Long-term efficacy and safety of microwave ablation for hepatocellular carcinoma adjacent to the gallbladder with a diameter ≤ 5 cm: a multicenter, propensity score matching study.

OBJECTIVE: To compare the long-term efficacy and safety of microwave ablation (MWA) as first-line therapy for hepatocellular carcinoma (HCC) adjacent versus nonadjacent to the gallbladder. MATERIALS AND METHODS: From 2006 to 2018, 657 patients with ≤5 cm HCC who underwent percutaneous ultrasound-guided MWA as first-line therapy from 5 hospitals were enrolled in this retrospective study. Patients were grouped into the adjacent group (n = 49) and the nonadjacent group (n = 608) according to whether the tumor was adjacent to the gallbladder. Propensity score matching (PSM) was used to balance baseline variables between the two groups. RESULTS: Forty-eight patient pairs were matched after PSM. For the PSM cohort, during a median follow-up time of 60 months, there were no differences in PFS (hazard ratio [HR], 1.011; 95% confidence interval [CI], 0.647-1.578; p = 0.963) or OS (HR 0.925; 95% CI 0.522-1.639; p = 0.789) between the adjacent and nonadjacent groups. Univariate and multivariate analyses revealed that the tumor adjacent to the gallbladder was not an independent risk factor for PFS or OS (all p > 0.05). Subgroup analysis showed comparable PFS and OS between the two groups in the <3 cm subgroup and the 3-5 cm subgroups (all p > 0.05). In addition to more use of assistive technology (p < 0.05), the adjacent group shared comparable local tumor progression, complications, technical success rate, and hospital stay (all p > 0.05) to the nonadjacent group. CONCLUSION: There were comparable long-term efficacy and complications between patients with HCC adjacent and nonadjacent to the gallbladder treated with MWA.

The application of MWA to HCC adjacent and nonadjacent to the gallbladder resulted in comparable PFS and OS and complications.For both cohorts, MWA shared comparable complications (immediate and delayed), LTP, hospitalization, and operative time.MWA might be a first-line alternative for ≤5 cm HCC adjacent to the gallbladder with the use of assistive technologies and advances in technology.

Response to first-line treatment predicts progression-free survival benefit of small-cell lung cancer patients treated with anlotinib.

BACKGROUND: Anlotinib significantly extended progression-free survival (PFS) and overall survival (OS) in small-cell lung cancer (SCLC) as third or later line treatment. METHODS: In this study, we retrospectively analyzed the efficacy and safety of anlotinib in the clinical practice and aimed to identify risk factors for predicting the clinical benefit of anlotinib in SCLC patients. 29 SCLC patients treated with anlotinib monotherapy or combination therapy as second or later line treatment were included. PFS, OS, objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed. RESULTS: In whole patients, the median PFS was 2.1 months (95% confidence interval (CI): 1.1-3.2 months); The ORR and DCR were 10.3% and 48.3%, respectively; The median OS was 7.2 months (95%CI: 3.2-11.2 months). Cox regression analysis demonstrated that response to first-line treatment was the independent risk factor for PFS. The ORR (20.0% vs. 0%) and DCR (53.3% vs. 42.9%) were promoted in patients treated with anlotinib combination therapy comparing to anlotinib monotherapy. The most common AEs were hoarseness, fatigue, decreased appetite, oral mucositis, and anemia. No treatment-related AEs graded 3 or more. CONCLUSION: Anlotinib is an effective option for SCLC patients with tolerable toxicity as second or later line treatment. Patients sensitive to first-line treatment had longer PFS when treated with anlotinib. Anloitnib combined with other therapy increased the efficacy without adding toxicity.

Screening and identification of key genes between liver hepatocellular carcinoma (LIHC) and cholangiocarcinoma (CHOL) by bioinformatic analysis.

