Embryonal sarcoma of the liver in pediatric and young adult patients: A report from Children's Oncology Group study ARST0332.

BACKGROUND: Embryonal sarcoma of the liver (ESL) is a rare mesenchymal tumor most common in childhood; the optimal treatment approach is uncertain. The clinical features and outcomes of patients with ESL enrolled in a Children's Oncology Group (COG) clinical trial that evaluated a risk-based strategy for treating soft tissue sarcomas in patients aged <30 years were evaluated. METHODS: This subset analysis included patients with ESL enrolled in COG study ARST0332. Central review of records, pathology, and imaging confirmed the diagnosis, presenting features, and surgery extent and complications. All patients received dose-intensive ifosfamide/doxorubicin chemotherapy, with cycle timing dependent on surgery and radiotherapy. Tumor resection occurred before study entry or after four cycles of chemotherapy; radiotherapy for residual tumor was optional. RESULTS: Thirty-nine eligible/evaluable patients with ESL were analyzed. All tumors were >10 cm in diameter; four were metastatic. Tumor resection was performed upfront in 23 and delayed in 16. Positive surgical margins (n = 6) and intraoperative tumor rupture (n = 6) occurred only in upfront resections. Eight patients received radiotherapy. Estimated 5-year event-free and overall survival were 79% (95% confidence interval [CI], 65%-93%) and 95% (95% CI, 87%-100%), respectively. Positive margins increased the local recurrence risk. One of 13 patients with documented hemorrhagic ascites and/or tumor rupture developed extrahepatic intra-abdominal tumor recurrence. CONCLUSIONS: The treatment strategy used in ARST0332 achieved favorable outcomes for patients with ESL despite a substantial proportion having high-risk disease features. Deferring tumor resection until after neoadjuvant chemotherapy may decrease the risk of intraoperative tumor rupture and improve the likelihood of adequate surgical margins.

Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis.

BACKGROUND AND AIM: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. MATERIALS AND METHODS: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS: Among 91 eligible patients, with a median (interquartile range [IQR]) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years=0.72, 95% confidence interval [CI]=0.53, 0.99, P=0.044) and ICI washout time (aHR per 1 week=0.92, 95% CI=0.86, 0.99, P=0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p=0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8]) vs. 8.0 [9.0]); p=0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p=0.032) CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitors use prior to liver transplantation suggests acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without ICI exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies. CODE FOR INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): CRD42023494951.

Development of a Novel Comprehensive Hepatocellular Carcinoma Outcome Prognostic Scoring System With Integration of Imaging Features.

BACKGROUND: Accurate prognostic stratification of hepatocellular carcinoma (HCC) is vital for clinical trial enrollment and treatment allocation. Multiple scoring systems have been created to predict patient survival, but no standardized scoring systems account for radiologic tumor features. We sought to create a generalizable scoring system for HCC which incorporates standardized radiologic tumor features and more accurately predicts overall survival (OS) than established systems. METHODS: Clinicopathologic parameters were collected from a prospectively collected cohort of patients with HCC treated at a single institution. Imaging studies were evaluated for tumor characteristics. Patients were randomly divided into a training set for identification of covariates that impacted OS and a validation set. Cox models were used to determine the association of various factors with OS and a scoring system was created. RESULTS: We identified 383 patients with HCC with imaging and survival outcomes, n = 255 in the training set and 128 in the validation cohort. Factors associated with OS on multivariate analysis included: tumor margin appearance on CT or MRI (hazard ratio [HR] 1.37, 95% CI, 1.01-1.88) with infiltrative margins portending worse outcomes than encapsulated margins, massive tumor morphology (HR 1.64, 95% CI, 1.06-2.54); >2 lesions (HR 2.06, 95% CI, 1.46-2.88), Child-Turcotte-Pugh class C (HR 3.7, 95% CI, 2.23-6.16), and portal vein thrombus (HR 2.41, 95% CI, 1.71-3.39). A new scoring system was developed and more predictive of OS than other well-established systems. CONCLUSIONS: Incorporation of standardized imaging characteristics to established clinical and lab predictors of outcome resulted in an improved predictive scoring system for patients with HCC.

Association between blood lipid levels and the risk of liver cancer: a systematic review and meta-analysis.

