Size selection of intrahepatic lesions for cryoablation contributes to abscopal effect and long-term survival in patients with liver metastatic melanoma receiving PD-1 blockade therapy.

OBJECTIVES: In this study, we aimed to examine parameters of cryoablation, tumor characteristics, and their correlations with distant tumor response and survival of liver metastatic melanoma patients receiving cryoablation and PD-1 blockade (cryo-PD-1) combination treatment. MATERIALS AND METHODS: A retrospective study was conducted among 45 melanoma patients who received combined PD-1 blockade therapy and cryoablation for liver metastasis from 2018 to 2022. Cox regression was utilized to determine the associations between factors and overall survival (OS). Changes in cytokines and immune cell compositions in peripheral blood samples following the combined treatment were investigated, along with their correlations with treatment response. RESULTS: The mean cycle of cryo-PD-1 combination treatment was 2.2 (range, 1-6), and the 3-month overall response rate (RECIST 1.1 criteria) was 26.7%. Of the 21 patients who failed previous PD-1 blockade therapy after diagnosis of liver metastasis, 4 (19.0%) achieved response within 3 months since combination treatment. The diameter of ablated lesion ≤ 30 mm, metastatic organs ≤ 2, and pre-treatment LDH level ≤ 300 U/L were independent prognostic factors for favorable OS. Further analysis showed patients with intrahepatic tumor size of 15-45 mm, and ablated lesion size of ≤ 30 mm had significantly higher 3-month response rate (42.9% vs 12.5%; P = 0.022) and survival time (30.5 vs 14.2 months; P = 0.045) than their counterparts. The average increase in NLR among patients with ablated tumor size of ≤ 3 cm and > 3 cm were 3.59 ± 5.01 and 7.21 ± 12.57, respectively. The average increase in serum IL-6 levels among patients with ablated tumor size of ≤ 3 cm and > 3 cm were 8.62 ± 7.95 pg/ml and 15.40 ± 11.43 pg/ml, respectively. CONCLUSION: Size selection of intrahepatic lesions for cryoablation is important in order to achieve abscopal effect and long-term survival among patients with liver metastatic melanoma receiving PD-1 blockade therapy.

SurvivalPath:A R package for conducting personalized survival path mapping based on time-series survival data.

The survival path mapping approach has been proposed for dynamic prognostication of cancer patients using time-series survival data. The SurvivalPath R package was developed to facilitate building personalized survival path models. The package contains functions to convert time-series data into time-slices data by fixed interval based on time information of input medical records. After the pre-processing of data, under a user-defined parameters on covariates, significance level, minimum bifurcation sample size and number of time slices for analysis, survival paths can be computed using the main function, which can be visualized as a tree diagram, with important parameters annotated. The package also includes function for analyzing the connections between exposure/treatment and node transitions, and function for screening patient subgroup with specific features, which can be used for further exploration analysis. In this study, we demonstrate the application of this package in a large dataset of patients with hepatocellular carcinoma, which is embedded in the package. The SurvivalPath R package is freely available from CRAN, with source code and documentation hosted at https://github.com/zhangt369/SurvivalPath.

Benefits of step-by-step debulking microwave ablation for huge unresectable hepatocellular carcinoma patients after transcatheter arterial chemoembolization refractoriness.

