Pharmacokinetics and Early Tumor Response to Conventional Transarterial Chemoembolization with Sorafenib and Doxorubicin in a VX2 Rabbit Tumor Model

PurposeTo investigate the pharmacokinetics (PK) and early effects of conventional transarterial chemoembolization (TACE) using sorafenib and doxorubicin on tumor necrosis, hypoxia markers, and angiogenesis in a rabbit VX2 liver tumor model.Materials and MethodsVX2 tumor-laden New Zealand White rabbits (N = 16) were divided into 2 groups: 1 group was treated with hepatic arterial administration of ethiodized oil and doxorubicin emulsion (DOX-TACE), and the other group was treated with ethiodized oil, sorafenib, and doxorubicin emulsion (SORA-DOX-TACE). Animals were killed within 3 days of the procedure. Levels of sorafenib and doxorubicin were measured in blood, tumor, and adjacent liver using mass spectrometry. Tumor necrosis was determined by histopathological examination. Intratumoral hypoxia-inducible factor (HIF) 1α, vascular endothelial growth factor (VEGF), and microvessel density (MVD) were determined by immunohistochemistry.ResultsThe median intratumoral concentration of sorafenib in the SORA-DOX-TACE group was 17.7 μg/mL (interquartile range [IQR], 7.42–33.5 μg/mL), and its maximal plasma concentration (C_max) was 0.164 μg/mL (IQR, 0.0798–0.528 μg/mL). The intratumoral concentration and C_max of doxorubicin were similar between the groups: 4.08 μg/mL (IQR, 3.18–4.79 μg/mL) and 0.677 μg/mL (IQR, 0.315–1.23 μg/mL), respectively, in the DOX-TACE group and 1.68 μg/mL (IQR, 0.795–4.08 μg/mL) and 0.298 μg/mL (IQR, 0.241–0.64 μg/mL), respectively, in the SORA-DOX-TACE group. HIF-1α expression was increased in the SORA-DOX-TACE group than in the DOX-TACE group. Tumor volume, tumor necrosis, VEGF expression, and MVD were similar between the 2 groups.ConclusionsThe addition of sorafenib to DOX-TACE delivered to VX2 liver tumors resulted in high intratumoral and low systemic concentrations of sorafenib without altering the PK of doxorubicin.     

A Pilot First-in-Human Study of Embrace,a Polyethylene Glycol-Based Liquid Embolic Agent,in the Embolization of Malignant and Benign Hypervascular Tumors

PurposeTo investigate the safety and efficacy of an aqueous polyethylene glycol-based liquid embolic agent, Embrace Hydrogel Embolic System (HES), in the treatment of benign and malignant hypervascular tumors.Materials and MethodsA prospective, single-arm, multicenter study included 8 patients, 5 males and 3 females, with a median age of 58.5 years (30–85 years), who underwent embolization in 8 tumors between October 2019 and May 2020. Technical success was defined as successful delivery of HES to the index vessel, with disappearance of >90% of the targeted vascular enhancement or, for portal vein embolization, occlusion of the portal branches to the liver segments for future resection. The volume of HES administered, ease of use (5 point Likert scale), administration time, and adverse events (AEs) were recorded. Evaluation was performed at 7, 30, and 90 days via clinical assessment and blood testing, and follow-up imaging was performed at 30 days.ResultsEight patients were enrolled, and 10 embolizations were performed in 8 lesions. Tumors included hepatocellular carcinoma (n = 4), renal angiomyolipoma (n = 3), and intrahepatic cholangiocarcinoma (n = 1). Technical success was 100%, and the average ease of use was 3.3 ± 1.0 SD. The HES delivery time was 1–28 minutes (median, 16.5 minutes), and the HES volume injected was 0.4–4.0 mL (median, 1.3 mL). All patients reached 30-day follow-up with imaging, and 6 patients reached 90-day follow-up. There were 3 serious AEs in 2 patients that were unrelated to the embolic agent.ConclusionHES resulted in a 100% embolization technical success rate. The product ease of use was acceptable, and no target vessel recanalization was noted on follow-up imaging at 30 days.     