BACKGROUND: Liver hepatocellular carcinoma (LIHC) and cholangiocarcinoma (CHOL) are common primary liver cancers worldwide. Liver stem cells have biopotential to differentiate into either hepatocytes and cholangiocytes, the phenotypic overlap between LIHC and CHOL has been acceptable as a continuous liver cancer spectrum. However, few studies directly investigated the underlying molecular mechanisms between LIHC and CHOL. METHOD: To identify the candidate genes between LIHC and CHOL, three data series including GSE31370, GSE15765 and GSE40367 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and function enrichment analyses were performed. The protein-protein interaction network (PPI) was constructed and the module analysis was performed using STRING and Cytoscape. RESULTS: A total of 171 DEGs were identified, consisting of 49 downregulated genes and 122 upregulated genes. Compared with CHOL, the enriched functions of the DEGs mainly included steroid metabolic process, acute inflammatory response, coagulation. Meanwhile, the pathway of KEGG enrichment analyses showed that the upregulated gene(s) were mainly enriched complement and coagulation cascades, cholesterol metabolism and PPAR signaling pathway, while the downregulated gene(s) were mainly enriched in ECM-receptor interaction, focal adhesion, bile secretion. Similarly, the most significant module was identified and biological process analysis revealed that these genes were mainly enriched in regulation of blood coagulation, acute inflammatory response, complement and coagulation cascades. Finally, two (ITIH2 and APOA2) of 10 hub genes had been screened out to help differential diagnosis. CONCLUSION: 171 DEGs and two (ITIH2 and APOA2) of 10 hub genes identified in the present study help us understand the different molecular mechanisms between LIHC and CHOL, and provide candidate targets for differential diagnosis.

CSF1R and HCST: Novel Candidate Biomarkers Predicting the Response to Immunotherapy in Non-Small Cell Lung Cancer.

OBJECTIVE: Precision immunotherapy in non-small cell lung cancer (NSCLC) have been the focus of tumor immunity research. The aim of this study is to identify novel candidate biomarkers predicting the response to immunotherapy in NSCLC. METHODS: GSE126044 was obtained from Gene Expression Omnibus (GEO). According to the response to anti-PD-1 antibody, 2 groups were divided: response group and non-response group. Differentially expressed genes (DEGs) were screened using R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. ROC curves and possible pathways of the seed genes were further analyzed. RESULTS: In total, 588 DEGs (487 upregulated DEGs and 101 downregulated) were identified. GO and KEGG analyses showed that upregulated DEGs were mainly enriched in immune response and cell adhesion pathways, while VEGF signaling pathway and metabolic pathways were mainly enriched in downregulated DEGs. In addition, CSF1 R and HCST showed more powerful predictive ability than PDL1. More importantly, these candidate genes were not only positively correlated with the expression of PDL1 and the infiltration of CD8+ T cells in the immune microenvironment, but also might improve the prognosis in lung squamous cell carcinoma. CONCLUSIONS: CSF1 R and HCST might be novel predictive markers for immunotherapy in NSCLC.

Immune-Stromal Score Signature: Novel Prognostic Tool of the Tumor Microenvironment in Lung Adenocarcinoma.

Background: Immune and stromal cells in the tumor microenvironment (TME) significantly contribute to the prognosis of lung adenocarcinoma; however, the TME-related immune prognostic signature is unknown. The aim of this study was to develop a novel immune prognostic model of the TME in lung adenocarcinoma. Methods: First, the immune and stromal scores among lung adenocarcinoma patients were determined using the ESTIMATE algorithm in accordance with The Cancer Genome Atlas (TCGA) database. Differentially expressed immune-related genes (IRGs) between high and low immune/stromal score groups were analyzed, and a univariate Cox regression analysis was performed to identify IRGs significantly correlated with overall survival (OS) among patients with lung adenocarcinoma. Furthermore, a least absolute shrinkage and selection operator (LASSO) regression analysis was performed to generate TME-related immune prognostic signatures. Gene set enrichment analysis was performed to analyze the mechanisms underlying these immune prognostic signatures. Finally, the functions of hub IRGs were further analyzed to delineate the potential prognostic mechanisms in comprehensive TCGA datasets. Results: In total, 702 intersecting differentially expressed IRGs (589 upregulated and 113 downregulated) were screened. Univariate Cox regression analysis revealed that 58 significant differentially expressed IRGs were correlated with patient prognosis in the training cohort, of which three IRGs (CLEC17A, INHA, and XIRP1) were identified through LASSO regression analysis. A robust prognostic model was generated on the basis of this three-IRG signature. Furthermore, functional enrichment analysis of the high-risk-score group was performed primarily on the basis of metabolic pathways, whereas analysis of the low-risk-score group was performed primarily on the basis of immunoregulation and immune cell activation. Finally, hub IRGs CLEC17A, INHA, and XIRP1 were considered novel prognostic biomarkers for lung adenocarcinoma. These hub genes had different mutation frequencies and forms in lung adenocarcinoma and participated in different signaling pathways. More importantly, these hub genes were significantly correlated with the infiltration of CD4+ T cells, CD8+ T cells, macrophages, B cells, and neutrophils. Conclusions: The robust novel TME-related immune prognostic signature effectively predicted the prognosis of patients with lung adenocarcinoma. Further studies are required to further elucidate the regulatory mechanisms of these hub IRGs in the TME and to develop new treatment strategies.

