The Utility of Serum Alpha-fetoprotein for Monitoring for Relapse of Alpha-fetoprotein-Positive Hepatoblastoma.

Hepatoblastoma is the most common liver malignancy in children. Treatment typically involves surgery and cisplatin-based chemotherapy. After therapy completion, children undergo repetitive surveillance imaging to screen for relapse, which occurs in <12% of cases. Monitoring for relapse has gradually shifted to serial determination of serum alpha-fetoprotein (AFP) alone as most cases have AFP elevation at the time of relapse. Little primary data supports, such a practice, however, and herein we present both our institutional experience with relapsed hepatoblastoma and a careful review of published literature on this topic. While serial AFP monitoring may suffice for most patients, certain clinical characteristics should give pause to the practitioner, when considering posttreatment monitoring with serum AFP alone.

Analysis of the prognostic value of uric acid on the efficacy of immunotherapy in patients with primary liver cancer

Purpose Uric acid (UA) plays a dual role as an antioxidant and a prooxidant in patients with malignant tumors; however, the relationship between serum UA and malignancy is currently unclear. This study aims to investigate the prognostic value of serum uric acid level before immunotherapy on the efficacy of primary liver cancer (PLC) immunotherapy, which might provide a basis for optimizing the comprehensive treatment scheme. Methods Patients with PLC who were admitted to the First Affiliated Hospital of Gannan Medical College from January 2019 to June 2022 and underwent immunotherapy were collected retrospectively. The difference between serum UA levels in patients with PLC, the correlation between serum UA levels, and the clinical characteristics of patients with PLC were analyzed using the chi-square test, and the survival was estimated using the Kaplan–Meier analysis. To further assess the prognostic significance of UA concentrations, univariate and multivariate Cox regression analyses were performed. Results Ninety-nine patients were included in this study cohort. The median follow-up was 7 months (range: 1–29 months), and 76 (76.8%) of the 99 patients with PLC died as of December 31, 2022. Serum UA concentrations ranged from 105 to 670 μmol/l, with a median of 269 μmol/l. The results showed that the serum UA level of patients with PLC was higher than that of healthy subjects (P < 0.001). After subgroup analyses, only male patients with liver cancer had higher serum UA levels than healthy men (P = 0.001). The results of the Kaplan–Meier analysis showed that higher UA levels were associated with poor overall survival (OS) (P = 0.005) (AU)

Prognostic Nutritional Index as a Prognostic Factor for Very Early-Stage Hepatocellular Carcinoma.

INTRODUCTION: Field factors play more important roles in predicting the outcomes of patients compared with tumor factors in early-stage hepatocellular carcinoma (HCC). However, the prognostic ability of noninvasive serum marker scores for hepatic fibrosis and liver functional reserve on very early-stage HCC is still not yet determined. We aimed to investigate the performance of these serum marker scores in predicting the prognoses of patients with very early-stage HCC. METHODS: A total of 446 patients with very early-stage HCC from 2012 to 2022 were retrospectively enrolled. Serum biomarkers and prognostic scores determining overall survival (OS) were analyzed by Cox proportional hazards model. We compared the Akaike information criterion among the prognostic nutritional index (PNI), aspartate aminotransferase-to-platelet ratio index, albumin-bilirubin (ALBI) score, EZ (easy)-ALBI score, modified ALBI score, fibrosis-4 score, and lymphocyte-to-monocyte ratio to determine the predictability on the OS. RESULTS: After a median follow-up of 41.0 months (interquartile range 36.9-45.1 months), 81 patients died, with a 5-year OS rate of 71.0%. Among the noninvasive serum marker scores, PNI had the best performance in predicting the OS with the lowest Akaike information criterion (846.407) compared with other scores. Moreover, we stratified the patients into high-risk (PNI <45) and low-risk (PNI ≥45) groups. It showed that the 5-year OS rates were 83.4% and 60.8% in the low-risk and high-risk PNI groups, respectively ( P < 0.001). DISCUSSION: PNI had the best performance in predicting the OS for patients with very early-stage HCC.

Determination of five mTOR inhibitors in human plasma for hepatocellular carcinoma treatment using QuEChERS-UHPLC-MS/MS.

