Venous reconstruction using a round ligament-covered prosthetic vascular graft in right­lobe living­donor liver transplantation: a technical report.

PURPOSE: To evaluate the short term-outcomes of venous reconstruction using a round ligament-covered prosthetic vascular graft and assess its effectiveness in the prevention of prosthetic vascular graft migration in right­lobe living donor liver transplantation (LDLT). METHODS AND RESULTS: Thirty patients underwent reconstruction of the middle hepatic vein (MHV) tributaries during right lobe LDLT between January, 2021 and October, 2022. These patients were divided into the autologous vascular graft group (A group, n = 24) and the round ligament-covered prosthetic vascular graft group (RP group, n = 6). The computed tomography (CT) density ratio of the drainage area in the posterior segment of patent grafts was significantly higher in the RP group than in the A group (0.91 vs. 1.06, p = 0.0025). However, the patency rates of reconstructed MHV tributaries in the A and RP groups were 61% and 67%, respectively, with no significant difference between the groups (p = 0.72). Prosthetic vascular graft migration did not occur in the RP group. CONCLUSION: Venous reconstruction using round ligament-covered prosthetic vascular grafts is a feasible and simple method to prevent prosthetic vascular graft migration in right-lobe LDLT.

Multiparametric assessment of microvascular invasion in hepatocellular carcinoma using gadoxetic acid-enhanced MRI.

PURPOSE: To elucidate how precisely microvascular invasion (MVI) in hepatocellular carcinoma (HCC) can be predicted using multiparametric assessment of gadoxetic acid-enhanced MRI. METHODS: In this retrospective single-center study, patients who underwent liver resection or transplantation of HCC were evaluated. Data obtained in patients who underwent liver resection were used as the training set. Nine kinds of MR findings for predicting MVI were compared between HCCs with and without MVI by univariate analysis, followed by multiple logistic regression analysis. Using significant findings, a predictive formula for diagnosing MVI was obtained. The diagnostic performance of the formula was investigated in patients who underwent liver resection (validation set 1) and in patients who underwent liver transplantation (validation set 2) using a receiver operating characteristic curve analysis. The area under the curves (AUCs) of these three groups were compared. RESULTS: A total of 345 patients with 356 HCCs were selected for analysis. Tumor diameter (D) (P = 0.021), tumor washout (TW) (P < 0.01), and peritumoral hypointensity in the hepatobiliary phase (PHH) (P < 0.01) were significantly associated with MVI after multivariate analysis. The AUCs for predicting MVI of the predictive formula were as follows: training set, 0.88 (95% confidence interval (CI) 0.82,0.93); validation set 1, 0.81 (95% CI 0.73,0.87); validation set 2, 0.67 (95% CI 0.51,0.80). The AUCs were not significantly different among three groups (training set vs validation set 1; P = 0.15, training set vs validation set 2; P = 0.09, validation set 1 vs validation set 2; P = 0.29, respectively). CONCLUSION: Our multiparametric assessment of gadoxetic acid-enhanced MRI performed quite precisely and with good reproducibility for predicting MVI.

Development of predictive score for postoperative dysphagia after emergency abdominal surgery in patients of advanced age.

Aim: Postoperative dysphagia after emergency abdominal surgery (EAS) in patients of advanced age has become problematic, and appropriate dysphagia management is needed. This study was performed to identify predictive factors of dysphagia after EAS and to explore the usefulness of swallowing screening tools (SSTs). Methods: This retrospective study included 267 patients of advanced age who underwent EAS from 2012 to 2022. They were assigned to a dysphagia group and non-dysphagia group using the Food Intake Level Scale (FILS) (dysphagia was defined as a FILS level of <7 on postoperative day 10). From 2018, original SSTs including a modified water swallowing test were performed by nurses. Results: The incidence of postoperative dysphagia was 22.8% (61/267). Patients were significantly older in the dysphagia than non-dysphagia group. The proportions of patients who had poor nutrition, cerebrovascular disorder, Parkinson's disease, dementia, nursing-care service, high intramuscular adipose tissue content (IMAC), and postoperative ventilator management were much higher in the dysphagia than non-dysphagia group. Using logistic regression analysis, high IMAC, postoperative ventilator management, cerebrovascular disorder, and dementia were correlated with postoperative dysphagia and were assigned 10, 4, 3, and 3 points, respectively, according to each odds ratio. The optimal cut-off value was 7 according to a receiver operating characteristics curve. Using 1:1 propensity score matching for high-risk patients, the incidence of postoperative dysphagia was reduced by SSTs. Conclusions: The new prediction score obtained from this study can identify older patients at high risk for dysphagia after EAS, and SSTs may improve these patients' short-term outcomes.

