Sintilimab plus bevacizumab combined with radiotherapy as first-line treatment for hepatocellular carcinoma with portal vein tumor thrombus: A multicenter, single-arm, phase 2 study.

BACKGROUND AND AIMS: Systemic treatments are listed as first-line therapies for HCC with portal vein tumor thrombus (PVTT), resulting in modest efficacy. We aimed to evaluate the efficacy and safety of sintilimab plus bevacizumab combined with radiotherapy in HCC with PVTT and to identify prognostic biomarkers. APPROACH AND RESULTS: This open-label, multicenter, single-arm, phase 2 clinical trial was conducted at 3 tertiary hospitals in China. A total of 46 patients with HCC with PVTT were enrolled. All the patients received the first cycle of i.v. sintilimab (200 mg, day 1) plus bevacizumab (15 mg/kg, day 1) within 3 days after enrollment. Radiotherapy (30-50 Gy/10 fractions) was administered after 2 cycles of Sin-Bev. Sin-Bev was disrupted during radiotherapy and resumed 2 weeks after radiotherapy and continued every 3 weeks thereafter until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate. Patients obtained an objective response rate of 58.7% and a disease control rate of 100%. After a median follow-up time of 26.0 months (95% CI: 24.0-26.0), the median OS was 24.0 months (95% CI: 19.0 to not applicable) and the median progression-free survival was 13.8 months (95% CI: 12.0-21.0), respectively. No unexpected adverse events or treatment-related deaths occurred. Mutations of PCTMD1 were predictive of shorter OS and progression-free survival. CONCLUSIONS: Sintilimab plus bevacizumab combined with radiotherapy provides favorable treatment response and survival outcomes along with an acceptable safety profile in the first-line setting for patients with HCC with PVTT (ClinicalTrials.gov Identifier: NCT05010434).

Elevated SLC1A5 associated with poor prognosis and therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor, and glutamine is vital for tumor cells. The role of glutamine transporter SLC1A5 in tumor progression and transarterial chemoembolization (TACE) efficacy is under study. This research seeks to determine the impact of SLC1A5 expression on the prognosis and TACE efficacy of HCC and elucidate its mechanisms. METHODS: SLC1A5 expression in HCC, correlation with patient outcomes, and response to TACE were studied in an open access liver cancer dataset and confirmed in our cohort. Additionally, the correlation between SLC1A5 expression and hypoxia, angiogenesis and immune infiltration was analyzed and verified by immunohistochemistry, immunofluorescence and transcriptome sequencing. Liver cancer cell lines with SLC1A5 expression knockdown or overexpression were constructed, and cell proliferation, colony formation, apoptosis, migration and drug sensitivity as well as in vivo xenograft tumor were measured. A gene set enrichment analysis was conducted to determine the signaling pathway influenced by SLC1A5, and a western blot analysis was performed to detect protein expression alterations. RESULTS: SLC1A5 expression was higher in HCC tissue and associated with poor survival and TACE resistance. Hypoxia could stimulate the upregulation of glutamine transport, angiogenesis and SLC1A5 expression. The SLC1A5 expression was positively correlated with hypoxia and angiogenesis-related genes, immune checkpoint pathways, macrophage, Tregs, and other immunosuppressive cells infiltration. Knockdown of SLC1A5 decreased proliferation, colony formation, and migration, but increased apoptosis and increased sensitivity to chemotherapy drugs. Downregulation of SLC1A5 resulted in a decrease in Vimentin and N-cadherin expression, yet an increase in E-cadherin expression. Upregulation of SLC1A5 increased Vimentin and N-cadherin expression, while decreasing E-cadherin. Overexpression of ß-catenin in SLC1A5-knockdown HCC cell lines could augment Vimentin and N-cadherin expression, suppress E-cadherin expression, and increase the migration and drug resistance. CONCLUSIONS: Elevated SLC1A5 was linked to TACE resistance and survival shortening in HCC patients. SLC1A5 was positively correlated with hypoxia, angiogenesis, and immunosuppression. SLC1A5 may mediate HCC cell migration and drug resistance via Epithelial-mesenchymal transition (EMT) pathway.

Development and validation of survival prediction models for patients with hepatocellular carcinoma treated with transcatheter arterial chemoembolization plus tyrosine kinase inhibitors.

