High AFP Research Articles

Clinicopathological and prognostic value of preoperative lymphocyte to monocyte ratio for hepatocellular carcinoma following curative resection: A meta-analysis including 4,092 patients.

Background:Previous studies have reported that lymphocyte-to-monocyte ratio (LMR) had novel prognostic value in hepatocellular carcinoma (HCC). The purpose of this meta-analysis was to synthetically evaluate the prognostic role of preoperative LMR in HCC patients following curative resection.Methods:Eligible studies were acquired through searching Pubmed, Web of Science, Cochrane Library and EMbase update to September 2019. Merged hazard ratios (HRs) and 95% confidence intervals (CIs) were applied as effect sizes.Results:A total of ten studies containing 4,092 patients following liver resection were enrolled in this meta-analysis. The pooled results demonstrated that preoperative elevated LMR indicated superior survival outcome (HR: 0.58, 95% CI: 0.34–0.96, P = .035) and recurrence-free survival (RFS)/disease-free survival/time to recurrence (HR = 0.76, 95% CI: 0.58–0.98, P = .034). The significant prognostic role of preoperative LMR was detected in the subgroup of all publication year, country of origin, sample sizes <300, TNM stage of I–IV and LMR cut-off value ≤4. Furthermore, high LMR was significantly associated with male, high AFP, large tumor size, incomplete tumor capsule, advanced TNM stage and BCLC stage, and presence of PVTT.Conclusion:Elevated preoperative LMR indicated superior survival outcome in HCC patients following curative resection, and might serve as a novel prognostic biomarker.

Hepatic Stem Cell-like Subtypes of Hepatocellular Carcinoma Revealed from the Integrative Multi-omics Analysis Using Developmental Hierarchies of the Liver

Background: Hepatocellular carcinoma (HCC) is lethal malignancy showing high relapse rates after curative resection in early-stage. Aggressive tumor biology in resectable HCC remains unclear. Methods: Using human fetal liver signatures, multi-omics dataset from multiple clinical HCC cohorts were analyzed comprehensively to reveal molecular mechanisms for HCC stemness as well as potential biomarkers to enhance therapeutic efficacy for molecular targeted therapy or immunotherapy in stem cell-like HCC subtypes. Results: The patients predicted to the hepatic stem cell (HS) subtype showed aggressive tumor features including large tumor size, high AFP, vascular invasion, and extrahepatic metastasis as well as worst prognosis with early recurrence even in early-stage. The oncogenic pathways in terms of cell cycle, epithelial-mesenchymal transition, and TGF-beta pathway were highly upregulated in the HS subtype. Higher mutations of TP53, RB1 with PTEN deletion were significantly identified in the HS subtype. We also identified subtype-specific tissue and serum biomarkers. Predicted responders for immunotherapy were significantly lower in stem cell-like subtypes due to higher accumulation of TAM and MDSC. The HS subtype showed potential higher response to multi-tyrosine kinase inhibitors, especially sorafenib and lenvatinib. Conclusion: Stem cell-like HCC is not only associated with significantly higher relapse rate after curative resection but also with molecular biology for the aggressive subtype of HCC. We identified subtype-specific serum and tissue biomarkers for stem cell-like subtypes and precise therapeutic strategies for each subtype regarding immunotherapy and molecular-targeted treatment. Our findings may offer theoretical foundation of biomarker-based clinical trials for new therapeutic approaches to resectable early-stage HCC patients.

High FIB-4 Index Predicts Poor Prognosis in Alcoholic Drinkers with Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is one of the most aggressive cancer with a poor prognosis. Prediction of the prognosis is important to determine the treatment strategy. Alcohol consumption is a well-known major risk factor for liver fibrosis and HCC. FIB-4 index is a non-invasive and easily applicable indicator of liver fibrosis based on age, AST, ALT and platelets, which is a highly predictive risk factor for HCC. The aim of this study is to evaluate the association between preoperative FIB-4 index and prognosis in patients with HCC among alcohol drinkers. Methods: Consecutive 197 patients who underwent surgical resection of HCC between 2000 and 2018 were included. The cut off value of FIB-4 was determined by ROC analysis. We analyzed the relationship between clinicopathological variables including FIB-4 and survival after hepatectomy. Survival data were analyzed using the Log-rank test for univariate analysis and Cox proportional hazards for multivariate analysis. P value of < 0.05 was judged as significant. Results: A univariate analysis revealed that HCV positive (p=0.023), high preoperative ICG retention rate at 15 minutes (p=0.020), high AFP (p=0.030), high PIVKA-Ⅱ (p=0.005) and high FIB-4 index (≥2.6; p< 0.001) were significant poor prognostic factors for OS. FIB-4 index retained its significance on multivariate analysis for OS (HR 2.281, 95%CI 1.309-3.975) along with PIVKA-Ⅱ (p=0.0006). High FIB-4 index was also an independent prognostic factor for DFS (HR 1.772 95%CI 1.231-2.552). Conclusion: Preoperative high FIB-4 index is an independent prognostic factor for OS and DFS in resected HCC.

