Intrahepatic Tumor Research Articles

Genotyping of circulating tumor DNA in cholangiocarcinoma reveals diagnostic and prognostic information

Diagnosis of Cholangiocarcinoma (CCA) is difficult, thus a noninvasive approach towards (i) assessing and (ii) monitoring the tumor-specific mutational profile is desirable to improve diagnosis and tailor treatment. Tumor tissue and corresponding ctDNA samples were collected from patients with CCA prior to and during chemotherapy and were subjected to deep sequencing of 15 genes frequently mutated in CCA. A set of ctDNA samples was also submitted for 710 gene oncopanel sequencing to identify progression signatures. The blood/tissue concordance was 74% overall and 92% for intrahepatic tumors only. Variant allele frequency (VAF) in ctDNA correlated with tumor load and in the group of intrahepatic CCA with PFS. 63% of therapy naive patients had their mutational profile changed during chemotherapy. A set of 76 potential progression driver genes was identified among 710 candidates. The molecular landscape of CCA is accessible via ctDNA. This could be helpful to facilitate diagnosis and personalize and adapt therapeutic strategies.

Characteristics recurrence pattern of cholangiolocellular carcinoma as intrahepatic bile duct tumor growth following curative resection: a case report

BackgroundCholangiolocellular carcinoma (CoCC) is a rare primary liver tumor that shows mass-forming growth in most cases. At present, no effective treatment for hepatic recurrence CoCC has been established. We present a case involving a patient with recurrent disease that showed an intraductal growth (IG type) pattern of recurrence. The patient was treated with repeat hepatectomy with bile duct reconstruction.Case presentationThe patient was a 76-year-old man with a history of S8 subsegmentectomy for CoCC. At 8 months after surgery, tumor marker elevation was observed. Computed tomography revealed a tumor occupying the right hepatic duct (B5-8) to B4 and the junction of the cystic duct. Endoscopic retrograde cholangiopancreatography (ERCP) and a thrombus biopsy with peroral cholangioscopy (POCS) confirmed the recurrence of CoCC in the intrahepatic bile duct. Although extended right lobectomy with extrahepatic bile duct resection was the optimal curative procedure, it was thought that it would be difficult due to his poor liver function. However, a slow-glowing recurrent tumor blocked the posterior branch of the portal vein; thus, the right liver lobe gradually shrank, and the estimated remnant liver volume increased in response, allowing curative surgery to finally be performed. At 10 months after surgery, the patient is alive without recurrence.ConclusionsWe reported a case of IG-type recurrence in the bile duct, which is an unusual pattern of intrahepatic recurrence, after initial surgery for CoCC. A slow-growing recurrent tumor exerted similar effects to PVE, which allowed for curative surgery to be performed.

Parenchymal-sparing versus extended hepatectomy for colorectal liver metastases: A systematic review and meta-analysis.

AimsTo assess the safety and efficacy of parenchymal‐sparing hepatectomy (PSH) as a treatment of colorectal liver metastases (CLM).MethodsA comprehensive medical literature search was performed. Perioperative and long‐term survival outcomes were pooled. Subgroup analysis and meta‐regression analysis were performed to identify potential sources of heterogeneity.ResultsA total of 18 studies comprising 7081 CLM patients were eligible for this study. The PSH was performed on 3974 (56.1%) patients. We found that the OS (overall survival; hazard ratio [HR] = 1.01, 95% confidence interval [CI]: 0.94‐1.08) and RFS (recurrence‐free survival; HR = 1.00, 95% CI: 0.94‐1.07) were comparable between non‐PSH and PSH group. The perioperative outcomes were better in PSH than in non‐PSH group. Non‐PSH group was significantly associated with longer operative time (standard mean difference [SMD] = 1.17, 95% CI: 0.33‐2.00), increased estimated blood loss (SMD = 1.36, 95% CI: 0.64‐2.07), higher intraoperative transfusion rate (risk ratio [RR] = 2.27, 95% CI: 1.60‐3.23), and more postoperative complications (RR = 1.39, 95% CI: 1.16‐1.66). Meta‐regression analyses revealed that no variable influenced the association between surgical types and the survival outcomes.ConclusionsThis study shows that PSH is associated with better perioperative outcomes without compromising oncological outcomes. Given the increasing incidence of hepatic parenchyma, the PSH treatment offers a greater opportunity of repeat resection for intrahepatic recurrent tumors. It should be considered as an effective surgical approach for CLM.

