Integration of QTL and comprehensive analysis in the circulating inflammatory cytokines for pan-cancer.

BACKGROUND: Chemokines and cytokines are components of the tumor microenvironment and also influence tumorigenesis and its composition. However, whether they genetically proxy tumorigenesis is unclear. For causal inferences, eQTL and pQTL were used to determine the role of chemokines and cytokines in pan-cancer. The impact on the tumor immune microenvironment was also explored. METHODS: This study leveraged summary statistics from respective genome-wide association studies (GWAS) of 109 cytokines and chemokines in 18 types of solid tumors. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines and chemokines, located in or close to their coding gene (cis), were used as instrumental variables. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results. The impact on immune infiltration was investigated using the TIMER and TISIDB websites. Survival analysis was conducted using the K-M plotter and TIMER 2.0 websites. The TISCH and GEO databases were used to carry out scRNA cell analysis.Analyzing relevant proteins using the STRING database and conducting enrichment pathways for GO analysis of the identified proteins. RESULTS: The results of the inverse-variance weighted (IVW) method using cis-protein QTL (cis-pQTL) instruments showed the causal effects of TNF in reducing the risk of squamous cell lung cancer (LUSC) and HGF in reducing the risk of head and neck cancer (HNSC).The results were consistent with the eQTL. HGF was associated with better overall survival (OS) in HNSC, regardless of the types of cells enriched. However, high expression of the ligand MET for HGF leads to a decrease in overall survival in LUSC. TNF was related to poor OS in LUSC with no significant impact. However, in CD8 + T cell-enriched, eosinophil-enriched, macrophage-enriched, and NK cell-deficient types of LUSC, high expression of TNF leads to a poor prognosis, and there is statistical significance. The results showed a significant positive correlation between TNF and most immune cell infiltration, immunomodulator and chemokine in LUSC. HGF is positively correlated with the majority of immune cells except CD56 + cells, as well as some immune regulatory factors and chemotactic factors. According to single-cell sequencing results, HGF is mainly secreted by fibroblasts and myofibroblasts in HNSC, while in LUSC, it is primarily secreted by macrophages and CD8 + T cells secrete TNF. The GO/KEGG analysis suggests that proteins related to HGF are mainly involved in regulating peptidyl-tyrosine phosphorylation and positive regulation of the MAPK cascade. Proteins related to TNF are primarily associated with the regulation of I-kappaB kinase/NF-kappaB signaling and cytokine-mediated signaling pathway. CONCLUSIONS: HGF is primarily secreted by fibroblasts in HNSC and may have a protective effect on the occurrence and prognosis of HNSC. These effects are independent of immune cell influence, and this role may not necessarily be mediated through the HGF/MET pathway. On the other hand, TNF in LUSC is mainly secreted by immune cells like CD8 + T cell, and it may have a protective effect on the occurrence of LUSC. However, it's impact on the prognosis of LUSC through the immune microenvironment may have a different effect.

Chemokines and cytokines are not only components of the tumor microenvironment but also affect tumorigenesis and the composition of the tumor microenvironment. However, whether they genetically proxy tumorigenesis is unclear. For causal inferences, eQTL and pQTL were used to define the role of chemokines and cytokines in pan-cancer. The impact on the tumor immune microenvironment was also explored. This study leveraged the summary statistic from respective genome wide association study (GWAS) of 109 cytokines and chemokines to 18 types of solid tumor. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines and chemokines, located in or close to their coding gene (cis), were used as instrumental variables. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results. The results showed HGF is primarily secreted by fibroblasts in HNSC, and it may have a protective effect on the occurrence and prognosis of HNSC. These effects are independent of immune cell influence, and this role may not be mediated through the HGF/MET pathway. On the other hand, TNF in LUSC is mainly secreted by immune cells like CD8 + T cell, and it may have a protective effect on the occurrence of LUSC. However, it's impact on the prognosis of LUSC through the immune microenvironment may have a different effect.

First-line serplulimab in metastatic colorectal cancer: Phase 2 results of a randomized, double-blind, phase 2/3 trial.

