Tumor Microvascular Invasion Research Articles

Update results from ALTER-H004 study: Anlotinib combined with TACE as adjuvant therapy in patients with hepatocellular carcinoma (HCC) at high risk of recurrence after surgery: A single arm, multi-center, phase II clinical trial.

513 Background: High recurrence rate after curative resection significantly compromised the long-term survival of patients with HCC patients (pts). TACE as adjuvant therapy was proved to improve clinical outcomes for pts with high recurrence risk factors after hepatectomy. However, the prognosis of TACE reminded unsatisfactory and controversial. Therefore, this study aimed to identify the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. The update results were reported here with longer follow-up duration. Methods: HCC pts with one of the following high risk factors after hepatectomy: ≥5 cm and <10 cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng's classification I/II) were recruited. Eligible pts received cTACE treatment within 1-2 months after hepatectomy, on the 3-5th day after cTACE, oral anlotinib (12mg, qd, d1-d14, q3w) was given until disease recurrence or unacceptable toxicity. The predefined sample size was 30. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: The data cut-off date was March 2023, 29 pts were enrolled and 27 pts received at least once tumor assessment. The median follow-up was 21.8 (IQR, 17.3-26.3) months. Of 27 with assessable efficacy, mDFS was 24.2 (95% CI, not applicable-not applicable) months, with 12-, and 24-month DFS rates of 72.2% (95% CI, 50.4%-85.7), and 61.8% (95% CI, 38.8%-78.3%), respectively. 18 of 27 pts (66.7%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 4 pts (14.8%) included hypertension (7.4%), leukocytopenia (7.4%) and ascites (3.7%). No grade 4 or 5 TRAEs occurred. Conclusions: Anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited encouraging efficacy and tolerable safety profile. And the conclusions needed to be confirmed in large scale clinical trials subsequently. Clinical trial information: NCT04213118 .

Updated results from ALTER-H004 trial: Anlotinib combined with TACE as adjuvant therapy for patients with hepatocellular carcinoma at high risk of recurrence after surgery—A single arm, multi-center, phase II clinical trial.

e16222 Background: Hepatectomy is deemed as a curative treatment for patients (pts) with hepatocellular carcinoma (HCC). Unfortunately, high recurrent risk after curative resection compromised the long-term survival of HCC significantly. Transarterial chemoembolization (TACE) as adjuvant therapy was proved to improve therapeutic outcomes for pts with high recurrent risk after hepatectomy. However, the survival benefit of TACE remained unsatisfactory. ALTER-H004 trial was designed to identify the efficacy and safety of anlotinib as maintenance adjuvant treatment following TACE in pts with HCC. The preliminary results of ALTER-H004 had been reported at 2022 ASCO (e16120). Here we reported the results at the data cutoff of January 15, 2023. Methods: Pts with one of the following high risk factors after hepatectomy were eligible: ≥5cm and <10cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus (Cheng's classification I/II). Eligible pts received conventional TACE treatment within 1-2 months after hepatectomy, and on the 4th day after TACE treatment, oral anlotinib (12mg, qd, 2 weeks on 1 week off) was given until disease recurrence or unacceptable toxicity. The predefined sample size was 30. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: At January 15, 2023, 29 pts were enrolled and 28 pts were available for prognostic assessment, among whom, 11 pts were still on treatment and 9 relapsed, 3 withdrew the consent, 5 discontinued own to intolerable adverse reactions. The longest duration of treatment is 27.83 months. The median DFS has not reached yet and the 1-year DFS rate was 76.46% (95% CI: 54.83~88.70) and 2-year DFS rate was 65.41% (95% CI: 41.70~81.39). Safety profile indicated that 18 pts (64.3%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs were detected in 5 pts (17.9%) including hypertension (7.1%), leukocytopenia (7.1%) and ascites (3.6%). No grade 4 or 5 TRAEs were observed. Conclusions: Anlotinib combined with TACE as adjuvant therapy in pts with HCC at high recurrent risk exhibited promising prognosis and tolerable safety profile preliminarily, and the conclusion needed to be confirmed in large-scale clinical trials subsequently. Clinical trial information: NCT04213118 .