PURPOSE: The association between blood lipid levels and the risk of developing liver cancer remains a subject of ongoing debate. To elucidate this association, we conducted a meta-analysis by systematically incorporating data from all relevant prospective cohort studies. METHODS: We conducted a systematic search of the PubMed, Embase, Web of Science, and Cochrane Library databases covering studies published from database inception through July 2023. This study included prospective cohort studies related to lipid profiles (e.g., total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels) that reported hazard ratios (HRs) or relative risks (RRs) with corresponding 95% confidence intervals (95% CIs) to investigate their association with the risk of liver cancer. During the analysis process, we used fixed-effects or random-effects models based on the level of heterogeneity among the studies and obtained pooled risk ratios using these models. To ensure the robustness and reliability of the study findings, we also conducted sensitivity analyses and publication bias analyses. RESULTS: After conducting a systematic search, 12 studies were identified from a total of 11,904 articles and were included in the meta-analysis. These studies included a combined population of 10,765,221 participants, among whom 31,055 cases of liver cancer were reported. The analysis revealed that the pooled HR for the serum TC concentration (highest versus lowest) was 0.45 (95% CI = 0.35-0.58, I2 = 78%). For TGs, the HR was 0.67 (95% CI = 0.46-0.96, I2 = 86%), while for HDL-C, the HR was 0.72 (95% CI = 0.58-0.90, I2 = 65%). The HR for LDL-C was 0.51 (95% CI = 0.23-1.13, I2 = 93%). CONCLUSION: The findings of this study indicate that serum TC, TG, and HDL-C levels are negatively associated with liver cancer risk, suggesting that higher concentrations of these lipids are associated with a reduced risk of liver cancer. However, no significant association has been found between LDL-C levels and liver cancer risk.

Liver cancer in China: the analysis of mortality and burden of disease trends from 2008 to 2021.

BACKGROUND: Liver cancer is one of the most common cancers in China. To understand the basic death situation and disease burden change trend, we analyze the death information of liver cancer among Chinese residents from 2008 to 2021. METHODS: Data was collected from the Cause-of-Death Surveillance dataset of the National Cause-of-Death Surveillance System from 2008 to 2021. Excel 2016 was used for data entry and to calculate the Crude Mortality Rate (CMR), Age-Standardized Mortality Rate (ASMR), Potential Years of Life Lost (PYLL), and Potential Years of Life Lost Rate (PYLLR). SPSS 25.0 was used to statistically analyze CMR, ASMR, PYLL, and other indicators. Annual percent change (APC) and average APC(AAPC) was used for trend analysis and tested by t tests. Joinpoint 4.9.1.0 was used to calculate APC and AAPC. Age-Period-Cohort model was used to assess the effects of age, period, and birth cohort on liver cancer mortality. RESULTS: From 2008 to 2021, 491,701 liver cancer deaths were reported in the National Disease Surveillance Points System. The ASMR of liver cancer in Chinese residents decreased from 27.58/100,000 in 2008 to 17.95/100,000 in 2021 at an average annual rate of 3.40% (t = -5.10, P < 0.001). The mortality rate was higher in males than in females (all P < 0.001) and higher in rural areas than in urban areas (all P < 0.001). The mortality rate of liver cancer varied significantly among eastern, central, and western China (all P < 0.001). The PYLLR of liver cancer in Chinese residents decreased from 2.89‰ in 2008 to 2.06‰ in 2021 at an average annual rate of 2.40% (t = -5.10, P < 0.001). Males had a lower PYLLR than females, decreasing at average annual rates of 2.20% (t = -5.40, P < 0.001) and 2.90% (t = -8.40, P < 0.001), respectively. Urban areas had a lower PYLLR than rural areas, decreasing at average annual rate of 3.30% (t = -4.00, P < 0.001) and 2.50% (t = -11.60, P < 0.001), respectively. Eastern, central, and western China decreased at average annual rates of 3.40%, 2.30%, and 2.10%, respectively (t = -7.80, -3.60, -7.10, P < 0.001 for all). The risk of China liver cancer mortality increased with age, decreased with birth cohort. CONCLUSIONS: The mortality and disease burdens of liver cancer in China decreased yearly and were higher in males and in people living in rural areas, with significant differences among those living in eastern, central, and western China.

Liver transplantation and primary liver cancer in porphyria.

The porphyrias are a heterogeneous group of metabolic disorders that result from defects in heme synthesis. The metabolic defects are present in all cells, but symptoms are mainly cutaneous or related to neuropathy. The porphyrias are highly relevant to hepatologists since patients can present with symptoms and complications that require liver transplantation (LT), and some porphyrias are associated with a high risk for primary liver cancer (PLC). Among the cutaneous porphyrias, erythropoietic protoporphyria (EPP) can lead to cholestatic liver failure where LT cures the liver disease but not the porphyria. In acute porphyria (AP), neurotoxic porphyrin precursors are produced in the liver and LT is a curative treatment option in patients with recurrent severe neuropathic attacks. Patients with AP, mainly acute intermittent porphyria, have a significantly increased risk for PLC that warrants surveillance and adequate follow-up of high-risk groups. LT is well established in both EPP with liver failure and AP with recurrent attacks, but most transplant centres have little porphyria experience and cooperation between transplant hepatologists, and porphyria experts is important in the often-difficult decisions on timing and management of comorbid conditions.

Early post-treatment MRI predicts long-term hepatocellular carcinoma response to radiation segmentectomy.

