EGFR activation limits the response of liver cancer to lenvatinib.

Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options1. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit2. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. The combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effects in vitro in liver cancer cell lines that express EGFR and in vivo in xenografted liver cancer cell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibition of fibroblast growth factor receptor (FGFR)  by lenvatinib treatment leads to feedback activation of the EGFR-PAK2-ERK5 signalling axis, which is blocked by EGFR inhibition. Treatment of 12 patients with advanced HCC who were unresponsive to lenvatinib treatment with the combination of lenvatinib plus gefitinib (trial identifier NCT04642547) resulted in meaningful clinical responses. The combination therapy identified here may represent a promising strategy for the approximately 50% of patients with advanced HCC who have high levels of EGFR.

Safety and efficacy of microwave versus radiofrequency ablation for large hepatic hemangioma: a multicenter retrospective study with propensity score matching.

OBJECTIVES: To compare the safety and efficacy of microwave ablation (MWA) and radiofrequency ablation (RFA) for such hemangiomas (5-9.9 cm in diameter). METHODS: This multicenter retrospective cohort study investigated the differences in technical success, ablation time, complete ablation, complications, hospital stay, and clinical response between MWA and RFA. A total of 452 patients with hepatic hemangiomas were screened. Propensity score matching was performed. Univariable and multivariate regression analyses were used. RESULTS: Among the 452 patients, 394 met the eligibility criteria and completed the follow-up. After the propensity score matching analysis, 72 pairs of patients were created. No technical failures were found. The RFA group had a longer ablation time (48.63 ± 18.11 min versus [vs.] 37.18 ± 15.86 min, p < 0.001), higher morbidity of hemoglobinuria (77.78% vs. 50.00%, p < 0.001), and longer hospital stay (5.01 ± 1.56 days vs. 4.34 ± 1.42 days, p < 0.05) than the MWA group. The treatment methods (p = 0.032, OR = 0.105, 95% CI = 0.013-0.821), size of the hemangioma (p = 0.021, OR = 5.243, 95% CI = 1.285-21.391), and time of ablation (p = 0.031, OR = 1.145, 95% CI = 1.013-1.294) were significant independent risk factors associated with hemoglobinuria. No recurrence or delayed complications were observed. There were no differences in complete ablation, clinical response, and health-related quality of life between the groups. CONCLUSIONS: MWA and RFA appear to be effective treatments for large hepatic hemangiomas. However, MWA had a shorter ablation time than RFA, and MWA was associated with fewer hemolysis-related complications and shorter hospital stays. KEY POINTS: • MWA and RFA appear to be effective treatments for large hepatic hemangiomas. • MWA had a shorter ablation time than RFA. • MWA was associated with fewer hemolysis-related complications and shorter hospital stays.

Long-term results of percutaneous microwave ablation for colorectal liver metastases.

BACKGROUND: Radiofrequency ablation (RFA) has been used for therapy of colorectal liver metastases (CRLMs) several years, with considerable data confirming its safety and efficacy. However, there are few studies focusing on the long-term results of percrtaneous microwave ablation (PMWA) for CRLMs. The aim of this study was to evaluate the long-term survival and prognostic factors in patients with CRLMs undergoing PMWA. METHODS: We retrospectively analyzed treatment and survival parameters of 210 patients with CRLMs who had received PMWA in a single center from January 2010 to December 2017. Prognostic factors for survival were evaluated by means of univariate and multivariate analyses. RESULTS: The median follow-up time after PMWA was 48 months. The median overall survival (OS) time were 40.0 months (95% CI, 31.4 to 48.5 months), with 1-, 2, 3-, 4, and 5-year cumulative survival rates of 98.6%, 73.3%, 53.3%, 42.2%, and 32.9%, respectively. Tumor number (P = 0.004; HR: 1.838; CI: 1.213- 2.784), main tumor size (P = 0.017; HR: 1.631; CI: 1.093- 2.436), and serum CEA level (P = 0.032; HR: 1.559; CI: 1.039-2.340) were found as independent predictors of OS. The median OS time for patients with resectable lesions was 60.91 months (95% CI, 51.36 to 70.47 months), with 5-year cumulative survival rates of 53.5%. CONCLUSION: PMWA is a safe and effective treatment for CRLMs, with a favorable long-term outcome. Multiple lesions, main tumor diameter>3 cm, and serum CEA >30 ng/ml have a significant negative effect on OS.