A fast and reliable QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) method for pre-processing combined with Ultra - high performance liquid chromatography - tandem mass spectrometry (UHPLC-MS/MS) was established for the analysis of five mammalian rapamycin target protein (mTOR) inhibitors (vistusertib, AZD8055, pictilisib, everolimus, temsirolimus)in human plasma. Extraction was achieved by addition of acetonitrile to the sample followed by anhydrous magnesium sulfate and 30 mg C18 for salting out and purification, respectively. MTOR inhibitors were detected using selective response monitoring (SRM) under positive ion electrospray mode. Vistusertib, AZD8055 and pictilisib showed good linearity with a range of 1-80 ng/ml, Additionally, the concentration of everolimus and temsirolimus was 2.5-200 ng/ml and10-800 ng/ml, respectively. The linear correlation coefficient (R2) of each analysis was ≥ 0.9950. The limit of detection (LOD) and Limit of Quantitation (LOQ) were 0.015-0.75 ng/ml and 1-10 ng/ml, respectively. This method showed a high accuracy with high recovery rate and excellent stability. This method is fast, accurate and reliable, suitable for quantitative detection of mTOR inhibitors in human plasma.

[Expression and clinical significance of plasma methylated SEPT 9 gene in patients with primary liver cancer].

Objective: To investigate the expression and clinical significance of plasma methylated SEPT9 (mSEPT9) gene in patients with primary liver cancer. Methods: 393 cases who visited our hospital from May 2016 to October 2018 were selected. Among them, 75 cases were in the primary liver cancer (PLC) group, 50 cases were in the liver cirrhosis (LC) group, and 268 cases were in the healthy control group (HC). The three groups' positive rates of mSEPT9 expression in the peripheral plasma were detected by the polymerase chain reaction (PCR) fluorescent probe method. The correlational clinical features of liver cancer were analyzed. At the same time, the electrochemiluminescence detection method was used to compare the AFP positive rate. Statistical analysis was conducted using chi-square tests or continuity-corrected chi-square tests. Results: 367 cases actually had valid samples. There were 64, 42, and 64 cases in the liver cancer group, cirrhosis group, and healthy control group, respectively. Among them, 34 cases of liver cancer were verified from pathological tissues. The positive rate of plasma mSEPT9 was significantly higher in the liver cancer group than that in the liver cirrhosis and healthy control groups [76.6% (49/64), 35.7% (15/42), and 3.8% (10/261), respectively], and the differences were statistically significant (χ (2) = 176.017, P < 0.001). The sensitivity of plasma mSEPT9 detection (76.6%) was significantly better in liver cancer (76.6%) than that of AFP patients (54.7%), and the difference was statistically significant (χ (2) = 6.788, P < 0.01). Compared with the single detection, the sensitivity and specificity of plasma mSEPT9 combined with AFP were significantly improved (89.7% vs. 96.3%, respectively). Patients with liver cancer aged≥50 years, with clinical stage II or above, and those with pathological signs of moderate to low differentiation had higher levels of plasma mSEPT9 positive expression, and the differences were statistically significant (χ (2) = 6.41, 9.279, 6.332, P < 0.05). During the follow-up period, the survival time of liver cancer patients with positive plasma mSEPT9 expression was significantly shorter than that of those with negative expression (310 ± 26 days vs. 487 ± 59 days, respectively), with statistically significant differences (Log Rank P = 0.039). Conclusion: In China, the positive rate of plasma mSEPT9 detection in liver cancer patients is higher than that of AFP in relation to age, clinical stage, and degree of tissue differentiation; additionally, it has certain survival predictive values. As a result, detecting this gene has important clinical significance and potential clinical application value in the non-invasive diagnosis and prognosis assessment of patients with primary liver cancer.

Combining serum AFP and CEUS LI-RADS for better diagnostic performance in Chinese high-risk patients.

PURPOSE: To evaluate and compare the diagnostic performance of revised contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System version by combining LR-M category and serum alpha-fetoprotein (AFP) under different cut-off values. MATERIAL AND METHODS: This retrospective study enrolled 152 high-risk patients with 152 histology-proven nodules. For revised LI-RADS, nodules in LR-M with different elevated AFP thresholds have been reclassified as the LR-5 category. The diagnostic performances of original and revised CEUS LI-RADS were evaluated and compared. RESULTS: To compare with the original version, the sensitivity of revised LR-5 (adjusted with AFP value > 200 ng/ml or 400 ng/ml) for the diagnosis of hepatocellular carcinoma (HCC) improved from 52.5 to 69.2% or 65.0%, respectively (both p < 0.001) without compromising specificity (87.5% vs. 71.9% or 78.1%, respectively, both p > 0.05). For the diagnosis of non-HCC malignancy, the specificity of the LR-M after reclassification was improved (69.6% vs. 84.4% or 80.7%, respectively, both p < 0.001) with a non-significant sensitivity reduction (100.0 vs. 70.6% or 82.4%, respectively, both p > 0.05). After modification, the sensitivity of LR-5 also increased to 69.1% or 64.9% (both p < 0.001), while the specificity and PPV did not change (both p > 0.05) for larger nodules (> 20 mm). CONCLUSION: The diagnostic performance of CEUS LI-RADS can be further improved by reclassifying LR-M nodules with elevated AFP thresholds to LR-5.