Accurate prediction of microvascular invasion occurrence and effective prognostic estimation for patients with hepatocellular carcinoma after radical surgical treatment

BackgroundHepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide, with an overall 5-year survival rate of less than 18%, which may be related to tumor microvascular invasion (MVI). This study aimed to compare the clinical prognosis of HCC patients with or without MVI after radical surgical treatment, and further analyze the preoperative risk factors related to MVI to promote the development of a new treatment strategy for HCC.MethodsAccording to the postoperative pathological diagnosis of MVI, 160 study patients undergoing radical hepatectomy were divided into an MVI-negative group (n = 68) and an MVI-positive group (n = 92). The clinical outcomes and prognosis were compared between the two groups, and then the parameters were analyzed by multivariate logistic regression to construct an MVI prediction model. Then, the practicability and validity of the model were evaluated, and the clinical prognosis of different MVI risk groups was subsequently compared.ResultThere were no significant differences between the MVI-negative and MVI-positive groups in clinical baseline, hematological, or imaging data. Additionally, the clinical outcome comparison between the two groups presented no significant differences except for the pathological grading (P = 0.002) and survival and recurrence rates after surgery (P < 0.001). The MVI prediction model, based on preoperative AFP, tumor diameter, and TNM stage, presented superior predictive efficacy (AUC = 0.7997) and good practicability (high H-L goodness of fit, P = 0.231). Compared with the MVI high-risk group, the patients in the MVI low-risk group had a higher survival rate (P = 0.002) and a lower recurrence rate (P = 0.004).ConclusionMVI is an independent risk factor for a poor prognosis after radical resection of HCC. The MVI prediction model, consisting of AFP, tumor diameter, and TNM stage, exhibits superior predictive efficacy and strong clinical practicability for MVI prediction and prognostication, which provides a new therapeutic strategy for the standardized treatment of HCC patients.

Preoperative Prognostic Nutritional Index May Be a Strong Predictor of Hepatocellular Carcinoma Recurrence Following Liver Transplantation.

PurposeMalnutrition is a major risk factor of immune dysfunction and poor outcome in cancer patients. The prognostic nutritional index (PNI), which is established by serum albumin level and peripheral lymphocyte count, was shown to correlate with prognosis of hepatocellular carcinoma (HCC) patients following liver resection and non-surgical interventions. The aim of this study was to analyze the predictive value of preoperative PNI in liver transplantation (LT) patients with HCC.Patients and MethodsA total of 123 HCC patients that underwent LT were included in the analysis. The prognostic impact of preoperatively assessed clinical factors including the PNI on post-LT outcome was analyzed by uni- and multivariate analysis.ResultsPost-transplant tumor recurrence rates were 5.1% in high-PNI (> 42) and 55.6% in low-PNI (≤ 42) patients (p < 0.001). Preoperative high-PNI could be identified as a significant and independent promoter of both recurrence-free survival (hazard ratio [HR] = 10.12, 95% CI: 3.40–30.10; p < 0.001) and overall survival (HR = 1.69, 95% CI: 1.02–2.79; p = 0.004) following LT. Apart from that low-PNI proved to be a significant and independent predictor of microvascular tumor invasion (OR = 7.71, 95% CI: 3.17–18.76; p < 0.001). In contrast, no tumor morphology features including the Milan criteria revealed an independent prognostic value.ConclusionOur data indicate that preoperative PNI correlates with biological tumor aggressiveness and outcome following LT in HCC patients and may therefore be useful for refining oncologic risk stratification.

Update results from ALTER-H004 study: Anlotinib combined with TACE as adjuvant therapy in hepatocellular carcinoma patients at high risk of recurrence after surgery—A single-arm, multicenter, phase II clinical trial.

