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The wide application of low-dose computed tomography (CT) has led to an increase in the detection of small lung cancer lesions. Moreover, surgical recommendations for second primary non-small cell lung cancer (NSCLC) lesions ≤ 2 cm are obscure. This study compares the efficacy of wedge resection, lobectomy, and segmentectomy for small second primary NSCLC lesions.The cohort was established based on the SEER database. Univariate and multivariate cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression, and restricted mean survival time (RMST) values were applied to identify prognostic factors. We used the Kaplan-Meier method to plot the survival curves of the different subgroups according to propensity score matching (PSM) analysis to then compare the therapeutic efficacy of the surgical procedures.A total of 568 patients were enrolled in this study. Age, sex, grade, and lymph node ratio were selected as independent prognostic factors (p 0.05). No significant differences were observed in survival probabilities among the groups of patients who underwent segmentectomy, wedge resection, or lobectomy (p 0.05). We also established a nomogram model based on the four prognostic factors to guide clinical treatment.Based on the findings of our study, segmentectomy was more appropriate than lobectomy for patients with a second primary NSCLC lesion ≤ 2 cm in diameter. The evidence to support other recommendations is insufficient.

Introduction Combining lenvatinib with a programmed cell death protein-1 (PD-1) inhibitor has been explored for the treatment of un-resectable hepatocellular carcinoma (uHCC). This study aimed to investigate the real-world efficacy of and prognostic factors for survival associated with lenvatinib plus PD-1 inhibitor treatment in a large cohort of Asian uHCC patients even the global LEAP-002 study failed to achieve the primary endpoints. Methods Patients with uHCC treated with lenvatinib and PD-1 inhibitors were included. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR) and adverse events (AEs). Prognostic factors for survival were also analyzed. Results A total of 378 uHCC patients from two medical centers in China were assessed retrospectively. The median patient age was 55 years, and 86.5% of patients were male. Hepatitis B virus (HBV) infection (89.9%) was the dominant etiology of uHCC. The median OS was 17.8 (95% confidence interval (CI) 14.0–21.6) months. The median PFS was 6.9 (95% CI 6.0–7.9) months. The best ORR and disease control rate (DCR) were 19.6% and 73.5%, respectively. In multivariate analysis, Child‒Pugh grade, Barcelona Clinic Liver Cancer stage, Eastern Cooperative Oncology Group performance status score, involved organs, tumor burden score, and combination with local therapy were independent prognostic factors for OS. A total of 100% and 57.9% of patients experienced all-grade and grade 3/4 treatment-emergent AEs, respectively. Conclusion This real-world study of lenvatinib plus PD-1 inhibitor treatment demonstrated long survival and considerable ORRs and DCRs in uHCC patients in China. The tolerability of combination therapy was acceptable but must be monitored closely.

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two most common pathology subtypes of primary liver cancer (PLC). Identifying DNA methylation biomarkers for diagnosis of PLC and further distinguishing HCC from ICC plays a vital role in subsequent treatment options selection. To obtain potential diagnostic DNA methylation sites for PLC, differentially methylated CpG (DMC) sites were first screened by comparing the methylation data between normal liver samples and PLC samples (ICC samples and HCC samples). A random forest algorithm was then used to select specific DMC sites with top Gini value. To avoid overfitting, another cohort was taken as an external validation for evaluating the area under curves (AUCs) of different DMC sites combination. A similar model construction strategy was applied to distinguish HCC from ICC. In addition, we identified DNA Methylation-Driven Genes in HCC and ICC via MethylMix method and performed pathway analysis by utilizing MetaCore. Finally, we not only performed methylator phenotype based on independent prognostic sites but also analyzed the correlations between methylator phenotype and clinical factors in HCC and ICC, respectively. To diagnose PLC, we developed a model based on three PLC-specific methylation sites (cg24035245, cg21072795, and cg00261162), whose sensitivity and specificity achieved 98.8%,94.8% in training set and 97.3%,81% in validation set. Then, to further divide the PLC samples into HCC and ICC, we established another mode through three methylation sites (cg17769836, cg17591574, and cg07823562), HCC accuracy and ICC accuracy achieved 95.8%, 89.8% in the training set and 96.8%,85.4% in the validation set. In HCC, the enrichment pathways were mainly related to protein folding, oxidative stress, and glutathione metabolism. While in ICC, immune response, embryonic hepatocyte maturation were the top pathways. Both in HCC and ICC, methylator phenotype correlated well with overall survival time and clinical factors involved in tumor progression. In summary, our study provides the biomarkers based on methylation sites not only for the diagnosis of PLC but also for distinguishing HCC from ICC.

Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. Results: The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included TP53 (53%), KRAS (26%), ARID1A (18%), LRP1B (14%) and CDKN2A (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. TP53 and KRAS mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Conclusions: Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.

p97/VCP, an evolutionarily concerned ATPase, partakes in multiple cellular proteostatic processes, including the endoplasmic reticulum (ER)-associated protein degradation (ERAD). Elevated expression of p97 is common in many cancers and is often associated with poor survival. Here we report that the levels of p97 positively correlated with the histological grade, tumor size, and lymph node metastasis in breast cancers. We further examined p97 expression in the stem-like cancer cells or cancer stem cells (CSCs), a cell population that purportedly underscores cancer initiation, therapeutic resistance, and recurrence. We found that p97 was consistently at a higher level in the CD44+/CD24−, ALDH+, or PKH26+ CSC populations than the respective non-CSC populations in human breast cancer tissues and cancer cell lines and p97 expression also positively correlated with that of SOX2, another CSC marker. To assess the role of p97 in breast cancers, cancer proliferation, mammosphere, and orthotopic growth were analyzed. Similarly as p97 depletion, two pharmacological inhibitors, which targets the ER-associated p97 or globally inhibits p97’s ATPase activity, markedly reduced cancer growth and the CSC population. Importantly, depletion or inhibition of p97 greatly suppressed the proliferation of the ALDH+ CSCs and the CSC-enriched mammospheres, while exhibiting much less or insignificant inhibitory effects on the non-CSC cancer cells. Comparable phenotypes produced by blocking ERAD suggest that ER proteostasis is essential for the CSC integrity. Loss of p97 gravely activated the unfolded protein response (UPR) and modulated the expression of multiple stemness and pluripotency regulators, including C/EBPδ, c-MYC, SOX2, and SKP2, which collectively contributed to the demise of CSCs. In summary, p97 controls the breast CSC integrity through multiple targets, many of which directly affect cancer stemness and are induced by UPR activation. Our findings highlight the importance of p97 and ER proteostasis in CSC biology and anticancer therapy.

BackgroundThe gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims to investigate the relationship between the gut microbiome and the clinical response to anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced hepatobiliary cancers.MethodsPatients with unresectable hepatocellular carcinoma or advanced biliary tract cancers who have progressed from first-line chemotherapy (gemcitabine plus cisplatin) were enrolled. Fresh stool samples were collected before and during anti-PD-1 treatment and analyzed with metagenomic sequencing. Significantly differentially enriched taxa and prognosis associated taxa were identified. The Kyoto Encyclopedia of Genes and Genomes database and MetaCyc database were further applied to annotate the differentially enriched taxa to explore the potential mechanism of the gut microbiome influencing cancer immunotherapy.ResultsIn total, 65 patients with advanced hepatobiliary cancers receiving anti-PD-1 treatment were included in this study. Seventy-four taxa were significantly enriched in the clinical benefit response (CBR) group and 40 taxa were significantly enriched in the non-clinical benefit (NCB) group. Among these taxa, patients with higher abundance of Lachnospiraceae bacterium-GAM79 and Alistipes sp Marseille-P5997, which were significantly enriched in the CBR group, achieved longer progression-free survival (PFS) and overall survival (OS) than patients with lower abundance. Higher abundance of Ruminococcus calidus and Erysipelotichaceae bacterium-GAM147 enriched in the CBR group was also observed in patients with better PFS. In contrast, worse PFS and OS were found in patients with higher abundance of Veillonellaceae, which was significantly enriched in the NCB group. Functional annotation indicated that the taxa enriched in the CBR group were associated with energy metabolism while the taxa enriched in the NCB group were associated with amino acid metabolism, which may modulate the clinical response to immunotherapy in hepatobiliary cancers. In addition, immunotherapy-related adverse events were affected by the gut microbiome diversity and relative abundance.ConclusionsWe demonstrate that the gut microbiome is associated with the clinical response to anti-PD-1 immunotherapy in patients with hepatobiliary cancers. Taxonomic signatures enriched in responders are effective biomarkers to predict the clinical response and survival benefit of immunotherapy, which might provide a new therapeutic target to modulate the response to cancer immunotherapy.

