Multidisciplinary management of hepatobiliary tumors in the era of precision medicine

Hepatobiliary tumor (HBT), one of the leading causes of cancer deaths globally, is more frequent in East Asia including China [1].HBTincludeslivercancer,cholangiocarcinomaandgallbladder cancer.HBTburdenvariesmarkedlybygenderandgeographic regionduetotheexposureofriskfactors.MajorityofthehepatocellularcarcinomasareassociatedwithhepatitisB-typevirus

Prognostic significance of the fibrinogen-to-albumin ratio in gallbladder cancer patients

AIM To investigate the prognostic role of fibrinogen-toalbumin ratio(FAR) on patients with gallbladder cancer(Gbc) in this study.METHODS One hundred and fifty-four Gbc patients were retro-spectively analyzed, who received potentially curative cholecystectomy in our institute from March 2005 to December 2017. Receiver operating characteristic curve(ROc curve) was used to determine the optimal cut-offs for these biomarkers. In addition, Kaplan-Meier survival analysis as well as multivariate analysis were applied for prognostic analyses.RESULTS ROc curve revealed that the optimal cut-off value for FAR was 0.08. FAR was significantly correlated with age(P = 0.045), jaundice(P < 0.001), differentiation(P = 0.002), resection margin status(P < 0.001), T stage(P < 0.001), TNM stage(P < 0.001), and c A199(P < 0.001) as well as albumin levels(P < 0.001). Multivariate analysis indicated that the resection margin status [hazard ratio(HR): 2.343, 95% confidence interval(c I): 1.532-3.581, P < 0.001], TNM stage(P = 0.035), albumin level(HR = 0.595, 95%c I: 0.385-0.921, P = 0.020) and FAR(HR: 2.813, 95%c I: 1.765-4.484, P < 0.001) were independent prognostic factors in Gbc patients.CONCLUSION An elevated preoperative FAR was significantly correlated with unfavorable overall survival in Gbc patients, while an elevated preoperative albumin level was a protective prognostic factor for patients with Gbc. The preoperative FAR could be used to predict the prognosis of Gbc patients, which was easily accessible, costeffective and noninvasive.

Prognostic significance of combined preoperative fibrinogen and CA199 in gallbladder cancer patients

AIM To investigate the prognostic value of the combination of preoperative plasma fibrinogen and CA199 in patients with gallbladder carcinoma(GBC).METHODS The clinicopathological data of 154 GBC patients were retrospectively reviewed after surgery. A receiver operating characteristic(ROC) curve was plotted to verify the optimum cut-off values for plasma fibrinogen and CA199. Univariate and multivariate survival analyses were performed to identify the factors associated with GBC prognosis. based on the HRs calculated via multivariate survival analyses, patients with elevated plasma fibrinogen and CA199 levels were allocated a score of 2.1; those with an elevated plasma fibrinogen level only were allocated a score of 1, those with an elevated CA199 level only were allocated a score of 1.1, and those with neither of these abnormalities were allocated a score of 0.RESULTS ROC curve analysis showed that the optimum cut-off values for preoperative plasma fibrinogen and CA199 were 3.47 g/L and 25.45 U/mL, respectively. Multivariate analysis indicated that elevated preoperative plasma fibrinogen and CA199 levels were significantly correlated with worse overall survival(OS)(HR = 1.711, 95%CI: 1.114-2.627, P = 0.014, and HR = 1.842, 95%CI: 1.111-3.056, P = 0.018). When we combined these two parameters, the area under the ROC curve increased from 0.735(for preoperative plasma fibrinogen only) and 0.729(for preoperative CA199 only) to 0.765. When this combined variable was added to the multivariate analysis, the combination of plasma fibrinogen and CA199(P < 0.001), resection margin(P < 0.001) and TNM stage(P = 0.010) were independent prognostic factors for GBC.CONCLUSION The combination of plasma fibrinogen and CA199 may serve as a more efficient independent prognostic biomarker for postoperative GBC patients than either parameter alone.