Conditional disease-free survival after liver resection for HCC

Background: A high recurrence rate after resection of hepatocellular carcinoma (HCC) is one of the most debated issues in literature.Conditional survival is defined as the probability of surviving for another “Y” years, given that the person has already survived “X” years and is derived from the concept of conditional probability in biostatistics. The literature about conditional disease-free survival (CDFS) in patients with HCC after curative resection is very limited.The study aim was to investigate the long-term change in tumor recurrence risk in disease-free patients (DFS) after hepatic resection for HCC. Recurrence probability over time was estimated by CDFS analysis. Methods: 477 consecutive patients that underwent liver resection surgery with curative intent for HCC at the General and Hepatobiliary Surgery Department of the University of Verona from May 1989 to December 2020 were retrospectively analyzed.Long-term endpoints were the DFS, i.e., the time elapsed between the intervention and the first relapse (or the last follow up in case of no relapse) and calculation of the conditional disease-free survival (CDFS) specified as the 1, 2 and 3-year CDFS, which represents the probability of remaining disease-free for an additional 1, 2 and 3 years. Besides, prognostic factors associated with disease-free survival were identified and the change in their impact over time was analyzed. Results: Disease-free survival was 68.2%, 53.6%, 41.6% at 1, 2 and 3 years. Conditional disease-free survival rates of the entire study population based on the time already lived after surgical resection have been evaluated.There were significant differences between DFS and CDFS. The disease-free survival at 5 years was 27.0%, but patients who had already 3 years of disease-free after surgery, had a 64.9% chance of having a further 2 years of disease-free survival. Prognostic factors for DFS and their changes over time have been evaluated. We found that multinodular HCC, HCV, macrovascular invasion and high AFP were significantly related to DFS in baseline analysis, but these factors were no longer related with DFS after X months. Cirrhosis remains the only risk factor for recurrence with statistical significance over the 3 years of DFS. Conclusions: Conditional disease-free survival analysis shows that the prognosis varies over time and is an important tool that can provide more accurate and dynamic prognostic information useful to guide follow-up strategies.

Machine Learning Models in the&amp;nbsp;Prediction of One-Year&amp;nbsp;Mortality in Patients With Advanced Hepatocellular Cancer on&amp;nbsp;Immunotherapy

Introduction: Immunotherapy is a new promising treatment for patients with advanced hepatocellular carcinoma (HCC), but is costly and potentially associated with considerable side effects. This study aimed to evaluate the role of machine learning (ML) models in predicting the one-year cancer-related mortality in advanced HCC patients treated with immunotherapy. Method: 395 HCC patients who had received immunotherapy (including nivolumab, pembrolizumab or ipilimumab) in 2014 - 2019 in Hong Kong were included. The whole data set were randomly divided into training (n=316) and validation (n=79) set. The data set, including 45 clinical variables, was used to construct six different ML models in predicting the risk of one-year mortality. The performances of ML models were measured by the area under receiver operating characteristic curve (AUC) and the mean absolute error (MAE) using calibration analysis. Results: The overall one-year cancer-related mortality was 51.1%. Of the six ML models, the random forest (RF) has the highest AUC of 0.93 (95%CI: 0.86-0.98), which was better than logistic regression (0.82, p=0.01) and XGBoost (0.86, p=0.04). RF also had the lowest false positive (6.7%) and false negative rate (2.8%). High baseline AFP, bilirubin and alkaline phosphatase were three common risk factors identified by all ML models. Conclusion: ML models could predict one-year cancer-related mortality of HCC patients treated with immunotherapy, which may help to select patients who would most benefit from this new treatment option. Funding Information: None. Declaration of Interests: Nothing to disclose. Ethics Approval Statement: This study protocol was approved by the Institutional Review Board of the University of Hong Kong and the West Cluster of the Hong Kong Hospital Authority (reference no: UW 20-778).