Chelidonine enhances the antitumor effect of lenvatinib on hepatocellular carcinoma cells.

BackgroundLenvatinib is a newly approved molecular targeted drug for the treatment of advanced hepatocellular carcinoma (HCC). However, the high cost associated with this treatment poses a huge financial burden on patients and the entire public health system. Therefore, there is an urgent need to develop novel strategies that enhance the antitumor effect of lenvatinib.MethodsThe antitumor effects of chelidonine or/and lenvatinib on HCC cell lines MHCC97-H and LM-3 were examined using the 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2- H-tetrazolium bromide (MTT) assay. For the in-vivo investigation, the effect on subcutaneous or intrahepatic tumor growth in nude mice was also determined. The mRNA levels of epithelial mesenchymal transition (EMT)-related factors were examined through quantitative polymerase chain reaction or Western blot.ResultsIn the present study, we found that treatment with chelidonine enhanced the apoptotic effect of lenvatinib on HCC cells and the in-vivo growth of HCC tumors in nude mice. Mechanistically, treatment with chelidonine increased the expression of epithelial indicator E-cadherin, whereas it decreased the expression of mesenchymal indicators N-cadherin and Vimentin. These findings suggest that chelidonine restricted the EMT in HCC cells.ConclusionChelidonine inhibits the process of EMT and enhances the antitumor effect of lenvatinib on HCC cells.

Comparison Between Multidetector CT and High-Field 3T MR Imaging in Diagnostic and Tumour Extension Evaluation of Patients with Cholangiocarcinoma.

To compare multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) with cholangiopancreatography (MRCP) findings in the diagnostic evaluation of patients with cholangiocarcinoma (CCA) to establish tumour resectability. Thirty patients (22 M, 8 F) with pathologically proven CCA by post-surgical specimens (n = 20), core biopsy (n = 6) or cytology (n = 4) underwent both MDCT and MRI with MRCP. CCA lesions were classified on the basis of anatomical locations in intra-hepatic (iCCA), peri-hilar (pCCA) and distal (dCCA) tumours. Morphological tumour pattern, lesion size, biliary dilatation, tumour contrast enhancement type, lymph node involvement and vascular infiltration were directly compared between MDCT and MRI with MRCP. As a rule, a tumour resectability judgement for each patient was formulated by both imaging techniques comparing imaging results with direct surgical assessment (n = 20) or interventional procedures (n = 10). In terms of anatomical location, 14 iCCA, 8 pCCA and 8 dCCA were observed; both imaging techniques were concordant about the identification and morphological characterization of tumour lesions and in the evaluation of tumour features (lesion size, contrast enhancement pattern, capsular retraction, biliary dilatation, lymph node involvement and vascular infiltration) as well as in assessing lesion resectability; an excellent agreement (k = 1) for the assessment of all the parameters included in imaging analysis was observed. The comparative concordant results of our study suggest that MRI with MRCP represents a valid alternative to MDCT for the diagnostic evaluation of patients with CCA to establish tumour resectability providing multiplanar scanning of high-contrast imaging quality; MDCT should be preferred in uncooperative patients, in the presence of biliary stents or when MRI is absolutely contraindicated for incompatible medical devices.

Radioembolization-Induced Chronic Hepatotoxicity: A Single-Center Cohort Analysis.