Personal comorbidities and their subsequent risks for liver,gallbladder and bile duct cancers

Many environmental risk factors for hepatobiliary cancers are known but whether they are associated with specific cancer types is unclear. We present here a novel approach of assessing standardized incidence ratios (SIRs) of previously diagnosed comorbidities for hepatocellular carcinoma (HCC), gallbladder cancer (GBC), cholangiocarcinoma (CCA) and ampullary cancer. The 13 comorbidities included alcohol and nonalcohol related liver disease, chronic obstructive pulmonary disease, gallstone disease, viral and other kinds of hepatitis, infection of bile ducts, hepatic and other autoimmune diseases, obesity and diabetes. Patients were identified from the Swedish Inpatient Register from 1987 to 2018, and their cancers were followed from 1997 onwards. SIRs for HCC were 80 to 100 in men and women diagnosed with hepatitis C virus and they were also >10 in patients diagnosed with hepatitis B virus, other kind of hepatitis, hepatic autoimmune disease and nonalcohol related liver disease. Many of these risks, as well as alcohol related liver disease, were either specific to HCC or were shared with intrahepatic CCA. For GBC, CCA and ampullary cancer infection of bile ducts was the main risk factor. Gallstone disease, nonhepatic autoimmune diseases and diabetes were associated with all hepatobiliary cancers. The limitations of the study include inability to cover some rare risk factors and limited follow-up time. Many of the considered comorbidities are characterized by chronic inflammation and/or overt immune disturbance in autoimmune diseases. The results suggest that local chronic inflammation and a related immune disturbance is the carcinogenic trigger for all these cancers.     

Microwave Ablation as Bridging to Liver Transplant for Patients with Hepatocellular Carcinoma: A Single-Center Retrospective Analysis

PurposeTo evaluate the efficacy and safety of microwave (MW) ablation as first-line locoregional therapy (LRT) for bridging patients with hepatocellular carcinoma (HCC) to liver transplant.Materials and MethodsThis retrospective study evaluated 88 patients who received percutaneous MW ablation for 141 tumors as first-line LRT for HCC and who were listed for liver transplantation at a single medical center between 2011 and 2019. The overall survival (OS) rate statuses after liver transplant, waitlist retention, and disease progression were evaluated using the Kaplan-Meier techniques.ResultsAmong the 88 patients (72 men and 16 women; mean age, 60 years; Model for End-Stage Liver Disease score, 11.2) who were listed for transplant, the median waitlist time was 9.4 months (interquartile range, 5.5–18.9). Seventy-one (80.7%) patients received transplant after a median waitlist time of 8.5 months. Seventeen (19.3%) patients were removed from the waitlist; of these, 4 (4.5%) were removed because of tumors outside of the Milan criteria (HCC-specific dropout). No difference in tumor size or alpha-fetoprotein was observed in the transplanted versus nontransplanted patients at the time of ablation (2.1 vs 2.1 cm and 34.4 vs 34.7 ng/mL for transplanted vs nontransplanted, respectively; P > .05). Five (5.1%) of the 88 patients experienced adverse events after ablation; however, they all recovered. There were no cases of tract seeding. The local tumor progression (LTP) rate was 7.2%. The OS status after liver transplant at 5 years was 76.7%, and the disease-specific survival after LTP was 89.6%, with a median follow-up of 61 months for all patients.ConclusionsMW ablation appears to be safe and effective for bridging patients with HCC to liver transplant without waitlist removal from seeding, adverse events, or LTP.     

Immune microenvironment of hepatocellular carcinoma,intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: Relationship with histopathological and molecular classifications

Tumor tissue is composed of tumor cells and tumor stroma. Tumor stroma contains various immune cells and non-immune stromal cells, forming a complex tumor microenvironment which plays pivotal roles in regulating tumor growth. Recent successes in immunotherapies against tumors, including immune checkpoint inhibitors, have further raised interests in the immune microenvironment of liver carcinoma. The immune microenvironment of tumors is formed because of interactions among tumor cells, immune cells and non-immune stromal cells, including fibroblasts and endothelial cells. Different patterns of immune microenvironment are observed among different tumor subtypes, and their clinicopathological significance and intertumor/intratumor heterogeneity are being intensively studied. Here, we review the immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma, focusing on its histopathological appearance, clinicopathological significance, and relationship with histological and molecular classifications. Understanding the comprehensive histopathological picture of a tumor immune microenvironment, in addition to molecular and genetic approaches, will further potentiate the effort for precision medicine in the era of tumor-targeting immunotherapy.     