OBJECTIVES: To compare the safety and efficacy of step-by-step debulking Microwave Ablation (MWA) with Transarterial Chemoembolization (TACE) monotherapy for huge (≥10 cm in diameter) unresectable hepatocellular carcinoma (HCC) after TACE refractoriness. METHODS: This is a multi-center retrospective study carried out on 599 patients with huge unresectable HCC who received TACE as first-line therapy at five hospitals from January 2009 to December 2018. A total of 103 patients with TACE refractoriness were divided into two cohorts: monthly step-by-step debulking MWA (n = 52) or continued TACE (n = 51). Overall survival (OS) and progression-free survival (PFS) after refractory TACE were evaluated. Residual liver and tumor volume were recorded for the MWA group. RESULTS: Median follow-up period was 24.3 months and median OS and PFS were significantly longer in the MWA group than in the TACE group (OS 21.0 vs. 11.7 months, PFS 6.1 vs. 3.0 months, both p < 0.001). The one-, two-, and three-year OS rates in the MWA and TACE groups were 73.1%, 46.6%, and 37.2% versus 43.1%, 15.5%, and 2.9%, respectively. Furthermore, the 0.5-, 1-, and 2-year PFS rates in the MWA and TACE groups were 51.9%, 36.5%, and 25.0% versus 27.5%, 11.8%, and 0, respectively. Multivariate analyses confirmed that switching to debulking MWA treatment was an independent favorable prognostic factor for PFS and OS. In the MWA group, the average additions of residual liver volume/total liver volume were 7.7% ± 6.7%, 7.2% ± 10.2%, and 10.1% ± 8.8% after the first, second, and third MWA procedure. CONCLUSION: Step-by-step debulking MWA can significantly improve long-term OS and PFS in patients with huge unresectable HCCs compared with repeated TACE after TACE refractoriness. Key PointThe debulking MWA therapy provides significantly longer OS and PFS than continued TACE for patients with huge unresectable HCCs after TACE-refractory, especially with complete tumor ablation.The most common complications were fever (48.1%) and pain (46.2%) in the MWA group. Two major complications (abdominal infection) were recorded in the MWA group, which recovered after symptomatic treatment.During the course of repeated MWAs, liver hyperplasia appeared mainly after the second MWA procedure and the average maximum increased RLV/TLV rate was 16.3%±12.7%.

Single-nodule hepatitis B virus-associated hepatocellular carcinoma smaller than 3 cm: two phenotypes defined by cluster analysis and their association with the outcome of ablation as the first-line therapy.

OBJECTIVES: Hepatocellular carcinoma (HCC) is a heterogeneous disease. This study aimed to identify the heterogeneity related to the prognosis of ablation in patients with single-nodule hepatitis B virus (HBV)-associated HCC ≤3 cm. METHODS: A total of 359 patients with single-nodule HBV-associated HCC ≤3 cm treated with curative thermal ablation were retrospectively investigated. Hierarchical cluster analysis was applied to obtain more homogeneous patient clusters concerning demographic and physiological characteristics. Discriminant analysis was performed to identify the relatively important variables for cluster analysis. Multiple correspondence analysis (MCA) was used to clarify the relationship between clusters and categorical variables. Overall survival (OS) was compared among clusters using the Kaplan-Meier model. RESULTS: A two-cluster model was identified. Cluster 1 (n = 85) showed a higher percentage of female and older patients, higher inflammation response (higher prognostic nutritional index [PNI] and Glasgow prognostic score [GPS]), worse liver function (higher albumin-bilirubin grade and Child-Pugh grade), and relatively poorer immune status (higher neutrophil-to-lymphocyte ratio [NLR]) than cluster 2 (n = 274). NLR and GPS were the two most influential variables for cluster analysis (p < .0001). Cluster 2 had a significantly better prognosis than cluster 1. MCA revealed a clear negative correlation between inflammation status and liver function. Compared with cluster 1, the hazard ratios for OS of cluster 2 were 0.47 and 0.52 before and after adjusting for age, respectively (p < .05). CONCLUSIONS: This study identified two sub-phenotypes of patients with single-nodule HBV-associated HCC ≤3 cm and their association with the outcome of thermal ablation alone as the first-line therapy. Key points Thermal ablation alone as the first-line therapy is not suitable for all patients with single-nodule hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) ≤3 cm. Patients with single-nodule HBV-associated HCC ≤3 cm can be identified as two sub-phenotypes associated with the outcome of thermal ablation alone as the first-line therapy, based on key preoperative clinical characteristics, especially inflammatory response and immune status. Patients with single-nodule HBV-associated HCC ≤3 cm characterized by late-onset disease, worse liver function, poorer immune status, and higher inflammatory response (with higher inflammatory response being the most important factor) are not suitable for thermal ablation alone as the first-line therapy. In contrast, patients with single-nodule HBV-associated HCC ≤3 cm characterized by early-onset disease, better liver function, lower inflammatory response, and good immune status (with lower inflammatory response being the most important factor) are particularly suitable for thermal ablation alone. Implications for patient care In the treatment of patients with single-nodule HBV-associated HCC ≤3 cm, thermal ablation alone as the first-line therapy should be carefully considered after recognizing the key clinical characteristics, among which inflammatory response and immune status are the two most important factors involved in clinical heterogeneity, and inflammatory response is closely related to the prognosis of thermal ablation alone as the first-line therapy for these patients.

