The molecular characteristics could supplement the staging system of pT2/T3N0M0 esophageal squamous cell carcinoma: a translational study based on a cohort with over 20 years of follow-up.

OBJECTIVE: This study aimed to construct a model based on 23 enrolled molecules to evaluate prognoses of pT2/3N0M0 esophageal squamous cell carcinoma (ESCC) patients with up to 20 years of follow-up. METHODS: The lasso-Cox model was used to identify the candidate molecule. A nomogram was conducted to develop the survival model (molecular score, MS) based on the molecular features. Cox regression and Kaplan-Meier analysis were used in this study. The concordance index (C-index) was measured to compare the predicted ability between different models. The primary endpoint was overall survival (OS). RESULTS: A total of 226 patients and 23 proteins were enrolled in this study. Patients were classified into high-risk (MS-H) and low-risk (MS-L) groups based on the MS score of 227. The survival curves showed that the MS-L cohort had better 5-year and 10-year survival rates than the MS-H group (5-year OS: 51.0% vs. 8.0%; 10-year OS: 45.0% vs. 5.0%, all p < 0.001). Furthermore, multivariable analysis confirmed MS as an independent prognostic factor after eliminating the confounding factors (Hazard ratio 3.220, p < 0.001). The pT classification was confirmed to differentiate ESCC patients' prognosis (Log-rank: p = 0.029). However, the combination of pT and MS could classify survival curves evidently (overall p < 0.001), which showed that the prognostic prediction efficiency was improved significantly by the combination of the pT and MS than by the classical pT classification (C-index: 0.656 vs. 0.539, p < 0.001). CONCLUSIONS: Our study suggested an MS for significant clinical stratification of T2/3N0M0 ESCC patients to screen out subgroups with poor prognoses. Besides, the combination of pT staging and MS could predict survival more accurately for this cohort than the pT staging system alone.

Molecular docking and MD simulation studies of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as novel inhibitors targeted to CDK2/4/6.

PURPOSE: Nowadays, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been approved for treating metastatic breast cancer and have achieved inspiring curative effects. But some discoveries have indicated that CDK 4/6 are not the requisite factors in some cell types because CDK2 partly compensates for the inhibition of CDK4/6. Thus, it is urgent to design CDK2/4/6 inhibitors for significantly enhancing their potency. This study aims to explore the mechanism of the binding of CDK2/4/6 kinases and their inhibitors to design novel CDK2/4/6 inhibitors for significantly enhancing their potency in different kinds of cancers. MATERIALS AND METHODS: A series of 72 disparately functionalized 4-substituted N-phenylpyrimidin-2-amine derivatives exhibiting potent inhibitor activities against CDK2, CDK4 and CDK6 were collected to apply to this research. The total set of these derivatives was divided into a training set (54 compounds) and a test set (18 compounds). The derivatives were constructed through the sketch molecule module in SYBYL 6.9 software. A Powell gradient algorithm and Tripos force field were used to calculate the minimal structural energy and the minimized structure was used as the initial conformation for molecular docking. By the means of 3D-QSAR models, partial least squares (PLS) analysis, molecular dynamics (MD) simulations and binding free energy calculations, we can find the relationship between structure and biological activity. RESULTS: In this study, we used molecular docking, 3D-QSAR and molecular dynamics simulation methods to comprehensively analyze the interaction and structure-activity relationships of 72 new CDK2/4/6 inhibitors. We used detailed statistical data to reasonably verify the constructed 3D-QSAR models for three receptors (q2 of CDK2 = 0.714, R2pred = 0.764, q2 = 0.815; R2pred of CDK4 = 0.681, q2 = 0.757; R2pred of CDK6 = 0.674). MD simulations and decomposition energy analysis validated the reasonability of the docking results and identified polar interactions as crucial factors that influence the different bioactivities of the studied inhibitors of CDK2/4/6 receptors, especially the electrostatic interactions of Lys33/35/43 and Asp145/158/163. The nonpolar interaction with Ile10/12/19 was also critical for the differing potencies of the CDK2/4/6 inhibitors. We concluded that the following probably enhanced the bioactivity against CDK2/4/6 kinases: (1) electronegative groups at the N1-position and electropositive and moderate-sized groups at ring E; (2) electrogroups featured at R2; (3) carbon atoms at the X-position or ring C replaced by a benzene ring; and (4) an electrogroup as R4. CONCLUSION: Previous studies, to our knowledge, only utilized a single approach of 3D-QSAR and did not integrate this method with other sophisticated techniques such as molecular dynamics simulations to discover new potential inhibitors of CDK2, CDK4, or CDK6. So we applied the intergenerational technology, such as 3D-QSAR technology, molecular docking simulation techniques, molecular dynamics simulations and MMPBSA19/MMGBSA20-binding free energy calculations to statistically explore the correlations between the structure with biological activities. The constructed 3D-QSAR models of the three receptors were reasonable and confirmed by the excellent statistical data. We hope the results obtained from this work will provide some useful references for the development of novel CDK2/4/6 inhibitors.

