Bromodomain and extraterminal (BET) proteins: biological functions, diseases, and targeted therapy.

BET proteins, which influence gene expression and contribute to the development of cancer, are epigenetic interpreters. Thus, BET inhibitors represent a novel form of epigenetic anticancer treatment. Although preliminary clinical trials have shown the anticancer potential of BET inhibitors, it appears that these drugs have limited effectiveness when used alone. Therefore, given the limited monotherapeutic activity of BET inhibitors, their use in combination with other drugs warrants attention, including the meaningful variations in pharmacodynamic activity among chosen drug combinations. In this paper, we review the function of BET proteins, the preclinical justification for BET protein targeting in cancer, recent advances in small-molecule BET inhibitors, and preliminary clinical trial findings. We elucidate BET inhibitor resistance mechanisms, shed light on the associated adverse events, investigate the potential of combining these inhibitors with diverse therapeutic agents, present a comprehensive compilation of synergistic treatments involving BET inhibitors, and provide an outlook on their future prospects as potent antitumor agents. We conclude by suggesting that combining BET inhibitors with other anticancer drugs and innovative next-generation agents holds great potential for advancing the effective targeting of BET proteins as a promising anticancer strategy.

Metastatic lymph nodes and prognosis assessed by the number of retrieved lymph nodes in gastric cancer.

BACKGROUND: The prognostic value of quantitative assessments of the number of retrieved lymph nodes (RLNs) in gastric cancer (GC) patients needs further study. AIM: To discuss how to obtain a more accurate count of metastatic lymph nodes (MLNs) based on RLNs in different pT stages and then to evaluate patient prognosis. METHODS: This study retrospectively analyzed patients who underwent GC radical surgery and D2/D2+ LN dissection at the Cancer Hospital of Harbin Medical University from January 2011 to May 2017. Locally weighted smoothing was used to analyze the relationship between RLNs and the number of MLNs. Restricted cubic splines were used to analyze the relationship between RLNs and hazard ratios (HRs), and X-tile was used to determine the optimal cutoff value for RLNs. Patient survival was analyzed with the Kaplan-Meier method and log-rank test. Finally, HRs and 95% confidence intervals were calculated using Cox proportional hazards models to analyze independent risk factors associated with patient outcomes. RESULTS: A total of 4968 patients were included in the training cohort, and 11154 patients were included in the validation cohort. The smooth curve showed that the number of MLNs increased with an increasing number of RLNs, and a nonlinear relationship between RLNs and HRs was observed. X-tile analysis showed that the optimal number of RLNs for pT1-pT4 stage GC patients was 26, 31, 39, and 45, respectively. A greater number of RLNs can reduce the risk of death in patients with pT1, pT2, and pT4 stage cancers but may not reduce the risk of death in patients with pT3 stage cancer. Multivariate analysis showed that RLNs were an independent risk factor associated with the prognosis of patients with pT1-pT4 stage cancer (P = 0.044, P = 0.037, P = 0.003, P < 0.001). CONCLUSION: A greater number of RLNs may not benefit the survival of patients with pT3 stage disease but can benefit the survival of patients with pT1, pT2, and pT4 stage disease. For the pT1, pT2, and pT4 stages, it is recommended to retrieve 26, 31 and 45 LNs, respectively.

Changing trends of clinicopathologic features and survival duration after surgery for gastric cancer in Northeast China.

BACKGROUND: Through analyzing the data from a single institution in Northeast China, this study revealed the possible clinicopathologic characteristics that influence the prognosis of patients with gastric cancer (GC). AIM: To evaluate the changing trends of clinicopathologic features and survival duration after surgery in patients with GC in Northeast China, which is a high-prevalence area of GC. METHODS: The study analyzed the difference in clinicopathologic features and survival duration after surgery of 5887 patients who were histologically diagnosed with GC at the Harbin Medical University Cancer Hospital. The study mainly analyzed the data in three periods, 2000 to 2004 (Phase 1), 2005 to 2009 (Phase 2), and 2010 to 2014 (Phase 3). RESULTS: Over time, the postoperative survival rate significantly increased from 2000 to 2014. In the past 15 years, compared with Phases 1 and 2, the tumor size was smaller in Phase 3 (P < 0.001), but the proportion of high-medium differentiated tumors increased (P < 0.001). The proportion of early GC gradually increased from 3.9% to 14.4% (P < 0.001). A surprising improvement was observed in the mean number of retrieved lymph nodes, ranging from 11.4 to 27.5 (P < 0.001). The overall 5-year survival rate increased from 24% in Phase 1 to 43.8% in Phase 3. Through multivariate analysis, it was found that age, tumor size, histologic type, tumor-node-metastasis stage, depth of invasion, lymph node metastasis, surgical approach, local infiltration, radical extent, number of retrieved lymph nodes, and age group were independent risk factors that influenced the prognosis of patients with GC. CONCLUSION: The clinical features of GC in Northeast China changed during the observation period. The increasing detection of early GC and more standardized surgical treatment effectively prolonged lifetimes.

Prognostic significance of Borrmann type combined with vessel invasion status in advanced gastric cancer.

BACKGROUND: Borrmann classification (types I-IV) for the detection of advanced gastric cancer has been accepted worldwide, and lymphatic and/or blood vessel invasion (LBVI) status is related to the poor prognosis after gastric cancer. AIM: To evaluate the significance of Borrmann type combined with LBVI status in predicting the prognosis of advanced gastric cancer. METHODS: We retrospectively studied the clinicopathological characteristics and long-term survival data of 2604 patients who were diagnosed with advanced gastric adenocarcinoma at Harbin Medical University Cancer Hospital from January 2009 to December 2013. Categorical variables were evaluated by the Pearson's χ 2 test, the Kaplan-Meier method was used to identify differences in cumulative survival rates, and the Cox proportional hazards model was used for multivariate prognostic analysis. RESULTS: A total of 2604 patients were included in this study. The presence of LVBI [LBVI (+)] and Borrmann type (P = 0.001), tumor location (P < 0.001), tumor size (P < 0.001), histological type (P < 0.001), tumor invasion depth (P < 0.001), number of metastatic lymph nodes (P < 0.001), and surgical method (P < 0.001) were significantly correlated with survival. When analyzing the combination of the Borrmann classification and LBVI status, we found that patients with Borrmann type III disease and LBVI (+) had a similar 5-year survival rate to those with Borrmann IV + LBVI (-) (16.4% vs 13.1%, P = 0.065) and those with Borrmann IV + LBVI (+) (16.4% vs 11.2%, P = 0.112). Subgroup analysis showed that the above results were true for any pT stage and any tumor location. Multivariate Cox regression analysis showed that Borrmann classification (P = 0.023), vascular infiltration (P < 0.001), tumor size (P = 0.012), pT stage (P < 0.001), pN stage (P < 0.001), and extent of radical surgery (P < 0.001) were independent prognostic factors for survival. CONCLUSION: Since patients with Borrmann III disease and LBVI (+) have the same poor prognosis as those with Borrmann IV disease, more attention should be paid to patients with Borrmann III disease and LBVI (+) during diagnosis and treatment, regardless of the pT stage and tumor location, to obtain better survival results.