Microwave ablation versus transcatheter arterial embolization for large hepatic hemangiomas: clinical outcomes.

PURPOSE: To evaluate the safety and effect of microwave ablation (MWA) compared with transcatheter arterial embolization (TAE) for the treatment of large hepatic hemangiomas. MATERIALS AND METHODS: A total of 135 patients with symptomatic or/and enlarging hepatic hemangiomas (5-10 cm) from two centers underwent either MWA (n = 82) or TAE (n = 53) as first-line treatment. We compared the two groups in terms of radiologic response, clinical response, operative time, postoperative analgesic requirements, hospital stay and complications. RESULTS: MWA had a significantly higher rate of complete radiologic response (89.0% vs. 37.7%, p<.001) and complete clinical response (88.6% vs. 69.2%, p=.046), fewer minor complications (43.9% vs. 66.0%, p=.019), shorter time of using analgesics (p<.001) and shorter hospital stays (p=.003) than did TAE. The operative time and major complications were comparable between the two groups. CONCLUSION: Both MWA and TAE are safe and effective in treating patients with large hepatic hemangiomas. MWA had a higher rate of complete response than did TAE, and it was associated with fewer minor complications, faster recovery and shorter hospital stay.

Outcomes of ultrasound-guided percutaneous microwave ablation versus surgical resection for symptomatic large hepatic hemangiomas.

Purpose: Microwave ablation (MWA) has become increasingly popular as a minimally invasive treatment for benign and malignant liver tumors. However, few studies have demonstrated the benefits and disadvantages of MWA compared to surgical resection (SR) for large hepatic hemangiomas. This study aimed to evaluate the safety and effectiveness of MWA compared to SR for large (5-10 cm) hepatic hemangiomas. Methods and materials: This retrospective comparative study included 112 patients with large, symptomatic hepatic hemangiomas who had been treated with MWA (n = 44) or SR (n = 68) and followed up for a median of 44 months using enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Intraoperative information, postoperative recovery time, postoperative discomfort and complications and treatment effectiveness between groups were compared using a chi-square test or an independent t-test. Results: The operative time was significantly shorter (31.3 ± 21.76 versus 148.1 ± 59.3 min, p < .001) and the blood loss (10.2 ± 60.6 versus 227.9 ± 182.9 mL, p < .0001) and rate of prophylactic abdominal drainage [1 (2.3%) versus 57 (83.8%), p < .001] were significantly lower in the MWA group than in the SR group. Postoperative recovery of the MWA group in regard to indwelling catheter time, normal diet time, incision cicatrization time and hospital stay (p < .001) was significantly better than the SR group. However, no statistically significant difference in effectiveness was noted between the groups (p = .58). Conclusions: MWA may be as effective as SR, and potentially safer for treating large, symptomatic hepatic hemangiomas. To confirm our findings, large-sample, multicentered, randomized controlled trials are needed.

Oliguric acute kidney injury after microwave ablation of large liver tumors: incidence and preventive measures.

PURPOSE: Acute kidney injury (AKI), especially oliguric AKI, is a recognized complication following microwave ablation (MWA) of large liver tumors. This study evaluated the clinical features, mechanisms, risk factors and prevention strategies for oliguric AKI after MWA of large liver tumors. METHODS: From March 2011 to May 2015, 441 patients with liver tumors ≧5 cm received MWA in our hospital. The clinical features, prevention strategies, further mechanisms and possible risk factors for oliguric AKI after MWA were analyzed. RESULTS: One hundred four (23.6%) patients had AKI after MWA; 11 (10.6%) patients had oliguric AKI, and 93 (89.4%) patients had nonoliguric AKI. All patients with nonoliguric AKI recovered without any special treatments. The eleven patients with oliguric AKI received appropriate treatments and had completely normal renal function three months later. Using double needles for ablation was a risk factor for nonoliguric AKI, while high preoperative levels of red blood cells (RBC), hemoglobin (HGB) and albumin (Alb) were risk factors for oliguric AKI. The decrease levels of hemoglobin were significantly high in oliguric AKI patients (p < .05). Patients with oliguric AKI had abnormally high postoperative transaminase and renal function indicators. Compared to postoperative prevention, intraoperative prevention significantly lowered the occurrence of oliguric AKI (0% vs. 3.7%, p = .018) and shortened the hospital stay. CONCLUSIONS: Patients who underwent MWA for large liver tumors are prone to develop oliguric AKI. Implementation of intraoperative strategies during MWA can effectively prevent the occurrence of this severe complication.

