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

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

Angiographic Atlas of the Visceral Vascular Anatomy in Translational Rat Models.

PURPOSE: To characterize angiographic and cross-sectional imaging anatomy of the rat visceral vasculature in 2 translational models. MATERIALS AND METHODS: Animal studies were conducted in accordance with institutional guidelines and approval of the Institutional Animal Care and Use Committees. Retrospective review of digital subtraction arteriography was performed in 65 Wistar and 50 Sprague-Dawley male rats through a left common carotid artery or right common femoral artery approach. MR imaging of the abdomen was performed on the rats to correlate imaging modalities. RESULTS: Aortography was performed in 3 locations, including cranial to the celiac artery, cranial to the renal arteries, and cranial to the caudal (inferior) mesenteric artery, enabling characterization of the visceral branch arteries in all 65 Wistar rats. Selective arteriography of first-, second-, and third-order branch vessels of the aorta was performed allowing characterization of normal and variant anatomy. Dedicated selective arteriography was performed of the celiac artery in 65 Wistar and 10 Sprague-Dawley rats, of the common hepatic artery in 65 Wistar and 50 Sprague-Dawley rats, and of the cranial mesenteric artery in 43 Wistar rats. MR imaging enabled correlation with the lobar and portal venous anatomy. CONCLUSIONS: Analysis of arteriography and MR imaging in these rat models will provide translational researchers with anatomic details needed to develop new endovascular protocols for small animal research in interventional radiology.

Revealing editing and SNPs of microRNAs in colon tissues by analyzing high-throughput sequencing profiles of small RNAs.

BACKGROUND: Editing and mutations in microRNAs (miRNAs) can change the stability of pre-miRNAs and/or complementarities between miRNAs and their targets. Small RNA (sRNA) high-throughput sequencing (HTS) profiles contain miRNAs that are originated from mutated DNAs or are edited during their biogenesis procedures. It is largely unknown whether miRNAs are edited in colon tissues since existing studies mainly focused their attention on the editing of miRNAs in brain tissues. RESULTS: Through comprehensive analysis of four high-throughput sequencing profiles of normal and cancerous colon tissues, we identified 548 editing and/or SNPs in miRNAs that are significant in at least one of the sequencing profiles used. Our results show that the most abundant editing events of miRNAs in colon tissues are 3'-A and 3'-U. In addition to four known A-to-I editing sites previously reported in brain tissues, four novel A-to-I editing sites are also identified in colon tissues. CONCLUSIONS: This suggests that A-to-I editing of miRNAs potentially is a commonly existing mechanism in different tissues to diversify the possible functional roles of miRNAs, but only a small portion of different miRNAs are edited by the A-to-I mechanism at a significant level. Our results suggest that there are other types of editing in miRNAs through unknown mechanisms. Furthermore, several SNPs in miRNAs are also identified.

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

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

Ultrasound-guided percutaneous microwave ablation for hepatocellular carcinoma originating in the caudate lobe: A pilot clinical study.

OBJECTIVE: This study aimed to evaluate the efficacy, feasibility, and tolerability of ultrasound (US)-guided percutaneous microwave ablation (MWA) for treating hepatocellular carcinoma (HCC) originating in the caudate lobe. MATERIALS AND METHODS: The treatment and survival parameters of 32 patients with HCC in the caudate lobe, who met the inclusion criteria and had received US-guided percutaneous MWA in our department from November 2010 to October 2015, were retrospectively analyzed. Imaging examination (contrast-enhanced computed tomography or magnetic resonance) 1 month after MWA was used to evaluate the efficacy of US-guided MWA. RESULTS: Thirty-two patients underwent percutaneous MWA for caudate lobe HCC. The average tumor size was 3.42 ± 0.27 (range: 1-6.8) cm. The initial complete ablation (CA) rate was 87.5% (28/32), and the total CA rate was 96.88% (31/32). Furthermore, the median length of hospitalization was 4 days (range: 2-10 days), and no major complication was observed in this study. The overall survival rates were 87.5%, 50%, and 28.13% at 1, 2, and 3 years, respectively. The progression-free survival after MWA was 93.75%, 53.15%, and 28.13% at 6, 12, and 18 months, respectively. CONCLUSIONS: US-guided percutaneous MWA was a safe and effective treatment. It is a promising alternative therapy for HCC originating in the caudate lobe.

Prognostic Nomogram for Patients with Hepatocellular Carcinoma After Thermal Ablation.

PURPOSE: To develop an effective prognostic nomogram for patients with hepatocellular carcinoma (HCC) after thermal ablation. METHODS: A total of 772 patients with intrahepatic primary or recurrent HCC who underwent radiofrequency ablation or microwave ablation between March 2011 and October 2016 were included. 602 patients (mean age, 56.0 ± 11.9 years; 495 male/107 female) were included in the primary cohort to establish a prognostic nomogram. Significant prognostic factors for overall survival (OS) identified by Cox univariate and multivariate regression analyses were used to construct the nomogram. The remaining 170 patients (mean age, 55.9 ± 11.9 years; 145 male/25 female) were used to validate the predictive accuracy of the nomogram. RESULTS: During a mean follow-up period of 26 months (range 1-85 months), the median OS periods were 48.6 months and 44.0 months for the primary and validation cohorts. The 1-, 3-, and 5-year OS rates were 85.5%, 61.4%, and 43.3% in the primary cohort and 84.7%, 59.6%, and 43.3% in the prospective validation cohort, respectively. Multivariate analysis found that pre-ablation treatment, AFP, CEA, CA19-9, ALBI grade, tumor number, and tumor size (hazard ratio > 1, P < 0.05) were independent risk factors for OS. A nomogram was developed based on these seven variables. The calibration curve for predicting the probability of survival showed a good agreement between the nomogram and actual observation both in the primary (concrete index: 0.699) and validation cohorts (concrete index: 0.734). CONCLUSIONS: This simple nomogram based on seven variables including ALBI grade offers personalized prognostic data for HCC patients after ablation. LEVEL OF EVIDENCE: Level 4, case series.

