Whole-exome and targeted gene sequencing of large-cell lung carcinoma reveals recurrent mutations in the PI3K pathway.

BACKGROUND: Large cell lung carcinoma (LCLC) is an exceptionally aggressive disease with a poor prognosis. At present, little is known about the molecular pathology of LCLC. METHODS: Ultra-deep sequencing of cancer-related genes and exome sequencing were used to detect the LCLC mutational in 118 tumor-normal pairs. The cell function test was employed to confirm the potential carcinogenic mutation of PI3K pathway. RESULTS: The mutation pattern is determined by the predominance of A > C mutations. Genes with a significant non-silent mutation frequency (FDR) < 0.05) include TP53 (47.5%), EGFR (13.6%) and PTEN (12.1%). Moreover, PI3K signaling (including EGFR, FGRG4, ITGA1, ITGA5, and ITGA2B) is the most mutated pathway, influencing 61.9% (73/118) of the LCLC samples. The cell function test confirmed that the potential carcinogenic mutation of PI3K pathway had a more malignant cell function phenotype. Multivariate analysis further revealed that patients with the PI3K signaling pathway mutations have a poor prognosis (P = 0.007). CONCLUSIONS: These results initially identified frequent mutation of PI3K signaling pathways in LCLC and indicate potential targets for the treatment of this fatal type of LCLC.

Contrast-enhanced US Evaluation of Hepatocellular Carcinoma Response to Chemoembolization: A Prospective Multicenter Trial.

Background Contrast-enhanced (CE) US has been studied for use in the detection of residual viable hepatocellular carcinoma (HCC) after locoregional therapy, but multicenter data are lacking. Purpose To compare two-dimensional (2D) and three-dimensional (3D) CE US diagnostic performance with that of CE MRI or CT, the current clinical standard, in the detection of residual viable HCC after transarterial chemoembolization (TACE) in a prospective multicenter trial. Materials and Methods Participants aged at least 21 years with US-visible HCC scheduled for TACE were consecutively enrolled at one of three participating academic medical centers from May 2016 to March 2022. Each underwent baseline 2D and 3D CE US before TACE, 2D and 3D CE US 1-2 weeks and/or 4-6 weeks after TACE, and CE MRI or CT 4-6 weeks after TACE. CE US and CE MRI or CT were evaluated by three fellowship-trained radiologists for the presence or absence of viable tumors and were compared with reference standards of pathology (18%), angiography on re-treatment after identification of residual disease at 1-2-month follow-up imaging (31%), 4-8-month CE MRI or CT (42%), or short-term (approximately 1-2 months) CE MRI or CT if clinically decompensated and estimated viability was greater than 50% at imaging (9%). Diagnostic performance criteria, including sensitivity and specificity, were obtained for each modality and time point with generalized estimating equation analysis. Results A total of 132 participants were included (mean age, 64 years ± 7 [SD], 87 male). Sensitivity of 2D CE US 4-6 weeks after TACE was 91% (95% CI: 84, 95), which was higher than that of CE MRI or CT (68%; 95% CI: 58, 76; P < .001). Sensitivity of 3D CE US 4-6 weeks after TACE was 89% (95% CI: 81, 94), which was higher than that of CE MRI or CT (P < .001), with no evidence of a difference from 2D CE US (P = .22). CE MRI or CT had 85% (95% CI: 76, 91) specificity, higher than that of 4-6-week 2D and 3D CE US (70% [95% CI: 56, 80] and 67% [95% CI: 53, 78], respectively; P = .046 and P = .023, respectively). No evidence of differences in any diagnostic criteria were observed between 1-2-week and 4-6-week 2D CE US (P > .21). Conclusion The 2D and 3D CE US examinations 4-6 weeks after TACE revealed higher sensitivity in the detection of residual HCC than CE MRI or CT, albeit with lower specificity. Importantly, CE US performance was independent of follow-up time. Clinical trial registration no. NCT02764801 © RSNA, 2023 Supplemental material is available for this article.

Ultrasound-Based Machine Learning Approach for Detection of Nonalcoholic Fatty Liver Disease.