BACKGROUND: Whether or not the addition of immunotherapy to current standard-of-care treatments can improve efficacy in proficient mismatch repair (pMMR)/microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), the predominant type of mCRC, is unclear. METHODS: This randomized, double-blind, phase 2 part of a phase 2/3 trial was conducted at 23 hospitals across China (ClinicalTrials.gov: NCT04547166). Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomly assigned 1:1 to receive every-3-weeks intravenous serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (serplulimab group) or placebo (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (placebo group). The primary endpoint was independent radiology review committee (IRRC)-assessed progression-free survival (PFS). Secondary endpoints included other efficacy endpoints and safety. FINDINGS: Between July 16, 2021, and January 20, 2022, 114 patients were enrolled and randomly assigned to the serplulimab (n = 57) or placebo (n = 57) group. All patients had stage IV CRC, and 95.7% of the patients with available microsatellite instability (MSI) status were MSS. With a median follow-up duration of 17.7 months, median PFS was prolonged in the serplulimab group (17.2 vs. 10.7 months; hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.31-1.14). Although the median overall survival (OS) was not reached for either group, a trend of an OS benefit was observed for the serplulimab group (HR, 0.77; 95% CI, 0.41-1.45). 36 (65.5%) and 32 (56.1%) patients in the serplulimab and placebo groups had grade ≥3 treatment-related adverse events, respectively. CONCLUSIONS: Serplulimab plus HLX04 and XELOX exhibits promising efficacy and is safe and tolerable in patients with treatment-naive mCRC. FUNDING: This work was funded by Shanghai Henlius Biotech, Inc.

Circulating VEGF and inflammatory bowel disease: a bidirectional mendelian randomization.

Introduction: Prior observational studies have suggested an association between circulating vascular endothelial growth factor (VEGF) levels and inflammatory bowel disease (IBD). This study sought to demonstrate the directionality of the association between circulating VEGF and particular forms of IBD as well as if there is a causal relationship between them. Methods: We collected summary data from relevant genome-wide association studies (GWASs) to assess the validity of causality, and a two-sample bidirectional Mendelian randomization (MR) study and sensitivity testing were performed to assess the causal relationship between circulating VEGF and IBD risk, including Crohn's disease and ulcerative colitis. Results: Our findings revealed a direct causal link between circulating VEGF and Crohn's disease (b 0.195, se 0.078, p < 0.013). However, neither circulating VEGF nor ulcerative colitis were shown to be causally linked (p > 0.025), nor was there proof of a reverse causal relationship from IBD to VEGF. Discussion: In conclusion, circulating VEGF shows a cause-and-effect relationship with Crohn's disease.

Association of pathological response with long-term survival outcomes after neoadjuvant immunotherapy: A meta-analysis.

BACKGROUND: Complete pathological response (pCR) and major pathological response (MPR) have been proven to have a close association with improved event-free survival (EFS) and overall survival (OS) for patients accepting chemotherapy or chemoradiotherapy. However, further study focusing on neoadjuvant immunotherapy is limited. Here we provided an updated and comprehensive evaluation of the association between pathological response and long-term survival outcomes at patient level and trial level for neoadjuvant immunotherapy. METHODS: We systematically searched and assessed studies in PubMed, Embase, the Cochrane Library and relevant conference abstracts from inception to June 1, 2023. Studies reported EFS/OS results by pCR/MPR status were eligible. RESULTS: Forty-three studies comprising a total of 4100 patients were eligible for the analysis, which included 39 studies for the patient-level analysis and 5 randomized controlled trials for the trial-level analysis. Our results highlighted that pCR was associated with improved EFS (HR, 0.48 [95 % CI, 0.39-0.60]) and OS (HR, 0.55 [95 % CI, 0.41-0.74]). The magnitude of HRs by MPR status were similar to the results by pCR status (EFS HR, 0.31 [95 % CI, 0.18-0.53]) and OS HR, 0.43 [95 % CI, 0.19-0.96]). However, no association between pCR and EFS at trial level was found (P = 0.8, R2 = 0). CONCLUSION: Our meta-analysis demonstrates a strong association between pathological response and long-term survival outcomes at patient level across studies applying neoadjuvant immunotherapy in most solid tumors but we fail to validate the relationship at trial level. Therefore, an accepted surrogate endpoint applied to both patient and trial levels are waited for further search.