SEPT9 Expression in Hepatic Nodules: An Immunohistochemical Study of Hepatocellular Neoplasm and Metastasis.

The methylated SEPT9 DNA ( mSEPT9 ) in plasma is a US Food and Drug Administration (FDA)-approved screening biomarker in colorectal cancer and is emerging as a promising diagnostic and prognostic biomarker in hepatocellular carcinoma (HCC). We evaluated the SEPT9 protein expression by immunohistochemistry (IHC) in various hepatic tumors from 164 hepatectomies and explants. Cases diagnosed as HCC (n=68), hepatocellular adenoma (n=31), dysplastic nodule (n=24), and metastasis (n=41) were retrieved. SEPT9 stain was performed on representative tissue blocks showing tumor/liver interface. For HCC, archived IHC (SATB2, CK19, CDX2, CK20, and CDH17) slides were also reviewed. The findings were correlated with demographics, risk factors, tumor size, alpha fetoprotein levels at diagnosis, T stage and oncologic outcomes, with significance defined as P <0.05. Percentage of SEPT9 positivity differed significantly among hepatocellular adenoma (3%), dysplastic nodule (0%), HCC (32%), and metastasis (83%, P <0.001). Compared with patients with SEPT9- HCC, those with SEPT9+ HCC were older (70 vs. 63 y, P =0.01). The extent of SEPT9 staining correlated with age ( rs =0.31, P =0.01), tumor grade ( rs =0.30, P =0.01), and extent of SATB2 staining ( rs =0.28, P =0.02). No associations were found between SEPT9 staining and tumor size, T stage, risk factors, CK19, CDX2, CK20, or CDH17 expression, alpha fetoprotein levels at diagnosis, METAVIR fibrosis stage, and oncologic outcome in the HCC cohort. SEPT9 is likely implicated in liver carcinogenesis in a HCC subset. Similar to mSEPT9 DNA measurement in liquid biopsies, SEPT9 staining by IHC may prove helpful as an adjunct diagnostic biomarker with potential prognostic ramifications.

Isolated Hepatitis B Core Antibody Positivity and Long-Term Liver-Related Mortality in Korea: A Cohort Study.

INTRODUCTION: Whether isolated hepatitis B core antibody (anti-HBc) positivity is a risk factor for long-term liver-related outcomes in hepatitis B virus (HBV)-endemic areas remains unclear. We aimed to investigate liver-related and liver cancer mortality of isolated anti-HBc positivity in Korean adults. METHODS: A cohort study comprised 609,299 Korean adults who underwent hepatitis B serologic markers, as a part of health examination. Liver-related and liver cancer mortality were determined using the National Death Records. RESULTS: During a median follow-up of 9.0 years (interquartile range, 5.5-13.7 years), 554 liver-related deaths were identified (liver-related mortality, 9.6 cases per 10 5 person-years). The prevalence of isolated anti-HBc positivity was 3.8% (n = 23,399) and was age-dependent. After adjustment for age, sex, and other confounders, hazard ratios (95% confidence interval) for liver-related mortality in isolated anti-HBc-positive and hepatitis B surface antigen-positive subjects compared with HBV-unexposed subjects were 1.69 (1.22-2.33) and 27.02 (21.45-34.04), respectively. These associations were pronounced in the analyses using liver cancer mortality as an outcome. Among isolated anti-HBc-positive patients, the risks of liver-related and liver cancer mortality were significantly higher in those with high fibrosis-4 scores compared with patients unexposed to HBV with the multivariable-adjusted hazard ratios (95% confidence interval) of 15.59 (9.21-26.37) and 72.66 (36.96-142.86), respectively. DISCUSSION: In this cohort of Korean adults, isolated anti-HBc positivity was associated with an increased risk of liver-related and liver cancer mortality, especially when accompanied by a high fibrosis score. Isolated anti-HBc positivity may be an independent risk factor for liver-related outcomes, especially in high-endemic areas.