OBJECTIVES: Current diagnosis of nonalcoholic fatty liver disease (NAFLD) relies on biopsy or MR-based fat quantification. This prospective study explored the use of ultrasound with artificial intelligence for the detection of NAFLD. METHODS: One hundred and twenty subjects with clinical suspicion of NAFLD and 10 healthy volunteers consented to participate in this institutional review board-approved study. Subjects were categorized as NAFLD and non-NAFLD according to MR proton density fat fraction (PDFF) findings. Ultrasound images from 10 different locations in the right and left hepatic lobes were collected following a standard protocol. MRI-based liver fat quantification was used as the reference standard with >6.4% indicative of NAFLD. A supervised machine learning model was developed for assessment of NAFLD. To validate model performance, a balanced testing dataset of 24 subjects was used. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy with 95% confidence interval were calculated. RESULTS: A total of 1119 images from 106 participants was used for model development. The internal evaluation achieved an average precision of 0.941, recall of 88.2%, and precision of 89.0%. In the testing set AutoML achieved a sensitivity of 72.2% (63.1%-80.1%), specificity of 94.6% (88.7%-98.0%), positive predictive value (PPV) of 93.1% (86.0%-96.7%), negative predictive value of 77.3% (71.6%-82.1%), and accuracy of 83.4% (77.9%-88.0%). The average agreement for an individual subject was 92%. CONCLUSIONS: An ultrasound-based machine learning model for identification of NAFLD showed high specificity and PPV in this prospective trial. This approach may in the future be used as an inexpensive and noninvasive screening tool for identifying NAFLD in high-risk patients.

Sentinel Lymph Node Identification in Post Neoadjuvant Chemotherapy Breast Cancer Patients Undergoing Surgical Excision Using Lymphosonography.

OBJECTIVES: This study evaluated the efficacy of lymphosonography in the identification of sentinel lymph nodes (SLNs) in post neoadjuvant chemotherapy patients with breast cancer scheduled to undergo surgical excision. METHODS: Seventy-nine subjects scheduled for breast cancer surgery with SLN excision completed this IRB-approved study, out of which 18 (23%) underwent neoadjuvant chemotherapy before surgery. Subjects underwent percutaneous Sonazoid (GE Healthcare) injections around the tumor area for a total of 1.0 mL. Lymphosonography was performed using CPS on an S3000 HELX scanner (Siemens Healthineers) with a linear probe. Subjects received blue dye and radioactive tracer as part of their standard of care. Excised SLNs were classified as positive or negative for the presence of blue dye, radioactive tracer and Sonazoid. The results were compared between methods and pathology findings. RESULTS: Seventy-two SLNs were surgically excised from 18 subjects, 29 were positive for blue dye, 63 were positive for radioactive tracer and 57 were positive for Sonazoid. Comparison with blue dye showed that both radioactive tracer and lymphosonography achieved an accuracy of 53% (P > .50). Comparison with radioactive tracer showed that blue dye had an accuracy of 53%, while lymphosonography achieved an accuracy of 67% (P < .01). Of the 72 SLNs, 15 were determined malignant by pathology; the detection rate was 47% for blue dye (7/15), 67% for radioactive tracer (10/15) and 100% for lymphosonography (15/15) (P < .001). CONCLUSIONS: Lymphosonography achieved similar accuracy as radioactive tracer and higher accuracy than blue dye for identifying SLNs. The 15 SLNs positive for malignancy were all identified by lymphosonography.

Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring.

Primary lung cancer is one of the most common malignant tumors in China. Approximately 60% of lung cancer patients have distant metastasis at the initial diagnosis, so it is necessary to find new tumor markers for early diagnosis and individualized treatment. Tumor markers contribute to the early diagnosis of lung cancer and play important roles in early detection and treatment, as well as in precision medicine, efficacy monitoring, and prognosis prediction. The pathological diagnosis of lung cancer in small biopsy specimens determines whether there are tumor cells in the biopsy and tumor type. Because biopsy is traumatic and the compliance of patients with multiple biopsies is poor, liquid biopsy has become a hot research direction. Liquid biopsies are advantageous because they are nontraumatic, easy to obtain, reflect the overall state of the tumor, and allow for real-time monitoring. At present, liquid biopsies mainly include circulating tumor cells, circulating tumor DNA, exosomes, microRNA, circulating RNA, tumor platelets, and tumor endothelial cells. This review introduces the research progress and clinical application prospect of liquid biopsy technology for lung cancer.

Contrast-Enhanced Ultrasound in Small Intestinal Ischemia: Proof of Concept.