Severe COVID-19 and chronic kidney disease: bidirectional mendelian randomization study.

Traditional observational research has revealed an association between severe COVID-19 and chronic kidney disease (CKD). It is unclear whether there is a causative connection between them. Our goal was to determine whether genetically predicted CKD is associated with the risk of critical COVID-19. We aimed to investigate potential underlying genetic mechanisms that could explain this relationship, paving the way for personalized risk assessment and targeted interventions to mitigate the effects of COVID-19 on individuals with CKD. Using combined data from a GWAS on European ancestry and CKD (n = 117,165) and critical COVID-19 (n = 1,059,456), bidirectional Mendelian randomization analysis was performed. Four single nucleotide polymorphisms (SNPs) were chosen from the genome as CKD instrumental variables (IVs). In addition to MR‒Egger regression, weighted mode approaches, and weighted medians, we employed the inverse-variance weighted estimate as our primary analytical method. A significant association of CKD with critical COVID-19 (OR = 1.28, 95% confidence interval [CI]: 1.04-1.58, p = 0.01811) was found. However, using 6 genome-wide significant SNPs as IVs for critical COVID-19, we could not discover a meaningful correlation between severe COVID-19 and CKD (OR = 1.03, 95% CI: 0.96-1.10, p = 0.3947). We found evidence to support a causal relationship between CKD and severe COVID-19 in European population. This underscores the need for comprehensive monitoring and specialized care strategies for individuals with CKD to mitigate the heightened risk and severity of COVID-19 complications.

Predictive biomarkers for immune-related adverse events in cancer patients treated with immune-checkpoint inhibitors.

PURPOSE: The objective of this study was to identify potential predictors of immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitor therapy among serum indexes, case data, and liquid biopsy results. METHODS: We retrospectively analyzed 418 patients treated with anti-programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) inhibitors from January 2018 to May 2022 in our cancer center. We identified factors that correlated with the occurrence of irAEs and evaluated associations between irAEs and anti-PD-1/PD-L1 inhibitor responses. RESULTS: The incidence of irAEs was 42.1%, and pneumonitis (9.1%), thyroid toxicity (9.1%), cardiotoxicity (8.1%), and dermatologic toxicity (6.9%) were the four most common irAEs. Multivariate logistic analysis identified female sex, antibiotic use, higher post-treatment neutrophil-to-lymphocyte ratio (NLR), and higher baseline circulating tumor cell (CTC) level, as predictive biomarkers for the occurrence of irAEs. A lower baseline prognostic nutritional index (PNI), body mass index (BMI) ≥ 25 kg/m2, and higher post-treatment lactate dehydrogenase (LDH) level were predictive factors for more severe irAEs (higher severity grade). Patients without irAEs had better overall survival than those with irAEs. Specifically, pneumonitis and cardiotoxicity were found to be significant predictors of poor prognosis in the irAE subgroup with different organ-related irAEs. Low-dose steroid (dexamethasone 10 mg) treatment had no significant effect on outcomes. CONCLUSIONS: Gender, antibiotic use, post-treatment NLR, and baseline CTC level are potential predictive biomarkers of irAEs, while baseline PNI, BMI, and post-treatment LDH may predict the severity of irAEs. The predictive effect of irAE occurrence on survival benefit may depend on the type of irAE.

Efficacy and adverse events of immune checkpoint inhibitors in esophageal cancer patients: Challenges and perspectives for immunotherapy.

Esophageal cancer (EC) is the seventh most common cancer worldwide. Patients with EC have a generally poor prognosis mainly due to the lack of effective treatments. Cancer immunotherapy is a promising novel treatment option for EC. This literature review investigated the clinical efficacy of immunotherapy either alone or in combination with chemotherapy or targeted therapy. In addition, we analyzed the adverse events associated with immune checkpoint inhibitors (ICIs). In conclusion, ICIs increase the efficacy of EC treatments, thereby improving the outcomes of EC patients. The findings of this study may help enhance the response to immunotherapy, diminish toxicity, and thus eventually improve medical care for patients with EC.

Encephalitis in a patient with hypopharynx cancer treated with immune checkpoint inhibitors and radiotherapy: a case report and review of the literature.

