AFP Level Research Articles

Diagnosis of the Initial Stage of Hepatocellular Carcinoma: A Review.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There may be more than a million instances of hepatocellular carcinoma by 2025, making it a persistent concern for global health. The most common form of hepatocellular carcinoma accounts for more than 90% of cases. There is no known cure for hepatocellular carcinoma, which is usually detected late in life. Unlike most other common malignancies, such as lung, prostate, and breast cancers, where mortality rates are declining, rates of death are rising by around 2-3% every year. It is extremely difficult to diagnose hepatocellular carcinoma in its early stages. Alpha-fetoprotein serology studies and ultrasonography (US) monitoring were historically the primary methods for early detection of hepatocellular cancer. However, the sensitivity or specificity of ultrasonography/alpha-fetoprotein (US/AFP) is not high enough to detect hepatocellular carcinoma in its early stages. Alpha-fetoprotein, or AFP, is an amino acid that is normally produced by the liver or yolk sac of an embryonic baby. In adults, AFP levels are typically modest. Adults with high levels of AFP have been associated with several illnesses, the most well-known of which are certain types of cancer. It is still possible to diagnose hepatocellular carcinoma early because of current technological advancements. We address the advancements in the diagnosis of hepatocellular carcinoma in this article, with a focus on new imaging techniques and diagnostic markers for early-stage tumor identification.

Efficacy and safety of regorafenib combined with PD-1 inhibitors in patients with advanced hepatocellular beyond atezolizumab plus bevacizumab: A retrospective analysis of real-world evidence.

e16172 Background: In patients with advanced hepatocellular carcinoma (HCC) progressing after atezolizumab and bevacizumab, the optimal therapy scheme is debatable and the efficacy of regorafenib combined with PD-1 inhibitors is still unclear. Methods: In this retrospective study, advanced HCC patients who received regorafenib combined with PD-1 inhibitors progressing after atezolizumab plus bevacizumab were consecutively enrolled from February 2022 to January 2024. Main efficacy endpoint was overall survival (OS), following progression free survival (PFS), evaluated in accordance with RECIST v1.1. Adverse events (AEs) were recorded according to CTCAE v5.0. Results: A total of 11 eligible patients were enrolled, with 8 in Child-Pugh A and 3 in Child-Pugh B7. All patients had hepatitis B infection by with tumor embolus. All patients were classified as Barcelona Clinic Liver Cancer stage C. The AFP level is above 400ng/ml in all patients. At data cut-off at February 2024, the median OS was 16.9 months and the median PFS was 3.7 months. The 3-month and 6-month PFS rates were 70% and 35% , respectively. The 12-month OS rate was 71.4%. Grade≥3 TRAEs occurred in 9.1% (1/11) of the patients. Conclusions: Though application of regorafenib combined with PD-1 inhibitors progressing after atezolizumab plus bevacizumab present safe and effective in our cohort, these data need to be confirmed in prospective comparative studies. [Table: see text]

Efficacy and safety of transarterial therapy combined with donafenib plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma: A multicenter retrospective study.

e16133 Background: Based on the different anti-malignant mechanisms of tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) and transarterial therapy, several studies have demonstrated the potential of combining these three treatments to improve outcomes in patients with unresectable hepatocellular carcinoma (uHCC). This study aimed to evaluate the efficacy and safety of transarterial therapy plus donafenib and ICIs for uHCC patients in a real-world setting. Methods: This multicenter retrospective study included patients with uHCC who had received at least one cycle of transarterial therapy (hepatic arterial infusion chemotherapy, HAIC, or transarterial chemoembolization, TACE) and donafenib and ICIs (anti-PD-1 available in China) at five cancer centers. Other key inclusion criteria were: (1) no prior systemic treatment; (2) at least one follow-up image data. The primary endpoint was progression-free survival (PFS) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Secondary endpoints included overall survival (OS), objective response rate (ORR) and toxicity. Results: Of the 61 eligible patients enrolled, 56 (91.8%) were men, 54 (88.5%) had HBV infection, 26 (42.6%) had AFP level > 400 ng/mL, 38 (62.3%) were at BCLC stage C, 32 (52.5%) had macrovascular invasion, 14 (23.0%) had extrahepatic metastasis, 47 (77.0%) had multiple tumors and the median maximum tumor size was 86.0 mm (IQR, 61.5–122.6). Four kinds of ICIs were employed, including tislelizumab (n = 29), camrelizumab (n = 21), sintilimab (n = 9), toripalimab (n = 2). Up to the date of November 24, 2023, the median follow-up time was 13.0 months. The median PFS was 12.7 months (95%CI, 8.4–NA), with a 1-year PFS rate of 52.7% (95%CI, 37.9%–73.1%). The median OS was not reached, and 1-year OS rate was 88.4% (95%CI, 79.9%–97.8%). The ORR according to mRECIST was 70.5%. Twelve (19.7%) patients had received conversion resection, and the median conversion time was 3.1 months (95%CI, 2.37–NA). Overall, 51 (83.6%) patients experienced at least one treatment-related adverse events (TRAEs), 22 (36.1%) had grade 3 or 4 AEs, and no patients died due to AEs. The most common AEs greater than 15% were hand-foot skin reaction (47.5%), liver dysfunction (27.9%), decreased platelet count (19.7%) and hypoalbuminemia (16.4%). Conclusions: This retrospective real-world study showed that transarterial therapy combined with donafenib plus ICIs in the treatment of uHCC patients was well tolerated and comparable clinical efficacy to other triple therapies. This combination strategy may be an appropriate treatment option for uHCC patients.

