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Background Osimertinib demonstrates superior efficacy in patients with non-small cell lung cancer (NSCLC) who acquired EGFR T790M mutation as resistant mechanism to upfront EGFR tyrosine kinase inhibitors (TKIs). Not all the T790M-positive tumors are homogeneously sensitive to osimertinib, however, and the duration of response often varies. Previous studies suggest that loss of T790 M at osimertinib resistance is correlated with shortened survival benefit of osimertinib. The aim of this study is to investigate the prevalence of T790 M loss after progression to osimertinib in Chinese patients with NSCLC harboring EGFR T790 M mutation and to compare their clinical outcomes and characteristics when stratified by T790 M mutational status at osimertinib resistance. Patients and methods All patients with a secondary T790 M mutation after progression to prior-line EGFR TKIs and received single-agent osimertinib were reviewed. The patients who were reassessed for T790 M mutation post-osimertinib resistance were included in final analysis. Detailed clinicopathologic characteristics and response data were collected. Results Of the patients with confirmed T790 M mutation as acquired resistance to early-generation EGFR TKIs and subsequently received single-agent osimertinib, 84 patients experienced clinical progression after osimertinib treatment and were eligible for analysis. Among them, 31 patients underwent repeated T790 M mutation testing on osimertinib resistance. Sixteen patients had maintained T790 M mutation, whereas 15 patients lost T790 M at resistance. Loss of T790 M at resistance was remarkably correlated with shorter duration of response to osimertinib (P = 0.0005). Furthermore, the overall survival after osimertinib treatment was also decreased in T790M-loss group (P=0.021). The objective response rates were comparable between T790M-maintain and T790M-loss group (31.3% and 26.7%, respectively). In multivariate analysis, loss of T790M remained statistically associated with early progression to osimertinib. Conclusion Loss of T790 M mutation at resistance was correlated with early progression and overall survival in response to osimertinib treatment in Chinese patients with NSCLC harboring acquired T790 M mutation.

Gut microbiome plays a dominant role in modulating therapeutic efficacy of immune checkpoint inhibitors (ICIs) targeting the programmed cell death receptor/ligand-1 (PD-1/PD-L1) pathway, suggesting that co-administration of antibiotics (Abx), which might result in dysbacteriosis, can attenuate the clinical outcomes of ICIs. The current study aimed to investigate the predictive role of Abx on ICIs treatment in patients with advanced non-small cell lung cancer (NSCLC). The impact of proton pump inhibitors (PPIs), another medication that can induce dysbacteriosis, was also investigated.We retrospectively reviewed the medical records of eligible patients who received anti-PD-1-based therapies in our hospital. Tumor responses, patients' survival, the incidence of immune-related adverse events (irAEs) and other baseline variables were examined. The application of Abx or PPIs treatment were also collected. Clinical outcomes and clinicopathologic features were compared according to the status of Abx or PPIs co-administration.A total of 109 patients were included. Of them, 20 (18.3%) patients were categorized in Abx-treated group. No major difference in baseline characteristics was observed between Abx-treated and -untreated groups. Concomitant Abx treatment was significantly associated with shorter progression-free survival (PFS) (p 0.0001) and overall survival (OS) (p = 0.0021). And primary disease progression tended to increase in Abx-treated group (p = 0.092). Yet, the occurrence and grades of irAEs were comparable between two groups. In multivariable analysis, Abx treatment was markedly associated with worse PFS (HR=0.32, 95%CI 0.18-0.59, p 0.0001) and OS (HR=0.35, 95%CI 0.16-0.77, p = 0.009). Regarding the use of PPIs, no significant difference was observed in clinical outcomes between the patients with or without concomitant PPIs treatment.Abx treatment was significantly associated with attenuated clinical outcomes derived from anti-PD-1-based ICIs in a Chinese cohort of patients with advanced NSCLC.