BACKGROUND: Due to heterogeneity of molecular biology and microenvironment, therapeutic efficacy varies among hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs). We examined combined models using clinicoradiological characteristics, mutational burden of signaling pathways, and radiomics features to predict survival prognosis. METHODS: Two cohorts comprising 111 patients with HCC were used to build prognostic models. The training and test cohorts included 78 and 33 individuals, respectively. Mutational burden was calculated based on 17 cancer-associated signaling pathways. Radiomic features were extracted and selected from computed tomography images using a pyradiomics system. Models based on clinicoradiological indicators, mutational burden, and radiomics score (rad-score) were built to predict overall survival (OS) and progression-free survival (PFS). RESULTS: Eastern Cooperative Oncology Group performance status, Child-Pugh class, peritumoral enhancement, PI3K_AKT and hypoxia mutational burden, and rad-score were used to create a combined model predicting OS. C-indices were 0.805 (training cohort) and 0.768 (test cohort). The areas under the curve (AUCs) were 0.889, 0.900, and 0.917 for 1-year, 2-year, and 3-year OS, respectively. To predict PFS, alpha-fetoprotein level, tumor enhancement pattern, hypoxia and receptor tyrosine kinase mutational burden, and rad-score were used. C-indices were 0.782 (training cohort) and 0.766 (test cohort). AUCs were 0.885 and 0.925 for 6-month and 12-month PFS, respectively. Calibration and decision curve analyses supported the model's accuracy and clinical potential. CONCLUSIONS: The nomogram models are hopeful to predict OS and PFS in patients with intermediate-advanced HCC treated with TACE plus TKIs, offering a promising tool for treatment decisions and monitoring patient progress.

TREM2+ macrophages suppress CD8+ T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma.

BACKGROUND & AIMS: The immune landscape of hepatocellular carcinoma (HCC) following transarterial chemoembolisation (TACE) remains to be clarified. This study aimed to characterise the immune landscape following TACE and the underlying mechanism of HCC progression. METHODS: Tumour samples from five patients with treatment-naive HCC and five patients who received TACE therapy were collected and subjected to single-cell RNA sequencing. Another 22 paired samples were validated using immunofluorescence staining and flow cytometry. To clarify the underlying mechanisms, in vitro co-culture experiments and two types of TREM2-KO/WT mouse models, namely, an HCC cell orthotopic injection model and a spontaneous HCC model, were used. RESULTS: A reduced number of CD8+ T cells and an increased number of tumour-associated macrophages (TAMs) were observed in the post-TACE microenvironment. TACE therapy reduced the cluster CD8_C4, which was highly enriched with tumour-specific CD8+ T cells of pre-exhausted phenotype. TREM2 was found to be highly expressed in TAMs following TACE, which was associated with a poor prognosis. TREM2+ TAMs secreted less CXCL9 but more galectin-1 than did TREM2- TAMs. Galectin-1 promoted PD-L1 overexpression in vessel endothelial cells, impeding CD8+ T cell recruitment. TREM2 deficiency also increased CD8+ T cell infiltration, which inhibited tumour growth in both in vivo HCC models. More importantly, TREM2 deficiency enhanced the therapeutic effect of anti-PD-L1 blockade. CONCLUSIONS: This study shows that TREM2+ TAMs play an important role in suppressing CD8+ T cells. TREM2 deficiency increased the therapeutic effect of anti-PD-L1 blockade by enhancing antitumour activity of CD8+ T cells. These findings explain the reasons for recurrence and progression after TACE and provide a new target for HCC immunotherapy after TACE. IMPACT AND IMPLICATIONS: Studying the immune landscape in post-TACE HCC is important to uncover the mechanisms of HCC progression. By using scRNA sequencing and functional assays, we discovered that both the number and function of CD8+ T cells are compromised, whereas the number of TREM2+ TAMs is increased in post-TACE HCC, correlating with worse prognosis. Moreover, TREM2 deficiency dramatically increases CD8+ T cell infiltration and augments the therapeutic efficacy of anti-PD-L1 blockade. Mechanistically, TREM2+ TAMs display lower CXCL9 and increased Gal-1 secretion than do TREM2- TAMs, with Gal-1 mediating the overexpression of PD-L1 in vessel endothelial cells. These results suggest that TREM2 could be a novel immunotherapeutic target for patients treated with TACE in HCC. This provides an opportunity to break the plateau of limited therapeutic effect. This study has the value of understanding the tumour microenvironment of post-TACE HCC and thinking a new strategy of immunotherapy in the field of HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology.

Identifying optimal candidates for post-TIPS patients with HCC undergoing TACE: a multicenter observational study.

OBJECTIVE: To develop a prognostic model for post-transjugular intrahepatic portosystemic shunt (TIPS) patients with hepatocellular carcinoma (HCC) beyond the Milan criteria treated by transarterial chemoembolization (TACE). DESIGN: Between January 2013 and January 2020, 512 patients with HCC beyond the Milan criteria who underwent TACE after TIPS were retrospectively recruited from 15 tertiary centers. Patients were randomly sorted into a training set (n = 382) and a validation set (n = 130). Medical data and overall survival were assessed. A prediction model was developed using multivariate Cox regression analyses. Predictive performance and discrimination were evaluated and compared with other prognostic models. RESULTS: Vascular invasion, log10(AFP), 1/creatinine, extrahepatic spread, and log10(ALT) were the most significant prognostic factors of survival. These five parameters were included in a new VACEA score. This score was able to stratify patients in the training set into four distinct risk grades whose median overall survival were 25.2, 15.1, 8.9, and 6.2 months, respectively. The 6-month, 1-year, 2-year, and 3-year AUROC values and C-index of the VACEA model were 0.819, 0.806, 0.779, 0.825, and 0.735, respectively, and higher than those of other seven currently available models in both the training and validation sets, as well as in different subgroups. CONCLUSION: The VACEA score could stratify post-TIPS patients with HCC beyond the Milan criteria treated by TACE and help to identify candidates who benefit from this treatment. KEY POINTS: • Vascular invasion, AFP, creatinine, extrahepatic spread, and ALT were independent significant prognostic factors of survival for HCC patients who underwent TACE after TIPS. • Our new model, named VACEA score, can accurately predict prognosis at the individual level and stratify patients into four distinct risk grades. • The VACEA model showed better prognostic discrimination and calibration than other current TACE-/TIPS-specific models Graphical abstract.