Background/Aims: The incidence of gastric cancer (GC) ranks fifth among common tumors and GC is the third leading cause of cancer-related death worldwide. The aim of this study was to develop and validate a nomogram for predicting the overall survival (OS) of patients with GC. Methods: DNA methylation (DNAm)-driven genes were identified by integrating DNAm and gene expression profiling analyses from The Cancer Genome Atlas (TCGA) GC cohort. Then, a risk score model was built based on Kaplan-Meier (K-M), least absolute shrinkage and selector operation (LASSO), and multivariate Cox regression analyses. After analyzing the clinical parameters, a nomogram was constructed and assessed. Another cohort (GSE62254) was used for external validation. Results: Thirteen differentially expressed DNAm-driven genes were narrowed down to a six-gene signature (PODN, NPY, MICU3, TUBB6 and RHOJ were hypermethylated, and MYO1A was hypomethylated), which was associated with OS (P < 0.05) after survival and LASSO regression analyses. These differentially expressed genes (DEGs) with altered DNAm statuses were included in the prognostic risk score model. The univariate Cox regression analysis indicated that risk score, age, and number of positive lymph nodes were significantly associated with survival time in GC patients. The multivariate Cox regression analysis also indicated that these variables were significant prognostic factors for GC. A nomogram including these variables was constructed, and its performance in predicting the 1-, 3- and 5-year survival outcomes of GC patients was estimated through time-dependent receiver operating characteristic (ROC) curves. In addition, the clinical benefit of this model was revealed by decision curve analysis (DCA). Pathway enrichment analysis suggested that these DNAm-driven genes might impact tumor progression by affecting signaling pathways such as the “ECM RECEPTOR INTERACTION” and “DNA REPLICATION” pathways. Conclusions: The altered status of the DNAm-driven gene signature (PODN, MYO1A, NPY, MICU3, TUBB6 and RHOJ) was significantly associated with the OS of GC patients. A nomogram incorporating risk score, age and number of positive lymph nodes can be conveniently used to facilitate the individualized prediction of OS in patients with GC.

Injecting a room-temperature liquid metal into microchannels offers a simple, rapid, and low-cost method of fabricating microfluidic electrodes. In this work, these electrodes are used to develop a multichannel electroosmotic flow pump for high-flow-rate microfluidic bio analysis applications. In this pump, two identical square-wave shaped liquid metal electrodes were located at both ends of pumping channels on the same horizontal level, and were separated by polydimethylsiloxane gaps from the pumping channels. To test the pumping performance, fluorescent particles were diluted with deionized water and injected into the pumping channels to measure the flow velocity. The results show that the pump with five parallel pumping channels can drive water at a speed of 4.63–45.76 μm/s with applied voltage of 300–1000 V, when the pumping channels are 30 μm high, and 250 μm long with 30-μm polydimethylsiloxane gaps. It can reach its highest possible flow rate of 325 nl/min when the applied voltage reaches its limit 3900V (150 μm long pumping channels, 150 μm long nonpumping channels and 30 μm PDMS gap with 10 parallel pumping channels). This EOF pump should be potential in many high-flow-rate microfluidic applications.

