Microscopic Vascular Invasion Research Articles

Impact of everolimus on survival after liver transplantation for hepatocellular carcinoma.

Background/AimsThis study aimed to investigate whether everolimus (EVR) affects long-term survival after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC).MethodsThe data from 303 consecutive patients with HCC who had undergone LT from January 2012 to July 2018 were retrospectively reviewed. The patients were divided into two groups: 1) patients treated with EVR in combination with calcineurin inhibitors (CNIs) (EVR group; n=114) and 2) patients treated with CNI-based therapy without EVR (non-EVR group; n=189). Time to recurrence (TTR) and overall survival (OS) after propensity score (PS) matching were compared between the groups, and prognostic factors for TTR and OS were evaluated.ResultsThe EVR group exhibited more aggressive tumor biology than the non-EVR group, such as a higher number of tumors (P=0.003), a higher prevalence of microscopic vascular invasion (P=0.017) and exceeding Milan criteria (P=0.029). Compared with the PS-matched non-EVR group, the PS-matched EVR group had significantly better TTR (P<0.001) and OS (P<0.001). In multivariable analysis, EVR was identified as an independent prognostic factor for TTR (hazard ratio [HR], 0.248; P=0.001) and OS (HR, 0.145; P<0.001).ConclusionsCombined with CNIs, EVR has the potential to prolong long-term survival in patients undergoing LT for HCC. These findings warrant further investigation in a well-designed prospective study.

Lymphocyte-to-C-reactive protein ratio as a prognostic factor for hepatocellular carcinoma.

Systemic inflammation has been correlated with worse survival for some cancers. We evaluated prognostic values of various inflammatory factor combinations in patients who underwent resections for hepatocellular carcinoma (HCC). We retrospectively analysed 306 consecutive patients with HCC who underwent curative liver resections. After assessing eight combinations of inflammatory markers for predictive value for recurrence, we focused on lymphocyte-to-C-reactive protein ratio (LCR) to elucidate its associations with recurrence-free survival (RFS) and overall survival (OS) in univariate and multivariate analyses (Cox proportional hazards model). We also used immunohistochemical CD34 and CD8 staining to investigate the mechanism of LCR elevation. LCR showed the highest association with RFS in HCC patients among the compared indices. High preoperative LCR correlated with a high serum albumin concentration, small tumour size, early Barcelona Clinic Liver Cancer stage and low rates of microscopic vascular invasion and microscopic intrahepatic metastasis. Higher preoperative LCR was an independent predictor of longer RFS and OS in this cohort. High LCR patients had fewer vessels encapsulating tumour clusters, and higher intratumoural CD8+ T-cell counts than low LCR patients. Preoperative LCR is a novel and convenient prognostic marker for patients with HCC, and is associated with the tumour microenvironment immune status.

Post-resection prognosis of combined hepatocellular carcinoma-cholangiocarcinoma according to the 2019 WHO classification

Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA) has wide histologic diversity. This study investigated the prognostic impacts of cHCC-CCA histology according to the 2019 World Health Organization (WHO) classification. This retrospective observational study included 153 patients who underwent surgical resection for cHCC-CCA at Asan Medical Center between August 2012 and July 2019. During the study period, 153 patients, 112 (73.2%) men and 41 (26.8%) women with a mean age of 56.4 ± 10.8 years, underwent R0 resection for cHCC-CCA. Mean tumor diameter was 4.2 ± 2.6 cm, and 147 (96.1%) patients had solitary tumors. According to 2019 World Health Organization (WHO) classification, 111 (72.5%) patients had cHCC-CCA alone, and 29 of them (26.1%) showed stem cell features. cHCC-CCA-intermediate cell carcinoma and cHCC-CCA-cholangiolocellular carcinoma were identified in 27 (17.6%) and 15 (9.8%), respectively. The 1-, 3-, and 5-year tumor recurrence and patient survival rates were 31.8% and 92.1%, 49.8% and 70.9%, and 59.0% and 61.7%, respectively. Univariate analyses revealed that significant prognostic factors were tumor size > 5 cm, microscopic and macroscopic vascular invasion, lymph node metastasis, 8th American Joint Committee on Cancer (AJCC) tumor stage, and status of stem cell feature. Multivariate analysis revealed 8th AJCC tumor stage and status of stem cell features as independent prognostic factors. The 2019 WHO classification was not associated with post-resection prognosis. The 2019 WHO classification was not associated with post-resection prognosis, thus was considered as a simple histologic classification. We suggest that stem cell features should be included as an essential component of the pathology report for cHCC-CCA.