Feasibility, safety, and efficacy of ultrasound-guided percutaneous microwave ablation for giant hepatic hemangioma.

BACKGROUND: Hepatic hemangioma is a common benign liver tumor. The majority of cases are asymptomatic and require no specific treatment. The aim of this study was to evaluate the feasibility, safety and efficacy of microwave ablation (MWA) for symptomatic or enlarging giant hepatic hemangioma (≥10 cm). METHODS: From December 2013 to June 2016, 12 patients with giant hepatic hemangioma (≥10 cm) underwent ultrasound-guided percutaneous MWA, and ablation-related complications were observed. All patients were followed up with magnetic resonance or enhanced CT imaging at one month postoperatively to evaluate efficacy. RESULTS: This study included a total of 13 giant hepatic hemangiomas (mean: 11.7 ± 1.6 cm) in 12 patients who initially underwent 16 sessions of MWA; three lesions were treated with two sessions of planned ablation. The average ablation time for a single hepatic hemangioma was 39.0 ± 14.4 minutes. Two patients had acute postoperative non-oliguric renal insufficiency without intra-abdominal hemorrhage, liver failure or other complications. Initially, complete ablation was achieved in ten lesions in nine patients (76.9%, 10/13). One patient underwent a second session of MWA at 5 months postoperatively due to fast growing residual tissue; complete necrosis was achieved after treatment. The remaining two cases did not receive any invasive treatment due to small residual volumes. The total complete ablation rate was 84.6% (11/13). CONCLUSION: Image-guided MWA is a safe, feasible, effective treatment for giant hepatic hemangioma; these findings may open a new avenue for treatment.

Orthotopic Esophageal Cancers: Intraesophageal Hyperthermia-enhanced Direct Chemotherapy in Rats.

Purpose To determine the feasibility of using intraesophageal radiofrequency (RF) hyperthermia to enhance local chemotherapy in a rat model with orthotopic esophageal squamous cancers. Materials and Methods The animal protocol was approved by the institutional animal care and use committee and the institutional review board. Human esophageal squamous cancer cells were transduced with luciferase lentiviral particles. Cancer cells, mice with subcutaneous cancer esophageal xenografts, and nude rats with orthotopic esophageal cancers in four study groups of six animals per group were treated with (a) combination therapy of magnetic resonance imaging heating guidewire-mediated RF hyperthermia (42°C) plus local chemotherapy (cisplatin and 5-fluorouracil), (b) chemotherapy alone, (c) RF hyperthermia alone, and (d) phosphate-buffered saline. Bioluminescent optical imaging and transcutaneous ultrasonographic imaging were used to observe bioluminescence signal and changes in tumor size among the groups over 2 weeks, which were correlated with subsequent histologic results. The nonparametric Mann-Whitney U test was used for comparisons of variables. Results Compared with chemotherapy alone, RF hyperthermia alone, and phosphate-buffered saline, combination therapy with RF hyperthermia and chemotherapy induced the lowest cell proliferation (relative absorbance of formazan: 23.4% ± 7, 44.6% ± 7.5, 95.8% ± 2, 100%, respectively; P < .0001), rendered the smallest relative tumor volume (0.65 mm3 ± 0.15, P < .0001) and relative bioluminescence optical imaging photon signal (0.57 × 107 photons per second per square millimeter ± 0.15, P < .001) of mice with esophageal cancer xenografts, as well as the smallest relative tumor volume (0.68 mm3 ± 0.13, P < .05) and relative photon signal (0.56 × 107 photons per second per square millimeter ± 0.11. P < .001) of rat orthotopic esophageal cancers. Conclusion Intraesophageal RF hyperthermia can enhance the effect of chemotherapy on esophageal squamous cell cancers. © RSNA, 2016.

Radiofrequency hyperthermia-enhanced herpes simplex virus-thymidine kinase/ganciclovir direct intratumoral gene therapy of hepatocellular carcinoma.

