Prediction of Spread Through Air Spaces (STAS) By Intraoperative Frozen Section for Patients with cT1N0M0 Invasive Lung Adenocarcinoma: A Multi-Center Observational Study (ECTOP-1016).

OBJECTIVE: To investigate the value of intraoperative assessment of spread through air spaces (STAS) on frozen sections (FS) in peripheral small-sized lung adenocarcinoma. BACKGROUND: Surgical decision-making based on FS diagnosis of STAS may be useful to prevent local control failure after sublobar resection. METHODS: We conducted a multicenter prospective observational study of consecutive patients with cT1N0M0 invasive lung adenocarcinoma to evaluate the accuracy of FS for the intraoperative detection of STAS. The final pathology (FP) diagnosis of STAS was based on corresponding permanent paraffin sections. RESULTS: This study included 878 patients with cT1N0M0 invasive lung adenocarcinoma. A total of 833 cases (95%) were assessable for STAS on FS. 26.4% of the cases evaluated positive for STAS on FP, whereas 18.2% on FS. The accuracy, sensitivity, and specificity of FS diagnosis of STAS were 85.1%, 56.4%, and 95.4%, respectively, with moderate agreement (κ=0.575). Inter-observer agreement was substantial (κ=0.756) among the three pathologists. Subgroup analysis based on tumor size or consolidation-to-tumor ratio all showed moderate agreement for concordance. After rigorous reassessment of false-positive cases, the presence of artifacts may be the main cause of interpretation errors. Additionally, true positive cases showed more high-grade histological patterns and more advanced p-TNM stages than false negative cases. CONCLUSIONS: This is the largest prospective observational study to evaluate STAS on FS in patients with cT1N0M0 invasive lung adenocarcinoma. FS is highly specific with moderate agreement, but is not sensitive for STAS detection. While appropriately reporting STAS on FS may provide surgeons with valuable information for intraoperative decision-making, better approaches are needed.

UCK2 regulated by miR-139-3p regulates the progression of hepatocellular carcinoma cells.

Objective: This study mainly explores how UCK2 impacts the progression of hepatocellular carcinoma (HCC). Methods: Mature miRNA and mRNA expression data along with the clinical data of HCC were provided by The Cancer Genome Atlas to mine differentially expressed miRNAs and mRNAs. Expression levels of UCK2 and miR-139-3p in HCC were tested through quantitative real-time PCR. How UCK2 and miR-139-3p impacted HCC cell activities were detected by Transwell, wound healing and cell proliferation approaches. Whether miR-139-3p could bind to UCK2 was detected by dual-luciferase assay. Results: This investigation found evidently high levels of UCK2 in both HCC tissue and cells and its marked association with poor prognosis. Overexpression of UCK2 could significantly promote the behaviors of HCC cells. In addition, poorly expressed miR-139-3p was inversely associated with UCK2. Dual-luciferase method also proved the association. The rescue experiment showed that miR-139-3p regulated cell behaviors in HCC through targeting UCK2. Conclusion: Highly expressed UCK2 was mediated by miR-139-3p to modulate cell behaviors in HCC. It is assumed that UCK2 is a possible target of HCC for cancer therapy purposes.

Globally, a large number of patients succumb to hepatocellular carcinoma (HCC) each year. Only 10­37% patients can undergo surgery because of hepatic failure and advanced tumors. Though the recovery rate after excision is 20­30%, the 5-year survival rate is low, and postoperative recurrence rate is high. Despite the widespread application of HCC screening, only few patients in the early stage have been diagnosed. Hence, it is urgent to explore its potential mechanism. This study investigates the relationship between aberrant expression of mRNA and malignancy of HCC cells. Finally, the abnormally high expression of UCK2 is correlated with patients' low survival rate and poor prognosis.

Prediction of the pathological subtypes by intraoperative frozen section for patients with cT1N0M0 invasive lung adenocarcinoma (ECTOP-1015): a prospective multicenter study.