Limited tumour progression beyond Milan criteria while on the waiting list does not result in unacceptable impairment of survival

Defining optimum management of patients progressing beyond Milan criteria on the waiting list is a controversial topic. Our aim was to determine whether the policy of allowing a limited progression beyond enlistment criteria permits acceptable post-transplant outcomes in terms of survival and recurrence. Patients with hepatocellular carcinoma included on the waiting list for orthotopic liver transplantation (OLT) between January 1989 and December 2016 were analysed. Tumour features were assessed at inclusion on the waiting list, before OLT and at explant pathology. Patients were retained on the waiting list despite exceeding enlistment criteria if not presenting with macrovascular invasion, extrahepatic spread or cancer-related symptoms. A total of 495 patients constituted the target population. Comparison between the Milan-in (n= 434) and Milan-out (n= 61) groups showed statistically significant differences in: largest tumour size; BCLC stage; patients treated before OLT; alpha-fetoprotein, and time on the waiting list. Milan-out patients showed a significantly higher number of poorly differentiated nodules, satellitosis and microscopic vascular invasion. The 1-, 3-, 5- and 10-year survival rate was 89.6%, 82.5%, 75%, and 55.5%, vs. 83.6%, 70.5%, 65.5%, and 53.9% for Milan-in/Milan-out patients, respectively. Recurrence rates at 1, 3, 5 and 10 years were 1.2%, 3.3%, 5.5%, and 10.8% vs. 7.1% 14.5%, 23%, and 23% for Milan-in and Milan-out patients, respectively (p <0.01). This study shows that although limited tumour progression without reaching major adverse predictors (vascular invasion, extrahepatic spread, cancer symptoms) has an expected impact on recurrence rate, overall survival remains above the minimum proposed benchmark of 65% at 5 years. The clinically relevant increase in tumour recurrence must be considered when analysing the benefit of this approach in the face of limited organ supply. When considering orthotopic liver transplantation for patients with hepatocellular carcinoma, optimum results are achieved when transplanting patients within the Milan criteria. However, the most appropriate strategy for patients who progress beyond these criteria while on the waiting list is still unclear. Herein, we show that transplantation is associated with acceptable overall survival in select patients who progress beyond the Milan criteria, although recurrence rates were notably higher. Therefore, the assessment of transplantation viability in these patients must consider the availability of organs and the impact on other patient categories.

Sub-Classification of Cirrhosis Affects Surgical Outcomes for Early Hepatocellular Carcinoma Independent of Portal Hypertension.

Severity of liver cirrhosis is distinct from clinical portal hypertension because there exist different degrees of liver cirrhosis in hepatocellular carcinoma (HCC) patients without significant clinical portal hypertension. Whether severity of cirrhosis affects surgical outcomes for HCC patients in absence of portal hypertension or not remains unclear. This study aims to analyze the effect of cirrhotic severity on surgical outcomes for HCC patients with hepatitis B virus (HBV) infection in absence of portal hypertension. This retrospective study enrolled 166 patients who underwent curative resection for a single HCC ≤5 cm in absence of portal hypertension between February 2011 and December 2013. Liver cirrhosis was sub-classified into no/mild (no/F4A) and moderate/severe (F4B/F4C) according to the Laennec scoring system. The surgical outcomes and complications were analyzed. The surgical mortality was zero in this study. Major complications were apparently higher in the F4B/F4C group than in the no/F4A group (17.0% vs 7.4%, p <0.001). The 1-year, 3-year and 5-year overall survival (OS) rates were 98.5, 88.1 and 80%, respectively, in the no/F4A group, which were significantly higher than those in the F4B/F4C group (98.0, 69.2 and 54.7%, p = 0.001). Microscopic vascular invasion, absence of tumor capsule and severity of liver cirrhosis were independent risk factors of surgical outcomes for HCC patients without portal hypertension. In conclusion, severity of liver cirrhosis affected surgical outcomes for early-stage HCC patients independent of portal hypertension.

