Intratumoral heterogeneity is the main cause of tumor treatment failure, varying across disease sites (spatial heterogeneity) and polyclonal properties of tumors that evolve over time (temporal heterogeneity). As our understanding of intratumoral heterogeneity, the formation of which is mainly related to the genomic instability, epigenetic modifications, plastic gene expression, and different microenvironments, plays a substantial role in drug-resistant as far as tumor metastasis and recurrence. Understanding the role of intratumoral heterogeneity, it becomes clear that a single therapeutic agent or regimen may only be effective for subsets of cells with certain features, but not for others. This necessitates a shift from our current, unchanging treatment approach to one that is tailored against the killing patterns of cancer cells in different clones. In this review, we discuss recent evidence concerning global perturbations of intratumoral heterogeneity, associations of specific intratumoral heterogeneity in lung cancer, the underlying mechanisms of intratumoral heterogeneity potentially leading to formation, and how it drives drug resistance. Our findings highlight the most up-to-date progress in intratumoral heterogeneity and its role in mediating tumor drug resistance, which could support the development of future treatment strategies.

The levels of liver function tests (LFTs) are often used to assess liver injury and non-liver disease-related mortality. In our study, the relationship between pretreatment serum LFTs and overall survival (OS) was evaluated in esophageal squamous cell carcinoma (ESCC) patients. Our purpose was to investigate the prognostic value of the preoperative alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio and gamma glutamyltransferase (GGT) in ESCC patients. A retrospective study was performed in 447 patients with ESCC, and follow-up period was at least 60 months until death. The prognostic significance of serum LFTs were determined by univariate and multivariate Cox hazard models. LFTs including ALT, AST, LSR, GGT, TBA and LDH were analyzed. Serum LSR (HR: 0.592, 95% CI = 0.457–0.768, p < 0.001 and GGT (HR: 1.507, 95% CI = 1.163–1.953, p = 0.002) levels were indicated as significant predictors of OS. The 5-year OS among patients with higher LSR levels was longer compared with those patients with decreased LSR levels, not only in the whole cohort but also in the subgroups stratified by pathological stage (T1–T2 subgroup, T3–T4 subgroup, N0 subgroup and M0 subgroup). We also found that patients with a higher GGT might predict worse OS than patients with a normal GGT, not only in the whole cohort but also in the subgroups stratified by pathological stage (T3–T4 subgroup and N1-N2 subgroup). Both increased levels of LSR and decreased levels of GGT might predict shorter overall survival in ESCC patients. Our findings suggest that serum LSR and GGT levels could be used as a key predictor of survival in patients with ESCC.

Background and Objective: Tools for the non-invasive assessment of colorectal cancer (CRC) prognosis have profound significance. Although plasma coagulation tests have been investigated in a variety of tumours, the prognostic value of the prothrombin time (PT) and activated partial thromboplastin time (APTT) in CRC has not been discussed. Our study objective was to explore the prognostic significance of preoperative PT and APTT in CRC patients. Patients and Methods: A retrospective analysis of preoperative coagulation indexes including PT, PTA, INR, APTT, FIB, TT, PLT, NLR and PLR in 250 patients with CRC was performed. Kaplan–Meier and multivariate Cox regression analysis were used to demonstrate the prognostic value of these preoperative coagulation indexes. Results: The overall survival (OS, p< 0.05) and disease-free survival (DFS, p< 0.05) of CRC patients with lower PT and APTT levels were significantly prolonged. Based on univariate analysis, PT levels (p< 0.001, p< 0.001), PTA levels (p=0.001, p=0.001), APTT levels (p=0.001, p< 0.001), INR levels (p< 0.001, p< 0.001), fibrinogen levels (p=0.032, p=0.036), tumour status (p=0.005, p=0.003), nodal status (p< 0.001, p< 0.001), metastasis status (p< 0.001, p< 0.001) and TNM stages (p< 0.001, p< 0.001) were remarkably associated with DFS and OS. Multivariate Cox regression analysis suggested that the levels of PT (HR: 2.699, p=0.006) and APTT (HR: 1.942, p=0.015), metastasis status (HR: 2.091, p= 0.015) and TNM stage (HR: 7.086, p=0.006) were independent predictors of survival in CRC. In the whole cohort, the enrolled patients were then divided into three groups according to their PT and APTT levels. The OS and DFS differed notably among the low-risk (PT< 11.85 sec and APTT< 25.85 sec), medium-risk (PT≥ 11.85 sec or APTT≥ 25.85 sec), and high-risk (PT≥ 11.85 sec and APTT≥ 25.85 sec) groups. Conclusion: Elevated levels of preoperative PT and APTT were predictors of poor outcomes in CRC patients. Moreover, the combination of preoperative PT and APTT can be a new prognostic stratification approach for more precise clinical staging of CRC.