Background Although EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC), responses vary within individuals. The current study aimed to investigate whether serum levels of several cytokines and their dynamic changes during TKI treatment could be used to predict the efficacy of EGFR-TKIs. Materials and methods Pre-treatment and one-month post-treatment serum levels of hepatocyte growth factor (HGF), interleukin-10 (IL-10), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), interferon gamma (IFN-γ) and monocyte chemotactic protein-1 (MCP-1) were measured using enzyme-linked immunosorbent assay and U-plex biomarker group assays in patients with EGFR-mutant NSCLC received first-line EGFR-TKIs. Results Patients who had lower baseline serum levels of IL-6 had better object response rate (ORR) than those with high levels (74.2% vs 42.9%, p = 0.014). PFS was significantly longer in patients with low baseline level of IL-6 (19.57 vs. 13.73 months, p = 0.003) and in those with reduced serum VEGF and HGF levels after treatment (20.30 vs. 14.33 months, p = 0.009; 22.77 vs. 14.33 months, p = 0.002; respectively). Multivariate analyses showed that lower baseline serum IL-6 level was significantly associated with longer PFS (HR = 0.469, p = 0.022) and OS (HR = 0.181, p = 0.004). Reduction of serum VEGF and HGF levels after treatment was associated with significantly longer PFS (HR = 0.447, p = 0.017; HR = 0.365, p = 0.003; respectively). Lower pre-treatment serum VEGF level was associated with dramatically longer OS (HR = 0.277, p = 0.018). Conclusions Our study suggested that serum levels of HGF, IL-6 and VEGF and its dynamic change during TKI treatment could be used to predict the efficacy of EGFR-TKIs treatment in patients with EGFR-mutant NSCLC.

AIMS The protein expression of programmed death-ligand 1 (PD-L1) has been recognised as being a biomarker for poor prognosis in diffuse large B-cell lymphoma (DLBCL). The aims of this study were to determine PD-L1 DNA status and mRNA status, and to explore whether they contribute to protein expression and their clinicopathological correlation in DLBCL. METHODS AND RESULTS In this study, we used fluorescence in-situ hybridisation, RNA in-situ hybridisation and immunohistochemistry to determine PD-L1 status at three different levels in 287 DLBCL samples with follow-up. Their correlation and clinical pathological relevance were also analysed. Our results showed that 1.7% (3/175) of patients had PD-L1 DNA amplification, 19.9% (57/287) had high PD-L1 mRNA expression, and 11.8% (34/287) had high PD-L1 protein expression. Both mRNA and protein expression of PD-L1 were significantly higher in non-germinal centre B-cell-like (GCB) DLBCL than in GCB DLBCL (P

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Some histone deacetylases (HDACs) promote tumor cell growth and pan- or selective HDAC inhibitors are active in some cancers; however, the pivotal HDAC enzyme and its functions in human diffuse large B-cell lymphoma (DLBCL) remain largely unknown. Using NanoString nCounter assays, we profiled HDAC mRNA expression and identified HDAC6 as an upregulated HDAC family member in DLBCL tissue samples. We then found that HDAC6 plays an oncogenic role in DLBCL, as evidenced by its promotion of cell proliferation in vitro and tumor xenograft growth in vivo. Mechanistically, the interaction between HDAC6 and HR23B downregulated HR23B expression, thereby reducing the levels of casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin ligase for hepatocyte growth factor receptor (MET), which resulted in the inhibition of MET ubiquitination-dependent degradation. In addition, enhanced HDAC6 expression and decreased HR23B expression were correlated with poor overall survival rates among patients with DLBCL. Taken together, these results establish an HDAC6-HR23B-MET axis and indicate that HDAC6 is a potent promoter of lymphomagenesis in DLBCL. Thus, a therapeutic strategy based on HDAC6 inhibitors in combination with MET inhibitors is promising. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.

The lack of response to treatment in most lung cancer patients suggests the value of broadening the benefit of anti–PD-1/PD-L1 monotherapy. Judicious dosing of antiangiogenic agents such as apatinib (VEGFR2-TKI) can modulate the tumor immunosuppressive microenvironment, which contributes to resistance to anti–PD-1/PD-L1 treatment. We therefore hypothesized that inhibiting angiogenesis could enhance the therapeutic efficacy of PD-1/PD-L1 blockade. Here, using a syngeneic lung cancer mouse model, we demonstrated that low-dose apatinib alleviated hypoxia, increased infiltration of CD8+ T cells, reduced recruitment of tumor-associated macrophages in tumor and decreased TGFβ amounts in both tumor and serum. Combining low-dose apatinib with anti–PD-L1 significantly retarded tumor growth, reduced the number of metastases, and prolonged survival in mouse models. Anticancer activity was evident after coadministration of low-dose apatinib and anti–PD-1 in a small cohort of patients with pretreated advanced non–small cell lung cancer. Overall, our work shows the rationale for the treatment of lung cancer with a combination of PD-1/PD-L1 blockade and low-dose apatinib.

