Construction and validation of NSMC-ASIL,a predictive model for risk assessment of malignant hepatic nodules

Most malignant hepatic nodules (MHNs) eventually progress to hepatocellular carcinoma (HCC). However, assessment of the risk of malignancy in high-risk groups of patients with hepatic nodules remains a challenge. This study aimed to develop and validate a simple scoring system to predict the risk of development of MHNs. 1144 patients with primary nodular lesions of hepatic were divided into training cohort and validation cohort. The nomogram model for predicting the risk of MHNs was established according to age, sex, nodule size, prothrombin time (PT), alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), γ-glutamine acyltransferase isoenzyme (γ-GT), alanine aminotransferase (ALT), total bile acid (TBA), and total bilirubin (TBIL) in training cohort by logistic regression and validated in validation cohort. The area under receiver operating characteristic curve (AUC) of the predictive model for diagnosing MHNs in training cohort was 0.969 (95% CI: 0.959-0.979), with sensitivity 93.38% and specificity 90.75%, and the AUC in the validation cohort was 0.986 (95% CI: 0.975-0.996), with sensitivity 90.81% and specificity 94.26%. The AUC, sensitivity, and specificity of this model for the diagnosis of early-stage HCC were 0.942, 88.64% and 87.35% in training cohort, and 0.956, 87.04% and 91.85% in validation cohort, respectively. We established a nomogram model that used intuitive data for reliably predicting the risk of MHNs, and this model also showed good diagnostic accuracy in predicting early-stage HCC.     

Coupling radiomics analysis of CT image with diversification of tumor ecosystem: A new insight to overall survival in stage I−III colorectal cancer

ObjectiveThis study aimed to establish a method to predict the overall survival (OS) of patients with stage I−III colorectal cancer (CRC) through coupling radiomics analysis of CT images with the measurement of tumor ecosystem diversification.MethodsWe retrospectively identified 161 consecutive patients with stage I−III CRC who had underwent radical resection as a training cohort. A total of 248 patients were recruited for temporary independent validation as external validation cohort 1, with 103 patients from an external institute as the external validation cohort 2. CT image features to describe tumor spatial heterogeneity leveraging the measurement of diversification of tumor ecosystem, were extracted to build a marker, termed the EcoRad signature. Multivariate Cox regression was used to assess the EcoRad signature, with a prediction model constructed to demonstrate its incremental value to the traditional staging system for OS prediction.ResultsThe EcoRad signature was significantly associated with OS in the training cohort [hazard ratio (HR)=6.670; 95% confidence interval (95% CI): 3.433−12.956; P<0.001), external validation cohort 1 (HR=2.866; 95% CI: 1.646−4.990; P<0.001) and external validation cohort 2 (HR=3.342; 95% CI: 1.289−8.663; P=0.002). Incorporating the EcoRad signature into the prediction model presented a higher prediction ability (P<0.001) with respect to the C-index (0.813, 95% CI: 0.804−0.822 in the training cohort; 0.758, 95% CI: 0.751−0.765 in the external validation cohort 1; and 0.746, 95% CI: 0.722−0.770 in external validation cohort 2), compared with the reference model that only incorporated tumor, node, metastasis (TNM) system, as well as a better calibration, improved reclassification and superior clinical usefulness.ConclusionsThis study establishes a method to measure the spatial heterogeneity of CRC through coupling radiomics analysis with measurement of diversification of the tumor ecosystem, and suggests that this approach could effectively predict OS and could be used as a supplement for risk stratification among stage I−III CRC patients.     

Serum thioredoxin is a diagnostic marker for hepatocellular carcinoma

Here we found that serum levels of thioredoxin were increased in patients with hepatocellular carcinoma (HCC). The optimum diagnostic cutoff for thioredoxin was 20.5 ng/mL (area under curve [AUC] 0.946 [95% CI 0.923–0.969] in the training cohort; 0.941 [0.918–0.963] in the validation cohort). High serum concentrations of thioredoxin differentiated HCC from chronic liver diseases and cirrhosis (0.901 [0.875–0.923] in the training cohort; 0.906 [0.870–0.925] in the validation cohort). Furthermore, a higher proportion of patients with very early HCC had positive results for thioredoxin than for alpha-Fetoprotein (AFP) (73.7% VS.31.6%; P < 0.0001). Among AFP-negative patients with very early HCC, 18 (69.2%) of 26 had positive thioredoxin results. Our results indicate that serum thioredoxin complements measurement of AFP in the diagnosis of HCC, especially in very early disease. Combined model (thioredoxin and AFP) showed a significantly greater discriminatory ability as compared with those markers alone.     

