Preoperative Prediction of Microvascular Invasion with Gadoxetic Acid-Enhanced Magnetic Resonance Imaging in Patients with Single Hepatocellular Carcinoma: The Implication of Surgical Decision on the Extent of Liver Resection.

Introduction: Microvascular invasion (MVI) is one of the most important prognostic factors for hepatocellular carcinoma (HCC) recurrence, but its application in preoperative clinical decisions is limited. This study aimed to identify preoperative predictive factors for MVI in HCC and further evaluate oncologic outcomes of different types and extents of hepatectomy according to stratified risk of MVI. Methods: Patients with surgically resected single HCC (≤5 cm) who underwent preoperative gadoxetic acid-enhanced magnetic resonance imaging (MRI) were included in a single-center retrospective study. Two radiologists reviewed the images with no clinical, pathological, or prognostic information. Significant predictive factors for MVI were identified using logistic regression analysis against pathologic MVI and used to stratify patients. In the subgroup analysis, long-term outcomes of the stratified patients were analyzed using the Kaplan-Meier method with log-rank test and compared between anatomical and nonanatomical or major and minor resection. Results: A total of 408 patients, 318 men and 90 women, with a mean age of 56.7 years were included. Elevated levels of tumor markers (alpha-fetoprotein [α-FP] ≥25 ng/mL and PIVKA-II ≥40 mAU/mL) and three MRI features (tumor size ≥3 cm, non-smooth tumor margin, and arterial peritumoral enhancement) were independent predictive factors for MVI. As the MVI risk increased from low (no predictive factor) and intermediate (1-2 factors) to high-risk (3-4 factors), recurrence-free and overall survival of each group significantly decreased (p = 0.001). In the high MVI risk group, 5-year cumulative recurrence rate was significantly lower in patients who underwent major compared to minor hepatectomy (26.6 vs. 59.8%, p = 0.027). Conclusion: Tumor markers and MRI features can predict the risk of MVI and prognosis after hepatectomy. Patients with high MVI risk had the worst prognosis among the three groups, and major hepatectomy improved long-term outcomes in these high-risk patients.

Anti-4-1BB×PD-L1 Bispecific Antibody Reinvigorates Tumor-Specific Exhausted CD8+ T Cells and Enhances the Efficacy of Anti-PD-1 Blockade.

PURPOSE: To overcome the limited efficacy of immune checkpoint blockade, there is a need to find novel cancer immunotherapeutic strategies for the optimal treatment of cancer. The novel anti-4-1BB×PD-L1 bispecific antibody-ABL503 (also known as TJ-L14B)-was designed to simultaneously target PD-L1 and 4-1BB, and demonstrated strong antitumor T-cell responses without considerable toxicity. Here, we investigated how the combination of ABL503 and anti-PD-1 blockade affected the reinvigoration of exhausted tumor-infiltrating CD8+ T cells (CD8+ TILs) and anti-tumor efficacy. EXPERIMENTAL DESIGN: Single cell suspensions of hepatocellular carcinoma and ovarian cancer from treatment-naive patients were used for immunophenotyping of CD8+ TILs and in vitro functional assays. Humanized hPD-1/hPD-L1/h4-1BB triple knock-in mice were used to evaluate the effects of ABL503 and anti-PD-1 blockade in vivo. RESULTS: We observed that ABL503 successfully restored the functions of 4-1BB+ exhausted CD8+ TILs, which were enriched for tumor-specific T cells but unresponsive to anti-PD-1 blockade. Importantly, compared to anti-PD-1 blockade alone, the combination of ABL503 and anti-PD-1 blockade further enhanced the functional restoration of human CD8+ TILs in vitro. Consistently, the combination of ABL503 with anti-PD-1 in vivo significantly alleviated tumor growth, and induced enhanced infiltration and activation of CD8+ TILs. CONCLUSIONS: ABL503-a PD-L1 and 4-1BB dual-targeting bispecific antibody-elicits pronounced additive tumor growth inhibition, with increased infiltration and functionality of exhausted CD8+ T cells, which in turn enhances the anti-cancer effects of anti-PD-1 blockade. These promising findings suggest that ABL503 (TJ-L14B) in combination with PD-1 inhibitors will likely further enhance therapeutic benefit in clinical trials.

Surgical strategy for incidental intrahepatic cholangiocarcinoma in terms of lymph node dissection.