Factors and Survival Implications associated with biopsy of hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is one of the few cancers that can be diagnosed based on imaging findings alone. The factors associated with the decision to perform a biopsy and the clinical impact have not been previously studied. MethodsWe collected data of patients diagnosed with HCC between 2004 and 2015 from the National Cancer Database. We assessed associations between biopsy and survival with demographic and clinical factors. ResultsWe included 160,507 patients. The median age was 62 (40–90), 74.1% were male and 74.9% were white. Over the 12-year period, 47.7% (76,524/160,517) underwent a biopsy. Factors associated with a biopsy were black race, older age, presence of metastatic disease, larger tumor size, and treatment at a community cancer center. Factors associated with increased mortality were older age, higher comorbidity index, larger tumor size, presence of metastatic disease, higher AFP and elevated bilirubin. There was a significant decreased use of biopsy over successive years (2007–2015). After adjusting for prognostic factors, biopsy had no significant impact on survival HR 1.01 (95%CI 1.00–1.03. p = 0.07). ConclusionsA significant number of patients underwent a biopsy. Performing a biopsy did not have a significant impact on survival.

Current treatment options for hepatocellular carcinoma.

Hepatocellular carcinoma remains a serious global disease. Its incidence is increasing. Standard procedures have been developed for each stage. The complexity of this disease shows that the selection of patients in stage 0/A for different types of surgical treatment is very complicated. Treatment methods of stage B, especially locoregional treatment represented by TACE (transarterial chemoembolization or radioembolization of TARE), radiofrequency ablation and others, move freely to lower and higher stages as adjunctive therapy. Lenvatinib can replace TACE with equal efficacy in cases where locoregional treatment cannot be used. Until 2016, the only systemic treatment option for stage C was sorafenib. Lenvatinib became a second-line drug to show non-inferiority to sorafenib in OS. Retrospective analyzes revealed that patients who responded to the treatment with lenvatinib or sorafenib had a median survival of over 22 months. Sequential treatment with sorafenib and regorafenib in the RESOURCE study with a median survival of more than 24 months was similar. Ramucirumab was effective only in patients with high AFP levels. The study demonstrated the importance of selecting patients according to prognostic factors (extrahepatic spread and vascular invasion). Second-line cabozantinib has shown the same benefit as regorafenib. In the second line, immunotherapy represented by anti PD-1 antibodies nivolumab and pembrolizumab was used. Sequential administration after sorafenib prolonged the median overall survival of about 22 months. We currently have sorafenib and lenvatinib in the first line, regorafenib, cabozantinib, ramucirumab (AFP 400 &#956;g/L), pembrolizumab and nivolumab in the second line. The possibilities of monotherapy have been exhausted. The discovery of a synergistic effect of angiogenesis inhibitors, which convert a cold tumor into a hot one and facilitate the efficacy of anti-PD-1 / anti-PDL-1 antibodies, has led to a highly effective combination therapy. In study IMbrave150, the combination of atezolizumab and bevacizumab was successfully used compared to sorafenib in the first-line treatment. Additional studies are currently underway using other tyrosin kinase inhibitors - regorafenib, lenvatinib and cabozantinib - in combination with nivolumab, ipilimumab and pembrolizumab. This development of treatment at all stages evoked with renewed urgency the need to find a suitable way to search for the early stages of HCC and to create a more effective system for selecting patients for the most appropriate treatment.

Liver stiffness in magnetic resonance elastography is prognostic for sorafenib-treated advanced hepatocellular carcinoma.