High-risk characteristics of pathological stage I lung adenocarcinoma after resection: patients for whom adjuvant chemotherapy should be performed.

Background: The objective of the present study was to identify patients with pathologic stage I lung adenocarcinoma (LUAD) who are at high risk of recurrence and assess the efficacy of adjuvant chemotherapy (ACT) in these individuals. Methods: A retrospective study was conducted on 1504 patients with pathologic stage I LUAD who underwent surgical resection at Shanghai Pulmonary Hospital and Sun Yat-sen University Cancer Center. Cox proportional hazard regression analyses were performed to identify indicators associated with a high risk of recurrence, while the Kaplan-Meier method and Log-rank test were employed to compare recurrence-free survival (RFS) and overall survival (OS) between patients with ACT and those without it. Results: Four independent indicators, including age (≥62 years), visceral pleural invasion (VPI), predominant pattern (micropapillary/solid), and lymphovascular invasion (LVI), were identified to be significantly related with RFS. Subsequently, patients were classified into high-risk and low-risk groups by LVI, VPI, and predominant pattern. The administration of ACT significantly increased both RFS (P < 0.001) and OS (P = 0.03) in the high-risk group (n = 250). Conversely, no significant difference was observed in either RFS (P = 0.45) or OS (P = 0.063) between ACT and non-ACT patients in the low-risk group (n = 1254). Conclusions: Postoperative patients with stage I LUAD with factors such as LVI, VPI, and micropapillary/solid predominant pattern may benefit from ACT.

AMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational research.

BACKGROUND: The efficacy of monotherapy of AMG-510 is limited. This study explored whether the AMG-510 and cisplatin combination increases the anti-tumor effect in lung adenocarcinoma with the mutation of Kirsten rat sarcoma viral oncogene (KRAS) G12C. METHODS: Patients' data were used to analyze the proportion of KRAS G12C mutation. Besides, the next-generation sequencing data was used to uncover information about co-mutations. The cell viability assay, the concentration inhibiting 50% of cell viability (IC50) determination, colony formation, and cell-derived xenografts were conducted to explore the anti-tumor effect of AMG-510, Cisplatin, and their combination in vivo. The bioinformatic analysis was conducted to reveal the potential mechanism of drug combination with improved anticancer effect. RESULTS: The proportion of KRAS mutation was 2.2% (11/495). In this cohort with KRAS mutation, the proportion of G12D was higher than others. Besides, KRAS G12A mutated tumors had the likelihood of concurrent serine/threonine kinase 11 (STK11) and kelch-like ECH-associated protein 1 (KEAP1) mutations. KRAS G12C and tumor protein p53 (TP53) mutations could appear at the same time. In addition, KRAS G12D mutations and C-Ros oncogene 1 (ROS1) rearrangement were likely to be present in one tumor simultaneously. When the two drugs were combined, the respective IC50 values were lower than when used alone. In addition, there was a minimum number of clones among all wells in the drug combination. In in vivo experiments, the tumor size reduction in the drug combination group was more than twice that of the single drug group (p < 0.05). The differential expression genes were enriched in the pathways of phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling and extracellular matrix (ECM) proteoglycans compared the combination group to the control group. CONCLUSIONS: The anticancer effect of the drug combination was confirmed to be better than monotherapy in vitro and in vivo. The results of this study may provide some information for the plan of neoadjuvant therapy and the design of clinical trials for lung adenocarcinoma patients with KRAS G12C mutation.

Prediction of Long-Term Survival Outcome by Lymph Node Ratio in Patients of Parotid Gland Cancer: A Retrospective study.