Hepatic artery infusion chemotherapy (HAIC) plus sintilimab and bevacizumab biosimilar (IBI305) in initial unresectable hepatocellular carcinoma (HCC): A retrospective study.

e16185 Background: Combining sintilimab with IBI305 has shown significant survival benefits over sorafenib in first-line HCC treatment. Our prior study has indicated improved outcomes with sintilimab and bevacizumab biosimilar (IBI305) in combination with HAIC for HCC (Clinical trial: NCT05029973). This study aims to evaluate combining HAIC with sintilimab and IBI305 for initial unresectable HCC in real word. Methods: Eligible patients (pts) had histologically or cytologically diagnosed or clinically confirmed HCC, with China liver cancer staging (CNLC) stage Ib-IIIb, no prior systemic treatment, Child-Pugh A or B, and ECOG 0 or 1. Patients were administered FOLOFOX-HAIC, combined with intravenous Sintilimab (200 mg, Q3W) and intravenous IBI305 (7.5 mg/kg, Q3W). Primary endpoints included objective response rate (ORR) and disease control rate (DCR) per modified Response Evaluation Criteria in Solid Tumors (mRECIST). Secondary endpoints included surgical conversion rate, R0 resection rate, and pathological complete response (pCR) rate. Results: Data were collected from 106 patients (from Apr, 2021 to Jul, 2023), median age 61, with the majority being male (91, 85.9%), ECOG 0 (106, 100%), and classified as Child-Pugh A (82, 77.4%). CNLC staging: Ib (19), IIa (2), IIb (20), IIIa (42), IIIb (23). HBV infection: 84 (79.3%), HCV: 3 (2.8%). AFP levels were > 400ng/ml in 53 patients (50.0%), with tumor diameters > 10 cm in 47 patients (44.3%). Single tumors were noted in 35 patients (33.0%), vascular invasion in 60 patients (56.6%), and extrahepatic metastasis in 26 patients (24.5%). Among the 106 patients evaluable for response, ORR was 39.6% with 42 patients demonstrating partial responses (PR); DCR was 96.2% (102/106), comprising 42 PR, 60 stable disease (SD). The surgical conversion rate was 40.56% (43/106), achieving R0 resection in all 43 patients and complete pathological response (pCR) in 9/43(20.9%) patients and major pathological response (MPR) in 12/43 (27.9%). The 1-year progression-free survival (PFS) and overall survival (OS) rates were 54.5% and 74%, respectively. The 2-year PFS and OS rates were 41.4% and 58.6%, respectively. No new safety signals were observed, and no treatment-related adverse events (TRAEs) led to death. Conclusions: Combining HAIC with Sintilimab and IBI305 as conversion therapy for unresectable HCC shows promising benefits with manageable safety.

Predictors of poor response to immune-checkpoint inhibitor (ICI) treatment among patient with hepatocellular carcinoma (HCC).

e16212 Background: No established risk factors or toxicity biomarkers exist for HCCs treated with ICI, even though they are commonly used in clinical practice. The outcomes in real-world practice are worse than those reported in clinical trials. This retrospective review aims to identify HCC patients at high risk of failing ICI therapy. Methods: HCC patients who received at least one ICI dose between 1/1/2017 and 5/30/2023 (before tremelimumab/durvalumab approval) at the Ohio State University were included in this study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse event (irAE) details and survival outcomes. We examined BL characteristics significantly different in poor (progression-free survival (PFS) ≤ median (m)) and worst (PFS ≤ 25% percentile) responders, and poor (overall survival (OS) ≤ m) and worst (OS ≤ 25% percentile) survivors. Chi-square test and logistic regression were performed using JMP Pro 17 (SAS Institute Inc., Cary, NC). Results: Our cohort included 53 HCC patients. The median age was 66 years (range 40-86), with 81% male and 85% White (13% African American and 2% other). The median OS and PFS were 19 months (m) (95% confidence interval [CI], 8-26) and 5m (95% CI, 2-9), respectively. The poor responders (PFS ≤5m, N = 30) had patients with significantly higher alcohol history (AHx, 90% vs. 70%) and mean alpha-fetoprotein (AFP, 44, 155 vs. 811 ng/mL) levels, a higher proportion of Child-Pugh (CP) C (A/B/C %, 53/27/20 vs. 53/47/0), and negligible bevacizumab (bev, 77 vs. 24) use, all (p < 0.05). The worst response group (PFS ≤2m, N = 16), furthermore, had significantly (p < 0.05) higher Albumin-bilirubin (ALBI) grade (G) 3 patients (50% vs. 16%), higher mean total bilirubin (2 vs. 1,2 ng/mL), lower tyrosine-kinase inhibitor (TKI, 7% vs. 46%), and lower mean albumin (Ab, 3 vs. 3.4) levels. A significantly (p < 0.05) higher fraction (fx) of poor survivors (OS ≤19m, N = 33) got ICI In the first or second line (85% vs. 45%) and did not receive any locoregional therapy (LRT, 66% vs. 35%). The worst survivors (OS ≤8m, N = 14) got ICI in the first line (100% vs. 59%, p = 0.04, and significantly (p < 0.05) lower Alb (3 vs. 3,4) and higher AFP (90620 vs. 3104) levels. The irAE group (N = 10, 19%) had higher AFP (115289 vs. 3482, p = 0.01) and a lower distant metastasis rate (20% vs. 58%, p = 0.02), and none of them received bev (0% vs. 30, p = 0.04). Conclusions: Response to ICI depends on BL liver function (AHx, ALBI, CP, Alb) and combination therapy (bev). Survival depends on HCC management up to the administration of ICI (LRT and TKI).