To identify and characterize the delayed effects of transarterial radioembolization (TARE) on the liver. A single-institution retrospective analysis was undertaken of all patients who received TARE between 2005 and 2014 and survived at least 1 year from the initial TARE (n= 106). Patients were evaluated for the presence or absence of radioembolization-induced chronic hepatotoxicity (RECHT) occurring at least 6 months after TARE. The mean age of patients was 63 years of age, and the malignancy most commonly treated was neuroendocrine tumor (54%). Adjudication of hepatic decompensation to RECHT versus alternative causes was performed by a multidisciplinary panel of specialists from hepatology, radiation oncology, and interventional radiology. Eight patients were excluded from analysis because of liver transplantation (2) or incomplete data (6). RECHT occurred in 13 of 98 patients (13%), and 5 deaths (5%) occurred from hepatic decompensation. There were a total of 69 toxicity events in patients developing RECHT. The most common events were elevation of alkaline phosphatase (10), decrease in serum albumin (10), and development of ascites (9). RECHT patients had a higher intrahepatic tumor volume (P= .021) and a higher number of hepatic comorbidities leading to cirrhosis (P= .015). Delayed radiation-induced hepatic toxicity occurred in 13% of patients following radioembolization, with 5 fatalities adjudicated to be a result of the treatment. Tumor involvement of greater than 50% of the liver and cirrhosis were predisposing factors for RECHT.

Intrahepatic cholangiocarcinoma tumor burden: A classification and regression tree model to define prognostic groups after resection

BackgroundTumor burden is an important factor in defining prognosis among patients with primary and secondary liver cancers. Although the eighth edition of the American Joint Committee on Cancer staging system has changed the criteria for staging patients with intrahepatic cholangiocarcinoma to better define the effect of tumor burden on prognosis, the impact of intrahepatic cholangiocarcinoma tumor burden on overall survival has not been examined using a machine-learning tool. MethodsPatients who underwent resection of intrahepatic cholangiocarcinoma at 1 of 14 participating international hospitals between 1990 and 2015 were identified. Classical survival models and the Classification and Regression Tree model were used to identify groups of patients with a homogeneous risk of death and investigate the hierarchical association between variables and overall survival. ResultsAmong 1,116 patients included in the analysis, tumor size was ≤5 cm in 447 (40.1%) patients and >5 cm in 669 (59.9%) patients. Although 82.9% (n = 926) of patients had a single intrahepatic cholangiocarcinoma, 9.9% (n = 110) and 7.2% (n = 80) of patients had 2 and ≥3 tumors, respectively. Patients with intrahepatic cholangiocarcinoma tumors ≤5 cm and >5 cm had a 5-year overall survival of 51.7% and 32.6%, respectively (P < 0.001). Five-year overall survival decreased from 44.6% among patients with a single intrahepatic cholangiocarcinoma to 28.1% and 14.2% among patients with 2 and ≥3 intrahepatic cholangiocarcinomas, respectively (P < 0.001). Among the combinations of tumor size and intrahepatic cholangiocarcinoma tumor number used to estimate tumor burden, logarithmic transformation of tumor size (log tumor size) and intrahepatic cholangiocarcinoma tumor number had the highest concordance index. The Classification and Regression Tree model identified 8 classes of patients with a homogeneous risk of death, illustrating the hierarchical relationship between tumor burden (log tumor size and number of intrahepatic cholangiocarcinomas) and other factors associated with prognosis. ConclusionIntrahepatic cholangiocarcinoma tumor size and number demonstrated a strong nonlinear association with survival after resection of intrahepatic cholangiocarcinoma. A log-model Classification and Regression Tree–derived tumor burden score may be a better tool to estimate prognosis of patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma.

External-beam radiation therapy versus surgery in the treatment of hepatocellular carcinoma with inferior vena cava/right atrium tumor thrombi.

