We present a case of a 43-year-old man with advanced hepatocellular carcinoma (HCC) with portal vein tumour thrombus. Initially, transcatheter arterial chemoembolization (TACE) was performed. ...Although alpha-fetoprotein (AFP) levels decreased, circulating tumour DNA (ctDNA) levels showed an upward trend, and abdominal magnetic resonance imaging (MRI) showed that tumours in the portal vein had increased. Based on ctDNA profiling, apatinib and anti-programmed cell death protein 1 (anti-PD-1) antibodies and were sequentially administered. Approximately three months later, intrahepatic tumours had significantly diminished and AFP and ctDNA levels had reduced. The response was sustained at the 23-month follow-up and the patient was in good health. Combination treatment of TACE, apatinib and anti-PD-1 antibodies was effective, and profiling of ctDNA fragmentation may be beneficial in the therapeutic management of patients with HCC.
To investigate the incidence of FGFR1 amplification in Chinese non-small cell lung cancer (NSCLC) and to preclinically test the hypothesis that the novel, potent, and selective fibroblast growth ...factor receptor (FGFR) small-molecule inhibitor AZD4547 will deliver potent antitumor activity in NSCLC FGFR1-amplified patient-derived tumor xenograft (PDTX) models.
A range of assays was used to assess the translational relevance of FGFR1 amplification and AZD4547 treatment including in vitro lung cell line panel screening and pharmacodynamic (PD) analysis, FGFR1 FISH tissue microarray (TMA) analysis of Chinese NSCLC (n = 127), and, importantly, antitumor efficacy testing and PD analysis of lung PDTX models using AZD4547.
The incidence of FGFR1 amplification within Chinese patient NSCLC tumors was 12.5% of squamous origin (6 of 48) and 7% of adenocarcinoma (5 of 76). AZD4547 displayed a highly selective profile across a lung cell line panel, potently inhibiting cell growth only in those lines harboring amplified FGFR1 (GI(50) = 0.003-0.111 μmol/L). AZD4547 induced potent tumor stasis or regressive effects in four of five FGFR1-amplified squamous NSCLC PDTX models. Pharmacodynamic modulation was observed in vivo, and antitumor efficacy correlated well with FGFR1 FISH score and protein expression level.
This study provides novel epidemiologic data through identification of FGFR1 gene amplification in Chinese NSCLC specimens (particularly squamous) and, importantly, extends the clinical significance of this finding by using multiple FGFR1-amplified squamous lung cancer PDTX models to show tumor stasis or regression effects using a specific FGFR inhibitor (AZD4547). Thus, the translational science presented here provides a strong rationale for investigation of AZD4547 as a therapeutic option for patients with squamous NSCLC tumors harboring amplification of FGFR1.
Since there are few studies exploring genes associated with lymphatic metastasis of thyroid carcinoma (THCA), this study was conducted to explore genes associated with lymphatic metastasis of THCA ...and to investigate the relationship with immune infiltration.
Differentially expressed genes associated with THCA lymphatic metastasis were analyzed based on The Cancer Genome Atlas Program (TCGA) database; a protein-protein interaction(PPI)network was constructed to screen for pivotal genes. Based on the identified hub genes, their expression in THCA with and without lymphatic metastasis were determined. Functional enrichment analysis was performed. The correlation between the identified genes and immune cell infiltration was explored. LASSO logistic regression analysis was performed to determine the risk score of the most relevant gene constructs and multifactor COX regression analysis based on genes in the risk score formula.
A total of 115 genes were differentially expressed in THCA with and without lymphatic metastasis, including 28 upregulated genes and 87 downregulated genes. The PPI network identified seven hub genes (EVA1A, TIMP1, SERPINA1, FAM20A, FN1, TNC, MXRA8); the expression of all seven genes was upregulated in the group with lymphatic metastasis; Immuno-infiltration analysis showed that all seven genes were significantly positively correlated with macrophage M1 and NK cells and negatively correlated with T-cell CD4+ and myeloid dendritic cells. LASSO logistic regression analysis identified the five most relevant genes (EVA1A, SERPINA1, FN1, TNC, MXRA8), and multi-factor COX regression analysis showed EVA1A, SERPINA1 and FN1 as independent prognostic factors.
Seven genes were associated with lymphatic metastasis of THCA and with tumor immune cell infiltration.
Genome-wide chromosomal instability, instead of specific somatic mutations or copy-number alterations in selected genes, is a significant property of cancer and may suggest a new strategy for ...treatment. Here we utilized cell-free DNA (cfDNA) sequencing to display the whole picture of chromosomal instability in patients with metastatic breast cancer (MBC), and evaluate its predictive value for patient survival.
The clinical data of 65 patients who had frozen plasma and planned to change the therapeutic regimen were retrospectively enrolled. Low-coverage whole-genome sequencing of cfDNA was performed to generate the chromosomal instability represented by chromosomal instability (CIN) score.
