs). Because a growing body of evidence has recently shown that the number of lymphocytes that comprise NLR fluctuates according to nutritional status, this study examined whether the usefulness of NLR varies in ICI treatment due to changes in nutritional status. A retrospective analysis was performed on 1234 patients who received ICI treatment for malignant tumors at our hospital. Progression-free survival (PFS) was significantly prolonged in patients with NLR < 4. Multivariate analysis revealed that the factors associated with the occurrence of irAE were NLR < 4 and the use of ipilimumab. However, when limited to cases with serum albumin levels <3.8 g/dL, lymphocyte counts significantly decreased, and the associations between NLR and PFS and between NLR and irAE occurrence disappeared. In contrast, when limited to the cases with serum albumin levels ≥3.8 g/dL, the associations remained, with significantly prolonged PFS and significantly increased irAE occurrence at NLR < 4. NLR may be a good predictive tool for PFS and irAE occurrence during ICI treatment when a good nutritional status is maintained

Oxidative Stress Management in Chronic Liver Diseases and Hepatocellular Carcinoma

Chronic viral hepatitis B and C and non-alcoholic fatty liver disease (NAFLD) have been widely acknowledged to be the leading causes of liver cirrhosis and hepatocellular carcinoma. As anti-viral treatment progresses, the impact of NAFLD is increasing. NAFLD can coexist with chronic viral hepatitis and exacerbate its progression. Oxidative stress has been recognized as a chronic liver disease progression-related and cancer-initiating stress response. However, there are still many unresolved issues concerning oxidative stress, such as the correlation between the natural history of the disease and promising treatment protocols. Recent findings indicate that oxidative stress is also an anti-cancer response that is necessary to kill cancer cells. Oxidative stress might therefore be a cancer-initiating response that should be down regulated in the pre-cancerous stage in patients with risk factors for cancer, while it is an anti-cancer cell response that should not be down regulated in the post-cancerous stage, especially in patients using anti-cancer agents. Antioxidant nutrients should be administered carefully according to the patients' disease status. In this review, we will highlight these paradoxical effects of oxidative stress in chronic liver diseases, pre- and post-carcinogenesis

Effects of pulsing procedure of interleukin-12 in combination with interleukin-2 on the activation of peripheral blood lymphocytes derived from patients with hepatocellular carcinoma.

In patients with hepatocellular carcinoma (HCC), natural killer (NK) cell activity decreases significantly, and the reduced activity may be associated with the progression of HCC. In this study we evaluated the effects of pulsing with interleukin (IL)-2 and/or IL-12 on the activation of freshly isolated peripheral blood lymphocytes (PBL) derived from patients with HCC. PBL obtained from 9 HCC patients, 4 liver cirrhosis patients, and 9 normal subjects were cultured in the presence of IL-2 and/or IL-12. After 24 h of incubation, the levels of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha presented in the supernatants were determined by enzyme-linked immunosorbent assay (ELISA). The IFN-gamma and TNF-alpha production of PBL pulsed by a combination of IL-2 and IL-12 was significantly higher than those of PBL stimulated by either IL-2 or IL-12 alone. The mRNA encoding perforin, granzyme B, as well as IFN-gamma and TNF-alpha, were markedly enhanced in PBL stimulated with a combination of IL-12 and IL-2. The pulsing procedure of IL-12 in combination with IL-2 resulted in the increase of IFN-gamma and TNF-alpha, and the expression of perforin and granzyme B mRNA in PBL obtained from HCC patients, as well as in those obtained from normal subjects. These results indicate that adoptive immunotherapy based on PBL pulsed with a combination of IL-2 and IL-12 may be a promising adjunctive strategy for HCC treatment.</p

Management of Cirrhotic Ascites under the Add-on Administration of Tolvaptan

Tolvaptan is a recently available diuretic that blocks arginine vasopressin receptor 2 in the renal collecting duct. Its diuretic mechanism involves selective water reabsorption by affecting the water reabsorption receptor aquaporin 2. Given that liver cirrhosis patients exhibit hyponatremia due to their pseudo-aldosteronism and usage of natriuretic agents, a sodium maintaining agent, such as tolvaptan, is physiologically preferable. However, large scale studies indicating the patients for whom this would be effective and describing management under its use have been insufficient. The appropriate management of cirrhosis patients treated with tolvaptan should be investigated. In the present review, we collected articles investigating the effectiveness of tolvaptan and factors associated with survival and summarized their management reports. Earlier administration of tolvaptan before increasing the doses of natriuretic agents is recommended because this may preserve effective arterial blood volume

Autoimmune responses as assessed by hypergammaglobulinemia and the presence of autoantibodies in patients with chronic hepatitis C.

