Prediction of Microvascular Invasion and Its M2 Classification in Hepatocellular Carcinoma Based on Nomogram Analyses

Background and AimsAs a key pathological factor, microvascular invasion (MVI), especially its M2 grade, greatly affects the prognosis of liver cancer patients. Accurate preoperative prediction of MVI and its M2 classification can help clinicians to make the best treatment decision. Therefore, we aimed to establish effective nomograms to predict MVI and its M2 grade.MethodsA total of 111 patients who underwent radical resection of hepatocellular carcinoma (HCC) from January 2015 to September 2020 were retrospectively collected. We utilized logistic regression and least absolute shrinkage and selection operator (LASSO) regression to identify the independent predictive factors of MVI and its M2 classification. Integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were calculated to select the potential predictive factors from the results of LASSO and logistic regression. Nomograms for predicting MVI and its M2 grade were then developed by incorporating these factors. Area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were respectively used to evaluate the efficacy, accuracy, and clinical utility of the nomograms.ResultsCombined with the results of LASSO regression, logistic regression, and IDI and NRI analyses, we founded that clinical tumor-node-metastasis (TNM) stage, tumor size, Edmondson–Steiner classification, α-fetoprotein (AFP), tumor capsule, tumor margin, and tumor number were independent risk factors for MVI. Among the MVI-positive patients, only clinical TNM stage, tumor capsule, tumor margin, and tumor number were highly correlated with M2 grade. The nomograms established by incorporating the above variables had a good performance in predicting MVI (AUCMVI = 0.926) and its M2 classification (AUCM2 = 0.803). The calibration curve confirmed that predictions and actual observations were in good agreement. Significant clinical utility of our nomograms was demonstrated by DCA.ConclusionsThe nomograms of this study make it possible to do individualized predictions of MVI and its M2 classification, which may help us select an appropriate treatment plan.

SERUM AFP (ALPHA FETO PROTEIN) LEVELS PROFILE OF HEPATOCELLULAR CARCINOMA PATIENTS IN DR. SOETOMO GENERAL ACADEMIC HOSPITAL, SURABAYA, INDONESIA

Higlight:1. The USG results of AFP level can be used for early detection and therapy of hepatocellular carcinoma that can prevent metastasis, progressivity, and recurrence. 2. The most common patients with high AFP levels are those with hepatitis B depending on etiology, younger age, male, gender, high SGOT level and BCLC B patients.Abstract:Background: Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancer which is the second most common cause of cancer-related death worldwide. The incidence of HCC was 626.000 cases every year worldwide. Early detection and therapy can prevent metastasis, progressivity, and recurrence. AFP level ≥ 400 ng/ml and USG results can be used as a diagnosis parameter of hepatocellular carcinoma. Objective: To analyze the AFP level’s profile in hepatocellular carcinoma. Materials and Methods: Descriptive methods used in this study with data collected from medical records on patients that fulfilled the inclusion criteria in Dr. Soetomo General Academic Hospital, Surabaya, Indonesia during the periods of 1st January 2013- December 31st 2015. This study used various variables such as age, gender, etiology and size of the tumor, number of a nodule, hepatic function with child classification, staging BCLC, and AFP level. Results: This study found that the 98 patients with hepatocellular carcinoma with high AFP level or >400 ng/ml were dominated by younger patients with average age of 49.91 years, the most common etiology was hepatitis B (56.8%), poor results of laboratory tests (SGOT, SGPT), patients with all level of hepatic function based on Child-Pugh classification and staging B of the tumor (70.5%). Patients with normal AFP ≤20 ng/ml were dominated by female patients, with the most common etiology of fatty liver and others, and with BCLC A and C staging. Descriptively, there was no difference in AFP level based on the number of nodules and size of tumor. Conclusion: The most common patients with high AFP level are those who have hepatitis B as etiology, younger age, male gender, high SGOT level and BCLC B staging. Meanwhile, patients with normal AFP level dominated with female and non-hepatitis patients. In this research, we found no differences of AFP level based on number and size of tumor descriptively.

Prognostic Significance of Globulin/Low-Density Lipoprotein Ratio In Patients With Hepatocellular Carcinoma After Local Ablative Therapy