High incidence of recurrency had been a significant threat among glioma patients. Moreover, the performance of traditional therapies among recurrent gliomas was far from satisfying. Advances in the tumor microenvironment (TME) and immune responses on the brain inspired immunotherapy researches. Nevertheless, verification of classic PD-1/PD-L1 inhibitors failed in phase III clinical trials. Additional gene targets were required for future studies among glioma patients. Immune cell infiltration (ICI) scores, defined based on multiple prognostic genes, were proved as the marker for the sensitivity of immunotherapies in many tumors. However, relevant results were not reported in gliomas. In the study, a retrospective cohort of 495 patients was classified into two ICI score subgroups. High ICI scores were closely related to high tumor mutation burden (TMB) values, indicating a high instability of genes. Furthermore, ICI scores were proved as reliable prognostic predictors. And a predictive model was built based on the ICI scores and multiple clinical features. The model showed its superiority through both internal validation and external validation. The ICI scores and the predictive model showed significant clinical values through decision curve analysis (DCA) since high ICI scores were related to high sensitivity for treatment. The prognostic immune-related gene list provided targets for immunotherapy researches.

BackgroundHepatocellular carcinoma (HCC) has a high risk of recurrence after surgical resection, particularly among patients with multifocal HCC. Genomic heterogeneity contributes to the early recurrence. Few studies focus on targeted next-generation sequencing (tNGS) to depict mutational footprints of heterogeneous multifocal HCC.MethodsWe conducted tNGS with an ultra-deep depth on 31 spatially distinct regions from 11 resected multifocal HCC samples. Matched preoperative peripheral circulating-free DNA (cfDNA) were simultaneously collected. Genomic alterations were identified and compared to depict the heterogeneity of multifocal HCC.ResultsWidespread intertumoral heterogeneity of driver mutations was observed in different subfoci of multifocal HCC. The identified somatic mutations were defined as truncal drivers or branchy drivers according to the phylogenetic reconstruction. TP53 and TERT were the most commonly altered truncal drivers in multifocal HCC, while the most frequently mutated branchy driver was TSC2. HCC patients with a higher level of intertumoral heterogeneity, defined by the ratio of truncal drivers less than 50%, had a shorter RFS after surgical resection (HR=0.17, p=0.028). Genome profiling of cfDNA could effectively capture tumor-derived driver mutations, suggesting cfDNA was a non-invasive strategy to gain insights of genomic alterations in patients with resected multifocal HCC.ConclusionsTruncal mutations and the level of genomic heterogeneity could be identified by tNGS panel in patients with resected multifocal HCC. cfDNA could serve as a non-invasive and real-time auxiliary method to decipher the intertumoral heterogeneity and identify oncodrivers of multifocal HCC.

Background: Esophageal cancer (EC) is a lethal malignancy of the digestive tract with high morbidity and mortality rates, lacking molecular biomarkers for EC diagnosis and prognosis with high specificity and sensitivity.Methods: Downloaded from the Cancer Genome Atlas (TCGA), the high-throughput transcriptome sequencing mRNA data was normalized, after which dysregulated genes were identified via limma package. Weight gene coexpression network analysis (WGCNA) was performed to select diagnostic modules and candidate genes. Later, Hub genes were screened through functional enrichment, LASSO Cox regression and survival analysis. Furthermore, we performed comparation with other biomarkers and investigated the association between our target gene and immune microenvironment.Results: Esophageal adenocarcinoma subtype and esophageal squamous cell carcinoma subtype displayed similar expression patterns in terms of differentially expressed genes, which indicates the existence of consensus biomarkers. After a series of analyses, including weighted gene coexpression network analysis, Gene Ontology enrichment analysis and Cox regression analysis, CMA1 was identified as an abnormally upregulated biomarker with highest diagnostic and prognostic potential. Moreover, CMA1 might exert its effect by influencing the immune microenvironment. Conclusion: CMA1 is a potential biomarker for EC in not only diagnosis but also prognosis. Future prospective clinic trials are expected to evaluate its performance in clinical practice.