BACKGROUND: Although many guidelines recommend performing lymph node dissection (LND) during surgery for intrahepatic cholangiocarcinoma (ICC), there is no evidence for patients with incidentally detected ICC who did not undergo LND. This study aimed to identify the role of LND in patients with incidental ICC. METHODS: The data from 284 patients who had undergone radical surgery for ICC from 2000 to 2020 were retrospectively reviewed. The enrolled patients were divided into 3 groups according to their T stage (T1 vs T2 vs T3 + 4). Moreover, the patients of each T group were divided into 3 groups according to their nodal status (N0 vs N1 vs Nx) and their survival outcomes were compared. RESULTS: Survival outcomes of Nx group were statistically similar to that of N0 group in T1 stage (Nx vs N0: disease-free survival [DFS] [months], 129.0 [75.6-182.4] vs 125.0 [65.7-184.3], P = .948; overall survival [OS] [months], 175.0 [153.9-196.1] vs 173.0 [109.0-237.0], P = .443). In contrast, survival outcomes of Nx group in the other T stage (T2 and T3 + 4) were poorer than that of N0 group and were better than that of N1 group. In addition, in the Nx subgroup analysis according to T stage, T1 group showed significantly better survival outcomes than the other groups (T1 vs T2 vs T3 + 4: DFS [months], 129.0 [75.9-182.1] vs 16.0 [9.8-22.2] vs 13.0 [0.3-25.7], P < .001; OS [months], 175.0 [153.9-196.1] vs 53.0 [30.8-75.2] vs 37.0 [17.6-56.4], P < .001). CONCLUSION: Patients with ICC incidentally diagnosed as having T2 or above T stage may consider additional LND.

Liver-Directed Combined Radiation Therapy for Downstaging Beyond-Milan Hepatocellular Carcinoma to Liver Transplantation.

PURPOSE: Curative surgery involving either resection or liver transplantation (LT) is indicated only for early-stage hepatocellular carcinoma (HCC). Over the years, numerous efforts have been made to downstage advanced HCC to curative surgery using various locoregional therapies. In this study, we investigated the role of liver-directed combined radiation therapy (LD-CRT) as a downstaging strategy for converting beyond-Milan advanced HCC to LT. METHODS AND MATERIALS: From January 2009 to February 2022, 53 patients with HCC who were initially beyond-Milan criteria were treated with LD-CRT and subsequent LT. These patients were compared with those who underwent upfront LT for within-Milan HCCs. The primary endpoint was overall survival (OS) and the secondary endpoint recurrence-free survival (RFS). RESULTS: After LD-CRT, substantial downstaging was achieved in 35 patients (66%) who were initially beyond-Milan to within-Milan. At a median follow-up period of 47.6 months (range, 6.9-151.7 months), 5-year OS and 2-year RFS of the patients who received downstaging LD-CRT followed by LT were 66.9% and 63.2%, respectively. Patients who were successfully downstaged to within-Milan after LD-CRT had improved 5-year OS compared with their counterparts (81.9% vs 74.3%, P = .219). Recurrence after transplantation was observed in 18 patients (4 intrahepatic recurrences and 14 extrahepatic metastases). CONCLUSIONS: LD-CRT achieved favorable oncological outcomes as a downstaging strategy for LT in patients with beyond-Milan HCC. The findings of this study suggest that the active adoption of LD-CRT needs full consideration for patients with beyond-Milan HCC, presenting the possibility of curing patients with advanced HCC.

Additional nodules detected using EOB-MRI in patients with resectable single hepatocellular carcinoma: an implication for active treatment strategy.

BACKGROUND/AIM: Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOBMRI) further enhances the identification of additional hepatic nodules compared with computed tomography (CT) alone; however, the optimal treatment for such additional nodules remains unclear. We investigated the long-term oncological effect of aggressive treatment strategies for additional lesions identified using EOB-MRI in patients with hepatocellular carcinoma (HCC). METHODS: Data from 522 patients diagnosed with solitary HCC using CT between January 2008 and December 2012 were retrospectively reviewed. Propensity score-matched (PSM) analysis was used to compare the oncologic outcomes between patients with solitary HCC and those with additional nodules on EOB-MRI after aggressive treatment (resection or radiofrequency ablation [RFA]). RESULTS: Among the 383 patients included, 59 had additional nodules identified using EOB-MRI. Compared with patients with solitary HCC, those with additional nodules on EOB-MRI had elevated total bilirubin, aspartate transaminase, and alanine transaminase; had a lower platelet count, higher MELD score, and highly associated with liver cirrhosis (P<0.05). Regarding long-term outcomes, 59 patients with solitary HCC and those with additional nodules after PSM were compared. Disease-free survival (DFS) and overall survival (OS) were comparable between the two groups (DFS, 60.4 vs. 44.3 months, P=0.071; OS, 82.8 vs. 84.8 months, P=0.986). CONCLUSION: The aggressive treatment approach, either resection or RFA, for patients with additional nodules identified on EOBMRI was associated with long-term survival comparable with that for solitary HCC. However, further studies are required to confirm these findings.

