Correction: Systemic Delivery of MicroRNA-101 Potently Inhibits Hepatocellular Carcinoma In Vivo by Repressing Multiple Targets.

[This corrects the article DOI: 10.1371/journal.pgen.1004873.].

Postprogression treatment of lenvatinib plus PD-1 inhibitor in advanced hepatocellular carcinoma refractory to hepatic arterial infusion chemotherapy.

PURPOSE: This study compares the efficacy and safety of lenvatinib and programmed cell death protein (PD)-1 versus lenvatinib alone for advanced hepatocellular carcinoma (Ad-HCC) refractory to hepatic arterial infusion chemotherapy (HAIC). METHODS: From April 2016 to September 2021, 145 patients with Ad-HCC refractory to HAIC based on modified Response Evaluation Criteria in Solid Tumors criteria were enrolled by two radiologists and classified into the HAIC-lenvatinib group (H-L, n = 87) and HAIC-lenvatinib-PD-1 group (H-L-P, n = 58). A propensity score-matching method was used to reduce selective bias. The overall survival (OS) and postprogression-free survival (PPS) rates were compared using the Kaplan-Meier method with log-rank test. Multivariable analyses of independent prognostic factors were evaluated by means of the forward stepwise Cox regression model. RESULTS: After propensity score matching 1:1, the median OS was 43.6 months in the H-L-P group and was significantly longer than that (18.9 months) of the H-L group (p = .009). The median PPS was 35.6 months in the H-L-P group and was significantly longer than that (9.4 months) of the H-L group (p = .009). Multivariate analyses showed that the factors that significantly affected the OS were α-fetoprotein (hazard ratio [HR], 2.14; 95% CI, 1.26-3.98; p = .006), early response to HAIC (HR, 0.44; 95% CI, 1.20-3.85; p = .009), and H-L treatment (HR, 0.52; 95% CI, 0.30-0.86; p = .012). Modified albumin-bilirubin grade (HR, 1.32; 95% CI, 1.03-1.70; p = .026), early response to HAIC (HR, 0.44; 95% CI, 0.25-0.77; p = .004), and H-L (HR, 0.47 ; 95% CI, 0.28-0.78; p = .003) significantly affected the PPS. CONCLUSIONS: This combination therapy of PD-1 inhibitors plus lenvatinib has promising survival benefits in the management of patients with Ad-HCC refractory to HAIC. PLAIN LANGUAGE SUMMARY: Lenvatinib plus programmed death 1 inhibitor is an effective and safe postprogression treatment and improved significantly overall survival and postprogression-free survival compared with lenvatinib alone in patients with advanced hepatocellular carcinoma refractory to hepatic arterial infusion chemotherapy.

Global incidence, prevalence and disease burden of silicosis: 30 years' overview and forecasted trends.

BACKGROUND: Globally, silicosis accounts for 90% of all pneumoconiosis cases and is a serious public health issue. It is characterized by progressive inflammation and irreversible pulmonary fibrosis. A comprehensive analysis at temporal, spatial and population levels with the most updated data from GBD 2019 is provided in this study to estimate the disease burden of silicosis from 1990 to 2019 and make predictions to 2029. METHODS: We delineated silicosis data on incidence, prevalence, and disability-adjusted life years (DALYs) as well as age-standardized rates (ASRs) across 30 years from GBD 2019. Joinpoint regression analysis was employed to detect temporal changes and estimate annual percentage change (APC) of each trend segment. Measures were stratified by time, location, age, and sociodemographic index (SDI). Back propagation artificial neural network (BP-ANN) model was applied to elaborate ASR trends from 1990 to 2019 and projections to the next 10 years. RESULTS: Globally, silicosis incident, prevalent cases, and DALYs increased by 64.6%, 91.4%, and 20.8%, respectively. However, all the corresponding ASRs showed overall downward trends with an estimated average APC (AAPC) of -0.5(-0.7 to -0.3), -0.2(-0.5 to 0.0), and - 2.0(-2.2 to -1.8), respectively. Middle and high-middle SDI regions carried the heaviest disease burden. The highest disease burden of silicosis was mainly transferred to the older from 1990 to 2019. The trend of ASRs demonstrated a rapid decline between 2005 and 2019, followed by a continuous decline until 2029. CONCLUSION: Though disease burden of silicosis has been on a decline in general from 1990 to 2019, which shows a promising prospect but cannot be ignored. We should pay more attention to implementing preventive tactics and improving the life quality of present sufferers.