We investigated whether liver stiffness (LS) quantified using magnetic resonance elastography (MRE) could predict the prognosis of advanced hepatocellular carcinoma (HCC) patients treated with sorafenib. We selected 50 sorafenib-treated advanced HCC patients who underwent MRE within 3 months before drug administration from a prospectively maintained cohort of chronic liver disease patients, according to the inclusion and exclusion criteria. Univariate and multivariate analyses were performed to evaluate the prognostic role of laboratory data, tumor characteristics, and MRE-assessed LS for overall survival (OS), progression-free survival (PFS), and significant liver injury (grade ≥ 3) after sorafenib administration. High MRE-assessed LS either as continuous (per kPa, hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.23-1.92, p < 0.001) or categorical (> 7.5 kPa, HR 4.06, 95% CI 1.40-11.79, p < 0.01) variable was significantly associated with poor OS along with higher serum alpha-fetoprotein (AFP, ≥ 400 ng/mL) and advanced tumor stage (modified Union for International Cancer Control (mUICC) IVb). Higher MRE-assessed LS was also significantly associated with the development of significant liver injury after sorafenib administration (per kPa, HR 1.62, 95% CI 1.21-2.17, p = 0.001; > 7.5 kPa, HR 10.11, 95% CI 2.41-42.46, p = 0.002). PFS analysis identified higher serum AFP (≥ 400 ng/mL) and advanced tumor stage (mUICC IVb) as significant risk factors for early disease progression, whereas LS was not associated with PFS CONCLUSION: Higher MRE-assessed LS is a potential biomarker for predicting poor OS and significant liver injury in advanced HCC patients treated with sorafenib. • Higher pretreatment LS by MRE (> 7.5 kPa), higher AFP (≥ 400 ng/mL), and advanced tumor stage (mUICC IVb) were associated with poor OS in advanced HCC patients treated with sorafenib. • Higher pretreatment LS by MRE was associated with developing significant (grade ≥ 3) liver injury during sorafenib treatment, which required termination of the therapy. • Patients with high pretreatment LS by MRE should be monitored carefully for potential liver injury during sorafenib treatment.

Role of RBM3 in the regulation of cell proliferation in hepatocellular carcinoma

RNA binding motif protein 3 (RBM3) has been shown to be upregulated in several types of human tumors. Using tissue microarrays and immunohistochemistry, we showed here that both nuclear and cytoplasmic RBM3 expression levels were higher in hepatocellular carcinoma (HCC) tissues than in adjacent non-tumorous tissues. High nuclear RBM3 was found to be correlated with larger tumor size (P = 0.030), high serum AFP levels (P = 0.011), and advanced Edmonson grading (P = 0.006). Cytoplasmic RBM3 was associated with advanced Edmonson grading (P = 0.003). Kaplan-Meier survival analysis revealed that, although not statistically significant, there was a trend toward shortened overall survival in the subset of HCC patients with high RBM3 expression (both nuclear and cytoplasmic). In addition, we found that RBM3 could promote YAP1 expression in HCC cells. Moreover, we found that YAP1 played an essential part in RBM3-induced proliferation of HCC cells. Furthermore, we demonstrated that Verteporfin, a YAP1 inhibitor, could repress RBM3-induced proliferation of HCC cells. Our findings provide a new experimental basis for further understanding of the possible role of RBM3-YAP1 in the regulation of HCC proliferation.

No touch isolation technique for the prevention of postoperative recurrence of hepatocellular carcinoma after liver transplantation-combined with trans-arterial radioembolization

IntroductionTransarterial radioembolization (TARE) is recently emerging treatment modality using radiation from Yttrium-90 through the transarterial approach. It usually is used in the intermediate stage and unresectable hepatocellular carcinoma (HCC).No touch isolation technique is a way to prevent the spread of tumors by pre-ligating the vessels around the tumor with minimal touch during surgery. We hoped that if we were to use these techniques, we would be able to control all viable tumors before liver transplantation. Then we could get better outcomes even in the advanced hepatocellular carcinoma patients. MethodsWe performed living donor liver transplantation using no touch isolation technique in the patients who had multinodular hepatocellular carcinoma and extremely high AFP, PIVKA-II level after TARE and conventional TACE. Results36 years old female patient had liver cirrhosis with hepatitis B virus infection and multiple hepatocellular carcinoma in both lobes. Hepatologist decided to do TARE and additional conventional TACE for viable tumors. After that treatment, AFP and PIVKA-II level were dramatically decreased, we decided to proceed of living donor liver transplantation because the patient's treatment response was extremely good. ConclusionsNo touch isolation technique combined with TARE for recipient hepatectomy might be helpful in advanced stage hepatocellular carcinoma patients.