Comparison between surgery and thermal ablation for adrenal metastases: a retrospective study.

PURPOSE: To retrospectively compare the efficacy and safety of surgical resection (SR) and thermal ablation for the treatment of adrenal metastases. METHODS: From January 2008 to December 2018, 133 patients with adrenal metastases who underwent SR (n = 76) or thermal ablation (n = 57) were enrolled. The mean tumor size was 58.00 ± 10.65 mm (22-80 mm) in the SR group and 58.03 ± 12.76 mm (34-89 mm) in the thermal ablation group. Local progression-free survival (LPFS) and safety were compared between the two groups using the Kaplan-Meier method and log-rank tests. Cox proportional hazard regression models were used to evaluate the prognostic factors of LPFS. Complications, hospitalization days, and blood loss were also assessed. RESULTS: The median follow-up was 29.0 months (range, 20.4-37.6 months). No treatment-related mortality was observed. The 1-, 3- and 5-year LPFS rates were 74.0%, 62.8%, and 31.4% in the SR group and 72.8%, 68.7%, and 51.5% in the ablation group, with the median LPFS of 41.5 months (95% CI: 9.3-23.4 months) vs. 47.9 months (95% CI 20.6-75.8 months), respectively (p = 0.784). Tumor size ≥3 cm was the only significant risk factor for LPFS (p = 0.031). The ablation group was superior to the SR group with a lower major complication rate (4.1% vs. 14.5%, p = 0.03), less blood loss (1 ml vs. 100 ml, p < 0.001), and a shorter hospital stay (2 d vs. 6 d, p < 0.001). CONCLUSION: Thermal ablation provided a similar LPFS and less comorbidities than SR, indicating that it is an effective and safe treatment for adrenal metastases.

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.

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study.

BACKGROUND: The presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma. A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients. METHODS: This registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression. The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples. RESULTS: Of the 15 patients enrolled, no grade 3-4 adverse events or major complications were observed. One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response. The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3-49.0%) and 33.3% (95% CI 2.5-64.1%), respectively. Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment. The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5-5.5) and 5.73 (95% CI 1.1-10.4) months, respectively. A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of treatment in the combined stage. CONCLUSIONS: The CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.

The m6A methyltransferase METTL3 cooperates with demethylase ALKBH5 to regulate osteogenic differentiation through NF-κB signaling.

As a m6A methylation modifier, METTL3 is functionally involved in various biological processes. Nevertheless, the role of METTL3 in osteogenesis is not determined up to date. In the current study, METTL3 is identified as a crucial regulator in the progression of osteogenic differentiation. Loss of METTL3 significantly augments calcium deposition and enhances alkaline phosphatase activity of mesenchymal stem cells, uncovering an inhibitory role of METTL3 in osteogenesis. More importantly, the underlying molecular basis by which METTL3 regulates osteogenesis is illustrated. We find that METTL3 positively regulates expression of MYD88, a critical upstream regulator of NF-κB signaling, by facilitating m6A methylation modification to MYD88-RNA, subsequently inducing the activation of NF-κB which is widely regarded as a repressor of osteogenesis and therefore suppressing osteogenic progression. Moreover, the METTL3-mediated m6A methylation is found to be dynamically reversed by the demethylase ALKBH5. In summary, this study highlights the functional importance of METTL3 in osteogenic differentiation and METTL3 may serve as a promising molecular target in regenerative medicine, as well as in the field of bone tissue engineering.

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.

Microwave ablation versus sorafenib for intermediate-Stage Hepatocellular carcinoma with transcatheter arterial chemoembolization refractoriness: a propensity score matching analysis.

