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.

Albumin-to-alkaline phosphatase ratio: A novel prognostic index of overall survival in cholangiocarcinoma patients after surgery

AIM To clarify the prognostic significance of preoperative albumin-to-alkaline phosphatase ratio(AAPR) in cholangiocarcinoma(CCA) subjects receiving surgery.METHODS In this retrospective study, we included 303 CCA patients receiving surgery without preoperative therapy between 2002 and 2014. Clinicopathological characteristics(including AAPR) were analyzed to determine predictors of postoperative overall survival and recurrence-free survival(RFS). In addition,univariate and multivariate Cox proportional hazards models were conducted,followed by application of time-dependent receiver operating curves to identify the optimal cut-off.RESULTS Univariate and multivariate analyses revealed both decreased overall survival[hazard ratio(HR): 2.88, 95%CI: 1.19-5.78] and recurrence-free survival(HR: 2.31,95%CI: 1.40–3.29) in patients with AAPR < 0.41 compared to those with AAPR ≥0.41. The optimal cut-off of AAPR was 0.41. Of the 303 subjects, 253(83.5%) had an AAPR over 0.41. The overall 1-, 3- and 5-year survival rates were 70.2%, 38.0% and 16.5%, respectively in the low(< 0.41) AAPR group, which were significantly lower than those in the high(≥ 0.41) AAPR group(81.7%, 53.9%, and 33.4%,respectively)(P < 0.0001). Large tumor size, multiple tumors, and advanced clinical stage were also identified as significant predictors of poor prognosis.CONCLUSION Our outcomes showed that AAPR was a potential valuable prognostic indicator in CCA patients undergoing surgery, which should be further confirmed by prospective studies. Moreover, it is necessary to investigate the mechanisms concerning the correlation of low AAPR with poor post-operative survival in CCA patients.

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.

Clinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinoma

BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.

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.

Signature based on molecular subtypes of deoxyribonucleic acid methylation predicts overall survival in gastric cancer

BACKGROUND Gastric cancer(GC) ranks as the third leading cause of cancer-related death worldwide. Epigenetic alterations contribute to tumor heterogeneity in early stages.AIM To identify the specific deoxyribonucleic acid(DNA) methylation sites that influence the prognosis of GC patients and explore the prognostic value of a model based on subtypes of DNA methylation.METHODS Patients were randomly classified into training and test sets. Prognostic DNA methylation sites were identified by integrating DNA methylation profiles and clinical data from The Cancer Genome Atlas GC cohort. In the training set, unsupervised consensus clustering was performed to identify distinct subgroups based on methylation status. A risk score model was built based on Kaplan-Meier, least absolute shrinkage and selector operation, and multivariate Cox regression analyses. A test set was used to validate this model.RESULTS Three subgroups based on DNA methylation profiles in the training set were identified using 1061 methylation sites that were significantly associated with survival. These methylation subtypes reflected differences in T, N, and M category, age, stage, and prognosis. Forty-one methylation sites were screened as specific hyper-or hypomethylation sites for each specific subgroup. Enrichment analysis revealed that they were mainly involved in pathways related to carcinogenesis, tumor growth, and progression. Finally, two methylation sites were chosen to generate a prognostic model. The high-risk group showed a markedly poor prognosis compared to the low-risk group in both the training [hazard ratio(HR) = 2.24, 95% confidence interval(CI): 1.28-3.92, P < 0.001] and test(HR = 2.12, 95%CI: 1.19-3.78, P = 0.002) datasets.CONCLUSION DNA methylation-based classification reflects the epigenetic heterogeneity of GC and may contribute to predicting prognosis and offer novel insights for individualized treatment of patients with GC.

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.

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