Optimal time point of response assessment for predicting survival is associated with tumor burden in hepatocellular carcinoma receiving repeated transarterial chemoembolization.

OBJECTIVES: Objective response rate (ORR) under mRECIST criteria after transarterial chemoembolization (TACE) is a well-perceived surrogate endpoint of overall survival (OS). However, its optimal time point remains controversial and may be influenced by tumor burden. We aim to investigate the surrogacy of initial/best ORR in relation to tumor burden. METHODS: A total of 1549 eligible treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh score ≤ 7, and performance status score ≤ 1 undergoing TACE between January 2010 and May 2016 from 17 academic hospitals were retrospectively analyzed. Based on "six-and-twelve" criteria, tumor burden was graded as low, intermediate, and high if the sum of the maximum tumor diameter and tumor number was ≤ 6, > 6 but ≤ 12, and > 12, respectively. RESULTS: Both initial and best ORRs interacted with tumor burden. Initial and best ORRs could equivalently predict and correlate with OS in low (adjusted HR, 2.55 and 2.95, respectively, both p < 0.001; R = 0.84, p = 0.035, and R = 0.97, p = 0.002, respectively) and intermediate strata (adjusted HR, 1.81 and 2.22, respectively, both p < 0.001; R = 0.74, p = 0.023, and R = 0.9, p = 0.002, respectively). For high strata, only best ORR exhibited qualified surrogacy (adjusted HR, 2.61, p < 0.001; R = 0.70, p = 0.035), whereas initial ORR was not significant (adjusted HR, 1.08, p = 0.357; R = 0.22, p = 0.54). CONCLUSIONS: ORR as surrogacy of OS is associated with tumor burden. For patients with low/intermediate tumor burden, initial ORR should be preferred in its early availability upon similar sensitivity, whereas for patients with high tumor burden, best ORR has optimal sensitivity. Timing of OR assessment should be tailored according to tumor burden. KEY POINTS: • This is the first study utilizing individual patient data to comprehensively analyze the surrogacy of ORR with a long follow-up period. • Optimal timing of ORR assessment for predicting survival should be tailored according to tumor burden. • For patients with low and intermediate tumor burden, initial ORR is optimal for its timeliness upon similar sensitivity with best ORR. For patients with high tumor burden, best ORR has optimal sensitivity.

High-affinity neoantigens correlate with better prognosis and trigger potent antihepatocellular carcinoma (HCC) activity by activating CD39+CD8+ T cells.

OBJECTIVE: It remains controversial whether tumour mutational burden (TMB) or neoantigens are prognostic markers in hepatocellular carcinoma (HCC). This study aimed to define the function of TMB or neoantigens in antitumour immunotherapy. DESIGN: Neoantigens of patients (n=56) were analysed by pVAC tools with major histocompatibility complex-1 (MHC-I) algorithms based on whole exome sequencing and neoantigens with mutant type IC50 <50 nM were defined as high-affinity neoantigens (HANs). Patients were segregated into HAN-high/low groups by median of HAN value, and overall survival (OS) was analysed. Autologous organoid killing model was developed to clarify the antitumour activity of HANs. RESULTS: The value of HAN showed a better correlation with OS (p=0.0199) than TMB (p=0.7505) or neoantigens (p=0.2297) in patients with HCC and positively correlated with the frequency of CD39+CD8+ tumour infiltrating lymphocytes (TILs). Furthermore, HAN-specific CD8+ T cells were identified in CD39+CD8+ TILs, which showed better antitumour activity in HAN-high versus HAN-low group. In addition, more effective HAN peptides were identified in HAN-high versus HAN-low group. Besides, flow cytometry data showed that in fresh tumour, CD39+PD-1intCD8+ TILs displayed an effector phenotype and stronger antitumour activity in HAN-high versus HAN-low group. More importantly, patients in HAN-high versus HAN-low group showed a better prognosis after anti-PD-1 therapy. CONCLUSIONS: Our study first demonstrates that HAN value positively correlates with better OS in patients with HCC. HANs trigger antitumour activity by activating tumour-reactive CD39+CD8+ T cells, and patients in HAN-high group benefited more from anti-PD-1 therapy than HAN-low group. These findings may provide a novel strategy for personalised antitumour therapies for HCC.