A new approach to the use of α-fetoprotein as surveillance test for hepatocellular carcinoma in patients with cirrhosis

Background:

Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis. As α-fetoprotein (AFP) is considered a poor surveillance test, we tested the performance of its changes over time.

Methods:

Eighty patients were diagnosed with HCC (cases) during semiannual surveillance with ultrasonography and AFP measurement were recruited and matched for age, gender, etiology and Child-Pugh class with 160 contemporary cancer-free controls undergoing the same surveillance training group (TG). As a validation group (VG) we considered 36 subsequent patients diagnosed with HCC, matched 1 : 3 with contemporary cancer-free controls. α-Fetoprotein values at the time of HCC diagnosis (T0) and its changes over the 12 (Δ12) and 6 months (Δ6) before cancer detection were considered.

Results:

In both TG and VG, >80% of HCCs were found at an early stage. In TG, AFP significantly increased over time only in cases. T0 AFP and a positive Δ6 were independently associated with HCC diagnosis (odds ratio: 1.031 and 2.402, respectively). The area under the curve of T0 AFP was 0.76 and its best cutoff (BC) was 10 ng ml⁻¹ (sensitivity 66.3%, specificity 80.6%). The combination of AFP >10 ng ml⁻¹ or a positive Δ6 composite α-fetoprotein index (CAI) increased the sensitivity to 80% with a negative predictive value (NPV) of 86.2%. Negative predictive value rose to 99%, considering a cancer prevalence of 3%. In the VG, the AFP-BC was again 10 ng ml⁻¹ (sensitivity 66.7%, specificity 88.9%), and CAI sensitivity was 80.6% with a NPV value of 90.5%.

Conclusions:

CAI achieves adequate sensitivity and NPV as a surveillance test for the early detection of HCC in cirrhosis.     

α-Fetoprotein mRNA in situ hybridisation is a highly specific marker of hepatocellular carcinoma: a multi-centre study

Background Pathologic diagnosis of hepatocellular carcinoma (HCC) can be challenging in differentiating from benign and non-hepatocytic malignancy lesions. The aim of this study was to investigate the potential utility of α-fetoprotein (AFP) mRNA RNAscope, a sensitive and specific method, in the diagnosis of HCC.Methods Three independent retrospective cohorts containing 2216 patients with HCC, benign liver lesions, and non-hepatocytic tumours were examined. AFP was detected using ELISA, IHC (Immunohistochemistry), and RNAscope. Glypican3 (GPC3), hepatocyte paraffin-1 (HepPar-1), and arginase-1 (Arg-1) proteins were detected using IHC.Results AFP RNAscope improved the HCC detection sensitivity by 24.7–32.7% compared with IHC. In two surgical cohorts, a panel of AFP RNAscope and GPC3 provided the best diagnostic value in differentiating HCC from benign hepatocytic lesions (AUC = 0.905 and 0.811), and a panel including AFP RNAscope, GPC3, HepPar-1, and Arg-1 yielded the best AUC (0.971 and 0.977) when distinguishing HCC from non-hepatocytic malignancies. The results from the liver biopsy cohort were similar, and additional application of AFP RNAscope improved the sensitivity by 18% when distinguishing HCC from benign hepatocytic lesions.Conclusions AFP mRNA detected by RNAscope is highly specific for hepatocytic malignancy and may serve as a novel diagnostic biomarker for HCC.Subject terms: Diagnostic markers, Tumour biomarkers, Hepatocellular carcinoma     

A nomogram for predicting the risk of postoperative recurrence of hepatitis B virus-related hepatocellular carcinoma in patients with high preoperative serum glutamyl transpeptidase

BackgroundRecurrence is a major risk factor affecting the postoperative survival of patients with hepatocellular carcinoma (HCC), especially those with high preoperative serum γ-glutamyl transpeptidase (GGT) levels. This study had the aim of developing a personalized predictive tool to accurately determine the risk of postoperative recurrence of hepatitis B-virus (HBV)-related HCC in patients with high preoperative serum GGT levels.MethodsPatients who underwent curative liver resection of HBV-related HCC and had high preoperative GGT levels were consecutively enrolled between 2008 and 2011. Prognostic indicators for recurrence were determined using Cox regression analysis. A nomogram was then developed and assessed by integrating the independent risk factors into the model.ResultsA total of 603 eligible patients were included. The final nomogram for predicting HCC recurrence in patients with high preoperative GGT levels consisted of five independent prognostic factors: α-fetoprotein (AFP), HBV-DNA, satellite nodules, microvascular invasion, and tumor grade. The C-index of the nomogram for predicting recurrence was 0.759, and validation showed high accuracy and discriminatory.ConclusionsThe predictive nomogram developed and validated in this study performs well in predicting postoperative recurrence of HBV-related HCC in patients with high preoperative GGT levels. It can provide personalized assessments to inform the development of surveillance strategies and allows patients with a high risk of recurrence to be selected for further adjuvant treatment.     