e16120 Background: Hepatectomy is considered to be an effective curative treatment for hepatocellular carcinoma (HCC), however, high recurrence rate after curative resection severely reduces the long-term survival of HCC patients (pts). Transarterial chemoembolization (TACE) as adjuvant therapy has been proved to improve clinical outcomes for pts with high recurrence risk factors after hepatectomy, but the effect is still unsatisfactory. ALTER-H004 trial was designed to evaluate the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. Here we updated the results at the data cutoff of January 20, 2022. Methods: This single arm, multicenter, phase II trial of ALTER-H004 was planned to enroll 30 pts which with histologically confirmed HCC and undertook hepatectomy within 1-2 months. The recruited pts who did not recieve any previous tumor-related treatment must have any of the following high risk factors: ≥5 cm and &lt; 10 cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng's classification I/II). Eligible pts received conventional TACE treatment within 1-2 months after hepatectomy. On the 3-5th day after TACE treatment, oral anlotinib (12mg, qd, d1-d14, q3w) was given until disease recurrence or unacceptable toxicity. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: By the cutoff date of January 20, 2022, 26 pts were enrolled and 25 pts received at least once tumor assessment. According to RECIST 1.1, 14 of 25 did not progress were still on treatment and 7 relapsed. One withdrew the consent and 3 discontinued because of intolerable adverse events. The longest duration of treatment is 16.53 months. The DFS were not mature and the 6-month DFS rates were 77.45% (95% CI: 53.83̃89.99). 12 of 25 pts (48.0%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 pts (20.0%) included hypertension (8.0%), leukocytopenia (8.0%) and ascites (4.0%). No grade 4 or 5 TRAEs occurred. Conclusions: The update results suggested that anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited promising clinical benefit and favorable safety profile, and the results needed to be confirmed in trials continued subsequently. Clinical trial information: NCT04213118.

Updated results of the phase II ALTER-H004: Anlotinib combined with TACE as adjuvant therapy in hepatocellular carcinoma patients at high risk of recurrence after surgery.

445 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and a leading cause of tumor related death. Hepatectomy is considered to be the main radical treatment for HCC. However, the high recurrence rate remains a major challenge. Adjuvant therapy to effectively reduce recurrence is particularly important for patients (pts) with high recurrence factors. Transarterial chemoembolization (TACE) as adjuvant therapy for pts with high recurrence risk factors after hepatectomy is recommended in several guidelines, but the effect is still unsatisfactory. Here, we updated the results of ALTER-H004 which aimed to evaluate the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. Methods: Pts with histologically confirmed HCC and undertook hepatectomy within 1-2 months will be recruited in this study. The recruited pts who did not recieve any previous tumor-related treatment must have any of the following high risk factors: ≥5 cm and &lt; 10 cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng's classification I/II). Eligible pts received conventional TACE treatment with pirarubicin and platinum within 1-2 months after hepatectomy. On the 4th day after TACE treatment, oral anlotinib (12mg, qd, 2 weeks on 1 week of) was given until disease recurrence or unacceptable toxicity. The calculated sample size was 48. The primary endpoint was disease free survival (DFS). Secondary endpoints were 1-year DFS rate, time to recurrence and safety. Results: As of September 14, 2021, 24 pts were enrolled and 23 pts received at least once tumor assessment. According to RECIST 1.1, 17 of 24 did not progress were still on treatment and 5 relapsed. One withdrew the consent and 1 discontinued because of intolerable adverse events. The longest duration of treatment is 15.24 months. The DFS were not mature and the 6-month DFS rates were 75.11% (95% CI: 46.28̃89.91). 12 of 24 pts (50.0%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 4 pts (16.7%) included hypertension (29.2%), hyperbilirubinemia and hematologic toxicities. No grade 4 or 5 TRAEs occurred. Conclusions: Preliminary results suggested that anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited encouraging efficacy and manageable adverse events, which should be validated in more pts consecutively. Clinical trial information: NCT04213118.

Preliminary results of the phase II ALTER-H004: Anlotinib combined with TACE as adjuvant therapy in hepatocellular carcinoma patients at high risk of post surgery recurrence.

