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Endoscopic considerations for the management of cholangiocarcinoma 内镜下胆管癌治疗的考虑
Pub Date : 2021-11-05 DOI: 10.1002/lci2.40
Joe Geraghty

Cholangiocarcinoma (CCA) is a rare malignancy of the biliary tract. The goals of endoscopy in CCA are to (a) provide an accurate diagnosis (tissue acquisition) and staging of disease and (b) relieve biliary obstruction and associated symptoms such as pruritis (stent placement). This then facilitates optimal treatment to occur; be this surgical resection, uninterrupted chemotherapy or improvement in symptoms. Endoscopy can involve endoscopic retrograde cholangiopancreatography with or without cholangioscopy, or endoscopic ultrasound with fine-needle aspiration to support these goals of making surgery safer and chemotherapy possible while avoiding endoscopy compilations such as pancreatitis and sepsis.

胆管癌(CCA)是一种罕见的胆道恶性肿瘤。CCA内窥镜检查的目的是(a)提供疾病的准确诊断(组织采集)和分期,以及(b)缓解胆道梗阻和相关症状,如瘙痒症(支架置入)。这有利于进行最佳治疗;无论是手术切除、不间断化疗还是症状改善。内窥镜检查可以包括带或不带胆道镜的内窥镜逆行胰胆管造影,或带细针抽吸的内窥镜中超声检查,以支持这些目标,即使手术更安全和化疗成为可能,同时避免胰腺炎和败血症等内窥镜并发症。
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引用次数: 1
Hepatotoxicity of systemic therapies for unresectable hepatocellular carcinoma 不可切除的肝细胞癌全身治疗的肝毒性
Pub Date : 2021-10-12 DOI: 10.1002/lci2.38
Ciro Celsa, Paolo Giuffrida, Carmelo Marco Giacchetto, Caterina Stornello, Gabriele Rancatore, Mauro Grova, Maria Rita Ricciardi, Sergio Rizzo, Calogero Cammà, Giuseppe Cabibbo

The number of effective systemic therapies for the treatment of unresectable hepatocellular carcinoma (uHCC) is rapidly increasing and the advent of immunotherapy changed the treatment paradigm for these patients, leading to a significant improvement in survival outcomes. While sorafenib, a tyrosine-kinase inhibitor monotherapy, remained the only effective treatment for almost a decade, the combination of atezolizumab, an immune checkpoint inhibitor (ICI) targeting programmed death-ligand 1, plus bevacizumab, an antiangiogenic agent targeting vascular endothelial growth factor, now represents the new standard of care for patients with uHCC. Moreover, several further clinical trials are ongoing to evaluate novel combinations between ICIs with other drugs, belonging to the same class or to other classes. As HCC occurs in most cases in the setting of cirrhosis, the evaluation of the risk/benefit ratio of systemic treatments represents a critical point. The underlying liver disease significantly influences the safety and the effectiveness of current and future systemic treatments for uHCC. For this reason, the hepatotoxicity profile and impact on liver function of these molecules should be carefully assessed in both clinical trials and in the real-world setting. Here, we review hepatotoxicity data on systemic treatments for uHCC and offer suggestions on monitoring and managing liver-related adverse events occurring during the treatment.

治疗不可切除肝细胞癌(uHCC)的有效全身疗法的数量正在迅速增加,免疫疗法的出现改变了这些患者的治疗模式,导致生存结果的显着改善。近十年来,酪氨酸激酶抑制剂索拉非尼(sorafenib)单药治疗仍然是唯一有效的治疗方法,而atezolizumab(一种靶向程序性死亡配体1的免疫检查点抑制剂(ICI)和贝伐珠单抗(一种靶向血管内皮生长因子的抗血管生成药物)的联合治疗现在代表了uHCC患者的新标准治疗。此外,正在进行几项进一步的临床试验,以评估ici与属于同一类别或其他类别的其他药物之间的新组合。由于HCC多数发生在肝硬化背景下,因此评估全身治疗的风险/收益比是一个关键点。潜在的肝脏疾病显著影响当前和未来系统性治疗uHCC的安全性和有效性。因此,在临床试验和现实环境中,应仔细评估这些分子的肝毒性特征和对肝功能的影响。在这里,我们回顾了uHCC全身治疗的肝毒性数据,并提出了监测和管理治疗过程中发生的肝脏相关不良事件的建议。
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引用次数: 3
Multicentre external validation of the GES score for predicting HCC risk in Japanese HCV patients who achieved SVR following DAAs 在DAAs后达到SVR的日本HCV患者中,GES评分用于预测HCC风险的多中心外部验证
Pub Date : 2021-10-06 DOI: 10.1002/lci2.41
Kazumichi Abe, Masashi Fujita, Manabu Hayashi, Atsushi Takahashi, Hiromasa Ohira, Nabiel Mikhail, Reham Soliman, Gamal Shiha