Clinical significance of mechanistic target of rapamycin expression in vessels that encapsulate tumor cluster-positive hepatocellular carcinoma patients who have undergone living donor liver transplantation.

Background: There is limited published information regarding the expression of mechanistic target of rapamycin (mTOR) in vessels that encapsulate tumor cluster (VETC)-positive hepatocellular carcinoma (HCC). The mTOR inhibitor, everolimus, has been approved as an immunosuppressant for use in HCC patients after living donor liver transplantation (LDLT). Methods: Using a database of 214 patients who underwent LDLT for HCC, we examined the mTOR protein and angiopoietin-2 (Ang-2) in VETC-positive HCC by immunohistochemical staining. The presence of VETC and mTOR expression were evaluated in both primary and recurrent HCC lesions. Results: Forty-three of the 214 patients (20.1%) were VETC-positive, and 29 of these 43 patients (67.4%) expressed mTOR. Relative Ang-2 expression was significantly higher in the mTOR-positive than in the mTOR-negative group (p = 0.037). Thirty-four of the 214 patients experienced HCC recurrence after LDLT; 20 of these were operable. The primary lesions of six of these 20 patients were VETC-positive; five of these six patients also had VETC-positive recurrent lesions (p < 0.001). The expression of mTOR was significantly higher in the VETC-positive lesions (p = 0.0018). Conclusions: We showed that mTOR expression was higher in the VETC-positive primary and recurrent lesions than in the VETC-negative ones.

Feasibility of venous cuff using an open round ligament or inferior mesenteric vein around the hepatic vein for a left lobe graft in living-donor liver transplantation.

Living-donor liver transplantation (LDLT) is an established treatment for patients with end-stage liver disease or acute liver failure, and outflow reconstruction is considered one of the most vital techniques in LDLT. To date, many strategies have been reported to prevent outflow obstruction, which can be refractory to liver dysfunction and can cause life-threatening graft loss or mortality. In addition, in this era of laparoscopic hepatectomy in donor surgery, especially LDLT using a left liver graft, it has been predicted that cutting the hepatic vein with automatic linear staplers will lead to more outflow-related problems than with conventional open hepatectomy because of the short neck of the anastomosis orifice. We herein review 10 cases of venoplasty performed with a novel venous cuff system using a donor's round ligament around the hepatic vein in LDLT with a left lobe graft, which makes anastomosis of the hepatic vein sterically easy for postoperative venous patency.

Treatment strategy for hepatocellular carcinoma recurrence in the transplant era: Focusing on the Japan criteria.

PURPOSE: To clarify the Japan criteria (JC), as proposed in 2019, in order to identify the most appropriate treatment methods for hepatocellular carcinoma (HCC) recurrence and assess the feasibility of pre-living donor liver transplantation (LDLT) downstaging within these criteria. METHODS: The subjects of this study were 169 LDLT patients with HCC recurrence. We performed univariate and multivariate analyses of the factors contributing to HCC recurrence after LDLT and clarified the post-transplant outcomes of pre-LDLT downstaging. RESULTS: Univariate and multivariate analysis identified beyond the JC (p = 0.0018) and a neutrophil-to-lymphocyte ratio > 2.01 (p = 0.029) as independent risk factors. Patients who met the JC had significantly higher recurrence-free and overall survival rates after LDLT (p < 0.0001) than those who did not (p = 0.0002). The post-transplant outcomes of patients within the JC after downstaging were significantly better than those of patients beyond the JC (p = 0.034) and equivalent to those within the JC without downstaging. CONCLUSION: Even for HCC recurrence, the JC could play an important role in deciding on the best treatment strategy, and downstaging within the JC had good post-transplant outcomes.