e16125 Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high incidence and mortality worldwide. Presumably, adjuvant therapy is an efficient treatment for reducing recurrence in patients (pts) with hepatectomy, especially in those with high recurrence factors. Transarterial chemoembolization (TACE) can block the blood supply of the tumor, besides, high concentration of chemotherapeutic drugs can be accumulated within the tumor. It is recommended in several guidelines prophylactic TACE for pts with high recurrence risk factors after hepatectomy, which mainly include grade 1-2 microvascular invasion (M1-2) and portal vein tumor thrombus resection. Moreover, angiogenic inhibitors based therapy has constituted the crucial treatment strategy in HCC. As a novel multitarget tyrosine kinase inhibitor, anlotinib was demonstrated to be an effective first and second-line monotherapy for pts with advanced or recurrent HCC in China. The aim of this phase II trial was to evaluate the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. Methods: A total of 48 histologically confirmed HCC pts who undertook hepatectomy within 1-2 months will be enrolled. The recruited pts who did not recieve any previous tumor-related treatment must have any of the following high risk factors: ≥5cm and &lt;10cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng’s classification Ⅰ/Ⅱ). Enrolled pts were received conventional TACE treatment with pirarubicin or epirubicin and platinum within 1-2 months after hepatectomy. On the 4th day after TACE treatment, oral anlotinib (12mg, qd, 2 weeks on 1 week off) was given until disease recurrence or unacceptable toxicity. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: By the cutoff date of January 26, 2021, 10 pts were enrolled and received at least once tumor assessment. According to RECIST version 1.1, 9 of them did not progress and 1 relapsed, in whom the DFS was 2.4 months. Most of treatment-related adverse events (TRAEs) were rash (20.0% Grade≤2), pain (20.0% Grade=1) and hypertension (10.0% Grade=1). Only one patient had grade 3 TRAE which was leukocytopenia (10.0%). No more grade 3 or above TRAEs occurred. Conclusions: The current results indicated that anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited preliminary and implicational anti-tumor efficacy and manageable toxicity. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04213118.

Indication of Liver Transplantation for Hepatocellular Carcinoma Should Be Reconsidered in Case of Microvascular Invasion and Multilocular Tumor Occurrence.

Liver transplantation (LT) is routinely performed for hepatocellular carcinoma (HCC) in cirrhosis without major vascular invasion. Although the adverse influence of microvascular invasion is recognized, its occurrence does not contraindicate LT. We retrospectively analyzed in our LT cohort the significance of microvascular invasion on survival and demonstrate bridging procedures. At our hospital, 346 patients were diagnosed with HCC, 171 patients were evaluated for LT, and 153 were listed at Eurotransplant during a period of 11 years. Among these, 112 patients received LT and were included in this study. Overall survival after 1, 3 and 5 years was 86.3%, 73.9%, and 67.9%, respectively. Microvascular invasion led to significantly reduced overall (p = 0.030) and disease-free survival (p = 0.002). Five-year disease-free survival with microvascular invasion was 10.5%. Multilocular tumor occurrence with simultaneous microvascular invasion revealed the worst prognosis. In our LT cohort, predominant bridging treatment was transarterial chemoembolization (TACE) and the number of TACE significantly correlated with poorer overall survival after LT (p = 0.028), which was confirmed in multiple Cox regression analysis for overall and disease-free survival (p = 0.015 and p = 0.011). Microvascular tumor invasion is significantly associated with reduced prognosis after LT, which is aggravated by simultaneous occurrence of multiple lesions. Therefore, indication strategies for LT should be reconsidered.

Development and validation of a novel nomogram predicting 10-year actual survival after curative hepatectomy for hepatocellular carcinoma

IntroductionAlthough hepatectomy is a curative treatment modality for hepatocellular carcinoma (HCC), the associated 10-year long-term actual survival are rarely reported. This study aims to develop and validate a predictive nomogram for 10-year actual survivors with HCC. Materials and methodsFrom 2004 to 2009, 753 patients with curative hepatectomy for HCC (development set, n = 325; validation set, n = 428) were included. In development set, comparison of clinic-pathological data was made between patients surviving ≥10 years and those surviving <10 years. Good independent prognostic factors identified by multivariate analysis were involved in a nomogram development, which was validated internally and externally using validation set. ResultsOn multivariate analysis, five independent good prognostic factors for 10-year survival were identified, including young age (OR = 0.943), good ASA status (≤2) (OR = 2.794), higher albumin level (OR = 1.116), solitary tumor (OR = 2.531) and absence of microvascular invasion (OR = 3.367). A novel nomogram was constructed with C-index of 0.801 (95% CI 0.762–0.864). A cut-off point of 167.5 had a sensitivity of 0.794 and specificity of 0.730. Internal validation using bootstrap sampling and external validation using validation set revealed C-index of 0.792 (95% CI, 0.741–0.853) and 0.761 (95% CI, 0.718–0.817). ConclusionA novel nomogram for 10-year HCC survivor using age, ASA status, preoperative albumin, tumor number and presence of microvascular tumor invasion was developed and validated with high accuracy.