Circulation long non-coding RNAs act as biomarkers for predicting tumorigenesis and metastasis in hepatocellular carcinoma

BACKGROUND & AIMS

Alpha Fetal Protein (AFP) was one of the traditional biomarker for diagnosis of Hepatocellular carcinoma (HCC) clinically, however, with the low specificity of AFP, the early diagnosis or the metastasis prediction of HCC is inferior. A new, minimally invasive and more specificity biomarker for the diagnosis or metastasis prediction of HCC are necessary.

METHODS

In this study, we applied an lncRNA microarray to screen the potential biomarker for HCC. The multi-stage validation and risk score formula detection was used for validation.

RESULTS

We discovered three lncRNA, RP11–160H22.5, XLOC_014172 and LOC149086, which were up-regulated in HCC comparing with the cancer-free controls with the merged area under curve (AUC) in training set and validation set of 0.999 and 0.896. Furthermore, XLOC_014172 and LOC149086 was confirmed highly increased in metastasis HCC patients with the merged AUC in training set and validation set of 0.900 and 0.934. Besides, most patients presented a decreased level of the three lncRNAs after operation, while the patients with secondary increased level might be associated with tumor hematogenous metastasis.

CONCLUSIONS

RP11–160H22.5, XLOC_014172 and LOC149086 might be the potential biomarker for the tumorigenesis prediction and XLOC_014172 and LOC149086 for metastasis prediction in the future.     

Using multiple cytokines to predict hepatocellular carcinoma recurrence in two patient cohorts

Background:

Cytokines are tightly linked to the carcinogenesis, development and prognosis of hepatocellular carcinoma (HCC). We determined the prognostic value of 39 circulating cytokines in HCC patients after radical resection and then developed a novel cytokine-based prognostic classifier (CBPC) for the prediction of patient prognosis.

Methods:

A total of 179 patients were divided into two cohorts based on the date of radical resection. Thirty-nine cytokines were simultaneously analysed in patient serum samples using multiplex bead-based Luminex technology. Support vector machine-based methods and Cox proportional hazard models were used to develop a CBPC from the training cohort, which was then validated in the validation cohort.

Results:

Among seven cytokines significantly correlating with the disease-free survival (DFS) in the training cohort, six of them were validated to be significant prognostic factors to predict DFS and overall survival (OS) in the validation cohort, namely fibroblast growth factor 2 (FGF-2), growth-regulated oncogene (GRO), interleukin 8 (IL-8), interferon gamma-induced protein 10 (IP-10), vascular endothelial growth factor (VEGF), and interferon alpha-2 (IFN-α2). By integrating six cytokines and three clinical characteristics, we developed a CBPC to predict the recurrence and 3-year OS of HCC patients (sensitivity, 0.648; specificity, 0.918). In the validation cohort, the CBPC were confirmed to have significant predictive power for predicting tumour recurrence and OS (sensitivity, 0.585; specificity, 0.857). Interestingly, IFN-α2 was the only cytokine being independent prognostic factor in both patient cohorts.

Conclusion:

Our study verifies the presence of specific cytokine–phenotype associations with patient prognosis in HCC. The CBPC developed include multiple circulating cytokines and may serve as a novel screening approach for identifying HCC patients with a high risk of post-resection recurrence and shorter OS. These individuals may also be suitable for cytokine-targeted therapies.     