The PPRD score stratifies patients with hepatocellular carcinoma and portal vein tumor thrombus treated with sorafenib plus transarterial chemoembolization.

OBJECTIVES: To identify clinical prognostic and predictive factors in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) undergoing sorafenib plus transarterial chemoembolization (TACE) and establish a prognostic score for these patients. METHODS: Between January 2012 and December 2017, 184 consecutive patients with HCC and PVTT were concurrently treated with sorafenib and TACE. Univariate and multivariate analyses were performed to explore the clinical factors independently correlated with overall survival (OS). A prognostic score was then developed to identify different prognoses in an initial cohort and validated in an external cohort (n = 72). RESULTS: In the multivariate analysis, performance status, extension of PVTT, initial radiological response, and sorafenib-related dermatologic toxicity were identified as predictors associated with OS. These factors were used to develop a prognostic score (PPRD score, range from 0 to 11). The median survival was found to decrease as the PPRD score increased, and patients were stratified into a favorable group (0 points), intermediate group (1-4 points), and dismal group (> 4 points). The median survival of patients in the three groups was 34.0 months, 20.0 months, and 7.0 months, respectively (p < 0.001). Additionally, the time to progression (TTP) (p < 0.001) was stratified along the same prognostic groups. The external validation cohort confirmed the prognostic scores. CONCLUSIONS: The proposed score system can accurately stratify the outcomes of patients with HCC and PVTT treated with sorafenib plus TACE to help identify which group of patients may benefit from treatment. KEY POINTS: • The survival benefits of patients with advanced HCC treated with sorafenib plus TACE remains controversial. • The independent factors associated with survival were identified to develop a prognostic score, called the PPRD score (standing for performance status, PVTT grade, radiological response, and sorafenib-related dermatologic toxicity); the median survival decreases as the score increases. • The scoring system can accurately stratify the survival benefits of patients with HCC and PVTT treated with combination therapy and help to identify which group of patients may benefit from the treatment. Graphical abstract.

Drug-eluting beads TACE is safe and non-inferior to conventional TACE in HCC patients with TIPS.

OBJECTIVES: This study aims to compare the safety and effectiveness between transarterial chemoembolization (TACE) with drug-eluting beads (DEB-TACE) and conventional TACE (cTACE) using lipiodol-based regimens in HCC patients with a transjugular intrahepatic portosystemic shunt (TIPS). METHODS: This retrospective study included patients with patent TIPS who underwent TACE from January 2013 to January 2019 that received either DEB-TACE (DEB-TACE group, n = 57) or cTACE (cTACE group, n = 62). The complications, liver toxicity, overall survival (OS), time to progression (TTP), and objective response rate (ORR) were compared between the groups. RESULTS: Altogether, 119 patients (50 ± 11 years, 107 men) were evaluated. The incidence of adverse events, including abdominal pain within 7 days (45.6% vs 79.0%, p < 0.001) and hepatic failure within 30 days (5.3% vs 19.4%, p = 0.027), were significantly lower in the DEB-TACE group than in the cTACE group. Compared to the cTACE group, the DEB-TACE group also showed mild liver toxicities in terms of increased total bilirubin (8.8% vs 22.6%), alanine aminotransferase (5.3% vs 21.0%), and aspartate aminotransferase (10.5% vs 29.0%) levels. The DEB-TACE group had better ORR than the cTACE group (70.2% vs 50.0%). The median OS and TTP were longer in the DEB-TACE group (11.4 vs 9.1 months, hazard ratio [HR] = 2.46, p < 0.001; 6.9 vs 5.2 months, HR = 1.47, p = 0.045). Multivariable analysis showed that α-fetoprotein levels, Barcelona clinic liver cancer stage, and treatment allocation were independent predictors of OS. CONCLUSION: DEB-TACE is safe and effective in HCC patients with a TIPS and is potentially superior to cTACE in terms of complications, liver toxicities, OS, TTP, and ORR. KEY POINTS: • DEB-TACE is safe and effective in HCC patients after a TIPS procedure. • DEB-TACE improves overall survival, objective response rate, and liver toxicities and is non-inferior to cTACE in terms of time to progression. • DEB-TACE might be a potential new therapeutic option for HCC patients with TIPS.

Postintervention Interleukin-6 (IL-6) Level, Rather than the Pretreatment or Dynamic Changes of IL-6, as an Early Practical Marker of Tumor Response in Hepatocellular Carcinoma Treated with Transarterial Chemoembolization.