PURPOSE: To determine the feasibility of using radiofrequency hyperthermia (RFH) and to enhance the therapeutic effect of herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Human HCC cells (HepG2) were first transfected with lentivirus/luciferase. For both in vitro confirmation and in vivo validation, luciferase-labeled HCC cells and HCC tumour xenografts on mice received different treatments: (i) combination therapy of intratumoral HSV-TK/GCV-mediated gene therapy plus magnetic resonance imaging heating guidewire (MRIHG)-mediated RFH; (ii) gene therapy only; (iii) RFH only; and (iv) phosphate-buffered saline (PBS) as control. Cell proliferation was quantified. Tumour changes were monitored by ultrasound imaging and bioluminescence optical imaging before and at days 7 and 14 after treatments, which were correlated with subsequent histology. RESULTS: In vitro, the lowest cell proliferation was seen in the combination therapy group compared with control groups (29 ± 6% vs. 56 ± 9%, 93 ± 4%, and 100 ± 5%, p < .05). Ultrasound imaging of treated animal xenografts showed smaller relative tumour volume in combination therapy group than those in three control groups (0.74 ± 0.19 vs. 1.79 ± 0.24, 3.14 ± 0.49 and 3.22 ± 0.52, p < .05). Optical imaging demonstrated significant decrease of bioluminescence signals of tumours in the combination therapy group, compared to those in three control groups (1.2 ± 0.1 vs. 1.9 ± 0.2% vs. 3.3 ± 0.6% vs. 3.5 ± 0.4%, p < .05). These imaging findings were correlated well with histologic confirmation. CONCLUSION: RFH can enhance HSV-TK/GCV-mediated gene therapy of HepG2 cell line and mice human HCC xenografts, which may open new avenues for effective management of HCC using MR/RFH integrated interventional gene therapy.

Gliomas: Motexafin Gadolinium-enhanced Molecular MR Imaging and Optical Imaging for Potential Intraoperative Delineation of Tumor Margins.

PURPOSE: To investigate the possibility of using motexafin gadolinium (MGd)-enhanced molecular magnetic resonance (MR) imaging and optical imaging to identify the true margins of gliomas. MATERIALS AND METHODS: The animal protocol was approved by the institutional animal care and use committee. Thirty-six Sprague-Dawley rats with gliomas were randomized into six groups of six rats. Five groups were euthanized 15, 30, 60, 120, and 240 minutes after intravenous administration of 6 mg/kg of MGd, while one group received only saline solution as a control group. After craniotomy, optical imaging and T1-weighted MR imaging were performed to identify the tumor margins. One-way analysis of variance was used to compare optical photon intensity and MR imaging signal-to-noise ratios. Histologic analysis was performed to confirm the intracellular uptake of MGd by tumor cells and to correlate the tumor margins delineated on both optical and MR images. RESULTS: Both optical imaging and T1-weighted MR imaging showed tumor margins. The highest optical photon intensity (2.6 × 10(8) photons per second per mm(2) ± 2.3 × 10(7); analysis of variance, P < .001) and MR signal-to-noise ratio (77.61 ± 2.52; analysis of variance, P = .006) were reached at 15-30 minutes after administration of MGd, with continued tumor visibility at 2-4 hours. Examination with confocal microscopy allowed confirmation that the fluorescence of optical images and MR imaging T1 enhancement exclusively originated from MGd that accumulated in the cytoplasm of tumor cells. CONCLUSION: MGd-enhanced optical and MR imaging can allow determination of glioma tumor margins at the optimal time of 15-120 minutes after administration of MGd. Clinical application of these results may allow complete removal of gliomas in a hybrid surgical setting in which intraoperative optical and MR imaging are available.

Interventional MRI-guided local delivery of agents into swine bile duct walls using MR-compatible needle-integrated balloon catheter system.

