Comparison of the diagnostic performances of US-guided fine needle aspiration cytology and thyroglobulin measurement for lymph node metastases in patients with differentiated thyroid carcinoma: a meta-analysis.

OBJECTIVES: Ultrasound (US)-guided fine needle aspiration cytology (FNAC) and thyroglobulin measurement (FNA-Tg) are two common methods for confirming lymph node metastases (LNM) in patients with differentiated thyroid carcinoma (DTC). This study aimed at comparing the diagnostic performance of FNAC, FNA-Tg alone, and in combination by means of a meta-analysis. METHODS: Eligible articles were selected according to predefined criteria, and their quality was evaluated as per the QUADAS-2 checklist. We calculated pooled sensitivity (Se), specificity (Sp), positive/negative likelihood ratio, and diagnostic odds ratio (DOR), and plotted the summary receiver operating characteristic (SROC) curve using the Meta-DiSc1.4 software. RESULTS: Twenty-one studies pooling 1662 malignant and 1279 benign LNs from 2712 patients with DTC were included. The results showed that FNAC was more specific (pooled Sp, 0.98) while FNA-Tg was more sensitive (pooled Se, 0.94). FNAC and FNAC+FNA-Tg performed better postoperatively than FNA-Tg, while FNA-Tg performed better preoperatively. The combination of FNAC and FNA-Tg could achieve a better diagnostic performance than each alone (DOR 446.00, area under the curve [AUC] 0.9862), no matter preoperatively (DOR 378.14, AUC 0.9879) or postoperatively (DOR 788.72, AUC 0.9930). Besides, the combination of FNAC and FNA-Tg/serum-Tg ratio obtained a higher Sp (0.98) than the combination of FNAC and FNA-Tg. CONCLUSION: The addition of FNA-Tg, especially the FNA-Tg/serum-Tg ratio, to FNAC could increase the diagnostic performance of LNM in both preoperative and postoperative patients with DTC. Since one test or test combinations could perform differently according to the clinical situation, the best-fitting test should be chosen accordingly. KEY POINTS: • FNAC is more specific than FNA-Tg while FNA-Tg is more sensitive than FNAC. • The combination of FNAC and FNA-Tg could achieve a better diagnostic performance than either alone, no matter preoperatively or postoperatively. • The combination of FNAC and FNA-Tg/serum-Tg ratio could reach a higher Sp than the combination of FNAC and FNA-Tg.

Fine needle aspiration biopsy indications for thyroid nodules: compare a point-based risk stratification system with a pattern-based risk stratification system.

OBJECTIVES: We aim to compare the diagnostic performance to assess thyroid nodules and reliability for recommending fine needle aspiration biopsy (FNAB) between American College of Radiology thyroid image reporting and data system (ACR TI-RADS) and American Thyroid Association (ATA) guidelines. METHODS: In total, this retrospective study included 1001 consecutive thyroid nodules in 918 patients from May 2016 to December 2017. US features of the thyroid nodules, including composition, echogenicity, shape, margins, echogenic foci, and size, were reviewed and were classified according to ACR TI-RADS and ATA guidelines, respectively. The diagnostic performance to assess thyroid nodules and reliability for recommending fine needle aspiration biopsy were compared between ACR TI-RADS and ATA guidelines. RESULTS: Of the 1001 thyroid nodules, 609 (60.8%) were benign and 392 (39.2%) were malignant. The sensitivity, specificity, PPV, NPV, and accuracy were 96.7%, 77.3%, 73.3%, 97.3%, and 84.9%, respectively, for ACR TI-RADS and 99.2%, 16.1%, 43.2%, 97.0%, and 48.7%, respectively, for ATA guidelines. AUC of ACR TI-RADS was significantly greater than ATA guidelines (0.935 (0.918, 0.949) vs 0.884 (0.862, 0.903), p < 0.001). Biopsy yield of malignancy, biopsy rate of malignancy, and unnecessary FNAB rate were 59.5%, 91.3%, and 40.5%, respectively, for ACR TI-RDS and 38.5%, 97.4%, and 61.5%, respectively, for ATA guidelines. CONCLUSIONS: ACR TI-RADS was more accurate than ATA guidelines for differentiating malignant thyroid nodules from benign nodules and more reliable than ATA guidelines for recommending thyroid nodules for FNAB. KEY POINTS: • Malignant risk of thyroid nodules can be stratified by ultrasound. • American College of Radiology guidelines were more accurate for differentiating malignant thyroid nodules from benign nodules. • American College of Radiology guidelines were more reliable for recommending thyroid nodules for biopsy.

Serum microRNA profiles as diagnostic biomarkers for HBV-positive hepatocellular carcinoma.