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials.

PURPOSE: Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC. PATIENTS AND METHODS: In two prospective phase I studies, adult patients with advanced GPC3+ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide- and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1). RESULTS: A total of 13 patients received a median of 19.9 × 108 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response. CONCLUSIONS: This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.

Mst1 and mst2 are essential regulators of trophoblast differentiation and placenta morphogenesis.

The placenta is essential for survival and growth of the fetus because it promotes the delivery of nutrients and oxygen from the maternal circulation as well as fetal waste disposal. Mst1 and Mst2 (Mst1/2), key components of the mammalian hpo/Mst signaling pathway, encode two highly conserved Ser/Thr kinases and play important roles in the prevention of tumorigenesis and autoimmunity, control of T cell development and trafficking, and embryonic development. However, their functions in placental development are not fully understood, and the underlying cellular and molecular mechanisms remain elusive. Here, we investigated the functions of Mst1/2 in mouse placental development using both conventional and conditional (endothelial) Mst1/2 double knockout mice. We found that the number of trophoblast giant cells dramatically increased while spongiotrophoblast cells almost completely disappeared in Mst1/2 deficient placentas. We showed that Mst1/2 deficiency down regulated the expression of Mash2, which is required for suppressing the differentiation of trophoblast giant cells. Furthermore, we demonstrated that endothelial-specific deletion of Mst1/2 led to impaired placental labyrinthine vasculature and embryonic lethality at E11.5, but neither affected vasculature in yolk sac and embryo proper nor endocardium development. Collectively, our findings suggest that Mst1/2 regulate placental development by control of trophoblast cell differentiation and labyrinthine vasculature at midgestation and Mst1/2 control labyrinth morphogenesis in trophoblast- and fetal endothelial-dependent manners. Thus, our studies have defined novel roles of Mst1/2 in mouse placental development.

Influence of short polyglutamine tracts and p160 coactivators on the transactivation of the androgen receptor.

The androgen receptor (AR) acting as a transcription factor plays a pivotal role in the occurrence and progression of prostate cancer (CaP). Several AR-related factors or modulators have been reported to influence AR activity. Whether and how these factors cooperatively modulate the AR activity has not been well defined. In the present study, the combined effect of p160 coactivators, short CAG length (encoding a short polyQ tract), and AR mutations on AR transactivation in a yeast system was evaluated. It was found that the short polyQ tract can upregulate the transactivation of the wild-type (WT) AR and partial-function (PF) AR mutants in response to a physiological level (10(-9) M) of dihydrotestosterone. Addition of a p160 coactivator (SRC-1 or TIF2) to the above systems resulted in a significant increase in the ligand-stimulated transactivation. Although the androgen antagonist bicalutamide could suppress the activity of androgen-activated WT or PF ARs, it was unable to do so for gain-of-function AR mutants. A combination of the short polyQ tract and coactivator TIF2 acted cooperatively on the WT AR and PF AR mutants to enhance their transactivation in response to either a low level of dihydrotestosterone (10(-10) M) or adrenal dehydroepiandrosterone. Taken together, this finding suggests that the modulated AR activity may involve early in the carcinogenesis of CaP. Additionally, these data support the concept that a given CaP in which the AR activity is modulated by multiple AR modulators may progress more readily to castrate resistance.

Identifying serum biomarkers for TACE therapy efficiency of hepatocellular carcinoma.

Transcatheter Arterial Chemoembolization (TACE) is the first line of treatment in inoperable hepatocellular carcinoma. Magnetic affinity beads can be used to extract peptides from un-fractionated serum samples. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) can detect the presence and the molecular mass of peptides. In this study, we used a highly optimized ClinProt-matrix-assisted laser desorption/ionization time-of flight mass spectrometer (MALDI-TOF-MS) to screen hepatocellular carcinoma markers for TACE. 40 sera from 20 patients, including before and after TACE to explore those biomarkers, might be related with therapy efficiency, and some of the patients who received another therapy were analyzed as well. The spectra were analyzed statistically using FlexAnalysis™ and Clin-Prot™ bioinformatic software. The seven most significant differential peaks (p < 0.0.5) were selected out by ClinProTool software to identify hepatocellular carcinoma markers for TACE therapy. Furthermore, the differential peptide of 3883Da was identified as plasma serine protease inhibitor precursor (Protein C inhibitor). This study provides a direct link between peptide marker profiles and TACE therapy, and the markers may have clinical utility for monitoring efficiency of therapy.