We performed this retrospective study to investigate whether the KRAS mutation status and its subtypes could predict the effect of first-line platinum-based chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC). Patients received who had KRAS mutations were enrolled. Correlations between KRAS mutations, specific mutant subtypes and responses to chemotherapy were analyzed using Kaplan-Meier and Cox proportional hazard methods. A total of 2,183 cases who received KRAS mutation detection were included. A total of 218 of these cases were indicated to have KRAS mutations. KRAS mutations were identified more commonly in males compared with females (P=0.035). The most common subtypes were G12C, G12D and G12V. Among 73 KRAS mutant patients and 100 EGFR/ALK/KRAS wild-type patients with advanced NSCLC, KRAS-mutant NSCLC patients had a significantly shorter progression-free survival (P=0.007) compared with NSCLC patients with KRAS wild-type. In addition, there was a shorter but marginally statistically significant progression-free survival (PFS) in KRAS mutant patients with adenocarcinoma compared with those with non-adenocarcinoma (P=0.051). In the KRAS mutant group, patients with the KRAS G12V mutation had the poorest PFS compared with non-G12V mutant cases (P=0.045). In conclusion, KRAS mutation was a negative predictive factor of PFS in Chinese patients with advanced NSCLC who received first platinum-based chemotherapy. Patients with KRAS G12V mutations exhibited the poorest PFS compared with those with other KRAS mutant types.

To investigate the prognostic value of PD‐L1 expression combined with CD8+ TILs density in patients with resected NSCLC and correlations with clinicopathological features. We retrospectively enrolled 178 patients with resected NSCLC from 2011 to 2015. All surgical primary and 58 matched metastatic lymph node specimens were tested for PD‐L1, CD8+ TILs, and oncogenic alterations. PD‐L1+ was detected in 71 (39.9%) and CD8high TILs in 74 (41.6%) cases. Smoking, SqCC, and EGFR − were associated with both PD‐L1+ and CD8high TILs. Patients with CD8high TILs had longer OS (P = 0.012). PD‐L1− was significantly associated with longer OS in patients with oncogenic alterations (P = 0.047). By multivariate analysis, CD8high TILs (HR = 0.411; 95% CI, 0.177–0.954; P = 0.038), rather than PD‐L1, was the independent predictive factor for OS. The longest and shortest OS were achieved in patients with PD‐L1+/CD8high and PD‐L1+/CD8low, respectively (P = 0.025). Inconsistent PD‐L1 expression levels were observed in 23 of 58 (39.7%) patients with primary and matched metastatic lymph node specimens. Of them, CD8high TILs was significantly associated with longer OS in patients with metastatic lymph nodes and/or consistent PD‐L1 expression (P = 0.017 and 0.049, respectively). The combination of PD‐L1 and CD8+ TILs density, instead of PD‐L1 alone, suggested impressive prognostic values in NSCLC patients. Less than half of patients with resected NSCLC experienced inconsistent PD‐L1 expression between primary and metastatic lesions. The level of PD‐L1 expression in advanced NSCLC needs to be evaluated more comprehensively.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Histone deacetylase 6 (HDAC6) is frequently altered in DLBCL and inhibition of HDAC6 has potent anti-tumor effects in vitro and in vivo. We profiled miRNAs that altered in the HDAC6 knockdown DLBCL cells with NanoString nCounter assay and identified microRNA-27b (miR-27b) as the most significantly increased miRNA. We validated decreased expression of miR-27b in DLBCL tissues, and we found that low expression of miR-27b was associated with poor overall survival of patients with DLBCL. In addition, forced expression of miR-27b suppressed DLBCL cell viability and proliferation in vitro, and inhibited tumor growth in vivo. Mechanistically, Rel A/p65 is found to negatively regulate miR-27b expression, and its acetylation and block of nuclear translocalization caused by HDAC6 inhibition significantly elevates miR-27b expression. Furthermore, miR-27b targets MET and thus represses the MET/PI3K/AKT pathway. These findings highlight an important role of miR-27b in the development of DLBCL and uncover a HDAC6-Rel A/p65-miR-27b-MET signaling pathway. Elevating miR-27b through HDAC6 inhibition would be a promising strategy for DLBCL treatment.

The authors' previous study demonstrated that the B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (BCL2L11) (Bim) deletion polymorphism was associated with poor clinical response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC) with EGFR mutations. The objective of the current study was to investigate the impact of the Bim deletion polymorphism among patients with anaplastic lymphoma kinase (ALK)-positive or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1)-positive NSCLC who were treated with crizotinib.A total of 55 patients with ALK-positive NSCLC and 14 patients with ROS1-positive NSCLC who were treated with crizotinib were enrolled into the current study. The Bim deletion polymorphism was analyzed by polymerase chain reaction. The clinical features of the Bim deletion polymorphism and its impact on the effect of crizotinib were investigated.The Bim deletion polymorphism was present in 9 of 69 patients with ALK-positive or ROS1-positive NSCLC (13.0%). There were no differences noted with regard to clinicopathological features between patients with and without the Bim deletion polymorphism. Patients with the Bim deletion polymorphism had a significantly shorter progression-free survival (PFS) and lower objective response rate compared with those without (median PFS, 182 days vs 377 days [P = .008]) (objective response rate, 44.4% vs 81.7% [P =.041]) in all populations. The significant difference in PFS was observed in patients with ALK-positive NSCLC (83 days vs 305 days [P =.0304]) compared with those with ROS1-positive NSCLC (218 days vs not reached [P =.082]). Multivariate analysis indicated that the Bim deletion polymorphism was an independent predictive factor for patients with ALK-positive NSCLC who were treated with crizotinib (hazard ratio, 4.786 [P =.006]).The Bim deletion polymorphism was found to be associated with poor clinical response to crizotinib in patients with ALK fusion-positive NSCLC. Cancer 2017;123:2927-35. © 2017 American Cancer Society.