Both surgery and external-beam radiotherapy are effective treatments for hepatocellular carcinoma (HCC) patients with inferior vena cava/right atrium (IVC/RA) tumor thrombi. At present, it is not clear which modality is more suitable. We therefore compared outcomes between surgery and radiotherapy for these patients. We retrospectively reviewed 108 HCC patients with IVC/RA tumor thrombi who were referred for surgery (n = 51) and external-beam radiotherapy (n = 57) at three institutions. Different surgical methods were selected according to the classification of the tumor thrombus. Radiotherapy was designed to focus on primary intrahepatic tumors and tumor thrombi. Predictors of time to progression (TTP) were identified by using univariate and multivariate analyses. The median TTP was significantly longer in the radiotherapy group than in the surgery group (5.0months vs 4.2months; P=0.010). The multivariate analysis revealed that independent factors predicting shorter TTP were treatment with surgery (HR = 0.577; 95% CI, 0.385-0.865; P=0.008) and intrahepatic tumor size larger than 10cm (HR = 0.561; 95% CI, 0.342-0.919; P=0.022). The median survival times for the radiotherapy and surgery groups were 12.8 and 14.5months, respectively; the two groups did not have a significant difference in survival (P=0.466). For HCC patients with IVC/RA tumor thrombi, treatment with external-beam radiotherapy and intrahepatic tumor size smaller than 10cm may predict longer TTP. Compared with complicated surgery, radiotherapy, as a noninvasive treatment modality, may be more likely to be accepted.

Predictive factors of treatment outcomes after percutaneous ablation of hepatocellular carcinoma in the caudate lobe: a retrospective study

BackgroundHepatocellular carcinomas (HCC) arising in the caudate lobe is rare and the treatment is difficult. The aim of this study is to summarize the experience of ultrasound-guided percutaneous ablation therapy for HCC located in the caudate lobe and to investigate the predictive factors of the treatment outcomes.MethodsFrom August 2006 to June 2017, 73 patients (63 males and 10 females; mean age, 54.9 ± 11.6 years; age range, 25–79 years) with 73 caudate lobe HCCs (mean size, 2.6 ± 1.1 cm; size range, 1.0–5.0 cm) were treated with percutaneous ablation, including 33 patients with radiofrequency ablation (RFA), 23 patients with ethanol ablation (EA), and 17 patients with combination of RFA and EA. The treatment outcome and survival after ablation for caudate lobe HCC were assessed and the predictive factors were calculated by univariate and multivariate analyses.ResultsA total of 72 patients achieved complete ablation after the first or second session of ablation. The treatment effectiveness was 98.6% (72/73). During the follow-up, 16 tumors developed local tumor progression (LTP) and a total of 61 patients (61/73, 83.6%) were detected distant recurrence (DR). According to univariate and multivariate analyses, tumor size > 2 cm (hazard ratio[HR] = 3.667; 95% confidence interval[CI], 1.043–12.889; P = 0.043) was a significant prognostic factor of LTP after ablation for HCC in the caudate lobe, while tumor number (HR = 2.245; 95%CI, 1.168–4.317; P = 0.015) was a significant prognostic factor of DR. The mean overall survival time after ablation was 28.7 ± 2.8 months, without independent predictive factors detected. Four patients (4/73, 5.5%) were detected treatment-related major complications, without independent predictive factor detected.ConclusionUltrasound-guided percutaneous ablation is a feasible treatment for a selected case with HCC in the caudate lobe. Tumor size > 2 cm increases the risk of LTP and intrahepatic tumor number is associated with DR after ablation.

The jigsaw of dual hepatocellular-intrahepatic cholangiocarcinoma tumours.

A new study involving integrative genomic and transcriptomic analysis of dual hepatocellular–intrahepatic cholangiocarcinoma tumours has identified distinct subtypes that display different clinical and molecular features, and that could be used to guide therapeutic decisions.

Hypofractionated radiotherapy as a salvage treatment for recurrent hepatocellular carcinoma with inferior vena cava/right atrium tumor thrombus: a multi-center analysis