Background: Lymph node ratio (LNR) has been reported to reliably predict cancer-specific survival (CSS) in parotid gland cancer (PGC). Our study was designed to validate the significance of LNR in patients with PGC. Methods: Patients diagnosed with stage I-IV PGC were enrolled from Surveillance Epidemiology and End Results database (SEER, N = 3529), which is the training group, and Sun Yat-sen University Cancer Center database (SYSUCC, N = 99), the validation group. We used X-tile software to choose the optimal cutoff value of LNR; then, univariable and multivariable analyses were performed, assessing the association between LNR and CSS. Results: The optimal cutoff value of LNR was 0.32 by X-tile based on 3529 patients from SEER. Cox proportional hazard regression analysis revealed better CSS for patients with LNR ≤ 0.32 (adjusted hazard ratio [HR] 1.612, 95% confidence interval [95% CI] 1.286-2.019; p < 0.001) compared with patients with LNR > 0.32 in SEER. In the SYSUCC cohort, patients with LNR ≤ 0.32 also had better CSS over patients with LNR > 0.32 (p < 0.001). In N2 and N3 stage groups, patients with LNR ≤ 0.32 had superior CSS outcomes over those with the LNR > 0.32 group, but this benefit was absent in the N1 stage group. Conclusions: In conclusion, the lymph node ratio turned out to be an independent prognostic factor for cancer-specific survival of PGC in this study. This valuable information could help clinicians to evaluate the prognosis of PGC and suggest that adequate lymph node dissection is necessary.

A Parsimonious Prognostic Model and Heat Map for Predicting Survival Following Adjuvant Radiotherapy in Parotid Gland Carcinoma With Lymph Node Metastasis.

OBJECTIVES: To construct a simplified prognostic risk model to predict overall survival after adjuvant radiotherapy for parotid gland carcinoma patients with stage T1-4aN1-3M0. MATERIALS AND METHODS: We evaluated 879 patients who were pathological diagnosed as stage T1-4aN1-3M0 parotid gland cancer. Those eligible patients treated with parotidectomy and neck lymph node dissection between 2004 and 2015 in the Surveillance Epidemiology and End Results database. All cases received adjuvant radiotherapy. Independent prognostic factors included in the original model were identified by Cox regression analysis. The primary endpoint was overall survival. The model's prediction power was evaluated by the concordance index. The entire cohort was categorized into new low- and high-risk groups using X-tile software according to the results of prognostic model. Kaplan-Meier method was used to depict the survival curves. And the statistical significance was determined by log-rank test. Besides, a heat map was visually described the association between the survival time and 2 most significant prognostic factors. RESULTS: In the univariable and multivariate analyses, 4 independent factors for overall survival were age, tumor size, pTNM stage, and the number of positive lymph nodes, which were all selected in the parsimonious prognostic model. The concordance indices of the prognostic model and pTNM stage were 0.652 and 0.565, respectively. Patients in the low-risk group had better overall survival over patients in the high-risk group [unadjusted hazard ratio = 2.578, 95% confidence interval 2.095-3.172, P < 0.001]. The results of the heat map revealed that patients with smaller tumor size and fewer positive lymph nodes had much longer survival time. CONCLUSIONS: This parsimonious prognostic model could estimate the long-term survival after adjuvant radiotherapy for parotid gland carcinoma with stage T1-4aN1-3N0M0. The tools may be valuable to guide multidisciplinary team in making treatment decisions.

A Nomogram to Predict Long-Term Survival Outcomes of Patients Who Undergo Pneumonectomy for Non-small Cell Lung Cancer With Stage I-IIIB.

Background: In this study, we aim to establish a nomogram to predict the prognosis of non-small cell lung cancer (NSCLC) patients with stage I-IIIB disease after pneumonectomy. Methods: Patients selected from the Surveillance, Epidemiology, and End Results (SEER, N = 2,373) database were divided into two cohorts, namely a training cohort (SEER-T, N = 1,196) and an internal validation cohort (SEER-V, N = 1,177). Two cohorts were dichotomized into low- and high-risk subgroups by the optimal risk prognostic score (PS). The model was validated by indices of concordance (C-index) and calibration plots. Kaplan-Meier analysis and the log-rank tests were used to compare survival curves between the groups. The primary observational endpoint was cancer-specific survival (CSS). Results: The nomogram comprised six factors as independent prognostic indictors; it significantly distinguished between low- and high-risk groups (all P < 0.05). The unadjusted 5-year CSS rates of high-risk and low-risk groups were 33 and 60% (SEER-T), 34 and 55% (SEER-V), respectively; the C-index of this nomogram in predicting CSS was higher than that in the 8th TNM staging system (SEER-T, 0.629 vs. 0.584, P < 0.001; SEER-V, 0.609 vs. 0.576, P < 0.001). In addition, the PS might be a significant negative indictor on CSS of patients with white patients [unadjusted hazard ration (HR) 1.008, P < 0.001], black patients (unadjusted HR 1.007, P < 0.001), and Asian or Pacific Islander (unadjusted HR 1.008, P = 0.008). In cases with squamous cell carcinoma (unadjusted HR 1.008, P < 0.001) or adenocarcinoma (unadjusted HR 1.008, P < 0.001), PS also might be a significant risk factor. Conclusions: For post-pneumonectomy NSCLC patients, the nomogram may predict their survival with acceptable accuracy and further distinguish high-risk patients from low-risk patients.