A simple score combining clinical and biochemical parameters (general evaluation score (GES)) has shown value in predicting hepatocellular carcinoma (HCC) risk after hepatitis C virus (HCV) eradication in Egyptian patients with HCV genotype 4. We aimed to apply the GES to predict HCC risk in Japanese HCV patients who achieved sustained virological response (SVR) following direct-acting antivirals (DAAs). This multicentre retrospective cohort study included 187 HCV patients without a history of HCC treatment who achieved SVR. The GES was calculated using pre- and post-treatment data. The median age of the patients was 66 years; 49% were male, 89% had cirrhosis and 69% had HCV genotype 1. During the mean 36-month follow-up, 19 (10.2%) developed HCC. Regarding the pretreatment scores, 75 (40.1%), 58 (31.0%) and 54 (28.9%) patients had low-, intermediate- and high-risk scores, respectively. The 4-year cumulative incidence (CumI) was 1.64% in the low-risk group, 2.82% in the intermediate-risk group and 6.88% in the high-risk group (log-rank P = .029). In patients with cirrhosis, 60 (36.1%), 57 (34.3%) and 49 (29.5%) had low-, intermediate- and high-risk scores respectively. The 4-year CumI was 0.98% in the low-risk group, 2.86% in the intermediate-risk group and 6.67% in the high-risk group (log-rank P = .02). The GES calculated with pretreatment data was more useful than that calculated with post-treatment data (Harrell's C statistic: 0.670 vs 0.587). This tool incorporates changes over time to estimate variations in HCC risk and could help identify low-risk patients for whom HCC surveillance can be discontinued.

结合临床和生化参数的简单评分(一般评价评分(GES))在预测埃及HCV基因型4的丙型肝炎病毒(HCV)根除后的肝细胞癌(HCC)风险方面显示出价值。我们的目的是应用GES来预测直接作用抗病毒药物(DAAs)后获得持续病毒学反应(SVR)的日本HCV患者的HCC风险。这项多中心回顾性队列研究纳入了187例无HCC治疗史且达到SVR的HCV患者。使用治疗前和治疗后的数据计算GES。患者年龄中位数为66岁;49%为男性,89%为肝硬化,69%为HCV基因1型。在平均36个月的随访中,19例(10.2%)发生HCC。在预处理评分方面,75例(40.1%)、58例(31.0%)和54例(28.9%)患者分别获得低、中、高风险评分。低危组的4年累积发病率(CumI)为1.64%,中危组为2.82%,高危组为6.88% (log - rank P = 0.029)。在肝硬化患者中,分别有60例(36.1%)、57例(34.3%)和49例(29.5%)为低、中、高风险评分。低危组的4年CumI为0.98%,中危组为2.86%,高危组为6.67% (log - rank P = 0.02)。使用预处理数据计算的GES比使用处理后数据计算的GES更有用(Harrell’s C统计量:0.670 vs 0.587)。该工具结合了随时间的变化来估计HCC风险的变化,并可以帮助识别可以停止HCC监测的低风险患者。
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引用次数: 0
Unmet needs in basic and translational research in Cholangiocarcinoma 胆管癌基础和转化研究中未满足的需求
Pub Date : 2021-10-02 DOI: 10.1002/lci2.39
M. Cadamuro, R. Macías, A. Strain, M. Strazzabosco, P. Simioni, J. Marin, L. Fabris
Despite the impact of cutting‐edge technologies in providing deep molecular phenotyping of many tumours, management of cholangiocarcinoma (CCA), a rare and insufficiently studied cancer with marked heterogeneity (including intrahepatic and extrahepatic variants), has remained limited and it has poor prognosis. Renewed interest in this enigmatic disease has been fostered in the last decade. Here, we will give an overview of the most important gaps in knowledge of the basic and translational research of CCA that must be prioritized to improve the CCA management in the future.
尽管前沿技术在提供许多肿瘤的深层分子表型方面产生了影响,但胆管癌(CCA)的治疗仍然有限,而且预后不良。CCA是一种罕见且研究不足的癌症,具有显著的异质性(包括肝内和肝外变异)。在过去的十年里,人们对这种神秘的疾病重新产生了兴趣。在这里,我们将概述在CCA的基础和转化研究知识方面最重要的差距,这些差距必须优先考虑,以改善未来的CCA管理。
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引用次数: 0
Safety of sitagliptin in treatment of hepatocellular carcinoma in chronic liver disease patients 西格列汀治疗慢性肝病患者肝细胞癌的安全性
Pub Date : 2021-08-28 DOI: 10.1002/lci2.36
Clémence Hollande, Jeremy Boussier, Estelle Mottez, Vincent Bondet, Tan Phuc Buivan, Bruno Charbit, Alba Llibre, Frédéric Charlotte, Eric Savier, Olivier Scatton, Darragh Duffy, Matthew Albert, Vincent Mallet, Stanislas Pol

Background & Aims

Systemic therapies for hepatocellular carcinoma (HCC) treatment have limited efficacy and poor safety. Dipeptidyl peptidase-4 inhibitors were initially developed and approved as treatment for type 2 diabetes, yet oral administration of sitagliptin has recently been shown to improve naturally occurring tumour immunity in animal models of HCC.