Updated results from first-in-human phase 1 dose-escalation trial of TAK-102, a GPC3-targeted armored CAR T cells, in patients with advanced solid tumors.

2543 Background: Glypican 3 (GPC3) is a member of the glypican family of heparan sulfate proteoglycans that are attached to the cell surface by a glycosylphosphatidylinositol anchor. High GPC3 expression rates are reported in numerous cancer types with a high unmet medical need, including hepatocellular carcinoma (HCC). TAK-102 is a GPC3-targeted autologous chimeric antigen receptor T cell (CAR-T) immunotherapy armored with IL-7 and CCL19. The addition of IL-7 and CCL19 to the construct was designed to support the expansion of memory subsets and persistence of CAR-T cells. We hypothesized TAK-102 would help overcome the challenges associated with an immunosuppressive tumor microenvironment that limit the activity of nonarmored CAR-T therapies in solid tumors. Methods: The first-in-human, Phase 1 dose escalation study evaluated TAK-102 in patients (pts) with GPC3-expressing solid tumors who were refractory or intolerant to standard treatments. TAK-102 was administered via a single infusion to 3 dose cohorts after lymphodepleting chemotherapy (LDC; consisting of fludarabine and cyclophosphamide): dose level (DL) 1 (starting cohort), 1x107 CAR+ cells/body; DL2, 1x108 CAR+ cells/body; DL3, 5x108 CAR+ cells/body. Objectives included evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, cellular kinetic (CK) parameters, tumor markers, cytokine/chemokine and antitumor activity based on RECIST 1.1. Results: Eleven pts were enrolled and infused TAK-102 (DL1: 3 pts, DL2: 3 pts, DL3: 5 pts): 1 gastric neuroendocrine carcinoma, 2 liposarcoma, 8 HCC. Five pts achieved stable disease (SD), HCC (GPC3 H-Score: 36) . In patients achieving SD, the greatest reduction in tumor size was 26.4%. No DLTs or neurotoxicity were observed. Six pts experienced cytokine release syndrome (Grade1: 5 pts, Grade2: 1 pt); all cases were manageable. AFP was measured as a tumor marker for HCC. Among 8 pts with HCC, 4 had SD after treatment with TAK-102 and 3 showed a decrease or stabilization of AFP levels corresponding to their clinical status. CK profiles for pts were assessed by flow cytometry and qPCR-based assays. Overall, there was improvement in TAK-102 exposure (Cmax, AUC) when escalating from DL1 to DL2. There was a slight decrease in Tmax from DL2 to DL3. Homeostatic cytokine (IL-7) spiked post-LDC and showed no further increase after TAK-102 infusion across all the DLs. There was dose-dependency observed in peak CCL19, IFN-γ and IL-6 levels. Conclusions: TAK-102, an armored CAR-T, is well tolerated and has a manageable safety profile with some early signs of anti-tumor activity. For CK, TAK-102 exposure (Cmax, AUC) showed improvement from DL1 to DL2, and slight decrease in Tmax from DL2 to DL3. Dose-dependency was observed in peak CCL19, IFN-γ and IL-6 levels, which may point towards increased signal of activity from DL1 to DL3. Clinical trial information: NCT04405778 .

Temporal dynamics and prognostic significance of cancer free status in patients with intermediate stage hepatocellular carcinoma: A multicenter cohort study.

e16236 Background: A proportion of patients with intermediate stage hepatocellular carcinoma (HCC) can achieve cancer free status (CFS) during treatment, the prognostic value of CFS across the period of dynamic surveillance and treatment remained unknown. Methods: This longitudinal cohort study examined data from the electronic medical record system of four hospitals in China between January 1, 2007 to May 31, 2019. The data from Sun Yat-sen University Cancer Center served as the derivation cohort and other centers as testing cohort. The time-series data were converted into data of time slices, with an interval of three months. Image CFS is defined as patients with no evidence of disease based on imaging exams after treatment and Image-Bio CFS is defined as achievement of Image CFS, together with normal AFP level. Based on the dynamic changes of disease during treatment, patients at specific time slice were classified into either “Arrive”, “Maintain”, or “Not reached” CFS subgroups. The correlations between CFS subgroups and overall survival (OS) were determined by Cox regression. Results: A total of 945 (42.2%) and 741 (33.1%) patients in derivation cohort reached Image CFS and Image-Bio CFS during treatment, respectively. The corresponding rates for Image CFS and Image-Bio CFS in testing cohort were 155 (37.4%) and 130 (31.4%), respectively. Maintaining Image CFS or Image-Bio CFS, rather than just arrive Image CFS or Image-Bio CFS, had stable predictive value for improved OS across different time slices. The merged Hazard ratio of Maintain Image-Bio CFS was 0.23 (95%CI, 0.20-0.25, P < 0.001). The patients achieved Image-Bio CFS could be further classified into three subgroups with differential prognosis based on duration of CFS (≤ 4.5months; 4.5-18.0 months; > 18.0 months). Maintaining Image-Bio CFS for more than 18.0 months predicted long term survival (5-year OS: 91.2% in derivation cohort, 94.7% in testing cohort). Conclusions: Maintaining CFS, rather than just arrive CFS, is a key marker of favorable survival during dynamic management of intermediate stage HCC. A duration of Image-Biochemical CFS for more than eighteen months predicts long-term survival.