The Association of Raised Mid-trimester Serum Human Chorionic Gonadotrophin (hCG) and Alpha-Fetoprotein with adverse Pregnancy Outcome

Background: Placenta is a temporary endocrine organ formed during pregnancy, which produces hormones important in the maintenance of a healthy pregnancy. hCG is the first one of these hormone that is measured in pregnancy test and used in the follow up of adverse pregnancy outcome, Alpha fetoprotein is a major plasma protein produced by the yolk sac and the fetal liver during fetal development.Aim of study :to study relationship between gestational complications and levels of maternal serum HCG and AFP and determine whether the semarkers are effective predictors adverse pregnancy outcomes. Patients &amp; Methods:Prospective cohorts study in AlDiwaniyah maternity and pediatrics teaching hospital.We enrolled a total of 230 women at 14-23 gestational weeks and measurement of maternal serum HCG &amp; AFP were done, of those with normal HCG &amp; AFP formed (group l), group 2 involved women with elevated AFP , group 3 with elevated HCG &amp; group 4 involved women with elevated both HCG &amp; AFP.Follow up weekly of the patients for the development of adversepregnancy outcome.Results: A significant relationship between adverse pregnancy outcomes and abnormal elevation of HCG &amp; AFP levels in the second trimester. In group 2 the patients developed higher rate of preterm labour &amp; pre-eclampsia compared with the group 1. In group 3 with raised HCG the rate of pre-eclampsia &amp; IUGR development were higher than group 1. In group 4 with elevated both HCG &amp; AFP higher incidence of pre-eclampsia &amp; placental abruption , with a specificity(p&lt;0.001). Conclusion: In the second trimester unexplained high AFP and HCG rates related to adverse maternal and perinatal outcomes.

Comparing clinicopathologic feature and treatment outcome of patients who underwent surgical resection or liver transplant for nonalcoholic fatty liver disease (NAFLD)-related and non-NAFLD related hepatocellular carcinoma (HCC).

e16675 Background: NAFLD associated HCC is rapidly increasing in frequency worldwide. In this study, we evaluated potential differences in clinical characteristics and outcomes of patients who underwent surgery or liver transplant for NAFLD-associated HCC compared to HCC from other etiologies. Methods: Demographic, clinicopathological features and outcomes of patients with HCC who underwent liver resection or liver transplant at Massachusetts General Hospital and Brigham and Women’s Hospital were collected (January 2004 - April 2018). Of 713 patients screened, 481were eligible: 260 underwent resection [NAFLD (n = 61), viral (n = 150), cryptogenic (CC) (n = 49)]. 221 underwent transplant [(NAFLD (n = 14), viral (n = 201), CC (n = 6)]. Results: In the Resected cohort, NAFLD patients presented with median age of (71.5 years) compared with Viral (63.4) and Cryptogenic (68.4). NAFLD patients had significantly higher Body Mass Index (BMI) &gt; 28.8 39(66%) p = &lt; 0.001, while patients with cryptogenic HCC presented with large tumor size (&gt;5cm) 37(75%) p = 0.001. In multivariate analysis, tumor size 5cm (HR1.78,p = 0.002), R1 or R2 resection (HR 2.48, p = &lt; 0.001and 2.8,p = 0.007), low platelet count (HR 2.8,p = 0.002) and diabetes (HR 1.5,p = 0.025) were poor prognostic factors in resection cohort. Median overall survival (OS) was not significantly different between NAFLD, Cryptogenic and Viral (47.2, 69.7 and 69.0 months, p = 0.18) etiologies, respectively. In the Transplant cohort, NAFLD patients had a median age of 65.5 and cryptogenic, viral (61.3 and 58.5 years) respectively. NAFLD and Cryptogenic HCC patients compared with viral HCC patients had low AFP median 3.7, 3.9 and 7.5 ng/mL(p = 0.012) respectively. In multivariate analysis patients with perineural invasion (HR 20.7,p = 0.009), disease recurrence (HR 2.5,p = 0.001) and high AFP (HR 2.1,p = 0.001) were at higher risk of death among transplant patients. No significant difference in median OS was seen between NAFLD, cryptogenic and viral (69.1,92.3 and 88.0 months, p = 0.38). Conclusions: NAFLD patients had higher BMI and had a lower AFP than viral and CC. NAFLD had similar median OS following resection and transplant when compared to those with Viral and CC.