Synergistic toxicity with copper contributes to NAT2-associated isoniazid toxicity.

Anti-tuberculosis (AT) medications, including isoniazid (INH), can cause drug-induced liver injury (DILI), but the underlying mechanism remains unclear. In this study, we aimed to identify genetic factors that may increase the susceptibility of individuals to AT-DILI and to examine genetic interactions that may lead to isoniazid (INH)-induced hepatotoxicity. We performed a targeted sequencing analysis of 380 pharmacogenes in a discovery cohort of 112 patients (35 AT-DILI patients and 77 controls) receiving AT treatment for active tuberculosis. Pharmacogenome-wide association analysis was also conducted using 1048 population controls (Korea1K). NAT2 and ATP7B genotypes were analyzed in a replication cohort of 165 patients (37 AT-DILI patients and 128 controls) to validate the effects of both risk genotypes. NAT2 ultraslow acetylators (UAs) were found to have a greater risk of AT-DILI than other genotypes (odds ratio [OR] 5.6 [95% confidence interval; 2.5-13.2], P = 7.2 × 10-6). The presence of ATP7B gene 832R/R homozygosity (rs1061472) was found to co-occur with NAT2 UA in AT-DILI patients (P = 0.017) and to amplify the risk in NAT2 UA (OR 32.5 [4.5-1423], P = 7.5 × 10-6). In vitro experiments using human liver-derived cell lines (HepG2 and SNU387 cells) revealed toxic synergism between INH and Cu, which were strongly augmented in cells with defective NAT2 and ATP7B activity, leading to increased mitochondrial reactive oxygen species generation, mitochondrial dysfunction, DNA damage, and apoptosis. These findings link the co-occurrence of ATP7B and NAT2 genotypes to the risk of INH-induced hepatotoxicity, providing novel mechanistic insight into individual AT-DILI susceptibility. Yoon et al. showed that individuals who carry NAT2 UAs and ATP7B 832R/R genotypes are at increased risk of developing isoniazid hepatotoxicity, primarily due to the increased synergistic toxicity between isoniazid and copper, which exacerbates mitochondrial dysfunction-related apoptosis.

Robotic and laparoscopic right lobe living donation compared to the open approach: A multicenter study on 1194 donor hepatectomies.

Due to the success of minimally invasive liver surgery, laparoscopic and robotic minimally invasive donor hepatectomies (MIDH) are increasingly performed worldwide. We conducted a retrospective, multicentre, propensity score-matched analysis on right lobe MIDH by comparing the robotic, laparoscopic, and open approaches to assess the feasibility, safety, and early outcomes of MIDHs. From January 2016 until December 2020, 1194 donors underwent a right donor hepatectomy performed with a robotic (n = 92), laparoscopic (n = 306), and open approach (n = 796) at 6 high-volume centers. Donor and recipients were matched for different variables using propensity score matching (1:1:2). Donor outcomes were recorded, and postoperative pain was measured through a visual analog scale. Recipients' outcomes were also analyzed. Ninety-two donors undergoing robotic surgery were matched and compared to 92 and 184 donors undergoing laparoscopic and open surgery, respectively. Conversions to open surgery occurred during 1 (1.1%) robotic and 2 (2.2%) laparoscopic procedures. Robotic procedures had a longer operative time (493 ± 96 min) compared to laparoscopic and open procedures (347 ± 120 and 358 ± 95 min; p < 0.001) but were associated with reduced donor blood losses ( p < 0.001). No differences were observed in overall and major complications (≥ IIIa). Robotic hepatectomy donors had significantly less pain compared to the 2 other groups ( p < 0.001). Fifty recipients of robotic-procured grafts were matched to 50 and 100 recipients of laparoscopic and open surgery procured grafts, respectively. No differences were observed in terms of postoperative complications, and recipients' survival was similar ( p =0.455). In very few high-volume centers, robotic right lobe procurement has shown to be a safe procedure. Despite an increased operative and the first warm ischemia times, this approach is associated with reduced intraoperative blood losses and pain compared to the laparoscopic and open approaches. Further data are needed to confirm it as a valuable option for the laparoscopic approach in MIDH.