Diagnostic approach to well-differentiated hepatocellular carcinoma

Well-differentiated hepatocellular mass-lesions in non-cirrhotic livers have a differential diagnosis of focal nodular hyperplasia, regenerative hepatic pseudotumors, hepatic adenoma, hepatocellular carcinoma, and fibrolamellar carcinoma. Despite significant advances in characterizing these pseudotumors and tumors, they remain a diagnostic challenge, especially on needle biopsy. This review focuses on a systematic diagnostic approach, one that allows confident diagnosis of these lesions.     

Quantitative Automated Segmentation of Lipiodol Deposits on Cone-Beam CT Imaging Acquired during Transarterial Chemoembolization for Liver Tumors: A Deep Learning Approach

PurposeTo show that a deep learning (DL)–based, automated model for Lipiodol (Guerbet Pharmaceuticals, Paris, France) segmentation on cone-beam computed tomography (CT) after conventional transarterial chemoembolization performs closer to the “ground truth segmentation” than a conventional thresholding-based model.Materials and MethodsThis post hoc analysis included 36 patients with a diagnosis of hepatocellular carcinoma or other solid liver tumors who underwent conventional transarterial chemoembolization with an intraprocedural cone-beam CT. Semiautomatic segmentation of Lipiodol was obtained. Subsequently, a convolutional U-net model was used to output a binary mask that predicted Lipiodol deposition. A threshold value of signal intensity on cone-beam CT was used to obtain a Lipiodol mask for comparison. The dice similarity coefficient (DSC), mean squared error (MSE), center of mass (CM), and fractional volume ratios for both masks were obtained by comparing them to the ground truth (radiologist-segmented Lipiodol deposits) to obtain accuracy metrics for the 2 masks. These results were used to compare the model versus the threshold technique.ResultsFor all metrics, the U-net outperformed the threshold technique: DSC (0.65 ± 0.17 vs 0.45 ± 0.22, P < .001) and MSE (125.53 ± 107.36 vs 185.98 ± 93.82, P = .005). The difference between the CM predicted and the actual CM was 15.31 mm ± 14.63 versus 31.34 mm ± 30.24 (P < .001), with lesser distance indicating higher accuracy. The fraction of volume present ([predicted Lipiodol volume]/[ground truth Lipiodol volume]) was 1.22 ± 0.84 versus 2.58 ± 3.52 (P = .048) for the current model’s prediction and threshold technique, respectively.ConclusionsThis study showed that a DL framework could detect Lipiodol in cone-beam CT imaging and was capable of outperforming the conventionally used thresholding technique over several metrics. Further optimization will allow for more accurate, quantitative predictions of Lipiodol depositions intraprocedurally.     