Development of Nomogram Predicting 10-Year Survivors after Curative Hepatectomy for Hepatocellular Carcinoma

Background: Although hepatectomy is a curative treatment modality for hepatocellular carcinoma (HCC), clinical outcome and predictive factors of 10-year long-term survivors are rarely reported in the literature. Aim of study: To analyze the clinico-pathological factors of 10-year long-term survivors following curative hepatectomy for HCC and to develop a predictive nomogram for 10-year survivors. Methods: From 2004 to 2009, 325 patients with HCC underwent curative hepatectomy. There were 95 patients (29.2%) surviving 10 years or more (group 1), whereas 230 patients (70.8%) surviving < 10 years (group 2). Comparison of clinic-pathological data was made between two groups. Good prognostic factors identified by multivariate analysis were used to construct a nomogram predicting 10-year survivors. Internal validation using bootstrap sampling was also performed. Results: Group 1 was younger, had more asymptomatic tumor, had more hepatitis B carriers, better functional status, better preoperative liver function, and higher albumin level, compared with group 2. Group 1 had smaller tumor, more solitary tumor, more tumor with microvascular invasion and rupture than Group 2. Independent good prognostic factors predicting 10-year survivor were young age, ASA status (≤ 2), high albumin, solitary tumor and no microvascular tumor invasion. A nomogram is constructed (Figure 1) with C-index of 0.801. Internal validation using bootstrap sampling reveals C-index of 0.792. Conclusion: There are 29.2% patients with curative hepatectomy for HCC can survive up to or more than 10 years. Nomogram using age, ASA status, preoperative albumin, solitary tumor and microvascular tumor invasion can accurately predict 10-year survivor.

High expression of TOP2A in hepatocellular carcinoma is associated with disease progression and poor prognosis.

Hepatocellular carcinoma (HCC) is a common malignant tumor in the clinic. Although there are increasing numbers of available treatment methods, their therapeutic effects are not satisfactory. The clinical indicators commonly used to predict the prognosis of HCC include tumor size, degree of cirrhosis, degree of tumor differentiation and tumor microvascular invasion; however, there are currently no molecular indicators that can predict the prognosis of HCC. Due to the differences in the progression of liver cancer among individuals, there is a growing need for prognostic biomarkers to accurately stratify patients for appropriate risk-adaptive treatment. The DNA topoisomerase 2-α (TOP2A) gene, which is located on human chromosome 17, encodes DNA topoisomerase IIα. Previous studies have demonstrated that TOP2A indicates a poor prognosis in patients with various types of tumors, but no such studies are currently available on HCC. By analyzing the differential expression of TOP2A in 50 pairs of tumor and paracancerous tissue samples in The Cancer Genome Atlas (TCGA) database, the present study revealed that the expression of TOP2A was significantly higher in tumor tissue compared with that in paracancerous tissue (P=6.319×10−16). In the collected clinical samples, the mRNA expression levels of TOP2A were significantly upregulated in HCC tumor tissues compared with those in the paracancerous tissues (P=6.40×10−3), suggesting that TOP2A was associated with the occurrence and development of liver cancer. In addition, the associations between TOP2A expression, clinicopathological features and prognosis were analyzed using a multi-center large sample dataset from TCGA database, and the results demonstrated that high expression of TOP2A was associated with a higher T stage, poorer clinical stage and higher histological grade compared with those in patients with low TOP2A expression. High expression of TOP2A was also identified to be associated with a poor prognosis of HCC, particularly in Asian populations. These results suggested that high expression of TOP2A in HCC tissues may be closely associated with tumor progression and metastasis, which may be used as a biological indicator to predict tumor prognosis in clinical practice.

1018TiP ALTER-H-004: A phase II study of anlotinib combined with TACE as adjuvant therapy in hepatocellular carcinoma patients at high risk of post-surgery recurrence

