Glutamine Transporter SLC1A5 Regulates Ionizing Radiation-Derived Oxidative Damage and Ferroptosis.

Ionizing radiation-derived oxidative stress and ferroptosis are one of the most important biological effects on destroying the liver tumor, whereas radioresistance of liver tumor remains a leading cause of radiotherapy (RT) failure mainly because of the protective antiferroptosis, in which oxidative stress and subsequent lipid peroxidation are the key initiators. Thus, it is of great importance to overcome ferroptosis resistance to improve the therapeutic efficacy of RT in liver tumor patients. Irradiation-resistant HepG2 cells (HepG2-IRR) were established by long-term exposure to X-ray (2 to 8 Gy), and targeted metabolomics analysis revealed an obvious increase in intracellular amino acids in HepG2-IRR cells upon ferroptosis stress. Among these amino acids with obvious changes, N-acetylglutamine, a derivative of glutamine, is essential for the redox homeostasis and progression of tumor cells. Interestingly, the treatment of glutamine starvation could promote the ferroptosis effect significantly, whereas glutamine supplementation reversed the ferroptosis effect completely. Consistent with the changes in amino acids pattern, the glutamine transporter SLC1A5 was verified in liver tumor samples from TCGA training and validation cohorts as an independent prognostic amino acid-ferroptosis gene (AFG). A risk score for screening prognosis based on the SLC1A5, SLC7A11, ASNS, and TXNRD1 demonstrated that a high-risk score was correlated with poor survival. In vitro studies had shown that the knockdown of SLC1A5 resulted in a significant decrease in cell viability and promoted lipid peroxidation and oxidative damage introduced by irradiation (10 Gy). Collectively, our findings indicated that SLC1A5 may act as a suppressor gene against ferroptosis and can be a potential target for ionizing radiation mediated effects.

Peroxisome-related genes in hepatocellular carcinoma correlated with tumor metabolism and overall survival.

BACKGROUND AND AIM: A prominent hallmark of tumors is aberrant lipid metabolism, and various peroxisome-related genes (PRGs) are associated with aberrant tumoral metabolic signaling. However, the influence of PRGs on the prognosis of hepatocellular carcinoma (HCC) patients remains debatable. Thus, the current study was designed to evaluate the effect of PRGs on HCC and construct a prognostic model for predicting survival. METHODS: We initially acquired HCC-related gene expression profiles from the Cancer Genome Atlas and International Cancer Genome Consortium databases. We then utilized Cox analysis and Lasso regression to identify suitable PRGs for the risk model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to clarify the functional roles of PRGs. Single-sample gene set enrichment analysis (ssGSEA) was conducted to confirm the relationship between PRGs and immunity. RESULTS: Four PRGs were correlated with HCC patient survival: 2 risk genes (MPV17, and ABCD1) and 2 protective genes (ACSL1 and ACSL6). We derived risk scores based on PRGs to construct a predictive model that could accurately predict overall survival (OS) among HCC patients. Furthermore, GO and KEGG analyses revealed that these PRGs were potentially involved in lipid metabolism and ferroptosis in HCC. Moreover, ssGSEA results demonstrated that high PRG scores were associated with immune suppressor activation, which caused the suppression of immune effectors (CD8+ T-cells, B cells, and NK cells) and the attenuation of the immune-mediated antitumor effect. CONCLUSION: PRGs act as key regulators in tumorigenesis and tumor progression by affecting lipid synthesis and utilization, which we used to predict the outcome of HCC patients. Moreover, PRGs have been shown to promote tumoral immune resistance by serving as a vital bridge between metabolism and immunity. Thus, a personalized treatment approach targeting PRGs would clinically benefit patients by blocking the interaction between tumor metabolism and immunity.

Fatty Acids Metabolism: The Bridge Between Ferroptosis and Ionizing Radiation.