BACKGROUND: Small intestinal ischemia is a challenging diagnosis to make, even with the combination of imaging, laboratory analysis, and physical exam. This pilot study investigated the role of CEUS in evaluating small bowel wall vascularity in participants with suspected ischemia. METHODS: In this IRB-approved pilot study, CEUS using perflutren lipid microspheres (DEFINITY®; Lantheus Medical Imaging Inc., N. Billerica, MA) was performed on participants determined by the clinical surgical team to have concerns for small intestinal ischemia. CEUS interpretations were performed at both the bedside and later by a blinded radiologist and compared to clinical imaging, surgical findings, or long-term clinical outcomes. RESULTS: Fifteen CEUS examinations were performed on 14 participants. Five of the participants underwent exploratory laparotomy. Of these, one had small intestinal ischemia (without necrosis). Point of care CEUS demonstrated no evidence of bowel necrosis in any case, and delayed enhancement (indicative of intestinal ischemia) in three cases, resulting in a sensitivity of 100% (95% CI 2.5-100%) and specificity of 85.7% (95% CI 57.2-98.2%). CEUS correctly ruled out ischemia in 91.7% of cases with CT suspicion of small bowel obstruction and 60% of cases that underwent surgical intervention. Additionally, the rate of agreement between bedside interpretation and later radiologist read was high (93%). CONCLUSIONS: CEUS is uniquely positioned for evaluating the small intestine, because of its high temporal resolution and immediacy of results. Combined with multi-sectional imaging for focal areas of ischemia and/or clinical suspicion for pan ischemia, CEUS may be a useful rule out test for small intestinal ischemia.

The power and the promise of circRNAs for cancer precision medicine with functional diagnostics and prognostic prediction.

Circular RNA (circRNA) is a large class of covalently closed circRNA. As a member of competitive endogenous RNA, it participates in the regulation of circRNA-miRNA-mRNA network and plays an important role in the regulation of physiology and pathology. CircRNA is produced by the reverse splicing of exon, intron or both, forming exon or intron circRNA. Studies have shown that circRNA is a ubiquitous molecule, which exceeds the linear mRNA distributed in human cells. Because of its covalent closed-loop structure, circRNA is resistant to RNase R, which is more stable than linear mRNA; circRNA is highly conserved in different species. It was found that circRNA competitively adsorbs miRNA, as a miRNA sponge, to involve in the expression regulation of a variety of genes and plays an important role in tumor development, invasion, metastasis and other processes. These molecules offer new potential opportunities for therapeutic intervention and serve as biomarkers for diagnosis. In this paper, the origin, characteristics and functions of circRNA and its role in tumor development, invasion and metastasis, diagnosis and prognosis are reviewed.

microRNA-320b suppresses HNF4G and IGF2BP2 expression to inhibit angiogenesis and tumor growth of lung cancer.

We examined the effect of microRNA-320b (miR-320b) on tumor growth and angiogenesis in lung cancer and also determined its downstream molecular mechanisms. Lung cancer tissues and adjacent non-cancerous tissues were collected from 66 patients with lung cancer. miR-320b expression was experimentally determined to be expressed at low level in cancer tissues. The results of gain-of-function experiments suggested that miR-320b overexpression suppressed cancer cell invasion, tube formation, tumor volume and angiogenesis in xenografted nude mice. Hepatocyte nuclear factor 4 gamma (HNF4G) was identified as a target of miR-320b based on in silico analysis. Dual-luciferase reporter gene assays further identified the binding relationship between HNF4G and miR-320b. Lung cancer tissues exhibited increased expression of HNF4G and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Meanwhile, HNF4G knockdown suppressed IGF2BP2 expression, thereby repressing cancer cell invasion and tube formation. Furthermore, IGF2BP2 modified m6A to increase the expression of thymidine kinase 1 (TK1), thus promoting angiogenesis. In nude mice, restoration of TK1 reversed the suppressive effect of miR-320b overexpression on tumor growth rate and CD31 expression. In conclusion, miR-320b suppresses lung cancer growth and angiogenesis by inhibiting HNF4G, IGF2BP2 and TK1.

Cancer-associated fibroblast-derived exosomal microRNA-24-3p enhances colon cancer cell resistance to MTX by down-regulating CDX2/HEPH axis.