OBJECTIVES: Radiation segmentectomy using yttrium-90 plays an emerging role in the management of early-stage HCC. However, the value of early post-treatment MRI for response assessment is uncertain. We assessed the value of response criteria obtained early after radiation segmentectomy in predicting long-term response in patients with HCC. MATERIALS AND METHODS: Patients with HCC who underwent contrast-enhanced MRI before, early, and 12 months after radiation segmentectomy were included in this retrospective single-center study. Three independent radiologists reviewed images at baseline and 1st follow-up after radiation segmentectomy and assessed lesion-based response according to mRECIST, LI-RADS treatment response algorithm (TRA), and image subtraction. The endpoint was response at 12 months based on consensus readout of two separate radiologists. Diagnostic accuracy for predicting complete response (CR) at 12 months based on the 1st post-treatment MRI was calculated. RESULTS: Eighty patients (M/F 60/20, mean age 67.7 years) with 80 HCCs were assessed (median size baseline, 1.8 cm [IQR, 1.4-2.9 cm]). At 12 months, 74 patients were classified as CR (92.5%), 5 as partial response (6.3%), and 1 as progressive disease (1.2%). Diagnostic accuracy for predicting CR was fair to good for all readers with excellent positive predictive value (PPV): mRECIST (range between 3 readers, accuracy: 0.763-0.825, PPV: 0.966-1), LI-RADS TRA (accuracy: 0.700-0.825, PPV: 0.983-1), and subtraction (accuracy: 0.775-0.825, PPV: 0.967-1), with no difference in accuracy between criteria (p range 0.053 to > 0.9). CONCLUSION: mRECIST, LI-RADS TRA, and subtraction obtained on early post-treatment MRI show similar performance for predicting long-term response in patients with HCC treated with radiation segmentectomy. CLINICAL RELEVANCE STATEMENT: Response assessment extracted from early post-treatment MRI after radiation segmentectomy predicts complete response in patients with HCC with high PPV (≥ 0.96). KEY POINTS: • Early post-treatment response assessment on MRI predicts response in patients with HCC treated with radiation segmentectomy with fair to good accuracy and excellent positive predictive value. • There was no difference in diagnostic accuracy between mRECIST, LI-RADS, and subtraction for predicting HCC response to radiation segmentectomy.

Preoperative assessment of microvascular invasion risk using gadoxetate-enhanced MRI for predicting outcomes after liver transplantation for single hepatocellular carcinoma within the Milan criteria.

OBJECTIVE: To compare therapeutic outcomes after liver transplantation (LT) between hepatocellular carcinomas (HCC) with low and high risk for microvascular invasion (MVI) within the Milan criteria evaluated preoperatively. METHODS: Eighty patients with a single HCC who underwent LT as the initial therapy between 2008 and 2017 were included from two tertiary referral medical centers in a HBV-predominant population. A preoperative MVI-risk model was used to identify low- and high-risk patients. Recurrence-free survival (RFS) after LT between the two risk groups was compared using Kaplan-Meier curves with the log-rank test. Prognostic factors for RFS were identified using a multivariable Cox hazard regression analysis. RESULTS: Eighty patients were included (mean age, 51.8 years +/- 7.5 [standard deviation], 65 men). Patients were divided into low-risk (n = 64) and high-risk (n = 16) groups for MVI. The RFS rates after LT were significantly lower in the MVI high-risk group compared to the low-risk group at 1 year (75.0% [95% CI: 56.5-99.5%] vs. 96.9% [92.7-100%], p = 0.048), 3 years (62.5% [42.8-91.4%] vs. 95.3% [90.3-100%], p = 0.008), and 5 years (62.5% [42.8-91.4%] vs. and 95.3% [90.3-100%], p = 0.008). In addition, multivariable analysis showed that MVI high risk was the only significant factor for poor RFS (p = 0.016). CONCLUSION: HCC patients with a high risk of MVI showed significantly lower RFS after LT than those without. This model could aid in selecting optimal candidates in addition to the Milan criteria when considering upfront LT for patients with HCC if alternative treatment options are available. CLINICAL RELEVANCE STATEMENT: High risk for microvascular invasion (MVI) in hepatocellular carcinoma patients lowered recurrence-free survival after liver transplantation, despite meeting the Milan criteria. Identifying MVI risk could aid candidate selection for upfront liver transplantation, particularly if alternative treatments are available. KEY POINTS: • A predictive model-derived microvascular invasion (MVI) high- and low-risk groups had a significant difference in the incidence of MVI on pathology. • Recurrence-free survival after liver transplantation (LT) for single hepatocellular carcinoma (HCC) within the Milan criteria was significantly different between the MVI high- and low-risk groups. • The peak incidence of tumor recurrence was 20 months after liver transplantation, probably indicating that HCC with high risk for MVI had a high risk of early (≤ 2 years) tumor recurrence.

