Development of a Clinically Oriented Model to Predict Antitumor Effects after PD-1/PD-L1 Inhibitor Therapy.

Immune checkpoint inhibitors (ICI) have created an advanced shift in the treatment of lung cancer (LC), but the existing biomarkers were not in clinical and widespread use. The purpose of this study was to develop a new nomogram with immune factors used for monitoring the response to ICI therapy. LC patients with PD-1/PD-L1 inhibitors treatment were included in this analysis. The immune biomarkers and clinicopathological characteristic values at baseline were used to estimate the tumor response. The nomogram was based on the factors that were determined by univariate and multivariate Cox hazard analysis. For internal validation, bootstrapping with 1000 resamples was used. The concordance index (C-index) and calibration curve were used to determine the predictive accuracy and discriminative ability of the nomogram. Overall survival (OS) was estimated using the Kaplan-Meier method. Patients with lung metastasis (P = 0.010), higher baseline neutrophil-lymphocyte ratio (NLR) level (P < 0.001), lower baseline lymphocyte-monocyte (LMR) (P = 0.019), and lower CD3+CD8+ T cell count (P = 0.009) were significantly related to the tumor response. The above biomarkers were contained into the nomogram. The calibration plot for the probability of OS showed an optimal agreement between the actual observation and prediction by nomogram at 3 or 5 years after therapy. The C-index of nomogram for OS prediction was 0.804 (95% CI: 0.739-0.869). Decision curve analysis demonstrated that the nomogram was clinically useful. Moreover, patients were divided into two distinct risk groups for OS by the nomogram: low-risk group (OS: 17.27 months, 95% CI: 14.75-19.78) and high-risk group (OS: 6.11 months, 95% CI: 3.57-8.65), respectively. A nomogram constructed with lung metastasis baseline NLR, LMR, and CD3+CD8+ T cell count could be used to monitor and predict clinical benefit and prognosis in lung cancer patients within ICI therapy.

A novel prognostic time window based on conditional survival and outcomes analyses of primary liver cancer patients.

BACKGROUND: Liver cancer is one of the most deadly and prevalent cancers. A routine follow-up plan for liver cancer is crucial but limited. In the present study, we aimed to disclose possible risk factors and critical survival time windows for primary liver cancer. METHODS: We enrolled 692 liver cancer patients from Sun Yat-sen University Cancer Center (SYSUCC). Univariate and multivariate logistic regression analyses of cirrhosis and recurrence were conducted. A meta-analysis was utilized to validate an indication of creatinine (CRE) in recurrence. Conditional survival analysis was performed using the Kaplan-Meier method. The results were further verified by the SYSUCC validation cohort and Surveillance, Epidemiology, and End Results (SEER) validation cohort. RESULTS: Our results indicated that A/G, history of hepatitis, history of alcohol consumption and platelet (PLT) might be potential prognostic factors for cirrhosis in liver cancer patients. CRE was significantly correlated with recurrence due to various therapies, especially after transarterial embolization. Moreover, 1.5 years to 2 years may be a critical time window for deterioration in survival rate based on the conditional survival analysis. CONCLUSION: A/G, history of hepatitis, alcohol consumption and PLT may be potential prognostic factors for cirrhosis in liver cancer patients. More attention should be focused on the renal function when treating the patients due to the significant role of CRE. 1.5 years to 2 years is a critical time window for deterioration in survival rate for liver cancer patients that contributes to determining the optimal follow-up plan in the future.

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome-Wide Association Study in Multiple Cohorts.

Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two-phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome-wide genotypes at 246 173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazard regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta-analysis of all samples (n = 5553) confirms that the presence of rs1131636-T, located in the 3'-UTR of RPA1, confers an inferior overall survival (HR = 1.33, 95% CI = 1.20-1.47, P = 6.31 × 10-8). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream RPA1. Functional studies further demonstrate that RPA1 promotes the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR-1253 is identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.

Development and validation of a prognostic nomogram in gastric cancer with hepatitis B virus infection.