MicroRNA-24-3p (miR-24-3p) has been implicated as a key promoter of chemotherapy resistance in numerous cancers. Meanwhile, cancer-associated fibroblasts (CAFs) can secret exosomes to transfer miRNAs, which mediate tumour development. However, little is known regarding the molecular mechanism of CAF-derived exosomal miR-24-3p in colon cancer (CC). Hence, this study intended to characterize the functional relevance of CAF-derived exosomal miR-24-3p in CC cell resistance to methotrexate (MTX). We identified differentially expressed HEPH, CDX2 and miR-24-3p in CC through bioinformatics analyses, and validated their expression in CC tissues and cells. The relationship among HEPH, CDX2 and miR-24-3p was verified using ChIP and dual-luciferase reporter gene assays. Exosomes were isolated from miR-24-3p inhibitor-treated CAFs (CAFs-exo/miR-24-3p inhibitor), which were used in combination with gain-of-function and loss-of-function experiments and MTX treatment. CCK-8, flow cytometry and colony formation assays were conducted to determine cell viability, apoptosis and colony formation, respectively. Based on the findings, CC tissues and cells presented with high expression of miR-24-3p and low expression of HEPH and CDX2. CDX2 was a target gene of miR-24-3p and could up-regulate HEPH. Under MTX treatment, overexpressed CDX2 or HEPH and down-regulated miR-24-3p reduced cell viability and colony formation and elevated cell apoptosis. Furthermore, miR-24-3p was transferred into CC cells via CAF-derived exosomes. CAF-derived exosomal miR-24-3p inhibitor diminished cell viability and colony formation and increased cell apoptosis in vitro and inhibited tumour growth in vivo under MTX treatment. Altogether, CAF-derived exosomal miR-24-3p accelerated resistance of CC cells to MTX by down-regulating CDX2/HEPH axis.

KDM5A silencing transcriptionally suppresses the FXYD3-PI3K/AKT axis to inhibit angiogenesis in hepatocellular cancer via miR-433 up-regulation.

Hepatocellular cancer (HCC) has been reported to belong to one of the highly vascularized solid tumours accompanied with angiogenesis of human umbilical vein endothelial cells (HUVECs). KDM5A, an attractive drug target, plays a critical role in diverse physiological processes. Thus, this study aims to investigate its role in angiogenesis and underlying mechanisms in HCC. ChIP-qPCR was utilized to validate enrichment of H3K4me3 and KDM5A on the promotor region of miR-433, while dual luciferase assay was carried out to confirm the targeting relationship between miR-433 and FXYD3. Scratch assay, transwell assay, Edu assay, pseudo-tube formation assay and mice with xenografted tumours were conducted to investigate the physiological function of KDM5A-miR-433-FXYD3-PI3K-AKT axis in the progression of HCC after loss- and gain-function assays. KDM5A p-p85 and p-AKT were highly expressed but miR-433 was down-regulated in HCC tissues and cell lines. Depletion of KDM5A led to reduced migrative, invasive and proliferative capacities in HCC cells, including growth and a lowered HUVEC angiogenic capacity in vitro. Furthermore, KDM5A suppressed the expression of miR-433 by demethylating H3K4me3 on its promoterregion. miR-433 negatively targeted FXYD3. Depleting miR-433 or re-expressing FXYD3 restores the reduced migrative, invasive and proliferative capacities, and lowers the HUVEC angiogenic capacity caused by silencing KDM5A. Therefore, KDM5A silencing significantly suppresses HCC tumorigenesis in vivo, accompanied with down-regulated miR-433 and up-regulated FXYD3-PI3K-AKT axis in tumour tissues. Lastly, KDM5A activates the FXYD3-PI3K-AKT axis to enhance angiogenesis in HCC by suppressing miR-433.

US-triggered Microbubble Destruction for Augmenting Hepatocellular Carcinoma Response to Transarterial Radioembolization: A Randomized Pilot Clinical Trial.