A novel prognostic nomogram based on microvascular invasion and hematological biomarkers to predict survival outcome for hepatocellular carcinoma patients

PurposeThis study aimed to develop and validate a nomogram for overall survival (OS) prediction in which combine clinical characteristics and hematological biomarkers in patients with hepatocellular carcinoma (HCC).MethodsWe performed a retrospective analysis of 807 HCC patients. All the clinical data of these patients were collected through electronic medical record (EMR). The independent predictive variables were identified by cox regression analysis. We tested the accuracy of the nomograms by discrimination and calibration, and then plotted decision curves to assess the benefits of nomogram-assisted decisions in a clinical context, and compared with the TNM staging systems and microvascular invasion (MVI) on HCC prognosis.ResultsThe primary cohort consisted of 545 patients with clinicopathologically diagnosed with HCC from 2008 to 2013, while 262 patients from 2014 to 2016 in external validation cohort. Variables included in the nomograms were TNM Stage, microvascular invasion (MVI), alpha fetoprotein (AFP), platelet to lymphocyte ratio (PLR) and prothrombin time (PT). The C-index of nomogram was 0.768, which was superior than the C-index of TNM Stage (0.660, P < 0.001) and MVI(0.664, P < 0.001) alone in the primary cohort. In the validation cohort, the models had a C-index of 0.845, and were also statistically higher when compared to C-index values for TNM Stage (0.687, P < 0.001) and MVI(0.684, P < 0.001). Calibration curves showed adequate calibration of predicted and reported OS prediction throughout the range of HCC outcomes. Decision curve analysis demonstrated that the nomogram was clinically useful than the TNM Stage and MVI alone. Moreover, patients were divided into three distinct risk groups for OS by the nomogram: low risk group, middle risk group and a high risk group, respectively.ConclusionThe nomogram presents more accurate and useful prognostic power, which could be used to predict OS for patients with HCC.     

Prognostic impact of lymph node harvest for patients with node-negative esophageal squamous cell carcinoma: a large-scale multicenter study

BackgroundWe examined the association between the number of resected lymph nodes and survival to determine the optimal lymphadenectomy for thoracic esophageal squamous cell carcinoma (ESCC) patients with negative lymph node.MethodsWe included 1,836 patients from Chinese three high-volumed hospitals with corresponding clinicopathological characters such as gender, age, tumor location, tumor grade and TNM stage of patients. The median follow-up of included patients was 45.7 months (range, 1.03–117.3 months). X-Tile plot was used to identify the lowest number of lymphadenectomy. The multivariate model’s construction was in use of parameters with clinical significance for survival and a nomogram based on clinical variable with P<0.05 in Cox regression analysis. Both two models were validated using a cohort extracted from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database between 1975 and 2016 (n=951).ResultsMore lymphadenectomy numbers were significantly associated with better survival in patients both in training cohort [hazard ratio (HR) =0.980; 95% confidence interval (CI): 0.971–0.988; P<0.001] and validation cohort (HR =0.980; 95% CI: 0.968–0.991; P=0.001). Cut-off point analysis determined the lowest number of 9 for thoracic ESCC patients in N0 stage through training cohort (C-index: 0.623; sensitivity: 80.7%; 1 − specificity: 72.5%) when compared with 10 in validation cohort (C-index: 0.643; sensitivity: 78.2%; 1 − specificity: 63.0%). The cut-off points of 9 were examined in training cohort and validated in the divided cohort from validation cohort (all P<0.05). Meanwhile, nomograms for both cohorts were constructed and the calibration curves for both cohorts agreed well with the actual observations in terms of predicting 3- and 5-year survival, respectively.ConclusionsLarger number for lymphadenectomy was associated with better survival in thoracic ESCC patients in N0 stage. Nine was what we got as the lowest number for lymphadenectomy in pN0 ESCC patients through this study, and our result should be confirmed further.     

Longitudinal change in fine motor skills after brain radiotherapy and in vivo imaging biomarkers associated with decline

BackgroundWe explored fine motor skills (FMS) before and after brain radiotherapy (RT), analyzing associations between longitudinal FMS and imaging biomarkers of cortical and white matter (WM) integrity in motor regions of interest (ROIs).MethodsOn a prospective trial, 52 primary brain tumor patients receiving fractionated brain RT underwent volumetric brain MRI, diffusion tensor imaging, and FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS], Grooved Pegboard Dominant Hands [PDH], and Grooved Pegboard Nondominant Hands [PNDH]) at baseline and 3-, 6-, and 12-month post-RT. Motor ROIs autosegmented included: sensorimotor cortices and superficial WM, corticospinal tracts, cerebellar cortices and WM, and basal ganglia. Volume (cc) was measured in all ROIs at each timepoint. Diffusion biomarkers (FA [fractional anisotropy] and MD [mean diffusivity]) were additionally measured in WM ROIs. Linear mixed-effects models assessed biomarkers as predictors of FMS scores. P values were corrected for multiple comparisons.ResultsHigher RT dose was associated with right paracentral cortical thinning (β = −2.42 Gy/(month × mm), P = .03) and higher right precentral WM MD (β = 0.69 Gy/(month × µm²/ms), P = .04). Higher left (β = 38.7 points/(month × µm²/ms), P = .004) and right (β = 42.4 points/(month × µm²/ms), P = .01) cerebellar WM MD, left precentral cortical atrophy (β = −8.67 points/(month × mm), P = .02), and reduced right cerebral peduncle FA (β = −0.50 points/month, P = .01) were associated with worse DKEFS-MS performance. Left precentral cortex thinning was associated with worse PDH scores (β = −17.3 points/(month × mm), P = .02). Left (β = −0.87 points/(month × cm³), P = .001) and right (β = −0.64 points/(month × cm³), P = .02) cerebellar cortex, left pons (β = −19.8 points/(month × cm³), P = .02), and right pallidum (β = −10.8 points/(month × cm³), P = .02) atrophy and reduced right internal capsule FA (β = −1.02 points/month, P = .03) were associated with worse PNDH performance.ConclusionsBiomarkers of microstructural injury in motor-associated brain regions were associated with worse FMS. Dose avoidance in these areas may preserve FMS.     