Exposure of tumor cells to ionizing radiation (IR) alters the microenvironment, particularly the fatty acid (FA) profile and activity. Moreover, abnormal FA metabolism, either catabolism or anabolism, is essential for synthesizing biological membranes and delivering molecular signals to induce ferroptotic cell death. The current review focuses on the bistable regulation characteristics of FA metabolism and explains how FA catabolism and anabolism pathway crosstalk harmonize different ionizing radiation-regulated ferroptosis responses, resulting in pivotal cell fate decisions. In summary, targeting key molecules involved in lipid metabolism and ferroptosis may amplify the tumor response to IR.

Clinical outcomes of percutaneous thermal ablation for pulmonary metastases from hepatocellular carcinoma: a retrospective study.

Purpose: To determine the effectiveness of ablation for pulmonary metastases (PM) from hepatocellular carcinoma (HCC).Methods: Between 2010 and 2017, the study analyzed 39 patients who had a median age of 59 years. Primary HCC was under control and the number of PM was less than 5 (median: 2), with a maximum diameter of ≤60 mm (median: 15 mm). The primary endpoints were overall survival (OS) and local tumor progression-free survival (LTPFS). Secondary endpoints included technique success (TS), complication and tumor response. TS referred to PM treated using the treatment protocol. Multivariate analysis using the Cox proportional hazard model was conducted on the potential risk factors (univariate: p < 0.5) to determine the independent factors (multivariate: p < 0.05).Results: The TS rate was 100%. Major complications included pneumothorax (n = 3) requiring chest tube placement and pleural effusion requiring drainage (n = 2). Complete ablation was achieved in 32/38 patients (valid percent: 84.2%) at 1 month after ablation. The 1-, 3- and 5-year OS rates were 79.8, 58 and 30.9%, respectively. The 1-, 3- and 5-year LTPFS rates were 60.7, 34.2 and 22.8%, respectively. The extent (unilateral vs. bilateral) of PM (hazard ratio (HR): 0.197, 95% confidence interval (CI): 0.043-0.890, p = 0.035) and the number (≤2 vs. >2) of PM (HR: 0.555, 95% CI: 0.311-0.991, p = 0.047) were found to be the independent risk factors for predicting OS.Conclusion: Percutaneous thermal ablation is a safe and effective treatment for PM from HCC.

Long-term outcome and prognostic nomogram for intrahepatic cholangiocarcinoma after thermal ablation: a retrospective study.

BACKGROUND: To evaluate the efficacy of thermal ablation and transcatheter arterial chemoembolization (TACE) in treating intrahepatic cholangiocarcinoma (ICC), and to propose a prognostic nomogram to predict overall survival (OS) after ablation. METHODS: ICC patients (n=58) undergoing percutaneous CT-guided ablation with or without pre-ablation TACE at our institute from 2009 to 2013 were enrolled in the primary cohort. All treatments were performed under conscious sedation and local anesthesia. Prognostic factors for OS were identified to establish the nomogram. The nomogram was accessed by the concordance index (C-index) and calibration curve, and compared with 11 currently available prognostic systems. The nomogram was further evaluated in a validation cohort (n=19) of patients with ICC who underwent thermal ablation and TACE from 2014 to 2016. RESULTS: In the primary cohort, the median OS was 17.9 months and the 1-, 3-, 5-year OS rates were 69.6%, 29.5%, 23.6%, respectively. Three single independent predictors (number of tumors, vascular invasion and lymph node metastasis) for OS were identified by multivariate analysis and used to formulate the nomogram. The C-index of the nomogram was 0.834 [95% confidence interval (CI), 0.765 to 0.904], significantly higher than that of ten current prognostic systems for ICC, and similar with that of the Wang nomogram. The performance of the proposed nomogram was also confirmed in the validation cohort (C-index, 0.839). CONCLUSIONS: Thermal ablation appears to be effective for ICC patients. The proposed nomogram is helpful for predicting patient survival after ablation treatment.

Efficacy of ultrasound-, computed tomography-, and magnetic resonance imaging-guided radiofrequency ablation for hepatocellular carcinoma.