BackgroundRecurrent hepatocellular carcinoma (HCC) with a tumor thrombus (TT) extending into the inferior vena cava (IVC)/right atrium (RA) is generally regarded as a terminal-stage condition and there is no worldwide consensus on the proper management of this situation. In the present study, we report the efficacy of hypofractionated radiotherapy (HFRT) as a salvage treatment for recurrent HCC with IVC/RA TT.MethodsWe retrospectively reviewed 75 HCC patients with an IVC/RA TT who were referred for HFRT at three institutions between 2008 and 2016. 57 cases had a TT located in the IVC (IVC group), and 18 cases had a TT located in the IVC and RA (IVC + RA group). HFRT was designed to focus on the TT with or without the primary intrahepatic tumors.ResultsIn all cases, the TT completely disappeared (CR) in 17 patients (22.7%), 55 patients (73.3%) had a partial response (PR), and 3 patients (4.0%) had a stable disease (SD). There were no cases of progressive disease (PD). The 1-, 2-, and 3-year overall survival rates of the 75 patients were 38.7% (29/75), 13.3% (10/75) and 5.3% (4/75), respectively. The overall median survival time was 10 months. The mean survival times for the IVC group and IVC+ RA group were 13.8 ± 1.1 and 11.6 ± 2.5 months, respectively. There was no significant difference in survival between the two groups (p = 0.205). Log-rank test revealed that factors predicting poor survival were Child-Pugh B liver function classification, AFP ≥ 400 μg/L, intrahepatic multiple tumors, distant metastases, only the TT as the target, a biological effective dose (BED) < 55 Gy and no chance of further radiotherapy.ConclusionsHFRT appears to be an effective and reasonable treatment option for recurrent HCC patients with IVC/RA TT. The location of the tumor thrombus, either in IVC or in IVC and RA, is not the factor that influences the efficacy of radiotherapy or survival.

Abstract 2178: Targeted delivery of chemotherapeutic agents employing nanovesicles effectively reduced intrahepatic tumors

Abstract Background and Aims: Currently there is no appropriate method for effective and targeted delivery of chemotherapeutic agents to tumor sites. The conventional chemotherapy is afflicted with lack of effective drug delivery to the tumor site, unwanted injury to actively dividing healthy cells, and numerous side effects due to toxicity. The present study was aimed to develop a biologically derived nanoparticle based drug delivery system for the effective treatment of primary hepatic tumors. Methods: Intrahepatic tumors were induced in immunosuppressed mice using PLC/PRF/5 hepatocellular carcinoma (HCC) cells stably transfected with a mammalian expression vector carrying luciferase gene for in-vivo imaging. Nanovesicles ranging from 80-150 nm were isolated from bovine skim milk using ultracentrifugation and characterized using nanoparticle tracking analysis (NTA) and electron microscopy. Purified nanovesicles were loaded with chemotherapeutic agents and antisense oligonucleotides for grossly deregulated microRNAs specific to HCC. Animals with uniform intrahepatic tumors were injected with nanovesicle loaded anticancer agents through tail vein. Tumor regression was monitored weekly using in-vivo imaging system and the animals were maintained up to 8 weeks. Results: Bioluminescence based in-vivo imaging demonstrated significant reduction of tumor size in treated animals compared to untreated controls. There was increased survival rate and complete absence of metastasis in all treated animals. Untreated mice developed large intrahepatic tumors, which also metastasized to other organs. There were no side effects or immunological reactions in animals injected with plain nanovesicles without loading of any anticancer agents. Conclusions: The present study demonstrated that milk derived nanovesicles can be effectively used for successful delivery of anticancer agents into intrahepatic tumors. Nanovesicle based targeted drug delivery system could be an effecient method for the treatment of primary hepatic tumors.* Presenting author E-mail: georgej@kanazawa-med.ac.jp Note: This abstract was not presented at the meeting. Citation Format: Joseph George, Nobuhiko Hayashi, Takashi Saito, Mikihiro Tsutsumi, Mutsumi Tsuchishima. Targeted delivery of chemotherapeutic agents employing nanovesicles effectively reduced intrahepatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2178.

Reduction of Intrahepatic Tumour by Hepatic Arterial Infusion Chemotherapy Prolongs Survival in Hepatocellular Carcinoma.