Hypopharyngeal cancer (HPC) has one of the most unfavorable prognoses among head and neck squamous cell carcinomas. Immunotherapy in combination with chemotherapy, the same as conventional induction chemotherapy, has emerged as a vital part of the induction therapy protocol for HPC. Meanwhile, the incidence of immune-related adverse events is increasing. In this light, we present the first reported case of immune-associated encephalitis in a patient with hypopharyngeal cancer treated with Camrelizumab (a PD-1 inhibitor). After receiving immunotherapy combined with chemotherapy as induction therapy, along with concurrent chemoradiotherapy, the patient presented with symptoms of fatigue, tremors, drowsiness, and an abnormal signal in the right temporal lobe as shown on a brain magnetic resonance imaging (MRI). Despite the minor elevation in protein and IgG index observed in the lumbar puncture, there is no evidence of abnormal autoantibodies or evidence of pathogenic infection. Following a thorough multidisciplinary consultation, the patient is suspected to be afflicted with immune-related autoimmune encephalitis. Intravenous methylprednisolone was prescribed as an empirical treatment at an initial dosage of 120 mg/day for 3 days, followed by steroid tapering. Finally, the patient experienced complete neurologic and radiographic (brain MRI) recovery. This case serves as a critical reminder that encephalitis is a potential diagnosis that should never be overlooked in patients undergoing immunotherapy who present with abnormal signs of the brain. The timely diagnosis and initiation of immunosuppressive therapy are key components of treating ICI-associated encephalitis.

METTL14­mediated RNA methylation in digestive system tumors.

N6­methyladenosine (m6A) RNA methylation is one of the most common post­transcriptional modification mechanism in eukaryotes. m6A is involved in almost all stages of the mRNA life cycle, specifically regulating its stability, splicing, export and translation. Methyltransferase­like 14 (METTL14) is a particularly important m6A methylation 'writer' that can recognize RNA substrates. METTL14 has been documented to improve the activity and catalytic efficiency of METTL3. However, as individual proteins they can also regulate different biological processes. Malignancies in the digestive system are some of the most common malignancies found in humans, which are typically associated with poor prognoses with limited clinical solutions. METTL14­mediated methylation has been implicated in both the potentiation and inhibition of digestive system tumor growth, cell invasion and metastasis, in addition to drug resistance. In the present review, the research progress and regulatory mechanisms of METTL14­mediated methylation in digestive system malignancies were summarized. In addition, future research directions and the potential for its clinical application were examined.

Perioperative Chemotherapy versus Adjuvant Chemotherapy in Patients with Resectable Gastric Cancer: A Systematic Review with meta-analysis.

PURPOSE: The study aimed to investigate the prognosis and safety of perioperative chemotherapy (PC) compared with adjuvant chemotherapy (AC). METHODS: We systematically searched and assessed studies in PubMed, Embase, and the Cochrane Library from inception to 1st September 2022. RESULTS: Eighteen studies were eligible for the analysis, including 4686 patients in total. Our study found that patients with resectable gastric cancer undergoing PC had favorable prognosis on OS (HR 0.77; 95% CI 0.69 to 0.87) and DFS (HR 0.76; 95% CI 0.69 to 0.84) than those who undergoing AC. Addition of neoadjuvant chemotherapy (NAC) to AC provided higher R0 resection rate but did not increase the risk of postoperative complication rate and most of the adverse event rates. CONCLUSION: Our study demonstrated that PC shows better OS and DFS in Asians with resectable gastric cancer compared with AC. PC should be preferred because of its favorable prognosis and similar safety.

Identification of novel serum autoantibody biomarkers for early esophageal squamous cell carcinoma and high-grade intraepithelial neoplasia detection.