Methods

We conducted a phase Ib clinical trial to evaluate the impact of a pre-operative 3-week DPP4 inhibitor (sitagliptin) treatment in HCC patients undergoing liver resection. The primary objective was to evaluate the safety of a sitagliptin treatment in each of the three groups of patients, according to an escalating dosage of sitagliptin (100, 200 and 600 mg/d). Secondary objectives included the assessment of DPP4 activity, cytokine expression in plasma samples and circulating immune populations.

Results

Fourteen patients were included and analysed. In all three dose groups, no severe adverse event related to sitagliptin was reported. A significant inhibition of DPP4 activity was observed upon sitagliptin treatment, which prevented the N-terminal truncation of CXCL10, leading to a mobilization of circulating CD8+ T cells and eosinophils. Immunochemistry analysis showed a lymphoid infiltration in all tumour samples with the presence of a population of CXCR3+ T cells in all but one of the tumours. Positivity for CXCL10 (IP10) and CCR3 in tumour and/or stroma cells was found in all resection pieces.

Conclusion

In summary, sitagliptin can be used safely in patients with chronic liver disease and HCC, and could be tested in phase 2 trial, as an adjuvant in combination with others drugs, for the treatment of HCC patients.

肝细胞癌(HCC)的系统治疗疗效有限,安全性差。二肽基肽酶-4抑制剂最初被开发并批准用于治疗2型糖尿病,但最近在HCC动物模型中口服西他列汀可提高自然发生的肿瘤免疫力。
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引用次数: 1
Treating patients with advanced hepatocellular carcinoma and impaired liver function: Broadening the reach of anti-cancer therapy 治疗晚期肝细胞癌和肝功能受损患者:扩大抗癌症治疗的范围
Pub Date : 2021-08-18 DOI: 10.1002/lci2.37
Antonio D'Alessio, Claudia Angela Maria Fulgenzi

Hepatocellular carcinoma (HCC) usually arises on the background of liver cirrhosis, which carries an intrinsic risk of death because of liver failure and poses a major treatment challenge. Patient stratification is therefore important to avoid unnecessary treatment for those who are more likely to die from underlying liver disease rather than from cancer. In clinical practice, the severity of liver disfunction is commonly graded with the Child–Pugh (CP) score, which divides patients into three categories (A–B–C), with worsening liver function according to clinical and laboratory criteria.1 For CP-C patients, exclusive supportive care is recommended. CP-B patients, which represent a high percentage of HCC cases, are a heterogeneous category including patients presenting with both mild and moderate–severe liver function. Treatment options for these patients are limited, and they are usually excluded from clinical trials as their impaired liver function is thought to act as a strong confounder and a competitive cause of death.

According to the Barcelona Clinic Liver Cancer (BCLC) classification, patients with very early (BCLC-0) and early (BCLC-A) disease can undergo a potentially curative approach, such as surgical resection, local ablative therapies and orthotopic liver transplantation (OLT), which is the only curative approach for both HCC and liver cirrhosis. In particular, according to the EASL and the AASLD guidelines, surgical resection is indicated only in patients with good liver function (CP-A) because of the risk of post-surgical liver failure.2, 3 Concerning local ablative strategies (radiofrequency ablation, microwave ablation and percutaneous ethanol injection), the treatment choice should be personalised, since there is no a priori contraindication for CP-B patients, but these patients often suffer from ascites and coagulation disorders, which are known contraindications for local ablation.4 In cases of BCLC B HCC, the recommended treatment is trans-arterial chemoembolization. AASLD guidelines restrict this approach to CP-A patients and only limited CP-B patients,3 whereas EASL guidelines include also asymptomatic patients with CP B7, with particular precautions because of the risk of post-treatment liver failure and ischaemic necrosis.2

Systemic therapies are the treatment of choice for patients with advanced (BCLC-C) or intermediate stage (BCLC-B) liver cancer not amenable for loco-regional therapies. While any systemic agent would be contraindicated for CP-C patients, there is a subgroup of CP-B patients which could still be potential candidates for systemic therapy. Data from clinical trials are scattered in this subgroup and most of the evidence comes from real-life experiences and is therefore limited for newly approved drugs. In particular, the only positive large phase III study enrolling patie