Fat-containing hepatocellular carcinoma in patients with cirrhosis: proposal of a diagnostic modification regarding enhancement characteristics.

OBJECTIVES: The aim of this study was to develop and validate an algorithm for the non-invasive diagnosis of these fat-containing HCCs. METHODS: Eighty-four cirrhotic patients with 77 fat-containing HCCs and 11 non-HCC fat-containing nodules were retrospectively included. All MRIs were reviewed; nodule characteristics, European Association for the Study of the Liver (EASL) and LI-RADS classifications, and survival were collected. One of the major features of LI-RADS v2018 (non-rim-like arterial phase hyperenhancement [APHE]) was changed to include different enhancing patterns at arterial phase and a new fat-LI-RADS algorithm was created for fat-containing nodules in cirrhosis. Its diagnostic performance was evaluated in both a derivation and external validation cohort (external cohort including 58 fat-containing HCCs and 10 non-HCC fat nodules). Reproducibility of this new algorithm was assessed. RESULTS: In the derivation cohort, 54/77 (70.1%) fat-containing HCCs had APHE, 62/77 (80.5%) had enhancement compared to the nodule itself at arterial phase (APE), 43/77 (55.8%) had washout, and 20/77 (26.0%) had an enhancing capsule. EASL and LI-RADS had a sensitivity of 37.7% (29/77) and 36.4% (28/77), respectively, for the diagnosis of fat-containing HCC and both had a specificity of 100% (11/11). The new fat-LI-RADS algorithm increased sensitivity to 50.6% (39/77) without decreasing the specificity of 100% (11/11). The validation cohort confirmed the increased sensitivity, with a slight decrease in specificity. The concordance for the diagnosis of HCC for fat-LR5 was 85.3% (58/68). CONCLUSION: The new fat-LI-RADS algorithm proposed here significantly improves the performance of the non-invasive diagnosis of fat-containing HCC and thus could reduce the number of biopsies conducted for fat-containing HCCs. CLINICAL RELEVANCE STATEMENT: The European Association for the Study of the Liver and LI-RADS guidelines are poorly sensitive for the diagnosis of fat-containing HCC, mainly because of the low rate of arterial phase hyperenhancement (APHE) displayed by fat-containing HCC. Using all types of enhancement instead of APHE improves sensitivity of LI-RADS. KEY POINTS: • Fat-containing HCCs on MRI account for 7.5% of HCCs and have different imaging characteristics from non-fatty HCCs. • The European Association for the Study of the Liver and LI-RADS algorithms for the non-invasive diagnosis of HCC have low sensitivity for the diagnosis of fat-containing HCC with MRI (37.7% and 36.4%, respectively). • The new fat-LI-RADS, which includes a slight modification of the "arterial enhancement" criterion, improves the sensitivity for the diagnosis of fat-containing HCC using MRI, without degrading the specificity.

Performance of LI-RADS category 5 vs combined categories 4 and 5: a systemic review and meta-analysis.

OBJECTIVE: Computed tomography (CT)/magnetic resonance imaging (MRI) Liver Imaging Reporting and Data System (LI-RADS, LR) category 5 has high specificity and modest sensitivity for diagnosis of hepatocellular carcinoma (HCC). The purpose of this study was to compare the diagnostic performance of LR-5 vs combined LR-4 and LR-5 (LR-4/5) for HCC diagnosis. METHODS: MEDLINE and EMBASE databases through January 03, 2023 were searched for studies reporting the performance of LR-5 and combined LR-4/5 for HCC diagnosis, using CT/MRI LI-RADS version 2014, 2017, or 2018. A bivariate random-effects model was used to calculate the pooled per-observation diagnostic performance. Subgroup analysis was performed based on imaging modalities and type of MRI contrast material. RESULTS: Sixty-nine studies (15,108 observations, 9928 (65.7%) HCCs) were included. Compared to LR-5, combined LR-4/5 showed significantly higher pooled sensitivity (83.0% (95% CI [80.3-85.8%]) vs 65.7% (95% CI [62.4-69.1%]); p < 0.001), lower pooled specificity (75.0% (95% CI [70.5-79.6%]) vs 91.7% (95% CI [90.2-93.1%]); p < 0.001), lower pooled positive likelihood ratio (3.60 (95% CI [3.06-4.23]) vs 6.18 (95% CI [5.35-7.14]); p < 0.001), and lower pooled negative likelihood ratio (0.22 (95% CI [0.19-0.25]) vs 0.38 (95% CI [0.35-0.41]) vs; p < 0.001). Similar results were seen in all subgroups. CONCLUSIONS: Our meta-analysis showed that combining LR-4 and LR-5 would increase sensitivity but decrease specificity, positive likelihood ratio, and negative likelihood ratio. These findings may inform management guidelines and individualized management. CLINICAL RELEVANCE STATEMENT: This meta-analysis estimated the magnitude of changes in the sensitivity and specificity of imaging criteria when LI-RADS categories 4 and 5 were combined; these findings can inform management guidelines and individualized management. KEY POINTS: There is no single worldwide reporting system for liver imaging, partly due to regional needs. Combining LI-RADS categories 4 and 5 increased sensitivity and decreased specificity and positive and negative likelihood ratios. Changes in the sensitivity and specificity of imaging criteria can inform management guidelines and individualized management.