The outcomes and prognostic factors of patients with hepatocellular carcinoma and normal serum alpha fetoprotein levels.

BACKGROUND: Alpha fetoprotein (AFP) is the most widely used tumor marker for hepatocellular carcinoma (HCC). Nevertheless, few studies have investigated the prognostic factors of HCC patients with normal serum AFP levels. METHODS: We retrospectively enrolled 2198 patients with HCC and normal serum AFP levels (<20 ng/mL) from 2007 to 2020. Overall survival (OS) rates were calculated by the Kaplan-Meier method, and analyses of the prognostic factors were performed using a Cox proportional hazard model. RESULTS: Among the enrolled patients, 1385 (63%) patients were in the low-normal AFP group (serum AFP levels ≤7 ng/mL), and 813 (37%) patients were in the high-normal AFP group (serum AFP levels between 7 and 20 ng/mL). The high-normal AFP group had poorer liver functional reserve, more multiple tumors, and smaller tumor size compared to those in the low-normal AFP group. After a median follow-up of 32.4 months, 942 patients died, and the 5-year OS rate was 54.4%. The 5-year OS rates were 57.4% and 49.8% in the low-normal AFP group and high-normal AFP group, respectively (p = 0.001). A multivariate analysis showed the independent prognostic factors of poor OS were no anti-viral therapy, advanced albumin-bilirubin grades, the presence of vascular invasion, tumor size ≥5 cm, and non-curative treatment modalities. Serum AFP levels were not associated with OS according to the multivariate analysis. CONCLUSION: Liver functional reserve, anti-viral therapy, tumor size, vascular invasion, and treatment modalities, determined the outcomes of HCC patients with normal serum AFP levels, but serum AFP levels did not.

OMA1 and YME1L as a Diagnostic Panel in Hepatocellular Carcinoma.

Identifying new hepatocellular carcinoma (HCC)-driven signaling molecules and discovering their molecular mechanisms are crucial for efficient and better outcomes. Recently, OMA1 and YME1L, the inner mitochondrial proteases, were displayed to be associated with tumor progression in various cancers; however, their role in HCC has not yet been studied. Therefore, we evaluated the possible role of OMA1/YME1L in HCC staging and discussed their potential role in cellular apoptosis and proliferation. Our study was performed using four groups of male albino rats: a normal control and three diethyl nitrosamine-treated groups for 8, 16, and 24 weeks. The OMA1 and YME1L, matrix-metalloproteinase-9 (MMP-9), and cyclin D1 content were measured in liver tissues, while alpha-fetoprotein (AFP) level was assessed in serum. Additionally, Ki-67 expression was evaluated by immunohistochemistry. The relative hepatic expression of Bax, and tissue inhibitor matrix metalloproteinase (TIMP-3) was measured. Herein, we confirmed for the first time that OMA1 is down-regulated while YME1L is up-regulated in HCC in the three studied stages with subsequent inhibition of apoptosis and cell cycle progression. Furthermore, these proteases have a possible role in metastasis. These newly recognized results suggested OMA1 and YME1L as possible diagnostic tools and therapeutic targets for HCC management.

Expression Levels and Clinical Significance of Serum miR-497, CEA, CA24-2, and HBsAg in Patients with Colorectal Cancer.

The objective of the current study was to look at the levels of blood micro ribonucleic acid- (miR-) 497, carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 24-2, and hepatitis B surface antigen (HBsAg) in patients with colorectal cancer (CRC), as well as the clinical importance of these markers in CRC patients. The serum levels of miR-497, CEA, CA24-2, and HBsAg were compared between 60 patients with CRC (observation group) and another 60 patients with colorectal polyps (control group). The 4 indicators in patients with lymph node metastasis and liver metastasis were compared. The diagnostic effects of 4 detection methods and the combined detection were analyzed, and the influence of 4 indicators on the 5-year cumulative survival rate of patients was discussed. The results showed that the serum levels of miR-497 and HBsAg were lower, and the levels of CEA and CA24-2 were higher in the observation group (P < 0.05). The combined detection had the best diagnostic effect, and CEA alone had the best prediction effect. The serum level of miR-497 was significantly lower in patients with lymphatic metastasis, with the significantly higher levels of CEA and CA24-2 (P < 0.05). The HBsAg level of patients with liver metastases was greatly lower than that of patients without liver metastases (P < 0.05). The 5-year cumulative survival rate of patients with high levels of CEA and CA24-2 was significantly lower than that of patients with low level of CEA. The 5-year cumulative survival rate was lower in patients with low level of HBsAg, but the difference was small. The 5-year cumulative survival rate of patients with elevated serum miR-497 was observably lower. In conclusion, combined detection could diagnose CRC more accurately. Serum miR-497, CEA, and CA24-2 were important in the diagnosis of lymph node metastasis of CRC. HBsAg did a better job of predicting liver metastases in CRC patients. High level of CEA significantly reduced the cumulative survival rate of CRC patients and could predict the long-term survival rate of patients. Serum levels of miR-497, CEA, CA24-2, and HBsAg played a positive role in the diagnosis and evaluation of CRC and could identify lymph node and liver metastases, having a high clinical guidance value.