PURPOSES: This study aimed to investigate the efficacy of ultrasound (US)-, computed tomography (CT)-, and magnetic resonance imaging (MRI)-guided radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This retrospective study included 141 patients with HCC who were treated with US-guided (n = 29), CT-guided (n = 50), or MRI-guided RFA (n = 62). The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), technique success (TS), and technique efficacy (TE). Cox model and logistic regression were used to determine the risk factors for tumor recurrence and TE. RESULTS: The US, CT, and MRI groups did not show a significant difference in terms of baseline variables. The three groups did not differ significantly in PFS rate (P = 0.072) and OS rate (P = 0.231). The PFS rates at 3 years for the US, CT, and MRI groups were 40.90%, not reached, and 14.80%, respectively. The OS rates at 3 years were 94.70%, 97.50%, and 85.50% for US, CT, and MRI groups, respectively. No significant differences were observed between the three groups in terms of TS rate (P = 0.113) and TE rate (P = 0.682). In multivariate analysis, liver cirrhosis (P = 0.001), level of alpha-fetoprotein (AFP, P = 0.004), and number of tumors (P = 0.012) were independent risk factors for PFS. For TE, the level of AFP (P = 0.018) was an independent factor. CONCLUSION: US-, CT-, and MRI-guided RFA was effective for treating HCC patients. Liver cirrhosis, AFP level, and tumor number were associated with tumor recurrence, and the level of AFP was an independent risk factor affecting TE.

Safety and technical feasibility of percutaneous ablation for lymph node metastases of hepatocellular carcinoma.

PURPOSE: This study aimed to assess the safety and technical feasibility of percutaneous ablation therapy for lymph node (LN) metastases of hepatocellular carcinoma (HCC). MATERIAL AND METHODS: A total of 31 consecutive HCC patients with LN metastases who were treated with ablation were included in this retrospective study. Percutaneous ablation was performed under local anesthesia and computed tomography-guidance. The primary endpoint was technique success; secondary endpoints were overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS). Survival curves were constructed using Kaplan-Meier method. RESULTS: The median diameter of metastatic LNs was 30 mm (range, 10-77 mm). The 1-, 3-, and 5-year OS rates were 74.6%, 50.3%, and 50.3%, respectively. The 1-, 3-, and 5-year PFS rates were 24.7%, 0%, and not available for calculation (NA), respectively. The 1-, 3-, and 5-year LPFS rates were 78.7%, 69.9%, and 69.9%, respectively. The technique success and technical effectiveness rates were 100% and 64.5%, respectively. The technical effectiveness rates were 65.4% (17/26) and 60% (3/5) in abdominal LN metastases and distant LN metastases, respectively. Only one patient (1/31, 3.2%) had major complications (massive pleural effusion and severe pneumonia) related to ablation. Minor complications related to ablation included mild abdominal pain (10/31, 32.3%) and self-limiting hematoma (2/31, 6.5%). No ablation-related death occurred. CONCLUSION: Percutaneous ablation appears to be a safe and feasible method for treatment of metastatic LNs in patients with HCC.

A Meta-Analysis of Clinical Outcomes After Radiofrequency Ablation and Microwave Ablation for Lung Cancer and Pulmonary Metastases.

PURPOSE: We conducted a meta-analysis assessing clinical outcomes of radiofrequency ablation (RFA) and microwave ablation (MWA) for treating lung cancer. METHODS: Databases were searched up to 2017 to identify high-quality studies. The results were presented as pooled estimates with 95% confidence intervals (CIs). RESULTS: Fifty-three studies were included, and up to 3,432 patients were pooled. The estimated 1-, 2-, 3-, 4-, and 5-year overall survival (OS) rates were higher for RFA-treated patients compared with those treated by MWA. The median OS, median progression-free survival (PFS), median local tumor PFS, complete ablation rate, and adverse events did not differ significantly. Subgroup analyses by tumor type showed that the median OS for RFA-treated patients with pulmonary metastases was higher than that of the MWA-treated patients. CONCLUSION: Thermal ablation, both RFA and MWA, is an effective approach for treating lung cancer with low risk of adverse events. RFA is associated with longer survival than MWA, and patients with pulmonary metastases showed better survival after RFA compared with MWA-treated patients.