Background and objectives: Recurrent malignancies had become a significant problem for the treatment of gliomas. Though immunotherapy was regarded as a possible solution, verification of immune-checkpoint inhibitors in multiple clinical cases failed. We aimed to explore target genes for immunotherapy and evaluate the genes through new scoring criteria.Methods: We firstly classified the patients through k-means clustering in immune cell level and gene level. Differential prognostic genes were weighted through principal component analysis (PCA) and Boruta algorithm. The comprehensive scoring of each component was defined as the ICI score. We further analyzed the relationship between ICI score and various clinical factors and prognosis. Moreover, a nomogram based on the ICI scores was built and validated through both internal and external validation.Results: The study cohort finally enrolled 495 patients. We identified a list of differential genes of which the expression level was closely related to prognosis. ICI scores were calculated for each case according to the expression level of prognostic genes. The cases in high ICI score group showed significantly lower survival probabilities (log-rank test; pConclusions: The differential genes were listed for further studies. ICI score had been confirmed to be closely related to prognosis and even genome instability. And the nomogram model based on ICI scores showed the feasibility in clinical practice in both internal and external validation.

BackgroundThis study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers.MethodsThree cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel.ResultsBased on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank pConclusionsThe CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.

BackgroundPD-1/L1 inhibitor-based immunotherapy is currently under investigation in biliary tract cancer (BTC). Apatinib combined with camrelizumab has achieved promising results in various tumor types. The aim of this study was to assess the safety and efficacy of apatinib plus camrelizumab for advanced biliary tract cancer patients who have received previously treatments.MethodsThis prospective, non-randomized, open-label trial was conducted at Peking Union Medical College Hospital (PUMCH). All included patients received apatinib orally at 250 mg per a day and camrelizumab intravenously at 200 mg every three weeks until disease progression or intolerable toxicity occurred. Efficacy was evaluated based on the Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 (RECIST 1.1). Adverse events (AEs) were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0).ResultsA total of 22 patients were consecutively enrolled from 1st December, 2018 until 1st August, 2020. Among 21 patients for whom we could conduct efficacy evaluations, no patients achieved a complete response (CR), 4 patients (19%) achieved partial response (PR), and 11 patients had stable disease with a disease control rate of 71.4%. The median overall survival was 13.1 months (95% CI, 8.1-18.2), and the median progression-free survival was 4.4 months (95% CI, 2.4-6.3). All patients experienced treatment related AEs, and grade 3 or 4 AEs occurred in 14 (63.6%) of 22 patients. No treatment related deaths were observed.ConclusionsThis is the first report focusing on the efficacy and safety of camrelizumab plus apatinib in pretreated biliary tract cancer patients. The finding suggests this regimen has favorable therapeutic effects with relatively manageable toxicity. Further trials with a control arm are required to investigate.Clinical Trial Registrationidentifier NCT04642664.

Glioma is the most common type of primary malignant tumor in the central nervous system. Tumor recurrence and progression are common in lower-grade glioma (LGG). Immune checkpoint blockade (ICB), as an emerging immunotherapy, is expected to improve the prognosis of patients undergoing conventional treatment, but it currently performs poorly in glioma. We divided patients into genome-stable and -unstable groups according to the somatic mutation count and then found that the expression of CDC20 was positively correlated with genomic instability. We compared the differences in long non-coding RNA (lncRNA) expression and immune infiltration between the two groups. Five lncRNAs and three immune cell types were identified to construct risk models and a nomogram combing clinical features. Through internal and external validation, the models exhibited sufficient ability to predict the prognosis and the possible response to ICB therapy of patients. This study provided a potential predictive approach for the precise application of ICB and support for improving the prognosis of LGG patients., Graphical abstract, This study analyzed the genomic instability in lower-grade glioma from the perspective of long non-coding RNA and immune infiltration. Related risk models and a nomogram were constructed and validated to accurately predict patients’ survival outcomes and responses to immune checkpoint blockade therapy.