Although Berberine (BER) is popular in treating gastrointestinal (GI) disorders, its mechanisms are not clear yet. In order to investigate the effects and possible mechanism of BER on GI motility in rodents, we first explored GI motility by recording the myoelectrical activity of jejunum and colon in rats, and upper GI transit with a charcoal marker in mice. Then, the plasma levels of gastrin, motilin, somatostatin and glucagon-like-peptide-1 (Glp-1) were measured by ELISA or radioimmunoassay (RIA). Furthermore, endogenous opioid-peptides (β-endorphin, dynorphin-A, met-enkephalin) were detected by RIA after treatment with BER. Our results showed that BER concentration-dependently inhibited myoelectrical activity and GI transit, which can be antagonized by opioid-receptor antagonists to different extents. The elevated somatostatin and Glp-1, and decreased gastrin and motilin in plasma, which were caused by BER application, also could be antagonized by the opioid-receptor antagonists. Additionally, plasma level of β-endorphin, but not dynorphin-A and met-enkephalin, was increased by applying BER. Taken together, these studies show that BER plays inhibiting roles on GI motility and up-regulating roles on somatostatin, Glp-1 and down-regulating roles on gastrin, motilin. The pharmacological mechanisms of BER on GI motility and plasma levels of GI hormones were discovered to be closely related to endogenous opioid system.

Purpose To investigate the effects of trastuzumab (herceptin) and fulvestrant (falsodex) either in combination or alone, on downstream cell signaling pathways in lab-cultured human HR+/HER2+ breast cancer cell lines ZR-75-1 and BT-474, as well as on protein expression levels in mouse xenograft tissue. Methods Cells were cultivated in the presence of trastuzumab or fulvestrant or both. Molecular events that resulted in an inhibition of cell proliferation and cell cycle progression or in an increased rate of apoptosis were studied. The distribution and abundance of the proteins p-Akt and p-Erk expressed in these cells in response to single agents or combinatorial treatment were also investigated. In addition, the effects of trastuzumab and fulvestrant, either as single agents or in combination on tumor growth as well as on expression of the protein p-MED1 expressed in in vivo mouse xenograft models was also examined. Results Cell proliferation was increasingly inhibited by trastuzumab or fulvestrant or both, with a CI1 in both human cell lines. The rate of apoptosis increased only in the BT-474 cell line and not in the ZR-75-1 cell line upon treatment with fulvestrant and not trastuzumab as a single agent (P0.05). Cell accumulation in the G1 phase of cell cycle was investigated in all treatment groups (P

The aim of this study was to assess associations between ER, Ki67, Her-2 phenotypes, molecular subtypes of breast cancer and circulating levels of lymphocyte subsets (CD4+, CD8+, NK, CD19+, CD20+) and the ratio of CD4+ to CD8+ prior to treatment. Cells from peripheral blood were counted by flow cytometry, ER, Her-2, and Ki67 expressions were detected by pathological examination, and Her-2 was also detected by FISH. We conducted a case–case comparison of 494 women with newly diagnosed breast cancer to evaluate association between levels of lymphocyte subsets in peripheral blood and breast cancer phenotypes [ER− vs. ER+; Ki67 ≥ 14 % vs. Ki67 < 14 %; Her-2+ vs. Her-2−; triple-negative breast cancer (TNBC) vs. luminal A]. Women with the highest levels of CD3+ (OR 0.45, 95 % CI 0.22–0.94), CD4+ (OR 0.22, 95 % CI 0.08–0.59), and the ratio of CD4+/CD8+ (OR 0.17, 95 % CI 0.06–0.47) were least likely to have TNBCs compared with luminal A cancers. The highest tertile of CD8+ (OR 3.67, 95 % CI 1.06–12.72) and NK (OR 2.64, 95 % CI 1.12–6.24) was significantly associated with TNBC compared with luminal A cancer. ER−, Ki67 ≥ 14 %, Her-2+ were associated with low levels of CD4+ and CD4+/CD8+ compared with ER+, Ki67 < 14 %, Her-2−. Women in the highest level of CD8+ had more likelihood to have ER− and Her-2+ compared with ER+ and Her-2−. High levels of NK cells were associated with increased risk of ER− compared with ER+ cancers. Highest levels of CD19+ and CD20+ were associated with low risk of ER−, compared with ER+ cancers. These findings show that immune function differs among different breast cancer phenotypes or subtypes and is associated with ER−, Her-2+, Ki67 ≥ 14 %, and TNBC which are likely to be aggressive phenotypes.