Nomogram to predict overall survival after gallbladder cancer resection in China

AIM To integrate clinically significant variables related to prognosis after curative resection for gallbladder carcinoma(GBC) into a predictive nomogram.METHODS One hundred and forty-two GBC patients who underwent curative intent surgical resection at Peking Union Medical College Hospital(PUMCH) were included. This retrospective case study was conducted at PUMCH of the Chinese Academy of Medical Sciences and Peking Union Medical College(CAMS & PUMC) in China from January 1, 2003 to January 1, 2018. The continuous variable carbohydrate antigen 19-9(CA19-9) was converted into a categorical variable(cCA19-9) based on the normal reference range. Stages 0 to IIIA were merged into one category, while the remaining stages were grouped into another category. Pathological grade X(GX) was treated as a missing value. A multivariate Cox proportional hazards model was used to select variables to construct a nomogram. Discrimination and calibration of the nomogram were performed via the concordance index(C-index) and calibration plots. The performance of the nomogram was estimated using the calibration curve. Receiver operating characteristic(ROC) curve analysis and decision curve analysis(DCA) were performed to evaluate the predictive accuracy and net benefit of the nomogram, respectively.RESULTS Of these 142 GBC patients, 55(38.7%) were male, and the median and mean age were 64 and 63.9 years, respectively. Forty-eight(33.8%) patients in this cohort were censored in the survival analysis. The median survival time was 20 months. A series of methods, including the likelihood ratio test and Akaike information criterion(AIC) as well as stepwise, forward, and backward analyses, were used to select the model, and all yielded identical results. Jaundice [hazard ratio(HR) = 2.9; 95% confidence interval(CI): 1.60-5.27], cCA19-9(HR = 3.2; 95%CI: 1.91-5.39), stage(HR = 1.89; 95%CI: 1.16-3.09), and resection(R)(HR = 2.82; 95%CI: 1.54-5.16) were selected as significant predictors and combined into a survival time predictive nomogram(C-index = 0.803; 95%CI: 0.766-0.839). High prediction accuracy(adjusted C-index = 0.797) was further verified via bootstrap validation. The calibration plot demonstrated good performance of the nomogram. ROC curve analysis revealed a high sensitivity and specificity. A high net benefit was proven by DCA.CONCLUSION A nomogram has been constructed to predict the overall survival of GBC patients who underwent radical surgery from a clinical database of GBC at PUMCH.

Prognostic impact of the red cell distribution width in esophageal cancer patients: A systematic review and meta-analysis

AIM To clarify the previous discrepant conclusions, we performed a meta-analysis to evaluate the prognostic value of red cell distribution width(RDW) in esophageal cancer(EC). METHODS We searched the PubM ed, EMBASE, Web of Science and Cochrane Library databases to identify clinical studies, followed by using STATA version 12.0 for statistical analysis. Studies that met the following criteria were considered eligible:(1) Studies including EC patients who underwent radical esophagectomy;(2) studies including patients with localized disease without distant metastasis;(3) studies including patients without preoperative neoadjuvant therapy;(4) studies including patients without previous antiinflammatory therapies and with available preoperative laboratory outcomes;(5) studies reporting association between the preoperative RDW and overall survival(OS)/disease-free survival(DFS)/cancer-specific survival(CSS); and(6) studies published in English.RESULTS A total of six articles, published between 2015 and 2017, fulfilled the selection criteria in the end. Statistical analysis showed that RDW was not associated with the prognosis of EC patients, irrespective of OS/CSS [hazard ratio(HR) = 1.27, 95% confidence interval(CI): 0.97-1.57, P = 0.000] or DFS(HR = 1.42, 95%CI: 0.96-1.88, P = 0.000). Subgroup analysis indicated that elevated RDW was significantly associated with worse OS/CSS of EC patients when RDW > 13%(HR = 1.45, 95%CI: 1.13-1.76, P = 0.000), when the patient number ≤ 400(HR = 1.45, 95%CI: 1.13-1.76, P = 0.000) and when the study type was retrospective(HR = 1.42, 95%CI : 1.16-1.69, P = 0.000).CONCLUSION Contrary to our general understanding, this meta-analysis revealed that RDW cannot serve as an indicator of poor prognosis in patients with EC. However, it may still be a useful predictor of unfavorable prognosis using an appropriate cut-off value.