This study aimed to identify the survival benefit of intrahepatic tumour control by hepatic arterial infusion chemotherapy (HAIC) in hepatocellular carcinoma (HCC) patients with portal vein tumour thrombus (PVTT) or extrahepatic metastasis. Between 2010 and 2017, a total of 187 consecutive patients with advanced HCC were treated with HAIC. The survival outcomes and response rates to HAIC were analysed. The intrahepatic objective response (OR) rate of all enrolled patients was 18.7%. The survival outcome of patients with OR was significantly better from those without OR, irrespective of initial distant metastasis. Achievement of intrahepatic OR by HAIC and favourable liver function at the time of best response evaluation were two independent factors associated with better OS. HAIC-induced intrahepatic tumour reduction significantly prolonged patient survival, irrespective of PVTT or initial distant metastasis.

Extremes of Liver Transplantation for Hepatocellular Carcinoma.

The aim of this retrospective observational study was to evaluate outcomes of patients with extremely advanced hepatocellular carcinoma (HCC) after liver transplantation. A total of 285 HCC patients after liver transplantation were screened for eligibility based on either intrahepatic dissemination (≥10 tumors) or macrovascular invasion. Tumor recurrence was the primary end-point. The study cohort comprised 26 patients. Median recurrence-free survival was 23.2 months with hepatitis B virus (HBV) infection (p = 0.038), higher AFP model score (p = 0.001), prolonged graft ischemia (p = 0.004), and younger donor age (p = 0.016) being significant risk factors. Median recurrence-free survival of HBV-negative and HBV-positive patients was 29.8 and 9.3 months, respectively (p = 0.053). In patients with macrovascular invasion, recurrence-free survival at 3 years was 46.3% with no specific predictors. Tumor size (p = 0.044), higher AFP model score (p = 0.019), prolonged graft ischemia (p = 0.016), and younger donor age (p = 0.041) were significant risk factors in patients with intrahepatic dissemination. Superior 3-year outcomes were observed in patients with intrahepatic dissemination and tumor size <3.5 cm (83.3%, p = 0.027) and HBV-negative patients with ischemia <9.7 h (85.7%, p = 0.028). In conclusion, patients with extremely advanced HCCs are remarkably heterogeneous with respect to their profile of tumor recurrence risk. This heterogeneity is largely driven by factors other than standard predictors of post-transplant HCC recurrence.

Block of NF-kB signaling accelerates MYC-driven hepatocellular carcinogenesis and modifies the tumor phenotype towards combined hepatocellular cholangiocarcinoma.

Primary liver cancer ranks among the leading causes of cancer death worldwide. Risk factors are closely linked to inflammation, such as viral hepatitis and alcoholic as well as non-alcoholic steatohepatitis. Among the pathways involved in the pathogenesis of malignant liver tumors, dysregulation of NF-κB signaling plays a prominent role. It provides a link between inflammation and cancer. To examine the role of NF-κB in a MYC-induced model of hepatocellular carcinoma we deleted NEMO (IKKγ) specifically from hepatocytes. NEMO deletion accelerated tumor development and shortened survival, suggesting a tumor-suppressive function of NF-κB signaling. We observed increased proliferation, inflammation and fibrosis, as well as activation of MAPK and STAT signaling. Importantly, deletion of NEMO modified the tumor phenotype from hepatocellular carcinoma to combined hepatocellular cholangiocarcinoma. The intrahepatic cholangiocarcinoma tumor component showed increased expression of progenitor markers such as Sox9 and reduced expression of mature hepatic markers such as CPS1. In both cases tumorigenesis was reversible by turning off MYC expression. To our knowledge this is the first mouse model of combined hepatocellular cholangiocarcinoma and may provide insights into the development of this rare malignant tumor.