A paradoxical result of using antibiotics to eradicate microbial pathogens is the emergence of a vast number of resistant microbes in various environments. The concern that environmental microbes will inevitably become resistant to virtually every clinically usable antibiotics has been exacerbated by the spread of these resistance genes across different environments and the emergence of multidrug resistant phenotypes. Here, we provide metagenomic insights into the microbiomes and resistomes of 16 soil samples collected from hospitals, residential areas, and forest parks in the megacity of Beijing and deep forests in the Yunnan province. Using Illumina HiSeq sequencing, we investigated the microbial diversity within the metagenomic shotgun reads and identified 486 antibiotic-resistant genes (ARGs) classified into 30 types from these samples, among which multidrug resistance genes were the most abundant. Our results present an important reference and direct comparison of microbial antibiotic resistomes of soil samples from a megacity and deep forests and extend our understanding of the spread of ARGs in modern urban and natural environments.

Purpose: There is limited standard treatment for patients with advanced cholangiocarcinoma after refractory of chemotherapy. Apatinib is a tyrosine kinase inhibitor targeting VEGFR-2, which exhibited broad-spectrum antitumor activities in previous studies. We aim to evaluate the efficacy and safety of apatinib as non-first-line treatment in patients with advanced cholangiocarcinoma. Methods: This was a prospective open-label phase II trial (NCT03251443). Patients with pathology-confirmed cholangiocarcinoma after prior systemic therapy were enrolled. Participants were treated with apatinib 500 mg orally once daily. The primary end point was overall response rate (ORR). Results: Between August 8, 2017 and November 13, 2018, 30 patients participated in this study, and 26 patients received apatinib treatment except 4 patients withdrew consent before the first dosage. For full analysis set, the ORR was 11.5% and the disease control rate was 50.0%. 3 patients (11.5%) achieved partial response and no patients achieved complete response. The median progression free time was 2.0 (95% CI: 0.7-3.3) months and median overall survival was 9. 0 (95% CI: 4.6-13.4) months. The most common adverse events of any grade were fatigue (80.8%), hypertension (73.1%) and decreased appetite (38.5%). Grade 3 adverse events occurred in 23.1% patients and no grade 4 adverse events occurred. The most common grade 3 adverse events were hypertension (23.1%) and elevated transaminase (11.5%). Conclusion: Apatinib as non-first-line monotherapy has potential therapeutic efficacy in patients with advanced cholangiocarcinoma.

Background A therapeutic strategy involving combined treatment with lenvatinib plus pembrolizumab (LEP) has demonstrated a relatively high antitumor response in several solid tumors; however, the efficacy and safety of LEP in patients with refractory bile tract carcinoma (BTC) remains unknown. Methods This is a single-arm study for a preliminary assessment of the efficacy and tolerability of LEP in patients who experienced progression from prior systemic treatments. Pre-treatment tumor tissues were collected to retrospectively evaluate the expression status of PDL1. Results Thirty-two patients received second-line and above treatment with LEP. Overall, the objective response rate (ORR) was 25%, the disease control rate (DCR) was 78.1%, and the clinical benefit rate (CBR) was 40.5%. The median progression-free survival (PFS) was 4.9 months (95% CI: 4.7-5.2 months), and the median overall survival (OS) was 11.0 months (95% CI: 9.6-12.3 months). For tolerability, no grade 5 serious adverse events (AEs) were reported. All patients had any-grade AEs, and 59.3% of the patients experienced grade 3 AEs, while only 1 patient experienced a grade 4 AE of stomach bleeding. Fatigue was the most common AE, followed by hypertension and elevated aminotransferase levels. Retrospective analysis for PDL1 expression revealed that PDL1 positive tumor cells were associated with improved clinical benefits and survival outcomes. Conclusions LEP is a promising alternative as a non-first-line therapeutic regimen for patients with refractory BTC. Furthermore, well-designed prospective clinical trials with a control arm are still needed to obtain more evidences to confirm the efficacy and safety of this particular regimen as well as the role of PDL1 expression.