Efficacy and safety of lenvatinib for patients with advanced hepatocellular carcinoma: A retrospective, real-world study conducted in China

BACKGROUND Lenvatinib has become an indispensable part of treatment regimens for patients with advanced hepatocellular carcinoma(aHCC).Several recent real-world studies appear to have confirmed this;however,there are etiological differences.This necessitates further real-world studies of lenvatinib across diverse populations,such as in China.AIM To investigate the efficacy and safety of lenvatinib in a Chinese HCC patient population under real-world conditions.METHODS This is a retrospective and multiregional study involving patients with aHCC receiving lenvatinib monotherapy.Efficacy was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1.Baseline characteristics and adverse events(AEs)were recorded throughout the entire study.RESULTS In total,54 HCC patients treated with lenvatinib monotherapy were included for final analysis.The objective response rate was 22%(n=12)with a progressionfree survival(PFS)of 168 d;however,AEs occurred in 92.8%of patients.Multivariate analysis showed that the Barcelona Clinic Liver Cancer stage[hazard ratio(HR)0.465;95%CI:0.23-0.93;P=0.031],portal vein tumor thrombus(HR 0.38;95%CI:0.15-0.94;P=0.037)and Child-Pugh classifications(HR 0.468;95%CI:and specificity(83.3%)of decreasing serum biomarkers including alphafetoprotein were calculated in order to predict tumor size reduction.Gene sequencing also provided insights into potential gene mutation signatures related to the effect of lenvatinib.CONCLUSION Our findings confirm previous evidence from the phase III REFLECT study.The majority of patients in this Chinese sample were suffering from concomitant hepatitis B virus-related HCC.However,further analysis suggested that baseline characteristics,changes in serum biomarkers and gene sequencing may hold the key for predicting lenvatinib responses.Further large-scale prospective studies that incorporate more basic medical science measures should be conducted.

Precision medicine: In need of guidance and surveillance

Precision medicine,currently a hotspot in mainstream medicine,has been strongly promoted in recent years. With rapid technological development,such as next-generation sequencing,and fierce competition in molecular targeted drug exploitation,precision medicine represents an advance in science and technology; it also fulfills needs in public health care. The clinical translation and application of precision medicine-especially in the prevention and treatment of tumors-is far from satisfactory; however,the aims of precision medicine deserve approval. Thus,this medical approach is currently in its infancy; it has promising prospects,but it needs to overcome numbers of problems and deficiencies. It is expected that in addition to conventional symptoms and signs,precision medicine will define disease in terms of the underlying molecular characteristics and other environmental susceptibility factors. Those expectations should be realized by constructing a novel data network,integrating clinical data from individual patients and personal genomic background with existing research on the molecular makeup of diseases. In addition,multi-omics analysis and multi-discipline collaboration will become crucial elements in precision medicine. Precision medicine deserves strong support,and its development demands directed momentum. We propose three kinds of impetus(research,application and collaboration impetus) for such directed momentum toward promoting precision medicine and accelerating its clinical translation and application.

Threonine and tyrosine kinase may serve as a prognostic biomarker for gallbladder cancer

AIM To detect the expression of threonine and tyrosine kinase(TTK) in gallbladder cancer(GBC) specimens and analyze the associations between TTK expression and clinicopathological parameters and clinical prognosis.METHODS A total of 68 patients with GBC who underwent surgical resection were enrolled in this study. The expression of TTK in GBC tissues was detected by immunohistochemistry. The assessment of TTKexpression was conducted using the H-scoring system. H-score was calculated by the multiplication of the overall staining intensity with the percentage of positive cells. The expression of TTK in the cytoplasm and nucleus was scored separately to achieve respective H-s c o r e v a l u e s. T h e c o r r e l a t i o n s b e t w e e n T T K expression and clinicopathological parameters and clinical prognosis were analyzed using Chi-square test, Kaplan-Meier method and Cox regression.RESULTS In both the nucleus and cytoplasm, the expression of TTK in tumor tissues was significantly lower than that in normal tissues(P < 0.001 and P = 0.026, respectively). Using the median H-score as the cutoff value, it was discovered that, GBC patients with higher levels of TTK expression in the nucleus, but not the cytoplasm, had favorable overall survival(P < 0.001), and it was still statistically meaningful in Cox regression analysis. Further investigation indicated that there were close negative correlations between TTK expression and tumor differentiation(P = 0.041), CA 19-9 levels(P = 0.016), T stage(P < 0.001), nodal involvement(P < 0.001), distant metastasis(P = 0.024) and TNM stage(P < 0.001). CONCLUSION The expression of TTK in GBC is lower than that in normal tissues. Higher levels of TTK expression in GBC are concomitant with longer overall survival. TTK is a favorable prognostic biomarker for patients with GBC.