Elevated serum CEA is associated with liver metastasis and distinctive circulating tumor DNA alterations in patients with castration-resistant prostate cancer.

BACKGROUND: Elevated serum carcinoembryonic antigen (CEA) is used to identify "treatment emergent" forms of castration-resistant prostate cancer (CRPC) such as aggressive variant prostate cancer (AVPC). However, its individual utility as a prognostic marker and the genetic alterations associated with its expression have not been extensively studied in CRPC. METHODS: This study retrospectively analyzed clinical outcomes and circulating tumor DNA profiles in 163 patients with CRPC and elevated or normal serum CEA. These same patients were then classified as AVPC or non-AVPC and compared to determine the uniqueness of CEA-associated gene alterations. RESULTS: Patients with elevated CEA demonstrated higher rates of liver metastasis (37.5% vs. 19.1%, p = 0.02) and decreased median overall survival from CRPC diagnosis (28.7 vs. 73.2 mo, p < 0.0001). In addition, patients with elevated CEA were more likely to harbor copy number amplifications (CNAs) in AR, PIK3CA, MYC, BRAF, CDK6, MET, CCNE1, KIT, RAF1, and KRAS. Based on variant allele frequency we also defined "clonal" single-nucleotide variants (SNVs) thought to be driving disease progression in each patient and found that CEA expression was negatively correlated with clonal AR SNVs and positively correlated with clonal TP53 SNVs. Of these genetic associations, only the increases in clonal TP53 SNVs and KRAS amplifications were recapitulated among patients with AVPC when compared to patients without AVPC. CONCLUSIONS: Together these findings suggest that CEA expression in CRPC is associated with aggressive clinical behavior and gene alterations distinct from those in AVPC.

Development of nomogram models of inflammatory markers based on clinical database to predict prognosis for hepatocellular carcinoma after surgical resection.

BACKGROUND: Inflammation plays a significant role in tumour development, progression, and metastasis. In this study, we focused on comparing the predictive potential of inflammatory markers for overall survival (OS), recurrence-free survival (RFS), and 1- and 2-year RFS in hepatocellular carcinoma (HCC) patients. METHODS: A total of 360 HCC patients were included in this study. A LASSO regression analysis model was used for data dimensionality reduction and element selection. Univariate and multivariate Cox regression analyses were performed to identify the independent risk factors for HCC prognosis. Nomogram prediction models were established and decision curve analysis (DCA) was conducted to determine the clinical utility of the nomogram model. RESULTS: Multivariate Cox regression analysis indicated that the prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) were independent prognostic factors of OS, and aspartate aminotransferase-to-platelet ratio (APRI) was a common independent prognostic factor among RFS, 1-year RFS, and 2-year RFS. The systemic inflammation response index (SIRI) was an independent prognostic factor for 1-year RFS in HCC patients after curative resection. Nomograms established and achieved a better concordance index of 0.772(95% CI: 0.730-0.814), 0.774(95% CI: 0.734-0.815), 0.809(95% CI: 0.766-0.852), and 0.756(95% CI: 0.696-0.816) in predicting OS, RFS, 1-year RFS, and 2-year RFS respectively. The risk scores calculated by nomogram models divided HCC patients into high-, moderate- and low-risk groups (P < 0.05). DCA analysis revealed that the nomogram models could augment net benefits and exhibited a wider range of threshold probabilities in the prediction of HCC prognosis. CONCLUSIONS: The nomograms showed high predictive accuracy for OS, RFS, 1-year RFS, and 2-year RFS in HCC patients after surgical resection. The nomograms could be useful clinical tools to guide a rational and personalized treatment approach and prognosis judgement.

Long non-coding RNA H19 as a biomarker for hepatocellular carcinoma.