Predictive Value of Interferon γ Receptor Gene Polymorphisms for Hepatocellular Carcinoma Susceptibility

Background:Recent reports suggested relation between Interferon Gamma (IFN-γ) gene polymorphism and the risk of development of HCC on top of hepatic cirrhosis. The aim of this study was to address the predictive value of Interferon Gamma gene receptor (IFN-γR) polymorphisms for the occurrence of hepatocellular carcinoma on top of liver cirrhosis. Patients and Methods:This is a case control study performed on patients selected from the outpatient hepatology clinic, specialized medical hospital, Mansoura University, Egypt, from August 2017 to February 2019. The included patients were categorized into two groups; 60 patients with HCC on top of cirrhosis and 20 patients with hepatic cirrhosis. For all patients IFN-γR polymorphism was identified by RFLP. Results:Our study showed that HCC patients had male predominance. Additionally, diabetes mellitus (DM) was found in 28.3% of total HCC patients. Half of HCC patients in this study were from rural areas (50%). The frequency of AA at position -611 in the IFN-γR (-611 IFN-γR) was significantly higher in the HCC group as compared to cirrhotic group (P=0.021). Moreover; the frequency of CC and CT genotypes of IFN-γR -56 was not significantly different in HCC group as compared to control group (P>0.05). The IFN-γR (-611 IFN-γ) AA genotype significantly increased risk of HCC (OR= 0.78, 95% CI= 0.10-6.39; P= 0.042).Conclusion:The analysis of IFN-γR -611 single nucleotide gene polymorphism could be a valuable marker for predicting subgroup of cirrhotic patients with high risk of developing HCC. Cirrhotic patients have AA genotype of IFN-γR-611 recommended to be under close follow up.Key Words: Cirrhosis, HCC, interferon gamma receptor, polymorphism     

Serum N-glycan profiling as a diagnostic biomarker for the identification of hepatitis B virus-associated hepatocellular carcinoma

BackgroundChanges in N-glycosylation of proteins are thought to play a key role in cancer. This study aims to investigate the changes in the serum N-glycan profiles of patients with hepatitis B virus (HBV)-related liver disease, and to evaluate the role of N-glycan markers in the noninvasive diagnosis of hepatocellular carcinoma (HCC).MethodsSerum samples were available for 21 patients with HCC, 20 patients with liver cirrhosis (LC), 20 patients with chronic hepatitis B (CHB), and 20 healthy subjects. Serum N-glycans were released and analyzed using DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE). Serum AFP was determined by electrochemiluminescence (ECL) (AFP reference value range: <10 ng/mL).ResultsThere were characteristic changes in the serum N-glycan profiles of patients with HBV-related liver disease, including NA2FB, NA3, and NA3Fb. NA2FB was the most abundant in LC patients, while NA3Fb abundance was the highest in HCC patients. For HCC screening in patients, especially in patients with LC, the sensitive of Log peak 9 (94.4%) and Log (peak 9/peak 7) (88.9%) were better than alpha-fetoprotein (AFP) (33.3–61.1%), and their specificity was similar to that of AFP. The receiver operating characteristic (ROC) curve showed that the accuracy of Log peak 9 (AUC: 0.81±0.07) and Log (peak 9/peak 7) (AUC: 0.87±0.06) was better than that of AFP (AUC: 0.72±0.09), while the accuracy of AFP combined with the above 2 indexes was better than that of a single index. Moreover, Log (peak 9/peak 7) combined with AFP (AUC: 0.89±0.06) had the best accuracy in the diagnosis of HCC.ConclusionsOur research indicates that N-glycan may serve a new, valuable, and noninvasive alternative method for diagnosing HCC, and it may be a supplement to AFP in the diagnosis of HCC in patients with HBV-related liver disease.     