Analysis of competing endogenous RNA network identifies a poorly differentiated cancer-specific RNA signature for hepatocellular carcinoma.

Plenty of evidence has suggested that long noncoding RNAs (lncRNAs) play a vital role in competing endogenous RNA (ceRNA) networks. Poorly differentiated hepatocellular carcinoma (PDHCC) is a malignant phenotype. This paper aimed to explore the effect and the underlying regulatory mechanism of lncRNAs on PDHCC as a kind of ceRNA. Additionally, prognosis prediction was assessed. A total of 943 messenger RNAs (mRNAs), 86 miRNAs, and 468 lncRNAs that were differentially expressed between 137 PDHCCs and 235 well-differentiated HCCs were identified. Thereafter, a ceRNA network related to the dysregulated lncRNAs was established according to bioinformatic analysis and included 29 lncRNAs, 9 miRNAs, and 96 mRNAs. RNA-related overall survival (OS) curves were determined using the Kaplan-Meier method. The lncRNA ARHGEF7-AS2 was markedly correlated with OS in HCC (P = .041). Moreover, Cox regression analysis revealed that patients with low ARHGEF7-AS2 expression were associated with notably shorter survival time (P = .038). In addition, the area under the curve values of the lncRNA signature for 1-, 3-, and 5-year survival were 0.806, 0.741, and 0.701, respectively. Furthermore, a lncRNA nomogram was established, and the C-index of the internal validation was 0.717. In vitro experiments were performed to demonstrate that silencing ARHGEF7-AS2 expression significantly promoted HCC cell proliferation and migration. Taken together, our findings shed more light on the ceRNA network related to lncRNAs in PDHCC, and ARHGEF7-AS2 may be used as an independent biomarker to predict the prognosis of HCC.

Microwave ablation after downstaging of hepatocellular carcinoma: outcome was similar to tumor within Milan criteria.

OBJECTIVES: The aim of this study was to evaluate the clinical outcome of patients receiving microwave ablation (MWA), either after downstaging of hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE), or without downstaging when meeting initially the Milan criteria. METHODS: From January 2012 to January 2018, 66 patients with HCC beyond the Milan criteria who were downstaged by TACE previous to MWA comprised the study group. The control group comprised 190 patients who underwent MWA as first-line treatment as they met initially the Milan criteria. Cumulative overall survival (OS) and recurrence-free survival (RFS) rates were compared. The propensity score analysis was performed to reduce potential bias. RESULTS: Baseline characteristics were balanced between the two groups after 1:1 propensity score matching. The OS rates were 100%, 79%, and 73% at 1, 3, and 5 years in the downstaging group and 95%, 83%, and 72%, respectively, in the Milan group. The corresponding RFS rate were 77%, 40%, and 31% in the downstaging group and 76%, 45%, and 34% in the Milan group. There were no significant differences in the OS and RFS rates between the two groups (p = 0.981 and p = 0.586). CONCLUSIONS: The long-term therapeutic outcomes of MWA for downstaged HCC with TACE were similar to HCC that initially met the Milan criteria. KEY POINTS: • Patients treated with MWA of HCC after downstaging with transarterial chemoembolization (TACE) were similar to those with HCC that initially met Milan criteria. • Microwave ablation (MWA) can be an effective treatment for hepatocellular carcinoma (HCC) that is downstaged to the Milan criteria.

The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma.