Hepatocellular carcinoma with tumor thrombus in portal vein branch: Transarterial chemoembolization combined with Iodine125 brachytherapy versus transarterial chemoembolization combined with sorafenib.

e15646 Background: Patients with hepatocellular carcinoma (HCC) accompanied with portal vein tumor thrombus (PVTT) have a poor prognosis. Although transarterial chemoembolization (TACE) plus sorafenib (TACE-S) could lead to an improved survival than TACE alone in HCC patients with first- or second-branch PVTT (branch PVTT), the survival was very limited. We compared the safety and efficacy of TACE plus Iodine125 brachytherapy (TACE-I) with TACE-S in patients with unresectable HCC and branch PVTT. Methods: The medical records of consecutive patients with HCC and branch PVTT who underwent TACE-I (TACE-I group) or TACE-S (TACE-S group) from January 2015 to December 2017 were retrospectively evaluated. Iodine125 seeds were implanted into the PVTT under CT guidance 3-5 days after the initial TACE. The matched peripheral dose of Iodine125 brachytherapy was set to be 120-140 Gy. Sorafenib was administered 400 mg twice daily. Outcomes of patients who underwent TACE-I, including adverse events, treatment responses, time to progression (TTP), and overall survival (OS), were compared with those of patients who underwent TACE-S. Results: One hundred and twenty patients were included in the analysis; 62 patients underwent TACE-I and 58 underwent TACE-S. The overall incidence of adverse events was significantly lower in TACE-I group than in TACE-S group (58.1% vs. 93.1%, P &lt; .001), and incidence of grade 3 or higher adverse events also was significantly lower in TACE-I group than in TACE-S group (3.2% vs. 27.6%, P &lt; .001). PVTT OR rates at 12 weeks (58.1% vs. 13.8%, P &lt; .001) and at 24 weeks after the treatment (68.9 % vs. 10.9%, P &lt; .001) in TACE-I group were higher than those in TACE-S group. TACE-I led to significantly longer TTP (median, 11.2 months vs. 6.2 months, P &lt; .001) and OS (median, 20.9 months vs. 14.0 months, P &lt; .001) than TACE-S. In uni- and multivariable analyses, TACE-I treatment, PVTT extent, tumor size ≥10 cm, PVTT OR at 12 weeks, and intrahepatic tumor OR at 12 weeks were independent prognostic factors for OS. Conclusions: TACE-I had less side effects and may improve OS than TACE-S for HCC patients with branch PVTT.

Microwave ablation assisted by three-dimensional visualization system as local therapy for relapsed hepatoblastoma: a small pilot study.

We aimed to explore the feasibility of microwave ablation (MWA) assisted by three-dimensional visualization system for relapsed HB in children. From August 2014 to February 2017, five patients with relapsed HB were enrolled. A total of 12 liver tumors were treated with MWA assisted by a three-dimensional visualization system. Follow-up data were obtained in all patients. The residual liver volume, local tumor progression, new intrahepatic tumors, survival outcome, and complications were analyzed. All tumors were completely ablated in a single session. The mean ablation time per tumor was 9.7 ± 8.6min, and the median ablation/liver volume ratio was 2.37%. No local tumor progression was observed during a follow-up period of 9-39months. All patients were still alive at the end of the follow-up. The median progression-free survival time after ablation was 9months, and the median survival time after ablation was 12months. No other complications were observed except for fever. MWA assisted by three-dimensional visualization system appears to be a safe and feasible local treatment for recurrent HB in pediatric patients.

Pressure enabled drug delivery of anti-CEA CAR-T cells increases intra-hepatic CAR-T tumor penetration and therapeutic index in a murine model of liver metastasis