Deep learning reconstruction CT for liver metastases: low-dose dual-energy vs standard-dose single-energy.

OBJECTIVES: To assess image quality and liver metastasis detection of reduced-dose dual-energy CT (DECT) with deep learning image reconstruction (DLIR) compared to standard-dose single-energy CT (SECT) with DLIR or iterative reconstruction (IR). METHODS: In this prospective study, two groups of 40 participants each underwent abdominal contrast-enhanced scans with full-dose SECT (120-kVp images, DLIR and IR algorithms) or reduced-dose DECT (40- to 60-keV virtual monochromatic images [VMIs], DLIR algorithm), with 122 and 106 metastases, respectively. Groups were matched by age, sex ratio, body mass index, and cross-sectional area. Noise power spectrum of liver images and task-based transfer function of metastases were calculated to assess the noise texture and low-contrast resolution. The image noise, signal-to-noise ratios (SNR) of liver and portal vein, liver-to-lesion contrast-to-noise ratio (LLR), lesion conspicuity, lesion detection rate, and the subjective image quality metrics were compared between groups on 1.25-mm reconstructed images. RESULTS: Compared to 120-kVp images with IR, 40- and 50-keV VMIs with DLIR showed similar noise texture and LLR, similar or higher image noise and low-contrast resolution, improved SNR and lesion conspicuity, and similar or better perceptual image quality. When compared to 120-kVp images with DLIR, 50-keV VMIs with DLIR had similar low-contrast resolution, SNR, LLR, lesion conspicuity, and perceptual image quality but lower frequency noise texture and higher image noise. For the detection of hepatic metastases, reduced-dose DECT by 34% maintained observer lesion detection rates. CONCLUSION: DECT assisted with DLIR enables a 34% dose reduction for detecting hepatic metastases while maintaining comparable perceptual image quality to full-dose SECT. CLINICAL RELEVANCE STATEMENT: Reduced-dose dual-energy CT with deep learning image reconstruction is as accurate as standard-dose single-energy CT for the detection of liver metastases and saves more than 30% of the radiation dose. KEY POINTS: • The 40- and 50-keV virtual monochromatic images (VMIs) with deep learning image reconstruction (DLIR) improved lesion conspicuity compared with 120-kVp images with iterative reconstruction while providing similar or better perceptual image quality. • The 50-keV VMIs with DLIR provided comparable perceptual image quality and lesion conspicuity to 120-kVp images with DLIR. • The reduction of radiation by 34% by DLIR in low-keV VMIs is clinically sufficient for detecting low-contrast hepatic metastases.

Effect of Total SMS Activity on LDL Catabolism in Mice.

BACKGROUND: Sphingomyelin (SM) and cholesterol are 2 key lipid partners on cell membranes and on lipoproteins. Many studies have indicated the influence of cholesterol on SM metabolism. This study examined the influence of SM biosynthesis on cholesterol metabolism. METHODS: Inducible global Sms1 KO (knockout)/global Sms2 KO mice were prepared to evaluate the effect of whole-body SM biosynthesis deficiency on lipoprotein metabolism. Tissue cholesterol, SM, ceramide, and glucosylceramide levels were measured. Triglyceride production rate and LDL (low-density lipoprotein) catabolism were measured. Lipid rafts were isolated and LDL receptor mass and function were evaluated. Also, the effects of exogenous sphingolipids on hepatocytes were investigated. RESULTS: We found that total SMS (SM synthase) depletion significantly reduced plasma SM levels. Also, the total deficiency significantly induced plasma cholesterol, apoB (apolipoprotein B), and apoE (apolipoprotein E) levels. Importantly, total SMS deficiency, but not SMS2 deficiency, dramatically decreased LDL receptors in the liver and attenuated LDL uptake through the receptor. Further, we found that total SMS deficiency greatly reduced LDL receptors in the lipid rafts, which contained significantly lower SM and significantly higher glucosylceramide, as well as cholesterol. Furthermore, we treated primary hepatocytes and Huh7 cells (a human hepatoma cell line) with SM, ceramide, or glucosylceramide, and we found that only SM could upregulate LDL receptor levels in a dose-dependent fashion. CONCLUSIONS: Whole-body SM biosynthesis plays an important role in LDL cholesterol catabolism. The total SMS deficiency, but not SMS2 deficiency, reduces LDL uptake and causes LDL cholesterol accumulation in the circulation. Given the fact that serum SM level is a risk factor for cardiovascular diseases, inhibiting SMS2 but not SMS1 should be the desirable approach.