Identification of candidate genes and prognostic value analysis in patients with PDL1-positive and PDL1-negative lung adenocarcinoma.

BACKGROUND: Increasing bodies of evidence reveal that targeting a programmed cell death protein 1 (PD-1) monoclonal antibody is a promising immunotherapy for lung adenocarcinoma. Although PD receptor ligand 1 (PDL1) expression is widely recognized as the most powerful predictive biomarker for anti-PD-1 therapy, its regulatory mechanisms in lung adenocarcinoma remain unclear. Therefore, we conducted this study to explore differentially expressed genes (DEGs) and elucidate the regulatory mechanism of PDL1 in lung adenocarcinoma. METHODS: The GSE99995 data set was obtained from the Gene Expression Omnibus (GEO) database. Patients with and without PDL1 expression were divided into PDL1-positive and PDL1-negative groups, respectively. DEGs were screened using R. The Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed using the Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction (PPI) networks of DEGs was visualized using Cytoscape, and the MNC algorithm was applied to screen hub genes. A survival analysis involving Gene Expression Profiling Interactive Analysis was used to verify the GEO results. Mutation characteristics of the hub genes were further analyzed in a combined study of five datasets in The Cancer Genome Atlas (TCGA) database. RESULTS: In total, 869 DEGs were identified, 387 in the PDL1-positive group and 482 in the PDL1-negative group. GO and KEGG analysis results of the PDL1-positive group mainly exhibited enrichment of biological processes and pathways related to cell adhesion and the peroxisome proliferators-activated receptors (PPAR) signaling pathway, whereas biological process and pathways associated with cell division and repair were mainly enriched in the PDL1-negative group. The top 10 hub genes were screened during the PPI network analysis. Notably, survival analysis revealed BRCA1, mainly involved in cell cycle and DNA damage responses, to be a novel prognostic indicator in lung adenocarcinoma. Moreover, the prognosis of patients with different forms of lung adenocarcinoma was associated with differences in mutations and pathways in potential hub genes. CONCLUSIONS: PDL1-positive lung adenocarcinoma and PDL1-negative lung adenocarcinoma might be different subtypes of lung adenocarcinoma. The hub genes might play an important role in PDL1 regulatory pathways. Further studies on hub genes are warranted to reveal new mechanisms underlying the regulation of PDL1 expression. These results are crucial for understanding and applying precision immunotherapy for lung adenocarcinoma.

Clinical Analysis and Prognostic Significance of Hepatitis B Virus Infections with Diffuse Large B-Cell Lymphoma.

BACKGROUND: China is a high endemic area for the hepatitis B virus (HBV). The studies established the epidemiology between HBV and diffuse large B-cell lymphoma (DLBCL), but further research is necessary to clarify the potential link between HBV and DLBCL. PATIENTS AND METHODS: A total of 319 patients diagnosed with DLBCL were recruited as cases at First Medical Centre of Chinese PLA General Hospital from September 2010 to December 2018. During the same time, two age- and sex-matched controls were selected for each case, and the control groups comprised of 319 patients with non-hematological malignancy and 319 subjects with non-malignant conditions. Relative risk of developing DLBCL among individuals tested positive for hepatitis B surface antigen was calculated. After that, we retrospectively analyzed clinical data from DLBCL patients with different HBV infection statuses. RESULTS: The HBV infection rate of patients with DLBCL (11.60%) was significantly higher than the other two control groups (5.02% and 4.08%), indicating the risk of DLBCL may increased in HBV infections. Meanwhile, this study demonstrated an independent association between HBV infection and poorer clinical outcomes. CONCLUSION: Our study demonstrated that HBV infection may play an important role in the pathogenesis of DLBCL and show poor outcomes in HBV-endemic China.