BACKGROUND: Patients with HBsAg-positive gastric cancer (GC) are a heterogeneous group, and it is not possible to accurately predict the overall survival (OS) in these patients. METHODS: We developed and validated a nomogram to help improve prediction of OS in patients with HBsAg-positive GC. The nomogram was established by a development cohort (n = 245), and the validation cohort included 84 patients. Factors in the nomogram were identified by univariate and multivariate Cox hazard analysis. We tested the accuracy of the nomograms by discrimination and calibration, and plotted decision curves to assess the benefits of nomogram-assisted decisions in a clinical context. Then we evaluated the risk in the two cohort. RESULTS: Significant predictors were age, tumor stage, distant metastases, gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. The nomogram had a concordance index (C-index) of 0.812 (95% CI 0.762-0.862), which was superior than the C-index of AJCC TNM Stage (0.755, 95% CI 0.702-0.808). The calibration plot in the validation cohort based on 5 predictors suggested good agreement between actual and nomogram-predicted OS probabilities. The decision curve showed that the nomogram in predicting OS is better than that of TNM staging system in all range. Moreover, patients were divided into three distinct risk groups for OS by the nomogram: low risk group, middle risk group and high risk group, respectively. CONCLUSION: This nomogram, using five pre-treatment characteristics, improves prediction of OS in patients with HBsAg-positive gastric cancer. It represents an improvement in prognostication over the current TNM stage. To generalize the use of this nomogram in other groups, additional validation with data from other institutions is required.

Development and Validation of a Prognostic Nomogram in AFP-negative hepatocellular carcinoma.

The aim of this study is to establish and validate an effective prognostic nomogram in patients with AFP-negative hepatocellular carcinoma (HCC). The nomogram was based on a primary cohort that consisted of 419 patients with clinicopathologically diagnosed with HCC, all the data was gathered from 2008 to 2014 in Sun Yat-sen University Cancer Center. All the model factors were determined by univariate and multivariate Cox hazard analysis. The concordance index (C-index) and calibration curve were used to determine the predictive accuracy and discriminative ability of the nomogram, and compared with the TNM staging systems on HCC. Internal validation was assessed. An independent validation cohort contained 150 continuous patients from 2014 to 2015. Independent factors for overall survival (OS) were body mass index (BMI), tumor stage, distant metastases, HBs Ag, lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), and albumin (ALB), which were all contained into the nomogram. The calibration curve for probability of OS showed good agreement between prediction by nomogram and actual observation. The C-index of nomogram was 0.807 (95% CI: 0.770-0.844), which was superior to the C-index of AJCC TNM Stage (0.697). The AUC was 0.809(95%CI: 0.762-0.857). In the validation cohort, the nomogram still gave good discrimination (C-index: 0.866, 95% CI: 00.796-0.936; AUC: 0.832, 95%CI: 0.747-0.917) and good calibration. Decision curve analysis demonstrated that the nomogram was clinically useful. 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. The proposed nomogram presents more accurate and useful prognostic prediction for patients with AFP-negative HCC.

A retrospective discussion of the prognostic value of combining prothrombin time(PT) and fibrinogen(Fbg) in patients with Hepatocellular carcinoma.

Aims: The levels of coagulation system tests have been studied in various cancers. In this study, our aim is to evaluate the prognostic value of pretreatment plasma coagulation tests in hepatocellular carcinoma (HCC) patients. Patient and methods: A retrospective study was performed in 539 patients with HCC, and follow-up period was at least 60 months until recurrence or death. The prognostic significance of coagulation system tests (prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen) were determined by univariate and multivariate Cox hazard models. Then, according to the results of the multivariate analyses, we proposed the coagulation-Based Stage, which combined the independent risk factors (prothrombin time and fibrinogen). Results: Coagulation system tests including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fbg) were analyzed. Patients with prolonged PT (≥12.1 sec) levels had significantly poor overall survival (OS) and disease-free survival (DFS), not only in the entire cohort (HR: 1.661, 95%CI: 1.125-2.451, p=0.011 vs. HR: 1.660, 95%CI: 1.125-2.451, p=0.011), but also in the subgroups stratified by pathological stage (stage I-II and stage III-IV). Additionally, high Fbg (≥2.83 g/L) levels experienced significantly decreased OS and DFS (HR: 2.158, 95%CI: 1.427-3.263, p<0.001 vs. HR: 2.161, 95%CI: 1.429-3.267, p<0.001), not only in the entire cohort but also in the subgroups stratified by pathological stage (stage I-II and stage III-IV). All the patients were then stratified (based on combined PT and Fbg) into three groups, The OS for HCC patients were (41.37±17.76), (31.83±19.84) and (18.68±18.41) months, and the DFS for HCC patients were (41.15±17.88), (31.65±19.81) and (18.66±18.39) months. Conclusions: Our findings suggest that the combination of plasma PT and Fbg levels should be evaluated as the valuable predictor of survival in patients with HCC.