Mutational profile of hepatocellular carcinoma by liquid biopsy of Hispanics in central California.

e16621 Background: Hepatocellular carcinoma (HCC) when localized to liver is typically diagnosed with Characteristic radiographic features while tumor tissue sampling is not warranted anymore. Recently, circulating tumor DNA (ctDNA) has been used to evaluate mutational profile in solid tumors in order to personalize treatments. However, it is not established well in HCC, specifically in Hispanic patients. This study aims to describe the mutational profile of Hispanic patients with ctDNA analysis as a single center experience. Methods: We enrolled 33 patients with diagnosis of HCC from 1/2016 to 12/2019. Diagnosis of HCC was based on Characteristic radiological features, defined by Liver Imaging Reporting and Data System (LI-RADS category 5). 18 patients self-identified as Hispanic while remaining were mainly Caucasians. FoundationOne Liquid genomic testing by Foundation Medicine was used for profiling of 77 most commonly mutated genes of sampled blood. Results: Baseline patient characteristics were similar between Hispanic and non-Hispanic population. Median age of diagnosis was 64 in this cohort with 23(70%) males and 10(30%) females. 30 patients had underlying cirrhosis with hepatitis C present in 19(58%) and heavy alcohol abuse in 15(45%) of cirrhotic. 32 patients had liver-only disease, while we had one patient with extrahepatic disease. 22 of these 33 patients had a single HCC lesion while 11 had multifocal HCC. 20 patients (60.6%) had at least 1 pathogenic mutation. 13 patients (39.4%) did not have any pathogenic mutations. The frequency of commonly mutated genes for our Hispanics versus non-Hispanics were following: CTNNB1(45.5% vs 44.4%), TERT (45.5% vs 55.6%), TP53(36.4% vs 55%), CNK2A (18.2% vs 0). Median of Allele frequency percentage was 0.81%. Mutations in TP53 was commonly detected at codon 249(R249S). Presence of these pathogenic mutations were associated with poor clinical features such as multifocal disease and higher AFP values &gt; 59 as compared to 15 without mutations. Other mutations present at lower percentage include ERBB2, PIK3CA, DNMT3A, GNAS, KDR, RB1, PTEN and their frequency was similar in both Hispanic and non-Hispanic groups. Conclusions: Genomic profiling of ctDNA by liquid biopsy in our Hispanic patients with HCC appears similar to established mutational profile of HCC in Caucasian and Asian populations. These findings can be verified in heterogeneous populations in order to serve as a potential prognostic tool and help with personalized medicine.

Laporan Kasus: Transarterial Chemoembolization (Tace) Sebagai Terapi Pilihan Pada Karsinoma Hepatoselular

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and occupies the top 10 most cancers in Indonesia. Men are likely to develop HCC, and 90% cases of HCC develop in the background of chronic liver disease, which associates with hepatitis B and C virus infection. There are numerous treatment options for HCC, however in intermediate-advanced stage, palliative treatment such as transarterial chemoembolization (TACE) and systemic chemotherapy are the management of choice. A 51 years old male with HCC based on history, physical examination, radiology and laboratory result was referred to interventional radiology department for TACE consideration. Barcelona Clinic Liver Cancer (BCLC) B was concluded in this patient after thorough evaluation. There was history of hepatitis B infection, ascites, low albumin level, high AFP, and from Abdominal CT Scan with contrast showed large lobulated mass on the right lobe, without evidence of portal vein thrombosis. TACE was eligible and done using mixed of doxorubicin 50 mg and lipiodol, and embolization using gel foam. After 8 weeks CT evaluation was done and showed increase area of tumor necrosis, while tumor size was stable. Necrosis area expansion is the standard used for evaluating this patient which fell into partial response criteria. TACE is a palliative therapy of choice in accordance with BCLC B recommendation. Evaluation of TACE performance is more optimal by assessing the size of necrosis area compared to mass measurement.

Multiphase Liver MRI for Identifying the Macrotrabecular-Massive Subtype of Hepatocellular Carcinoma.