The purpose of this study was to investigate the feasibility of interventional MRI-guided local agent delivery into pig common bile duct (CBD) walls using a newly designed MR-compatible, needle-integrated balloon catheter system. We first designed a needle-integrated balloon catheter system that comprised of a 22 G MR-compatible Chiba biopsy needle and a conventional 12 mm × 2 cm balloon catheter. Under fluoroscopy guidance, a custom needle-balloon system was positioned in the target CBD via a transcholecystic access. T1-weighted MRI was used to localize and reposition the needle-balloon system in the target. A 0.5 mL mixture of motexafin gadolinium (MGd) and trypan blue dye as well as 5-fluorouracil was delivered into the CBD wall through the needle-balloon system. Post-infusion T1-weighted MRI was obtained and contrast-to-noise ratios (CNRs) of CBD walls of pre- and post-MGd-blue infusions were compared by a paired t-test. In addition, post-infusion x-ray cholangiography was achieved to evaluate the potential injuries of CBDs by the needle-balloon system. Subsequent histologic analysis was performed to correlate and confirm the imaging findings. A post-infusion cholangiogram did not show any extravasation of contrast agent, indicating no procedure-related damage to the CBDs. MRI demonstrated clear enhancement of the target bile duct walls infused with MGd-trypan blue dye with average penetration depth of 4.7 ± 1.2 mm and an average MGd perfusion length of 21 ± 1.5 mm in the bile ducts and their surrounding tissues. The average CNR of the post-infusion bile ducts was significant higher than that of the pre-infusion bile ducts (110.6 ± 22 versus 5.7 ± 2.8, p < 0.0001). Histology depicted the blue dye staining and red fluorescence of MGd through the target CBD walls, which was well correlated with the imaging findings. It is feasible to use the new MR-compatible, needle-integrated balloon catheter system for intrabiliary local agent delivery into CBD walls under MRI guidance, which may open new avenues for efficient management of pancreatobiliary malignancies using MR-guided interventional oncology.

Single-cell transcriptome analysis of liver immune microenvironment changes induced by microplastics in mice with non-alcoholic fatty liver.

Recent studies have discovered that tiny particles of microplastics (MPs) at the nano-scale level can enter the body of organisms from the environment, potentially causing metabolic ailments. However, further investigation is required to understand the alterations in the immune microenvironment associated with non-alcoholic fatty liver disease (NAFLD) occurrence following exposure to MPs. Experiments were performed using mice, which were given a normal chow or high-fat diet (NCD or HFD, respectively) plus free drinking of sterile water with or without MPs, respectively. Employing an impartial technique known as unbiased single-cell RNA-sequencing (scRNA-seq), the cellular (single-cell) pathology landscape of NAFLD and related changes in the identified immune cell populations induced following MPs plus HFD treatment were assessed. The results showed that mice in the HFD groups had remarkably greater NAFLD activity scores than those from the NCD groups. Moreover, administration of MPs plus HFD further worsened the histopathological changes in the mice's liver, leading to hepatic steatosis, inflammatory cell infiltrations and ballooning degeneration. Following the construction of a sing-cell resolution transcriptomic atlas of 43,480 cells in the mice's livers of the indicated groups, clear cellular heterogeneity and potential cell-to-cell cross-talk could be observed. Specifically, we observed that MPs exacerbated the pro-inflammatory response and influenced the stemness of hepatocytes during HFD feeding. Importantly, treatment with MPs significantly increase the infiltration of the infiltrating liver-protecting Vsig4+ macrophages in the liver of the NAFLD mouse model while remarkably decreasing the angiogenic S100A6+ macrophage subpopulation. Furthermore, mice treated with MPs plus HFD exhibited significantly increased recruitment of CD4+ cells and heightened exhaustion of CD8+ T cells than those from the control group, characteristics typically associated with the dysregulation of immune homeostasis and severe inflammatory damage. Overall, this study offers valuable perspectives into comprehending the potential underlying cellular mechanisms and regulatory aspects of the microenvironment regarding MPs in the development of NAFLD.

Radiofrequency Ablation of Unifocal Papillary Thyroid Microcarcinoma With BRAF V600E Mutation.

CONTEXT: To date there is no study on the feasibility of radiofrequency ablation (RFA) for papillary thyroid microcarcinomas (PTMCs) with BRAF V600E mutation. OBJECTIVE: This study was designed to evaluate the efficiency, safety, and prognosis of ultrasound (US)-guided percutaneous RFA for unifocal PTMCs with BRAF V600E mutation. MATERIALS AND METHODS: Sixty patients with 60 unifocal BRAF V600E mutation-positive PTMCs who received US-guided RFA between January 2020 and December 2021 were retrospectively analyzed. The mean maximum PTMC tumor diameter was 5.8 ± 1.7 mm (range, 2.5-10.0 mm). All PTMCs were pathologically confirmed by fine needle aspiration or core needle biopsy, and BRAF V600E mutation was confirmed to be positive by real-time fluorescent quantitative polymerase chain reaction. Contrast-enhanced ultrasound (CEUS) was performed immediately after RFA to evaluate whether PTMCs were extendedly ablated. Ultrasound was performed 1, 3, 6, and 12 months after RFA and every 6 months thereafter to evaluate the changes in the ablation zone, local recurrence, and cervical lymph node metastasis (LNM). The complications were recorded and evaluated. RESULTS: Extended ablation was achieved in all enrolled patients. The ablation zone sizes increased immediately after RFA compared with those of tumors before treatment. One month later, the ablation zone sizes were smaller than immediately after RFA. At the last follow-up assessment, 42 nodules (70.0%) completely disappeared and the ablation zones of 18 nodules (30.0%) showed fissure-like changes. No local recurrence or cervical LNM was detected. Voice change (1.7%) was the only major complication. CONCLUSION: RFA is effective and safe in treating unifocal PTMCs with BRAF V600E mutation, especially when surgery is not feasible or refused by patients who are unwilling to continue active surveillance.