BACKGROUND & AIMS: The discovery of effective and reliable biomarkers to detect hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC) at an early stage may improve the survival of HCC. The aim of this study was to establish serum microRNA (miRNA) profiles as diagnostic biomarkers for HBV-positive HCC. METHODS: We used deep sequencing to screen serum miRNAs in a discovery cohort (n=100). Quantitative polymerase chain reaction (qPCR) assays were then applied to evaluate the expression of selected miRNAs. A diagnostic 2-miRNA panel was established by a logistic regression model using a training cohort (n=182). The predicted probability of being detected as HCC was used to construct the receiver operating characteristic (ROC) curve. Area under the ROC curve (AUC) was used to assess the diagnostic performance of the selected miRNA panel. RESULTS: The predicted probability of being detected as HCC by the 2-miRNA panel was calculated by: logit P=-2.988 + 1.299 × miR-27b-3p + 1.245 × miR-192-5p. These results were further confirmed in a validation cohort (n=246).The miRNA panel provided a high diagnostic accuracy of HCC (AUC=0.842, P<.0001 for training set; AUC=0.836, P<.0001 for validation set respectively). In addition, the miRNA panel showed better prediction of HCC diagnosis than did alpha-foetoprotein (AFP). The miRNA panel also differentiated HCC from healthy (AUC=0.823, P<.0001), and cirrhosis patients (AUC=0.859, P<.0001) respectively. CONCLUSIONS: Differentially expressed serum miRNAs may have considerable clinical value in HCC diagnosis, and be particularly helpful for AFP-negative HCC.

Integrin α6 Targeted Near Infrared Fluorescent Imaging and Photoacoustic Imaging of Hepatocellular Carcinoma in Mice.

Background and Aims: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death and ranks sixth in terms of incident cases worldwide. The purpose of this study was to develop an effective and sensitive method to distinguish liver cancer tissues from normal tissues in HCC patients. Integrin α6 is a promising cell surface target for molecular imaging of HCC, where it is overexpressed and is a prognostic biomarker. We previously identified an integrin α6-targeted peptide CRWYDENAC (RWY) that has been used for positron emission tomography (PET) imaging of HCC in mouse models. Methods: We labeled the integrin α6-targeted RWY peptide with cyanine 7 (Cy7) to form an optical probe (Cy7-RWY) for near infrared fluorescent (NIRF) and photoacoustic (PA) imaging in HCC. Mice transplanted with subcutaneous HCC-LM3 or orthotopic HCC-H22 cells that overexpressed integrin α6 were intravenously injected with Cy7-RWY and its corresponding Cy7-control. NIRF and PA images of mice were collected from 0 to 48 h after injection. Results: Both NIRF and PA signals started to accumulate in the tumor 2 h after injection of Cy7-RWY and peaked at 24 h. Conclusions: Cy7-RWY is a promising optical probe for NIRF and PA imaging of HCC in mice, and has potential clinical application for HCC detection.

NK homeobox 2.2 functions as tumor suppressor in colorectal cancer due to DNA methylation.

Aim: The role of NK homeobox 2.2 (NKX2.2) in human colorectal cancer (CRC) remains to be unveiled. This study was designed to explore the epigenetic regulation and function of NKX2.2 in human CRC. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to assess the methylation data of NKX2.2 in CRC. Six CRC cell lines (HCT116, SW480, HT29, LOVO, SW1116, SW640) and 20 pairs of primary CRC tumor and normal tissues were utilized to explore the function of NKX2.2 in CRC using Sequenom EpiTYPER®, verified by cloning-based bisulfite sequencing analysis, semi-quantitative reverse transcription PCR, western blot, cell viability assessment, plate clone formation assay , and transwell assays. Results: Bioinformatic analysis showed that NKX2.2 was significantly hypermethylated in primary tumors compared to normal tissues (p < 0.05). Our study also found that NKX2.2 methylation was upregulated (p<0.05) in tumors than normal tissues. In vitro experiments demonstrated that 5-aza-2'-deoxycytidine downregulated the methylation of NKX2.2 and retrieved its expression of mRNA and protein levels (p<0.05). No significant association was found between the NKX2.2 methylation and sex, age, tumor differentiation, TNM stage, CEA, CA199, and fecal occult blood (p>0.05). Kaplan-Meier analysis indicated that NKX2.2 hypermethylation showed a trend but not statistical significance for predicting poor overall survival in CRC patients (p=0.33). NKX2.2 overexpression suppressed cell proliferation, colony formation, and inhibited tumor invasion and migration in CRC cells (both p<0.05). Conclusions: This study indicates that NKX2.2 is a tumor suppressor in CRC due to hypermethylation.

Advance in plasma SEPT9 gene methylation assay for colorectal cancer early detection.