肝细胞癌(HCC)通常发生在肝硬化的背景下,肝硬化具有因肝衰竭而死亡的内在风险,是一个主要的治疗挑战。因此,对于那些更有可能死于潜在肝病而非癌症的患者,患者分层对于避免不必要的治疗至关重要。在临床实践中,肝功能紊乱的严重程度通常用Child-Pugh(CP)评分来分级,该评分将患者分为三类(A-B-C),根据临床和实验室标准,肝功能恶化。1对于CPC患者,建议进行专门的支持性护理。CPB患者在HCC病例中所占比例很高,是一个异质性类别,包括表现为轻度和中度-重度肝功能的患者。这些患者的治疗选择是有限的,他们通常被排除在临床试验之外,因为他们的肝功能受损被认为是一个强大的混杂因素和竞争性的死亡原因。根据巴塞罗那临床癌症(BCLC)分类,患有非常早期(BCLC0)和早期(BCLCD)疾病的患者可以接受潜在的治疗方法,如手术切除、局部消融治疗和原位肝移植(OLT),这是HCC和肝硬化的唯一治疗方法。特别是,根据EASL和AASLD指南,由于术后肝功能衰竭的风险,手术切除仅适用于肝功能良好(CPA)的患者。2,3关于局部消融策略(射频消融、微波消融和经皮乙醇注射),治疗选择应个性化,因为CPB患者没有先验禁忌症,但这些患者经常患有腹水和凝血障碍,这是已知的局部消融禁忌症。4在BCLC B HCC的病例中,推荐的治疗方法是经动脉化疗栓塞。AASLD指南将这种方法限制在CPA患者和仅限于CPB患者,3而EASL指南也包括CP B7的无症状患者,由于治疗后肝功能衰竭和缺血性坏死的风险,特别要注意。2系统治疗是晚期(BCLCC)或中期(BCLCB)癌症患者不适合局部治疗的选择。虽然任何系统性药物都是CPC患者的禁忌症,但有一个CPB患者亚组仍然可能是系统性治疗的潜在候选者。临床试验的数据分散在这一亚组中,大多数证据来自现实生活中的经历,因此仅限于新批准的药物。特别是,纳入CPB患者的唯一一项阳性的大型III期研究是SHARP试验,该试验导致索拉非尼被历史上批准为晚期HCC的第一种治疗方法。5一项大型荟萃分析包括30项不同临床试验中接受索拉非尼治疗的8678名患者,发现尽管预期生存率更差,但CPB患者取得了相当的疗效,与CPA患者相比,索拉非尼的安全性和耐受性。6值得注意的是,CPB占所有分析患者的19%,CPA组的中位总生存期(OS)为4.6个月,而CPA组为8.8个月。其他多激酶抑制剂(MKI)的数据不太可靠。在对参加REFLECT试验的患者进行的一项事后分析中,乐伐替尼被证明是安全有效的,即使对那些在治疗期间肝功能恶化为CPB的患者也是如此。在该亚组中,乐伐替尼的总有效率(ORR)为28.3%(CPA组为42.9%),治疗相关不良事件(TRAE)≥3级的发生率为71.7%(CPA组则为54.7%),尽管与CPA患者相比OS较差。8专注于二线选择,卡博扎替尼在CELESTIAL试验中治疗第8周时肝功能恶化至CPB的患者的OS和无进展生存期(PFS)也得到了显著改善。9此外,与其他人群相比,这些患者的剂量减少率和毒性相关的治疗中断率相似。另一方面,与CPA相比,瑞戈非尼在CPB患者中的存活率和毒性表现明显较差,因此阻碍了其在这一亚组患者中的使用。10此外,在最初的REACH研究中,雷莫昔单抗对AFP<400 ng/mL的CPB患者没有被证明是有效的,同时导致34级不良事件的发生率更高,11,因此,随后的III期REACH2研究仅包括CP<7.12的患者
{"title":"Treating patients with advanced hepatocellular carcinoma and impaired liver function: Broadening the reach of anti-cancer therapy","authors":"Antonio D'Alessio,&nbsp;Claudia Angela Maria Fulgenzi","doi":"10.1002/lci2.37","DOIUrl":"10.1002/lci2.37","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) usually arises on the background of liver cirrhosis, which carries an intrinsic risk of death because of liver failure and poses a major treatment challenge. Patient stratification is therefore important to avoid unnecessary treatment for those who are more likely to die from underlying liver disease rather than from cancer. In clinical practice, the severity of liver disfunction is commonly graded with the Child–Pugh (CP) score, which divides patients into three categories (A–B–C), with worsening liver function according to clinical and laboratory criteria.<span><sup>1</sup></span> For CP-C patients, exclusive supportive care is recommended. CP-B patients, which represent a high percentage of HCC cases, are a heterogeneous category including patients presenting with both mild and moderate–severe liver function. Treatment options for these patients are limited, and they are usually excluded from clinical trials as their impaired liver function is thought to act as a strong confounder and a competitive cause of death.</p><p>According to the Barcelona Clinic Liver Cancer (BCLC) classification, patients with very early (BCLC-0) and early (BCLC-A) disease can undergo a potentially curative approach, such as surgical resection, local ablative therapies and orthotopic liver transplantation (OLT), which is the only curative approach for both HCC and liver cirrhosis. In particular, according to the EASL and the AASLD guidelines, surgical resection is indicated only in patients with good liver function (CP-A) because of the risk of post-surgical liver failure.<span><sup>2, 3</sup></span> Concerning local ablative strategies (radiofrequency ablation, microwave ablation and percutaneous ethanol injection), the treatment choice should be personalised, since there is no a priori contraindication for CP-B patients, but these patients often suffer from ascites and coagulation disorders, which are known contraindications for local ablation.<span><sup>4</sup></span> In cases of BCLC B HCC, the recommended treatment is trans-arterial chemoembolization. AASLD guidelines restrict this approach to CP-A patients and only limited CP-B patients,<span><sup>3</sup></span> whereas EASL guidelines include also asymptomatic patients with CP B7, with particular precautions because of the risk of post-treatment liver failure and ischaemic necrosis.<span><sup>2</sup></span></p><p>Systemic therapies are the treatment of choice for patients with advanced (BCLC-C) or intermediate stage (BCLC-B) liver cancer not amenable for loco-regional therapies. While any systemic agent would be contraindicated for CP-C patients, there is a subgroup of CP-B patients which could still be potential candidates for systemic therapy. Data from clinical trials are scattered in this subgroup and most of the evidence comes from real-life experiences and is therefore limited for newly approved drugs. In particular, the only positive large phase III study enrolling patie","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"2 2","pages":"31-32"},"PeriodicalIF":0.0,"publicationDate":"2021-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/lci2.37","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44403645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 5
Mutations in circulating cell-free tumour DNA: Predictors of survival in hepatocellular carcinoma 循环中无细胞肿瘤DNA的突变:肝细胞癌生存率的预测因素
Pub Date : 2021-08-05 DOI: 10.1002/lci2.34
Jessica Howell, Stephen R. Atkinson, David J. Pinato, Shahid A Khan, Rosalba Minisini, Michela E. Burlone, Monica Leutner, Mario Pirisi, Reinhard Büttner, Margarete Odenthal, Rohini Sharma

