Integrated profiling identifies DXS253E as a potential prognostic marker in colorectal cancer.

BACKGROUND: Increasing evidence suggests that DXS253E is critical for cancer development and progression, but the function and potential mechanism of DXS253E in colorectal cancer (CRC) remain largely unknown. In this study, we evaluated the clinical significance and explored the underlying mechanism of DXS253E in CRC. METHODS: DXS253E expression in cancer tissues was investigated using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The Kaplan-Meier plot was used to assess the prognosis of DXS253E. The cBioPortal, MethSurv, and Tumor Immune Estimation Resource (TIMER) databases were employed to analyze the mutation profile, methylation, and immune infiltration associated with DXS253E. The biological functions of DXS253E in CRC cells were determined by CCK-8 assay, plate cloning assay, Transwell assay, flow cytometry, lactate assay, western blot, and qRT-PCR. RESULTS: DXS253E was upregulated in CRC tissues and high DXS253E expression levels were correlated with poor survival in CRC patients. Our bioinformatics analyses showed that high DXS253E gene methylation levels were associated with the favorable prognosis of CRC patients. Furthermore, DXS253E levels were linked to the expression levels of several immunomodulatory genes and an abundance of immune cells. Mechanistically, the overexpression of DXS253E enhanced proliferation, migration, invasion, and the aerobic glycolysis of CRC cells through the AKT/mTOR pathway. CONCLUSIONS: We demonstrated that DXS253E functions as a potential role in CRC progression and may serve as an indicator of outcomes and a therapeutic target for regulating the AKT/mTOR pathway in CRC.

Tandem Mass Tag-Based Proteomic Profiling Identifies Biomarkers in Drainage Fluid for Early Detection of Anastomotic Leakage after Rectal Cancer Resection.

Anastomotic leakage (AL), one of the most severe complications in rectal surgery, is often diagnosed late because of the low specificity of the clinical symptoms and limitations of current clinical investigations. Identification of patients with early AL remains challenging. Here, we explored the protein expression profiles of AL patients to provide potential biomarkers to identify AL in patients who undergo surgery for rectal cancer. We screened differentially expressed proteins (DEPs) in drainage fluid from AL and non-AL patients using a tandem mass tag method. A total of 248 DEPs, including 98 upregulated and 150 downregulated proteins, were identified between AL and non-AL groups. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses suggested that DEPs were enriched in neutrophil degranulation, bacterial infection, proteolysis, hemostasis, and complement and coagulation cascades. The results of enzyme-linked immunosorbent assay validated that the expression of the top three upregulated DEPs, AMY2A, RETN, and CELA3A, was significantly increased in the drainage fluid of AL patients, compared with that of non-AL patients (AMY2A, P = 0.001; RETN, P < 0.0001; and CELA3A, P = 0.023). Thus, our findings provide several potential biomarkers for the early diagnosis of AL after rectal cancer resection.

Genome-wide circular RNA (circRNA) and mRNA profiling identify a circMET-miR-410-3p regulatory motif for cell growth in colorectal cancer.

Circular RNA (circRNA) is a non-coding RNA molecule that lacks polyadenylated tails and is highly stable, abundant, and conserved in human cells. CircRNAs can serve as a competing endogenous RNA (ceRNA) to sponge microRNAs (miRNA) and block their effects on target mRNA expression. CircRNAs also have possible relevance to cancer and therefore may be considered as ideal biomarkers for monitoring cancer progression. Of the about 300,000 predicted human circRNAs, only a few have validated biological functions related to cancer. To better understand the ceRNA role of circRNAs in colorectal cancer (CRC), we performed genome-wide circRNA-based RNA-sequencing (RNA-Seq) on nine CRC tumor samples and their paired histologically normal adjacent tissue samples. By profiling the mRNA expression in the same patients, we further explored the expression correlation between circRNAs and mRNAs generated from the same parental gene. Focusing on the concordant differential expression between circRNAs and mRNAs, we substantially reduced the regulatory noise. In total, we identified 694 circRNA-mRNA pairs that were consistently up or downregulated between tumor and normal tissues. These 694 circRNA-mRNA pairs are from 182 protein-coding genes associated with hormone responses and chemotaxis. Of these 182 genes, 43 are downstream targets of three highly conserved miRNAs (miR-410-3p, miR-135a, and miR-30a). Interestingly, these 43 genes are highly mutated in another cohort from eight independent CRC studies, which have significant effects on patient survival time. Focusing on miR-410-3p and its target oncogene MET, we experimentally validated the ceRNA regulatory motif of circMET. Notably, circMET is substantially upregulated in CRC cell lines and could promote cell proliferation and growth. By confirming the regulatory relationship between miR-410-3p and circMET, we propose a new mechanism for the observed sustained activation of MET in CRC. In conclusion, our work identifies a novel regulatory role of circMET and provides a potential diagnostic biomarker for CRC.