We investigated autoimmunity, as assessed by hypergammaglobulinemia and the presence of autoantibodies including anti-nuclear antibodies (ANA) and anti-liver membrane antibodies (LMA), in 149 patients with chronic hepatitis C, 55 patients with chronic hepatitis B and 11 patients with autoimmune hepatitis. There was no significant difference in the incidence of these autoantibodies between chronic hepatitis C and chronic hepatitis B. Nine patients with chronic hepatitis C satisfied the serological criteria of autoimmune hepatitis (ANA positive and gammaglobulin or serum IgG greater than 2500 mg/dl), but none of the patients with chronic hepatitis B met the criteria. This suggests that autoimmunity is greater in chronic hepatitis C than in chronic hepatitis B. Of the 9 patients with chronic hepatitis C, all 4 patients tested for human leukocyte antigen (HLA) phenotype had HLA-DR4, which is known to be associated with autoimmune hepatitis in Japanese patients. We believe that hepatitis C virus (HCV) infection enhances the initiation and perpetuation of autoimmunity in susceptible individuals

Specificities and Clinical Significance of Anti-Cytoskeleton Antibodies in Anti-Smooth Muscle Antibody-Positive Patients with Chronic Liver Disease C

We investigated the specificities and characteristics of anti-cytoskeleton antibodies in 13 anti-smooth muscle antibody (ASMA)-positive patients with chronic liver disease C (CLD-C), and compared them with those in 7 ASMA-positive patients with autoimmune hepatitis (AIH), and 6 ASMA-positive patients with chronic liver disease B (CLD-B). Anti-microfilaments (anti-MF) were found not only in 6/7 AIH patients (85.7%), but also in 8/13 CLD-C patients (61.5%) with a relatively high incidence, when compared with 1/6 CLD-B patients (16.7%), while, there was no significant difference in the incidence of anti-intermediate filaments (anti-IMF), especially anti-IMF IgM, among these patient groups. Among the patients with CLD-C, the mean levels of serum gammaglobulin and IgG in the anti-MF-positive patients were 2.46 +/- 1.03 g/dl and 3277 +/- 1089 mg/dl, respectively, which were higher than those in the anti-MF-negative patients (1.60 +/- 0.53 g/dl, 2245 +/- 610 mg/dl) and those in the patients with CLD-B (1.60 +/- 0.57 g/dl, 2192 +/- 339 mg/dl). Furthermore, 4 of the 8 anti-MF-positive patients with CLD-C satisfied the serological criteria for the diagnosis of AIH. These findings suggest that autoimmune mechanisms might be involved in the pathogenesis of anti-MF-positive CLD-C, and that anti-MF might be used as a marker

History of Transcatheter Arterial Chemoembolization Predicts the Efficacy of Hepatic Arterial Infusion Chemotherapy in Hepatocellular Carcinoma Patients

This study sought to identify factors that are predictive of a therapeutic response to hepatic arterial infusion chemotherapy (HAIC) by focusing on the number of prior transcatheter arterial chemoembolization (TACE) sessions. To determine the parameters predicting a good response to HAIC, we retrospectively analyzed 170 patients with hepatocellular carcinoma (HCC) who received HAIC regimens comprising low-dose cisplatin combined with 5-fluorouracil (LFP) or cisplatin (CDDP) for the first time. In both the LFP and CDDP regimens, the response rates were significantly lower in patients with three or more prior TACE sessions than in those with two or fewer prior TACE sessions (LFP 57% versus 28%; p=0.01, CDDP 27% versus 6%; p=0.01). Multivariable logistic regression analysis revealed that the number of prior TACE sessions (≥ 3) was significantly associated with non-responder status (odds ratio 4.17, 95% Confidence Interval (CI) 1.76-9.86) in addition to the HAIC regimen. Multivariable analysis using the Cox proportional hazards model revealed that a larger number of prior TACE sessions (≥ 3) was a significant risk factor for survival (hazard ratio 1.60, 95% CI 1.12-2.29) in addition to Child-Pugh class, serum alpha-fetoprotein concentration, and maximum diameter of HCC. HCC patients who receive fewer prior TACE sessions (≤ 2) were found to be better responders to HAIC

Eradication of Hepatitis C Virus Subgenomic Replicon by Interferon Results in Aberrant Retinol-Related Protein Expression

Hepatitis C virus (HCV) infection induces several changes in hepatocytes, such as oxidative stress, steatosis, and hepatocarcinogenesis. Although considerable progress has been made during recent years, the mechanisms underlying these functions remain unclear. We employed proteomic techniques in HCV replicon-harboring cells to determine the effects of HCV replication on host-cell protein expression. We examined two-dimensional electrophoresis (2-DE) and mass spectrometry to compare and identify differentially expressed proteins between HCV subgenomic replicon-harboring cells and their “cured” cells. One of the identified proteins was confirmed using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Full-length HCV genome RNA replicating and cured cells were also assessed using ELISA. Replicon-harboring cells showed higher expression of retinal dehydrogenase 1 (RALDH-1), which converts retinol to retinoic acid, and the cured cells showed higher expression of retinol-binding protein (RBP), which transports retinol from the liver to target tissues. The alteration in RBP expression was also confirmed by ELISA and Western blot analysis. We conclude that protein expression profiling demonstrated that HCV replicon eradication affected retinol-related protein expression