Synergistic impact of resection margin and microscopic vascular invasion for patients with HBV-related intrahepatic cholangiocarcinoma

ABSTRACT Objectives The resection margin (RM) status and microscopic vascular invasion (MVI) are known prognostic factors for intrahepatic cholangiocarcinoma (ICC). An enhanced understanding of their impact on long-term prognosis is required to improve oncological outcomes. Methods A total of 711 consecutive patients who underwent curative liver resection for hepatitis B virus–related ICC were retrospectively analyzed. The different impact of the RM status (narrow, <1 cm, or wide, ≥1 cm) and MVI (positive, +, or negative, -) on overall survival (OS) and recurrence-free survival (RFS) were analyzed. Results The 1-, 3-, and 5-year OS rates were 67.6%, 42.5%, and 33.2% in wide RM & MVI (-), 58.0%, 36.1%, and 26.5% in narrow RM & MVI (-), 51.0%, 27.0%, and 24.3% in wide RM & MVI (+), and 39.0%, 20.4% and 14.3% in narrow RM & MVI (+) (p < 0.001). Multivariate analysis showed that RM & MVI were independent risk factors for the OS and RFS. Conclusion Combined analysis of RM and MVI can better stratify the risks of postoperative death and recurrence in patients with HBV-related ICC, which may help subsequent adjuvant therapy and closer follow-up.

Post-resection prognosis of combined hepatocellular carcinoma-cholangiocarcinoma cannot be predicted by the 2019 World Health Organization classification

BackgroundCombined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA) has wide histologic diversity. This study investigated the prognostic impacts of cHCC-CCA histology according to the 2019 World Health Organization (WHO) classification. MethodsThis retrospective observational study included 153 patients who underwent surgical resection for cHCC-CCA at Asan Medical Center between August 2012 and July 2019. ResultsDuring the study period, 153 patients, 112 (73.2%) men and 41 (26.8%) women with a mean age of 56.4 ± 10.8 years, underwent R0 resection for cHCC-CCA. Mean tumor diameter was 4.2 ± 2.6 cm, and 147 (96.1%) patients had solitary tumors. According to 2019 WHO classification, 111 (72.5%) patients had cHCC-CCA alone, and 29 of them (26.1%) showed stem cell features. cHCC-CCA-intermediate cell carcinoma and cHCC-CCA-cholangiolocellular carcinoma were identified in 27 (17.6%) and 15 (9.8%), respectively. The 1-, 3-, and 5-year tumor recurrence and patient survival rates were 31.8% and 92.1%, 49.8% and 70.9%, and 59.0% and 61.7%, respectively. Univariate analyses revealed that significant prognostic factors were tumor size >5 cm, microscopic and macroscopic vascular invasion, lymph node metastasis, 8th American Joint Committee on Cancer (AJCC) tumor stage, and status of stem cell features. Multivariate analysis revealed 8th AJCC tumor stage and status of stem cell features as independent prognostic factors. 2019 WHO classification was not associated with post-resection prognosis. Conclusions2019 WHO classification was not associated with post-resection prognosis, thus was considered as simplified histologic classification requiring prognostic validation. We suggest that stem cell features should be included as an essential component of the pathology report for cHCC-CCA.

Multi-institutional validation of novel models for predicting the prognosis of patients with huge hepatocellular carcinoma.

