Monocytes (CD14
cells) from advanced-stage hepatocellular carcinoma (HCC) patients express programmed death 1 ligand (PD-L)/PD-1 and suppress the host antitumor immune response. However, it is ...unclear whether cancer progression is associated with CD14
cells. We compared CD14
cell properties before and after cancer progression in the same HCC patients and examined their role in antitumor immunity. CD14
cells were isolated from 15 naïve early-stage HCC patients before treatment initiation and after cancer progression to advanced stages. Although CD14
cells from patients at early HCC stages exhibited antitumor activity in humanized murine chimera, CD14
cells from the same patients after progression to advanced stages lacked this activity. Moreover, CD14
cells from early HCC stages scantly expressed PD-L1 and PD-L2 and produced few cytokines, while CD14
cells from advanced stages showed increased PD-L expression and produced IL-10 and CCL1. CD14
cells were also isolated from five naïve advanced-stage HCC patients before treatment as well as after treatment-induced tumor regression. The CD14
cells from patients with advanced-stage HCC expressed PD-L expressions, produced IL-10 and CCL1, and exhibited minimal tumoricidal activity. After treatment-induced tumor regression, CD14
cells from the same patients did not express PD-Ls, failed to produce cytokines, and recovered tumoricidal activity. These results indicate that PD-L expression as well as CD14
cell phenotype depend on the tumor stage in HCC patients. PD-L expressions of monocytes may be used as a new marker in the classification of cancer progression in HCC.
We investigated the impact of C-reactive protein to albumin ratio (CAR) on predicting outcomes in 522 patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib. We determined ...the optimal CAR cutoff value with time-dependent receiver operating characteristic curve analysis. Additionally, we clarified the relationship between CAR and liver function or HCC progression. Median overall survival was 20.0 (95% confidence interval (CI), 17.2-22.6) months. The optimal CAR cutoff value was determined to be 0.108. Multivariate analysis showed that high CAR (≥ 0.108) (hazard ratio (HR), 1.915; 95% CI, 1.495-2.452), Eastern Cooperative Oncology Group performance status ≥ 1 (HR, 1.429), and α-fetoprotein ≥ 400 ng/mL (HR, 1.604) were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high CAR (p < 0.001). Median progression-free survival was 7.5 (95% CI, 6.7-8.1) months. Multivariate analysis showed that age, CAR ≥ 0.108 (HR, 1.644; 95% CI, 1.324-2.043), and non-hepatitis B, non-hepatitis C etiology (HR, 0.726) were independently associated with progression-free survival. Cumulative progression-free survival differed significantly between patients with low versus high CAR (p < 0.001). CAR values were significantly higher as Japan Integrated Staging score increased (p < 0.001). In conclusion, CAR can predict outcomes in patients with unresectable HCC treated with lenvatinib.
Although low-dose aspirin (LDA) is known to induce small intestinal mucosal injury, the effect of dual antiplatelet therapy (DAPT; LDA + clopidogrel) on small intestinal mucosa in patients after ...percutaneous coronary intervention (PCI) for coronary stenosis is unknown. Fifty-one patients with a history of PCI and LDA use were enrolled, and 45 eligible patients were analyzed. Patients were grouped based on DAPT (DAPT: n = 10 and non-DAPT: n = 35) and proton pump inhibitor (PPI) use (PPI user: n = 22 and PPI-free patients: n = 23) to compare small intestinal endoscopic findings. The relationship between LDA-use period and small intestinal endoscopic findings was also examined. Multivariate analysis was performed to identify risk factors for LDA-induced mucosal injury using age, sex, DAPT, PPI, gastric mucoprotective drug, and LDA-use period. The rate of small intestinal mucosal injury incidence did not significantly differ between DAPT and non-DAPT patients (50% vs 51.1%, respectively; p = 0.94), or PPI users and PPI-free patients (50% vs 52.2%, respectively; p = 0.88). Additionally, LDA-use period of ≤24 months (n = 15) yielded a significantly higher rate of small intestinal mucosal injury incidence than LDA-use period >24 months (n = 30) (80% vs 36.7%, respectively; p = 0.006). Multivariate analysis revealed that a LDA-use period of ≤24 months was a significant risk factor for small intestinal mucosal injury (odds ratio: 19.5, 95% confidence interval: 2.48–154.00, p = 0.005). Following PCI for coronary stenosis, neither DAPT nor PPI affected LDA-induced small intestinal mucosal injury. Moreover, patients who used LDA within the last 24 months were at a greater risk of small intestinal mucosal injury.