Background: Low-density lipoprotein (LDL) and globulin have been found to be predictors for some malignant tumors, but their predictive value in hepatocellular carcinoma (HCC) has hardly to be elucidated. This study assessed the prognostic significance of globulin to low-density lipoprotein ratio (GLR) in HCC patients before ablation.Materials and methods: This study analyzed 312 HCC patients hospitalized and underwent ablative treatment in Beijing You 'an Hospital, Capital Medical University, from January 1, 2012 to January 1, 2017. Cox regression analysis was used to assess the factors independently associated with recurrence and survival. The optimal cut-off value and prognostic role of GLR and other markers were evaluated via the receiver operating characteristic-ROC curves and the Youden index. Overall survival (OS) and recurrence-free survival (RFS) were calculated by Kaplan-Meier analysis, and compared between groups using the log-rank.Result: Univariate and multivariate analysis found that the tumor number (HR: 1.676;95%CI: 1.113-2.526), tumor size (HR: 1.967;95%CI: 1.251-3.092), GLR (HR: 1.028;95%CI: 1.004-1.052) were independent risk factors of relapse; while etiology (HR: 1.328;95%CI: 1.052-1.677), tumor number (HR: 1.615;95%CI: 1.015-2.570), tumor size (HR: 2.061; 95%CI: 1.243-3.418), Fib (HR: 0.73; 95%CI: 0.535-0.996) and GLR (HR: 1.031;95%CI: 1.003-1.06) were related to overall survival. We classified the patients into groups with high and low levels of GLR based on the optimal cut-off value of GLR identified by generating receiver operating characteristics (ROC) curve. The cumulative 1-, 3-, and 5-year RFS rates in the low GLR group were 76.4%, 53.8% and 43.4%, while those in the high GLR group were 71%, 31% and 22%, respectively (P <0.001). Concerning OS, the low GLR group showed a 1-, 3- and 5-year OS of 99.5%, 92.0% and 80.2% versus 98%, 73% and 63% for the high GLR group (P <0.001). Finally, patients were stratified by GLR and tumor size. The outcomes revealed that patients in group A (GLR<16.54 and tumor size ≤30mm) showed better prognosis than group B (GLR≥16.54 and tumor size≤30mm or GLR<16.54 and tumor size >30mm) and group C (GLR≥16.54 and tumor size >30mm) (P <0.001). Conclusions: Preoperative GLR ratio could serve as a biomarker to predict prognosis in HCC patients who underwent complete ablation.

Transarterial Chemoembolization Combined with Lenvatinib plus PD-1 Inhibitor for Advanced Hepatocellular Carcinoma: A Retrospective Cohort Study

Purpose To investigate the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib plus PD-1 inhibitor (TACE-L-P) versus TACE combined with lenvatinib (TACE-L) for patients with advanced hepatocellular carcinoma (HCC).Methods Data of advanced HCC patients treated with TACE-L-P or TACE-L from January 2019 to December 2020 were retrospectively analyzed. The differences in overall survival (OS), progression-free survival (PFS), tumor responses (based on modified Response Evaluation Criteria in Solid Tumors) and adverse events (AEs) were compared between the two groups. Potential factors affecting OS and PFS were determined.Results A total of 81 patients were included in this study (41 received TACE-L-P and 40 received TACE-L). The patients in TACE-L-P group had prolonged OS (median, 16.9 vs. 12.1 months, p=0.009), longer PFS (median, 7.3 vs. 4.0 months, p=0.002) and higher objective response rate (56.1% vs. 32.5%, p=0.033) and disease control rate (85.4% vs. 62.5%, p=0.019) than those in TACE-L group. Multivariate analyses revealed that the treatment option of TACE-L, main portal vein invasion and extrahepatic metastasis were the independent risk factors for OS, while TACE-L and extrahepatic metastasis were the independent risk factors for PFS. In subgroup analyses, a superior survival benefit was achieved with TACE-L-P in patients with extrahepatic metastasis or tumor number >3 but not in those with main portal vein invasion. The incidence and severity of AEs in TACE-L-P group were comparable to those in TACE-L group (any grade, 92.7% vs. 95.0%, p=1.000; grade 3, 36.6% vs. 32.5%, p=0.699).Conclusion TACE-L-P significantly improved survival over TACE-L with an acceptable safety profile in advanced HCC patients, especially those with extrahepatic metastasis or tumor number >3 but without main portal vein invasion.

Prognostic value and predication model of microvascular invasion in patients with intrahepatic cholangiocarcinoma: a multicenter study from China