Background

Hepatocellular carcinoma (HCC) incidence is increasing worldwide and prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Circulating cell-free DNA of tumour origin (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We determined the utility of ctDNA as a prognostic biomarker of survival in HCC.

Methods

Plasma cell-free DNA and matched germline DNA were isolated from patients with HCC (n = 51) and cirrhosis (n = 10). Targeted, multiplex PCR ultra-deep sequencing was performed using a liver cancer-specific primer panel for genes ALB, AMPH, APC, ARID1A, ARID2, ATM, AXIN1, BAZ2B, BRAF, CSMD3, CTNNB1, DSE, ERBB2, HNF1A, IGFR2, IGSF10, KEAP1, MET, TP53, UBR3, USP25, ZIC3 and ZNF226. Associations between mutations in ctDNA and overall survival were analysed using Cox proportional hazards modelling.

Results

114 putative mutations (70 unique) in were detected in plasma ctDNA in 35 of 51 patients with HCC (69%). On univariable analysis, CSMD3 gene mutations were associated with shorter overall survival (Logrank HR 3.18, 95% CI 1.14-8.86, P = .027). The median survival time was 15.5 months (IQR 7.77-16.5 months) in patients with CSMD3 mutations compared with the median survival of 26.5 months (IQR 16.93-46.07 months) in patients without CSMD3 mutations. Other factors associated with overall survival were advanced BCLC stage (HR 16.52, 95% CI 2.22-122.94, P = .006) and Child-Pugh Class (CPC HR 7.98, 95% CI 2.31-27.61, P = .001). Cox proportional hazards modelling showed mutations in CSMD3 remained a significant independent risk for shorter overall survival in HCC when adjusted for age, BCLC stage and Child-Pugh class (HR 4.91, 95% CI 1.60-15.02, P = .005).

Conclusion

Detection of CSMD3 mutations in plasma ctDNA is associated with reduced overall survival in HCC patients, adjusted for potential confounding factors.