HCC is one of the most common malignant tumors with high incidence and mortality worldwide. It is acceptable that adjuvant therapy is an efficient treatment for reducing recurrence in patients with hepatectomy, especially in those with high recurrence factors. Regional therapies and tyrosine kinase inhibitors (TKIs), which were recommended as standard treatments for unresectable and advanced HCC pts, had limited and minimal disease free survival as adjuvant therapy, respectively. Anlotinib, a novel multi-target TKI, mainly targeting VEGFR1-3, showed durable anti-tumor activity and manageable toxicity as first or second-line treatment of advanced HCC pts in an open-label phase II trial (NCT02809534). Consistent with these, we conducted a multicenter open label, phase Ⅱ study to evaluate anti-tumor efficacy and safety for anlotinib plus TACE in HCC pts with high recurrence risks after surgery. This was a single arm, multicenter phase II trial. A total number of 48 pts with histologically confirmed HCC would be enrolled. The eligibility criteria included: previously not receive any tumor-related treatment except hepatectomy and met any of the following high recurrence factors: ≥5cm and <10cm of tumor diameter, tumor number ≥3, tumor microvascular invasion grade M1 or M2, portal vein carcinoma thrombus resection (Cheng’s classificationⅠorⅡ); aged 18-75; Child-Pugh Score A5-B7; ECOG 0-1 and HBV-DNA<1000IU/ml for patients with HBV. Treatment regimens were as follows. Pts were received conventional TACE treatment with pirarubicin and lobaplatin within 1-2 months after hepatectomy. On the 4th day after TACE treatment, oral anlotinib (12mg, qd, 2 weeks on 1 week off) was given until disease progression or unacceptable toxicity. Tumor assessment was taken every 3 months according to RECIST v1.1. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Two patients were enrolled from April 21th, 2020. NCT04213118. The authors.

Is It Just a Matter of Surgical Extension to Achieve the Cure of Hepatocarcinoma? A Meta-Analysis of Propensity-Matched and Randomized Studies for Anatomic Versus Parenchyma-Sparing Liver Resection

BackgroundThe benefit of anatomic (AR) versus parenchyma-sparing resection (PSR) in hepatocarcinoma (HCC) is still debated. The aim of the study was to compare AR vs. PSR in terms of overall survival (OS) and disease-free survival (DFS). MethodsA systematic review was conducted using Medline and Google Scholar. To reduce intra- and inter-study heterogeneity, only propensity-matched studies and randomized clinical trials (RCT) were evaluated and a generic inverse variance meta-analysis was run. A sub-analysis was performed in case of tumor microvascular invasion (MVI). ResultsEleven propensity-matched and one RCT were evaluated, with a total of 3445 patients (AR = 1776 and PSR = 1669). Tumor burden and liver function were comparable among studies (I2 < 50%, p > 0.5). OS was similar between AR and PSR (HR 0.93; 95%CI, 0.75–1.15; p = 0.50, I2 = 41%). DFS was improved in AR at 1 year (RR 0.84; 95%CI, 0.72–0.97; p = 0.02; I2 = 36%) and 3 years (RR 0.90; 95%CI, 0.83–0.98; p = 0.02; I2 = 40%) but not at 5 years (RR 0.94; 95%CI, 0.87–1.01; p = 0.07; I2 = 41%). Furthermore, in the presence of MVI, no difference in OS and DFS was observed between AR and PSR. ConclusionWhen liver function and tumor burden are comparable, AR and PSR achieved similar overall survival. AR improved local control in the early period after surgery. Furthermore, in the presence of MVI, the extension of surgery was not associated with better OS and DFS.

The role of ¹⁸F-FDG PET/CT predicting microvascular tumor invasion in patients with hepatocellular carcinoma

The role of ¹⁸F-FDG PET/CT predicting microvascular tumor invasion in patients with hepatocellular carcinoma

A nomogram predicting the recurrence of hepatocellular carcinoma in patients after laparoscopic hepatectomy

BackgroundPatients with hepatocellular carcinoma (HCC) undergoing surgical resection still have a high 5-year recurrence rate (~ 60%). With the development of laparoscopic hepatectomy (LH), few studies have compared the efficacy between LH and traditional surgical approach on HCC. The objective of this study was to establish a nomogram to evaluate the risk of recurrence in HCC patients who underwent LH.MethodsThe clinical data of 432 patients, pathologically diagnosed with HCC, underwent LH as initial treatment and had surgical margin > 1 cm were collected. The significance of their clinicopathological features to recurrence-free survival (RFS) was assessed, based on which a nomogram was constructed using a training cohort (n = 324) and was internally validated using a temporal validation cohort (n = 108).ResultsHepatitis B surface antigen (hazard ratio [HR], 1.838; P = 0.044), tumor number (HR, 1.774; P = 0.003), tumor thrombus (HR, 2.356; P = 0.003), cancer cell differentiation (HR, 0.745; P = 0.080), and microvascular tumor invasion (HR, 1.673; P =0.007) were found to be independent risk factors for RFS in the training cohort, and were used for constructing the nomogram. The C-index for RFS prediction in the training cohort using the nomogram was 0.786, which was higher than that of the 8th edition of the American Joint Committee on Cancer TNM classification (C-index, 0.698) and the Barcelona Clinic Liver Cancer staging system (C-index, 0.632). A high consistency between the nomogram prediction and actual observation was also demonstrated by a calibration curve. An improved predictive benefit in RFS and higher threshold probability of the nomogram were determined by receiver operating characteristic curve analysis, which was also confirmed in the validation cohort compared to other systems.ConclusionsWe constructed and validated a nomogram able to quantify the risk of recurrence after initial LH for HCC patients, which can be clinically implemented in assisting the planification of individual postoperative surveillance protocols.