Background At present, hepatectomy is still the most common and effective treatment method for intrahepatic cholangiocarcinoma (ICC) patients. However, the postoperative prognosis is poor. Therefore, the prognostic factors for these patients require further exploration. Whether microvascular invasion (MVI) plays a crucial role in the prognosis of ICC patients is still unclear. Moreover, few studies have focused on preoperative predictions of MVI in ICC patients. Methods Clinicopathological data of 704 ICC patients after curative resection were retrospectively collected from 13 hospitals. Independent risk factors were identified by the Cox or logistic proportional hazards model. In addition, the survival curves of the MVI-positive and MVI-negative groups before and after matching were analyzed. Subsequently, 341 patients from a single center (Eastern Hepatobiliary Hospital) in the above multicenter retrospective cohort were used to construct a nomogram prediction model. Then, the model was evaluated by the index of concordance (C-Index) and the calibration curve. Results After propensity score matching (PSM), Child-Pugh grade and MVI were independent risk factors for overall survival (OS) in ICC patients after curative resection. Major hepatectomy and MVI were independent risk factors for recurrence-free survival (RFS). The survival curves of OS and RFS before and after PSM in the MVI-positive groups were significantly different compared with those in the MVI-negative groups. Multivariate logistic regression results demonstrated that age, gamma-glutamyl transpeptidase (GGT), and preoperative image tumor number were independent risk factors for the occurrence of MVI. Furthermore, the prediction model in the form of a nomogram was constructed, which showed good prediction ability for both the training (C-index = 0.7622) and validation (C-index = 0.7591) groups, and the calibration curve showed good consistency with reality. Conclusion MVI is an independent risk factor for the prognosis of ICC patients after curative resection. Age, GGT, and preoperative image tumor number were independent risk factors for the occurrence of MVI in ICC patients. The prediction model constructed further showed good predictive ability in both the training and validation groups with good consistency with reality.

Concurrent Cholecystectomy Is Associated with a Lower Risk of Recurrence after Curative Resection in Early-Stage Hepatocellular Carcinoma: A 10 Year Observational Single-Center Study

Background: Cholecystectomy has been reported to be associated with increased risk of developing hepatocellular carcinoma (HCC). However, there is little information about the impact of cholecystectomy on the outcome of HCC. Aims: To evaluate the long-term effect of concurrent cholecystectomy on recurrence and overall survival in HCC after curative hepatectomy. Patients and Methods: We retrospectively enrolled 857 patients with BCLC stage 0 or A HCC who underwent primary resection from January 2001 to June 2016. The impact of concurrent cholecystectomy on overall survival (OS) and recurrence-free survival (RFS) were analyzed by Cox’s proportional hazards models after one-to-one propensity score matching (PSM). Results: Of the 857 patients, 539 (62.9%) received concurrent cholecystectomy (cholecystectomy group) and 318 (37.1%) did not (non-cholecystectomy group). During the mean follow-up period of 75.0 months, 471 (55.0%) patients experienced recurrence, and 321 (37.5%) died. RFS and OS were not significantly different between the groups. After PSM, a total of 298 patients were enrolled in each group. RFS was significantly higher in the cholecystectomy than non-cholecystectomy group (p = 0.044). In multivariate analysis, age (p = 0.022), serum AFP (p = 0.008), liver cirrhosis (p < 0.001), diabetes (p = 0.004), tumor number (p = 0.005), tumor size (p = 0.002), histological grade (p = 0.001), microvascular invasion (p < 0.001) and cholecystectomy (p = 0.021) were independent risk factors for HCC recurrence. However, there were no significant differences in OS between the cholecystectomy and non-cholecystectomy groups. Conclusions: Concurrent cholecystectomy may reduce recurrence in early-stage HCC after curative resection. Further studies are needed to validate our results.

ONECUT2 facilitates hepatocellular carcinoma metastasis by transcriptionally upregulating FGF2 and ACLY

Metastasis is the predominant reason for high mortality of hepatocellular carcinoma (HCC) patients. It is critical to explore the molecular mechanism underlying HCC metastasis. Here, we reported that transcription factor One Cut homeobox 2 (ONECUT2) functioned as an oncogene to facilitate HCC metastasis. Elevated ONECUT2 expression was positively correlated with increased tumor number, tumor encapsulation loss, microvascular invasion, poor tumor differentiation, and advanced TNM stage. Mechanistically, ONECUT2 directly bound to the promoters of fibroblast growth factor 2 (FGF2) and ATP citrate lyase (ACLY) and transcriptionally upregulated their expression. Knockdown of FGF2 and ACLY inhibited ONECUT2-mediated HCC metastasis, whereas upregulation of FGF2 and ACLY rescued ONECUT2 knockdown-induced suppression of HCC metastasis. ONECUT2 expression was positively correlated with FGF2 and ACLY expression in human HCC tissues. HCC patients with positive coexpression of ONECUT2/FGF2 or ONECUT2/ACLY exhibited the worst prognosis. In addition, FGF2 upregulated ONECUT2 expression through the FGFR1/ERK/ELK1 pathway, which formed an FGF2-FGFR1-ONECUT2 positive feedback loop. Knockdown of ONECUT2 inhibited FGF2-induced HCC metastasis. Furthermore, the combination of FGFR1 inhibitor PD173074 with ACLY inhibitor ETC-1002 markedly suppressed ONECUT2-mediated HCC metastasis. In summary, ONECUT2 was a potential prognostic biomarker in HCC and targeting this oncogenic signaling pathway may provide an efficient therapeutic strategy against HCC metastasis.