BACKGROUND: The aim of this study was to determine the potential prognostic roles of the perioperative interleukin-6 (IL-6) level and its dynamic changes in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). MATERIALS AND METHODS: Sixty patients with hepatitis B virus-associated HCC receiving TACE were enrolled in the study. Serum IL-6 levels were determined at baseline and 1 day after TACE by immunoassay. Response to TACE was evaluated after a 4-6-week interval. Factors associated with tumor response were analyzed by univariate and multivariate analysis in a Cox regression model. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive performance of the included variables on tumor response in patients with HCC undergoing TACE. RESULTS: The serum IL-6 level was significantly elevated 1 day after TACE. Patients in the low postintervention IL-6 level group had a high probability of achieving an objective response (OR) (66.7% vs. 18.8%, p = .021). Post-TACE IL-6 level (≤12.7 pg/mL) and post-/pre-TACE neutrophils ratio (>2.47) were independently correlated with OR after TACE. ROC curve analysis showed that a combined index based on those two factors exhibited optimal predictive power of tumor response among all the included variables (area under the curve = 0.740, 95% confidence interval: 0.601-0.879). Additionally, high post-TACE plasma IL-6 level was associated with maximum tumor size, vascular invasion, post-TACE aspartate aminotransferase, and Barcelona Clinic Liver Cancer stage. CONCLUSION: Our study suggests that the post-treatment serum IL-6 level, rather than pretreatment or dynamic changes of IL-6, serves as a powerful predictor for tumor response. These findings provide evidence to help discriminate between patients who will particularly benefit from TACE and those who require more personalized therapeutic regimens and rigorous surveillance. IMPLICATIONS FOR PRACTICE: Transarterial chemoembolization (TACE) is a major therapeutic regimen for advanced hepatocellular carcinoma. Thus, identification of early practical markers of tumor response to TACE is of high importance. This study indicated that the post-treatment serum interleukin-6 (IL-6) level, rather than the pretreatment or dynamic changes of IL-6, serves as a powerful predictor for tumor response. A combined index based on the post-TACE IL-6 level and post-/pre-TACE neutrophils ratio is optimal for predetermining an objective response after TACE, which may be helpful in guiding individualized treatments and surveillance.

Efficacy of intra-arterial chemotherapy combined with intravesical chemotherapy in T1G3 bladder cancer when compared with intravesical chemotherapy alone after bladder-sparing surgery: a retrospective study.

PURPOSE: To assess the efficacy of intra-arterial chemotherapy (IAC) combined with intravesical chemotherapy (IVC) in T1G3 bladder cancer (Bca) after transurethral resection of bladder tumor (TURBT). METHODS: Our study retrospectively reviewed 200 patients with T1G3 BCa who had all undergone TURBT. The patients' medical records were divided into two groups, one group only had IVC with pirarubicin after surgery, and the other group had IAC (cisplatin and epirubicin) combined with IVC after surgery. The patients were monitored regularly by urine cytology and cystoscopy. Survival and recurrence curves were calculated using the Kaplan-Meier method. Tumor recurrence, progression and tumor-specific death rate were compared with Chi-square test. A multivariate analysis was carried out to find out potential confounders. RESULTS: A total of 200 medical record was analyzed, 131 patients received IVC, 69 IAC + IVC treatment, tumor-specific death rate between the combined IAC and IVC compared to IVC alone was 7.25 and 17.6%, respectively (p < 0.05); the tumor recurrence rate between the two groups was 31.8% (22/69) and 44.3%, respectively (58/131) (p < 0.05), and tumor recurred later in the IAC + IVC group (p < 0.05), tumor progression rate was 18.8% (13/69) and 28.2% (37/131), respectively, with p < 0.05. Overall survival was longer in IAC + IVC group (p < 0.05). Using the multivariable regression model, IAC was significantly related to disease recurrence (p < 0.05) and overall survival (p < 0.05). CONCLUSION: T1G3 BCa post-TURBT surgery patients who underwent IAC combined with IVC had a longer overall survival and increased time interval to first recurrence, lower tumor recurrence rate, progression rate and tumor-specific death rate than compared with those who only underwent IVC alone.

Apatinib for Patients With Sorafenib-Refractory Advanced Hepatitis B Virus Related Hepatocellular Carcinoma: Results of a Pilot Study.