Downregulation of STK25 promotes autophagy via the Janus kinase 2/signal transducer and activator of transcription 3 pathway in colorectal cancer.

Autophagy plays a crucial role in colorectal cancer (CRC) development. Our previous study suggested that serine/threonine protein kinase 25 (STK25) regulates aerobic glycolysis in CRC cells. Glycolysis modulates cellular autophagy during tumor growth; however, the role of STK25 in autophagy remains unclear. In this study, we found that STK25 expression was decreased in CRC tissues and CRC patients with high STK25 expression had a favorable prognosis. Functional assays suggested that STK25 inhibition promoted autophagy in CRC cells. Overexpression of STK25 exhibited the opposite effects. Moreover, the results of western blot demonstrated that silencing STK25 induced autophagy by activating the JAK2/STAT3 pathway. Therefore, STK25 could be a potential indicator for therapies targeting the JAK2/STAT3 pathway in CRC.

Hexameric Silver(I) Pyrazolate: Synthesis, Structure, and Isomerization.

The first binary hexameric silver(I) pyrazolate (Ag6pz6) has been prepared, and X-ray analysis demonstrated that it takes a rare figure-eight shape (pz- = deprotonated tert-butyl 3,5-diphenyl-1H-pyrazole-4-carboxylate). The hexamer can be easily converted to its tetrameric isomer (Ag4pz4) by recrystallization from ether. On the basis of the 1H NMR and mass spectrometry measurements, it is conjectured that the hexamer, after dissolving in CHCl3, quickly achieves equilibrium with Ag4pz4 and Ag3pz3, with the equilibrium lying far to the side of smaller rings.

XRCC1 and ERCC1 polymorphisms are related to susceptibility and survival of colorectal cancer in the Chinese population.

Excision repair cross complementing group 1 (ERCC1) and X-ray repair cross-complementing groups 1 (XRCC1) are DNA repair enzymes. Polymorphisms in DNA repair genes may be important factors affecting cancer susceptibility, prognosis and therapy outcome. The purpose of this study was to investigate the correlation of ERCC1 and XRCC1 polymorphisms with colorectal cancer (CRC) risk, and explore the effect of polymorphisms on event-free, overall survival and oxaliplatin-based therapy in CRC patients. Genotyping was examined with the iMLDR technique. An unconditional logistic regression model was used to estimate the association of certain polymorphisms with CRC risk. The Kaplan-Meier method, log-rank test and Cox regression model were employed to evaluate the effects of polymorphisms on survival analysis. Results showed that Trp/Trp genotype of XRCC1 Arg194Trp and AA genotype of ERCC1 rs2336219 have a significantly increased risk of CRC; Trp allele of XRCC1 Arg194Trp and CC genotype of ERCC1 rs735482 were associated with lower response to oxaliplatin-based chemotherapy, a shorter survival and a higher risk of relapse or metastasis. 194Trp/280Arg/399Arg haplotype was associated with a significant resistance, and the ERCC1 protein expression was statistically higher in tumours with rs735482 CC genotype than with AA genotype. Our studies indicate that XRCC1 and ERCC1 polymorphisms probably affect susceptibility, chemotherapy response and survival of CRC patients.

Polymorphisms of Toll-like receptor 9 are associated with nasopharyngeal carcinoma susceptibility.