TUBB4B is a novel therapeutic target in non-alcoholic fatty liver disease-associated hepatocellular carcinoma.

Non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) is an emerging malignancy due to the rising prevalence of NAFLD. However, no drug is available to target NAFLD-HCC. In this study, we aim to unravel novel therapeutic targets of NAFLD-HCC utilizing a high-throughput CRISPR/Cas9 screening strategy. We utilized the Epi-drug CRISPR/Cas9 library consisting of single-guide RNAs (sgRNAs) targeting over 1,000 genes representing the FDA-approved drug targets and epigenetic regulators to perform loss-of-function screening in two NAFLD-HCC cell lines (HKCI2 and HKCI10). CRISPR/Cas9 library screening unraveled TUBB4B as an essential gene for NAFLD-HCC cell growth. TUBB4B was overexpressed in NAFLD-HCC tumors compared with adjacent normal tissues (N = 17) and was associated with poor survival (p < 0.01). RNA-sequencing and functional assays revealed that TUBB4B knockout in NAFLD-HCC promoted cell apoptosis, cell cycle arrest, and cellular senescence, leading to suppressed NAFLD-HCC growth in vitro and in vivo. We identified that TUBB4B inhibitor mebendazole (MBZ), an FDA-approved drug, inhibited NAFLD-HCC growth by inducing apoptosis and cellular senescence. Since protein expression of pro-survival Bcl-xL was induced in TUBB4B knockout NAFLD-HCC cells, we examined combination of TUBB4B inhibition with navitoclax, a Bcl-xL inhibitor that selectively targets senescent cells. Consistent with our hypothesis, either TUBB4B knockout or MBZ synergized with navitoclax to inhibit NAFLD-HCC cell growth via the induction of intrinsic and extrinsic apoptosis pathways. In summary, TUBB4B is a novel therapeutic target in NAFLD-HCC. Inhibition of TUBB4B with MBZ in combination with navitoclax synergistically inhibited NAFLD-HCC cell growth, representing a promising strategy for the treatment of NAFLD-HCC. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Accuracy of contrast-enhanced CT in liver neoplasms in children under 2 years age.

BACKGROUND: Multiple differentials exist for pediatric liver tumors under 2 years. Accurate imaging diagnosis may obviate the need for tissue sampling in most cases. OBJECTIVE: To evaluate the imaging features and diagnostic accuracy of computed tomography (CT) in liver tumors in children under 2 years. METHODS: Eighty-eight children under 2 years with treatment naive liver neoplasms and baseline contrast-enhanced CT were included in this institutional review board approved retrospective study. Two blinded onco-radiologists assessed these tumors in consensus. Findings assessed included enhancement pattern, lobulated appearance, cystic change, calcifications, central scar-like appearance, and metastases. The radiologists classified the lesion as hepatoblastoma, infantile hemangioma, mesenchymal hamartoma, rhabdoid tumor, or indeterminate, first based purely on imaging and then after alpha-fetoprotein (AFP) correlation. Multivariate analysis and methods of comparing means and frequencies were used for statistical analysis wherever applicable. Diagnostic accuracy, sensitivity, and positive predictive values were analyzed. RESULTS: The mean age of the sample was 11.4 months (95% CI, 10.9-11.8) with 50/88 (57%) boys. The study included 72 hepatoblastomas, 6 hemangiomas, 4 mesenchymal hamartomas, and 6 rhabdoid tumors. Presence of calcifications, multilobular pattern of arterial enhancement, lobulated morphology, and central scar-like appearance was significantly associated with hepatoblastomas (P-value < 0.05). Fourteen out of eighty-eight lesions were called indeterminate based on imaging alone; six lesions remained indeterminate after AFP correlation. Pure radiology-based diagnostic accuracy was 81.8% (95% CI, 72.2-89.2%), which increased to 92.1% (95% CI, 84.3-96.7%) (P-value > 0.05) after AFP correlation, with one hepatoblastoma misdiagnosed as a rhabdoid tumor. If indeterminate lesions were excluded for biopsy, the accuracy would be 98.8% (95% CI, 93.4-99.9%). CONCLUSION: CT had high accuracy for diagnosing liver neoplasms in the under 2-year age population after AFP correlation. Certain imaging features were significantly associated with the diagnosis of hepatoblastoma. A policy of biopsying only indeterminate lesions after CT and AFP correlation would avoid sampling in the majority of patients.

Recipient blood group does not affect hepatocellular carcinoma recurrence after living donor liver transplantation in Korea.