Efficacy and safety of donafenib as adjuvant therapy for patients with hepatocellular carcinoma undergoing curative resection: A retrospective, multicenter cohort study.

e16234 Background: A growing incidence of hepatocellular carcinoma and its high risk of recurrence after curative-intent treatment underscore the need for effective adjuvant treatment options. This study aimed to assess the efficacy of adjuvant donafenib in patients with hepatocellular carcinoma (HCC) following radical resection. Methods: This multicenter, real-world study retrospectively gathered clinical data of 82 patients who had undergone radical resection of HCC and received adjuvant therapy with donafenib. The primary endpoint was recurrence-free survival (RFS). The secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analysis was performed to evaluate RFS and OS, while the Cox proportional-hazards model was used to estimate risk factors for tumor recurrence and death. Results: A total of 82 patients with HCC who received donafenib following surgical resection were included in the study, of which were classified as high risk for tumor recurrence (with multiple or large tumor, microvascular invasion, poor tumor differentiation). The median duration of donafenib adjuvant therapy was 10.6 months (range: 0.2–26.1 months). All patients completed follow-up as required, with a median follow-up time of 19.4 months (range: 2.8–57.6 months). During the follow-up period, a totally postoperative recurrence rate was 15.9% (13/82). 1-year recurrence rate and 2-year recurrence rate were 7.3% (6/82) and 12.2% (10/82), and 1-year survival rate and 2-year survival rate were 95.1% (78/82) and 93.9% (77/82). Kaplan-Meier analysis demonstrated that patients with higher preoperative AFP level (AFP > 400ng/mL), higher preoperative PIVKA-II level (PIVKA-II > 40mAU/mL), or poor tumor differentiation (Edmondson stage III-IV) exhibited higher rate of tumor recurrence after operation (all p value < 0.05). Multivariate analysis indicated that preoperative AFP level was an independent risk factor for tumor recurrence in patients with donafenib treatment. Treatment-related adverse events (TRAEs) occurred in 67.1% (55/82) of patients, of which the most frequent were hand-foot syndrome (25.6%, 21/82), diarrhea (20.7%, 17/82), and fatigue (17.1%, 14/82). Only 8.5% (7/82) of patients had a grade ≥3 TRAEs, with the most common being hand-foot syndrome (2.4%, 2/82) and hypertension (2.4%, 2/82). No treatment-related deaths were reported. Conclusions: This study represents the largest multicenter investigation of adjuvant therapy with donafenib to date, and the findings indicate that donafenib has the potential to be an effective treatment option for preventing postoperative recurrence in HCC. Furthermore, the preoperative AFP ≤400ng/mL can serve as an effective biomarker for postoperative administration of donafenib in HCC patients.

Association of chr11q13 amplification with survival and recurrence in patients with surgically treated hepatocellular carcinoma.

e16253 Background: Hepatocellular carcinoma (HCC) is a highly lethal and aggressive malignant tumor characterized by high rates of recurrence and metastasis, and low survival outcomes. The current treatments available for HCC have shown limited success, and the prevalence of genomic characterization and their association with survival and recurrence in HCC patients are largely unknown. Methods: The investigation enrolled 1,221 Chinese individuals diagnosed with primary HCC. This study collected samples including tumor and paired tumor-free tissues and clinical characteristics. Among them, 348 patients' clinical outcome data, including overall survival (OS) and recurrence-free survival (RFS) were gathered. Genomic analysis was conducted through panel sequencing by OrigiMed. Hazard ratios were calculated employing both univariate and multivariate Cox proportional hazards regression models. The log-rank test and Kaplan-Meier plots were used to assess comparison of clinical outcomes by various prognostic factors. For other statistical analyses, a two-tailed unpaired t-test and Fisher's exact test were applied. Results: With a median age of 54, 87% of the cases were male. Pertaining to risk factors, 74% cases had HBV infection and 62% cases were cirrhosis. Meanwhile, serum AFP levels greater (or less) than 400 ng/mL were present in 299 cases (or 485 cases). Panel sequencing identified the most prevalent mutations ( > 10%, excluding copy number variations) in TP53 (60%), TERT (40%), CTNNB1 (21%), AXIN1 (14%), LRP1B (14%), ARID1A (13%), RB1 (12%) and TSC2 (11%). The most frequently amplified genes were located at chr11q13, including CCND1 (9%), FGF19 (9%), FGF4 (7%) and FGF3 (7%). Survival analysis indicated that patients with Chr11q13 amp had significantly shorter OS and RFS. Further studies revealed a higher incidence of Chr11q13 amp in patients at advanced stages III/IV (64/564, 11%) compared to early-stage I/II (38/523, 7%), and in patients with vascular invasion (31/220, 14%) versus those without (44/599, 7%). No significant differences were observed in tumor mutational burden and HLA-I evolutionary divergence between patients with various Chr11q13 amp statuses. Furthermore, multivariate Cox proportional hazards regression models were utilized to examine the relationship between Chr11q13 amp status, characteristics and outcomes. Among the 248 patients with comprehensive clinical characteristics and available OS and RFS data, analyses indicated significant negative correlations between Chr11q13 amp and embolus with both OS and RFS. Conclusions: Our study elucidates that the presence of Chr11q13 amp was significantly associated with worse survival and increased risk of recurrence among a large cohort of Chinese patients with HCC. This discovery yields important insights into the understanding of HCC and has the potential to benefit personalized therapy.