Toll-like receptor 9 (TLR9) plays a pivotal role in sensing a wide range of pathogens, including bacteria, fungi, and viruses. A dysregulation of TLR9 signaling may contribute to a higher risk of developing cancers. A hospital-based case-control study, including 356 nasopharyngeal carcinoma (NPC) cases and 356 controls, was conducted to assess the relationship between TLR9 -1237T/C, -1486T/C, and 2848G/A polymorphisms and NPC risk as well as clinical characteristics. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Protein level of transforming growth factor-ß1 (TGF-ß1), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6) in NPC biopsies was measured by enzyme-linked immunosorbent assay (ELISA). We found that -1486T/C CC genotype had an increased NPC risk at odds ratio (OR) = 1.808 with 95% confidence interval (CI) 1.169 ∼ 2.798 (P = 0.008). The patients with -1486 CC genotype are inclined to advanced tumor stage and lymph node metastasis. In addition, protein concentration of VEGF in NPC biopsies with -1486 CC genotype was significantly increased compared patients with -1486 TT genotype. For the first time, our data suggested that TLR9 -1486T/C may be a risk biomarker of NPC.

Effect of consumption of micronutrient enriched wheat steamed bread on postprandial plasma glucose in healthy and type 2 diabetic subjects.

BACKGROUND: Steamed wheat bread have previously been shown to induce comparatively high postprandial plasma glucose responses, on the contrary, buckwheat products induced lower postprandial plasma glucose. The present study was to assess the effects of micronutrient enriched bread wheat variety Jizi439 and buckwheat on postprandial plasma glucose in healthy and diabetic subjects comparing with buckwheat and other bread wheat varieties. METHODS: Two experiments were conducted to study the effects of bread wheat variety Jizi439 on the postprandial plasma glucose levels of the randomly selected subjects. The first experiment involved three types of steamed bread with equivalent of 50 g available carbohydrate fed to 10 normal weight young healthy subjects. Two types of steamed bread were made from two purple-grain bread wheat varieties, Jizi439 and Chu20, respectively, and the third type was made from the mixture of different white grain wheat varieties. Plasma glucose levels of each subject were measured at 15, 30, 45, 60, 120 min after eating. Glucose was used as a reference, the total area under curve (AUC) and glycemic index (GI) was calculated for test meal. The second experiment was performed among ten type 2 diabetics who were served equivalent of 50 g available carbohydrate of steamed bread made from Jizi 439, the mixture of white grain bread wheat and buckwheat, respectively. The plasma glucose increment was determined two hours thereafter. RESULTS: In the first experiment, consumption of the steamed bread made from Jizi439 resulted in the least increase in plasma glucose and the GI was significantly lower than that of Chu20 and the mixture. In the second experiment, the average of postprandial 2 h plasma glucose increment of Jizi439 was 2.46 mmol/L which was significantly lower than that of the mixture of white wheat but was not significantly different from buckwheat. CONCLUSIONS: The results indicated that consumption of Jizi439 steamed bread resulted in significantly lower plasma glucose in both healthy and diabetic subjects, compared with other types of test foods, except buckwheat bread. The steam bread made from Jizi439 would be an ideal food for preventing and treatment of diabetes.

[Association between different EGFR mutation status and survival in pemetrexed-based chemotherapy for advanced non-small cell lung cancer].