Abstract Introduction We have demonstrated safety and clinical activity with anti-CEA CAR-T (Sorrento/TNK Therapeutics, Inc.) regional infusions for treatment of liver metastases (LM) using a pressure-enabled drug delivery device (PEDD™, TriSalus™ Life Sciences, Inc.) to increase CAR-T penetration. To further explore the potential benefit of PEDD, we developed a pre-clinical murine LM model that enables correlation of infusion pressure with response. Methodology Mice with CEA+ LM were infused with anti-CEA CAR-T into the portal vein with specified rate and pressure levels. Flow cytometry (FC), bioluminescence imaging (BLI), and serum liver function tests (LFTs) were conducted at multiple time points. Results Flow-pressure relationship was established with ΔP of 7.23 mmHg vs 2.33 mmHg (p=0.01) in high-pressure (10 mL/min, HP) and low-pressure (1 mL/min, LP) cohorts. FC assessment of hepatic non-parenchymal cells 1d after infusion demonstrated 15.9% CD3+CAR+ in HP, compared to 5.1% in LP (p=0.0004). Tumor BLI at day 3 (geometric mean relative to baseline) showed significantly enhanced therapeutic effect in HP, −18% relative signal intensity (RSI), compared to +148% RSI in LP (p=0.05) or +178% RSI in controls (p=0.04). LFTs were similar in LP and HP groups with AST 302 vs 437 U/L (p=0.60) and total bilirubin 0.25 vs 0.7 mg/dL (p=0.33), respectively. Conclusions HP delivery correlated with enhanced CAR-T delivery and control of tumor growth, without an increase in liver toxicity. Follow up to this proof of concept study will investigate multiple infusions with combinatorial approaches with the goal of durable tumor eradication. An ongoing clinical study will further explore CAR-T PEDD in patients.

Ovarian Sertoli-Leydig Cell Tumor With Heterologous Hepatocytes and a Hepatocellular Carcinomatous Element

Sertoli-Leydig cell tumors are a group of tumors composed of variable proportions of Sertoli cells, Leydig cells, and sometimes heterologous elements. We describe the case of a 68-yr-old woman who presented with abdominal distention. A computed tomographic scan revealed a large right adnexal mass without evidence of intrahepatic tumors, and a complete cytoreductive surgery was performed. Pathologic examination revealed a moderately differentiated Sertoli-Leydig cell tumor with various heterologous elements, including gastrointestinal-type glands, insular carcinoid, and aggregations of hepatocytes without significant cytologic atypia. Moreover, adjacent to these hepatocytes, extensive overgrowth of highly atypical hepatocyte-like cells, providing a striking morphologic similarity to hepatocellular carcinoma of the liver, was identified. Both the heterologous hepatocytes and hepatocellular carcinomatous tumor cells were immunohistochemically positive for alpha-fetoprotein, hepatocyte paraffin 1, and arginase-1. Some Sertoli cells adjacent to the heterologous hepatocytes were also positive for alpha-fetoprotein and hepatocyte paraffin 1. The present case showed that a tumor morphologically and immunohistochemically analogous to hepatocellular carcinoma of the liver can arise in the ovary, in association with Sertoli-Leydig cell tumors.

Hepatocellular carcinoma with extrahepatic metastasis: Are there still candidates for transarterial chemoembolization as an initial treatment?

Background and aimCurrently, sorafenib is indicated for hepatocellular carcinoma (HCC) with extrahepatic metastasis (EHM), and many other systemic agents are becoming available. However, a few HCC patients with EHM still undergo transarterial chemoembolization (TACE) for intrahepatic tumor control. We aimed to investigate whether TACE is appropriate for patients with EHM, and if so, which subgroup may benefit from TACE.MethodsA total of 186 consecutive HCC patients (median: 55 years, male: 86.0%, hepatitis B virus: 81.7%, Child-Pugh Class A: 83.3%) with EHM (nodal metastasis: 60.8%, distant metastasis: 39.2%) between 2010 and 2014 were analyzed. Initial treatment included sorafenib in 69 patients, and TACE in 117 patients.ResultsDuring a median follow-up of 6.6 months (range: 0.2–94.6 months), mortality was observed in 90.3% (168/186). The median survival was better for patients who received TACE than those treated with sorafenib (8.2 months vs. 4.6 months, p < 0.001). However, baseline characteristics varied between patients initially treated with TACE and sorafenib, and the treatment modality was not an independent factor associated with overall survival (hazard ratio: 1.19, 95% confidence interval: 0.81–1.75, p = 0.36). In sub-group analysis, TACE was associated with better survival only among younger patients and those with segmental/lobar portal vein invasion.ConclusionIn HCC patients with EHM, TACE was not an independent favorable prognostic factor compared to sorafenib. The concept of intrahepatic control in HCC patients with EHM may need to be reevaluated in the era of promising systemic therapies, although there can be specific subgroups who still benefit from TACE.