PURPOSE: This study assessed whether or not the ABO blood type affects the incidence of HCC recurrence after living donor liver transplantation (LDLT). METHODS: This retrospective observational study included 856 patients with hepatocellular carcinoma (HCC) who underwent LDLT between January 2006 and December 2016 at the Asan Medical Center. RESULTS: This study included 324 patients (37.9%) with blood type A, 215 (25.1%) with blood type B, 210 (24.5%) with blood type O, and 107 (12.5%) with blood type AB. ABO-incompatible LT was performed in 136 (15.9%) patients. The independent risk factors for the disease-free survival (DFS) were maximal tumor diameter, microvascular invasion, and Milan criteria. The only independent risk factor for the overall survival (OS) was microvascular invasion. The ABO blood group did not affect the DFS (P = 0.978) or OS (P = 0.261). The DFS according to the ABO blood group did not differ significantly between the ABO-compatible (p = 0.701) and ABO-incompatible LDLT recipients (p = 0.147). The DFS according to the ABO blood group did not differ significantly between patients within the Milan criteria (p = 0.934) and beyond the Milan criteria (p = 0.525). The DFS did not differ significantly between recipients with and without type A blood (p = 0.941). CONCLUSIONS: This study demonstrated that the ABO blood group system had no prognostic impact on the oncological outcomes of patients undergoing LT for HCC.

Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review.

BACKGROUND: Perihilar cholangiocarcinoma (phCCC) is a dismal malignancy. There is no consensus regarding the best treatment for patients with unresectable phCCC. The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice. DATA SOURCES: The search was conducted in PubMed, Embase, Cochrane, and LILACS. The related references were searched manually. Inclusion criteria were: reports in English or Portuguese literature that a) patients with confirmed diagnosis of phCCC; b) patients treated with a curative intent; c) patients with the outcomes of liver resection and liver transplantation. Case reports, reviews, letters, editorials, conference abstracts and papers with full-text unavailability were excluded from the analysis. RESULTS: Most of the current literature is based on observational retrospective studies with low grades of evidence. Liver resection has better long-term outcomes than systemic chemotherapy or palliation therapy and liver transplantation is a good alternative for selected patients with unresectable phCCC. All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahepatic diseases. As a general rule, patients presenting with a tumor having a longitudinal size > 3 cm or extending below the cystic duct, lymph node disease, confirmed extrahepatic dissemination; intraoperatively diagnosed metastatic disease; a history of other malignancies within the last five years, and did not complete chemoradiation regimen and were medically unfit should not be considered for transplantation. Some of these criteria should be individually assessed. Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers, and any decision-making must be based on a multidisciplinary evaluation. CONCLUSIONS: phCCC is a complex condition with high morbidity. Surgical therapies, including hepatectomy and liver transplantation, are the best option for better long-term disease-free survival.

Comprehensive review of hepatocellular carcinoma with portal vein tumor thrombus: State of art and future perspectives.

BACKGROUND: Despite advances in the diagnosis of patients with hepatocellular carcinoma (HCC), 70%-80% of patients are diagnosed with advanced stage disease. Portal vein tumor thrombus (PVTT) is among the most ominous signs of advanced stage disease and has been associated with poor survival if untreated. DATA SOURCES: A systematic search of MEDLINE (PubMed), Embase, Cochrane Library and Database for Systematic Reviews (CDSR), Google Scholar, and National Institute for Health and Clinical Excellence (NICE) databases until December 2022 was conducted using free text and MeSH terms: hepatocellular carcinoma, portal vein tumor thrombus, portal vein thrombosis, vascular invasion, liver and/or hepatic resection, liver transplantation, and systematic review. RESULTS: Centers of surgical excellence have reported promising results related to the individualized surgical management of portal thrombus versus arterial chemoembolization or systemic chemotherapy. Critical elements to the individualized surgical management of HCC and portal thrombus include precise classification of the portal vein tumor thrombus, accurate identification of the subgroups of patients who may benefit from resection, as well as meticulous surgical technique. This review addressed five specific areas: (a) formation of PVTT; (b) classifications of PVTT; (c) controversies related to clinical guidelines; (d) surgical treatments versus non-surgical approaches; and (e) characterization of surgical techniques correlated with classifications of PVTT. CONCLUSIONS: Current evidence from Chinese and Japanese high-volume centers demonstrated that patients with HCC and associated PVTT can be managed with surgical resection with acceptable results.

Surgical margin status outcome of intraoperative indocyanine green fluorescence-guided laparoscopic hepatectomy in liver malignancy: a systematic review and meta-analysis.