Background: Early diagnosis of esophageal squamous cell carcinoma (ESCC) is critical for effective treatment and optimal prognosis; however, less study on serum biomarkers for the early ESCC detection has been reported. The aim of this study was to identify and evaluate several serum autoantibody biomarkers in early ESCC. Methods: We initially screened candidate tumor-associated autoantibodies (TAAbs) associated with ESCC by serological proteome analysis (SERPA) combined with nanoliter-liquid chromatography combined with quadrupole time of flight tandem mass spectrometry (nano-LC-Q-TOF-MS/MS), and the TAAbs were further subjected to analysis by Enzyme-linked immunosorbent assay (ELISA) in a clinical cohort (386 participants, including 161 patients with ESCC, 49 patients with high-grade intraepithelial neoplasia [HGIN] and 176 healthy controls [HC]). Receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic performance. Results: The serum levels of CETN2 and POFUT1 autoantibodies which were identified by SERPA were statistically different between ESCC or HGIN patients and HC in ELISA analysis with the area under the curve (AUC) values of 0.709 (95%CI: 0.654-0.764) and 0.741 (95%CI: 0.689-0.793), 0.717 (95%CI: 0.634-0.800) and 0.703 (95%CI: 0.627-0.779) for detection of ESCC and HGIN, respectively. Combining these two markers, the AUCs were 0.781 (95%CI: 0.733-0.829), 0.754 (95%CI: 0.694-0.814) and 0.756 (95%CI: 0.686-0.827) when distinguishing ESCC, early ESCC and HGIN from HC, respectively. Meanwhile, the expression of CETN2 and POFUT1 was found to be correlated with ESCC progression. Conclusions: Our data suggest that CETN2 and POFUT1 autoantibodies have potential diagnostic value for ESCC and HGIN, which may provide novel insights for early ESCC and precancerous lesions detection.

SLC27A2 mediates FAO in colorectal cancer through nongenic crosstalk regulation of the PPARs pathway.

BACKGROUND: Peroxisome proliferator activated receptors (PPARs) are a nuclear hormone receptors superfamily that is closely related to fatty acid (FA) metabolism and tumor progression. Solute carrier family 27 member 2 (SLC27A2) is important for FA transportation and metabolism and is related to cancer progression. This study aims to explore the mechanisms of how PPARs and SLC27A2 regulate FA metabolism in colorectal cancer (CRC) and find new strategies for CRC treatment. METHODS: Biological information analysis was applied to detect the expression and the correlation of PPARs and SLC27A2 in CRC. The protein-protein interaction (PPI) interaction networks were explored by using the STRING database. Uptake experiments and immunofluorescence staining were used to analyse the function and number of peroxisomes and colocalization of FA with peroxisomes, respectively. Western blotting and qRT‒PCR were performed to explore the mechanisms. RESULTS: SLC27A2 was overexpressed in CRC. PPARs had different expression levels, and PPARG was significantly highly expressed in CRC. SLC27A2 was correlated with PPARs in CRC. Both SLC27A2 and PPARs were closely related to fatty acid oxidation (FAO)‒related genes. SLC27A2 affected the activity of ATP Binding Cassette Subfamily D Member 3 (ABCD3), also named PMP70, the most abundant peroxisomal membrane protein. We found that the ratios of p-Erk/Erk and p-GSK3ß/GSK3ß were elevated through nongenic crosstalk regulation of the PPARs pathway. CONCLUSIONS: SLC27A2 mediates FA uptake and beta-oxidation through nongenic crosstalk regulation of the PPARs pathway in CRC. Targeting SLC27A2/FATP2 or PPARs may provide new insights for antitumour strategies.

Identification of hub genes and potential molecular mechanisms related to radiotherapy sensitivity in rectal cancer based on multiple datasets.