Purpose: To compared the benefits of sorafenib with microwave ablation (MWA) in intermediate-stage hepatocellular carcinoma (HCC) patients with tumor size ≤7 cm and tumor number ≤5 after Transcatheter Arterial Chemoembolization (TACE) failure.Methods: A retrospective, single-center study was conducted using a one-to-one propensity score matching (PSM) analysis and involved 52 intermediate-stage HCC patients with absence of evidence of intrahepatic vascular invasion and extrahepatic metastasis after TACE failure and underwent treatment with MWA or sorafenib between 2007 and 2019. The overall survival (OS) and progression-free survival (PFS) were evaluated by the Kaplan-Meier method. The factors with OS and PFS were determined by Cox regression.Results: Of the 52 patients included in our study, 30 (57.7%) underwent MWA and 22 (42.3%) received sorafenib. After PSM, 22 pairs were enrolled into different groups for further analysis. Patients in the MWA-group had a significantly longer median PFS than patients in the sorafenib-group on both before (median, 9.3 vs. 2.8 months, p = .001) and after PSM (median, 9.0 vs. 2.8 months, p = .006). They also had a significantly longer median OS than patients in the sorafenib-group on before (median, 48.8 vs. 16.6 months, p = .001) and after PSM (median, Not reached vs. 16.6 months, p = .001). Besides, Cox regression analysis showed that the treatment and age were the independent prognostic factors of OS and PFS (p＜0.05).Conclusions: MWA was superior to sorafenib in improving survival for intermediate-stage hepatocellular carcinoma (HCC) patients with tumor size ≤7 cm and tumor number ≤5 after TACE failure.Key PointsCompared with sorafenib, microwave ablation may be a more reasonable alternative treatment for intermediate-stage hepatocellular carcinoma (HCC) patients with tumor size ≤7 cm and tumor number ≤5 after TACE refractoriness.The treatment (MWA vs sorafenib) and the age of patients were the independent prognostic factors of OS and PFS.

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.

Efficacy and safety of CT-guided percutaneous thermal ablation for hepatocellular carcinoma adjacent to the second porta hepatis.

Purpose: This study assessed the efficacy and safety of computed tomography (CT)-guided percutaneous thermal ablation for hepatocellular carcinoma adjacent to the second porta hepatis.Methods: From January 2011 to June 2018, 59 consecutive patients (51 men and 8 women aged 29-85 years) with 65 tumors (mean maximum tumor diameter: 20.5 ± 1.2 mm; range: 5-50 cm) adjacent to the second porta hepatis underwent percutaneous CT-guided thermal ablation. The complete ablation rate, local progression-free survival (LPFS), progression-free survival (PFS), prognostic factors for local progression, and safety of this technique were assessed.Results: No more than three sessions were performed to complete a patient's treatment. Technical success was achieved for all tumors. In the median follow-up of 18.5 months, local tumor progression occurred in 32.2% (19/59) of patients, while tumor progression occurred in 71.2% (42/59). The median LPFS was 37.4 months. The 1-, 2-, and 3-year LPFS rates were 86.2%, 66.5%, and 66.5%, respectively. The median PFS was 11.0 months. The 1-, 2-, and 3-year PFS rates were 47.9%, 27.0%, and 20.2%, respectively. The tumor size (P = .007) and distance between the tumor and inferior vena cava (P = 0.018) were the independent prognostic factors for local tumor progression.Conclusion: We showed that CT-guided percutaneous microwave ablation and radiofrequency ablation are effective and safe treatments for tumors adjacent to the second porta hepatis, particularly in patients with lesions less than 3 cm and a distance between the tumor and inferior vena cava of more than 5 mm.

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.

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.

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.

Percutaneous irreversible electroporation for breast tissue and breast cancer: safety, feasibility, skin effects and radiologic-pathologic correlation in an animal study.