More than half of the patients with advanced hepatocellular carcinoma (HCC) do not respond to primary treatment with sorafenib. Currently, there are no universally accepted methods for further treatment. This pilot study was performed to assess the safety and effectiveness of apatinib as an optional treatment for patients with sorafenib-refractory HCC. Between January 2015 and May 2017, 43 consecutive patients with sorafenib-refractory advanced HCC who received apatinib were reviewed. The objective response rate (ORR) and disease control rate (DCR) were assessed using modified response evaluation criteria in solid tumors. The time to progression (TTP) and overall survival (OS) were determined using the Kaplan-Meier method. Toxicities associated with apatinib were assessed. All patients had hepatitis B virus (HBV) related HCC. The mean follow-up time was 11 months (range: 3-37) and the mean duration of apatinib was 7.6 months (range: 1-32). After treatment, 11 patients had partial response (PR), 18 had stable disease (SD), and 14 had progressive disease (PD); accordingly, the ORR and DCR were 25.6% and 67.4%, respectively. The median TTP and OS were 3 months (95% confidence interval [CI]: 1.9-4.1) and 8 months (95% CI: 6.9-9.0), respectively. The median OS times for PR, SD, and PD were 19 months (95% CI: 15.8-22.2), 8 months (95% CI: 7.3-8.7), and 4 months (95% CI: 3.1-4.9), respectively (P < .001). The median TTP for PR, SD, and PD was 14 months (95% CI: 11.9-16.1), 3 months (95% CI: 2.3-3.7) and 1 month, respectively (P < .001). No patients experienced toxicity-related death. The most common toxicities were weight loss, hand-foot skin reaction, and hypertension. Twelve adverse events of grade 3 or higher were observed. Based on our findings, apatinib is a promising treatment for patients with sorafenib-refractory advanced HBV-related HCC.

Gefitinib with or without Transarterial Infusion Chemotherapy (Cisplatin) for Large Nonsmall Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations.

PURPOSE: To retrospectively investigate the safety and benefit of gefitinib plus transarterial infusion (TAI) therapy as a first-line treatment compared to gefitinib alone for patients with large (>7 cm) nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. MATERIALS AND METHODS: Between January 2010 and December 2013, 92 consecutive treatment-naïve patients with large NSCLC with EGFR mutations, who were treated using gefitinib plus TAI (G+T, n = 42) or gefitinib alone (G, n = 50) were reviewed. The primary endpoints were the objective response rate (ORR) and tumor reduction rate. The secondary endpoints were progression-free survival (PFS) and overall survival (OS), and safety was also assessed. RESULTS: The baseline characteristics of the 2 groups were balanced, and no patients experienced treatment-related death. Toxicity outcomes did not differ between the G+T and G groups. The tumor reduction rate in the G+T group was significantly higher than that in the G group (42.9 vs 31.9%, P = .028). The ORR was 83% in the G+T group and 72% in the G group (P = .197). The median PFS was significantly longer in the G+T group than in the G group (14.0 vs 10.0 months, P = .023). The median OS was 30.0 months in the G+T group and 27.0 months in the G group (P = .235). CONCLUSIONS: This study suggests that compared with gefitinib alone, combination therapy with gefitinib plus TAI was well tolerated and potentially improved the tumor reduction rate and PFS in patients with large NSCLC with EGFR mutations.

A novel mechanism of the M1-M2 methionine adenosyltransferase switch-mediated hepatocellular carcinoma metastasis.

Hepatocellular carcinoma (HCC) manifests as a highly metastatic cancer with extremely poor prognosis. However, mechanisms underlying metastasis of HCC are not fully understood. Here, we showed that switching gene expression from MAT1A to MAT2A (M1-M2 switch) promoted cancer invasion and metastasis. Reversion of the M1-M2 switch repressed, whereas enhancing the M1-M2 switch promoted the ability of HCC cells to metastasize. Moreover, we provided clinical data showing that tipping the balance between MAT1A and MAT2A expression correlated with increased metastasis and inferior recurrence-free survival in HCC patients. Molecular pathways analysis showed that downregulation of MAT1A, which augmented osteopontin (OPN) expression through decreasing methylation of the OPN promoter, and MAT2A upregulation, which induced integrin ß3 (ITGB3) expression by binding to ITGB3 promoter, collaboratively triggered ERK signaling and thereby promoted metastasis. Thus, the simultaneous downregulation of MAT1A and upregulation of MAT2A are necessary and sufficient for HCC metastasis in the process of M1-M2 switch. Our findings provide novel mechanistic insights into cancer metastasis. Inhibition and prevention of the M1-M2 switch would offer a novel therapeutic option for treatment of HCC.

Comparison of α-Fetoprotein Criteria and Modified Response Evaluation Criteria in Solid Tumors for the Prediction of Overall Survival of Patients with Hepatocellular Carcinoma after Transarterial Chemoembolization.