BACKGROUND: Blocking the programmed death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in hepatocellular carcinoma (HCC) is a very promising approach in immunotherapy. However, the correlation and prognostic values of serum soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have not been explored conjointly in HCC patients. METHODS: This study retrospectively included 120 HCC patients receiving radical resection. The serum levels of sPD-1/sPD-L1 and inflammatory cytokines were measured by antibody array assay. Immunohistochemistry was applied to assess both the expression of membrane-bound PD-L1, and the number of CD4+ tumor-infiltrating lymphocytes (TILs) and CD8+ TILs. RESULTS: The best cut-off values of sPD-1 and sPD-L1 for predicting disease-free survival (DFS) were 33.0 µg/ml and 11.2 µg/ml, respectively. Multivariable analysis showed that sPD-L1 was a negative independent prognostic factor [DFS, Hazard Ratio (HR) 2.58, 95% CI 1.14-5.84, P = 0.023; overall survival (OS), HR 1.77, 95% CI 1.01-3.12, P = 0.048], while sPD-1 was a favorable independent prognostic factor (DFS, HR 0.32, 95% CI 0.14-0.74, P = 0.007; OS, HR 0.54, 95% CI 0.30-0.98, P = 0.044) in HCC patients. We also observed some similar associations between inflammatory cytokines (IL-10, IL-17, TNF-α) and sPD-1 or sPD-L1, as well as a close positive association between sPD-1 and sPD-L1. No significant associations of sPD-1/sPD-L1 with either intra-tumoral PD-L1 expression, or the numbers of CD4+ TILs and CD8+ TILs were determined. CONCLUSIONS: Our findings indicate that sPD-1 and sPD-L1 are independent prognostic factors with opposite prognostic roles in predicting both DFS and OS in HCC patients.

Radiofrequency Ablation Following Downstaging of Hepatocellular Carcinoma by Using Transarterial Chemoembolization: Long-term Outcomes.

Background Transarterial chemoembolization (TACE) is an effective downstaging procedure for hepatocellular carcinoma (HCC). However, knowledge of the effectiveness of radiofrequency ablation (RFA) after downstaging of HCC is currently lacking. Purpose To evaluate the clinical outcomes of RFA after downstaging of HCC by using TACE. Materials and Methods This retrospective study investigated a cohort of patients who underwent RFA with curative intent after downstaging with TACE to meet Milan criteria (one lesion up to 5 cm or no more than three lesions ≤3 cm without vascular invasion or extrahepatic metastasis) from January 2012 to July 2017. A control group of patients initially meeting the Milan criteria also underwent RFA as first-line treatment in the same period. Overall survival (OS), disease-free survival (DFS), and major complication rates were compared by using the log-rank test. To reduce potential bias, a propensity score analysis was also performed. Results There were 72 patients (median age, 56.5 years; range, 30-78 years; 67 men) in the downstaging group and 357 patients meeting the Milan criteria (median age, 58.0 years; range, 25-87 years; 313 men) included in this study. After propensity score matching, the 1-, 3-, and 5-year OS rates were 99%, 80%, and 66%, respectively, for the patients in the downstaging group and 94%, 84%, and 69%, respectively, for the patients in the Milan criteria group. The 1-, 3-, and 5-year DFS rate were 73%, 34%, and 24% for the downstaging group and 74%, 43%, and 37% for the Milan criteria group. There were no differences in the OS, DFS, or major complication rates between the two groups (P = .74, P = .39, P = .73, respectively). Conclusion The long-term patient survival and major complication rates of radiofrequency ablation following transarterial chemoembolization downstaging for hepatocellular carcinoma were similar to that of patients initially meeting the Milan criteria. © RSNA, 2019 See also the editorial by vanSonnenberg and Mueller in this issue.

Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin in Hepatocellular Cancer with Extrahepatic Spread.