The population of patients with huge hepatocellular carcinoma (H-HCC diameter > 10.0 cm) is an odd group that is not well adjudicated in the current staging systems, whose prognosis after curative resection varies. We aimed to develop novel models to predict the long-term outcomes of patients with H-HCC without portal vein tumor thrombus after hepatectomy. There were 1076 H-HCC patients enrolled who underwent curative liver resection in five institutions in China. In total, 670 patients were recruited from our center and randomly divided into the training cohort (n = 502) and internal validation (n = 168) cohorts. Additionally, 406 patients selected from other four centers as the external validation cohort. Novel models were constructed based on independent preoperative and postoperative predictors of postsurgical recurrence (PSR) and postsurgical mortality (PSM) determined in multivariable cox regression analysis. The predictive accuracy and discriminative ability of the model were measured using Harrell's concordance index (C index) and calibration curve and compared with five conventional HCC staging systems. PSR model and PSM model were constructed based on tumor number, microscopic vascular invasion, tumor differentiation, preoperative alpha-fetoprotein level, albumin-bilirubin grade, liver segment invasion, neutrophil-to-lymphocyte ratio or platelet-to-neutrophil ratio, and surgical margin or intraoperative blood transfusion. The C-indexes were 0.84 (95% CI, 0.78-0.90) and 0.85 (95% CI, 0.78-0.91) for the PSR and PSM models, respectively, which were substantially higher than those of the five conventional HCC staging systems (0.63-0.75 for PSR; 0.66-0.77 for PSM). The two novel models achieved more accurate prognostic predictions of PSR and PSM for H-HCC patients after curative liver resection.

Prognostic significance of systemic inflammation score in patients who undergo hepatic resection for hepatocellular carcinoma

Systemic inflammation score (SIS) is a novel prognostic score (0, 1, or 2) for various cancers, based on preoperative serum albumin level and lymphocyte-to-monocyte ratio (LMR); modified SIS (mSIS) uses a different LMR cutoff value and was thought to be a more accurate predictor for cancer prognosis. Here, we assessed the prognostic value of SIS and mSIS in patients who receive hepatic resection for hepatocellular carcinoma (HCC). We retrospectively evaluated SIS and mSIS of 314 patients after hepatic resection for HCC, against their clinicopathological factors and outcomes, using receiver operating characteristics (ROC) analysis over time. Among patients with preoperative SIS 2, significantly more HCC specimens were poorly differentiated (P = 0.0281), larger (P = 0.0006), and had more microscopic vascular invasion (P = 0.0136) than the SIS 0-1 group; the mSIS 2 group also had significantly larger tumors (P = 0.0039) than the mSIS 0-1 group. In ROC analysis, SIS was a better predictor of overall survival (OS) and recurrence-free survival (RFS) than mSIS. The SIS 2 group had shorter OS (P = 0.0015) and RFS (P = 0.0065) than other patients. In multivariate analysis, SIS 2 was an independent risk factor for shorter OS (hazard ratio (HR) 1.53, P = 0.0497) and RFS (HR 1.58, P = 0.0053). SIS is superior to mSIS in predicting prognosis of patients with HCC. mSIS is not a great predictor of prognosis in resected HCC.

CT-derived radiomic features to discriminate histologic characteristics of pancreatic neuroendocrine tumors