BACKGROUND: To study the safety, feasibility and skin effects of irreversible electroporation (IRE) for breast tissue and breast cancer in animal models. METHODS: Eight pigs were used in this study. IRE was performed on the left breasts of the pigs with different skin-electrode distances, and the right breasts were used as controls. The electrodes were placed 1-8 mm away from the skin, with an electrode spacing of 1.5-2 cm. Imaging and pathological examinations were performed at specific time points for follow-up evaluation. Vital signs, skin damage, breast tissue changes and ablation efficacy were also closely observed. Eight rabbit models with or without VX2 breast tumor implantations were used to further assess the damage caused by and the repair of thin skin after IRE treatment for breast cancer. Contrast-enhanced ultrasound and elastosonography were used to investigate ablation efficacy and safety. RESULTS: During IRE, the color of the pig breast skin reversibly changed. When the skin-electrode distance was 3 mm, the breast skin clearly changed, becoming white in the center and purple in the surrounding region during IRE. One small purulent skin lesion was detected several days after IRE. When the skin-electrode distance was 5-8 mm, the breast skin became red during IRE. However, the skin architecture was normal when evaluated using gross pathology and hematoxylin-eosin staining. When the skin-electrode distance was 1 mm, skin atrophy and yellow glabrescence occurred in the rabbit breasts after IRE. When the skin-electrode distance was ≥5 mm, there was no skin damage in the rabbit model regardless of breast cancer implantation. After IRE, complete ablation of the targeted breast tissue or cancer was confirmed, and apoptosis was detected in the target tissue and outermost epidermal layer. In the ablated breasts of the surviving animals, complete mammary regeneration with normal skin and hair was observed. Furthermore, no massive fibrosis or mass formation were detected on ultrasound or through hematoxylin-eosin staining. CONCLUSIONS: After IRE, the skin architecture was well preserved when the skin-electrode distance was ≥5 mm. Moreover, breast regeneration occurred without mass formation or obvious fibrosis.

Critical weight loss predicts poor prognosis in nasopharyngeal carcinoma.

BACKGROUND: The impacts of weight loss on prognosis in nasopharyngeal carcinoma (NPC) remain unclear. The present study was therefore undertaken to investigate the association between critical weight loss and long-term survival in NPC patients. METHODS: The eligible 2399 NPC patients were reviewed. Weight change was categorized into critical weight loss (CWL) and non-critical weight loss (Non-CWL). The associations of CWL with long-term survival were analyzed by Cox regression in the entire patient and two subsets. Propensity score matching was performed to reduce the effects of confounding factors. RESULTS: CWL was defined as body weight loss of ≥4.6 %. Compared with patients without CWL, patients with CWL had significantly lower 5-year OS (72.4 vs. 79.3 %, P < 0.001), FFS (71.1 vs. 78.4 %, P <0.001), and LR-FFS (78.1 vs. 84.8 %, P <0.001), respectively. After adjustment for potential confounders, CWL remained an independence prognostic factor for OS (HR = 1.352; 95 % CI 1.160-1.576; P < 0.001), FFS (HR = 3.275; 95 % CI 1.101-9.740; P = 0.033), and LR-FFS (HR = 6.620; 95 % CI 2.990-14.658; P < 0.001), respectively. Furthermore, subgroup analysis in the cohort of patients received concurrent chemoradiotherapy or radiotherapy alone confirmed the results in the entire patient even after the propensity-score matching. In IMRT cohort, CWL was also significantly associated with a lower OS (P = 0.04) and FFS (P = 0.04). CONCLUSIONS: CWL has a significant and independent impact on long-term survival in nasopharyngeal carcinoma patients.

M1 stage subdivision and treatment outcome of patients with bone-only metastasis of nasopharyngeal carcinoma.

BACKGROUND: The current M1 stage in nasopharyngeal carcinoma (NPC) does not differentiate patients based on metastatic site and number of metastases. This study aims to subdivide the M1 stage of NPC patients with bone-only metastases and to identify the patients who may benefit from combined chemoradiotherapy (CRT). METHODS: Between 1998 and 2007, 312 patients diagnosed with bone-only metastasis at Sun Yat-sen University Cancer Center were enrolled. Various possible subdivisions of M1 stage were considered, including by the time order of metastasis (synchronous vs. metachronous), involvement of specific bone metastatic site, the number of metastatic sites, and the number of metastases. The correlation of the subdivisions of M1 stage with overall survival (OS) was determined by Cox regression. RESULTS: The median OS was 23.4 months. Patients with more than three metastatic sites had significantly poorer OS than patients with three or fewer metastatic sites (16.2 vs. 32.4 months; p < .001). Metastasis to the spine was significantly associated with unfavorable OS (20.4 vs. 37.9 months; p < .001). Multivariate analysis showed that number of metastatic sites (more than three vs. three or fewer), spine involvement (present vs. absent), and treatment modality (CRT vs. chemotherapy or radiotherapy only) were independent prognostic factors for OS. In stratified analysis, compared with chemotherapy or radiotherapy alone, combined chemoradiotherapy could significantly benefit the patients with single bone metastasis (hazard ratio: 0.21; 95% confidence interval: 0.09-0.50). CONCLUSION: Metastasis to the spine and having more than three bone metastatic sites are independent unfavorable predictors for OS in NPC patients with bone-only metastasis. Combined chemoradiotherapy should be considered for patients with single bone metastasis.