Background US contrast agents are gas-filled microbubbles (MBs) that can be locally destroyed by using external US. Among other bioeffects, US-triggered MB destruction, also known as UTMD, has been shown to sensitize solid tumors to radiation in preclinical models through localized insult to the vascular endothelial cells. Purpose To evaluate the safety and preliminary efficacy of combining US-triggered MB destruction and transarterial radioembolization (TARE) in participants with hepatocellular carcinoma (HCC). Materials and Methods In this pilot clinical trial, participants with HCC scheduled for sublobar TARE were randomized to undergo either TARE or TARE with US-triggered MB destruction 1-4 hours and approximately 1 and 2 weeks after TARE. Enrollment took place between July 2017 and February 2020. Safety of US-triggered MB destruction was evaluated by physiologic monitoring, changes in liver function tests, adverse events, and radiopharmaceutical distribution. Treatment efficacy was evaluated by using modified Response Evaluation Criteria in Solid Tumors (mRECIST) on cross-sectional images, time to required next treatment, transplant rates, and overall survival. Differences across mRECIST reads were compared by using a Mann-Whitney U test, and the difference in prevalence of tumor response was evaluated by Fisher exact test, whereas differences in time to required next treatment and overall survival curves were compared by using a log-rank (Mantel-Cox) test. Results Safety results from 28 participants (mean age, 70 years ± 10 [standard deviation]; 17 men) demonstrated no significant changes in temperature (P = .31), heart rate (P = .92), diastolic pressure (P = .31), or systolic pressure (P = .06) before and after US-triggered MB destruction. No changes in liver function tests between treatment arms were observed 1 month after TARE (P > .15). Preliminary efficacy results showed a greater prevalence of tumor response (14 of 15 [93%; 95% CI: 68, 100] vs five of 10 [50%; 95% CI: 19, 81]; P = .02) in participants who underwent both US-triggered MB destruction and TARE (P = .02). Conclusion The combination of US-triggered microbubble destruction and transarterial radioembolization is feasible with an excellent safety profile in this patient population and appears to result in improved hepatocellular carcinoma treatment response. © RSNA, 2020.

Long non-coding RNA NORAD promotes pancreatic cancer stem cell proliferation and self-renewal by blocking microRNA-202-5p-mediated ANP32E inhibition.

BACKGROUND: Cancer stem cells (CSCs) are key regulators in the processes of tumor initiation, progression, and recurrence. The mechanism that maintains their stemness remains enigmatic, although the role of several long noncoding RNAs (lncRNAs) has been highlighted in the pancreatic cancer stem cells (PCSCs). In this study, we first established that PCSCs overexpressing lncRNA NORAD, and then investigated the effects of NORAD on the maintenance of PCSC stemness. METHODS: Expression of lncRNA NORAD, miR-202-5p and ANP32E in PC tissues and cell lines was quantified after RNA isolation. Dual-luciferase reporter assay, RNA pull-down and RIP assays were performed to verify the interactions among NORAD, miR-202-5p and ANP32E. We then carried out gain- and loss-of function of miR-202-5p, ANP32E and NORAD in PANC-1 cell line, followed by measurement of the aldehyde dehydrogenase activity, cell viability, apoptosis, cell cycle distribution, colony formation, self-renewal ability and tumorigenicity of PC cells. RESULTS: LncRNA NORAD and ANP32E were upregulated in PC tissues and cells, whereas the miR-202-5p level was down-regulated. LncRNA NORAD competitively bound to miR-202-5p, and promoted the expression of the miR-202-5p target gene ANP32E thereby promoting PC cell viability, proliferation, and self-renewal ability in vitro, as well as facilitating tumorigenesis of PCSCs in vivo. CONCLUSION: Overall, lncRNA NORAD upregulates ANP32E expression by competitively binding to miR-202-5, which accelerates the proliferation and self-renewal of PCSCs.

Combined hepatocellular-cholangiocarcinoma: can we use contrast-enhanced ultrasound Liver Imaging Reporting and Data System (LI-RADS) to predict the patient's survival?