To assess the ability of radiomic features (RF) extracted from contrast-enhanced CT images (ceCT) and non-contrast-enhanced (non-ceCT) in discriminating histopathologic characteristics of pancreatic neuroendocrine tumors (panNET). panNET contours were delineated on pre-surgical ceCT and non-ceCT. First- second- and higher-order RF (adjusted to eliminate redundancy) were extracted and correlated with histological panNET grade (G1 vs G2/G3), metastasis, lymph node invasion, microscopic vascular infiltration. Mann-Whitney with Bonferroni corrected p values assessed differences. Discriminative power of significant RF was calculated for each of the end-points. The performance of conventional-imaged-based-parameters was also compared to RF. Thirty-nine patients were included (mean age 55-years-old; 24 male). Mean diameters of the lesions were 24 × 27mm. Sixty-nine RF were considered. Sphericity could discriminate high grade tumors (AUC = 0.79, p = 0.002). Tumor volume (AUC = 0.79, p = 0.003) and several non-ceCT and ceCT RF were able to identify microscopic vascular infiltration: voxel-alignment, neighborhood intensity-difference and intensity-size-zone families (AUC ≥ 0.75, p < 0.001); voxel-alignment, intensity-size-zone and co-occurrence families (AUC ≥ 0.78, p ≤ 0.002), respectively). Non-ceCT neighborhood-intensity-difference (AUC = 0.75, p = 0.009) and ceCT intensity-size-zone (AUC = 0.73, p = 0.014) identified lymph nodal invasion; several non-ceCT and ceCT voxel-alignment family features were discriminative for metastasis (p < 0.01, AUC = 0.80-0.85). Conventional CT 'necrosis' could discriminate for microscopic vascular invasion (AUC = 0.76, p = 0.004) and 'arterial vascular invasion' for microscopic metastasis (AUC = 0.86, p = 0.001). No conventional-imaged-based-parameter was significantly associated with grade and lymph node invasion. Radiomic features can discriminate histopathology of panNET, suggesting a role of radiomics as a non-invasive tool for tumor characterization. NCT03967951, 30/05/2019.

Postresection prognosis of combined hepatocellular carcinoma-cholangiocarcinoma according to the 2010 World Health Organization classification: single-center experience of 168 patients.

PurposeCombined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) has wide histologic diversity. This study investigated the effects of cHCC-CC histology, according to the 2010 World Health Organization (WHO) classification, on patient prognosis.MethodsThe medical records of patients who underwent surgical resection for cHCC-CC at our institution between July 2012 and June 2019 were retrospectively evaluated.ResultsDuring the study period, 168 patients, 122 males (72.6%) and 46 females (27.4%), underwent surgical resection for cHCC-CC, including 159 patients (94.6%) who underwent R0 resection. Mean tumor diameter was 4.4 ± 2.8 cm, and 161 patients (95.8%) had solitary tumors. Histologically, 86 patients (51.2%) had classical type, and 82 (48.8%) had tumors with stem cell (SC) features, including 33 (19.6%) with intermediate-cell and 23 (13.7%) each with typical SC and cholangiolocellular features; 3 tumors (1.8%) were unclassifiable. At 1, 3, and 5 years, tumor recurrence rates were 31.9%, 49.6%, and 58.1%, respectively, and patient survival rates were 91.0%, 70.2%, and 60.3%, respectively. Univariate analysis showed that tumor size of >5 cm, microscopic and macroscopic vascular invasion, lymph node metastasis, 8th edition of the American Joint Committee on Cancer (AJCC) tumor stage, and 2010 WHO classification were significantly prognostic. Multivariate analysis showed that the 8th AJCC tumor stage and 2010 WHO histologic classification were independently prognostic for tumor recurrence and patient survival. There were no significant prognostic differences among the 3 SC subtypes.ConclusionPostresection outcomes are better in patients with SC-type than with classical-type cHCC-CC.

Early and late recurrence of surgically resected hepatitis B virus-related hepatocellular carcinoma on nucleos(t)ide analogues therapy