Unusual grafts for living-donor liver transplantation.

PURPOSE: Unusual grafts, including extended left liver plus caudate lobe, right anterior section, and right posterior section grafts, are alternatives to left and right lobe grafts for living-donor liver transplantation. This study aimed to investigate unusual grafts from the perspectives of recipients and donors. METHODS: From 2016 to 2021, 497 patients received living-donor liver transplantation at Severance Hospital. Among them, 10 patients received unusual grafts. Three patients received extended left liver plus caudate lobe grafts, two patients received right anterior section grafts, and five patients received right posterior section grafts. Liver volumetrics and anatomy were analyzed for all recipients and donors. We collected data on laboratory examinations (alanine aminotransferase, total bilirubin, international normalized ratio), imaging studies, graft survival, and complications. A 1:2 ratio propensity-score matching method was used to reduce selection bias and balance variables between the unusual and conventional graft groups. RESULTS: The median of Model for End-stage Liver Disease score of unusual graft recipients was 13.5 (interquartile range 11.5-19.3) and that of graft-recipient weight ratio was 0.767 (0.7-0.9). ABO incompatibility was observed in four cases. The alanine aminotransferase level, total bilirubin level, and international normalized ratio decreased in both recipients and donors. Unusual and conventional grafts had similar survival rates (p = 0.492). The right and left subgroups did not differ from each counter-conventional subgroup (p = 0.339 and p = 0.695, respectively). The incidence of major complications was not significantly different between unusual and conventional graft recipients (p = 0.513). Wound seromas were reported by unusual graft donors; the complication ratio was similar to that in conventional graft donors (p = 0.169). CONCLUSION: Although unusual grafts require a complex indication, they may show feasible surgical outcomes for recipients with an acceptable donor complication.

Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) occurs due to the accumulation of fat in the liver, leading to fatal liver diseases such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Elucidation of the molecular mechanisms underlying NAFLD is critical for its prevention and therapy. Here, we observed that deubiquitinase USP15 expression was upregulated in the livers of mice fed a high-fat diet (HFD) and liver biopsies of patients with NAFLD or NASH. USP15 interacts with lipid-accumulating proteins such as FABPs and perilipins to reduce ubiquitination and increase their protein stability. Furthermore, the severity of NAFLD induced by an HFD and NASH induced by a fructose/palmitate/cholesterol/trans-fat (FPC) diet was significantly ameliorated in hepatocyte-specific USP15 knockout mice. Thus, our findings reveal an unrecognized function of USP15 in the lipid accumulation of livers, which exacerbates NAFLD to NASH by overriding nutrients and inducing inflammation. Therefore, targeting USP15 can be used in the prevention and treatment of NAFLD and NASH.

Hepatic arterial infusion in combination with systemic chemotherapy in patients with hepatic metastasis from colorectal cancer: a randomized phase II study - (NCT05103020) - study protocol.

BACKGROUND: Although 80% of patients with metastatic colorectal cancer (CRC) experience liver metastases, only 10-25% undergo resection at the time of diagnosis. Even in initially unresectable conditions, if appropriate treatment is provided, such as surgical conversion through a combination of hepatic arterial infusion (HAI) chemotherapy and systemic chemotherapy (sys-CT), better overall survival can be expected. Therefore, this study aims to evaluate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy in patients with unresectable CRC with liver-only metastasis. METHODS: This is a single-center, randomized, open-label phase II trial (NCT05103020). Patients with untreated CRC, who have liver-only metastases and for whom liver resection is potentially possible but deemed infeasible at the time of initial diagnosis by a multidisciplinary team, will be eligible. Patients will be randomly assigned in a 1:1 ratio to either the combined HAI oxaliplatin and modified systemic 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus targeted therapy group or the systemic FOLFIRI plus targeted therapy group. Both regimens will be repeated every 2 weeks for a total of 12 cycles. The primary objective of this study is to compare the rate of conversion to liver resection. The surgical conversion rate is expected to increase by 25% with HAI oxaliplatin in combination with sys-CT plus targeted therapy (40% in the experimental arm versus 15% in the control arm) (power, 80%; two-sided alpha-risk, 5%). The secondary objectives include overall survival, progression-free survival, and objective response rate. DISCUSSION: This is the first randomized controlled trial to investigate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy as first-line treatment from the initial diagnosis in patients with unresectable CRC with liver-only metastasis, aiming to significantly increase the surgical conversion rate. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT05103020). Trial registration date: November 2, 2021.