BACKGROUND: Radiotherapy resistance is the main cause of low tumor regression for locally advanced rectum adenocarcinoma (READ). The biomarkers correlated to radiotherapy sensitivity and potential molecular mechanisms have not been completely elucidated. METHODS: A mRNA expression profile and a gene expression dataset of READ (GSE35452) were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differentially expressed genes (DEGs) between radiotherapy responder and non-responder of READ were screened out. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for DEGs were performed. Random survival forest analysis was used to identified hub genes by randomForestSRC package. Based on CIBERSORT algorithm, Genomics of Drug Sensitivity in Cancer (GDSC) database, Gene set variation analysis (GSVA), enrichment analysis (GSEA), nomogram, motif enrichment and non-coding RNA network analyses, the associations between hub genes and immune cell infiltration, drug sensitivity, specific signaling pathways, prognosis prediction and TF - miRNA regulatory and ceRNA network were investigated. The expressions of hub genes in clinical samples were displayed with the online Human Protein Atlas (HPA). RESULTS: In total, 544 up-regulated and 575 down-regulated DEGs in READ were enrolled. Among that, three hubs including PLAGL2, ZNF337 and ALG10 were identified. These three hub genes were significantly associated with tumor immune infiltration, different immune-related genes and sensitivity of chemotherapeutic drugs. Also, they were correlated with the expression of various disease-related genes. In addition, GSVA and GSEA analysis revealed that different expression levels of PLAGL2, ZNF337 and ALG10 affected various signaling pathways related to disease progression. A nomogram and calibration curves based on three hub genes showed excellent prognosis predictive performance. And then, a regulatory network of transcription factor (ZBTB6) - mRNA (PLAGL2) and a ceRNA network of miRNA (has-miR-133b) - lncRNA were established. Finally, the results from HPA online database demonstrated the protein expression levels of PLAGL2, ZNF337 and ALG10 varied widely in READ patients. CONCLUSION: These findings indicated that up-regulation of PLAGL2, ZNF337 and ALG10 in READ associated with radiotherapy response and involved in multiple process of cellular biology in tumor. They might be potential predictive biomarkers for radiotherapy sensitivity and prognosis for READ.

Raltitrexed enhanced antitumor effect of anlotinib in human esophageal squamous carcinoma cells on proliferation, invasiveness, and apoptosis.

BACKGROUND: Anlotinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) which has exhibited encouraging clinical activity in advanced non-small cell lung cancer (NSCLC) and soft tissue sarcoma. Raltitrexed is well known to be effective in the treatment of colorectal cancer in China. The present study aims to investigate the combinatory antitumor effect of anlotinib and raltitrexed on human esophageal squamous carcinoma cells and further explore the molecular mechanisms in vitro. METHODS: Human esophageal squamous cell lines KYSE-30 and TE-1 were treated with anlotinib or raltitrexed, or both, then cell proliferation was measured by MTS and colony formation assay; cell migration and invasion were detected by wound-healing and transwell assays; cell apoptosis rate was studied by flow cytometry and the transcription of apoptosis-associated proteins were monitored by quantitative polymerase chain reaction (qPCR) analysis. Finally, western blot was performed to check phosphorylation of apoptotic proteins after treatment. RESULTS: Treatment with raltitrexed and anlotinib showed enhanced inhibitory effects on cell proliferation, migration and invasiveness compared with raltitrexed or anlotinib monotherapy. Meanwhile, raltitrexed combined with anlotinib strongly increased cell apoptosis percentage. Moreover, the combined treatment down-regulated mRNA level of the anti-apoptotic protein Bcl-2 and invasiveness-associated protein matrix metalloproteinases-9 (MMP-9), while up-regulated pro-apoptotic Bax and caspase-3 transcription. Western blotting showed that the combination of raltitrexed and anlotinib could inhibit the expression of phosphorylated Akt (p-Akt), Erk (p-Erk) and MMP-9. CONCLUSIONS: This study indicated that raltitrexed enhanced the antitumor effects of anlotinib on human ESCC cells by down-regulating phosphorylation of Akt and Erk, providing a novel treatment option for patients with esophageal squamous cell carcinoma (ESCC).

Alteration in the Immune Microenvironment Based on APC Status in MSS/pMMR Colon Cancer.