PURPOSE: To evaluate the value of α-fetoprotein (AFP) classification criteria in predicting tumor response and patient survival and to discuss the agreement between AFP criteria and modified Response Evaluation Criteria In Solid Tumors (mRECIST). MATERIALS AND METHODS: Between January 2011 and December 2014, 147 patients with unresectable hepatocellular carcinoma (HCC) with baseline AFP levels ≥ 400 ng/mL who underwent transarterial chemoembolization as initial treatment were retrospectively enrolled for AFP/imaging correlation analysis. AFP-based response was classified as complete response (CR) in cases of AFP level normalization, partial response (PR) in cases of > 50% decrease vs baseline, stable disease (SD) in cases of -50% to +30% change vs baseline, or progressive disease (PD) in cases of > 30% increase vs baseline. Intermethod agreement between the 2 methods was assessed by Cohen κ coefficient. Response rates according to AFP and mRECIST were compared, and the association between response rate and overall survival (OS) was evaluated. RESULTS: The κ value for agreement between AFP criteria and mRECIST was 0.549 (ie, moderate), with objective response and disease control rates of 36.1% and 63.3% per AFP criteria and 34.7% and 46.3% per RECIST (P = .807 and P = .003), respectively. Although AFP criteria and mRECIST showed significantly prognostic strata for CR, PR, SD, and PD after chemoembolization (P < .001 for both), some overlap in radiologic PD survival curves was observed. The OS of AFP-based disease control (ie, CR/PR/SD) was significantly longer than that of AFP-based PD among patients with radiologic PD (9.0 vs 6.0 mo; P < .001). CONCLUSIONS: The defined AFP response moderately correlated with mRECIST response and yielded accurate prognostic prediction in patients with HCC and AFP levels ≥ 400 ng/mL treated with chemoembolization.

Is Emergency Transcatheter Hepatic Arterial Embolization Suitable for Spontaneously Ruptured Hepatocellular Carcinoma in Child-Pugh C Cirrhosis?

PURPOSE: To evaluate the utility of emergent transcatheter arterial embolization for spontaneously ruptured hepatocellular carcinoma (HCC) in patients with Child-Pugh class C (CPC) liver cirrhosis presenting hemorrhagic shock. MATERIALS AND METHODS: A study of all 94 patients was retrospectively conducted from January 2006 to January 2016. Sixty patients underwent conservative treatment (control group) and 34 underwent embolization. RESULTS: Embolization provided better stabilization of hemodynamic status than conservative treatment (91.2% vs 61.7%), with greater overall survival (OS) rates at 30, 60, and 120 days (73.5%, 52.9%, and 29.4% vs 33.3%, 13.3%, and 0%, respectively). Mean follow-up duration was 51.07 days (range, 3-237 d). Median survival time was longer for the embolization group than the control group, specifically for patients with a shock index (SI) of ≥ 0.6 to < 1 (106.0 d ± 39.4 vs 34.0 d ± 4.7) or ≥ 1 (18.0 d ± 7.5 vs 11.0 d ± 3.2), those with CPC scores 10 or 11 (88.0 d ± 29.4 vs 28.0 d ± 4.5), and those with segmental (165.0 d ± 20.6 vs 34.0 d ± 9.7) or lobar (54.0 d ± 7.9 vs 26.0 d ± 3.4) portal vein tumor thrombus (PVTT). SI ≥ 1, Child-Pugh score of 12/13, tumor size ≥ 10 cm, and PVTT were independent factors in poor prognosis for OS. CONCLUSIONS: Emergent transcatheter arterial embolization is an effective intervention for ruptured HCC in patients with CPC liver function in hemorrhagic shock, particularly those with a SI ≥ 1, Child-Pugh scores of 10/11, and first- or lower-order PVTT.

Large hepatocellular carcinomas: treatment with transarterial chemoembolization alone or in combination with percutaneous cryoablation.

PURPOSE: To evaluate the safety and efficacy of transarterial chemoembolization (TACE) combined with cryoablation (TACE-cryoablation) in large (main tumor ≥5 cm in diameter) hepatocellular carcinomas (HCCs). METHODS: From January 2010 to December 2015, 56 lesions in 56 patients were treated with combination therapy via a single TACE session followed by one to three percutaneous cryoablation sessions twice a week (TACE-cryoablation group). A total of 54 lesions in 54 patients were treated with TACE alone for two to six sessions once a month (TACE group). The decision between TACE and TACE cryoablation was based on patient choice. Outcomes of patients in two groups were compared according to the largest tumor diameter (subgroup): Group A (5 cm ≤ tumor <10 cm), Group B (10 cm ≤ tumor <15 cm), and Group C (tumor ≥15 cm). RESULTS: The mean number of cryoablation sessions per patient was 2.3 (range: 1-6). Within Group B, TACE-cryoablation significantly improved survival compared with TACE alone (11.0 vs 6.0 months; p = .008). This was also seen in Group C (8.0 vs 5.0 months; p = .001). However, no significant difference was noted in Group A (17.0 vs 13.0 months; p = .674). The complications related to TACE were comparable between the two groups. Two adverse events of grade 3 - 4 related to cryoablation occurred in two patients (3.6%). The independent prognostic factors for survival included: TACE cryoablation, AFP level, main tumor size and extrahepatic metastasis. CONCLUSIONS: TACE-cryoablation may improve overall survival in patients with HCC who presented with a tumor diameter ≥10 cm, with minimal complications, when compared with TACE alone.

Comparison between microwave ablation and lobectomy for stage I non-small cell lung cancer: a propensity score analysis.