Sustained activation of EGFR-ERK1/2 signaling limits the response to tigecycline-induced mitochondrial respiratory deficiency in liver cancer.

BACKGROUND: Identification of tumor dependencies is important for developing therapeutic strategies for liver cancer. METHODS: A genome-wide CRISPR screen was performed for finding critical vulnerabilities in liver cancer cells. Compounds screen, RNA sequencing, and human phospho-receptor tyrosine kinase arrays were applied to explore mechanisms and search for synergistic drugs. FINDINGS: We identified mitochondrial translation-related genes associated with proliferation for liver cancer cells. Tigecycline induced deficiency of respiratory chain by disturbing mitochondrial translation process and showed therapeutic potential in liver cancer. For liver cancer cells extremely insensitive to tigecycline, a compounds screen was applied to identify MEK inhibitors as synergistic drugs to tigecycline-insensitive liver cancer cells. Mechanistically, sustained activation of EGFR-ERK1/2-MYC cascade conferred the insensitivity to tigecycline, which was mediated by enhanced secretion of EREG and AREG. Moreover, glycolytic enzymes, such as HK2 and PKM2 were upregulated to stimulate glycolysisin a MYC-dependent manner. Tigecycline induced respiratory chain deficiency in combination with cutting off EGFR-ERK1/2-MYC cascade by MEK inhibitors or EGFR inhibitors, resulting in decrease of both oxidative phosphorylation and glycolysis in liver cancer cells. INTERPRETATION: Our study proved that blocking EGFR-ERK1/2-MYC cascade combined with tigecycline could be a potential therapeutic strategy for liver cancer. FUNDING: This work was funded by grants from the National Natural Science Foundation of China (82073039,82222047, 81920108025), Program of Shanghai Academic/Technology Research Leader (22XD1423100), Shanghai Municipal Science and Technology Project (20JC1411100), 111 Project (B21024), Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212700, SHSMU-ZDCX20210802) and Shanghai Jiao Tong University School of Medicine (YG2019GD01).

Loss of hepatic FTCD promotes lipid accumulation and hepatocarcinogenesis by upregulating PPARγ and SREBP2.

Background & Aims: Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets. Methods: The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout (Ftcd-LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells. Results: FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spontaneous hepatocarcinogenesis in mice. Multi-omics analysis showed that loss of FTCD affected fatty acid and cholesterol metabolism in hepatocarcinogenesis. Mechanistically, loss of FTCD upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis. Conclusions: Taken together, we identified a FTCD-regulated lipid metabolic mechanism involving PPARγ and SREBP2 signaling in hepatocarcinogenesis and provide a rationale for therapeutically targeting of HCC driven by downregulation of FTCD. Impact and implications: Exploiting key molecules responsible for hepatocarcinogenesis is significant for the prevention and treatment of HCC. Herein, we identified formimidoyltransferase cyclodeaminase (FTCD) as the top enhanced gene, which could serve as a predictive and prognostic marker for patients with HCC. We generated and characterised the first Ftcd liver-specific knockout murine model. We found loss of FTCD expression upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis, and provided a rationale for therapeutic targeting of HCC driven by downregulation of FTCD.

Significance of radiofrequency ablation in large solid benign thyroid nodules.