PURPOSE: To compare treatment with hepatic arterial infusion of chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) with both extrahepatic spread (EHS) and intrahepatic tumor and patients with intrahepatic tumor only. MATERIALS AND METHODS: This single-center retrospective study comprised 116 patients with advanced HCC with both intrahepatic tumor and EHS (EHS group; n = 50) or with intrahepatic tumor only (non-EHS group; n = 66) treated with HAIC including oxaliplatin, fluorouracil, and leucovorin between June 2014 and July 2016. Overall survival (OS) and radiologic responses to treatment were determined and compared between the 2 groups. RESULTS: Both the objective response rate and the clinical benefit rate were higher in the non-EHS group than in the EHS group (37.9% vs 16% objective response rate, P = .010; 81.8% vs 62% clinical benefit rate, P = .017). Median OS was not statistically different between the 2 groups (14.8 months vs 9.8 months, P = .068). Subgroup analysis of OS found that patients with lung metastases survived for a shorter time (OS 7 months) than patients with other metastatic sites (P = .003) and patients free of metastases (P = .001). CONCLUSIONS: HAIC is a potential treatment option for advanced HCC with limited extrahepatic metastases in a population with hepatitis B virus infection.

The injury of recurrent laryngeal nerve and thyroid regeneration after irreversible electroporation ablation of most part of thyroid gland-an experimental study on swine model.

To study the thyroid regeneration and injury of recurrent laryngeal nerve after irreversible electroporation (IRE). 12 pigs were divided into three groups: six pigs underwent IRE, other pigs were used as controls. IRE was performed near tracheoesophageal groove, to ablate most part of thyroid gland. Parathyroid and thyroid function, recurrent laryngeal nerve injury and thyroid computed tomography (CT) imaging were regularly investigated. The histopathology results were analyzed to detect thyroid regeneration. Masson's trichrome method for collagen and immunohistochemistry were performed for Soluble protein-100 (S100) and neurofilaments on nerve section. In IRE group, there were no symptoms of recurrent laryngeal nerve-related injury. No abnormalities of recurrent laryngeal nerve were shown on hematoxylin-eosin (HE) staining, Masson's trichrome staining, Neurofilament (NF) staining and S100 staining. There were no significant changes for thyroid and parathyroid function in all pigs. Immediately after IRE, CT showed hypoattenuation in the ablated thyroid gland and it became swelling. 14 days after IRE, thyroid CT showed hetergenous attenuation in the electroporation zone, and the size and attenuation of thyroid gland were normal after two months. There was cell apoptosis in the thyroid gland after IRE. Seven and 14 days after IRE, there was fragmentation of nucleus within the follicle, and some follicles were empty. Two months later, complete regeneration of thyroid tissue was shown. IRE was shown to be both effective and safe with complete regeneration of thyroid tissue and preservation of the function and structure of the recurrent laryngeal nerve.

Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma.

BACKGROUND & AIMS: To compare the overall survival (OS) and disease progression free survival (PFS) in patients with advanced hepatocellular carcinoma (Ad-HCC) who are undergoing hepatic arterial infusion (HAI) of oxaliplatin, fluorouracil/leucovorin (FOLFOX) treatment vs. sorafenib. METHODS: This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients before treatment. HAI of FOLFOX (HAIF) was recommended as an alternative treatment option for patients who refused sorafenib. Of the 412 patients with Ad-HCC (376 men and 36 women) between Jan 2012 to Dec 2015, 232 patients were treated with sorafenib; 180 patients were given HAIF therapy. The median age was 51 years (range, 16-82 years). Propensity-score matched estimates were used to reduce bias when evaluating survival. Survival curves were calculated by performing the Kaplan-Meier method and compared by using the log-rank test and Cox regression models. RESULTS: The median PFS and OS in the HAIF group were significantly longer than those in the sorafenib group (PFS 7.1 vs. 3.3 months [RECIST]/7.4 vs. 3.6 months [mRECIST], respectively; OS 14.5 vs. 7.0 months; p <0.001 for each). In the propensity-score matched cohorts (147 pairs), both PFS and OS in the HAIF group were longer than those in the sorafenib group (p <0.001). At multivariate analysis, HAIF treatment was an independent factor for PFS (hazard ratio [HR] 0.389 [RECIST]/0.402 [mRECIST]; p <0.001 for each) and OS (HR 0.129; p <0.001). CONCLUSION: HAIF therapy may improve survival compared to sorafenib in patients with Ad-HCC. A prospective randomized trial is ongoing to confirm this finding. LAY SUMMARY: We compared the hepatic arterial infusion of FOLFOX (a combination chemotherapy) with sorafenib (a tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma, retrospectively. It was found that hepatic arterial infusion of FOLFOX therapy may improve both progression free and overall survival in patients with advanced hepatocellular carcinoma.