OBJECTIVES: To evaluate the relationship between contrast-enhanced (CE) ultrasound Liver Reporting and Data System (LI-RADS) classification of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and their histopathological component predominance, and to determine if the CEUS LI-RADS category can be used to predict the patient's survival after surgical resection. METHODS: Between January 2011 and December 2018, medical records and CEUS of patients with pathologically proven cHCC-CCA were studied. The predominance of hepatocellular carcinoma (HCC)/intrahepatic cholangiocarcinoma (ICC) component of cHCC-CCA was analyzed by histopathology. The proportion of HCC-predominant cHCC-CCA in different LI-RADS category was compared by using Fisher's exact test. Factors affecting tumor recurrence were analyzed by Cox proportional hazard model. Disease-free survival (DFS) was estimated by using Kaplan-Meier survival curve and compared by log-rank test. RESULTS: The study included 37 cHCC-CCA patients (33 men, 4 women; average age, 50.4 ± 11.0 years) and 37 nodules (mean diameter, 6.1 ± 3.9 cm). According to CEUS LI-RADS, 62.2% (23/37), 18.9% (7/37), and 18.9% (7/37) of cHCC-CCA were classified as LR-M, LR-5, and LR-TIV, respectively. The ratio of HCC predominance in LR-5 was 100% (10/10) vs 81.5% (22/27) in the LR-M group (p = 0.591). In our population, LR-5 patients had longer DFS than LR-M and LR-TIV patients combined (median DFS: 18.0 vs 6.4 months, p = 0.016). Multiple lesions (hazard ratio, 3.1; p = 0.007), tumor size (≥ 5 cm, hazard ratio, 4.1; p = 0.003), and CEUS LI-RADS category (LR-M and LR-TIV, hazard ratio, 4.7; p = 0.011) showed independent association with shorter DFS. CONCLUSION: cHCC-CCA characterized as LR-5 on CEUS tend to represent HCC-predominant tumors with significantly longer disease-free survival compared to cHCC-CCA categorized as LR-M and LR-TIV. KEY POINTS: • By using the American College of Radiology contrast-enhanced ultrasound Liver Imaging Reporting and Data System (CEUS LI-RADS), majority (30/37, 81.1%) of cHCC-CCA tumors were classified as LR-M or LR-TIV and only 18.9% (7/30) of cHCC-CCA were categorized as LR-5. • Patients with CEUS LR-5 cHCC-CCA had statistically significant longer disease-free time than those with LR-M and TIV cHCC-CCA (median DFS: 18.0 vs 6.4 months, p = 0.016). • Multiple lesions (hazard ratio, 3.1; p = 0.007), tumor size (≥ 5 cm, hazard ratio, 4.1; p = 0.003), and CEUS LI-RADS category (LR-M and LR-TIV, hazard ratio, 4.7; p = 0.011) showed independent association with shorter DFS.

The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide due to its high degree of malignancy, high incidence, and low survival rate. However, the underlying mechanisms of hepatocarcinogenesis remain unclear. Long non coding RNA (lncRNA) has been shown as a novel type of RNA. lncRNA by acting as ceRNA can participate in various biological processes of HCC cells, such as tumor cell proliferation, migration, invasion, apoptosis and drug resistance by regulating downstream target gene expression and cancer-related signaling pathways. Meanwhile, lncRNA can predict the efficacy of treatment strategies for HCC and serve as a potential target for the diagnosis and treatment of HCC. Therefore, lncRNA serving as ceRNA may become a vital candidate biomarker for clinical diagnosis and treatment. In this review, the epidemiology of HCC, including morbidity, mortality, regional distribution, risk factors, and current treatment advances, was briefly discussed, and some biological functions of lncRNA in HCC were summarized with emphasis on the molecular mechanism and clinical application of lncRNA-mediated ceRNA regulatory network in HCC. This paper can contribute to the better understanding of the mechanism of the influence of lncRNA-mediated ceRNA networks (ceRNETs) on HCC and provide directions and strategies for future studies.

Assessment of Axillary Lymph Nodes for Metastasis on Ultrasound Using Artificial Intelligence.

The purpose of this study was to evaluate an artificial intelligence (AI) system for the classification of axillary lymph nodes on ultrasound compared to radiologists. Ultrasound images of 317 axillary lymph nodes from patients referred for ultrasound guided fine needle aspiration or core needle biopsy and corresponding pathology findings were collected. Lymph nodes were classified into benign and malignant groups with histopathological result serving as the reference. Google Cloud AutoML Vision (Mountain View, CA) was used for AI image classification. Three experienced radiologists also classified the images and gave a level of suspicion score (1-5). To test the accuracy of AI, an external testing dataset of 64 images from 64 independent patients was evaluated by three AI models and the three readers. The diagnostic performance of AI and the humans were then quantified using receiver operating characteristics curves. In the complete set of 317 images, AutoML achieved a sensitivity of 77.1%, positive predictive value (PPV) of 77.1%, and an area under the precision recall curve of 0.78, while the three radiologists showed a sensitivity of 87.8% ± 8.5%, specificity of 50.3% ± 16.4%, PPV of 61.1% ± 5.4%, negative predictive value (NPV) of 84.1% ± 6.6%, and accuracy of 67.7% ± 5.7%. In the three external independent test sets, AI and human readers achieved sensitivity of 74.0% ± 0.14% versus 89.9% ± 0.06% (p = .25), specificity of 64.4% ± 0.11% versus 50.1 ± 0.20% (p = .22), PPV of 68.3% ± 0.04% versus 65.4 ± 0.07% (p = .50), NPV of 72.6% ± 0.11% versus 82.1% ± 0.08% (p = .33), and accuracy of 69.5% ± 0.06% versus 70.1% ± 0.07% (p = .90), respectively. These preliminary results indicate AI has comparable performance to trained radiologists and could be used to predict the presence of metastasis in ultrasound images of axillary lymph nodes.