This review article summarizes the research advances of the plasma-based SEPT9 gene methylation assay for the clinical detection of colorectal cancer and its limitations. Colorectal cancer is a common malignancy with a poor prognosis and a high mortality, for which early detection and diagnosis are particularly crucial for the high-risk groups. Increasing evidence supported that SEPT9 gene methylation is associated with the pathogenesis of colorectal cancer and that detecting the level of methylation of SEPT9 in the peripheral blood can be used for screening of colorectal cancer in susceptible populations. In recent years, the data obtained in clinical studies demonstrated that the SEPT9 gene methylation assay has a good diagnostic performance with regard to both sensitivity and specificity with the advantage of better acceptability, convenience and compliance with serological testing compared with fecal occult blood tests and carcinoembryonic antigen for colorectal cancer (CRC). Furthermore, the combination of multiple methods or markers has become a growing trend for CRC detection and screening. Nevertheless, the clinical availability of the methylated SEPT9 assay is still limited because of the large degree of sample heterogeneity caused by demographic characteristics, pathological features, comorbidities and/or technique selection. Another factor is the cost-effectiveness of colorectal cancer screening strategies that hinders its large-scale application. In addition, improvements in its accuracy in detecting adenomas and premalignant polyps are required.

Meta-analysis of the clinical characteristics and prognostic relevance of NOTCH1 and FBXW7 mutation in T-cell acute lymphoblastic leukemia.

The NOTCH1 signaling pathway is crucial for T-cell development, and NOTCH1 and/or FBXW7 mutations are frequently detected in T-cell acute lymphoblastic leukemia (T-ALL). We performed a systematic review and meta-analysis of 18 randomized controlled trials (RCTs) to assess the prognostic impact of mutations in the NOTCH1 pathway. After retrieving relevant articles from PubMed, EMBASE, and the Cochrane Library, we investigated overall survival (OS) and event-free survival (EFS) with hazard ratios (HRs) using fixed-effects or random-effects models and conducted subgroup analyses based on population and mutation status. NOTCH1/FBXW7 mutations correlated significantly with better prognosis (5-year EFS: HR, 0.57; 95% confidence interval [CI], 0.46 to 0.68; P < 0.001 and 5-year OS: HR, 0.61; 95% CI, 0.51 to 0.74; P < 0.001). The HR for 5-year EFS and OS with NOTCH1 mutations were 0.63 (95% CI, 0.53 to 0.75) and 0.76 (95% CI, 0.60 to 0.95), respectively; with FBXW7 mutations, they were 0.82 (95% CI, 0.60 to 1.11) and 0.79 (95% CI, 0.55 to 1.12), respectively. However, differences between children and adults showed no significance. We conclude that the presence of NOTCH1/FBXW7 mutations is an independent prognostic factor for 5-year EFS and 5-year OS.

Serum microRNA profiles as prognostic biomarkers for HBV-positive hepatocellular carcinoma.

To establish serum microRNA profiles as prognostic biomarkers in hepatocellular carcinoma patients (HCCs), we used deep sequencing to screen serum microRNAs in a discovery set .Twelve up-regulated serum miRNAs were selected for qPCR analysis in a training set. MiR-192-5p and miR-29a-3p were identified and associated with HCC prognosis. HCCs with high concentrations of miR-192-5p and miR-29a-3p had poorer overall survival (OS) and progression-free survival (PFS) than those with low concentrations. We calculated a prognostic index (PI) score and classified patients into low-, medium- and high-risk groups. OS and PFS among the 3 groups from the training set were significantly different (all P < 0.05). PI (PIOS, PIPFS) score was the only independent prognostic predictor for OS and PFS of HCCs in the training set. These results were further confirmed in a validation set. In conclusion, differentially expressed serum miRNAs can be helpful for predicting survival in HCCs.

SPECT and near-infrared fluorescence imaging of breast cancer with a neuropilin-1-targeting peptide.

Breast cancer is the most common malignant cancer and is the leading cause of cancer death among females. Molecular imaging is a promising approach for the early detection and staging of breast cancer as well as for assessing therapeutic responses. Tumor-targeting peptides are effective targeting vehicles for molecular imaging. Here, we identified a breast cancer-targeting peptide CLKADKAKC (CK3) contains a cryptic C-end rule motif that may mediate its binding to neuropilin-1 (NRP-1), an attractive therapeutic target which expression was associated with poor outcome of the patients with breast cancer. Phage CK3 bound to NRP-1-positive breast cancer cells, which could be inhibited by peptide CK3 in a dose-dependent manner or by knock-down NRP-1 expression. Consistently, NRP-1 overexpression in cells increased the binding of phage CK3. Furthermore, peptide CK3 co-localized with NRP-1. Importantly, unlike previously reported NRP-1-targeting peptides with exposed C-end rule motifs, peptide CK3 did not penetrate into lungs and heart in vivo, which could make it more clinically applicable. Single-photon emission CT (SPECT) and near-infrared fluorescence (NIRF) imaging showed enrichment of peptide CK3 to the xenograft tumors in nude mice. In conclusion, as a novel NRP-1-targeting peptide, peptide CK3 could be used for breast cancer molecular imaging, which may represent a new avenue for breast cancer diagnostics, staging and assessments of therapeutic response.