BACKGROUND AND AIMS: Liver cancer stem cells (CSCs) could be involved in the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). The aim of this study was to explore the role of lncRNA-H19 as a biomarker for liver cancer. METHODS: LncRNA-H19 expression levels and the functional assays were conducted in EpCAM+ CD133+ CSCs and C57BL/6J mice fed with a high-fat high-cholesterol carbohydrate (HFHCC) or standard diet for 52 weeks. Liver tissue and plasma samples from patients with cirrhosis, with or without HCC, were used for the analyses of gene expression and circulating lncRNA-H19 levels in an estimation and validation cohort. RESULTS: EpCAM+ CD133+ cells showed a stem cell-like phenotype, self-renewal capacity, upregulation of pluripotent gene expression and overexpressed lncRNA-H19 (p < .001). Suppression of lncRNA-H19 by antisense oligonucleotide treatment significantly reduced the self-renewal capacity (p < .001). EpCAM, CD133 and lncRNA-h19 expression increased accordingly with disease progression in HFHCC-fed mice (p < .05) and also in liver tissue from HCC patients (p = .0082). Circulating lncRNA-H19 levels were significantly increased in HCC patients in both cohorts (p = .013; p < .0001). In addition, lncRNA-H19 levels increased accordingly with BCLC staging (p < .0001) and decreased after a partial and complete therapeutic response (p < .05). In addition, patients with cirrhosis who developed HCC during follow-up showed higher lncRNA-H19 levels (p = .0025). CONCLUSION: LncRNA-H19 expression was increased in CSCs, in liver tissue and plasma of patients with HCC and decreased after partial/complete therapeutic response. Those patients who developed HCC during the follow-up showed higher levels of lncRNA-H19. LncRNA-H19 could constitute a new biomarker of HCC.

Prognostic utility of systemic inflammatory markers and chronic hepatitis C virus infection status in hepatocellular carcinoma patients treated with local ablation.

BACKGROUND: Hepatocellular carcinoma (HCC) has high incidence and mortality worldwide. Local ablation using radiofrequency ablation (RFA) or microwave ablation (MWA) is potentially curative for early-stage HCC with outcomes comparable to surgical resection. We explored the influence of demographic, clinical, and laboratory factors on outcomes of HCC patients receiving ablation. METHODS: This retrospective cohort study included 221 HCC patients receiving local ablation at Mayo Clinic between January 2000 and October 2018, comprising 140 RFA and 81 MWA. Prognostic factors determining overall survival (OS) and disease-free survival (DFS) were identified using multivariate analysis. RESULTS: There was no clinically significant difference in OS or DFS between RFA and MWA. In multivariate analysis of OS, pre-ablation lymphocyte-monocyte ratio [Hazard ratio (HR) 0.7, 95% confidence interval (CI) 0.58-0.84, P = 0.0001], MELD score [HR 1.12, 95%CI 1.068-1.17, P <  0.0001], tumor number [HR 1.23, 95%CI 1.041-1.46, P = 0.015] and tumor size [HR 1.18, 95%CI 1.015-1.37, P = 0.031] were clinically-significant prognostic factors. Among HCC patients with chronic hepatitis C (HCV) infection, positive HCV PCR at HCC diagnosis was associated with 1.4-fold higher hazard of death, with 5-year survival of 32.8% vs 53.6% in HCV PCR-negative patients. Regarding DFS, pre-ablation lymphocyte-monocyte ratio [HR 0.77, 95%CI 0.66-0.9, P = 0.001], MELD score [HR 1.06, 95%CI 1.022-1.11, P = 0.002], Log2 AFP [HR 1.11, 95%CI 1.033-1.2, P = 0.005], tumor number [HR 1.29, 95%CI 1.078-1.53, P = 0.005] and tumor size [HR 1.25, 95%CI 1.043-1.51 P = 0.016] were independently prognostic. CONCLUSIONS: Pre-ablation systemic inflammation represented by lymphocyte-monocyte ratio is significantly associated with OS and DFS in HCC patients treated with local ablation. HCV viremia is associated with poor OS. Tumor biology represented by tumor number and size are strongly prognostic for OS and DFS while AFP is significantly associated with DFS only.

Current Role of Atezolizumab Plus Bevacizumab Therapy in the Sequential Treatment of Unresectable Hepatocellular Carcinoma.