Curative surgery for multiple hepatocellular carcinomas after lenvatinib plus transarterial chemoembolization: a case report.

Surgical therapy following lenvatinib (LEN) plus transarterial chemoembolization (TACE) is a useful therapeutic option for intermediate-stage hepatocellular carcinoma (HCC). A 66-year-old man with a history of hepatitis C was detected four masses in the caudate lobe and segment 6/7 of the liver, with a maximum lesion diameter of 14 cm by computed tomography. The patient was diagnosed with intermediate-stage HCC and received LEN plus TACE. After resuming LEN for 8 weeks, computed tomography showed weakened stained areas of the tumors, and no new lesions. Thus, the patient was evaluated as having a partial response in the modified Response Evaluation Criteria in Solid Tumors. The patient underwent hepatic caudate lobectomy, partial hepatectomy of S6/7, and S6 microwave coagulation therapy for radical resection. The patient is currently alive and recurrence-free at 12 months postoperatively. In patients with multiple HCC lesions, hepatic resection combined with local therapy might be an effective treatment option.

Impact of portal-phase signal intensity of dynamic gadoxetic acid-enhanced magnetic resonance imaging in hepatocellular carcinoma.

PURPOSE: To evaluate the prognostic impact of dynamic gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) in patients with hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed the data of 206 patients with HCC who underwent preoperative Gd-EOB-DTPA-enhanced MRI and hepatectomy and quantitatively evaluated the signal intensity ratio of the tumor to the surrounding liver tissue in the portal phase (SIRPP). We verified the survival rates and assessed the prognostic factors associated with overall survival (OS) and recurrence-free survival (RFS) using SIRPP. RESULTS: Multivariate analysis revealed that the independent predictive factors for poorly-differentiated HCC were α-fetoprotein > 20 ng/mL (hazard ratio [HR]: 3.1909, 95% confidence interval [CI]: 1.3464-7.5622, p = .0084) and SIRPP ≤ 0.85 (HR: 3.7155, 95% CI: 1.521-9.076, p = .004). The 5-year OS and RFS rates in the high and low SIRPP groups were 83.2 and 52.1%, respectively (p < .0001) and 49.7 and 18.5%, respectively (p = .0003). Multivariate analysis revealed that SIRPP ≤ 0.68 was an independent prognostic factor related to OS (HR: 4.4537, 95% CI: 1.6581-11.9626, p = .003). CONCLUSION: The SIRPP of preoperative Gd-EOB-DTPA-enhanced MRI might predict the histological differentiation and prognosis of HCC.

Transferrin Receptor is Associated with Sensitivity to Ferroptosis Inducers in Hepatocellular Carcinoma.

PURPOSE: Transferrin receptor (TFR), a membrane protein that has a critical role in the transport of iron into cells, is known to be a ferroptosis-related marker. Although TFR is reported to be abundantly expressed in tumor cells, its relationship with ferroptosis inducers in hepatocellular carcinoma (HCC) remains unclear. METHODS: The authors performed immunohistochemical staining of TFR and divided 350 HCC patients into two groups according to its expression. They analyzed the association between TFR expression and prognosis or clinicopathologic factors. In addition, the regulation of malignant activity and its effect on the efficacy of ferroptosis inducers were investigated in vitro. RESULTS: For this study, 350 patients were divided into TFR-positive (n =180, 51.4%) and TFR-negative (n = 170, 48.6%) groups. The TFR-positive group had more hepatitis B surface antigen (HBs-Ag) (p = 0.0230), higher α-fetoprotein (AFP) levels (p = 0.0023), higher des-gamma-carboxyprothrombin (DCP) levels (p = 0.0327), a larger tumor size (p = 0.0090), greater proportions of Barcelona Clinic Liver Cancer (BCLC) stage B or C (p = 0.0005), poor differentiation (p < 0.0001), and microscopic intrahepatic metastasis (p = 0.0066). In the multivariate analyses, TFR expression was an independent prognostic factor in disease-free survival (p = 0.0315). In vitro, TFRC knockdown decreased cell motility. In addition, TFRC knockdown abolished artesunate (AS)-, lenvatinib-, and sorafenib-induced ferroptosis in HCC cell lines. The study demonstrated that simultaneous treatment of AS with multi-kinase inhibitor augmented the ferroptosis-inducing effects of AS in HCC cell lines. CONCLUSION: TFR expression is a poor prognostic factor in HCC, but its expression increases sensitivity to ferroptosis-inducing agents.