Objective: The aim of this study is to explore efficacy and safety for radiofrequency ablation (RFA) among cases attacked by large benign solid thyroid nodules, mainly focusing on volume reduction, complication rate, and thyroid function. Methods and materials: From June 2015 to November 2019, 24 patients with 25 large benign solid thyroid nodules (more than 25 ml) underwent single or sequential RFA in our institution. Eleven nodules achieved complete ablation after single RFA, whereas the other 14 nodules received sequential RFA. Volume reduction in large nodules was evaluated. Following single or sequential RFA, all patients received clinical and ultrasound evaluations, and the median follow-up duration among them was 23.5 months. Technical success, complication rate, and recurrence rate were assessed as well. Results: In single RFA group, volume reduction ranged from 62.6% to 99.4% (mean ± SD, 93.6 ± 9.9%) 6 months after RFA. In sequential RFA group, volume reduction ranged from 30.6% to 92.9% (mean ± SD, 67.4 ± 17.8%) after the first RFA and was between 83.4% and 98.4% (mean ± SD, 94.8± 3.8%) 6 months after the second RFA. The concentrations of FT3 and FT4 increased slightly 1 day after RFA and returned to normal level 1 month after. Conclusions: Single or sequential RFA is safe and effective in treating large benign solid thyroid nodules (more than 25 ml) that cause obvious compressive symptoms. Hence, compression symptoms and cosmetic conditions could be effectively improved through single or sequential RFA without marginal recurrence.

360° open-ended and navigated magnetic resonance-guided microwave ablation for hepatic tumors in risk areas.

Context: Image-guided local ablation has becoming a promising treatment option for patients unsuitable for surgical resection. Currently, magnetic resonance (MR) imaging has been used as guidance for ablation due to its good soft-tissue contrast, high image quality and absence of ionizing radiation. However, the limited operating space and interrupted and delayed imaging of the conventional MR equipment increased the difficulty of puncture during operation. Therefore, we utilized an easy-to-use optical navigation system with a 0.4 T 360° open MR system to perform MR-guided microwave ablation (MWA) to treat liver tumor patients in risk areas. Aim: To evaluate the safety and efficacy of MR-guided MWA in treating liver tumors using a 0.4 T open and navigated MR system. Materials and Methods: A retrospective analysis was performed on 19 liver tumor patients who underwent MR-guided MWA between August 2014 and August 2017. The complications, complete ablation, and long-term outcomes were analyzed and evaluated. Results: It was found that navigated MRI guidance allowed for precise needle placement in the targeted tumor, and ablation was successfully performed in all patients without serious intraoperative complications and death. Additionally, complete ablation was reached at 94.74% (18/19), with only one patient discovered with residual tumor, and therefore received another MWA session within three months. Conclusion: 360° open MR system combined with navigation systems conveniently enhanced the operation of MR-guided ablation, producing effective outcomes. Therefore, this option may be a safe and effective therapy for liver tumors in patients, especially for those situated in risk areas and those not visible to identify by ultrasound or computerized tomography.

Pathologic Diagnosis and Genetic Analysis of Sequential Biopsy Following Coaxial Low-Power Microwave Thermal Coagulation For Pulmonary Ground-Glass Opacity Nodules.

PURPOSE: To evaluate the feasibility, safety, and diagnostic performance of sequential core-needle biopsy (CNB) technique following coaxial low-power microwave thermal coagulation (MTC) for ground-glass opacity (GGO) nodules. MATERIALS AND METHODS: From December 2017 to July 2019, a total of 32 GGOs (with diameter of 12 ± 4 mm) in 31 patients received two times of CNBs, both prior to and immediately after MTC at a power of 20 watts. The frequency and type of complications associated with CNBs were examined. The pathologic diagnosis and genetic analysis were performed for specimens obtained from the two types of biopsy. RESULTS: The technical success rates of pre- and post-MTC CNBs were 94% and 100%, respectively. The complication rate was significantly lower with post-MTC CNB as compared to pre-MTC CNB (42% versus 97%, p < 0.001). Larger amount of specimens could be obtained by post-MTC CNB. The pathological diagnosis rate of post-MTC CNB was significantly higher than that of pre-MTC CNB (100% versus 75%, p = 0.008), whereas the success rates of genetic analysis were comparable between the two groups (100% versus 84%, p = 0.063). Regular ablation could be further performed after post-MTC CNB to achieve local tumor control. CONCLUSION: Sequential biopsy following coaxial low-power MTC can reduce the risk of complications and provide high-quality specimens for pulmonary GGOs. Combining this technique with standard ablation allows for simultaneous diagnosis and treatment within a single procedure.