Tumors with diverse status of hormone receptor and HER2 represented diverse chromosomal instability across the whole genome. According to the receiver operating characteristic curve and the statistical distribution, CIN score exceed 3881 was defined as “High”. 32 (53.3%) patients with high CIN score had similar clinicopathologic characteristics compared with low CIN score patients. The median overall survival of patients with high CIN score was 21.2 months (95% CI 14.1–28.3), which was significantly inferior to those with low CIN score (not reached, P = 0.006). Regardless of various treatment regimens, the median progression free survival in patients with high CIN score was 7.3 months, which was significantly worse than those in the low CIN score population (11.0 months, P = 0.034). Multivariate analysis revealed that CIN score was an independent prognostic factor, with hazard ratio of 3.563 (P = 0.005).
To our knowledge, this is the first study illustrating the prognostic value of chromosomal instability derived from cfDNA in MBC.
•Novel UCAD pipeline to profile genome-wide chromosomal instability in cfDNA.•Genome-wide chromosomal instability is a robust independent prognostic biomarker.•HER2 amplification was successfully identified from cfDNA in our cohort.
Objective
Tic disorders (TDs) are common mental disorders in children and adolescents, and the clinical application of acupuncture for treating TDs is becoming increasingly widespread. However, the ...criteria for selecting acupoint prescriptions and combinations have not been summarized. Therefore, data mining was used herein to determine the treatment principles and the most effective acupoint selection and compatibility criteria for the treatment of TDs.
Methods
Clinical studies and observations of the efficacy of acupuncture treatment for TDs were obtained from the PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang, VIP, and Chinese Biomedical (CBM) databases. The data on the acupoint prescriptions applied in these studies were collected, and network and association analyses were used to reveal the relationships between acupoints and to identify acupoint combinations. Additionally, the principles of acupuncture for TDs were determined through cluster analysis. Subgroup analysis of acupuncture prescriptions based on specific categorical diagnoses was performed to further assess the selection of acupoints.
Results
Eighty-six trials were identified, and 257 groups of effective prescriptions involving 121 acupoints were extracted. Bai-hui (DU20), Feng-chi (GB20), Tai-chong (LR3), He-gu (LI4), and San-yin-jiao (SP6) were the most regularly used acupoints for treating TDs. The Governor Vessel, gallbladder, and large intestine meridians were more commonly used than other meridians. Moreover, most acupoint sites focused on the head and neck. Network analysis revealed potentially effective acupoint prescriptions for their commonly used acupoints, namely, Bai-hui (DU20), Si-shen-cong (EX-HN1), Feng-chi (GB20), Nei-guan (PC6), Shen-men (HT7), He-gu (LI4), Zu-san-li (ST36), San-yin-jiao (SP6) and Tai-chong (LR3). Association rule mining indicated that potential point combinations that should be prioritized in TD treatment are Bai-hui (DU20), Neiguan (PC6) and Sanyinjiao (SP6). Cluster analysis revealed the treatment principle of “coordinating yin and yang, tonifying qi and blood, dispelling pathogenic wind and eliminating phlegm”. The core acupoint prescription of TS treatment comprised He-gu (LI4), Feng-chi (GB20), Tai-chong (LR3), Bai-hui (DU20), Yin-tang (EX-HN3), Si-shen-cong (EX-HN1), San-yin-jiao (SP6), and Nei-guan (PC6). The core group included He-gu (LI4) and Feng-chi (GB20). Proximal points were usually used in TS as an additional method of point selection.
Conclusion
Using data mining analysis of published studies, this study provides valuable information regarding the selection of the most effective acupoints and point combinations for clinical acupuncture practice for treating TDs.
To gain molecular insights of HBV integration that may contribute to HCC tumorigenesis, we performed whole transcriptome sequencing and whole genome copy number profiling of hepatocellular carcinoma ...(HCC) samples from 50 Chinese patients. We identified a total of 33 HBV-human integration sites in 16 of 44 HBV-positive HCC tissues, which were enriched in HBV genotype C-infected patients. In addition, significantly recurrent HBV-MLL4 integration (18%; 8/44) was found in this cohort of patients. Using long-range PCR and Sanger sequencing, we comprehensively characterized gDNA and cDNA sequences that encode for the HBV-MLL4 transcripts, and we revealed that HBV integration into MLL4 exons led to much higher mRNA expression of MLL4 than the integration into MLL4 introns due to an alternative splicing mechanism. Moreover, the HBV-MLL4 integration occurred almost exclusively in CTNNB1 and TP53 wild-type patients. The integration was also associated with a distinct gene expression profile. In conclusion, this is the first report on the molecular basis of the MLL4 integration driving MLL4 over-expression. HBV-MLL4 integration occurred frequently in Chinese HCC patients, representing a unique molecular segment for HCC with HBV infection.
This study aims to provide a better set of DNA methylation markers in urine sediments for sensitive and specific detection of bladder cancer.