Hepatocellular carcinoma (HCC) is a highly recurrent tumor. Antiviral therapy with nucleos(t)ide analogues (NUCs) may reduce the risk of recurrence in hepatitis B virus (HBV)-related HCC. The risk factors associated with recurrence in HCC patients after surgical resection and with NUCs treatment should be delineated. Consecutive 339 HBV-related HCC patients receiving surgical resection of HCC with NUCs therapy (including 256 entecavir, 36 tenofovir, and 18 lamivudine) after the surgery were retrospectively reviewed. Factors related to the recurrence-free survival (RFS) and overall survival (OS) were evaluated. After a median of 48.5 months of follow-up, 183 (54%) patients developed HCC recurrence, with the 5-year RFS of 42.8% and OS of 79%. Male gender (HR=1.736, p=0.037), baseline HBsAg level >200 IU/ml (HR=1.748, p=0.008), platelet count ≦100 (109/L) (HR=1.592, p=0.023), presence of microscopic vascular invasion (MVI) (HR=1.499, p=0.026), safety cut margin of ≦0.5cm (HR=1.507, p=0.013), and Ishak fibrosis score 5-6 (HR=1.579, p=0.009) were independent factors associated with RFS in multivariate analysis. While tumor burden, platelet count, MVI, and safety cut margin were factors associated with early recurrence; baseline HBsAg level, and platelet count were independent factors associated with late recurrence. Ishak fibrosis score 5-6, poor differentiation, MVI, diabetes mellitus were factors associated with OS in multivariate analysis. For HBV-HCC patients on NUCs treatment, tumor factors are associated with early recurrence, while HBsAg level and thrombocytopenia determines late recurrence. For patient with a high baseline HBsAg level, warning of higher risk of recurrence is required even under NUCs treatment.

Follicular Variant of Papillary Carcinoma Thyroid with Massive Angioinvasion of the Internal Jugular Vein: Our Approach

Follicular variant of papillary carcinoma thyroid is an aggressive variant of papillary carcinoma thyroid. It is more commonly associated with extrathyroidal extension and regional lymphadenopathy. It can rarely be associated with microscopic vascular invasion but tumor thrombus into great veins is a rare phenomenon. We present a case of 60-year-old male with follicular variant of papillary carcinoma thyroid with tumor thrombosis in superior thyroid vein and internal jugular vein (IJV). We report a case of a 60-year-old male who presented with a large swelling in the lower part of left side of neck for 4 months. Clinical examination revealed a hard swelling of 12x8 cm in left side of neck. Ultrasonography showed a solitary thyroid mass of the left lobe and a dilated left superior thyroid vein and ipsilateral IJV. Fine-needle aspiration cytology revealed follicular variant of PTC cells. Total thyroidectomy was done. A tumor thrombus was discovered in the superior thyroid vein and left IJV was found to be dilated. The left IJV with superior thyroid vein was ligated and excised. The patient recovered well after the operation with no local or distant metastasis detected. Follicular variant of PTC commonly spreads to the lymph nodes. Vascular spread via direct intravascular extension through superior thyroid vein is extremely rare. On palpation cord like IJV is felt on the involved side. Neck ultrasound play important role in the diagnosis. Aggressive surgical treatment with IJV ligation above and below the tumor thrombus is recommended to minimize the risk of potentially fatal complications of the intraluminal masses. Intravascular tumor extension into IJV of neck in follicular variant of PTC is rare and can be associated with serious consequences. Total thyroidectomy with thrombectomy with ligation of IJV must be done.

Transarterial Chemoembolization Combined With Hepatectomy for the Treatment of Intermediate-Stage Hepatocellular Carcinoma

BackgroundTransarterial chemoembolization (TACE) is currently the recommended treatment for intermediate-stage hepatocellular carcinoma (HCC). Liver resection (LR) may be an effective option, although recurrences are not uncommon. TACE prior to LR has been proposed as an even better alternative.MethodsPatients with intermediate-stage HCC who underwent curative resection were enrolled between January 2007 and December 2015. We compared overall survival (OS) and recurrence-free survival (RFS) for the 2 groups using the Kaplan-Meier method, and we determined independent risk factors for death and recurrence using multivariate regression analyses.ResultsA total of 488 patients with HCC at BCLC B (265 patients with LR, 223 patients with TACE+LR) enrolled from our center. Mean follow-up was 40.2 (range, 3.0–128.7) months. For patients receiving TACE+LR and LR, estimated 1-, 3-, and 5-year OS rates were 90.6% and 73.3%, 61.7% and 43.5%, and 52.9% and 33.8%, respectively (all P < 0.001) and estimated 1-, 2-, and 3-year RFS rates were 54.6% and 39.4%, 41.4% and 29.4%, and 36.3% and 26.3%, respectively (P < 0.001, P = 0.002, and P = 0.008, respectively). Significant independent predictors of poor OS were more than 3 (vs. 3 or fewer) tumors (HR=2.19, 95% CI 1.69–2.84), non-anatomical (vs. anatomical) hepatectomy (HR=1.29, 95% CI 1.01–1.66), microscopic vascular invasion (HR=1.46, 95% CI 1.15–.90), cirrhosis (HR=2.41, 95%CI 1.88–3.01), and intraoperative blood transfusion (HR=1.29, 95% CI 1.01–1.66).ConclusionPreoperative TACE with LR may result in better oncological outcomes than either TACE or LR alone, without a substantial increase in morbidity, and could be considered an effective combination treatment for intermediate-stage HCC.