Introduction: Immunotherapy is currently the most promising antitumor treatment approach. However, the colon cancer immunotherapy indication dMMR/MSI-H do not cover all colon cancer patients suitable for immunotherapy. We performed transcriptome-wide expression profile analyses of pMMR/MSS colon adenocarcinoma (COAD) specimens from TCGA database to identify a genetype signature associated with tumor immune microenvironment types (TIMTs). Methods: TCGA database was used to identify tumor genotypes suitable for antitumor immunotherapy. We analyzed RNA-sequencing profiles of 338 COAD targeted to the pMMR/MSS group from TCGA public dataset. The ESTIMATE and the CIBERSORT were used to analyze the pMMR/MSS COAD immune microenvironment between APC wild and APC mutation. Furthermore, we further verified the relationship between APC genotype and TIMTs and the efficacy of immunotherapy in 42 colon cancer specimens. Results: We identified that in APC-wt/MSS colon cancer, the expressions of PD-1, PD-L1, CTLA4, and CYT (GZMA and PRF1) were increased. The TMB, Immunoscore, and the proportion of CT8+ T cell infiltration also were identified increasing in these patients. And pathway enrichment analysis for differentially expressed genes (DEGs) between APC-wt and APC-mt MSS COAD was done to further explore their biological function. Similarly, the significant pathways for DEGs were mainly enriched in the immune response, extracellular matrix, and cell adhesion which involved in immune response. Specimens from 42 colon cancer patients, including 22 APC-mt/MSS and 20 APC-wt/MSS, were immunohistochemically evaluated for expression of CD8 and PD-L1. And APC-wt/MSS tumors showed significantly higher expression of CD8 and PD-L1 than APC-mt/MSS tumor. Moreover, APC-wt was compared with APC-mt MSS/pMMR colon cancer (DOR, 45% and 26.7%, respectively; P < 0.05). Conclusion: Based on the results, we found that more colon cancers of APC-wt/MSS are classified by TMIT I. And APC-wt/MSS colon cancer patients are more likely to benefit from antitumor immunotherapy.

Absolute eosinophil count may be an optimal peripheral blood marker to identify the risk of immune-related adverse events in advanced malignant tumors treated with PD-1/PD-L1 inhibitors: a retrospective analysis.

BACKGROUND: This study aimed to investigate the predictive values of serum biomarkers including absolute eosinophil count (AEC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) with respect to immune-related adverse events (irAEs) during anti-PD-1/PD-L1 inhibitor treatment in patients with advanced malignant tumors. METHODS: We retrospectively analyzed 95 patients with advanced cancer who were treated with anti-PD-1/PD-L1 inhibitors from January 1, 2017, to May 1, 2020, in our cancer center. We then analyzed associations between irAEs and anti-PD-1/PD-L1 inhibitor responses and evaluated the predictive values of serum biomarkers with respect to the risk of irAEs. RESULTS: The incidence of irAEs was 55.8%. There were no statistically significant differences between the irAEs and no-irAEs groups in an objective response rate (ORR) or disease control rate (DCR). However, landmark analysis showed that the irAEs group had better survival after 120 days following the initiation of anti-PD-1/PD-L1 inhibitor treatment, compared with the no-irAEs group. The incidences of irAEs were greater in the high-AEC and low-NLR groups than in the low-AEC and high-NLR groups. Univariate logistic analysis showed that low NLR, ECOG performance status (0-1), and high AEC were risk factors for irAEs. Multivariate logistic analysis showed that high AEC and good ECOG performance status were independent predictors for irAEs. CONCLUSIONS: irAEs may be associated with a survival benefit. Baseline AEC is a strong predictor of irAEs in patients undergoing treatment with anti-PD-1/PD-L1 inhibitors.

Research Progress of Biomarkers for Immune Checkpoint Inhibitors on Digestive System Cancers.

Immunotherapy represented by immune checkpoint inhibitors has gradually entered a new era of precision medicine. In view of the limited clinical benefits of immunotherapy in patients with digestive system cancers, as well as the side-effects and high treatment costs, development of biomarkers to predict the efficacy of immune therapy is a key imperative. In this article, we review the available evidence of the value of microsatellite mismatch repair, tumor mutation burden, specific mutated genes or pathways, PD-L1 expression, immune-related adverse reactions, blood biomarkers, and patient-related biomarkers in predicting the efficacy of immunotherapy against digestive system cancers. Establishment of dynamic personalized prediction models based on multiple biomarkers is a promising area for future research.

Efficacy and safety of adjuvant EGFR-TKIs for resected non-small cell lung cancer: a systematic review and meta-analysis based on randomized control trials.