BACKGROUND/AIM: Atezolizumab plus bevacizumab therapy is the new standard treatment option for advanced hepatocellular carcinoma (HCC). The clinical details and sequential course after atezolizumab plus bevacizumab therapy remain to be determined. PATIENTS AND METHODS: Thirty-four consecutive patients who received atezolizumab plus bevacizumab therapy were evaluated. Their clinical outcomes were assessed according to liver function classified by modified albumin-bilirubin (ALBI) grade 1 and 2a (1/2a) versus 2b and treatment line (first-line versus second- or later-line). Furthermore, the treatment sequence after atezolizumab plus bevacizumab therapy was also assessed. RESULTS: The objective response and disease control rates were 15.6% and 93.8%, respectively. The median proportions of ALBI scores at 1, 2, and 3 months relative to the baseline scores were 0.94, 0.97, and 0.93, respectively. The median proportions of α-fetoprotein (AFP) scores at 1, 2, and 3 months relative to the baseline scores were 0.98, 1.12, and 1.83, respectively. There were no significant differences in the changes in the proportions of AFP and ALBI scores according to both liver function and treatment line. Twelve patients were administered lenvatinib treatment after the failure of atezolizumab plus bevacizumab therapy. The proportions of AFP and ALBI scores at 1 month relative to the baseline scores were 0.55 and 0.81, respectively. CONCLUSION: Atezolizumab plus bevacizumab therapy can be effective for advanced HCC irrespective of the patients' liver function and treatment line. Lenvatinib administration after atezolizumab plus bevacizumab therapy can be effective, although special attention should be paid to the deterioration of liver function.

sIL-2R- an Immuno-biomarker for Prediction of Metastases in Uveal Melanoma.

BACKGROUND/AIM: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. High serum levels of soluble IL-2 receptor (sIL-2R) have been reported in acute inflammations and metastatic cancers. This study evaluated the potential of high/increasing sIL-2R levels in predicting metastases. PATIENTS AND METHODS: The study included a total of 1,546 sera samples of subjects from three groups: 119 healthy controls (73 subjects), 566 UM 10 year (10y) disease-free (DF) (220 patients), 861 metastatic UM (268 patients). Patients were followed-up biannually with liver ultrasound and liver function tests for the presence of metastases (Mets). Blood samples to measure the levels of sIL-2R were obtained at the time of primary diagnosis, soon after initial treatment (enucleation, brachytherapy), every 6 months, 10 years from diagnosis, at Mets confirmation by CT, and after additional treatments. RESULTS: Significantly higher sIL-2R levels were detected in the Mets patients compared to healthy controls and 10y DF patients. Compared to the upper limit of the normal levels of sIL-2R, 1,000 U/ml, its levels in metastatic UM were 61%, 25% in 10y DF UM, and 6.25% in the controls. High levels of sIL-2R in metastatic patients, decreased significantly post treatments. Individual kinetics of markers, indicated similar trends of sIL-2R compared to osteopontin and S-Protein 100, predicting metastases, which were confirmed on liver imaging. CONCLUSION: Significantly higher sIL-2R levels were evident in all UM patients with Mets. Significant increases in sIL-2R levels on serial evaluations indicated and predicted UM Mets, enabling earlier treatment of Mets, to improve survival.

C-Reactive Protein Levels Predict Responses to PD-1 Inhibitors in Hepatocellular Carcinoma Patients.

Background: Serum C-reactive protein (CRP) is a biomarker of an acute inflammatory response and has been successfully used as a prognostic predictor for several malignancies. However, the clinicopathological significance of CRP levels in hepatocellular carcinoma (HCC) patients being treated with PD-1 inhibitors remains unclear. Methods: Serum CRP levels were measured for a total of 101 HCC patients that had been treated with PD-1 inhibitors from July 2018 to November 2019. The clinicopathological data was retrospectively analyzed to identify any clinical implications between CRP levels and responses to PD-1 inhibitors and patients' progression-free survival (PFS). Results: The median PFS was 8.87 months in the CRP-low subgroup and 3.67 months in the CRP-high subgroup (P = 0.009). Univariate and multivariate Cox regression analysis demonstrated that both serum CRP and AFP levels were independent risk factors for the PFS of HCC patients treated with PD-1 inhibitors (P < 0.05). Moreover, Cox regression analysis after Propensity Score Matching showed the similar results. A prognostic model combining CRP and AFP levels could significantly stratify HCC patients receiving PD-1 inhibitors into low-, intermediate-, and high-risk subgroups (P < 0.001). Patients in the risk subgroups reported similar overall response rates (P = 0.625) and significantly different disease control rates (low- vs. intermediate- vs. high-risk groups: 81.6% vs. 65.1% vs. 35%, respectively, P = 0.002). Conclusions: The results of this study support the association between high serum CRP levels with the response and PFS for HCC patients receiving PD-1 inhibitors. Furthermore, the levels of both CRP and AFP in an HCC patient before treatment initiation show great potential for determining the efficacy of PD-1 inhibitors.