Early intervention with supplemental parenteral nutrition reduces the incidence of granulocytopenia-related infections in patients with lung cancer: a retrospective cohort study.

BACKGROUND AND OBJECTIVES: The optimal timing for initiating supplemental parenteral nutrition in chemotherapy- induced severe granulocytopenia in patients with lung cancer remains uncertain. METHODS AND STUDY DESIGN: A retrospective study was conducted among patients with lung cancer from February 2016 to June 2018. In total, 182 eligible patients were included and divided into 2 groups according to the time of supplemental parenteral nutrition intervention: early initiation (within 72 hours of development of granulocytopenia) and late initiation (over 72 hours). The primary outcomes of the study were bacterial infection and fungal infection, and the secondary outcomes were duration of absolute neutrophil count less than 1.0×109 cells/L, length of hospital stay, mortality rate, and rate of chemotherapy (4 cycles) completion. RESULTS: The incidence rates of bacterial infection and fungal infection were significantly lower among patients who received supplemental parenteral nutrition early than among patients who received it late. No significant difference in mortality was observed between the groups. In addition, compared with late supplemental parenteral nutrition, early supplemental parenteral nutrition was associated with a higher rate of completion of 4 chemotherapy cycles and shorter hospital stays and leukocyte recovery periods in our cohort. Univariate and multivariate logistic regression analyses revealed that the subgroup of patients with an NRS-2002 score of 2 benefited from early supplemental parenteral nutrition. CONCLUSIONS: Early supplemental parenteral nutrition after chemotherapy-induced severe granulocytopenia could reduce the risk of infection, improve the likelihood of chemotherapy completion, and shorten hospital stays and leukocyte recovery times.

Isoalantolactone induces apoptosis in human breast cancer cells via ROS-mediated mitochondrial pathway and downregulation of SIRT1.

Isoalantolactone possessed various biological activities. However, whether it could treat breast cancer and its underlying mechanism remained largely unknown. This study was designed to evaluate the anticancer effects of isoalantolactone on breast cancer and explored the molecular mechanism. Two human breast cancer cell lines (MDA-MB-231 and MCF-7) and one normal breast cell line (MCF-10A) were applied. Our data suggested that isoalantolactone decreased breast cancer cell viability in a dose-dependent manner, but showed almost no toxicity to MCF-10A cells. The anticancer effects of isoalantolactone were related to the overexpression of reactive oxygen species. Isoalantolactone significantly induced breast cancer cell apoptosis by activating caspase cascade, cleaving poly (ADP-ribose) polymerase. Increase of Bax/Bcl-2 ratio, depolarization of mitochondrial membrane potential, release of cytochrome c from mitochondria to cytoplasm and cell cycle arrest at G2/M phase were associated to the apoptosis induction. Additionally, isoalantolactone increased the protein expression of p38 MAPK and JNK. The apoptosis-induction of isoalantolactone could be abrogated by co-treatment with SB203580 (inhibitor of p38 MAPK) or SP600125 (inhibitor of JNK). Furthermore, isoalantolactone induced breast cancer cells apoptosis in a caspase-independent pathway, which was downregulation of SIRT1. Therefore, isoalantolactone may serve as a chemotherapeutic agent for the treatment of human breast cancer.

Serum interleukin-33 levels in patients with gastric cancer.