Although Berberine (BER) is popular in treating gastrointestinal (GI) disorders, its mechanisms are not clear yet. In order to investigate the effects and possible mechanism of BER on GI motility in rodents, we first explored GI motility by recording the myoelectrical activity of jejunum and colon in rats, and upper GI transit with a charcoal marker in mice. Then, the plasma levels of gastrin, motilin, somatostatin and glucagon-like-peptide-1 (Glp-1) were measured by ELISA or radioimmunoassay (RIA). Furthermore, endogenous opioid-peptides (β-endorphin, dynorphin-A, met-enkephalin) were detected by RIA after treatment with BER. Our results showed that BER concentration-dependently inhibited myoelectrical activity and GI transit, which can be antagonized by opioid-receptor antagonists to different extents. The elevated somatostatin and Glp-1, and decreased gastrin and motilin in plasma, which were caused by BER application, also could be antagonized by the opioid-receptor antagonists. Additionally, plasma level of β-endorphin, but not dynorphin-A and met-enkephalin, was increased by applying BER. Taken together, these studies show that BER plays inhibiting roles on GI motility and up-regulating roles on somatostatin, Glp-1 and down-regulating roles on gastrin, motilin. The pharmacological mechanisms of BER on GI motility and plasma levels of GI hormones were discovered to be closely related to endogenous opioid system.

Objective : To conduct a systematic review, with meta-analysis, of studies assessing the association between night work and the risk of breast cancer, using available epidemiological evidence. Method : Relevant studies were identified by searching several databases and the reference lists of retrieved articles. We combined the relative risks (RR) from individual studies using a random-effects model. Subgroup analysis was carried out as the data showed statistically significant heterogeneity. Results : Thirteen studies consisting of eight case–control studies and five cohort studies were included in the analysis. In the combined analysis of all studies, night work was associated with an increased risk for breast cancer (RR=1.20, 95%CI=1.08–1.33). The higher-quality studies showed a similar finding with a pooled RR of 1.40 (95%CI=1.13–1.73). Both case–control studies (RR=1.32, 95%CI=1.17–1.50) and cohort studies (RR=1.08, 95%CI=0.97–1.21) showed a positive association between night work and the risk of breast cancer. No publication bias was found either from Begg's funnel plot ( P =0.086) or the Egger's test ( P =0.107). Additional well-conducted and large-scale epidemiological studies are needed.

Aim: The major obstacles of autologous fat grafting after surgery for breast cancer were low graft survival and high resorption rate. The purpose of this study was to explore adipose-derived stem cells with a new scaffold could control release vascular endothelial growth factor (VEGF) to promote transplant survival and neovascularization. Methods: Polylactic acid fiber catheters loaded with VEGF were included in a gelatin scaffold produced by freeze crosslinking. The release dose and persistence of VEGF from the tridimensional structures were determined using the enzyme-linked immunosorbent assay (ELISA). Human adipose-derived stem cells (hASCs) were extracted and expanded ex vivo, seeded to the scaffold and cultured to test the biocompatibility using the WST-1 assay. Three days after co-cultured with hASCs, the scaffolds were transplanted to the back of nude mice, the control groups were only inject hASCs, transplanted control scaffold with hASCs. Three months later, transplants volume and histology were evaluated and neovascularization was determined by the quantity of capillary and the positive of endothelial cell marker CD31 in immunohistochemistry. Results: The tridimensional structures could release VEGF stable and durable, which had no significant cytotoxicity on hASCs. The transplants volume and the capillary quantity of hASCs with the control release VEGF polylactic acid fiber catheters gelatin scaffold group was significantly larger than other two groups. Immunohistochemistry analysis revealed the transplants were rich in CD31-positive cells. Conclusions: Adipose-derived stem cells together with the control release VEGF polylactic acid fiber catheters gelatin scaffold could significantly promoted vasculogenesis and reduced absorption and necrosis after transplant. Disclosure: All authors have declared no conflicts of interest.