HEPATOCELLULAR CARCINOMA IN CHILDREN: 2 CASE REPORT

Background:Hepatocellular carcinoma (HCC) is the second most common liver cancer in children.In this article we sought, through our two observations, to examine the evolving clinical aspect as well as the therapeutic management of hepatocellular carcinoma in children, since this affection is rare in the childhood. Case presentation:We report two cases of hepato carcinoma. The first case of an 11-year-old girl from Marrakech with glycogenosis complicated by hepatic cirrhosis at the portal hypertension stage. After diagnostic confirmation; the patient benefited from systemic treatment with Atezolimumab + Bevacizumab with good progress in the short term (5 months follow-up). The second case concerns a 14-year-old girl from Marrakech region with hepato carcinoma on a healthy liver who received the same treatment but the evolution was marked in the long term by an increase in the size of the mass and portal hypertension and death at age 17 years old. Conclusion: HCC is rare in childhood. The etiological predisposition and biological behavior differ from adults. In cases of cirrhosis or liver disease, HCC must be suspected based on a high AFP level and an abnormal nodule on ultrasound. Hepatoblastoma should be considered first in the differential diagnosis. Treatment of pediatric HCC is difficult. Complete surgical resection is essential to cure it. For tumors that cannot be resected, liver transplantation is decided on a case-by-case basis. However , HCC remains difficult to treat as cure requires complete surgical resection.

Evaluation of the risk of developing hepatocellular carcinoma in chronic Hepatitis C patients receiving antiviral treatment.

Chronic HC leads to the development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The treatment of chronic HC with DAAs reduces mortality from LC and HCC.The study aimed to investigate the serological markers specific to HCC (PIVKA-II and AFP) in patients with chronic HC before and after DAA treatment. The study involved 35 HCV patients (mean age: 56.23 ± 1.45) divided into two groups. Group 1 included 15 HCV + HCC patients and Group 2 included 20 HCV non-HCC patients. At the end of treatment all the patients were HCV RNA negative. Three months after the end of antiviral treatment, HCV RNA was undetectable in all patients, while a complete biochemical and virological response was observed in 66.7% of HCV + HCC patients and 85.0% of HCV non-HCC patients. PIVKA-II levels before the initiation of antiviral treatment were high in all patients. At the end of the treatment, in the HCV non-HCC group, normalization of PIVKA-II levels was observed only in 20.0% cases, and in 60.0% of cases 3 months after the treatment. Meanwhile, in patients with HCC and chronic HCV, PIVKA-II levels were within the normal range 3 months after treatment in only 13.3% of patients. It is necessary to monitor HCV patients with cirrhosis (F4) and severe fibrosis (F3) without HCC, who have high PIVKA-II and AFP levels and/or ALT activity despite obtaining sustained virologic response 3 months after treatment with DAAs.

Comparative Immunohistochemical Analysis of Clinicopathological Subgroups in Hepatocellular Carcinomas from Japan and Indonesia

BackgroundStandardized pathological evaluation based on immunohistochemical (IHC) analysis could improve HCC diagnoses worldwide. We evaluated differences in clinicopathological subgroups in HCCs from two academic institutions in Tokyo-Japan, and Jakarta-Indonesia. MethodsClinicopathological parameters and molecular expression patterns were evaluated in 35 HCCs from Indonesia and 41 HCCs from Japan. IHC analysis of biliary/stem-cell (B/S) markers (cytokeratin 19, sal-like protein 4, epithelial cell adhesion molecule) and Wnt/β-catenin (W/B) signaling-related molecules (β-catenin, glutamine synthetase) could determine the IHC-based subgroups. For immunosubtypes categorization, CD3/CD79α double immunohistochemistry was done to evaluate the infiltration of T and B cells. CD34 staining allowed identification of vessels that encapsulated tumor clusters (VETC). ResultsIndonesian HCC patients were mostly <60 years old (66%) with a hepatitis B virus (HBV) background (82%), in contrast to Japanese HCC patients (8% and 19%, respectively, both P<0.001). In comparison with Japanese, Indonesian cases more frequently had >5 cm tumor size (74% vs 23%, P=0.001), poor differentiation (40% vs 24%), portal vein invasion (80% vs 61%), and AFP levels >500 ng/ml (45% vs 13%, P=0.005). No significant differences were found in the proportions of B/S, W/B, and -/- subgroups from both countries. No Immune-high tumors were observed among Indonesian cases, and Immune-low tumors (66%) were more common than in Japanese cases (54%). VETC-positive tumors in Indonesia were significantly more common (29%), and most were in the HBV (90%) and -/- subgroups (90%), whereas Japanese VETC cases (10%, P=0.030) were nonviral (100%) and W/B subgroups (75%). ConclusionIHC-based analysis more precisely reflected the clinicopathological differences of HCCs in Japan and Indonesia. These findings provide new insights into standardization attempts and HCC heterogeneity among countries.