BACKGROUND: Postoperative adjuvant cisplatin-based chemotherapy had been the standard care in patients with completely resected high-risk stage IB to IIIA non-small cell lung cancer (NSCLC) for decades. However, the survival benefits were far from satisfactory in clinical practice. Thus, this meta-analysis was performed to compare the efficacy and safety of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with resected NSCLC based on updated literature and research. METHODS: A systematic literature search based on random control trials (RCTs) was conducted with keywords on PubMed, Embase and the Cochrane library databases. All articles compared EGFR-TKIs to placebo or chemotherapy as adjuvant therapies for early-stage resected NSCLC. A meta-analysis was performed to generate combined hazard ratio (HR) with 95% confidence intervals (CI) for disease-free survival (DFS), overall survival (OS), and risk ratio (RR) with 95% CI for disease recurrence and adverse events (AEs). The Stata statistical software (version 14.0) was used to synthesis the data. RESULTS: A total of 9 RCTs comprising 3098 patients were included. Adjuvant EGFR-TKIs could significantly prolong DFS in patient with resected NSCLC harboring epidermal growth factor receptor (EGFR) mutations (HR 0.46, 95% CI 0.29-0.72), but had no impact on OS (HR 0.87, 95% CI 0.69-1.11). The subgroup analyses indicated that adjuvant EGFR-TKIs were superior in regard to DFS in most subgroups, including varied smoking status, EGFR mutations type, gender, age, Eastern Cooperative Oncology Group performance status and adenocarcinoma. Osimertinib resulted in decreased brain recurrence than first generation of EGFR-TKIs (RR 0.12, 95% CI 0.04-0.34 vs. RR 1.07, 95% CI 0.64-1.78, respectively). The AEs were generally manageable and tolerable. The incidence of high-grade (≥ 3) AEs including diarrhea (RR 5.68, 95% CI 2.94-10.98) and rash (RR 27.74, 95% CI 11.43-67.30) increased after adjuvant EGFR-TKIs treatment. CONCLUSIONS: Adjuvant EGFR-TKIs therapy could significantly prolong DFS in patients with completely resected early-stage EGFR mutation-positive NSCLC, but had no impact on OS. Adjuvant EGFR-TKIs could be an important treatment option in patients with resected early-stage EGFR-mutant NSCLC.

The Prognostic Value of Albumin-Globulin Ratio and Eosinophil-Neutrophil Ratio in Patients with Advanced Tumors Undergoing Treatment with PD-1/PD-L1 Inhibitors.

We investigated the prognostic value of peripheral serum biomarkers, including albumin-globulin ratio (AGR) and eosinophil-neutrophil ratio (ENR), in patients with advanced tumors treated with PD-1/PD-L1 inhibitors. We also retrospectively analyzed the clinical efficacy of PD-1/PD-L1 inhibition in 95 patients with advanced tumors treated at our center. The prognostic value of baseline AGR, baseline ENR, and baseline neutrophil-lymphocyte ratio (NLR) in the serum were evaluated. We also developed a risk scoring tool to stratify patients based on their prognosis. Univariate Cox regression analysis revealed that age, NLR, Eastern Cooperative Oncology Group (ECOG) performance status (PS), platelet-neutrophil ratio (PLR), ENR, AGR, lactate dehydrogenase levels, treatment line, and treatment type were correlated with progression-free survival (PFS). Multivariate Cox regression analysis showed that age, AGR, ENR, and treatment type were independent prognostic factors for PFS. Patients in the low-risk group had significantly longer PFS than those in the high-risk group. The nomogram concordance index (C-index) was 0.716. Patients with a decrease in AGR of over 20% after the first and second treatment cycles had significantly worse PFS than those without decreased AGR. These findings suggest that baseline AGR and ENR may be useful prognostic biomarkers for patients with advanced tumors treated with PD-1/PD-L1 inhibitors.

Drug therapy for bone metastasis of malignant tumor: theory, progress, and potential.

Bone is a common metastatic site of malignancies, caused by the complex interaction between tumor cells and the bone microenvironment. The complicated procedure covers multiple targets for therapeutic strategies against bone metastasis. At the present, only bisphosphonates and denosumab are currently approved for the prevention of skeletal-related events. But it is still ineffective for some patients, and none of them are proven to prolong the overall survival of patients with bone metastasis. Thus, new bone-modifying agents and therapeutic strategies are required. The review aimed to generalize the basic theory of bone metastasis and major put emphasis on the development of fundamental and potential target drugs in the behavior of bone metastasis. The summary of the drug development process helps to provide ideas for finding new and effective treatments for bone metastasis.