OBJECTIVE: To explore the association between different epidermal growth factor receptor (EGFR) mutation status and survival in pemetrexed-based chemotherapy for advanced non-small-cell lung cancer (NSCLC). METHODS: A retrospective cohort study was performed to assess 146 patients with advanced NSCLC at Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. The first-line regimens included pemetrexed based chemotherapy (pemetrexed first-line therapy group, n = 79), pemetrexed based chemotherapy plus pemetrexed maintenance chemotherapy (pemetrexed maintenance therapy group, n = 38) and pemetrexed based chemotherapy plus tyrosine kinase inhibitors (TKI) maintenance therapy (TKI maintenance therapy group, n = 29). Median progression-free survival (PFS) was determined.For comparison, median PFS was evaluated for EGFR-positive,EGFR-negative versus EGFR mutation unknown NSCLC patients in first-line pemetrexed therapy and pemetrexed maintenance therapy groups. RESULTS: The median PFS was 4.6 (95%CI: 2.8-6.4), 9.8 (95%CI: 6.1-13.5) and 14.5 (95%CI: 11.8-17.2) months in pemetrexed first-line therapy, pemetrexed maintenance therapy and TKI maintenance therapy groups respectively (P = 0.000). No difference existed in PFS for pemetrexed first-line therapy group with a median PFS of 5.2 (95%CI: 2.8-7.7), 4.0 (95%CI: 0-10.8) and 4.6 (95%CI: 3.4-5.8) months respectively (P = 0.661). Among EGFR-positive,EGFR-negative and EGFR mutation status unknown patients in pemetrexed maintenance therapy group, the median PFS was 8.5 (95%CI: 4.0-13.1), 12.6 (95%CI: 11.6-13.7) and 8.0 (95%CI: 5.8-10.3) months with no significant statistical difference (P = 0.468). CONCLUSIONS: No significant difference exists in survival between different EGFR mutation status for pemetrexed based first-line chemotherapy. And TKI maintenance therapy is associated with better survival than pemetrexed maintenance therapy regardless of EGFR status.

Efficacy and safety of albumin-bound paclitaxel in treating recurrent advanced non-small-cell lung cancer.

OBJECTIVE: To observe the efficacy and safety of albumin-bound paclitaxel (ABP) monotherapy in treating recurrent advanced non-small-cell lung cancer (NSCLC). METHODS: We retrospectively analyzed the short-term efficacy and toxicities of ABP monotherapy in treating 21 patients who had previously undergone multiple cycles of therapy for their advanced NSCLC in our hospital since 2010. The treatment-related survival was also analyzed. RESULTS: Of these 21 patients, the best overall response was partial response (PR) in 6 patients (28.6%), stable disease (SD) in 10 patients (47.6%), and progressive disease (PD) in 5 patients (23.8%). The overall response rate (ORR) was 28.6% and the disease control rate (DCR) (PR + SD) was 76.2%. The median progression-free survival (PFS) was 4.0 months (95% CI, 5.0-7.0 months). The main grade 3/4 toxicities included neutropenia (11.1%), peripheral nerve toxicity (5.6%), muscle and joint aches (5.6%), and fatigue (5.6%). CONCLUSIONS: The ABP monotherapy can achieve good objective response in advanced NSCLC patients who have previously received multiple cycles of treatment and be well tolerated.

Genome-wide transcriptomics and copy number profiling identify patient-specific CNV-lncRNA-mRNA regulatory triplets in colorectal cancer.

Screening cancer genomes has provided an in-depth characterization of genetic variants such as copy number variations (CNVs) and gene expression changes of non-coding transcripts. Single-dimensional experiments are often designed to differentiate a patient cohort into various sets with the aim of identifying molecular changes among groups; however, this may be inadequate to decipher the causal relationship between molecular signatures in individual patients. To overcome this challenge with respect to personalized medicine, we implemented a patient-specific multi-dimensional integrative approach to uncover coherent signals from multiple independent platforms. In particular, we focused on the consistent gene dosage effects of CNVs for both mRNA and long non-coding RNA (lncRNA) expression in nine colorectal cancer patients. We identified 511 CNV-lncRNA-mRNA regulatory triplets associated with CNVs and aberrant expression of both mRNAs and lncRNAs. By filtering out inconsistent changes among CNVs, mRNAs, and lncRNAs, we further characterized 165 coherent motifs associated with 56 genes. In total, 108 motifs were linked with 31 copy number gains, 44 upregulated lncRNAs, and 45 upregulated mRNAs. Another 57 coherent downregulated motifs were also collected. We discuss how for many of these CNV-lncRNA-mRNA regulatory triplets, their clinical impact remains to be explored, including survival time, microsatellite instability, tumor stage, and primary tumor sites. By validating two example CNV-lncRNA-mRNA triplets with up- and down-regulation, we confirmed that individual variations in multiple dimensions are a robust tool to identify reliable molecular signals for personalized medicine. In summary, we utilized a patient-specific computational pipeline to explore the consistent CNV-driven motifs consisting of lncRNAs and mRNAs. We also identified LSM14B as a potential promoter in colorectal cancer progression, suggesting that it may serve as a target for colorectal cancer treatment.