BACKGROUND: This study aims to assess the diagnostic accuracy of the intraoperative frozen section (FS) in determining the pathological subtypes among patients diagnosed with cT1N0M0 invasive lung adenocarcinoma. MATERIALS AND METHODS: This was a prospective, multicenter (seven centers in China) clinical trial of Eastern Cooperative Thoracic Oncology Projects (ECTOP-1015). Patients with cT1N0M0 invasive lung adenocarcinoma were enrolled in the study. Pathological images obtained from FS and final pathology (FP) were reviewed by at least two pathologists. The primary endpoint was the concordance between FS and FP diagnoses. The interobserver agreement for identifying pathological subtypes on FS was evaluated among three pathologists. RESULTS: A total of 935 patients were enrolled. The best sensitivity of diagnosing the predominant subtype was 78.2% in the evaluation of the acinar pattern. The presence of an acinar pattern diagnosed by FS was an independent factor for the concordance between FS and FP ( P =0.007, 95% confidence interval: 2.332-4.736). Patients with tumor size >2 cm measured by pathology showed a better concordance rate for the predominant subtype (81.6% vs. 74.6%, P =0.023). The presence of radiological ground glass opacity component did not affect the diagnosis accuracy of FS for the predominant subtype (concordance rate: 76.4% vs. 75.2%, P =0.687). Patients with ground glass opacity component showed better accuracy of the identification in the presence of lepidic pattern-predominant adenocarcinoma (82.1% vs. 71.0%, P =0.026). Substantial agreement between the FS diagnosis from three pathologists for the predominant pathological pattern was revealed with κ=0.846. CONCLUSIONS: This is the largest prospective trial evaluating FS diagnosing pathological subtype in cT1N0M0 invasive lung adenocarcinoma. A favorable concordance in the assessment of the pathological subtypes between FS and FP was observed, indicating the feasibility of utilizing accurate intraoperative pathological diagnoses from FS in guiding surgical strategies. A combination of radiology could improve the precision of FS.

MiR-30a-5p hampers proliferation of lung squamous cell carcinoma through targeting FBXO45.

OBJECTIVE: Studies have elaborated the inhibition of miR-30a-5p on the proliferation of cancer cells. However, the regulatory mechanism of how miR-30a-5p works in lung squamous cell carcinoma (LUSC) cells is obscure. METHODS: Data of miRNAs/mRNAs in LUSC tissue (The Cancer Genome Atlas (TCGA)) were accessed. A differential upstream miRNA (miR-30a-5p) was obtained by differential analysis. Downstream target mRNAs were predicted and screened by several databases. The function pathways of target protein in cells were determined by gene set enrichment analysis (GSEA). Abnormal expression levels of FBXO45 and miR-30a-5p were evaluated in three LUSC cell lines. The expression levels of FBXO45 mRNA and miR-30a-5p were analyzed by qRT-PCR. Western blot method was employed to assess protein levels of FBXO45, Cyclin E1, Cdk4 and Cyclin D1. How the two researched genes interact was testified by dual-luciferase method. Cell proliferative ability was compared by CCK-8 and colony formation methods. Moreover, cell cycle was tested by flow cytometry. RESULTS: MiR-30a-5p was tested to be noticeably down-regulated in LUSC cell lines. Up-regulated FBXO45 in LUSC was targeted by miR-30a-5p. Overexpressing miR-30a-5p modulated proliferation and cell cycle in LUSC via inhibiting FBXO45. CONCLUSION: MiR-30a-5p hindered FBXO45 expression to repress the proliferation of LUSC. FBXO45/miR-30a-5p may shed light on future molecular treatment of LUSC.

Landscape of potentially targetable receptor tyrosine kinase fusions in diverse cancers by DNA-based profiling.

Recurrent fusions of receptor tyrosine kinases (RTKs) are often driving events in tumorigenesis that carry important diagnostic value and are potentially targetable by the increasing number of tyrosine kinase inhibitors (TKIs). Here, we characterized the spectrum of 1324 RTK fusions with intact kinase domains in solid tumors by DNA-based high-throughput sequencing. Overall, the prevalence of RTK fusions were 4.7%, with variable frequencies and diverse genomic structures and fusion partners across cancer types. Cancer types, such as thyroid cancers, urological cancers and neuroendocrine tumors are selective in the RTK fusions they carry, while others exhibit highly complex spectra of fusion events. Notably, most RTKs were promiscuous in terms of the partner genes they recombine with. A large proportion of RTK fusions had one of the breakpoints localized to intergenic regions. Comprehensive genomic profiling revealed differences in co-mutational patterns pre- and post-TKI treatments across various RTK fusions. At baseline, multiple cases were detected with co-occurring RTK fusions or concomitant oncogenic mutations in driver genes, such as KRAS and EGFR. Following TKI resistance, we observed differences in potential on- and off-target resistance mutations among fusion variants. For example, the EML4-ALK v3 variant displayed more complex on-target resistance mechanisms, which might explain the reduced survival outcome compared with the v1 variant. Finally, we identified two lung cancer patients with MET+ and NTRK1+ tumors, respectively, who responded well to crizotinib treatment. Taken together, our findings demonstrate the diagnostic and prognostic values of screening for RTK fusions using DNA-based sequencing in solid tumors.