肝细胞癌(HCC)的发病率在全球范围内不断上升,迫切需要预后生物标志物来指导治疗和降低死亡率。循环无细胞肿瘤起源DNA (ctDNA)是一种新的、微创的检测癌症基因改变的方法。我们确定了ctDNA作为HCC生存预后生物标志物的效用。
{"title":"Mutations in circulating cell-free tumour DNA: Predictors of survival in hepatocellular carcinoma","authors":"Jessica Howell,&nbsp;Stephen R. Atkinson,&nbsp;David J. Pinato,&nbsp;Shahid A Khan,&nbsp;Rosalba Minisini,&nbsp;Michela E. Burlone,&nbsp;Monica Leutner,&nbsp;Mario Pirisi,&nbsp;Reinhard Büttner,&nbsp;Margarete Odenthal,&nbsp;Rohini Sharma","doi":"10.1002/lci2.34","DOIUrl":"10.1002/lci2.34","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) incidence is increasing worldwide and prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Circulating cell-free DNA of tumour origin (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We determined the utility of ctDNA as a prognostic biomarker of survival in HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Plasma cell-free DNA and matched germline DNA were isolated from patients with HCC (n = 51) and cirrhosis (n = 10). Targeted, multiplex PCR ultra-deep sequencing was performed using a liver cancer-specific primer panel for genes <i>ALB, AMPH, APC, ARID1A, ARID2, ATM, AXIN1, BAZ2B, BRAF, CSMD3, CTNNB1, DSE, ERBB2, HNF1A, IGFR2, IGSF10, KEAP1, MET, TP53, UBR3, USP25, ZIC3</i> and <i>ZNF226</i>. Associations between mutations in ctDNA and overall survival were analysed using Cox proportional hazards modelling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>114 putative mutations (70 unique) in were detected in plasma ctDNA in 35 of 51 patients with HCC (69%). On univariable analysis, <i>CSMD3</i> gene mutations were associated with shorter overall survival (Logrank HR 3.18, 95% CI 1.14-8.86, <i>P</i> = .027). The median survival time was 15.5 months (IQR 7.77-16.5 months) in patients with <i>CSMD3</i> mutations compared with the median survival of 26.5 months (IQR 16.93-46.07 months) in patients without <i>CSMD3</i> mutations. Other factors associated with overall survival were advanced BCLC stage (HR 16.52, 95% CI 2.22-122.94, <i>P</i> = .006) and Child-Pugh Class (CPC HR 7.98, 95% CI 2.31-27.61, <i>P</i> = .001). Cox proportional hazards modelling showed mutations in <i>CSMD3</i> remained a significant independent risk for shorter overall survival in HCC when adjusted for age, BCLC stage and Child-Pugh class (HR 4.91, 95% CI 1.60-15.02, <i>P</i> = .005).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Detection of <i>CSMD3</i> mutations in plasma ctDNA is associated with reduced overall survival in HCC patients, adjusted for potential confounding factors.</p>\u0000 </section>\u0000 </div>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"2 2","pages":"54-62"},"PeriodicalIF":0.0,"publicationDate":"2021-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/lci2.34","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46629562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Focal nodular hyperplasia after systemic chemotherapy: Pathological features of a series of 15 cases 全身化疗后局灶性结节性增生15例的病理特征
Pub Date : 2021-08-04 DOI: 10.1002/lci2.32
Anaïs Brunet, Aurélie Beaufrère, François Cauchy, Valérie Paradis

Introduction

Chemotherapy, particularly oxaliplatin, has been associated with the development of focal nodular hyperplasia (FNH). Imaging diagnosis of FNH is well standardized, but it can be misdiagnosed as liver metastasis. The aim of this study was to describe the pathological features of FNH occurring after systemic chemotherapy.

Materials and methods

From our pathological files for 1990-2021, we retrieved 15 cases of resected newly developed FNH in adults with liver metastasis treated with systemic chemotherapy. Pathological features of FNH nodules and non-tumoral liver samples were reviewed.

Results

In 11/15 (73%) cases, FNH developed after an oxaliplatin-based regimen. The median interval from the beginning of chemotherapy to the FNH diagnosis was 15 months. FNH was unique in 11 (73%) cases, and the median size of nodules was 1.1 cm [range 0.5-2.5]. Histologically, 9 (60%), 11 (73%) and 11 (73%) cases exhibited fibrous central scar, dystrophic vessels and ductular proliferation, respectively, with all three criteria present in five (33%) cases. Eight (53%) cases showed intralesional steatosis and nine (60%) cases showed a glutamine synthetase immunostaining map-like pattern. In non-tumoral liver, eight (53%) cases exhibited sinusoidal obstruction syndrome and four (27%) nodular regenerative hyperplasia.

Conclusion

The occurrence of FNH after systemic chemotherapy is an emerging condition challenging the imaging diagnosis because typical morphological features are frequently missing. The presence of sinusoidal changes, including regenerative hyperplasia, in non-tumoral liver supports the potential role of chemotherapy in the pathogenesis of FNH.