L-arginine combination with 5-fluorouracil inhibit hepatocellular carcinoma cells through suppressing iNOS/NO/AKT-mediated glycolysis.

L-arginine can produce nitric oxide (NO) under the action of inducible nitric oxide synthase (iNOS), while 5-fluorouracil (5-FU) can induce the increase of iNOS expression. The present study was to investigate the mechanism of L-arginine combined with 5-FU regulating glucose metabolism of hepatocellular carcinoma (HCC) through iNOS/NO/AKT pathway. The combination of L-arginine and 5-FU resulted in decreased cell survival and exhibited synergistic cytotoxic effects in HepG2 and SMMC7721 cells. Meanwhile, L-arginine increased 5-FU inhibitory effect on HepG2 and SMMC7721 cells by increasing NO production. Co-treatment with L-arginine and 5-FU resulted in a significant decrease in both G6PDH and LDH enzymatic activities, as well as reduced levels of ATP and LD compared to treatment with L-arginine or 5-FU alone. Moreover, the combination of L-arginine and 5-FU resulted in a decrease in the expression of GLUT1, PKM2, LDHA, p-PI3K and p-AKT. Furthermore, the combination demonstrated a synergistic effect in downregulating the expression of HIF-1α and β-catenin, which were further diminished upon the addition of shikonin, a specific inhibitor of PKM2. LY294002 treatment further reduced the expression of GLUT1, PKM2, and LDHA proteins induced by combined L-arginine and 5-FU treatment compared to the combined group. However, the reduction in p-PI3K, p-AKT, and GLUT1 expression caused by L-arginine and 5-FU combination was also reversed in HepG2 and SMMC7721 cells with iNOS knockdown, respectively. Additionally, the combination of L-arginine and 5-FU led to a greater reduction in the enzymatic activity of ALT, AST, G6PDH and LDH, as well as a significant reduction in hepatic index, AFP, AFP-L3, ATP and LD levels in a rat model of HCC. Moreover, the simultaneous administration of L-arginine and 5-FU significantly improved the gross morphology of the liver, reduced nuclear atypia, inhibited the proliferation of cancer cells, and decreased the expression levels of p-PI3K, p-AKT, GLUT1, PKM2, and LDHA, while iNOS expression was increased in the combination group. Taking together, L-arginine and 5-FU combination resulted in the inhibition of enzymes in aerobic glycolysis via the iNOS/NO/AKT pathway, which led to the suppression of glucose metabolism and downregulation of nuclear transcription factors, thereby impeding the proliferation of hepatocellular carcinoma cells.

ASSESSEMENT IN PERFORMANCE OF LI-RADS ALGORITHM IN DETECTING TREATMENT RESPONSE OF HEPATOCELLULAR CARCINOMA AFTER TRANS-ARTERIAL CHEMOEMBOLIZATION

Background:Trans-arterial hemoembolization (TACE) usually indicated for unresectable hepatocellular carcinoma (HCC) on purpose as a bridging, downstaging or palliative treatment. Liver Imaging Reporting and Data Systems Treatment Response (LR-TR) was created to evaluate each lesion post-TACE, which has localized and is suitable for determining whether the tumor is still viable or Non-viable. Purpose: To assess the completion of LI-RADS version 2018 on computer tomography in the evaluation of HCC after TACE. Materials and Methods: A retrospective cross-sectional study involved 58 patients with hepatocellular carcinoma (HCC) who underwent treatment base TACE from June 2021 – September 2022. The clinical situation, AFP levels, and computer tomography (CT) of the patient after treatment were analyzed. The Radiologist evaluated pre- and post-treatment CT findings using LR-TR category, appropriately. The pooled sensitivity, specificity, and accuracy correclated between LR-TR with standard reference. Results: A total 58 patients with HCC (M/F: 13:1, mean age 56.9±11.0 years). For demonstrating the treatment response after first TACE on CT, Non-viable resulted in 32.8%(19/58), and LR-TR Viable was 67.2%(39/58), sensitivity value of 90% (36/40), specificity value of 83.3% (15/18), positive predictor value of 16.7% (3/18), a negative predictor value of 10% (4/40), accuracy value of 87.9% (51/58). The performance status response- AFP response- imaging response correlation was not statistically different, p= 0.552 and p=0.647. Conclusion: Using LR-TR on CT detects treatment response of HCC post-TACE was useful, and high sensitivity, specificity, and accuracy.