A Nomogram Model for Predicting the Response to Transcatheter Arterial Embolization in Patients With Symptomatic Hepatic Hemangioma

Background: Transcatheter arterial embolization (TAE) is regarded as an effective treatment for patients with symptomatic hepatic hemangioma. However, few studies have evaluated the efficacy of TAE alone for treating hepatic hemangioma. The aim of this study was to identify the factors that influence the response to TAE and formulate a quantitative nomogram to optimize the individualized management of hepatic hemangioma.Methods: We retrospectively studied 276 patients treated with TAE for hepatic hemangioma at our center from January 2011 to December 2019. The full cohort was randomly divided into training and validation cohorts. After assessing the potential predictive factors for the efficacy of TAE in the training cohort, a nomogram model was established and evaluated by discrimination and calibration.Results: During follow-up, the symptom relief rate was 100%. The tumor blood supply (p &lt; 0.001), tumor number (p = 0.004), and tumor size (p = 0.006) were identified as significant predictors of the failure of tumor shrinkage in response to TAE. The nomogram model showed favorable discrimination and calibration, with a C-index of 0.775 (95% CI, 0.705–0.845) in the training cohort, which was further confirmed in the validation cohort (C-index 0.768; 95% CI, 0.680–0.856). The side effects of TAE were relatively minor and included mainly abdominal pain, nausea, vomiting, fever, and the presence of elevated hepatic transaminases.Conclusion: TAE is a safe and effective treatment for symptomatic hepatic hemangioma. The established nomogram performed well for the estimation of the effect of TAE in patients with hepatic hemangioma and can facilitate the selection of patients who would benefit most from the treatment.

The Incidence of Bacteremia and Risk Factors of Post-Radiofrequency Ablation Fever for Patients with Hepato-Cellular Carcinoma

Post-radiofrequency ablation (RFA) fever is a self-limited complication of RFA. The correlation between post-RFA fever and bacteremia and the risk factors associated with post-RFA fever have not been evaluated. Patients with newly diagnosed or recurrent hepatocellular carcinoma who underwent ultrasonography-guided RFA between April 2014 and February 2019 were retrospectively enrolled. Post-RFA fever was defined as any episode of body temperature >38.0 °C after RFA during hospitalization. A total of 272 patients were enrolled, and there were 452 applications of RFA. The frequency of post-RFA fever was 18.4% (83/452), and 65.1% (54/83) of post-RFA fevers occurred on the first day after ablation. Patients with post-RFA fever had a longer hospital stay than those without (9.06 days vs. 5.50 days, p < 0.001). Only four (4.8%) patients with post-RFA fever had bacteremia. The independent factors associated with post-RFA fever were younger age (adjusted odds ratio (OR) = 0.96, 95% CI, 0.94–0.99, p = 0.019), low serum albumin level (adjusted OR = 0.49, 95% CI, 0.25–0.95, p = 0.036), general anesthesia (adjusted OR = 2.06, 95% CI, 1.15–3.69, p = 0.015), tumor size (adjusted OR = 1.52, 95% CI, 1.04–2.02, p = 0.032), and tumor number (adjusted OR = 1.71, 95% CI, 1.20–2.45, p = 0.003).

Circulating Tumor Cell Is a Clinical Indicator of Pretransplant Radiofrequency Ablation for Patients with Hepatocellular Carcinoma

Introduction. It is of great significance to confirm reliable indicators for the guidance of pretransplant radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). In this study, we aim to investigate whether circulating tumor cell (CTC) status is a clinical indicator for RFA before liver transplantation (LT) in HCC patients. Method. CTC analyses were measured in 79 HCC patients. Clinical outcomes including progression-free (PFS) and overall survival (OS) were compared and analyzed between patients with and without pretransplant RFA. Result. Forty-two patients were detected as CTC-positive and 18 patients received pretransplant RFA. Recurrence was correlated with CTC count ( P = 0.024 ), tumor number ( P = 0.035 ), liver cirrhosis ( P = 0.001 ), Milan criteria ( P = 0.003 ), and University of California San Francisco (UCSF) criteria ( P = 0.001 ). Kaplan–Meier analysis revealed that patients with CTC-positive had a lower PFS rate ( P = 0.0257 ). For CTC-positive patients, the PFS rate of the pretransplant RFA group was significantly higher than the non-pretransplant RFA group (100% vs. 46.7%, P = 0.0236 ). For CTC-negative patients, both PFS rate and OS rate were similar and without significant differences. In multivariate analysis, pretransplant RFA was the independent factor for PFS ( P = 0.025 ). Conclusion. Pretransplant CTC status can guide the administration of pretransplant RFA in HCC patients which can improve PFS in CTC-positive HCC patients.