Medicine for chronic atrophic gastritis: a systematic review, meta- and network pharmacology analysis.

PURPOSE: The aim of this study is to determine the effectiveness and reliability of adding traditional Chinese medicine (TCM) in the clinical intervention and explore mechanisms of action for chronic atrophic gastritis (CAG) through meta- and network pharmacology analysis (NPAs). METHODS: A predefined search strategy was used to retrieve literature from PubMed, Embase database, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM), Wan Fang Data and China Science and Technology Journal Database (VIP). After applying inclusion and exclusion criteria, a total of 12 randomized controlled trials (RCTs) were included for meta-analysis to provide clinical evidence of the intervention effects. A network meta-analysis using Bayesian networks was conducted to observe the relative effects of different intervention measures and possible ranking of effects. The composition of the TCM formulation in the experimental group was analysed, and association rule mining was performed to identify hub herbal medicines. Target genes for CAG were searched in GeneCards, Online Mendelian Inheritance in Man, PharmGKB, Therapeutic Target Database and DrugBank. A regulatory network was constructed to connect the target genes with active ingredients of the hub herbal medicines. Enrichment analyses were performed using the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) to examine the central targets from a comprehensive viewpoint. Protein-protein interaction networks (PPINs) were constructed to identify hub genes and conduct molecular docking with differentially expressed genes (DEGs) and corresponding active molecules. RESULTS: A total of 1140 participants from 12 RCTs were included in the statistical analysis, confirming that the experimental group receiving the addition of TCM intervention had better clinical efficacy. Seven hub TCMs (Paeonia lactiflora, Atractylodes macrocephala, Pinellia ternata, Citrus reticulata, Codonopsis pilosula, Salvia miltiorrhiza and Coptis chinensis) were identified through association rule analysis of all included TCMs. Thirteen hub genes (CDKN1A, CASP3, STAT1, TP53, JUN, MAPK1, STAT3, MAPK3, MYC, HIF1A, FOS, MAPK14 and AKT1) were obtained from 90 gene PPINs. Differential gene expression analysis between the disease and normal gastric tissue identified MAPK1 and MAPK3 as the significant genes. Molecular docking analysis revealed that naringenin, luteolin and quercetin were the main active compounds with good binding activities to the two hub targets. GO analysis demonstrated the function of the targets in protein binding, while KEGG analysis indicated their involvement in important pathways related to cancer. CONCLUSIONS: The results of a meta-analysis of 12 RCTs indicate that TCM intervention can improve the clinical treatment efficacy of CAG. NPAs identified seven hub TCM and 13 target genes associated with their actions, while bioinformatics analysis identified two DEGs between normal and CAG gastric tissues. Finally, molecular docking was employed to reveal the mechanism of action of the active molecules in TCM on the DEGs. These findings not only reveal the mechanisms of action of the active components of the TCMs, but also provide support for the development of new drugs, ultimately blocking the progression from chronic gastritis to gastric cancer.

Influence of PD-L1 expression on the efficacy of EGFR-TKIs in EGFR-mutant non-small cell lung cancer.