Background The recently described "macrotrabecular-massive" (MTM) histologic subtype of hepatocellular carcinoma (HCC) (MTM-HCC) represents an aggressive form of HCC and is associated with poor survival. Purpose To investigate whether preoperative MRI can help identify MTM-HCCs in patients with HCC. Materials and Methods This retrospective study included patients with HCC treated with surgical resection between January 2008 and February 2018 and who underwent preoperative multiphase contrast material-enhanced MRI. Least absolute shrinkage and selection operator (LASSO)-penalized and multivariable logistic regression analyses were performed to identify clinical, biologic, and imaging features associated with the MTM-HCC subtype. Early recurrence (within 2 years) and overall recurrence were evaluated by using Kaplan-Meier analysis. Multivariable Cox regression analysis was performed to determine predictors of early and overall recurrence. Results One hundred fifty-two patients (median age, 64 years; interquartile range, 56-72 years; 126 men) with 152 HCCs were evaluated. Twenty-six of the 152 HCCs (17%) were MTM-HCCs. LASSO-penalized logistic regression analysis identified substantial necrosis, high serum α-fetoprotein (AFP) level (>100 ng/mL), and Barcelona Clinic Liver Cancer (BCLC) stage B or C as independent features associated with MTM-HCCs. At multivariable analysis, substantial necrosis (odds ratio = 32; 95% confidence interval [CI] = 8.9, 114; P < .001), high serum AFP level (odds ratio = 4.4; 95% CI = 1.3, 16; P = .02), and BCLC stage B or C (odds ratio = 4.2; 95% CI = 1.2, 15; P = .03) were independent predictors of MTM-HCC subtype. Substantial necrosis helped identify 65% (17 of 26; 95% CI: 44%, 83%) of MTM-HCCs (sensitivity) with a specificity of 93% (117 of 126; 95% CI: 87%, 97%). In adjusted models, only the presence of satellite nodules was independently associated with both early (hazard ratio = 3.7; 95% CI: 1.5, 9.4; P = .006) and overall (hazard ratio = 3.0; 95% CI: 1.3, 7.2; P = .01) tumor recurrence. Conclusion At multiphase contrast-enhanced MRI, substantial necrosis helped identify macrotrabecular-massive hepatocellular carcinoma subtype with high specificity. © RSNA, 2020.

An unusual case of metastatic gastric adenocarcinoma to the ovary with yolk sac differentiation and AFP production

Raised serum AFP in adults is most commonly associated with hepatocellular carcinoma (HCC) or yolk sac tumour (YST). However, studies have reported diseases other than HCC or YST which are associated with high serum AFP levels. We describe a case of metastatic adenocarcinoma to the ovary showing yolk sac differentiation, as a primary presentation of a gastric tumour.

Treatment efficacy of ramucirumab-based chemotherapy in patients with alpha-fetoprotein producing gastric cancer (AFPGC).

389 Background: AFPGC is an aggressive subgroup of gastric cancer and is associated with a worsened survival because of a high incidence of liver metastasis. Ramucirumab-based chemotherapy is the standard treatment as a second line in advanced gastric cancer. Recently ramucirumab has showed survival benefit in hepatocellular carcinoma, but only those with higher AFP levels. However, the efficacy of ramucirumab in AFPGC is unknown. Methods: We retrospectively assessed 283 patients who received paclitaxel or nab-paclitaxel combined with ramucirumab between July 2015 and December 2018. AFPGC was defined when serum AFP levels were elevated and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal when diagnosed. Other patients were excluded. Patients’ demographics, progression-free survival (PFS), overall survival (OS) and objective response rates (ORR) were compared between the two groups. Results: Among the 283 patients, 24 patients were AFPGC and 189 patients were non-AFPGC. AFPGC was associated with high incidences of intestinal histology (46%) and liver metastasis (63%), while AFPGC was associated with a low incidence of peritoneal metastasis (21%), compared with non-AFPGC. There was no significant difference in PFS and OS between the two groups. Median PFS were 5.4 (95%CI 3.6-6.7) months in AFPGC and 4.1 (3.7-5.1) months in non-AFPGC (HR 0.93 95%CI 0.60-1.46, p = 0.788), respectively. Median OS were 19.0 (95%CI 13.2-NA) months in AFPGC and 19.3 (17.9-20.1) months in non-AFPGC (HR 1.21 95%CI 0.70-2.10, p = 0.494), respectively. Regarding with ORR, AFPGC showed higher ORR with 52.6% (95%CI 30.2-75.1), while 37.3% (95%CI 26.4-48.3) in non-AFPGC (p = 0.296), although this was not statistically significant. Conclusions: Ramucirumab showed comparable survival and higher ORR in AFPGC than in non-AFPGC. Considering the generally poor prognosis of AFPGC, it is speculated that ramucirumab may have compensated for disadvantage in survival.