Hepatic artery infusion chemotherapy combined with camrelizumab plus rivoceranib for hepatocellular carcinoma with portal vein tumor thrombosis: a multicenter propensity score-matching analysis

BackgroundPortal vein tumor thrombosis (PVTT) signifies late-stage hepatocellular carcinoma (HCC) with high-risk progression and poor prognosis. As a standard treatment, sorafenib monotherapy has limited the efficacy in managing HCC with PVTT. Currently, both hepatic arterial infusion chemotherapy (HAIC) and the combination of camrelizumab and rivoceranib have shown favorable survival benefits for advanced HCC, surpassing the standard sorafenib treatment. In this study, we investigate the safety and efficacy of HAIC combined with camrelizumab and rivoceranib in treating HCC patients with PVTT.MethodsFrom January 2020 to December 2021, HCC patients with PVTT, who received either a triple regime of HAIC combined with camrelizumab and rivoceranib or a dual regime of camrelizumab and rivoceranib as their first-line treatment, were reviewed for eligibility at four hospital centers in China. To balance any intergroup differences, propensity score matching (PSM) was applied. The aim of this study is to compare the efficacy of the dual and triple combination treatment regimens based on survival prognosis and tumor response and evaluate the safety based on the occurrence of adverse reactions.ResultIn this study, a total of 411 patients who received either the triple treatment regime (HAIC combined with camrelizumab plus rivoceranib, referred to as the HAICCR group, n = 292) or the dual treatment regime (camrelizumab combined with rivoceranib, referred to as the CR group, n = 119) between January 2020 and December 2021 were included. The results showed that the HAICCR group exhibited significantly better overall survival (mOS: 19.60 months vs. 11.50 months, p < 0.0001) and progression-free survival (mPFS: 10.0 months vs. 5.6 months, p < 0.0001) compared to the CR group in the overall cohort. Moreover, the HAICCR group also had a significantly higher ORR (objective response rate, 55.5% vs. 42.0%, p = 0.013) and DCR (disease control rate, 89.0% vs. 79.0%) compared to the CR group. After PSM, a final matched cohort of 83 pairs was obtained, and the survival benefits were consistent in this cohort as well (mOS: 18.70 months vs. 11.0 months, p < 0.0001; mPFS: 10.0 months vs. 5.6 months, p < 0.0001). However, there was no significant difference in the ORR between the triple and dual combination regimes. Univariate and multivariate analysis showed that CTP (Child–Turcotte–Pugh) stage, ALBI (albumin–bilirubin index) grade, tumor number, and treatment regime were significant risk factors affecting overall survival, while AFP (α-fetoprotein) level, tumor number, metastasis, and treatment regime were significant risk factors affecting progression-free survival. As for safety, hypertension and hand–foot syndrome were the two most common adverse reactions in both groups, with no significant difference in the occurrence of adverse reactions between the two groups (p < 0.05).ConclusionIn the context of advanced HCC patients with PVTT, the combination regime of HAIC and camrelizumab plus rivoceranib demonstrates more excellent capacity for prolonging survival and offers a well-tolerated safety compared to the CR dual therapy approach. This triple regime represents a therapeutic modality of broad prospects and vast potential for HCC patients with PVTT.

Hepatocellular carcinoma in hepatitis C virus patients treated with direct acting antivirals (DAAs) and patients not exposed to DAAs: a large center comparative study

BackgroundHepatocellular carcinoma (HCC) is the first cause of cancer in Egypt. Recently, HCC developed post direct-acting antivirals (DAAs) differ in some characteristics from those developed without DAAs exposure regarding the biological features and behavior of HCC. We aimed to assess the epidemiological, clinical, laboratory, and radiological findings besides the biological behavior of HCC patients post DAAs in comparison to HCC not exposed to DAAs. An analytic cross-sectional research was performed at the National Liver Institute which is a tertiary multidisciplinary HCC center. Subjects included hepatitis C virus patients and were allocated into two groups: group I included 2036 HCC cases post-DAA treatment and group II included 6338 HCC cases who did not receive DAAs. Subjects were examined to evaluate clinical, laboratory, and radiological findings. Tumor staging was done using the BCLC staging system.ResultsGroup II showed a more advanced Child–Pugh score, FIB-4 index, and MELD score than Group I (P = 0.001). The multiplicity of hepatic focal lesions was elevated in group I than in group II (P = 0.033). AFP level was significantly elevated in group I than in group II (p = 0.012). Portal vein invasion was significantly elevated in group I than in group II patients (P = 0.001). Extrahepatic spread of HCC was significantly elevated in group I than in group II (P = 0.001). Infiltrative lesions were significantly elevated in group I than in group II (P = 0.002).ConclusionOur study detected that the behavior in HCC post DAAs treatment is more aggressive in respect of the number of lesions, PV invasion; local and distant metastasis, and serum AFP level than in patients unexposed to DAAs. Strict surveillance in cirrhotic patients treated with DAA should be followed according to the international guidelines for early diagnosis and treatment of HCC.