BACKGROUND: Evidence on the influence of programmed death-ligand 1 (PD-L1) expression on the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) patients is at variance. METHODS: A single-center retrospective study was conducted to evaluate the influence of PD-L1 expression on the efficacy of EGFR-TKIs for NSCLC patients with EGFR mutation. Clinical information was retrieved from electronic medical records. The patients were divided into three subgroups according to PD-L1 expression level: PD-L1 < 1% (negative), PD-L1 1%-49% and PD-L1 ≥ 50%. The clinicopathological features, overall response rate (ORR), progression-free survival (PFS) and comutation information were collected and compared between the three subgroups. RESULTS: A total of 117 patients were included. For PD-L1 < 1%, PD-L1 1%-49% and PD-L1 ≥ 50% group, there were 39 (33.3%), 51 (43.5%) and 27 (23.0%) patients respectively, and the ORR was 43.2%, 64.0%, and 51.9%, respectively (p = 0.162), and the median progression-free survival (mPFS) was 22.0 months (95% CI: 14.0-29.9 months), 15.4 months (95% CI: 8.9-21.8 months) and 13.0 months (95% CI: 10.6-15.3 months), respectively (log-rank, p = 0.01). The mPFS was negatively correlated with PD-L1 expression level (r = -0.264, p = 0.041) and PD-L1 expression was an independent risk factor for worse PFS of EGFR-TKIs in multivariate Cox regression. Patients with concurrent TP53 mutation had shorter PFS (p = 0.039) and the patients harboring both mutant TP53 and positive PD-L1 had the shortest PFS (p = 0.006). CONCLUSIONS: The efficacy of EGFR-TKIs was influenced by the baseline PD-L1 expression. Higher PD-L1 expression was associated with shorter PFS. The combined indicators of TP53 and PD-L1 identified subgroups showing divergent benefits from EGFR-TKIs.

WFDC3 inhibits tumor metastasis by promoting the ERß-mediated transcriptional repression of TGFBR1 in colorectal cancer.

Estrogen plays a protective role in colorectal cancer (CRC) and primarily functions through estrogen receptor ß (ERß). However, clinical strategies for CRC therapy associated with ERß are still under investigation. Our discoveries identified WFDC3 as a tumor suppressor that facilitates estrogen-induced inhibition of metastasis through the ERß/TGFBR1 signaling axis. WFDC3 interacts with ERß and increases its protein stability by inhibiting its proteasome-dependent degradation. WFDC3 represses TGFBR1 expression through ERß-mediated transcription. Blocking TGFß signaling with galunisertib, a drug used in clinical trials that targets TGFBR1, impaired the migration of CRC cells induced by WFDC3 depletion. Moreover, there was clinical significance to WFDC3 in CRC, as CRC patients with high WFDC3 expression in tumor cells had favorable prognoses. Therefore, this work suggests that WFDC3 could be an indicator for therapies targeting the estrogen/ERß pathway in CRC patients.

[Clinical analysis of childhood and adolescent Hodgkin's lymphoma: a report of 88 cases].

OBJECTIVE: The aim of this study was to investigate the clinicopathological characteristics, effective treatment and prognosis in childhood and adolescent Hodgkin's lymphoma. METHODS: A total of 88 patients with childhood and adolescent Hodgkin's lymphoma were treated in the Cancer Hospital of CAMS from 1998 to 2005. The clinicopathological and follow-up data of the patients were retrospectively reviewed. The survival rate was calculated by Kaplan-Meier method and compared by log-rank test. COX multivariate prognosis analysis was performed. RESULTS: The 2-year event-free survival rate of the 88 patients was 86.4%, the 5-year event-free survival rate was 61.4%, and the 5-year overall survival rate was 95.5%. Univariate analysis showed that the stage of disease (P = 0.033), "B" symptoms (P = 0.028), bulky disease (P = 0.007), splenomegaly (P = 0.050), LDH elevation (P = 0.020), chemotherapy regimen (P = 0.003) were prognostic factors in the 5-year event-free survival rate. Splenomegaly (P = 0.039), LDH elevation (P = 0.033), chemotherapy regimen (P = 0.008) were prognostic factors of 5-year overall survival rate. Multivariate analysis showed that chemotherapy regimen (P = 0.033), stage of disease (P = 0.023), LDH elevation (P = 0.008), "B" symptoms (P = 0.044), bulky disease (P = 0.009) were independent prognostic factors of 5-year event-free survival rate. The chemotherapy regimen (P = 0.012) and LDH elevation (P = 0.046) were independent prognostic factors of 5-year overall survival rate. CONCLUSIONS: The non-ABVD chemotherapy regimen, stage IV disease, LDH elevation, associated with "B" symptoms and bulky disease are independent prognostic factors of 5-year event-free survival rate. LDH elevation and non-ABVD chemotherapy regimen are independent prognostic factors of 5-year overall survival rate.