TGF-Β1 & PNPLA3 Genetic Variants and the Risk of Hepatic Fibrosis and HCC in Egyptian Patients with HCV-Related Liver Cirrhosis

Objective:The clinical outcomes of hepatitis C virus (HCV) infection and its sequelae including liver cirrhosis and hepatocellular carcinoma (HCC) are greatly affected by host genetic factors; however, the possible mechanisms are still largely unclear. This work aimed to assess transforming growth factor-β1 (TGF-β1), and patatin-like phospholipase domain containing-protein 3 (PNPLA3) genetic variants as risk factors for hepatic fibrosis and hepatocellular carcinoma (HCC) in Egyptian patients with HCV-related liver cirrhosis. Methods:Seventy HCV-related liver cirrhosis patients (Total cirrhosis) who were divided into two groups; 34 patients with HCC (HCC group), and 36 patients without HCC (LC group) and 20 healthy volunteers (control group) were included. Routine laboratory investigations and imaging studies were determined. TGF-β1 (Arg25Pro; 915G>C) and PNPLA3 (I148M; C>G) variants were evaluated using real-time polymerase chain reaction (real-time PCR). Results:HCC group showed a significantly higher GG genotype distribution of TGF-β1 (Arg25Pro) than the LC group (P= 0.008, OR: 7.083, CI 95%: 1.422 – 35.282). The distributions of GG genotype (P= 0.047) and G allele (P= 0.002, OR: 4.395, CI 95%: 1.622 – 11.911) of PNPLA3 (I148M) were significantly higher in total cirrhosis patients than controls. Conclusion:TGF-β1 (Arg25Pro) GG variant may be associated with HCC risk in HCV-related liver cirrhosis patients, while PNPLA3 (I148M) GG variant may be associated with cirrhosis development but not HCC risk in HCV-related liver cirrhosis patients. Key Words: Gene polymorphism, liver fibrosis, HCC, HCV     

Alpha-fetoprotein response at different time-points is associated with efficacy of nivolumab monotherapy for unresectable hepatocellular carcinoma

Nivolumab monotherapy has a modest objective response rate (ORR) in hepatocellular carcinoma (HCC). To overcome the lack of biomarkers that predict delayed alpha-fetoprotein (AFP) response beyond 4 weeks, we applied a novel 50-10 rule of AFP response for unresectable HCC patients under nivolumab monotherapy and proposed an algorithm based on on-treatment AFP reduction at different time-points. Ninety unresectable HCC patients who underwent nivolumab monotherapy in 2015-2019 were retrospectively recruited and divided into four classes: rapid AFP decrease of ≥ 50% of baseline at week 4 (class I), AFP changes within ± 50% of baseline at week 4 that later decreased to ≥ 10% of baseline (class II) or not (class III) at week 12, and rapid AFP increase of ≥ 50% of baseline at week 4 (class IV). ORR was 47.4%, 36.0%, 7.7%, and 5.0% in class I-IV patients, respectively. Rapid (class I) and delayed (class II) AFP responders had significantly higher ORR, overall survival (OS) and progression-free survival (PFS) than non-responders (class III and IV) (ORR: 40.9% vs. 6.5%, P<0.001; median OS: not reached vs. 9.6 months, log-rank P<0.001; median PFS: 9.6 vs. 2.8 months, log-rank P<0.001). In multivariate analysis, AFP response was an independent factor associated with good OS (hazard ratio [HR]=0.301, P=0.001) and PFS (HR=0.332, P<0.001). Moreover, AFP responders had higher ORR and better OS as well as PFS than non-responders, regardless of nivolumab as a first- or more than a second-line therapy (all P<0.05). In conclusion, the novel 50-10 rule of AFP response provides practical guidance for nivolumab monotherapy in unresectable HCC patients. However, this algorithm remains to be verified in a large prospective cohort.     

HCC-ART score,a simple,highly sensitive and specific test for early diagnosis of hepatocellular carcinoma: a large-scale,multicentre study

Background:

A simple scoring system is needed to discriminate HCC from patients with chronic liver diseases (CLD). The simplest score would be one that requires only variables that can be documented simply from routine laboratory tests without the need for sophisticated tests.