BACKGROUND: Hepatectomy stands as a curative management for liver cancer. The critical factor for minimizing recurrence rate and enhancing overall survival of liver malignancy is to attain a negative margin hepatic resection. Recently, Indocyanine green (ICG) fluorescence imaging has been proven implemental in aiding laparoscopic liver resection, enabling real-time tumor identification and precise liver segmentation. The purpose of this study is to conduct a systematic review and meta-analysis to ascertain whether ICG-guided laparoscopic hepatectomy yields a higher incidence of complete tumor eradication (R0) resections. METHODS: The search encompassed databases such as PubMed, Cochrane Library database, Scopus, ScienceDirect, and Ovid in April 2024, in strict adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies involving patients with malignant liver lesions who underwent ICG-guided laparoscopic hepatectomy and reported R0 resection outcomes were eligible for inclusion in this review. RESULTS: In a total of seven studies, involving 598 patients, were included in the meta-analysis. The ICG demonstrated a significantly elevated R0 resection rate compared to the non-ICG group [98.6% (359/364) vs. 93.1% (339/364), odds ratio (OR) = 3.76, 95% confidence intervals (CI) 1.45-9.51, P = 0.005]. Notably, no heterogeneity was observed (I2 = 0%, P = 0.5). However, the subtype analysis focusing on hepatocellular carcinoma [98.2% (165/168) vs. 93.6% (161/172), OR = 3.34, 95% CI 0.94-11.91, P = 0.06) and the evaluation of margin distance (4.96 ± 2.41 vs. 2.79 ± 1.92 millimeters, weighted mean difference = 1.26, 95% CI -1.8-4.32, P = 0.42) revealed no apparent differences. Additionally, the incidence of overall postoperative complications was comparable between both groups, 27.6% (66/239) in the ICG group and 25.4% (75/295) in the non-ICG group (OR = 0.96, 95% CI 0.53-1.76, P = 0.9). No disparities were identified in operative time, intraoperative blood loss, postoperative blood transfusion, and length of hospital stay after the surgery. CONCLUSIONS: The implementation of ICG-guided laparoscopic hepatectomy can be undertaken with confidence, as it does not compromise either intraoperative or postoperative events. Furthermore, the ICG-guided approach is beneficial to achieving a complete eradication of the tumor during hepatic resection. TRIAL REGISTRATION: PROSPERO registration number CRD42023446440.

Early detection of HCC in patients with cirrhosis using AI; a Systematic Review.

Introduction: Hepatocellular carcinoma constitutes for approximately 75% of primary cancers of liver. Around 80- 90% of patients with HCC have cirrhosis at the time of diagnosis. Use of AI has recently gained significance in the field of hepatology, especially for the detection of HCC, owing to its increasing incidence and specific radiological features which have been established for its diagnostic criteria. Objectives: A systematic review was performed to evaluate the current literature for early diagnosis of hepatocellular carcinoma in cirrhotic patients. METHODS: Systematic review was conducted using PRISMA guidelines and the relevant studies were narrated in detail with assessment of quality for each paper. RESULTS: This systematic review displays the significance of AI in early detection and prognosis of HCC with the pressing need for further exploration in this field. CONCLUSIONS: AI can have a significant role in early diagnosis of HCC in cirrhotic patients.

External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection.

BACKGROUND & AIMS: HBV coinfection is common among people living with HIV (PLWH) and is the most important cause of hepatocellular carcinoma (HCC). While risk prediction tools for HCC have been validated in patients with HBV monoinfection, they have not been evaluated in PLWH. Thus, we performed an external validation of PAGE-B in people with HIV/HBV coinfection. METHODS: We included data on PLWH from four European cohorts who were positive for HBsAg and did not have HCC before starting tenofovir. We estimated the predictive performance of PAGE-B for HCC occurrence over 15 years in patients receiving tenofovir-containing antiretroviral therapy. Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as a covariate, and by calculating Harrell's c-index. Calibration was assessed by comparing our cumulative incidence with the PAGE-B derivation study using Kaplan-Meier curves. RESULTS: In total, 2,963 individuals with HIV/HBV coinfection on tenofovir-containing antiretroviral therapy were included. PAGE-B was <10 in 26.5%, 10-17 in 57.7%, and ≥18 in 15.7% of patients. Within a median follow-up of 9.6 years, HCC occurred in 68 individuals (2.58/1,000 patient-years, 95% CI 2.03-3.27). The regression slope of the prognostic index for developing HCC within 15 years was 0.93 (95% CI 0.61-1.25), and the pooled c-index was 0.77 (range 0.73-0.80), both indicating good model discrimination. The cumulative incidence of HCC was lower in our study compared to the derivation study. A PAGE-B cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. Restricting efforts to individuals with a PAGE-B of ≥10 would spare unnecessary HCC screening in 27% of individuals. CONCLUSIONS: For individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening. IMPACT AND IMPLICATIONS: Chronic HBV infection is the most important cause of hepatocellular carcinoma (HCC) among people living with HIV. Valid risk prediction may enable better targeting of HCC screening efforts to high-risk individuals. We aimed to validate PAGE-B, a risk prediction tool that is based on age, sex, and platelets, in 2,963 individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration, and a cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. These results indicate that PAGE-B is a simple and valid risk prediction tool to determine the need for HCC screening among people living with HIV and HBV.