: The geriatric nutritional risk index (GNRI) is an easily calculable index that can be determined using three common clinical variables. The GNRI is suggested to be related to sarcopenia in ...cirrhotic patients. However, the relationship between the GNRI and the prognosis in patients with liver cirrhosis (LC) has not been reported. The aim of the present research is to study the association of the GNRI with the nutritional status, hepatic function reserve, and prognosis in patients with liver cirrhosis (LC).
: A total of 370 cirrhotic patients whose nutritional statuses were evaluated using anthropometric measurements and bioimpedance analysis were studied. The associations between the GNRI and nutritional status and the GNRI and hepatic function reserve were analyzed. We also investigated the GNRI and prognosis of patients with LC.
: The median age of the enrolled patients was 66 years old, and 266 (71.9%) patients had viral hepatitis-related LC. The GNRI was shown to decrease with the progression of chronic liver disease, represented by an increased FIB-4 index and severe Child-Pugh and mALBI grades. In addition, a low GNRI (<92) was associated with severe cirrhosis-related metabolic disorders, including a low branched-chain amino acid-to-tyrosine ratio (BTR) and a low zinc value. The GNRI was positively correlated with two nutrition-related anthropometric variables (% arm circumference and % arm muscle circumference), and a low GNRI was related to a low skeletal muscle mass index (SMI) (<7.0 kg/m
for men or <5.7 kg/m
for women), as determined by using bioimpedance analysis. In addition, patients with a low GNRI (<92) had a poorer prognosis than those with a high GNRI (≥92) (log-rank test:
= 0.0161, and generalized Wilcoxon test,
= 0.01261).
: Our results suggest that a low GNRI is related to severe chronic liver disease, low muscle volume, and a poor prognosis of patients with cirrhosis.
We sought to elucidate the prognostic impact of the SARC-F score among patients with gastrointestinal advanced malignancies (
= 421). A SARC-F score ≥ 4 was judged to have a strong suspicion for ...sarcopenia. In patients with ECOG-PS 4 (
= 43), 3 (
= 61), and 0-2 (
= 317), 42 (97.7%), 53 (86.9%) and 8 (2.5%) had the SARC-F score ≥ 4. During the follow-up period, 145 patients (34.4%) died. All deaths were cancer-related. The 1-year cumulative overall survival (OS) rate in patients with SARC-F ≥ 4 (
= 103) and SARC-F < 4 (
= 318) was 33.9% and 61.6% (
< 0.0001). In the multivariate analysis for the OS, total lymphocyte count ≥ 1081/μL (
= 0.0014), the SARC-F score ≥ 4 (
= 0.0096), Glasgow prognostic score (GPS) 1 (
= 0.0147, GPS 0 as a standard), GPS 2 (
< 0.0001, GPS 0 as a standard), ECOG-PS 2 (
< 0.0001, ECOG-PS 0 as a standard), ECOG-PS 3 (
< 0.0001, ECOG-PS 0 as a standard), and ECOG-PS 4 (
< 0.0001, ECOG-PS 0 as a standard) were independent predictors. In the receiver operating characteristic curve analysis on the prognostic value of the SARC-F score, the sensitivity/specificity was 0.59/0.70, and best cutoff point of the SARC-F score was two. In conclusion, the SARC-F score is useful in patients with gastrointestinal advanced malignancies.
Functional disorders of various immune cells have been reported in hepatocellular carcinoma (HCC) patients. Recently, distinct subsets of neutrophils (polymorphonuclear leukocytes, PMN) have been ...identified in hosts with enhanced or impaired cell-mediated immunity. In this study, therefore, plasma factors and PMN from HCC patients were immunobiologically investigated. Plasma neopterin and CCL17 levels were measured by ELISA in 95 HCC patients. Peripheral PMN were isolated from each HCC patient and tested for CCL2 or CCL3 production by ELISA and flow cytometry. The results showed elevated plasma neopterin levels in HCC patients, while CCL17 levels decreased in correlation with tumor size. PMN from HCC patients produced CCL2, while PMN from healthy subjects did not. Moreover, CCL2 production by PMN was significantly increased in proportion to tumor load. When HCC patients were divided into two groups based on CCL2 produced by PMN, the survival rate of the CCL2 high group was significantly lower than that for other patients. While CCL3 production by PMN was also significantly increased in HCC patients, their CCL3 production did not correlate with tumor load and survival. The CCL2/CCL3 ratio in culture fluids of each PMN was also increased in proportion to tumor size. These results suggest that cell-mediated immunity may be impaired in advanced HCC patients. Moreover, distinct PMN subsets may exist in the peripheral blood of HCC patients. These PMN subsets, especially CCL2-producing PMN, may be involved in tumor extension and the survival outcomes for HCC patients.