Methods:

Data from the estimation group (1351 patients) and the validation group (2208 patients) were retrospectively analysed. Liver fibrosis-negative control and liver cirrhosis were compared with HCC. Area under ROC curve (AUC) were used to develop HCC-α-fetoprotein-routine test (HCC-ART).

Results:

Hepatocellular carcinoma-AFP-routine test showed diagnostic accuracy for liver cirrhosis vs HCC with ROC curves of 0.99%, sensitivity of 97%, and specificity of 96% in the estimation, and 0.95%, 90%, and 83%, respectively, in the validation. Sensitivity (97%) and specificity (100%) were obtained to discriminate HCC from liver fibrosis. Area under curve for AFP at 400 U l⁻¹ was 0.70, sensitivity was 41%, and specificity was 99% in the estimation, and 0.77%, 54%, and 99%, respectively, in the validation. The AUC for HCC-ART in HCC with single tumour, absent vascular invasion, size <2 cm and CLIP score (0–1) were 0.95, 0.93, 0.86, 0.87, respectively, compared with 0.72, 0.71, 0.71, 0.50, respectively, for AFP.

Conclusion:

Hepatocellular carcinoma-AFP-routine test could increase the accuracy of HCC screening and surveillances and could be used worldwide without extra efforts.     

Prediction of late recurrence after radiofrequency ablation of HBV-related hepatocellular carcinoma with the age-male-albumin-bilirubin-platelets (aMAP) risk score: a multicenter study

BackgroundLong-term survivals of patients with HBV-related hepatocellular carcinoma are limited by the high incidence of tumor recurrence after radiofrequency ablation (RFA), identification of the risk factors and understanding the patterns of recurrence can help to improve the comprehensive management of patients after RFA. Therefore, the purpose of the study is to explore the prognostic value of the age-male-albumin-bilirubin-platelets (aMAP) score in patients with early-stage HBV-related hepatocellular carcinoma (HCC) receiving RFA; investigate the risk factors and patterns of late recurrence (LR); and develop a nomogram to predict recurrence-free survival (RFS).MethodsA retrospective review of HBV-related HCC patients who underwent primary RFA from March 2012 to December 2020 was conducted. The prognostic value of the aMAP score was evaluated in a primary cohort (n=302) and then further validated in an independent validation cohort (n=143). The optimal threshold of aMAP scores was calculated by X-tile 3.6.1 software. A prognostic nomogram was constructed from multivariate analysis and validated in an external validation cohort.ResultsPatients with aMAP scores ≤63.8, 63.8–67.8, and >67.8 were classified into low-, medium-, and high-recurrence risk groups, respectively. The C-index to predict LR was 0.76 (95% CI: 0.700–0.810). The high-risk group was associated with the worst RFS (HR: 5.298; 95% CI, 2.697–10.408; P<0.001) and overall survival (OS) (HR: 2.639; 95% CI, 1.097–6.344; P=0.03) compared with medium- and low-risk groups. The aMAP score, multiple tumors and preoperative HBV DNA level were independent risk factors for LR. The proposed nomogram had excellent performance in predicting LR of HBV-related HCC [C-index: 0.82 (95% CI: 0.772–0.870)].ConclusionsThis study demonstrated that the aMAP score can serve as an objective predictor of LR for HBV-related HCC patients after RFA. The nomogram based on preoperative HBV DNA level, aMAP score, and number of tumors can reliably help clinicians to stratify the recurrence risk of HCC patients after RFA.     

A radiomics prognostic scoring system for predicting progression-free survival in patients with stage IV non-small cell lung cancer treated with platinum-based chemotherapy

ObjectiveTo develop and validate a radiomics prognostic scoring system (RPSS) for prediction of progression-free survival (PFS) in patients with stage IV non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy.MethodsIn this retrospective study, four independent cohorts of stage IV NSCLC patients treated with platinum-based chemotherapy were included for model construction and validation (Discovery: n=159; Internal validation: n=156; External validation: n=81, Mutation validation: n=64). First, a total of 1,182 three-dimensional radiomics features were extracted from pre-treatment computed tomography (CT) images of each patient. Then, a radiomics signature was constructed using the least absolute shrinkage and selection operator method (LASSO) penalized Cox regression analysis. Finally, an individualized prognostic scoring system incorporating radiomics signature and clinicopathologic risk factors was proposed for PFS prediction.ResultsThe established radiomics signature consisting of 16 features showed good discrimination for classifying patients with high-risk and low-risk progression to chemotherapy in all cohorts (All P<0.05). On the multivariable analysis, independent factors for PFS were radiomics signature, performance status (PS), and N stage, which were all selected into construction of RPSS. The RPSS showed significant prognostic performance for predicting PFS in discovery [C-index: 0.772, 95% confidence interval (95% CI): 0.765−0.779], internal validation (C-index: 0.738, 95% CI: 0.730−0.746), external validation (C-index: 0.750, 95% CI: 0.734−0.765), and mutation validation (C-index: 0.739, 95% CI: 0.720−0.758). Decision curve analysis revealed that RPSS significantly outperformed the clinicopathologic-based model in terms of clinical usefulness (All P<0.05).ConclusionsThis study established a radiomics prognostic scoring system as RPSS that can be conveniently used to achieve individualized prediction of PFS probability for stage IV NSCLC patients treated with platinum-based chemotherapy, which holds promise for guiding personalized pre-therapy of stage IV NSCLC.     

Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy

Background:

Interferon (IFN)-based therapies could eradicate hepatitis C (HCV) and reduce the risk of hepatocellular carcinoma (HCC). However, HCC could still happen after sustained virological response (SVR). We aimed to develop a simple scoring system to predict the risk of HCC development among HCV patients after antiviral therapies.

Methods:

From 1999 to 2009, 1879 patients with biopsy-proven HCV infection treated with IFN-based therapies were analyzed.

Results:

Multivariable analysis showed old age (adjusted HR (aHR)=1.73, 95% CI=1.13–2.65 for aged 60–69 and aHR=2.20, 95% CI=1.43–3.37 for aged ⩾70), Male gender (aHR=1.74, 95% CI=1.26–2.41), platelet count <150 × 10⁹/l (HR=1.91, 95% CI=1.27–2.86), α-fetoprotein ⩾20 ng ml⁻¹ (HR=2.23, 95% CI=1.58–3.14), high fibrotic stage (HR=3.32, 95% CI=2.10–5.22), HCV genotype 1b (HR=1.53, 95% CI=1.10–2.14), and non SVR (HR=2.40, 95% CI=1.70–3.38) were independent risk factors for HCC. Regression coefficients were used to build up a risk score and the accuracy was evaluated by using the area under the receiver operating characteristic curve (AUC). Three groups as low-, intermediate-, and high-risk are classified based on the risk scores. One hundred sixty patients (12.78%) in the derivation and 82 patients (13.08%) in the validation cohort developed HCC with AUC of 79.4%, sensitivity of 84.38%, and specificity of 60.66%. In the validation cohort, the 5-year HCC incidence was 1.81%, 12.92%, and 29.95% in low-, intermediate-, and high-risk groups, with hazard ratios 4.49 in intermediate- and 16.14 in high-risk group respectively. The risk reduction of HCC is greatest in patients with SVR, with a 5-year and 10-year risk reduction of 28.91% and 27.99% respectively.

Conclusion:

The risk scoring system is accurate in predicting HCC development for HCV patients after antiviral therapies.     

A novel classification in predicting prognosis and guiding postoperative management after R0 liver resection for patients with hepatocellular carcinoma and microvascular invasion

BackgroundMicrovascular invasion (MVI) is a significant risk factor affecting survival outcomes of patients after R0 liver resection (LR) for hepatocellular carcinoma (HCC). The current classification of MVI is not refined enough to prognosticate long-term survival of these patients, and a new MVI classification is needed.MethodsPatients with HCC who underwent R0 LR at the Eastern Hepatobiliary Surgery Hospital from January 2013 to December 2013 and with resected specimens showing MVI were included in this study with an aim to establish a novel MVI classification. The classification which was developed using multivariate cox regression analysis was externally validated.ResultsThere were 180 patients in the derivation cohort and 131 patients in the external validation cohort. The following factors were used for scoring: α-fetoprotein level (AFP), liver cirrhosis, tumor number, tumor diameter, MVI number, and distance between MVI and HCC. Three classes of patients could be distinguished by using the total score: class A, ≤3 points; class B, 3.5–5 points and class C, >5 points with distinct long-term survival outcomes (median recurrence free survival (mRFS), 22.6, 10.2, and 1.9 months, P < 0.001). The predictive accuracy of this classification was more accurate than the other commonly used classifications for HCC patients with MVI. In addition, the mRFS of class C patients was significantly prolonged (1.9 months vs. 6.2 months, P < 0.001) after adjuvant transcatheter arterial chemoembolization (TACE).ConclusionsA novel MVI classification was established in predicting prognosis of HCC patients with MVI after R0 LR. Adjuvant TACE was useful for class C patients.