Dynamic imaging and pathological changes in pig liver after MR-guided microwave ablation.

BACKGROUND: Magnetic resonance (MR)-guided microwave ablation is a well-developed technique for the treatment of tumors, especially hepatic carcinomas. However, there are no detailed reports on the changes in the MR images and histology observed after the ablation. This study aimed to dynamically map the pathological changes after ablation and the changes occurring on MR images. METHODS: We performed MR-guided microwave ablation in 10 Wuzhishan pigs and obtained an MR scan immediately after ablation (0 weeks) and at 1, 2, 3, and 4 weeks after ablation. We compared the ablation assessed on MR images to tissue specimens obtained during follow-up. RESULTS: We found no significant difference in the ablation size between MR images and tissue specimens; the mean length and width of the ablated zone were 4.27 cm and 2.42 cm, respectively, on MR images and 4.26 cm and 2.45 cm, respectively, on specimens (P > 0.05). Immediately after ablation, carbonization and cavities were observed in the center of the ablation zone. Surrounding layer cells were necrotic but maintained their original shapes. The outermost layer was inflamed, but gradually showed fibrotic characteristics. The MR images accurately reflected the exact histological tissue changes after the ablation procedure. CONCLUSION: The dynamic imaging and pathological features of liver ablation outlined in this study will provide a useful reference for patient follow-up after MR-guided microwave ablation.

Successful treatment with pazopanib plus PD-1 inhibitor and RAK cells for advanced primary hepatic angiosarcoma: a case report.

BACKGROUND: Primary hepatic angiosarcoma (PHA) is a rare and aggressive solid tumor, with high rates of local recurrence and distant metastasis, and poor prognosis. There are no established treatment guidelines for PHA. CASE PRESENTATION: A 78-year-old asymptomatic man with PHA that was successfully treated with pazopanib plus PD-1 inhibitor and RetroNectin-activated killer cells (RAK cells). After one month of treatment, there was a clear reduction in the size and number of the liver metastases; and after nearly 15 months, most of the lesions were stable, no new lesions had developed, and the side effect of treatment was minor. CONCLUSION: Pazopanib, PD-1 inhibitor and RAK cells could serve as a potential option for the treatment of advanced PHA.

High number of PD-1 positive intratumoural lymphocytes predicts survival benefit of cytokine-induced killer cells for hepatocellular carcinoma patients.

BACKGROUND & AIMS: Adjuvant cytokine-induced killer (CIK) cells treatment has shown potential in reducing the recurrence rate and prolonging the survival of patients with hepatocellular carcinoma (HCC). We aimed to identify the best predictive biomarker for adjuvant CIK cells treatment in patients with HCC after curative resection. METHODS: This study retrospectively included 145 pairs of HCC patients by one-to-one propensity score matching. One group received CIK cells transfusion after surgery (surgery-CIK group); the other one group underwent surgery only (surgery-only group). Immunohistochemistry (IHC) was used to measure PD-1, PD-L1, CD4, CD8 and Foxp3 expression in tumour tissues of surgery-CIK group; IHC of PD-1 and PD-L1 was conducted in the surgery-only group. RESULTS: The surgery-CIK group had a significantly higher disease-free survival (DFS) and overall survival (OS) rates compared to the surgery-only group. Of all the intratumoural biomarkers, in the surgery-CIK group, multivariate analysis showed that a high number of PD-1+ tumour infiltrative lymphocytes (TILs) was the only factor that independently predicted favourable OS and DFS. By contrast, in the surgery-only group, no significant correlations between PD-1/PD-L1 expression and survival of patients were identified. Further correlation analysis showed a high number of PD-1+ TILs associated with a high number of both CD4+ and CD8+ TILs in surgery-CIK group. CONCLUSIONS: A high number of PD-1+ TILs can serve as a potent biomarker for adopting CIK cells therapy in HCC patients after curative resection.