Preoperative HALP score is a prognostic factor for intrahepatic cholangiocarcinoma patients undergoing curative hepatic resection: association with sarcopenia and immune microenvironment.

BACKGROUND: The hemoglobin-albumin-lymphocyte-platelet (HALP) score is a combination index that assesses nutritional status and systemic inflammatory response and is reported to predict prognosis in several cancer types. However, researches about the usefulness of the HALP score in intrahepatic cholangiocarcinoma (ICC) are limited. METHODS: This was a single-center, retrospective study of 95 patients who underwent surgical resection for ICC between 1998 and 2018. We divided patients into two groups by calculating the cutoff value of the HALP score and examined clinicopathological characteristics, prognosis, and sarcopenia. Tumor-infiltrating lymphocytes (TILs), CD8 + TILs, and FOXP3 + TILs were evaluated by immunohistochemical staining of resected tumors. RESULTS: Of 95 patients, 22 were HALP-low. The HALP-low group had significantly lower hemoglobin (p = 0.0007), lower albumin (p = 0.0013), higher platelet counts (p < 0.0001), fewer lymphocytes (p < 0.0001), higher CA19-9 levels (p = 0.0431), and more lymph node metastasis (p = 0.0013). Multivariate analysis revealed that the independent prognostic factors for disease-free survival were maximum tumor size (≥ 5.0 cm) (p = 0.0033), microvascular invasion (p = 0.0108), and HALP score (≤ 25.2) (p = 0.0349), and that factors for overall survival were lymph node metastasis (p = 0.0020) and HALP score (≤ 25.2) (p = 0.0014). The HALP-low group contained significantly more patients with sarcopenia (p = 0.0015). Immunohistochemistry showed that counts of CD8 + TILs were significantly lower in the HALP-low group (p = 0.0075). CONCLUSIONS: We demonstrated that low HALP score is an independent prognostic factor for ICC patients undergoing curative hepatic resection and is associated with sarcopenia and the immune microenvironment.

Surgical treatment of hepatocellular carcinoma after Fontan operation: three case reports and review of the literature.

We herein describe three patients with Fontan-associated liver disease who developed hepatocellular carcinoma (HCC). The first patient was a 28-year-old woman who had undergone the Fontan operation (FO) at the age of 4 years. She was diagnosed with HCC (cT4aN0M0, Stage IVA, UICC 8th edition), for which she underwent extended posterior right sectionectomy and partial hepatectomy of S2. She developed recurrence of peritoneal dissemination after 12 months, and she was alive 18 months after surgery. The second patient was a 43-year-old man who had undergone the FO at the age of 3 years. He was diagnosed with HCC (cT2N0M0, Stage II), for which he underwent laparoscopic-assisted partial hepatectomy of S3. He remained free from recurrent HCC for 17 months. The third patient was a 21-year-old woman who had undergone the FO at the age of 3 years. She was diagnosed with HCC (cT3N0M0, Stage III), for which she underwent laparoscopic-assisted partial hepatectomy of S2 and S4. She remained free from recurrent HCC for 30 months. We reviewed 18 surgical cases of HCC arising from Fontan-associated liver disease, including our 3 cases, and found that a high preoperative alpha-fetoprotein concentration might be a predictor of HCC recurrence.