Subdivision of M category for nasopharyngeal carcinoma with synchronous metastasis: time to expand the M categorization system.

INTRODUCTION: The current metastatic category (M) of nasopharyngeal carcinoma (NPC) is a "catch-all" classification, covering a heterogeneous group of tumors ranging from potentially curable to incurable. The aim of this study was to design an M categorization system that could be applied in planning the treatment of NPC with synchronous metastasis. METHODS: A total of 505 NPC patients diagnosed with synchronous metastasis at Sun Yat-sen University Cancer Center between 2000 and 2009 were involved. The associations of clinical variables, metastatic features, and a proposed M categorization system with overall survival (OS) were determined by using Cox regression model. RESULTS: Multivariate analysis showed that Union for International Cancer Control (UICC) N category (N1-3/N0), number of metastatic lesions (multiple/single), liver involvement (yes/no), radiotherapy to primary tumor (yes/no), and cycles of chemotherapy (>4/≤4) were independent prognostic factors for OS. We defined the following subcategories based on liver involvement and the number of metastatic lesions: M1a, single lesion confined to an isolated organ or location except the liver; M1b, single lesion in the liver and/or multiple lesions in any organs or locations except the liver; and M1c, multiple lesions in the liver. Of the 505 cases, 74 (14.7%) were classified as M1a, 296 (58.6%) as M1b, 134 (26.5%) as M1c, and 1 was not specified. The three M1 subcategories showed significant difference in OS [M1b vs. M1a, hazard ratio (HR) = 1.69, 95% confidence interval (CI) = 1.16-2.48, P = 0.007; M1c vs. M1a, HR = 2.64, 95% CI = 1.75-3.98, P < 0.001]. CONCLUSIONS: We developed an M categorization system based on the independent factors related to the prognosis of patients with metastatic NPC. This system may be helpful to further optimize individualized care for NPC patients.

[Liver regeneration after radiofrequency ablation versus irreversible electroporation].

OBJECTIVE: To compare liver regeneration after radiofrequency ablation versus irreversible electroporation (IRE). METHODS: A total of 10 pigs were divided into IRE and radiofrequency ablation groups. And two ablation foci were established in the liver of each pig. Computed tomography (CT)-guided IRE and radiofrequency ablation were performed. Cell death, liver regeneration and recovery speed were compared. Before ablation, immediately, 1 and 3 weeks after ablation, contrast enhanced ultrasound, CT and magnetic resonance imaging (MRI) were regularly performed. Immediately after ablation, 24 hours, 3 days, 3 weeks and 6 weeks, biopsy and pathologic examination were performed. RESULTS: At 1-3 days after IRE ablation, apoptotic cells were detected in the ablation zone and numerous red blood cells were present in hepatic cords. Three days after IRE, fibroblasts were found. Three weeks after, most ablation lesions disappeared or significantly reduced. There was no formation of fibrous capsule. And indistinct boundary existed between the surrounding liver tissue and lesion. Immediately after ablation, coagulative necrosis of ablation zone in liver was confirmed. After 3 weeks, all lesions persisted in the radiofrequency ablation group. There was formation of fibrous capsule. Immediately after ablation, the ablation volume was similar between two groups on CT scan. Three weeks later, 6 ablation foci in IRE group disappeared while another 4 lesions shrank more than 50%. There was no significant volume reduction in the radiofrequency ablation group. CONCLUSION: Compared with radiofrequency ablation, IRE resulted in faster liver regeneration and intact extracellular structure.