Biopsy of peripheral lung nodules utilizing cone beam computer tomography with and without trans bronchial access tool: a retrospective analysis.

BACKGROUND: Currently there are several techniques for endoscopic diagnosis of parenchymal lung abnormalities. Electromagnetic navigation with or without endobronchial ultrasound for diagnosis of the above has been well described. Bronchoscopic Trans Bronchial Access Tool is a novel endoscopic technique that creates a virtual pathway to the lesion and is less limited by location of the airway. The CrossCountryTM Transbronchial Access Tool (CovidienTM, Plymouth, MN, USA) is a Food and Drug Administration (FDA) approved off airway device that utilizes a catheter equipped guide sheath for a trans-parenchymal approach to a distal lesion. Cone beam computer tomography (CBCT) is a real-time onsite extrathoracic navigational modality used in the bronchoscopy suite that allows for an open working channel. All three of the above modalities can have reasonable diagnostic yields when used independently. While utilizing the above tools we frequently found ourselves in situations where one technique was not enough, prompting the use of a combination of modalities to obtain the most efficient and accurate diagnosis. We are reporting the feasibility and safety of utilizing these three modalities in conjunction with one another. METHODS: Patients with peripheral pulmonary nodules on chest computed tomography underwent a navigation bronchoscopy under general anesthesia. CBCT and radial ultrasound was used in every case to confirm navigation to the target lesion. Lesions without definitive airways leading to them were accessed with the transbronchial access tool (TBAT). RESULTS: Electromagnetic bronchoscopy using CBCT and radial US was performed on 22 patients from April 2016 to September 2016. The TBAT tool was used in 7 patients. The overall diagnostic yield was 77.2% (17 of 22). Diagnostic yield of with use TBAT was 100% (7 of 7). There were no complications. Average case length was 79.95 (range, 50-124) minutes and average fluoroscopy time was 10.39 (1-21.7) minutes. CONCLUSIONS: TBAT is a useful and safe tool when accessing peripheral pulmonary nodules and is used in conjunctions with electromagnetic navigation and CBCT.

Efficacy of Percutaneous Thermal Ablation Combined With Transarterial Embolization for Recurrent Hepatocellular Carcinoma After Hepatectomy and a Prognostic Nomogram to Predict Survival.

AIM: This study aimed to evaluate the efficacy of percutaneous thermal ablation combined with transarterial embolization for recurrent hepatocellular carcinoma after hepatectomy and establish a prognostic nomogram to predict survival. METHODS: One hundred seventeen patients with recurrent hepatocellular carcinoma receiving ablation from 2009 to 2014 were included in primary cohort to establish a prognostic nomogram. Between 2014 and 2016, 51 patients with recurrent hepatocellular carcinoma treated by ablation were enrolled in the validation cohort to validate the predictive accuracy of the nomogram. All patients underwent locoregional ablation. Overall survival was the primary end point, and progression-free survival was the second end point. The performance of the nomogram was assessed through concordance index and calibration curve and compared with 5 conventional hepatocellular carcinoma staging systems. RESULTS: The 1-, 3-, and 5-year overall survival rates of primary cohort were 88.4%, 70.7%, and 64.1%, respectively. The 1-, 3-, and 5-year progression-free survival rates of primary cohort were 44%, 14%, and 8.7%, respectively. The results of multivariate analysis showed that tumor size ( P = .0469; hazard ratio, 1.020; 95% confidence interval, 1.0004-1.040), preoperative extrahepatic disease ( P = .0675; hazard ratio, 2.604; 95% confidence interval, 0.933-7.264), and close to hepatic hilum <2 cm ( P = .0053; hazard ratio, 3.691; 95% confidence interval, 1.474-9.240) were predictive factors for overall survival. The study established a nomogram to predict survival (concordance index, 0.752; 95% confidence interval, 0.656-0.849). According to the predicted overall survival, patients with recurrent hepatocellular carcinoma were divided into 3 risk classes ( P < .05): low-risk group (total score <55; predicted 5-year overall survival rate, 82.9%), intermediate-risk group (55 ≤ total score < 99; predicted 5-year overall survival rate, 52.8%), and high-risk group (hazard ratio, total score ≥99; predicted 5-year overall survival rate, not available). CONCLUSION: Percutaneous thermal ablation appears to be an effective procedure for the treatment of recurrent hepatocellular carcinoma after hepatectomy. The proposed nomogram provides a mechanism to accurately predict survival and could stratify risk among patients with recurrent hepatocellular carcinoma treated by ablation therapy.