Clinical association between intraoperative indocyanine green fluorescence imaging pattern, preoperative Gd-EOB-DTPA-enhanced magnetic resonance imaging findings, and histological differentiation in hepatocellular carcinoma.

AIM: We aimed to evaluate the association between the intraoperative indocyanine green (ICG) fluorescence imaging (FI) pattern, preoperative magnetic resonance imaging (MRI) findings using gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA), preoperative diffusion-weighted imaging (DWI) of MRI, and histological differentiation of hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed the data for 80 tumors of 64 patients. Intraoperative ICG FI patterns were classified into cancerous or rim-positive type. We evaluated the signal intensity ratio of the tumor and the surrounding liver tissue in the portal phase (SIRPP) and intensity in the hepatobiliary phase (HBP) of Gd-EOB-DTPA-enhanced MRI, the apparent diffusion coefficient (ADC) in the DWI of MRI, and clinicopathologic factors. RESULTS: In the rim-positive group, the rate of poorly differentiated HCC and hypointensity type in HBP were significantly higher, and SIRPP and ADC were significantly lower than the rim-negative group. In the cancerous group, the rate of well or moderately differentiated HCC and hyperintensity type in HBP, SIRPP, and ADC were significantly higher than the noncancerous group. Multivariate analysis identified low SIRPP, low ADC, and hypointensity type in HBP as the significant predictive factors for rim-positive HCC and high SIRPP, high ADC, and hyperintensity type in HBP as the significant predictive factors for cancerous HCC. The positive rate of programmed cell death 1-ligand 1 and vessels that encapsulate tumor clusters status of the rim-positive HCC and HCC with low SIRPP were significantly higher than the control group. CONCLUSIONS: The intraoperative ICG FI pattern of HCC closely correlated with histological differentiation, preoperative SIRPP and intensity type in the Gd-EOB-DTPA MRI, and preoperative ADC in the DWI of MRI.

Clinical Significance of Signal Regulatory Protein Alpha (SIRPα) Expression in Hepatocellular Carcinoma.

BACKGROUND: Signal regulatory protein alpha (SIRPα), expressed in the macrophage membrane, inhibits phagocytosis of tumor cells via CD47/SIRPα interaction, which acts as an immune checkpoint factor in cancers. This study aimed to clarify the clinical significance of SIRPα expression in hepatocellular carcinoma (HCC). METHODS: This study analyzed SIRPα expression using RNA sequencing data of 372 HCC tissues from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of our 189 HCC patient cohort. The correlation between SIRPα expression and clinicopathologic factors, patient survival, and intratumor infiltration of immune cells was investigated. RESULTS: Overall survival (OS) was significantly poorer with high SIRPα expression than with low expression in both TCGA and our cohort. High SIRPα expression correlated with lower recurrence-free survival (RFS) in our cohort. High SIRPα expression was associated with higher rates of microvascular invasion and lower serum albumin levels and correlated with greater intratumor infiltration of CD68-positive macrophages and myeloid-derived suppressor cells (MDSCs). Multivariate analysis showed that SIRPα expression and high infiltration of CD8-positive T cells and MDSCs were predictive factors for both RFS and OS. Patients with high SIRPα expression and infiltration of CD8-positive T cells and MDSCs had significantly lower RFS and OS rates. In spatial transcriptomics sequencing, SIRPα expression was significantly correlated with CD163 expression. CONCLUSIONS: High SIRPα expression in HCC indicates poor prognosis, possibly by inhibiting macrophage phagocytosis of tumor cells, promoting MDSC infiltration and inducing antitumor immunity. Treatment alternatives using SIRPα blockage should be considered in HCC as inhibiting macrophage antitumor immunity and MDSCs.

A rare case of unresectable, microsatellite instability-high hepatocellular carcinoma and an examination of the tumor microenvironment.

Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths worldwide, and the mortality rate of patients with unresectable HCC is very high. Microsatellite instability (MSI) is an essential biomarker for response to immune checkpoint inhibitors (ICI) in various tumors. However, the frequency of MSI in HCC is low (1.11%). There is only one case report of MSI-high HCC, and it is not well understood how high MSI affects the tumor microenvironment of HCC. Hence, we describe an interesting patient with unresectable MSI-high HCC, including the evaluation of immune status in the tumor microenvironment. A 68-year-old man presented to our department with HCC in liver segment 1. Contrast-enhanced CT revealed a liver tumor of 6.0 cm in maximum size. The patient underwent extended left and caudate lobectomy of the liver for HCC. Four months after surgical resection, contrast-enhanced computed tomography (CECT) detected 13 recurrent nodules. The patient was diagnosed with unresectable hepatocellular carcinoma recurrence, and we decided to administer systematic chemotherapy. Lenvatinib was administered over approximately 2 years as a first-line treatment, which resulted in intrahepatic tumor shrinkage. However, follow-up CECT showed new lesions, hepatogastric mesentery lymph node swelling, and peritoneal dissemination. After MSI-high status was identified, the patient began to receive pembrolizumab (200 mg, every 3 weeks). Eleven cycles of pembrolizumab therapy were administered over approximately 8 months, during which the diameter of the hepatogastric mesentery lymph node swelling and peritoneal dissemination showed shrinkage but later re-increased. As the third- and fourth-line therapy has been administered, the tumors and lymph nodes have shrunk. We report a rare case in which multikinase inhibitors were effectively used to treat MSI-high HCC.

The hemoglobin, albumin, lymphocyte, and platelet score is a prognostic factor for Child-Pugh A patients undergoing curative hepatic resection for single and small hepatocellular carcinoma.

AIM: The hemoglobin, albumin, lymphocyte, and platelet (HALP) score reflects the immune system and the nutritional status of patients, and prognosis in various cancers. However, the HALP score in hepatocellular carcinoma has not been reported. METHODS: Data were analyzed retrospectively from Child-Pugh A patients undergoing hepatic resection for single hepatocellular carcinoma ≤5 cm. For cross-validation, patients were divided into the training (332 patients) and validation cohort (210 patients). In the training cohort, we divided patients into two groups by appropriate cut-off value of the HALP score, and univariable and multivariable analyses were conducted for disease-free and overall survival (OS) between two groups. In the validation cohort, we examined OS by Kaplan-Meier analysis in the same cut-off value of the HALP score in the training cohort. RESULTS: The HALP-low group was significantly older (p = 0.0003), had fewer hepatitis B surface antigen-positive patients (p = 0.0369), higher prothrombin time (p = 0.0141), lower fibrosis-4 index (p = 0.0206), bigger maximum tumor size (p = 0.0196), and less histological liver fibrosis (p = 0.0077). Multivariate analysis showed that the independent prognostic factors for disease-free survival were fibrosis-4 index ≥2.67 (p = 0.0008), simple nodular type with extranodular growth or confluent multinodular type (p = 0.0221), and intrahepatic metastasis (p = 0.0233), and that for OS were fibrosis-4 index ≥2.67 (p = 0.0020), HALP ≤45.6 (p = 0.0228), and poor differentiation (p = 0.0305). In the validation cohort, Kaplan-Meier analysis revealed the trend toward significantly impaired OS (p = 0.0220) in the HALP-low group. CONCLUSION: We showed that a low HALP score is the independent prognostic factor for Child-Pugh A patients undergoing curative hepatic resection for single and small hepatocellular carcinoma.

Prognostic Impact of the Preoperative Systemic Inflammation Score in Patients With Pancreatic Ductal Adenocarcinoma.