Aim
Predicting the survival of hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/bev) remains a challenge. This study aims to validate the modified ...albumin–bilirubin grade and α-fetoprotein score (mALF score).
Methods
This retrospective, multicenter study included 426 HCC patients receiving Atez/Bev. Each patient was randomized 3:2 to a training set (
n
= 255) and a validation set (
n
= 171). We investigated prognostic factors in the training set and developed an easily applicable mALF score, which was evaluated in the validation set.
Results
We built the mALF score using baseline mALBI grade 2b or 3 (HR 2.36, 95% CI 1.37–4.05,
p
= 0.002) and α-fetoprotein ≥ 100 ng/ml (HR 2.61, 95% CI 1.49–4.55,
p
< 0.001), which were identified as unfavorable prognostic factors in a multivariate analysis. The 1-year OS rates were 82.7% (95% CI 68.9–90.8) in patients who meet neither of the criteria (mALF 0 points,
n
= 101), 61.7% (95% CI 44.5–74.9) in patients who meet either of the two criteria (mALF 1 point,
n
= 109), and 24.6% (95% CI 9.0–44.3) in patients who meet both criteria (mALF 2 points, n = 45); the difference was statistically significant (
p
< 0.001). The median PFS in patients with mALF 0, 1, and 2 points was 9.5 months (95% CI 4.3-NA), 6.6 months (95% CI 6.0–8.0), and 3.8 months (95% CI 3.0–5.2), respectively, which amounted to a significant difference (
p
< 0.001). These results were confirmed in the validation set (1-year OS rates, 0/1/2 points = 94.2%/62.1%/46.3%,
p
< 0.001; median PFS, 0/1/2 points = 9.3/6.7/4.7 months,
p
= 0.018).
Conclusion
The mALF score can reliably predict the prognosis of HCC patients receiving Atez/Bev.
Despite major advances in curative and palliative approaches, hepatocellular carcinoma (HCC) is still the third leading cause of cancer-related death worldwide. M1 macrophages (Mφ) play a key role in ...host antitumor defenses in HCC. In our study, CD14
+
cells were isolated from the peripheral blood of four groups of HCC patients (group-1, patients with stage 0 HCC; group-2, patients with stage A HCC; group-3, patients with stage B HCC; and group-4, patients with stage C HCC) and characterized phenotypically. Then, CD14
+
cells from group-2 and group-3 HCC patients were induced to polarize and tested for their antitumor abilities in a chimera model of HCC patients. Human HCCs (HepG2 solid tumors) grew in a chimera model of group-3 patients (group-3 HCC chimeras) but not in a chimera model of group-2 patients (group-2 HCC chimeras). In response to HCC antigens, the majority of CD14
+
cells from group-2 patients (group-2 CD14
+
cells) switched to the M1 phenotype (IL-12
+
IL-10
−
iNOS
+
cells), whereas the majority of CD14
+
cells from group-3 patients (group-3 CD14
+
cells) did not switch to the M1 phenotype and continued to express M2b phenotypic properties (IL-12
−
IL-10
+
CCL1
+
iNOS
−
cells). Group-3 CD14
+
cells showed M1Mφ polarization after treatment with CCL1 antisense oligodeoxynucleotide (ODN). Therefore, our study indicates that anti-HCC defenses of group-3 HCC chimeras are improved after CCL1 antisense ODN treatment.
Liver cirrhosis is the ultimate condition of chronic liver diseases. Non-alcoholic steatohepatitis and fatty liver diseases are emerging in association with metabolic syndrome largely due to excess ...nutrition. Stromal cells of adipose tissue are enriched mesenchymal stem cells which are pluripotent and immunomodulatory, which are expected to be applied for repairing/regenerative therapy of the impaired organs.
We conducted the multi-institutional clinical trial (Japanese UMIN Clinical Trial Registry: UMIN000022601) of cell therapy using freshly isolated autologous adipose tissue-derived regenerative (stem) cells (ADRCs), which are obtained by the investigational trial device, adipose tissue dissociation device, for liver cirrhosis patients due to non-alcoholic steatohepatitis or fatty liver disease, to exploratory assess efficacy as well as safety of this trial. We completed treatment and 24 weeks follow-up for 7 patients.
We observed that 6 out of 7 patients' serum albumin concentration was improved. As for prothrombin activity, 5 out of 7 patients showed improvement. No trial-related adverse events, which were serious or non-serious, was observed. Besides, no malfunction of the investigational trial device was encountered.
Thus, treatment with autologous ADRCs obtained with the investigational trial device in steatohepatitis-related cirrhosis was confirmed to be safely conductible and potentially promising for the retaining or improving the impaired hepatic reserve.
PDF