Correction: Percutaneous thermal ablation combined with TACE versus TACE monotherapy in the treatment for liver cancer with hepatic vein tumor thrombus: A retrospective study.

[This corrects the article DOI: 10.1371/journal.pone.0201525.].

Percutaneous thermal ablation combined with TACE versus TACE monotherapy in the treatment for liver cancer with hepatic vein tumor thrombus: A retrospective study.

PURPOSE: To investigate the efficacy of percutaneous thermal ablation combined with transarterial chemoembolization (TACE) versus TACE monotherapy in treating primary liver cancer with hepatic vein tumor thrombus (HVTT), and to identify potential factors of overall survival after combination therapy. MATERIALS AND METHODS: Patients with primary liver cancer and HVTT from 2011 to 2016 at our institute were retrospectively identified. They were divided into two groups (group A and group B). Patients in group A underwent TACE with subsequent percutaneous thermal ablation, while patients in group B who were unsuitable for ablation received TACE monotherapy. Characteristics and survival data of the two groups were analyzed and compared. Relevant factors for overall survival (OS) of group A were explored by univariate analysis. RESULTS: Twenty-six patients were included and analyzed. The median OS for group A (n = 13) was 18 months, while the 1-, 2- and 3-year survival rates were 58.6%, 46.9% and 46.9%, respectively. The median OS for group B (n = 13) was 6.5 months and the 1-year survival rate was 10.9%. The survival of group A was significantly better than group B (P = 0.02). The following factors were related with overall survival of group A: ablation technique, complete response of tumor and HVTT, Child-pugh grade, pre-operative extrahepatic metastases and lymph node metastases. In group A, patients who achieved complete response had the longest average survival time (42.1 months). CONCLUSION: For patients with primary liver cancer and HVTT, percutaneous thermal ablation and TACE present better efficacy than TACE monotherapy. Long-term survival could be achieved in selected patients.

Combination therapy of TACE and CT-guided partial hepatic segment ablation for liver cancer.

Aim: This study aimed to investigate the safety and efficacy of combination therapy of transcatheter arterial chemoembolization (TACE) and CT-guided percutaneous partial hepatic segment ablation. Material and methods: Liver cancer patients undergoing TACE plus partial segment ablation from 2012 to 2016 were retrospectively analyzed. Patient characteristics were collected. TACE was performed for all patients before ablation. After ablation, CT imagings were used to evaluate treatment and follow-up. Overall survival (OS) and local tumor progression free survival (LTPFS) were calculated. Results: Twenty-three patients with 68 liver tumors were included. The median tumor maximum diameter was 55 mm (range, 24 to 91 mm). The complete response rate of combination therapy was 87%. The one-, two-, three- and four-year overall survival rates were 78%, 65%, 54% and 54%, respectively. The three-year survival rate for BCLC stage C HCC patients was 53%. The one-, two- and three-year LTPFS rates were 54%, 35% and 35%, respectively. Tumor maximum diameter, vascular invasion and partial treatment response were independent risk factors for LTPFS. Only one patient suffered a major complication. Conclusion: TACE combined with partial hepatic segment thermal ablation is a safe and effective treatment for liver cancer patients, especially for those with more advanced disease.