PURPOSE: To compare the effectiveness and complication between microwave ablation and lobectomy for stage I non-small cell lung cancer. MATERIALS AND METHODS: This retrospective study was approved by two institutional ethics committees and all patients were provided with informed consent. From January 2000 to December 2010, 54 and 795 stage I patients who underwent microwave ablation and lobectomy were included in this study. A matched cohort composed of 54 and 108 patients in the microwave ablation and the lobectomy group were selected after adjustment with 1:2 propensity score matching. The overall survival and disease-free survival were evaluated. Survival curves were constructed with the Kaplan-Meier method and compared by using the log-rank test. RESULTS: The 1, 3 and 5-year Overall survive were 100, 92.6 and 50.0% for MWA group and 100, 90.7 and 46.3% for lobectomy group. The 1, 3 and 5-year disease free survival was 98.1, 79.6 and 37.0% for MWA group and 98.1, 81.5 and 29.6% for lobectomy group. There was no significant difference between two groups in overall survival (p = 0.608) and disease free survival (p = 0.672). Additionally, local or distant metastasis rate (p = 0.544) were not significantly different between two groups while the complication rate in the MWA group was significantly lower than the lobectomy group (p = 0.008). CONCLUSION: Microwave ablation has similar therapeutic effect compared with lobectomy for stage I non-small cell lung cancer, but with fewer complication and less pain.

Feasibility and Efficacy of Microwave Ablation Combined with Iodine-125 Seed Implantation in Local Control of Recurrent Retroperitoneal Liposarcomas: Initial Clinical Experience.

INTRODUCTION: The objective of the present study was to evaluate the feasibility, safety, and short-term efficacy of microwave ablation (MWA) combined with iodine-125 (125I) seed implantation in recurrent retroperitoneal liposarcomas (rRPLs). MATERIALS AND METHODS: From September 2012 to March 2015, 11 patients were enrolled in this prospective study. Eleven tumors (median, 9 cm; range, 5.5-12.5 cm) were treated with computerized tomography-guided MWA for 11 sessions and 125I seed implantation for 18 sessions. 125I seed implantation was performed 4 weeks after MWA. RESULTS: There were no procedure-related deaths. Post-MWA pain (grade ≥2) was the most common complication (6 of 11 patients, 54.5%), and fever (grade ≥2) was observed in two patients. Reversible nerve injury, defined as transient limb paresthesia or leg weakness, was observed in one patient. There were fewer complications associated with the 125I seed implantation procedure compared with the MWA procedure. All 11 patients who underwent the MWA procedure achieved a partial response (PR), according to the modified Response Evaluation Criteria in Solid Tumors, 1 month post-ablation; after 125I seed implantation was performed, a complete response was observed in three, five, and six target tumors in 3, 6, and 12 months, respectively. CONCLUSION: In selected patients with rRPLs, MWA combined with 125I seed implantation is feasible and safe with favorable local control efficacy. IMPLICATIONS FOR PRACTICE: This study evaluated the feasibility, safety, and short-term efficacy of microwave ablation (MWA) combined with iodine-125 (125I) seed implantation in recurrent retroperitoneal liposarcomas (rRPLs). Results suggest that a single session of MWA may be not sufficient in large-volume rRPLs and that as a supplement treatment, 125I seed implantation is safe and easy accessible. MWA combined with 125I seed has excellent local control effectiveness, and long-term efficacy and survival benefit still need to be more comprehensively evaluated.

The safety and efficacy of percutaneous intraductal radiofrequency ablation in unresectable malignant biliary obstruction: A single-institution experience.

BACKGROUND: Patients with unresectable malignant biliary obstruction have limited life expectancy because of limited stent patency and tumor progression. The aim of our study was to retrospectively evaluate the safety and efficacy of combining intraductal RFA with biliary metal stent placement for patients with malignant biliary obstruction. METHODS: Patients who received percutaneous intraductal RFA and biliary stent placement for malignant biliary obstruction between 2013 and 2015 were identified. Outcomes were stent patency, technique and clinical success rate, overall survival (OS) and complication rates. Kaplan-Meier and Cox regression analyses were used to examine the association of various factors with stent patency and OS. Complications and laboratory abnormalities were recorded. RESULTS: Fifty patients were treated with percutaneous RFA and stent placement. The rates of technical success and clinical success were 98% and 92%, respectively. The median stent patency was 7.0 (95% confidence interval [CI]: 5.3, 8.7) months and OS was 5.0 (95% CI: 4.0, 6.0) months. On univariable analysis, previously cholangitis was an independent poor prognosis factor for recurrent biliary obstruction. OS was improved in patients who received more than one intervention compared to those who received only one intervention (log-rank P = 0.007), and in those treated without versus those treated with sequential chemotherapy (log-rank P = 0.017). On multivariable analysis, the occurrence of more than one intervention (P = 0.019) had independent prognostic significance for OS. CONCLUSION: Percutaneous RFA and stent placement is a technically safe and feasible therapeutic option for the palliative treatment of malignant biliary obstruction. The long-term efficacy and safety of the procedure is promising, but further study is required via randomized and prospective trials.