Efficacy and safety of concomitant immunotherapy and denosumab in patients with advanced non-small cell lung cancer carrying bone metastases: A retrospective chart review.

Background: Synergistic anti-tumor effects were observed in vivo and in vitro when immune checkpoint inhibitors (ICIs) were combined with denosumab. However, the clinical benefit and safety of this synergy have not been adequately evaluated in non-small cell lung cancer (NSCLC). Methods: Consecutive charts of NSCLC patients with bone metastases between December 2020 and December 2021 in the Chinese National Cancer Center were reviewed. The entire cohort was divided into one experimental group (denosumab + ICIs [DI]) and three control groups (denosumab + non-ICIs [DnI], phosphates + ICIs [PI], phosphates + non-ICIs [PnI]). Real-world objective response rates (ORRs), median progression-free survival (mPFS), skeletal-related events (SREs), and adverse events (AEs) were compared between groups. Results: A total of 171/410 (41.7%) patients with advanced or recurrent NSCLC carrying bone metastases who received bone-targeted therapy were eligible for analysis. Although the DI group showed a better benefit trend, differences were not statistically significant concerning the therapeutic efficacy among the DI group (n = 40), PI group (n = 74), DnI group (n = 15), and PnI group (n = 42) (ORRs: 47.5%, 43.2%, 33.3%, and 40.5%, respectively, p = 0.799; and mPFS: 378, 190, 170, and 172 days, respectively, p = 0.115; SREs: 5%, 10.8%, 13.3%, and 11.9%, respectively, p = 0.733). Nevertheless, further analysis in the NON-DRIVER cohort revealed a greater benefit for the DI group (p = 0.045). Additionally, the AEs of the DI group were not significantly different from those of the PI, DnI, and PnI groups (AEs: 27.5%, 39.2%, 26.7%, and 28.6%, respectively, p = 0.742). Furthermore, the multivariate analysis revealed the independent prognostic role of DI treatment for PFS in the overall cohort. Within the DI group, we did not observe differences in benefit among different mutational subgroups (p = 0.814), but patients with single-site bone metastasis (p = 0.319) and high PD-L1 expression (p = 0.100) appeared to benefit more, though no significant differences were observed. Conclusions: Denosumab exhibited synergistic antitumor efficacy without increasing toxicity when used concomitantly with ICIs in patients with advanced non-small cell lung cancer carrying bone metastases.

A real-world study of dacomitinib in later-line settings for advanced non-small cell lung cancer patients harboring EGFR mutations.

OBJECTIVE: Dacomitinib has been approved for the first-line treatment of non-small cell lung cancer (NSCLC) carrying classical epidermal growth factor receptor (EGFR) mutations; however, real-world data on its later-line application are lacking. MATERIALS AND METHODS: Patients' data were retrospectively collected from the Chinese National Cancer Center and the PLA hospital between August 2019 and August 2021. Kaplan-Meier method and Log-rank test were utilized to assess progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox regression analysis was conducted to determine prognostic indicators. RESULTS: In total, 56 NSCLC patients harboring EGFR mutations treated with later-line single dacomitinib or combinatory dacomitinib were enrolled. A total of 53 patients (94.6%) had treatment-related adverse events; eight patients (14.3%) had grade 3 or 4 events. Among 49 evaluable patients, 26.5% (13 patients) had a confirmed partial response and 73.5% (36 patients) had disease control; the median duration of follow-up was 9.6 months (95% confidence interval [CI], 8.4-10.8 months), the median progression-free survival was 5.4 months (95% CI, 3.5-7.3 months), and the half-year, 1-year, and 2-year OS rate were 79.2%, 70.6%, and 64.1%, respectively. Univariate analysis suggested that smoking, line of dacomitinib, and interval between last EGFR-tyrosine kinase inhibitor (TKI) and dacomitinib were associated with PFS and OS; chemotherapy between last EGFR-TKI and dacomitinib, and EGFR-TKI generation followed by dacomitinib were respectively associated with PFS and OS; multivariate analysis indicated chemotherapy between last EGFR-TKI and dacomitinib negatively affect PFS, and smoking and third-generation EGFR-TKI followed by dacomitinib negatively affect OS. CONCLUSIONS: This real-world study has shown that dacomitinib is active and well-tolerated in NSCLC patients harboring different EGFR mutations in later-line settings, even for those with brain metastases. Patients who benefited more from the first TKI were more likely to benefit from dacomitinib, and earlier application of dacomitinib after front-line TKI resistance may be considered.