Microscopic portal vein invasion is a powerful predictor of prognosis in patients with hepatocellular carcinoma who have undergone liver resection.

A recent study proposed simple classifications of microscopic vascular invasion (MVI): microscopic portal vein invasion (MPVI) and microvessel invasion (MI). We aim to validate these classifications of MVI. This retrospective study consecutively enrolled 514 Barcelona Clinic Liver Cancerstage 0, A, and B naïve hepatocellular carcinomapatients who underwent liver resection in our institution from 2011 to 2017. Among these 514 patients, 240 patients were classified as having no MVI at all (designated as no vascular invasion, NVI), 157 patients were classified as having MI only, and 117 patients were classified as having MPVI. The 5-year overall survival (OS) rate in the MI-only group was 83.3%, which was not significantly different from that of the NVI group (87.2%), p = .20. Using NVI as a reference, multivariate analysis showed that MI-only is not an independent variable associated with OS. The 5-year OS in the MPVI group was 59.2%, which was significantly lower than those for MI-only (p < .001) and NVI groups (p < .001). Using NVI as a reference, multivariate analysis showed that MPVI is an independent variable associated with OS (HR, 3.12; 95% CI, 1.80-5.40; p < .001). The results of this study validate the simple MVI classifications to be clinically useful.

Invited Commentary: Radiogenomics Applied to Select Abdominal Tumors.

Invited Commentary: Radiogenomics Applied to Select Abdominal Tumors.

Preoperative prediction score of hepatocellular carcinoma recurrence in living donor liver transplantation: Validation of SNAPP score developed at Asan Medical Center

Preoperative prediction score of hepatocellular carcinoma recurrence in living donor liver transplantation: Validation of SNAPP score developed at Asan Medical Center

Microvascular Venous Invasion in Hepatocellular Carcinoma: Why Do Recurrences Occur?

Hepatocellular carcinoma is the most common primary cancer of the liver. It is almost always associated with cirrhosis and it is usually diagnosed in later stages of the disease. Furthermore, recurrence rate following liver transplantation ranges between 15 and 30%. The most important factor determining the recurrence is vascular invasion. In this review, the issue of microvascular invasion causing hepatocellular carcinomarecurrence is reviewed.Macroscopic vascular invasion is almost easy to diagnose on radiologic evaluation. However, microscopic vascular invasion is almost always diagnosed with pathologic evaluation. On the other hand, microscopic vascular invasion is associated with early recurrences and reduced disease-free survival. The type of vessel that is invaded determines the nature of the spread of the tumor cells. Invasion of the hepatic venous tributaries leads to systemic metastasis whereas portal venous invasions lead to intrahepatic spread of the tumor. Microscopic vascular invasion should be diagnosed before liver transplantation or liver resection in order to deliver the appropriate therapy to the patients. Yet, there is no ideal marker to suggest microscopic vascular invasion before any intervention. Markers such as alpha-fetoprotein, des carboxy prothrombin, or gamma-glutamyl transferase have been found to be correlated with microscopic vascular invasion. These parameters are not very efficient to be used in routine clinical practice. Therefore, further research is needed to define ideal marker associated with microscopic vascular invasion.