Differentiation between hepatic angiomyolipoma and hepatocellular carcinoma in individuals who are not at-risk for hepatocellular carcinoma.

PURPOSE: To develop a practical methodfor differentiating hepatocellular carcinoma (HCC) from angiomyolipoma (AML) in individuals who are not at-risk for HCC. METHOD: We retrospectively enrolled consecutive patients who underwent gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) and pathological confirmation between January 2008 and April 2022. Patients who underwent prior treatment, those with multiple lesions, or those at-risk for HCC were excluded. The training cohort included patients with pathological confirmation between 2008 and 2019, whereas the validation cohort included the remaining cases. Independent reviews of the MRI were performed by two reviewers. Using the clinical and MRI findings, we developed AML-HCC score using Firth's logistic regression in the training cohort, and the diagnostic performance was validated in the validation cohort. RESULTS: Of the 206 patients, 156 were assigned to the training cohort (25 and 131 patients with AML and HCC, respectively) and 50 were assigned to the validation cohort (4 and 46 patients with AML and HCC, respectively). The AML-HCC score was defined as the sum of female (score 1), early draining vein (score 2), T2 homogeneity (score 1), necrosis or severe ischaemia (score -2), and HBP hyperintensity to spleen (score -1). When the AML-HCC score was ≥1, the sensitivity and specificity were 80% and 95% for the training cohort and 100% and 80% for the validation cohort, respectively. CONCLUSIONS: We developed and validated an AML-HCC score to differentiate between AML and HCC in individuals who are not at-risk for HCC, and our model demonstrated good diagnostic performance.

Prognostic impact of R1 resection margin in synchronous and simultaneous colorectal liver metastasis resection: a retrospective cohort study.

BACKGROUND: A margin ≥ 1 mm is considered a standard resection margin for colorectal liver metastasis (CRLM). However, microscopic incomplete resection (R1) is not rare since aggressive surgical resection has been attempted in multiple and bilobar CRLM. This study aimed to investigate the prognostic impact of resection margins and perioperative chemotherapy in patients with CRLM. METHODS: A total of 368 of 371 patients who underwent simultaneous colorectal and liver resection for synchronous CRLM between 2006 and June 2017, excluding three R2 resections, were included in this study. R1 resection was defined as either abutting tumor on the resection line or involved margin in the pathological report. The patients were divided into R0 (n = 304) and R1 (n = 64) groups. The clinicopathological characteristics, overall survival, and intrahepatic recurrence-free survival were compared between the two groups using propensity score matching. RESULTS: The R1 group had more patients with ≥ 4 liver lesions (27.3 vs. 50.0%, P < 0.001), higher mean tumor burden score (4.4 vs. 5.8%, P = 0.003), and more bilobar disease (38.8 vs. 67.2%, P < 0.001) than the R0 group. Both R0 and R1 groups showed similar long-term outcomes in the total cohort (OS, P = 0.149; RFS, P = 0.414) and after matching (OS, P = 0.097, RFS: P = 0.924). However, the marginal recurrence rate was higher in the R1 group than in the R0 group (26.6 vs. 16.1%, P = 0.048). Furthermore, the resection margin did not have a significant impact on OS and RFS, regardless of preoperative chemotherapy. Poorly differentiated, N-positive stage colorectal cancer, liver lesion number ≥ 4, and size ≥ 5 cm were poor prognostic factors, and adjuvant chemotherapy had a positive impact on survival. CONCLUSIONS: The R1 group was associated with aggressive tumor characteristics; however, no effect on the OS and intrahepatic RFS with or without preoperative chemotherapy was observed in this study. Tumor biological characteristics, rather than resection margin status, determine long-term prognosis. Therefore, aggressive surgical resection should be considered in patients with CRLM expected to undergo R1 resection in this multidisciplinary approach era.

Increased expression of sodium-glucose cotransporter 2 and O-GlcNAcylation in hepatocytes drives non-alcoholic steatohepatitis.