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. 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. 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. 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.

Background: Prognostic assessment is crucial for optimal treatment. The aim of our study was to investigate the potential impact of estrogen receptor-α (ER-α) and progesterone receptor (PR) on the prognosis of colorectal cancer (CRC) patients who received curative resection. Methods: Retrospective evaluation of two independent cohorts of CRC patients maintained prospectively in 2009–2010 (training set) (n = 148) and 2007–2009 (internal validation set) (n = 485). Furthermore, we used an external independent CRC cohort from The Cancer Genome Atlas (TCGA) (n = 511) for further validation. ER-α and PR expression as well as other potential prognostic factors were retrospectively evaluated in training set with respect to overall survival (OS), local relapse free survival (LRFS) and distant metastasis free survival (DMFS). The prognostic factors found in training set will be validated in two validation cohorts. Results: On univariate analysis for the training set, OS, LRFS and DMFS were not associated with PR expression. While patients with ER-αexpression were found to have poor prognosis. In addition, multivariate analysis showed that ER-αexpression maintained significance with respect to OS (HR, 5.06; p = 0.002), LRFS (HR, 8.81; p = 0.002) and DMFS (HR, 8.07; p = 0.004). Similarly, ER-α expression showed prognostic significance with respect to OS with hazard ratios (HRs) of 1.572 (95% CI: 1.001–2.467, p = 0.049) and 1.624 (95% CI: 1.047–2.520, p = 0.031) for the internal and external validation cohort, respectively. Conclusion: ER-α expression was a biomarker of poor prognosis and it might inform treatment decision for high risk CRC patients. However, PR expression was not associated with survival outcomes.

Noninvasive tools for the prognosis of α-fetoprotein negative hepatocellular carcinoma (HCC) are urgently needed. The present study proposed a prognostic system based on preoperative plasma prothrombin time and fibrinogen (PT/Fbg system). With respect to α-fetoprotein (AFP)-negative HCC, we compared the prognostic value in PT/Fbg system, Glasgow Prognostic Score, and aminotransferase/aspartate aminotransferase ratio. The present study retrospectively analyzed patient characteristics, clinicopathological factors, and the level of pretreatment biomarkers in 628 patients with HCC. Patients with increased PT and Fbg levels were allocated a score of 2, patients with only one of these abnormalities were assigned score 1, and patients with neither of these abnormalities were allocated a score of 0. The following distributions of the PT/Fbg system scores were observed: 187 (29.78%) patients had a score of 0, 305 (30.65%) had a score of 1, and 134 (22.69%) patients had a preoperative score of 2. The prognostic significance of the PT/Fbg system was determined using univariate and multivariate Cox hazard analyses in AFP-negative HCC. Multivariate analysis revealed that patients with a higher PT/Fbg system exhibited worse overall survival (OS) than patients with a lower PT/Fbg system. Our study proposes preoperative evaluation of the plasma PT/Fbg system to predict the OS of patients with AFP-negative HCC.