化疗,特别是奥沙利铂,与局灶性结节性增生(FNH)的发展有关。FNH的影像学诊断是标准化的,但也可能被误诊为肝转移。本研究的目的是描述全身化疗后FNH的病理特征。
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引用次数: 1
Recalibrating survival prediction among patients receiving trans-arterial chemoembolization for hepatocellular carcinoma 肝细胞癌经动脉化疗栓塞患者的再校准生存预测
Pub Date : 2021-07-18 DOI: 10.1002/lci2.33
Alessandro Cucchetti, Edoardo G. Giannini, Cristina Mosconi, Maria Corina Plaz Torres, Giulia Pieri, Fabio Farinati, Gian Ludovico Rapaccini, Maria Di Marco, Eugenio Caturelli, Rodolfo Sacco, Giuseppe Cabibbo, Claudia Campani, Andrea Mega, Maria Guarino, Antonio Gasbarrini, Gianluca Svegliati-Baroni, Francesco Giuseppe Foschi, Gabriele Missale, Alberto Masotto, Gerardo Nardone, Giovanni Raimondo, Gianpaolo Vidili, Maurizia Rossana Brunetto, Vito Sansone, Marco Zoli, Francesco Azzaroli, Franco Trevisani, the ITA.LI.CA Study Group

Background & Aims

The Pre-TACE-Predict model was devised to assess prognosis of patients treated with trans-arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). However, before entering clinical practice, a model should demonstrate that it performs a useful role.

Methods

We performed an independent external validation of the Pre-TACE model in a cohort that differs in setting and time period from the one that generated the original model. Data from 826 patients treated with TACE for naïve HCC (2008-2018) were used to assess calibration and discrimination of the Pre-TACE-Predict model.

Results

The four risk-categories identified by the Pre-TACE-Predict model had gradient monotonicity, with median survivals of 52.0, 36.2, 29.9, and 14.1 months respectively. However, predicted survivals systematically underestimated observed survivals (R2: 0.667). A recalibration was adopted maintaining fixed the prognostic index and modifying the baseline survival function. This resulted in an almost perfect calibration (R2: 0.995) in all the four risk categories. Cox regressions showed that aetiology and macrovascular invasion, included in the Pre-TACE-Predict model, had no prognostic impact in the present study population, and that coefficients for tumour size and multiplicity were overestimated. The c-index was similar to that of the m-HAP-III, but higher than those of HAP, m-HAP-II and the six-and-twelve models.

Conclusions

The recalibration of Pre-TACE-Predict model improved the estimation of survival probabilities of HCC patients treated with TACE. The highest discriminatory ability of the Pre-TACE-model in comparison to other available models, together with risk stratification and recalibration, makes it the best prognostic tool currently available for these patients.

TACE前预测模型用于评估肝细胞癌(HCC)经动脉化疗栓塞(TACE)治疗患者的预后。然而,在进入临床实践之前,模型应该证明它发挥了有用的作用。
{"title":"Recalibrating survival prediction among patients receiving trans-arterial chemoembolization for hepatocellular carcinoma","authors":"Alessandro Cucchetti,&nbsp;Edoardo G. Giannini,&nbsp;Cristina Mosconi,&nbsp;Maria Corina Plaz Torres,&nbsp;Giulia Pieri,&nbsp;Fabio Farinati,&nbsp;Gian Ludovico Rapaccini,&nbsp;Maria Di Marco,&nbsp;Eugenio Caturelli,&nbsp;Rodolfo Sacco,&nbsp;Giuseppe Cabibbo,&nbsp;Claudia Campani,&nbsp;Andrea Mega,&nbsp;Maria Guarino,&nbsp;Antonio Gasbarrini,&nbsp;Gianluca Svegliati-Baroni,&nbsp;Francesco Giuseppe Foschi,&nbsp;Gabriele Missale,&nbsp;Alberto Masotto,&nbsp;Gerardo Nardone,&nbsp;Giovanni Raimondo,&nbsp;Gianpaolo Vidili,&nbsp;Maurizia Rossana Brunetto,&nbsp;Vito Sansone,&nbsp;Marco Zoli,&nbsp;Francesco Azzaroli,&nbsp;Franco Trevisani,&nbsp;the ITA.LI.CA Study Group","doi":"10.1002/lci2.33","DOIUrl":"10.1002/lci2.33","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background &amp; Aims</h3>\u0000 \u0000 <p>The Pre-TACE-Predict model was devised to assess prognosis of patients treated with trans-arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). However, before entering clinical practice, a model should demonstrate that it performs a useful role.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed an independent external validation of the Pre-TACE model in a cohort that differs in setting and time period from the one that generated the original model. Data from 826 patients treated with TACE for naïve HCC (2008-2018) were used to assess calibration and discrimination of the Pre-TACE-Predict model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The four risk-categories identified by the Pre-TACE-Predict model had gradient monotonicity, with median survivals of 52.0, 36.2, 29.9, and 14.1 months respectively. However, predicted survivals systematically underestimated observed survivals (<i>R</i><sup>2</sup>: 0.667). A recalibration was adopted maintaining fixed the prognostic index and modifying the baseline survival function. This resulted in an almost perfect calibration (<i>R</i><sup>2</sup>: 0.995) in all the four risk categories. Cox regressions showed that aetiology and macrovascular invasion, included in the Pre-TACE-Predict model, had no prognostic impact in the present study population, and that coefficients for tumour size and multiplicity were overestimated. The <i>c</i>-index was similar to that of the m-HAP-III, but higher than those of HAP, m-HAP-II and the six-and-twelve models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The recalibration of Pre-TACE-Predict model improved the estimation of survival probabilities of HCC patients treated with TACE. The highest discriminatory ability of the Pre-TACE-model in comparison to other available models, together with risk stratification and recalibration, makes it the best prognostic tool currently available for these patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"2 2","pages":"45-53"},"PeriodicalIF":0.0,"publicationDate":"2021-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/lci2.33","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45475488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 3
Salivary metabolites are promising non-invasive biomarkers of hepatocellular carcinoma and chronic liver disease 唾液代谢物是肝细胞癌和慢性肝病有前途的非侵入性生物标志物
Pub Date : 2021-05-20 DOI: 10.1002/lci2.25
Courtney E. Hershberger, Alejandro I. Rodarte, Shirin Siddiqi, Amika Moro, Lou-Anne Acevedo-Moreno, J. Mark Brown, Daniela S. Allende, Federico Aucejo, Daniel M. Rotroff

Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. Improved tools are needed for detecting HCC so that treatment can begin as early as possible. Current diagnostic approaches and existing biomarkers, such as alpha-fetoprotein (AFP) lack sensitivity, resulting in too many false negative diagnoses. Machine learning may be able to identify combinations of biomarkers that provide more robust predictions and improve sensitivity for detecting HCC. We sought to evaluate whether metabolites in patient saliva could distinguish those with HCC, cirrhosis, and those with no documented liver disease.

Methods and Results

We tested 125 salivary metabolites from 110 individuals (43 healthy, 37 HCC, 30 cirrhosis) and identified four metabolites that displayed significantly different abundance between groups (FDR P < .2). We also developed four tree-based, machine-learning models, optimized to include different numbers of metabolites, that were trained using cross-validation on 99 patients and validated on a withheld test set of 11 patients. A model using 12 metabolites –octadecanol, acetophenone, lauric acid, 1-monopalmitin, dodecanol, salicylaldehyde, glycyl-proline, 1-monostearin, creatinine, glutamine, serine and 4-hydroxybutyric acid – had a cross-validated sensitivity of 84.8%, specificity of 92.4% and correctly classified 90% of the HCC patients in the test cohort. This model outperformed previously reported sensitivities and specificities for AFP (20-100 ng/mL) (61%, 86%) and AFP plus ultrasound (62%, 88%).

Conclusions and Impact

Metabolites detectable in saliva may represent products of disease pathology or a breakdown in liver function. Notably, combinations of salivary metabolites derived from machine learning may serve as promising non-invasive biomarkers for the detection of HCC.

肝细胞癌(HCC)是世界范围内癌症死亡的主要原因。需要改进检测HCC的工具,以便尽早开始治疗。目前的诊断方法和现有的生物标志物,如甲胎蛋白(AFP)缺乏敏感性,导致太多的假阴性诊断。机器学习可能能够识别生物标志物的组合,从而提供更可靠的预测并提高检测HCC的灵敏度。我们试图评估患者唾液中的代谢物是否可以区分HCC、肝硬化和无肝脏疾病的患者。方法和结果我们检测了110个人(43人健康,37人HCC, 30人肝硬化)的125种唾液代谢物,并确定了4种代谢物在组间表现出显著不同的丰度(FDR P <2)。我们还开发了四个基于树的机器学习模型,对其进行了优化,以包含不同数量的代谢物,并对99名患者进行了交叉验证,并在11名患者的保留测试集上进行了验证。使用十二种代谢物(十八醇、苯乙酮、月桂酸、1-单棕榈醇、十二醇、水杨醛、甘酰脯氨酸、1-单硬脂酸、肌酐、谷氨酰胺、丝氨酸和4-羟基丁酸)建立的模型,交叉验证的敏感性为84.8%,特异性为92.4%,对试验队列中90%的HCC患者进行了正确分类。该模型优于先前报道的AFP (20-100 ng/mL)(61%, 86%)和AFP +超声(62%,88%)的敏感性和特异性。结论和影响:唾液中检测到的代谢物可能是疾病病理或肝功能衰竭的产物。值得注意的是,来自机器学习的唾液代谢物组合可能作为检测HCC的有前途的非侵入性生物标志物。
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引用次数: 13
期刊
Liver cancer international
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