Stratification of Patients With Stage IB NSCLC Based on the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging Manual.

Objective: To assess the postoperative prognosis of patients with stage IB non-small cell lung cancer (NSCLC), using a prognostic model (PM). Methods: Patients with stage IB of NSCLC from the two academic databases {the Surveillance, Epidemiology, and End Results [SEER-A, N = 1,746 (training cohort)], Sun Yat-sen University Cancer Center [SYSUCC, N = 247 (validation cohort)], and SEER-B (N = 1,745)} who had undergone lung surgery from 2001 to 2015 were enrolled. The primary clinical endpoint was cancer-specific survival (CSS). Covariate inclusion of prognostic indicators was carried out using a multivariable two-sided P < 0.05. We identified and integrated significant prognostic factors for survival in the training cohort to build a model that could be validated in the validation cohort. We used univariate analysis to evaluate the utilized ability of PM in the different races/ethnicities. Results: CSS discrimination in the PM was comparable in both the training and validation cohorts [C index = 0.66(SEER-A), 0.67(SYSUCC), and 0.61(SEER-B), respectively]. Discretization with a fixed PM cutoff of 291.5 determined from the training dataset yielded low- and high-risk subgroups with disparate CSS in the validation cohort (training cohort: hazard ratio [HR] 2.724, 95% confidence intervals [CI], 2.074-3.577; validation cohort: SEER-B HR 1.679, 95% CI, 1.310-2.151, SYSUCC HR 3.649, 95% CI 2.203-6.043, all P < 0.05). Our five-factor PM was able to predict CSS; 48-month CSS was 87% in the low-risk subgroup vs. 69% in the high-risk subgroup for the training cohort, while in the validation cohort, they were 80 vs. 73%(SEER-B) and 84 vs. 60% (SYSUCC), respectively. In addition, the results showed that PM with all unadjusted HR > 1 was a significant risk prognostic indictor in white men (P < 0.001), Chinese people (P < 0.001), and other races (P = 0.012). Conclusion: We established and validated a PM that may predict CSS for patients with IB NSCLC in different races/ethnicities, and thus, help clinicians screen subgroups with poor prognosis. In addition, further prospective studies and more cases from different regions are necessary to confirm our findings.

Expression of PD-1/PD-L1 in head and neck squamous cell carcinoma and its clinical significance.

OBJECTIVE: To investigate the role of programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and P16 in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: A total of 95 paraffin-embedded samples of tumorous tissue of HNSCC were collected. Expression levels of PD-1, PD-L1, and P16 were determined by immunohistochemistry. RESULTS: A significantly higher proportion of PD-1 among patients infected with the human papillomavirus was found. PD-L1 expression is closely associated with the primary site of the tumor, postoperative recurrence, survival, PD-1 expression and P16 expression. Univariable analysis indicated that T stage, N stage, tumor node metastasis stage, tumor differentiation, and PD-L1 expression were all shown to be prognostic variables for overall survival in patients with HNSCC. In the multivariate analysis, only N stage (P = 0.010) and PD-L1 expression (P = 0.001) were found to be independent prognostic variables for overall survival. In addition, for disease recurrence, multivariate analysis showed that only PD-L1 expression was the associated independent risk factor. For the patients with negative PD-L1 expression, Kaplan-Meier analysis revealed that they had significantly worse outcomes in terms of overall survival (P = 0.001). Similarly, compared with the patients with positive PD-L1 expression, those with negative PD-L1 expression had a higher probability of recurrence (P = 0.026). CONCLUSIONS: The expression of PD-L1, PD-1, and P16 in HNSCC is significantly correlated. Human papillomavirus infection (P16 positive) is negatively related to postoperative recurrence. HNSCC patients with positive PD-L1/PD-1 expression tend to have better overall survival outcomes and lower probability of recurrence, providing more evidence for the PD-l-targeted immunotherapy of HNSCC.