Diagnostic Accuracy of CEUS LI-RADS for the Characterization of Liver Nodules 20 mm or Smaller in Patients at Risk for Hepatocellular Carcinoma.

Background American College of Radiology contrast agent-enhanced US Liver Imaging Reporting and Data System (CEUS LI-RADS) was developed to improve the accuracy of hepatocellular carcinoma (HCC) diagnosis at contrast agent-enhanced US. However, to the knowledge of the authors, the diagnostic accuracy of the system in characterization of liver nodules 20 mm or smaller has not been fully evaluated. Purpose To evaluate the diagnostic accuracy of CEUS LI-RADS in diagnosing HCC in liver nodules 20 mm or smaller in patients at risk for HCC. Materials and Methods Between January 2015 and February 2018, consecutive patients at risk for HCC presenting with untreated liver nodules 20 mm or less were enrolled in this retrospective double-reader study. Each nodule was categorized according to the CEUS LI-RADS and World Federation for Ultrasound in Medicine and Biology (WFUMB)-European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) criteria. Diagnostic performance of CEUS LI-RADS and WFUMB-EFSUMB characterization was evaluated by using tissue histologic analysis, multiphase contrast-enhanced CT and MRI, and imaging follow-up as reference standard and compared by using McNemar test. Results The study included 175 nodules (mean diameter, 16.1 mm ± 3.4) in 172 patients (mean age, 51.8 years ± 10.6; 136 men). The sensitivity of CEUS LR-5 versus WFUMB-EFSUMB criteria in diagnosing HCC was 73.3% (95% confidence interval [CI]: 63.8%, 81.5%) versus 88.6% (95% CI: 80.9%, 94%), respectively (P < .001). The specificity of CEUS LR-5 versus WFUMB-EFSUMB criteria was 97.1% (95% CI: 90.1%, 99.7%) versus 87.1% (95% CI: 77%, 94%), respectively (P = .02). No malignant lesions were found in CEUS LR-1 and LR-2 categories. Only two nodules (of 41; 5%, both HCC) were malignant in CEUS LR-3 category. The incidences of HCC in CEUS LR-4, LR-5, and LR-M were 48% (11 of 23), 98% (77 of 79), and 75% (15 of 20), respectively. Two of 175 (1.1%) histologic analysis-confirmed intrahepatic cholangiocarcinomas were categorized as CEUS LR-M by CEUS LI-RADS and misdiagnosed as HCC by WFUMB-EFSUMB criteria. Conclusion The contrast-enhanced US Liver Imaging Reporting and Data System (CEUS LI-RADS) algorithm was an effective tool for characterization of small (≤20 mm) liver nodules in patients at risk for hepatocellular carcinoma (HCC). Compared with World Federation for Ultrasound in Medicine and Biology-European Federation of Societies for Ultrasound in Medicine and Biology criteria, CEUS LR-5 demonstrated higher specificity for diagnosing small HCCs with lower sensitivity. Published under a CC BY 4.0 license. See also the editorial by Crocetti in this issue.

New Therapeutic Options for Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), one of the most common lethal diseases in the world, has a 5-year survival rate of only 7%. Hepatocellular carcinoma has no symptoms in the early stage but obvious symptoms in the late stage, leading to delayed diagnosis and reduced treatment efficacy. In recent years, as the scope of HCC research has increased in depth, the clinical development and application of molecular targeted drugs and immunotherapy drugs have brought new breakthroughs in HCC treatment. Targeted therapy drugs for HCC have high specificity, allowing them to selectively kill tumor cells and minimize damage to normal tissues. At present, these targeted drugs are mainly classified into 3 categories: small molecule targeted drugs, HCC antigen-specific targeted drugs, and immune checkpoint targeted drugs. This article reviews the latest research progress on the targeted drugs for HCC.

Power and Promise of Next-Generation Sequencing in Liquid Biopsies and Cancer Control.