Novel Models Predict Postsurgical Recurrence and Overall Survival for Patients with Hepatitis B Virus-Related Solitary Hepatocellular Carcinoma ≤10 cm and Without Portal Venous Tumor Thrombus.

The predictive model of postsurgical recurrence for solitary early hepatocellular carcinoma (SE-HCC) is not well established. The aim of this study was to develop a novel model for prediction of postsurgical recurrence and survival for patients with hepatitis B virus (HBV)-related SE-HCC ≤10 cm. Data from 1,081 patients with HBV-related SE-HCC ≤10 cm who underwent curative liver resection from 2003 to 2016 in our center were collected retrospectively and randomly divided into the derivation cohort (n = 811) and the internal validation cohort (n = 270). Eight hundred twenty-three patients selected from another four tertiary hospitals served as the external validation cohort. Postsurgical recurrence-free survival (RFS) and overall survival (OS) predictive nomograms were generated. The discriminatory accuracies of the nomograms were compared with six conventional hepatocellular carcinoma (HCC) staging systems. Tumor size, differentiation, microscopic vascular invasion, preoperative α-fetoprotein, neutrophil-to-lymphocyte ratio, albumin-to-bilirubin ratio, and blood transfusion were identified as the risk factors associated with RFS and OS. RFS and OS predictive nomograms based on these seven variables were generated. The C-index was 0.83 (95% confidence interval [CI], 0.79-0.87) for the RFS-nomogram and 0.87 (95% CI, 0.83-0.91) for the OS-nomogram. Calibration curves showed good agreement between actual observation and nomogram prediction. Both C-indices of the two nomograms were substantially higher than those of the six conventional HCC staging systems (0.54-0.74 for RFS; 0.58-0.76 for OS) and those of HCC nomograms reported in literature. The novel nomograms were shown to be accurate at predicting postoperative recurrence and OS for patients with HBV-related SE-HCC ≤10 cm after curative liver resection. This multicenter study proposed recurrence or mortality predictive nomograms for patients with hepatitis B virus-related solitary early hepatocellular carcinoma ≤10 cm after curative liver resection. A close postsurgical surveillance protocol and adjuvant therapy should be considered for patients at high risk of recurrence.

ASTN1 is associated with immune infiltrates in hepatocellular carcinoma, and inhibits the migratory and invasive capacity of liver cancer via the Wnt/β‑catenin signaling pathway.

Astrotactin 1 (ASTN1) is known to serve a physiological role in neuronal migration; however its role in liver cancer remains to be determined. In the present study, ASTN1 levels were lower in liver cancer tissues compared with those in matching normal tissue. ASTN1 levels were negatively associated with microscopic vascular invasion, advanced clinical stage and a less favorable prognosis in patients with hepatocellular carcinoma (HCC). Furthermore, ASTN1 overexpression in a liver cancer cell line reduced the migratory and invasive capacity of the cells. Based on bioinformatics analysis, ASTN1 levels were negatively associated with the Wnt signaling pathway. In addition, ASTN1 downregulated the protein expression levels of β-catenin, T-cell factor (TCF)1, TCF4, Jun proto-oncogene (C-jun), Myc proto-oncogene (C-myc), cyclooxygenase-2 (COX2), metalloproteinase (MMP)2, MMP9 and vascular endothelial growth factor (VEGF) protein levels, indicative of suppression of Wnt signaling. Furthermore, XAV939-induced Wnt signaling suppression reversed the ASTN1-mediated inhibition of invasion and migration in cells. Overexpression of ASTN1 in xenografts reduced cancer development as well as Wnt signaling. TIMER analysis showed that ASTN1 expression was negatively correlated with B cell, macrophage and neutrophil infiltrating levels in HCC. Together, the results of the present study showed that ASTN1 reduced the migratory and invasive capacity of liver cancer cells, potentially served as a candidate biomarker for diagnosis and prediction of the prognosis of HCC, and was associated with immune infiltration. Understanding the underlying mechanisms of action of ASTN1 may facilitate the development of novel strategies for prevention and treatment of liver cancer.