AIMS: Steatosis reducing effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in non-alcoholic steatohepatitis (NASH) has been consistently reported in humans, but their mechanism remains uncertain. In this study, we examined the expression of SGLT2 in human livers and investigated the crosstalk between SGLT2 inhibition and hepatic glucose uptake, intracellular O-GlcNAcylation, and autophagic regulation in NASH. MATERIALS AND METHODS: Human liver samples obtained from subjects with/without NASH were analyzed. For in vitro studies, human normal hepatocytes and hepatoma cells were treated with SGLT2 inhibitor under high-glucose and high-lipid conditions. NASH in vivo was induced by a high-fat, -fructose, and -cholesterol Amylin liver NASH (AMLN) diet for 10 weeks followed by an additional 10 weeks with/without SGLT2 inhibitor (empagliflozin 10 mg/kg/day). RESULTS: Liver samples from subjects with NASH were associated with increased SGLT2 and O-GlcNAcylation expression compared with controls. Under NASH condition (in vitro condition with high glucose and lipid), intracellular O-GlcNAcylation and inflammatory markers were increased in hepatocytes and SGLT2 expression was upregulated; SGLT2 inhibitor treatment blocked these changes by directly reducing hepatocellular glucose uptake. In addition, decreased intracellular O-GlcNAcylation by SGLT2 inhibitor promoted autophagic flux through AMPK-TFEB activation. In the AMLN diet-induced NASH mice model, SGLT2 inhibitor alleviated lipid accumulation, inflammation, and fibrosis through autophagy activation related to decreased SGLT2 expression and O-GlcNAcylation in the liver. CONCLUSIONS: This study firstly demonstrates increased SGLT2 expression in NASH and secondly reveals the novel effect of SGLT2 inhibition on NASH through autophagy activation mediated by inhibition of hepatocellular glucose uptake and consequently decreased intracellular O-GlcNAcylation.

Effect of High-Versus Low-Frequency of Abdominopelvic Computed Tomography Follow-Up Testing on Overall Survival in Patients With Stage II Or III Colon Cancer.

BACKGROUND: Intensive surveillance of colon cancer by using the abdominopelvic computed tomography (AP-CT) is common in real world practice; however, it is still unclear whether high-frequency surveillance using AP-CT in patients with these risk factors is superior to that in the low-frequency surveillance. PATIENTS AND METHODS: We retrospectively reviewed 1803 patients with stage II-III colon cancer receiving curative surgery between January 1, 2005 to December 31, 2015. We evaluated the average scan-to-scan intervals of postoperative AP-CT testing and assigned patients with an interval of 5 to 8 and 9 to 13 months to the high-frequency (HF) and low-frequency (LF) groups, respectively. The cutoff value of preoperative and postoperative CEA levels was 5 ng/mL. We also applied propensity score matching (PSM) and inverse probability of treatment weighting to adjust clinicopathologic differences between the 2 groups. RESULTS: We matched 1:1 for each surveillance group yielding a cohort of 776 matched patients. After PSM, Baseline demographics were overall well balanced between 2 groups. Stage III (OR, 2.00; 95% Confidence interval [CI], 1.21-3.30) and postoperative CEA elevation (OR, 2.30; 95% CI, 1.08-4.92) were independent risk factors of recurrence in multivariate analyses. Patient in the HF group had more surgery plus chemo- or radiotherapy as postrecurrence treatment than patient in the LF group (46.2% vs. 23.1%, P = .017). This trend was retained after PSM, although it is not significant (44.4% vs. 23.1%, P = .060). However, survival outcomes of high-frequency AP-CT surveillance were not superior to those of low-frequency surveillance in all subgroups, including stage III (HR 0.99, 95% CI 0.40-2.47) and postoperative CEA elevation (HR 1.36, 95% CI 0.45-4.11). CONCLUSION: High-frequency AP-CT testing is associated with a higher proportion of surgery plus chemo- or radiotherapy as postrecurrence treatment, without improvement in 5-year overall survival.

Effect of sarcopenia on postoperative ICU admission and length of stay after hepatic resection for Klatskin tumor.