ß-elemene increases the sensitivity of gastric cancer cells to TRAIL by promoting the formation of DISC in lipid rafts.

ß-Elemene, an anti-cancer drug extracted from traditional Chinese medicinal herb, showed anti-tumor effects on gastric cancer cells. Our previous studies reported gastric cancer cells are insensitive to TRAIL. However, whether ß-elemene could enhance anti-cancer effects of TRAIL on gastric cancer cells is unknown. In our present study, ß-elemene prevented gastric cancer cell viability in dose-dependent manner, and when combined with TRAIL, obviously inhibited proliferation and promoted apoptosis in gastric cancer cells. Compared to ß-elemene or TRAIL alone, treatment with ß-elemene and TRAIL obviously promoted DR5 clustering as well as translocation of Caspase-8, DR5 and FADD into lipid rafts. This led to cleavage of Caspase-8 and the formation of death-inducing signaling complex (DISC) in lipid rafts. The cholesterol-sequestering agent nystatin partially reversed DR5 clustering and DISC formation, preventing apoptosis triggered by the combination of ß-elemene and TRAIL. Our results suggest that ß-elemene increases the sensitivity of gastric cancer cells to TRAIL partially by promoting the formation of DISC in lipid rafts.

Comparison of glycemic control and ß-cell function in new onset T2DM patients with PCOS of metformin and saxagliptin monotherapy or combination treatment.

BACKGROUND: Impaired insulin activity in women with polycystic ovary syndrome might differ from that seen in type 2 diabetes mellitus without polycystic ovary syndrome. This study was designed to compare the effects of treatment with metformin, saxagliptin, and their combination in newly diagnosed women with type 2 diabetes mellitus and polycystic ovary syndrome in China. METHODS: A total of 75 newly diagnosed patients from Shanghai, China with type 2 diabetes mellitus and polycystic ovary syndrome were included in this randomized, parallel, open-label study. All patients received treatment for 24 weeks with metformin, saxagliptin, or their combination. Patients were allocated to one of three treatment groups by a computer-generated code that facilitated equal patient distribution of 25 patients per group. The primary outcome was a change in glycemic control and ß-cell function. RESULTS: A total of 63 patients completed the study (n = 21, for each group). The reduction in hemoglobin A1c was significant in the combination group, compared to the monotherapy groups (saxagliptin vs. combination treatment vs. metformin: - 1.1 vs. -1.3 vs. -1.1%, P = 0.016), whereas it was comparable between the metformin and saxagliptin groups (P > 0.05). Saxagliptin, metformin, and the combination treatment significantly reduced the homeostasis model assessment- insulin resistance index and increased the deposition index (P < 0.01 for all). However, no significant change was observed in the homeostasis model assessment- ß-cell function among the metformin and combination groups, and no significant changes were observed in the insulinogenic index among all three groups (P > 0.05 for all). In addition, saxagliptin and metformin treatments significantly reduced body mass index and high-sensitivity C-reactive protein levels (P < 0.01 for both). CONCLUSIONS: Saxagliptin and metformin were comparably effective in regulating weight loss, glycemic control, and ß-cell function, improving lipid profiles, and reducing inflammation in newly diagnosed type 2 diabetes mellitus patients with polycystic ovary syndrome. TRIAL REGISTRATION: ChiCTR-IPR-17011120 (retrospectively registered on 2017-04-12).

Percutaneous CT-guided radiofrequency ablation for patients with extrahepatic oligometastases of hepatocellular carcinoma: long-term results.