Outcome of MAFLD-related HCC in Egyptian patients: a single center study

BackgroundGlobally, MAFLD becomes in the top list of causes of liver disease. Its effect ranges from steatosis, metabolic steato-hepatitis to MAFLD-related cirrhosis and hepatocellular carcinoma. There is a growing evidence that MAFLD-related HCC seems to be different from HCCs of other causes pathologically, so the purpose of our study was to assess the effect of MAFLD on the prognosis of HCC regarding outcome after management of HCC and survival rate in comparison to a group of patients with HCV-related HCC.ResultsTwenty-nine patients with MAFLD related HCC were included in group A, while 58 patients with HCV related HCC were enrolled as group B. Both groups were matched regarding age and gender. The mean age in group A and B was 58.86 (±8.47) years and 60/05(± 6.83) years respectively. Comparison between both groups regarding tumor burden and characteristics of HCC, type of management, and post intervention follow-up showed no significant statistical difference between both groups except for lymph node metastases which was higher in patients with HCV related HCC with p = 0.045. Also, a significant difference between both studied groups regarding AFP was detected; the median of AFP in MAFLD-related HCC was (7.2 ng/ml) but much higher in HCV-related HCC group (129.2 ng/ml) with p = 0.001.ConclusionOur data showed no significant difference between the two studied groups regarding outcome of HCC or survival rate except for AFP level before and after management which was higher in HCV patients related HCC. Although both of inclusion and exclusion criteria were strict to the criteria, so the number of participants in the research were not large enough; to our knowledge, this is the first study on MAFLD-HCC in Egypt and Africa. More studies on prospective bases are essentially needed to stand on solid conclusion about the nature and outcome of MAFLD-related HCC.

Ameliorative effect of licorice extract against the detrimental effect of glyphosate-based pesticide: Toxicity and health

This study sheds the light on the potential of licorice (Glycyrrhiza glabra) root aqueous extract as a cornerstone for mitigating and detoxifying the residues of the widely used agricultural Glyphosate-based pesticides (GBPs). This study examined the GBPs toxic effects on kidney, liver, thyroid functions, and apoptosis using 50 adult male albino rats. All rats were divided into 5 groups, with 10 each. Control: served as untreated rats. GBP: rats were treated with 1 mL glyphosate solution 24 % orally for three weeks. The glyphosate-treated rats were gavaged with licorice root aqueous extractsolution (100, 200, and 300 mg/mLdistilled water, respectively) daily for three weeks. Licorice root aqueous extract solution (300 mg/mL distilled water) yielded notable reductions in liver, kidney enzymes, albumin, and AFP levels within the serum. Immunological tests, including immunohistochemical evaluations of caspase-3 and TNF-α expressions revealed a dose-dependent attenuation of apoptosis and inflammation with licorice intervention. This will provide a valuable perspective for agricultural practices future and paving the way for a more sustainable approach for using GBPs in animal agriculture industries.

Establishing Neonate-Specific Prognostic Markers in Acute Liver Failure: Admission Alpha Fetoprotein and Novel Neonatal Acute Liver Failure Scores Predict Patient Outcomes

ObjectivesTo develop neonate-specific prediction models for survival with native liver (SNL) in neonatal acute liver failure (ALF) and to determine if these prediction models have superior accuracy to existing models for older children with ALF. Study designA single-center, retrospective chart review was conducted on neonates ≤ 30 days of life between 2005 and 2022 with ALF (INR ≥ 2 or prothrombin time [PT] ≥ 20s and liver dysfunction). Statistical analysis included comparison of patients by outcome of SNL and generalized linear modeling to derive prediction models. The predictive accuracy of variables was evaluated by receiver operating characteristic (ROC) analysis and Kaplan-Meier survival analysis. Results51 patients met inclusion criteria. The most common causes of neonatal ALF included ischemia (22%), infection (20%), and gestational alloimmune liver disease (GALD) (16%). Overall SNL rate was 43% (n=22). AFP levels were higher in SNL patients (p=0.034) and differed more significantly by SNL status among non-GALD patients (n=21, p=0.001). An AFP < 4775 ng/mL had 75% sensitivity and 100% specificity to predict death or transplant in non-GALD patients with an area under the ROC curve (AUROC) of 0.81. A neonate-specific admission model (INR and ammonia) and peak model (PT and ammonia) also predicted SNL with good accuracy (AUROC = 0.73 and 0.82 respectively). ConclusionsWe identified neonate-specific prognostic variables for SNL in ALF. Findings from our study may help early risk stratification to guide medical decision-making and consideration for liver transplantation.

Current Roles of Ramucirumab in the Sequential Treatment of Unresectable Hepatocellular Carcinoma.

The treatment algorithm for systemic therapies for advanced hepatocellular carcinoma (HCC) has changed dramatically; however, the therapeutic landscape for sequential second-line or later-line treatments, including ramucirumab, remains controversial. This study aimed to investigate the role of ramucirumab for treating HCC. We retrospectively analyzed data from 17 patients with advanced HCC who received ramucirumab, and 8 of them who received lenvatinib re-administration after ramucirumab treatment failure. The median overall survival of 17 patients treated with ramucirumab was 11.5 months. The median ratios of the 1-month post-treatment α-fetoprotein (AFP) levels and albumin-bilirubin (ALBI) scores to the pre-treatment AFP levels and ALBI scores following ramucirumab treatment were 0.880 and 0.965, respectively. The median ratios of the 1-month post-treatment AFP and ALBI levels to the pre-treatment levels were 1.587 and 0.970 for mALBI grade 1/2a, and 1.313 and 0.936 for mALBI grade 2b/3, respectively. Six of the eight patients who received lenvatinib rechallenge treatment exhibited a decrease in AFP levels one month post-lenvatinib treatment. Deterioration of liver function 3 months post-lenvatinib treatment was noted in five of the eight patients who received lenvatinib rechallenge treatment after ramucirumab. Ramucirumab may be equally useful in patients with unresectable HCC who have poor liver function or whose liver function is aggravated by other therapies. Rechallenge treatment with lenvatinib after ramucirumab may be a valid treatment option for HCC.