C反应蛋白和白蛋白比值预测单发小肝癌患者微血管侵犯的价值研究

背景 既往对肝癌微血管侵犯病理诊断的重要性重视不够，目前国内外缺乏对微血管侵犯统一的病理诊断标准，也未将微血管侵犯列为病理常规诊断指标。C反应蛋白/白蛋白比值（CAR）作为新型系统性炎性因子，与肝癌的增殖、侵袭转移等恶性生物学行为密切相关。 目的 探讨CAR预测单发小肝癌患者微血管侵犯的价值。 方法 选择2017年6月至2021年6月在新疆医科大学第一附属医院行肝切除术的单个、肿瘤直径≤5 cm的术后病理检查证实为肝癌的患者346例为研究对象。收集患者一般资料，并计算CAR。绘制CAR预测单发小肝癌患者微血管侵犯的受试者工作特征（ROC）曲线，并计算CAR的最佳诊断截点，根据CAR最佳诊断截点将患者进行分组，采用1∶1最近邻居倾向性评分匹配（PSM）法将Logistic模型估计的倾向性评分相近患者进行配对，得到两组间各临床特征比较均衡性较高的样本。比较匹配后两组患者微血管侵犯率，采用Logistic回归分析评估匹配前、后CAR对单发小肝癌患者微血管侵犯的预测价值。 结果 346例患者中微血管侵犯阳性131例（37.9%），微血管侵犯阴性215例（62.1%）。ROC曲线分析结果显示，CAR预测单发小肝癌患者微血管侵犯的灵敏度为82.9%，特异度为76.4%，ROC曲线下面积为0.787〔95%CI（0.697，0.877）〕，最佳诊断截点为0.03。根据CAR最佳诊断截点，将患者分为CAR<0.03组（A组，n=145）和CAR≥0.03组（B组，n=201）。采用1∶1最近邻居PSM法，共92对匹配成功，匹配后两组临床资料均衡。匹配后，B组患者微血管侵犯发生率〔43.5%（40/92）〕高于A组〔13.0%（12/92）〕（χ2=6.314，P=0.013）。采用3种Logistic回归分析结果显示，匹配前、后CAR均为单发小肝癌患者微血管侵犯的独立影响因素（P<0.05）。 结论 CAR作为新型系统性炎症指标，可用于预测单发小肝癌微血管侵犯，当CAR≥0.03时提示单发小肝癌微血管侵犯发生率较高。     

The impact of the COVID-19 pandemic on hepatitis B virus vaccination and transmission among men who have sex with men: A mathematical modelling study

BackgroundDuring the COVID-19 pandemic, the number of hepatitis B virus (HBV) vaccinations among men who have sex with men (MSM) has been considerably lower than before the pandemic. Moreover, less frequent HBV testing and a reduction in numbers of sex partners have been reported. We assessed the impact of these COVID-19-related changes on HBV transmission among MSM in the Netherlands.MethodsWe estimated the changes in sexual activity, HBV testing, and HBV vaccination among MSM during the pandemic from Dutch data. We used a deterministic compartmental model and investigated scenarios with small or large declines in sexual activity, testing, and vaccination for the current phase of the pandemic (without available data). We examined the increase in HBV vaccinations needed to prevent further increase in HBV incidence.ResultsWith a decrease in numbers of sex partners of 15–25% during the first lockdown and 5% during the second lockdown, we found a decline of 6.6% in HBV incidence in 2020, despite a >70% reduction in HBV testing and vaccination during the first lockdown. With numbers of sex partners rebounding close to pre-pandemic level in 2021, and a reduction of 15% in testing and 30% in vaccination in 2021, we found an increase of 1.4% in incidence in 2021 and 3.1% in 2026. With these changes, an increase of ≥60% in HBV vaccinations in 2022 would be needed to bring the HBV incidence in 2023 back to the level that it would have had if the COVID-19-related changes had not occurred.ConclusionsDespite reductions in sexual activity during the COVID-19 pandemic, the decrease in HBV vaccinations may result in a small increase in HBV incidence after 2021, which may persist for years. It is important to restore the vaccination level and limit further increase in HBV transmission among MSM.     

呫吨酮并吡啶衍生物XP-15联合紫杉醇对耐药肝癌细胞QGY-7701 的体外抑制作用

目的:探索呫吨酮并吡啶衍生物XP-15联合紫杉醇对人肝癌QGY-7701耐药细胞株的体外抗肿瘤作用。方法:运用CCK8法、Transwell实验和流式细胞仪检测凋亡技术观察细胞功能学变化，运用Western Blot蛋白免疫印迹技术探索其可能的作用机制。结果:XP-15可明显增强紫杉醇对耐药QGY-7701细胞的抑制作用，XP-15联合紫杉醇作用于耐药QGY-7701细胞24 h后，QGY-7701细胞活力明显减弱，且其侵袭迁移能力明显降低，同时流式细胞仪凋亡检测提示细胞凋亡百分比明显增加。Western Blot蛋白免疫印迹亦证实细胞抗凋亡蛋白bcl-2表达明显降低，肝癌增殖分化相关PI3K及AKT蛋白分子表达减少。结论:XP-15具有增敏紫杉醇诱导耐药QGY-7701细胞凋亡同时抑制其增殖活力的作用，其作用机制可能与下调PI3K-AKT通路活性，同时减少bcl-2抑制凋亡蛋白表达相关。