Prognostic and Clinical Significance of Aspartate Aminotransferase-to-Lymphocyte Ratio Index in Individuals with Liver Cancer: A Meta-Analysis.

OBJECTIVE: This study was aimed at exploring the prognostic and clinicopathological roles of aspartate aminotransferase-to-lymphocyte ratio index (ALRI) in patients with hepatocellular carcinoma via a meta-analysis. METHODS: The PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases were comprehensively searched from inception to November 20, 2021. Pooled hazard ratio (HR) and corresponding 95% confidence interval (CI) were used to evaluate the relationship between ALRI and overall survival (OS) as well as progression-free survival (PFS) in patients with hepatocellular carcinoma. Odds ratio (OR) and the corresponding 95% CI were also used to investigate correlations between clinical factors and ALRI in patients with hepatocellular carcinoma. RESULTS: A total of 3914 patients with hepatocellular carcinoma from eleven retrospective cohorts were included in this meta-analysis. The combined results revealed that patients with hepatocellular carcinoma with elevated ALRI tended to have unfavorable OS (HR 1.53 [95% CI 1.25-1.82]; P < 0.001). Pooled HRs revealed that high ALRI was an independent risk factor for inferior PFS in patients with hepatocellular carcinoma (HR 1.36 [95% CI 1.10-1.63]; P < 0.001). In addition, high ALRI was strongly associated with male sex (OR 1.32 [95% CI 1.02-1.70]; P = 0.035), presence of cirrhosis (OR 1.68 [95% CI 1.01-2.81]; P = 0.046), larger tumor size (OR 2.25 [95% CI 1.31-3.88]; P < 0.001), presence of portal vein tumor thrombus (OR 2.50 [95% CI 1.52-4.11]; P < 0.001), and distant metastasis (OR 1.72 [95% CI 1.05-2.82]; P = 0.031). CONCLUSION: Elevated ALRI in patients with hepatocellular carcinoma predicted inferior survival outcomes and was strongly associated with some important features of hepatocellular carcinoma.

Potential plasma biomarkers: miRNA-29c, miRNA-21, and miRNA-155 in clinical progression of Hepatocellular Carcinoma patients.

This study evaluated differences in the clinical appearance of patients with hepatocellular carcinoma (HCC) based on plasma level and regulation of microRNAs (miRNA-29c, miRNA-21, and miRNA-155). The observational-analytical study with a cross-sectional design was conducted on 36 HCC patients and 36 healthy controls. The blood samples were collected from 2 Province Hospitals (Dr. Sardjito Hospital and Prof. Dr. Margono Soekarjo Hospital) for HCC and the Blood Bank Donor of the Indonesian Red Cross for 36 healthy controls. These blood samples were treated as follows: plasma isolation, RNA isolation, cDNA synthesis, quantification by qRT-PCR using a sequence-specific forward primer, and normalization of miRNA using housekeeping-stably miRNA-16. There were only 27 HCC patients with complete clinical variables (neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), platelet count, albumin, C-reactive protein (CRP), and cholinesterase (ChE)) that were able to analyses for regulation miRNAs based on its fold change expression miRNA target. All 27 HCC subjects were follow-up until 3-years of monitoring for their overall survival. The miRNA plasma expression was analyzed by Bio-Rad CFX 96 Manager software to determine the cycle of quantification, followed by the calculation of expression levels using Livak's methods. Data were analyzed using STATA 11.0, with a significant value of p<0.05. The miRNAs expression of HCC subjects were lower than that healthy control subjects in miRNA-29c (down-regulation 1.83-fold), higher than that healthy control subjects in miRNA 21 and miRNA-155 (up-regulation, 1.74-fold; 1.55-fold) respectively. NLR, CRP, ChE, and platelet count showed a significant difference in miRNA-29c regulation, though neutrophil count showed a significant difference in miRNA-21 and miRNA-155 regulation (p<0.05). Conclusion: Plasma biomarkers: miRNA-21 and miRNA-155 might be potential biomarkers as onco-miR in HCC subjects, while miRNA-29c might act as a tumor suppressor. Significant evidence was identified with clinical progression based on the regulation of miRNAs, which was consistent with miRNA -29c.