Tumour mutation burden (TMB) and the immune microenvironment (IME) are reportedly associated with immunotherapy responses, but this relationship remains unclear in hepatocellular carcinoma (HCC). We classified HCC patients in the liver hepatocellular carcinoma cohort from The Cancer Genome Atlas into low- and high-TMB groups and evaluated differences in immune infiltrates. Additionally, differentially expressed genes in the low- and high-TMB groups were identified, and functional analyses were conducted. A risk score model was constructed based on three differentially expressed immune genes (DEIGs). The Tumor Immune Estimation Resource database was utilized to analyse how the IME was affected by the three hub DEIGs. Finally, a prognostic nomogram combining risk scores and stages was established and externally validated with the International Cancer Genome Consortium and GSE14520 cohorts. High-TMB (top 20%) patients exhibited a worse prognosis (P = 0.017). Follicular helper cells (P = 0.001) and activated natural killer cells (P = 0.003) were enriched in high-TMB patients, while resting dendritic cells (P = 0.002) were enriched in low-TMB samples. A risk score model was generated with three hub DEIGs (CCR7, STC2 and S100A9) to predict overall survival in HCC cohorts. Moreover, copy number variations mainly reduced infiltration levels. The nomogram performed better than the risk score model in the training and validation datasets. Higher TMB was associated with IME diversification and worse prognosis in HCC. Mutations in three hub TMB-associated DEIGs correlated with lower immune cell infiltration.

Colon adenocarcinoma (COAD) is a common noncutaneous carcinoma worldwide with high morbidity and mortality. Effective prevention methods are far from being met. Both diagnostic and prognostic models that can precisely and accurately predict the status and survival time of COAD are urgently needed. In the field of COAD, there have been limited studies on molecular biomarkers that can predict disease status and prognosis. Hence, an important task is to identify these biomarkers. We aimed to identify important risk genes that have the ability not only to diagnose tumors but also to predict overall survival. A comprehensive analysis was performed in this study. Finally, carbonic anhydrase 1 (CA1) and CA4 were identified as potential biomarkers due to their predictive roles in diagnosis and prognosis, and the results were further confirmed by a series of analyses. Overall, these findings are of great importance and may facilitate individualized treatment in diagnosis and prognosis.

The aim of this study was to investigate the expression level of Ras homolog gene family, member A (RhoA) in patients with hepatocellular carcinoma (HCC) and to investigate the prognostic and diagnostic value of RhoA. Data mining from various data bases and wet experiments on samples from Peking Union Medical College Hospital showed that RhoA mRNA and protein expression were significantly higher in the HCC tissues than in the normal tissues. Higher expression at both the mRNA and protein levels was associated with a poorer prognosis. High sensitivity (92.5%) and specificity (90.0%) were observed in the diagnostic model based on protein level rather than mRNA level. RhoA expression was modulated by genetic amplification. The lysosome, pathogenic Escherichia coli infection, purine metabolism and pyrimidine metabolism pathways were mainly enriched in the high RhoA level group, while the hedgehog signaling, linoleic acid metabolism, olfactory transduction and taste transduction pathways were enriched in the low RhoA level group. RhoA is commonly upregulated in HCC tissues, and its expression at both the mRNA and protein levels is associated with poor prognosis. Notably, RhoA protein levels serve as a diagnostic biomarker for HCC.