The role of preoperative albumin-bilirubin grade for oncological risk stratification in liver transplant patients with hepatocellular carcinoma.

Albumin-bilirubin (ALBI) score was shown to correlate with liver function and tumor recurrence after hepatectomy for hepatocellular carcinoma (HCC). The aim of this study was to assess the prognostic value of ALBI grade in liver transplantation (LT) patients with HCC. Pre-LT available independent predictors of recurrence-free survival (RFS) and microvascular tumor invasion (MVI) were determined in 123 patients with HCC. Posttransplant HCC recurrence rates were 10.5%, 15.9%, and 68.2% in ALBI grade 1, 2, and 3, respectively (P < .001). Along with serum α-fetoprotein (AFP) and C-reactive protein (CRP) levels, ALBI grades 1 or 2 was identified as an independent predictor of RFS (hazard ratio, 3.52; 95% confidence interval [CI], 1.577-7.842; P = .002). Furthermore, ALBI grade 3 proved to be the strongest indicator of MVI (odds ratio, 11.59; 95% CI, 3.412-39.381; P < .001). A novel oncological risk score-based on AFP, CRP, and ALBI grade provided the best discriminative capacity (c-statistic 0.806) in selecting liver recipients with low oncological risk profile. Preoperative ALBI grade seems to be valuable for refinement of oncological risk stratification at LT for HCC.

Follow-Up Liver Stiffness Measurements after Liver Resection Influence Oncologic Outcomes of Hepatitis-B-Associated Hepatocellular Carcinoma with Liver Cirrhosis.

The severity of liver fibrosis can be noninvasively evaluated by measuring liver stiffness (LS) using transient elastography. This study aimed to evaluate the prognostic value of achieving low liver stiffness measurement (LSM) in patients with cirrhosis confirmed from the resected liver due to hepatocellular carcinoma (HCC). A total of 184 patients that received curative surgery for HCC related to the hepatitis B virus at Barcelona Clinic Liver Cancer stage 0–A, and had a METAVIR fibrosis score of 4 were investigated. LSM significantly decreased after antiviral therapy during follow-up (p = 0.001), and achieving LSM ≤8 kilopascal (kPa) suggested a reduced risk of late recurrence (>12 months) (hazard ratio (HR), 0.519; 95% confidence interval (CI), 0.307–0.877; p = 0.014). Older age at surgery (≥45 years) and multiple HCC nodules predicted an increased risk of late recurrence (HR, 3.270; 95% CI, 1.296–8.251; p = 0.012; and HR, 3.146; 95% CI, 1.396–7.089; p = 0.006). Decreased LSM also suggested decreased mortality (HR, 0.251; 95% CI, 0.086–0.756; p = 0.045) along with baseline low aspartate aminotransferase-to-platelet ratio index (APRI) score (<1.5) (HR, 0.251; 95% CI, 0.086–0.759; p = 0.041). Having early HCC recurrence (HR, 9.416; 95% CI, 3.566–24.861; p < 0.001) and microvascular tumor invasion (HR, 3.191; 95% CI, 1.188–8.568; p = 0.021) predicted increased mortality. Among HCC patients with liver cirrhosis under antiviral therapy, achieving low LSM (≤8 kPa) predicted reduced late HCC recurrence.

Prediction of Microvascular Tumor Invasion in Liver Transplant Candidates With Hepatocellular Carcinoma: A Feasible Concept or a Misleading Illusion?