BACKGROUND: The aim of this study was to evaluate the therapeutic outcome of percutaneous computed tomography (CT)-guided radiofrequency ablation (RFA) for extrahepatic oligometastases of hepatocellular carcinoma (HCC). METHODS: Institutional review board approval was obtained for this retrospective study, and all patients provided written informed consent. Between April 2004 and December 2015, 116 oligometastases (diameter, 5-50 mm; 20.3 ± 10.4) in 79 consecutive HCC patients (73 men and 6 women; average age, 50.3 years ±13.0) were treated with RFA. We focussed on patients with 1-3 extrahepatic metastases (EHM) confined to 1-2 organs (including the lung, adrenal gland, bone, lymph node and pleura/peritoneum) who were treated naïve with curative intent. Survival, technical success and safety were evaluated. The log-rank test and Cox proportional hazards regression models were used to analyse the survival data. RESULTS: No immediate technical failure occurred, and at 1 month, the technique effectiveness rate was determined to be 95.8%. After a median follow-up time of 28.0 months (range, 6-108 months), the 1-, 2- and 3-year overall survival (OS) rates were 91, 70 and 48%, respectively, with a median survival time of 33.5 months. Time to unoligometastatic progression (TTUP) of less than 6 months (p < 0.001) and a Child-Pugh score of more than 5 (p = 0.001) were significant indicators of shorter OS. The 1-, 2- and 3-year disease free survival (DFS) rates were 34, 21 and 8%, respectively, with a median DFS time of 6.8 months. DFS was better for those with lung metastases (p = 0.006). Major complication occurred in nine (9.5%, 9/95) RFA sessions without treatment-related mortality. CONCLUSIONS: CT-guided RFA for oligometastatic HCC may provide favourable efficacy and technical success with a minimally invasive approach.

Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets.

Targeted therapy based on adjustment of microRNA (miRNA)s activity takes great promise due to the ability of these small RNAs to modulate cellular behavior. However, the efficacy of miR-101 replacement therapy to hepatocellular carcinoma (HCC) remains unclear. In the current study, we first observed that plasma levels of miR-101 were significantly lower in distant metastatic HCC patients than in HCCs without distant metastasis, and down-regulation of plasma miR-101 predicted a worse disease-free survival (DFS, P<0.05). In an animal model of HCC, we demonstrated that systemic delivery of lentivirus-mediated miR-101 abrogated HCC growth in the liver, intrahepatic metastasis and distant metastasis to the lung and to the mediastinum, resulting in a dramatic suppression of HCC development and metastasis in mice without toxicity and extending life expectancy. Furthermore, enforced overexpression of miR-101 in HCC cells not only decreased EZH2, COX2 and STMN1, but also directly down-regulated a novel target ROCK2, inhibited Rho/Rac GTPase activation, and blocked HCC cells epithelial-mesenchymal transition (EMT) and angiogenesis, inducing a strong abrogation of HCC tumorigenesis and aggressiveness both in vitro and in vivo. These results provide proof-of-concept support for systemic delivery of lentivirus-mediated miR-101 as a powerful anti-HCC therapeutic modality by repressing multiple molecular targets.

Percutaneous CT-guided Radiofrequency Ablation for Lymph Node Oligometastases from Hepatocellular Carcinoma: A Propensity Score-matching Analysis.

Purpose To assess the effectiveness and safety of percutaneous computed tomography (CT)-guided radiofrequency ablation (RFA) for lymph node (LN) oligometastases from hepatocellular carcinoma (HCC). Materials and Methods This retrospective study was approved by the institutional ethics committee, and all patients provided written informed consent. From January 2004 to December 2013, 119 consecutive patients with HCC and LN oligometastases (115 men [mean age, 51.3 years; age range, 16-83 years] and four women [mean age, 38.2 years; age range, 23-47 years]) were included in this study. A matched cohort composed of 46 patients from each group was selected after adjustment with propensity score matching. The median follow-up time was 14.0 months in the RFA group and 13.8 months in the non-RFA group. The overall survival (OS), local control rate, and complications were evaluated. Survival curves were constructed with the Kaplan-Meier method and compared by using the log-rank test. Results Eighty-seven patients had LN metastases located in the regional site, and 32 patients had LN metastases in the distant site. No significant differences were observed in the baseline characteristics between groups after propensity score matching adjustment. The RFA group showed higher 6-month and 1-year OS rates compared with the non-RFA group (87.0% and 58.3% vs 62.4% and 17.9%, respectively; P = .001). The 3-month local control rate after RFA was 84.4%, including complete response in 71.1% of patients and partial response in 13.3%. The complications of RFA were short-term abdominal pain and self-limited local hematoma, which occurred in 10 patients (21.7%) and five patients (10.9%), respectively. Conclusion Percutaneous CT-guided RFA may be a safe and effective treatment for the LN oligometastases generated by HCC. © RSNA, 2016.