Fifty-nine tumor-associated genes were profiled in three ...bladder cancer cell lines, a small cohort of cancer biopsies and urine sediments by methylation-specific PCR. Twenty-one candidate genes were then profiled in urine sediments from 132 bladder cancer patients (8 cases for stage 0a; 68 cases for stage I; 50 cases for stage II; 4 cases for stages III; and 2 cases for stage IV), 23 age-matched patients with noncancerous urinary lesions, 6 neurologic diseases, and 7 healthy volunteers.
Despite six incidences of four genes reported in 3 of 23 noncancerous urinary lesion patients analyzed, cancer-specific hypermethylation in urine sediments were reported for 15 genes (P < 0.05). Methylation assessment of an 11-gene set (SALL3, CFTR, ABCC6, HPR1, RASSF1A, MT1A, RUNX3, ITGA4, BCL2, ALX4, MYOD1, DRM, CDH13, BMP3B, CCNA1, RPRM, MINT1, and BRCA1) confirmed the existing diagnosis of 121 among 132 bladder cancer cases (sensitivity, 91.7%) with 87% accuracy. Significantly, more than 75% of stage 0a and 88% of stage I disease were detected, indicating its value in the early diagnosis of bladder cancer. Interestingly, the cluster of reported methylation markers used in the U.S. bladder cancers is distinctly different from that identified in this study, suggesting a possible epigenetic disparity between the American and Chinese cases.
Methylation profiling of an 11-gene set in urine sediments provides a sensitive and specific detection of bladder cancer.
Non-invasive, especially the urine-based diagnosis of prostate cancer (PCa) remains challenging. Although prostate cancer antigen (PSA) is widely used in prostate cancer screening, the false ...positives may result in unnecessary invasive procedures. PSA elevated patients are triaged to further evaluation of free/total PSA ratio (f/t PSA), to find out potential clinically significant PCa before undergoing invasive procedures. Genomic instability, especially chromosomal copy number variations (CNVs) were proved much more tumor specific. Here we performed a prospective study to evaluate the diagnostic value of CNV via urine-exfoliated cell DNA analysis in PCa.
We enrolled 28 PSA elevated patients (≥ 4 ng/ml), including 16 PCa, 9 benign prostate hypertrophy (BPH) and 3 prostatic intraepithelial neoplasia (PIN). Fresh initial portion urine was collected after hospital admission. Urine exfoliated cell DNA was analyzed by low coverage Whole Genome Sequencing, followed by CNV genotyping by the prostate cancer chromosomal aneuploidy detector (ProCAD). CNVs were quantified in absolute z-score (|Z|). Serum free/total PSA ratio (f/t PSA) was reported altogether.
In patients with PCa, the most frequent CNV events were chr3q gain (n = 2), chr8q gain (n = 2), chr2q loss (n = 4), and chr18q loss (n = 3). CNVs were found in 81.2% (95% Confidence Interval (CI) 53.7-95.0%) PCa. No CNV was identified in BPH patients. A diagnosis model was established by incorporating all CNVs. At the optimal cutoff of |Z|≥ 2.50, the model reached an AUC of 0.91 (95% CI 0.83-0.99), a sensitivity of 81.2% and a specificity of 100%. The CNV approach significantly outperformed f/t PSA (AUC = 0.62, P = 0.012). Further analyses showed that the CNV positive rate was significantly correlated with tumor grade. CNVs were found in 90.9% (95% CI 57.1-99.5%) high grade tumors and 60.0% (95% CI 17.0-92.7%) low grade tumors. No statistical significance was found for patient age, BMI, disease history and family history.
Urine exfoliated cells harbor enriched CNV features in PCa patients. Urine detection of CNV might be a biomarker for PCa diagnosis, especially in terms of the clinically significant high-grade tumors.
Hepatocellular carcinoma (HCC) is the fifth most common type of cancers worldwide. However, current therapeutic approaches for this epidemic disease are limited, and its 5-year survival rate hasn't ...been improved in the past decades. Patient-derived xenograft (PDX) tumor models have become an excellent in vivo system for understanding of disease biology and drug discovery. In order to identify new therapeutic targets for HCC, whole-exome sequencing (WES) was performed on more than 60 HCC PDX models. Among them, four models exhibited protein-altering mutations in JAK1 (Janus Kinase 1) gene. To explore the transforming capability, these mutations were then introduced into HEK293FT and Ba/F3 cells. The results demonstrated that JAK1S703I mutation was able to activate JAK-STAT (Signal Transducer and Activator of Transcription) signaling pathway and drive cell proliferation in the absence of cytokine stimulation in vitro. Furthermore,the sensitivity to the treatment of a JAK1/2 inhibitor, ruxolitinib, was observed in JAK1S703I mutant PDX model, but not in other non-activating mutant or wild type models. Pharmacodynamic analysis showed that phosphorylation of STAT3 in the Ruxolitinib-treated tumor tissues was significantly suppressed. Collectively, our results suggested that JAK1S703I is an activating mutation for JAK-STAT signaling pathway in vitro and in vivo, and JAK-STAT pathway might represent a new therapeutic approach for HCC treatment. Monotherapy using a more potent and specific JAK1 inhibitor and combinatory therapy should be further explored in JAK1 mutant PDX models.
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