IntroductionHepatocellular carcinoma (HCC) in cirrhosis is a widely accepted indication for liver transplantation (LT). Many scoring systems have been proposed intending to an extension of the established Milan criteria. Bridging treatments are systematically applied in order to maintain or to downstage such patients to the listing criteria. The objective of our study was to estimate the feasibility of the prediction of microvascular tumor invasion in transplant candidates. Patients and methodsData corresponding to transplanted HCC patients were reviewed for the purposes of this study. All tumor slices were blindly re-evaluated by a single pathologist in order to score for tumor necrosis and microvascular invasion. Recipients of pediatric or split LT were excluded. ResultsEighty patients (30 women and 50 men) were included in the study. Tumor necrosis was absent in 29 of 80 liver explants (36.25%). In the majority of instances (63.75%) tumor necrosis was evident in proportions between 5% and 100%. In 58 liver explants showing 0%-60% tumor necrosis and 22 liver explants showing > 60% tumor necrosis, microvascular tumor invasion was detectable in 11 and 0 cases, respectively (P = .0385). ConclusionIn about one-fourth of the cases (27.5%) microvascular tumor invasion could not be detected due to extended areas of tumor necrosis. Preoperative detection of microvascular invasion is misleading.

CDCA5 overexpression is an Indicator of poor prognosis in patients with hepatocellular carcinoma (HCC)

BackgroundAccurate and early prognosis of disease is essential to clinical decision making, particularly in diseases, such as HCC, that are typically diagnosed at a late stage in the course of disease and therefore carry a poor prognosis. CDCA5 is a cell cycle regulatory protein that has shown prognostic value in several cancers.MethodsWe retrospectively evaluated 178 patients with HCC treated with curative liver resection between September 2009 and September 2012 at Nanchong Central Hospital in Nanchong, Sichuan Province, China. Patients were screened for their CDCA5 expression levels and assigned to either the high or low expression group. Patient demographics, comorbidities, clinicopathologic data, such as tumor microvascular invasion status and size, and long-term outcomes were compared between the two groups. The effect of CDCA5 on the proliferation of liver cancer cells was analyzed using in vitro and in vivo assays.ResultsThe present study found that increased CDCA5 expression was associated with increased tumor diameter and microvascular invasion in HCC. It was also found that CDCA5 overexpression may be associated with liver cancer cells. Additionally, this study confirmed that CDCA5 expression was increased in HCC tissue versus normal liver tissue, that CDCA5 expression was associated with decreased survival and that CDCA5 knockdown using shRNA led to cell cycle arrest in the G2/M phase.ConclusionsThese findings suggest that CDCA5 expression is associated with poor prognosis in patients with hepatocellular carcinoma.

Serological Risk Index Based on Alpha-Fetoprotein and C-Reactive Protein to Indicate Futile Liver Transplantation Among Patients with Advanced Hepatocellular Carcinoma.

The aim of this study was to establish a preoperatively available serological risk index using alpha-fetoprotein (AFP) and C-reactive protein (CRP) for predicting oncologically futile liver transplantation (LT) in hepatocellular carcinoma (HCC) patients. A total of 119 liver transplant patients with HCC were retrospectively analyzed. The prognostic impact of clinical and histopathologic factors including pre-LT serum AFP and CRP values was determined. Apart from microvascular tumor invasion (MVI; odds ratio [OR] 15.77), pretransplant serum levels of AFP > 100ng/ml (OR 13.31) and CRP > 0.8mg/dl (OR 13.97) were identified as independent predictors of HCC recurrence. The cumulative risk of HCC relapse at 5years post-LT was 2.3% in low serological tumor activity (STA) index (AFP ≤ 100ng/ml + CRP ≤ 0.8mg/dl), 17.1% in intermediate STA (AFP ≤ 100ng/ml or CRP ≤ 0.8mg/dl), and 91.6% in high STA index (AFP > 100ng/ml + CRP > 0.8mg/dl; p < 0.001), respectively. High STA index was identified as most powerful pre-LT available predictor of MVI (OR 15.31) and posttransplant HCC recurrence (OR 54.44). Five-year recurrence-free survival rate in Milan Out patients with high STA was 0%, compared to 91.7% and 83.6% in those with low or intermediate STA index (p < 0.001), respectively. Our proposed serological risk index based on pretransplant serum AFP and CRP values is able to predict oncologically futile LT among advanced HCC patients.