Background: Hepatic resection of Klatskin tumors usually requires postoperative intensive care unit (ICU) admission because of its high morbidity and mortality. Identifying surgical patients who will benefit most from ICU admission is important because of scarce resources but remains difficult. Sarcopenia is characterised by the loss of skeletal muscle mass and is associated with poor surgical outcomes. Methods: We retrospectively analysed th.e relationship between preoperative sarcopenia and postoperative ICU admission and length of ICU stay (LOS-I) in patients who underwent hepatic resection for Klatskin tumors. Using preoperative computed tomography scans, the cross-sectional area of the psoas muscle at the level of the third lumbar vertebra was measured and normalised to the patient's height. Using these values, the optimal cut-off for diagnosing sarcopenia was determined using receiver operating characteristic curve analysis for each sex. Results: Of 330 patients, 150 (45.5%) were diagnosed with sarcopenia. Patients with preoperative sarcopenia presented significantly more frequently to the ICU (77.3% vs. 47.9%, p < 0.001) and had longer total LOS-I (2.45 vs 0.89 days, p < 0.001). Moreover, patients with sarcopenia showed a significantly higher postoperative length of hospital stay, severe complication rate, and in-hospital mortality. Conclusions: Sarcopenia correlated with poor postoperative outcomes, especially with the increased requirement of postoperative ICU admission and prolonged LOS-I after hepatic resection in patients with Klatskin tumors.

Tcf7l2 in hepatocytes regulates de novo lipogenesis in diet-induced non-alcoholic fatty liver disease in mice.

AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) associated with type 2 diabetes may more easily progress towards severe forms of non-alcoholic steatohepatitis (NASH) and cirrhosis. Although the Wnt effector transcription factor 7-like 2 (TCF7L2) is closely associated with type 2 diabetes risk, the role of TCF7L2 in NAFLD development remains unclear. Here, we investigated how changes in TCF7L2 expression in the liver affects hepatic lipid metabolism based on the major risk factors of NAFLD development. METHODS: Tcf7l2 was selectively ablated in the liver of C57BL/6N mice by inducing the albumin (Alb) promoter to recombine Tcf7l2 alleles floxed at exon 5 (liver-specific Tcf7l2-knockout [KO] mice: Alb-Cre;Tcf7l2f/f). Alb-Cre;Tcf7l2f/f and their wild-type (Tcf7l2f/f) littermates were fed a high-fat diet (HFD) or a high-carbohydrate diet (HCD) for 22 weeks to reproduce NAFLD/NASH. Mice were refed a standard chow diet or an HCD to stimulate de novo lipogenesis (DNL) or fed an HFD to provide exogenous fatty acids. We analysed glucose and insulin sensitivity, metabolic respiration, mRNA expression profiles, hepatic triglyceride (TG), hepatic DNL, selected hepatic metabolites, selected plasma metabolites and liver histology. RESULTS: Alb-Cre;Tcf7l2f/f essentially exhibited increased lipogenic genes, but there were no changes in hepatic lipid content in mice fed a normal chow diet. However, following 22 weeks of diet-induced NAFLD/NASH conditions, liver steatosis was exacerbated owing to preferential metabolism of carbohydrate over fat. Indeed, hepatic Tcf7l2 deficiency enhanced liver lipid content in a manner that was dependent on the duration and amount of exposure to carbohydrates, owing to cell-autonomous increases in hepatic DNL. Mechanistically, TCF7L2 regulated the transcriptional activity of Mlxipl (also known as ChREBP) by modulating O-GlcNAcylation and protein content of carbohydrate response element binding protein (ChREBP), and targeted Srebf1 (also called SREBP1) via miRNA (miR)-33-5p in hepatocytes. Eventually, restoring TCF7L2 expression at the physiological level in the liver of Alb-Cre;Tcf7l2f/f mice alleviated liver steatosis without altering body composition under both acute and chronic HCD conditions. CONCLUSIONS/INTERPRETATION: In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation. Therefore, TCF7L2 could be a promising regulator of the NAFLD associated with high-carbohydrate diets and diabetes since TCF7L2 deficiency may lead to development of NAFLD by promoting utilisation of excess glucose pools through activating DNL. DATA AVAILABILITY: RNA-sequencing data have been deposited into the NCBI GEO under the accession number GSE162449 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162449 ).

Intraindividual Comparison of MRIs with Extracellular and Hepatobiliary Contrast Agents for the Noninvasive Diagnosis of Hepatocellular Carcinoma Using the Korean Liver Cancer Association-National Cancer Center 2022 Criteria.