Increased PD-L1 expression in breast and colon cancer stem cells.

Here we report the expression of programmed cell death ligand 1/2 (PD-L1/L2) in breast and colon cancer stem cells (CSCs). The stemness of these cells was confirmed by their surface markers. Using flow cytometry analysis we demonstrated that PD-L1 expression was higher in CSCs of both cancers compared to non-stem like cancer cells. Consistent with this, detection of cellular PD-L1 proteins by western blot assay also showed increased PD-L1 protein in CSCs. In contrast, only trace amounts of PD-L2 were detected in CSCs of both cancers. Our results suggest that breast and colon cancers may be sensitive to PD1/PD-L1 immunotherapy and thus warrant further investigations of CSC targeted PD1/PD-L1 therapy.

Image-based Multilevel Subdivision of M1 Category in TNM Staging System for Metastatic Nasopharyngeal Carcinoma.

Purpose To establish an image-based M1 category subdivision system for personalized prognosis prediction and treatment planning in patients with metastatic nasopharyngeal carcinoma (NPC). Materials and Methods A total of 1172 patients with metachronous metastasic NPC were retrospectively enrolled (the dataset is from Sun Yat-sen University Cancer Center for derivation, and the combined datasets are from Guangzhou Medical University Cancer Center and the Fifth Affiliated Hospital of Sun Yat-sen University for validation). The Ethics Committee of the three centers approved this study. A general subdivision system of the M1 category was established on the basis of the most influential metastatic features for overall survival (OS). The following multilevel subdivision system for precise subdivision of the M1 category was designed: M [number of locations]-Location [number of lesions], with B indicating bone, L indicating the lung, H indicating the liver, and N indicating a node. The correlation of the M1 subdivisions with OS was determined with Cox regression. The best treatment response was assessed with Response Evaluation Criteria in Solid Tumors 1.1 guidelines and modified Response Evaluation Criteria in Solid Tumors criteria. Results Multivariate analysis in the derivation cohort showed that the number of metastatic lesions (multiple or single), the number of metastatic locations (multiple or single), liver involvement, and bone involvement were independent prognostic factors for OS. In general, subdividing the cohort by the number of metastatic lesions and the number of metastatic locations resulted in three subcategories of differential OS: M1a, a single lesion in a single organ or location; M1b, multiple lesions in a single organ or location; and M1c, metastases in multiple locations (for M1b vs M1a, hazard ratio [HR] = 2.28, 95% confidence interval [CI]: 1.71, 3.05; for M1c vs M1a, HR = 3.65, 95% CI: 2.75, 4.85); these subdivisions were externally validated. The multilevel subdivision system could be further used to discriminate among subgroups of differential OS under the M1b subcategory. Findings from analysis of multilevel subgroups suggested that patients with a single metastatic lesion (M1-B1, M1-L1, M1-H1, M1-N1) or two lesions in the liver only (M1-H2) had high rates of complete response (CR) or complete surgical resection (CSR) and 3-year OS after treatment (CR plus CSR rates >30%, and 3-year OS rates >50%); there were high 3-year OS rates (>50%) in patients with stage M1-B2, M1-L2, or M1-H3 disease but relatively low rates of CR or CSR. Conclusion Use of the multilevel M1 subdivision system in patients with NPC could facilitate more precise prognosis prediction and better identification of patients who will respond well to treatment than the conventional subdivision strategy. (©) RSNA, 2016 Online supplemental material is available for this article.