The MDM2 protein encoded by the mouse double minute 2 (MDM2) gene is the primary negative regulatory factor of the p53 protein. MDM2 can ligate the p53 protein via its E3 ubiquitin ligase, and the ubiquitinated p53 can be transferred to the cytoplasm and degraded by proteasomes. Therefore, MDM2 can maintain the stability of p53 signaling pathway. MDM2 amplification has been detected in many human malignancies, including lung cancer, colon cancer and other malignancies. MDM2 overexpression is associated with chemotherapeutic resistance in human malignancies. The mechanisms of chemotherapeutic resistance by MDM2 overexpression mainly include the p53–MDM2 loop-dependent and p53–MDM2 loop-independent pathways. But the role of MDM2 overexpression in tyrosine kinase inhibitors resistance remains to be further study. This paper reviews the possible mechanisms of therapeutic resistance of malignancies induced by MDM2 amplification and overexpression, including chemotherapy, radiotherapy, targeted agents and hyperprogressive disease of immunotherapy. Besides, MDM2-targeted therapy may be a potential new strategy for treating advanced malignancies.

Background: IBM Watson for Oncology (WFO), which can use natural language processing to evaluate data in structured and unstructured formats, has begun to be used in China. It provides physicians with evidence-based treatment options and ranks them in three categories for treatment decision support. This study was designed to examine the concordance between the treatment recommendation proposed by WFO and actual clinical decisions by oncologists in our cancer center, which would reflect the differences of cancer treatment between China and the U.S. Patients and Methods: Retrospective data from 362 patients with cancer were ingested into WFO from April 2017 to October 2017. WFO recommendations were provided in three categories: recommended, for consideration, and not recommended. Concordance was analyzed by comparing the treatment decisions proposed by WFO with those of the multidisciplinary tumor board. Concordance was achieved when the oncologists' treatment decisions were in the recommended or for consideration categories in WFO. Results: Ovarian cancer showed the highest concordance, which was 96%. Lung cancer and breast cancer obtained a concordance of slightly above 80%. The concordance of rectal cancer was 74%, whereas colon cancer and cervical cancer showed the same concordance of 64%. In particular, the concordance of gastric cancer was very low, only 12%, and 88% of cases were under physicians choice. Conclusion: Different cancer types showed different concordances, and only gastric cancers were significantly less likely to be concordant. Incidence and pharmaceuticals may be the major cause of discordance. To be comprehensively and rapidly applied in China, WFO needs to accelerate localization. ClinicalTrials.gov Identifier: NCT03400514.

Background: The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non–small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments. Methods: Eligible studies were identified by searching the online databases PubMed, Embase, Medline, The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: In total, 15 studies with 1342 patients were included for final analysis. Overall, concurrent TP53 mutation was associated with unfavorable progression-free survival (PFS) (HR = 1.88, 95%CI: 1.59–2.23, p < 0.001, I² = 0.0%, P = 0.792) and overall survival (OS) (HR = 1.92, 95%CI: 1.55–2.38, p < 0.001, I² = 0.0%, P = 0.515). Subgroup analysis based on type of targeted therapy (EGFR-TKIs or ALK-TKIs, pathological type of cancer (adenocarcinoma only or all NSCLC subtypes) and line of treatment (first-line only or all lines) all showed that TP53 mutations was associated with shorter survivals of patients with EGFR-TKIs or ALK-TKIs treatments. Particularly, in patients with first-line EGFR-TKIs treatment, significantly poorer prognosis was observed in patients with TP53 concurrent mutations (pooled HR for PFS: 1.69, 95% CI 1.25–2.27, P < 0.001, I² = 0.0%, P = 0.473; pooled HR for OS: 1.94, 95% CI 1.36–2.76, P < 0.001, I² = 0.0%, P = 0.484). Begg’s funnel plots and Egger’s tests indicated no significant publication bias in this study. Conclusions: This meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced NSCLC.

Colorectal cancer (CRC) is a growing health problem throughout the world. Strong evidences have supported that gut microbiota can influence tumorigenesis; however, little is known about what happens to gut microbiota following surgical resection. Here, we examined the changes of gut microbiota in CRC patients after the surgical resection. Using the PCoA analysis and dissimilarity tests, the microbial taxonomic compositions and diversities of gut microbiota in post-surgery CRC patients (A1) were significantly different from those in pre-surgery CRC patients (A0) and healthy individuals (H). Compared with A0 and H, the Shannon diversity and Simpson diversity were significantly decreased in A1 (P < 0.05). Based on the LEfSe analysis, the relative abundance of phylum Proteobacteria in A1 was significantly increased than that in A0 and H. The genus Klebsiella in A1 had higher proportions than that in A0 (P < 0.05). Individual variation was distinct; however, 90% of CRC patients in A1 had more abundances of Klebsiella than A0. The Klebsiella in A1 was significantly associated with infectious diseases (P < 0.05), revealed by the correlation analysis between differentiated genera and metabolic pathway. The Klebsiella (Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae) in A1 was significantly linked with lymphatic invasion (P < 0.05). Furthermore, the PCA of KEGG pathways indicated that gut microbiota with a more scattered distribution in A1 was noticeably different from that in A0 and H. The nodes, the links, and the kinds of phylum in each module in A1 were less than those in A0 and H, indicating that gut microbiota in A1 had a relatively looser ecologcial interaction network. To sum up, this pilot study identified the changes of gut microbiota in post-surgery CRC patients, and highlights future avenues in which the gut microbiota is likely to be of increasing importance in the care of surgical patients.

Purpose: The study investigated the impact of TP53 mutations on the clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors (TKIs) in Chinese patients with advanced or recurrent non-small-cell lung cancer (NSCLC). Patients and methods: Tissues from 163 NSCLC patients at the Affiliated Hospital of Qingdao University were analyzed by next-generation sequencing (NGS) to determine the mutational status of EGFR and concurrent genetic alterations. TP53 mutations were evaluated in relation to baseline patient characteristics and treatment outcomes (progression-free survival [PFS], overall survival [OS], objective response rate [ORR] and disease control rate [DCR]). Results: Among 163 patients with advanced NSCLC, 77 were identified as EGFR-mutant (47.2%). Six patients who did not receive TKI treatment were excluded. Among the remaining 71 patients with EGFR genetic alterations, the frequency of pathogenic TP53 mutations was 60.6% (43/71), while other concurrent mutations were rare events. Markedly shorter median PFS (mPFS) (6.5 versus 14.0 months, P=0.025) and median OS (mOS) (28.0 versus 52.0 months, P=0.023) were observed in TP53-mut patients than in TP53-wt controls. The overall DCR and ORR of TP53-mutant patients were both lower than those of the TP53-wt cases (DCR: 76.7% versus 89.3%, P=0.160; ORR: 25% versus 28%, P=0.374). Differences in prognosis were significant, especially in the subgroup of patients with TP53 non-missense mutations, non-disruptive mutations, mutations in exon 6, mutations in exon 7 and mutations in the non-DBD region among all TP53 mutations. Conclusion: TP53 mutations reduce responsiveness to TKIs and worsen the prognosis of EGFR-mutant NSCLC patients, especially for those with non-missense mutations and non-disruptive mutations, as well as mutations in exon 6, exon 7 and non-DBD region, thus acting as an independent predictor of poor outcome in advanced NSCLC patients treated with first-generation TKI therapy. Our study also suggests that TP53 mutation might be involved in primary resistance to EGFR-TKIs in Chinese NSCLC patients.