BACKGROUND: Interleukin-33 (IL-33) is a novel member of the IL-1 family of cytokines, and it is closely related to IL-18, one of the best characterized members of the IL-1 family. It's been demonstrated that elevated levels of IL-18 are involved in a wide variety of tumors, especially in gastric cancer. AIMS: The purpose of this study was to determine the correlations between serum IL-33 levels and the clinicopathologic features in gastric cancer patients. METHODS: Serum samples were collected from 68 patients with gastric cancer and 57 controls. Serum IL-33 levels were measured by ELISA. Classical tumor markers of CEA and CA19-9 levels were routinely detected by chemiluminescence immunoassay. Western blot analysis was used to detect IL-33 expression in gastric cancer tissue samples and cell lines. The relationship between serum levels of IL-33 and clinical characteristics in patients was analyzed. RESULTS: IL-33 levels in the serum of gastric cancer patients were significantly elevated in comparison with that of healthy volunteers. Furthermore, higher serum levels of IL-33 in gastric cancer patients were found to correlate with several poor prognostic factors like depth of invasion, distant metastasis and advanced stage (stage III/IV). On the other hand, serum IL-33 levels did not correlate with CEA and CA19-9. The expression of IL-33 protein was upregulated in carcinoma tissues in comparison with matched normal tissues, and no statistically significant difference was found between the four gastric cancer cell lines and human gastric epithelial cell line GES-1. CONCLUSIONS: Serum IL-33 may be a useful biomarker for predicting the prognosis of gastric cancer.

Sp1 upregulates expression of TRF2 and TRF2 inhibition reduces tumorigenesis in human colorectal carcinoma cells.

EXPERIMENTAL DESIGN: Telomere repeat binding factor 2 (TRF2) plays a key role in the protective activity of telomere and is overexpression in several kinds of solid cancer cells. However, the role of overexpressed TRF2 in colorectal carcinoma remains unclear. The aim of this study was to determine the expression of TRF2, address the mechanism of TRF2 overexpression in human colorectal carcinoma. In present study, we examined the expression of TRF2 in colorectal cancer tissues from 39 patients, peritumoral normal tissues from 21 patients, and colon carcinoma SW480 cell line by quantitative PCR, immunohistochemistry and western blot. After siRNA silencing TRF2 expression in SW480, tumorigenesis of TRF2 was tested by cell proliferation, soft agar assay, cytofluorimetric analysis and cytogenetic analysis. To discover transcription factor that mediated TRF2 expression, Chromatin Immunoprecipitation (Chip) Assay and Electrophoretic mobility shift assays (EMSA) were employed. RESULTS: Overexpression of TRF2 protein was detected in SW480 cells and 19 of 39 colorectal carcinoma tissues (49%), no overexpression was observed in 21 of 21 adjacent peritumoral normal colorectal tissues. After siRNA silencing TRF2 expression, the proliferation and colony formation of SW480 cells were significantly inhibited. Defective TRF2 induced apoptosis and increased chromosomal instability in SW480 cells, in which there were more end-to-end fusions and ring chromosomes. Chip assay and EMSA showed that transcription factor Sp1 is involved in upregulation of TRF2. These results indicate that TRF2 is overexpressed in colorectal carcinoma, Sp1 upregulates TRF2 expression, TRF2 inhibition reduces tumorigenesis of colorectal cancer, which suggests that TRF2 and SP1 may become new targets for the development of anti-cancer therapy in colorectal carcinoma.

An shRNA silencing a non-toxic transgene reduces nutrient consumption and increases production of adenoviral vectors in a novel packaging cell.

During production of an adenoviral vector in a packaging cell, transgene is expressed concomitantly with the adenoviral gene. Depending on the protein encoded by the transgene, the yield of an adenoviral vector can be reduced or blocked as a result of transgene expression in the packaging cell. We tested the effect of a short hairpin RNA (shRNA) inhibiting the expression of a transgene encoding hIcon, a therapeutic molecule that selectively destroys pathological angiogenic blood vessels, on the yield of an adenoviral vector containing the transgene. The results showed that the yield of infectious adenoviral vector particles was increased about 10-fold in a novel packaging cell with stable production of an shRNA that can silence the transgene, as compared to the yield in standard packaging line, and the consumption of nutrient in the novel packaging cell line is decreased due to silence of adenoviral transgene expression. The study indicates that shRNA can increase the production of adenoviral vectors by silencing transgene and reducing nutrient consumption of the novel packaging cell. The use of shRNA silencing expression of transgenes encoding therapeutic molecules can reduce the time and cost of producing adenoviral vectors for clinical use.