Background Immune checkpoint inhibitors (ICIs) have been used as a novel treatment for diffuse gliomas, but the efficacy varies with patients, which may be associated with the tumor mutational burden (TMB) and immune infiltration. We aimed to explore the relationship between the two and their impacts on the prognosis. Methods The data of the training set were downloaded from The Cancer Genome Atlas (TCGA). “DESeq2” R package was used for differential analysis and identification of differentially expressed genes (DEGs). A gene risk score model was constructed based on DEGs, and a nomogram was developed combined with clinical features. With the CIBERSORT algorithm, the relationship between TMB and immune infiltration was analyzed, and an immune risk score model was constructed. Two models were verification in the validation set downloaded from the Chinese Glioma Genome Atlas (CGGA). Results Higher TMB was related to worse prognosis, older age, higher grade, and higher immune checkpoint expression. The gene risk score model was constructed based on BIRC5, SAA1, and TNFRSF11B, and their expressions were all negatively correlated with prognosis. The nomogram was developed combined with age and grade. The immune risk score model was constructed based on M0 macrophages, neutrophils, naive CD4+ T cells, and activated mast cells. The proportions of the first two were higher in the high-TMB group and correlated with worse prognosis, while the latter two were precisely opposite. Conclusions In diffuse gliomas, TMB was negatively correlated with prognosis. The association of immune infiltration with TMB and prognosis varied with the type of immune cells. The nomogram and risk score models can accurately predict prognosis. The results can help identify patients suitable for ICIs and potential therapeutic targets, thus improve the treatment of diffuse gliomas.

Background: The aim of this study was to develop and validate a nomogram for predicting the overall survival of patients with gastric cancer (GC). Methods: DNA methylation (DNAm)-driven genes were identified by integrating DNAm and gene expression profiling analyses from The Cancer Genome Atlas (TCGA) GC cohort. Then a risk score model was built based on Kaplan-Meier analysis, the least absolute shrinkage and selector operation (LASSO), and multivariate Cox regression analysis. After analyzing with clinical parameters, a nomogram was conducted and assessed with respect to its calibration, discrimination, and clinical usefulness. Another cohort (GSE62254), retrieved from the Gene Expression Omnibus (GEO), was used for external validation at last. Findings: We built a six-gene signature (PODN, NPY, MICU3, TUBB6 and RHOJ were hypermethylated, and MYO1A was hypomethylated) associated with overall survival (OS) status (P < 0·05). Cox regression analysis indicated that risk score, age, and number of positive lymph nodes were significantly and independently associated with survival time in GC patients. A nomogram including these variables was constructed, which performed well in predicting the 1-, 3- and 5-year survival of GC patients. Pathway enrichment analysis suggested that these DNAm-driven genes might impact tumor progression by affecting signaling pathways such as the "ECM RECEPTOR INTERACTION" and "DNA REPLICATION" ones. Interpretation: The altered status of the DNAm-driven gene signature (PODN, MYO1A, NPY, MICU3, TUBB6 and RHOJ) was significantly associated with the OS of GC patients. A nomogram, incorporating the risk score, age and number of positive lymph nodes, can be conveniently used to facilitate the individualized prediction of OS in patients with GC after surgery. Funding Statement: This work was supported by the International Science and Technology Cooperation Projects (2016YFE0107100), the Capital Special Research Project for Health Development (2014-2-4012), the Beijing Natural Science Foundation (L172055 and 7192158), the National Ten-thousand Talent Program, the Fundamental Research Funds for the Central Universities (3332018032), the CAMS Innovation Fund for Medical Science (CIFMS) (2017-I2M-4-003 and 2018-I2M-3-001), the Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan (IDHT20190510), the Ministry of Science and Technology of People's Republic of China (2014CB910100), and the National Natural Science Foundation of China (81171899 and 81372230). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Not required.