A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway.

Genomic instability plays a key role in the initiation and progression of colorectal cancer (CRC). Although cancer driver genes in CRC have been well characterized, identifying novel genes associated with carcinogenesis and treatment remains challenging because of tumor heterogeneity. Here, we analyzed the genomic alterations of 45 samples from CRC patients in northern China by whole-exome sequencing. In addition to the identification of six well-known CRC driver genes (APC, TP53, KRAS, FBXW7, PIK3CA, and PABPC), two tumor-related genes (MTCH2 and HSPA6) were detected, along with RRP7A and GXYLT1, which have not been previously linked to cancer. GXYLT1 was mutated in 40% (18/45) of the samples in our cohort. Functionally, GXYLT1 promoted migration and invasion in vitro and metastasis in vivo, while the GXYLT1S212* mutant induced significantly greater effect. Furthermore, both GXYLT1 and GXYLT1S212* interacted with ERK2. GXYLT1 induced metastasis via a mechanism involving the Notch and MAPK pathways, whereas the GXYLT1S212* mutant mainly promoted metastasis by activating the MAPK pathway. We propose that GXYLT1 acts as a novel metastasis-associated driver gene and GXYLT1S212* might serve as a potential indicator for therapies targeting the MAPK pathway in CRC.

Afatinib and Dacomitinib Efficacy, Safety, Progression Patterns, and Resistance Mechanisms in Patients with Non-Small Cell Lung Cancer Carrying Uncommon EGFR Mutations: A Comparative Cohort Study in China (AFANDA Study).

(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.

Circulating tumor cells (CTCs)/circulating tumor endothelial cells (CTECs) and their subtypes in small cell lung cancer: Predictors for response and prognosis.

BACKGROUND: The aim of the study was to define the clinical significance of circulating tumor cells (CTCs)/circulating tumor endothelial cells (CTECs) and their subtypes in small cell lung cancer (SCLC) patients. METHODS: CTCs/CTECs and their subtypes were determined using SE-iFISH technology in 33 SCLC patients before initial treatment (B1), after two cycles of chemotherapy (B2), at the completion of chemotherapy (B3), and disease progression (B4). The correlations with clinical characteristics, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: CTCs and CTECs were detected in 96.6% and 65.5% of patients, respectively. Patients had higher levels of CTCs compared with CTECs in circulation (p < 0.05). Extensive-stage SCLC patients tended to have higher CTEC counts (p = 0.035), and the detection of CTC-white blood cell (CTC-WBC) clusters was associated with a worse response to treatment (p = 0.030). Patients with CTC-WBC clusters at B1 (17.3 vs. 22.6 months, p = 0.041) and B2 (19.9 vs. 25.2 months, p = 0.018) had significantly shorter OS than those with no detection. Additionally, their presence was revealed as independent predictors for a worse OS in multivariable analyses (B1: HR 9.3, 95% CI: 1.4-48, p = 0.0079; B2: HR 4.4, 95% CI: 1.1-18, p = 0.041). A high CTC level at B4 was an adverse prognostic factor for SCLC patients (PFS: 8.7 vs. 22.5 months, p = 0.0026; OS: 19 months vs. not reached, p = 0.0086). CTC clusters and CTECs also showed prognostic values. CONCLUSIONS: The presence of CTC-WBC clusters at baseline and after two-cycle chemotherapy and the total CTC counts at the completion of chemotherapy are strong predictors for the prognostic survival of SCLC patients receiving first-line treatment.