Traditional methods of cancer treatment are usually based on the morphological and histological diagnosis of tumors, and they are not optimized according to the specific situation. Precision medicine adjusts the existing treatment regimen based on the patient's genomic information to make it most suitable for patients. Detection of genetic mutations in tumors is the basis of precise cancer medicine. Through the analysis of genetic mutations in patients with cancer, we can tailor the treatment plan for each patient with cancer to maximize the curative effect, minimize damage to healthy tissues, and optimize resources. In recent years, next-generation sequencing technology has developed rapidly and has become the core technology of precise targeted therapy and immunotherapy for cancer. From early cancer screening to treatment guidance for patients with advanced cancer, liquid biopsy is increasingly used in cancer management. This is as a result of the development of better noninvasive, repeatable, sensitive, and accurate tools used in early screening, diagnosis, evaluation, and monitoring of patients. Cell-free DNA, which is a new noninvasive molecular pathological detection method, often carries tumor-specific gene changes. It plays an important role in optimizing treatment and evaluating the efficacy of different treatment options in clinical trials, and it has broad clinical applications.

Dynamic prostatic and laser-ablated lesion volume change after transperineal laser ablation in canine: preliminary observation and its clinical significance.

AIM: The purpose of this study is to observe the volume change of prostate and laser-ablated lesions in the canine and to explore the mechanism and clinical significance through histopathology. MATERIALS AND METHODS: Transperineal laser ablation (TPLA) was performed under the guidance of transrectal ultrasound (TRUS) in eight canines. Two canines were sacrificed 1 day and 1 week after TPLA, respectively. The remaining six canines were sacrificed after finishing transrectal contrast-enhanced ultrasound (TR-CEUS) at three phases. RESULTS: The prostatic volumes immediately following TPLA and 1 week later were larger than before TPLA (20.1 ± 3.9 vs 17.1 ± 3.8 ml; 21.7 ± 3.6 vs 17.1 ± 3.8 ml, p < 0.05), but 1 month later, returned to the preoperative level (17.4 ± 3.2 ml). At three time points, the mean volumes of laser-ablated lesions at 3 W/600 J were 0.6 ± 0.2, 1.1 ± 0.4, and 1.7 ± 0.5 ml, respectively, while those of laser-ablated lesions at 3 W/1200 J were 1.2 ± 0.2, 1.6 ± 0.3, and 2.2 ± 0.5 ml, respectively. The mean volumes of laser-ablated lesions increased significantly over time after TPLA (p < 0.050). CONCLUSION: The prostate volume transient enlarges after TPLA, which prompts for clinical application that it should prolong appropriately the duration of urinary catheterization to avoid acute urinary retention. Many inflammatory cells were observed in the laser-ablated lesions and adjacent normal prostate parenchyma through histopathology. It is speculated that the inflammatory response is involved in the progression of tissue damage.

Three-Dimensional Subharmonic Aided Pressure Estimation for Assessing Arterial Plaques in a Rabbit Model.

OBJECTIVES: To investigate 3-dimensional subharmonic aided pressure estimation (SHAPE) for measuring intraplaque pressure and the pressure gradient across the plaque cap as novel biomarkers for potentially predicting plaque vulnerability. METHODS: Twenty-seven rabbits received a high-cholesterol diet for 2 weeks before a balloon catheter injury to denude the endothelium of the aorta, followed by 8 to 10 weeks of the high-cholesterol diet to create arteriosclerotic plaques. SHAPE imagings of the resulting plaques were performed 12, 16, and 20 weeks after injury using a LOGIQ 9 scanner with a 4D10L probe (GE Healthcare, Milwaukee, WI) before and during an infusion of Definity (Lantheus Medical Imaging, North Billerica, MA) and Sonazoid (GE Healthcare, Oslo, Norway). The ratios of the maximum subharmonic magnitudes at baseline and during the infusion were correlated with the intraplaque pressure and pressure gradient across the plaque cap obtained from direct measurements. RESULTS: Ten rabbits died prematurely after the balloon injury procedure or due to toxicity from the high-cholesterol diet, whereas 2 rabbits were excluded for other conditions. Five rabbits were scanned in the 12-, 16-, and 20-week groups, respectively. Even after 20 weeks, the plaques that developed were very small (mean ± SD, 0.9 ± 0.4 × 0.14 ± 0.05 cm). Definity performed better than Sonazoid in this application but still only achieved a moderate correlation with pressure across the plaque cap (Definity, r = -0.40; Sonazoid, r = 0.22) and intraplaque pressure (Definity, r = -0.19; Sonazoid, r = -0.11). CONCLUSIONS: Initial findings from plaque pressure estimation using 3-dimensional SHAPE technique showed only moderate correlations with reference standards, but that may be have been due to weaknesses in the animal model studied.