PURPOSE: The aim of the present study was to evaluate the per-lesion sensitivity and specificity of the Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) 2022 criteria for the noninvasive diagnosis of hepatocellular carcinoma (HCC), with intraindividual comparison of the diagnostic performance of magnetic resonance imaging with extracellular agents (ECA-MRI) and hepatobiliary agents (HBA-MRI). Materials and Methods: Patients at high risk for HCC who were referred to a tertiary academic institution for hepatic lesions with size ≥ 10 mm between July 2019 and June 2022 were enrolled. A total of 91 patients (mean age, 58.1 years; 76 men and 15 women) with 118 lesions who underwent both ECA-MRI and HBA-MRI were eligible for final analysis. The per-lesion sensitivities and specificities of the KLCA-NCC 2022 criteria using ECA-MRI and HBA-MRI were compared using McNemar's test. RESULTS: The 118 lesions were 93 HCCs, 4 non-HCC malignancies, and 21 benign lesions. On HBA-MRI, the "definite" HCC category showed significantly higher sensitivity than ECA-MRI (78.5% vs. 58.1%, p < 0.001), with identical specificity (92.0% vs. 92.0%, p > 0.999). For "probable" or "definite" HCC categories, there were no differences in the sensitivity (84.9% vs. 84.9%, p > 0.999) and specificity (84.0% vs. 84.0%, p > 0.999) between ECA-MRI and HBA-MRI. CONCLUSION: The "definite" HCC category of the KLCA-NCC 2022 criteria showed higher sensitivity in diagnosing HCC on HBA-MRI compared with ECA-MRI, without compromising specificity. There were no significant differences in the sensitivity and specificity of "probable" or "definite" HCC categories according to ECA-MRI and HBA-MRI.

Integrative analysis of multiple genomic data from intrahepatic cholangiocarcinoma organoids enables tumor subtyping.

As genomic analysis technology has advanced, it has become possible to sub-classify intrahepatic cholangiocarcinoma (ICC) at the histological or molecular level. Here, we verify the recently suggested two subgroups of ICC in the organoids model, compare the characteristics between types. ICC patients are subclassified into small-duct (SD) and large-duct (LD) subtype according to histological characteristics. ICC organoids are established, and unsupervised principal component analysis clustering separates each type of ICC. Differential gene expression reveals enrichment on KRAS, TGFß and ERBB2 signaling pathways in LD-type compared with SD-type (P < 0.05). Gene set enrichment analysis demonstrates that the cholangiocarcinoma class 2 signature, defined by Andersen et al., is enriched in the LD-type (enrichment Score = 2.19, P < 0.001). A protein-protein interaction network analysis identifies ZNF217 as a significant hub protein (odds ratio = 4.96, P = 0.0105). We perform prospective modeling of histological subtype using patient-derived organoids. Moreover, gene expression profiling of ICC organoids enables identification of type-specific targetable pathways.

A preoperative scoring system to predict lymph node metastasis in intrahepatic cholangiocarcinoma.

BACKGROUND: The abnormality of imaging finding of lymph node (LN) has demonstrated unsatisfactory diagnostic accuracy for pathologic lymph node metastasis (LNM). We aimed to develop and validate a simple scoring system predicting LNM in patients with intrahepatic cholangiocarcinoma (iCCA) prior to surgery based on MRI and clinical findings. METHODS: We retrospectively enrolled consecutive patients who underwent surgical resection for treatment-naïve iCCA from six institutions between January 2009 and December 2015. Patients who underwent lymph node dissection (LND) were randomly assigned to the training and validation cohorts at a 2:1 ratio, an¹ìd pathologic LN status was evaluated. Patients who did not undergo LND were assigned to the test cohort, and clinical LN status was evaluated. Using MRI and clinical findings, a preoperative LNM score was developed in the training cohort and validated in the validation and test cohorts. RESULTS: The training, validation, and test cohorts included 102, 53, and 118 patients, respectively. The preoperative LNM score consisted of serum carcinoembryonic antigen and two MRI findings (suspicious LN and bile duct invasion). The preoperative LNM score was associated with pathologic LNM in training (p < 0.001) and validation (p = 0.010) cohorts and clinical LNM in test cohort (p < 0.001). The preoperative LNM score outperformed MRI-suspicious LN alone in predicting pathologic LNM (area under the curve, 0.703 vs. 0.604, p = 0.004). The preoperative LNM score was also associated with overall survival in all cohorts (p < 0.001). CONCLUSIONS: Our preoperative LNM score was significantly associated with pathologic or clinical LNM and outperformed MRI-suspicious LN alone.