NF90 stabilizes cyclin E1 mRNA through phosphorylation of NF90-Ser382 by CDK2

Nuclear factor 90 (NF90), an RNA-binding protein, has been implicated in regulating interleukin-2 (IL-2) and the immune response. It was recently reported that NF90 is upregulated in hepatocellular carcinoma (HCC) tissues and promotes HCC proliferation through upregulating cyclin E1 at the posttranscription level. However, the regulation of NF90 in HCC remains unclear. We demonstrate here that cyclin-dependent kinase (CDK) 2 interacts with NF90 and phosphorylated it at serine382. Mechanistically, phosphorylation of NF90-Ser382 determines the nuclear export of NF90 and stabilization of cyclin E1 mRNA. We also demonstrate that the phosphorylation deficient mutant NF90-S382A inhibits cell growth and induces cell cycle arrest at the G1 phase in HCC cells. Moreover, an NF90-S382A xenograft tumor had a decreased size and weight compared with the wildtype NF90. The NF90-S382A xenograft contained a significantly lower level of the proliferation marker Ki-67. Additionally, in HCC patients, NF90-Ser382 phosphorylation was stronger in tumor than in non-tumor tissues. Clinically, phosphorylation of NF90-Ser382 is significantly associated with larger tumor sizes, higher AFP levels, and shorter overall survival rates. These results suggest NF90-Ser382 phosphorylation serves as a potential diagnosis and prognostic marker and a promising pharmacological target for HCC.

Predictors of Recurrence of Hepatocellular Carcinoma after Transarterial Chemoembolization: Role of Hepatocyte Growth Factor

Background: Hepatocellular carcinoma is the third leading cause of tumor related mortality and develops mostly in patients with chronic liver disease and liver cirrhosis. Human hepatocyte growth factor (HGF) is produced in various organs of the body and is characterized as a multifunctional factor with various biologic activities. Aim: Our aim was to investigate the predictive factors of recurrence specially the role of HGF in patients with HCC treated with TACE. Patients and Methods: one hundred HCC patients treated by TACE who achieved complete response were included and divided into two groups according to disease free survival (DFS) status at 1 year: the non-early recurrence (NER) group (1) and the early recurrence (ER) group (2). Univariate binary logistic regression analysis for the possible risk factors of recurrence showed that AFP, multinodularity and HGF level were significant. Conclusion: high AFP, multinodularity and high HGF were inter-related possible risk factors for 1-year recurrence of HCC in patients with initial remission following TACE.

Hepatoid Adenocarcinoma of Stomach: Emphasis on the Clinical Relationship with Alpha-Fetoprotein-Positive Gastric Cancer.

Aims Both hepatoid adenocarcinoma of stomach (HAS) and alpha-fetoprotein-positive gastric cancer (AFPGC) are rare but aggressive subtypes of gastric cancer, but few studies focus on the clinicopathologic differences and prognostic factors between them because of their rarity and histologic overlap. And the significance of AFP level in HAS prognosis was not well studied. Methods 41 patients with AFPGC and 52 patients with HAS were included in this study. The clinicopathologic features were compared by Chi-square analysis. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analyzed with the Kaplan-Meier method. Results The patients with HAS were of a younger age compared with AFPGC, and nearly 60% of tumor located in the gastric antrum and the gastric fundus of cardia. The OS of AFPGC was shorter than that of HAS, due to a higher rate of metastasis. Furthermore, the survival analysis showed that HAS with high AFP expression (AFPHigh HAS) had a significantly poorer OS compared to HAS with low AFP expression (AFPLow HAS) (P=0.046). Conclusions Compared with AFPGC, the patients of HAS were of a younger age and had less rate of liver and other organ metastasis. The serum AFP level was a sensitive prognostic indicator for OS. Therefore, much attention should be paid to AFPHigh HAS in clinical practice.