BACKGROUD: The systemic inflammation score (SIS), which is based on the preoperative lymphocyte-to-monocyte ratio (LMR) and serum albumin (Alb) level, is a prognostic indicator for several cancer types. However, the prognostic significance of the SIS in pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: Seventy-eight patients who underwent radical surgery for PDAC were categorized as follows: SIS 0 (LMR ≥3.51 and Alb ≥4.0 g/dl), n = 26; SIS 1 (LMR <3.51 or Alb <4.0 g/dl), n = 29 and SIS 2 (LMR <3.51 and Alb <4.0 g/dl), n=23. RESULTS: The tumour size sequentially increased in SIS 0, 1 and 2 groups. A higher SIS was associated with increased vascular invasion, perineural invasion and surgical margin positivity rate. Recurrence-free survival (RFS) rates between the SIS 1 and 2 groups showed no significant difference However, patients of the SIS 1 and 2 groups had poorer outcomes than those of the SIS 0 group for RFS. Overall survival (OS) rates between the SIS 1 and 2 groups also showed no significant difference. However, patients of the SIS 1 and 2 groups had poorer outcomes than those of the SIS 0 group for OS. The SIS was an independent prognostic factor for RFS and OS. DISCUSSION: The SIS is a simplified prognostic factor for patients with PDAC.

Cancer-associated fibroblasts promote tumor cell growth via miR-493-5p in intrahepatic cholangiocarcinoma.

The association between tumor microenvironment (TME) and cancer-associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma (ICC) progression is poorly understood. This study aimed to reveal whether specific microRNAs (miRNAs) in extracellular vesicles (EVs) derived from CAFs were involved in ICC progression. Conditioned medium (CM) and EVs in the CM of CAFs and normal fibroblasts (NFs) derived from ICC specimens were used to investigate the effects on tumor cell lines. miRNA microarray assay was used to examine the miRNAs of EVs derived from CAFs and NFs in ICC, and the effects of miR-493-5p on tumor cell lines were examined. Additionally, databases were used to identify miR-493-5p targets, and the relationship between prognosis of ICC patients and cocaine- and amphetamine-regulated transcript propeptide (CARTPT), one of the targets of miR-493-5p, expression in ICC tissues was retrospectively analyzed. Compared with NF-derived CM and EVs, CAF-derived CM and EVs promoted cell lines in proliferation, scratch, migration, and invasion assays. miRNA microarray analysis revealed that miR-493-5p was significantly increased in CAF-derived EVs compared to NF-derived EVs. Tumor cell lines transfected with miR-493-5p were promoted in proliferation and scratch assays. Immunohistochemical staining was performed on 76 ICC specimens; both overall and recurrence-free survival rates were significantly worse in the CARTPT-negative group. Univariate and multivariate analyses showed that low CARTPT expression was an independent poor prognostic factor for overall and recurrence-free survival. Overall, our data suggest that CAFs in the ICC TME suppress CARTPT in tumor cells and promote tumor cells via miR-493-5p in EVs.

Predictive Factors for the Resectable Type of Hepatocellular Carcinoma Recurrence After Living Donor Liver Transplant.

Recurrence of hepatocellular carcinoma (HCC) after living donor liver transplant (LDLT) is an essential factor defining prognosis, and surgical resection is the only curative treatment. However, the factors that define whether surgical resection is possible remain unclear. Here, we compared resectable and unresectable HCC recurrence cases after LDLT and examined factors that determine whether surgical resection is possible. Resectable (n = 17) and unresectable (n = 14) groups among 264 patients who underwent LDLT for HCC from January 1999 to March 2020 were compared and examined for recurrence type, prognosis, and clinicopathologic factors. Overall survival after LDLT (median, 8.5 vs 1.7 years, P < .01) was significantly longer in the resectable group. In univariate analysis, female recipient rate, lymphocyte to monocyte ratio (LMR) ≥2.75, and tumor size ≤5.0 cm were significantly higher in the resectable group. Younger donors, lower Model for End-Stage Liver Disease scores, lower graft volume, and lower graft volume to standard liver volume ratio were evident in the resectable group. In multivariate analysis, female recipient rate (P = .0034) and LMR ≥2.75 (P = .0203) were independent predictive factors for resectable HCC recurrence after LDLT. Female recipient and LMR ≥2.75 before transplant could predict the surgically resectable type of HCC recurrence after LDLT.