Liver cancer international最新文献

{"title":"Safety of sitagliptin in treatment of hepatocellular carcinoma in chronic liver disease patients","authors":"Clémence Hollande,&nbsp;Jeremy Boussier,&nbsp;Estelle Mottez,&nbsp;Vincent Bondet,&nbsp;Tan Phuc Buivan,&nbsp;Bruno Charbit,&nbsp;Alba Llibre,&nbsp;Frédéric Charlotte,&nbsp;Eric Savier,&nbsp;Olivier Scatton,&nbsp;Darragh Duffy,&nbsp;Matthew Albert,&nbsp;Vincent Mallet,&nbsp;Stanislas Pol","doi":"10.1002/lci2.36","DOIUrl":"10.1002/lci2.36","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <h3> Background &amp; Aims</h3> \u0000 <p>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.</p> </section>\u0000 \u0000 <section>\u0000 <h3> Methods</h3> \u0000 <p>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.</p> </section>\u0000 \u0000 <section>\u0000 <h3> Results</h3> \u0000 <p>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.</p> </section>\u0000 \u0000 <section>\u0000 <h3> Conclusion</h3> \u0000 <p>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.</p> </section>\u0000 </div>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"2 3","pages":"73-81"},"PeriodicalIF":0.0,"publicationDate":"2021-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/lci2.36","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43110344","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}

{"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>¹</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>^{2, 3}</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>⁴</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>³</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>²</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}

{"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}

{"title":"Focal nodular hyperplasia after systemic chemotherapy: Pathological features of a series of 15 cases","authors":"Anaïs Brunet,&nbsp;Aurélie Beaufrère,&nbsp;François Cauchy,&nbsp;Valérie Paradis","doi":"10.1002/lci2.32","DOIUrl":"10.1002/lci2.32","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"2 3","pages":"67-72"},"PeriodicalIF":0.0,"publicationDate":"2021-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/lci2.32","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44290027","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}

{"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>²: 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>²: 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}

{"title":"Salivary metabolites are promising non-invasive biomarkers of hepatocellular carcinoma and chronic liver disease","authors":"Courtney E. Hershberger,&nbsp;Alejandro I. Rodarte,&nbsp;Shirin Siddiqi,&nbsp;Amika Moro,&nbsp;Lou-Anne Acevedo-Moreno,&nbsp;J. Mark Brown,&nbsp;Daniela S. Allende,&nbsp;Federico Aucejo,&nbsp;Daniel M. Rotroff","doi":"10.1002/lci2.25","DOIUrl":"10.1002/lci2.25","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>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 <i>P</i> &lt; .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%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Impact</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"2 2","pages":"33-44"},"PeriodicalIF":0.0,"publicationDate":"2021-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/lci2.25","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39433907","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}

{"title":"Prognostic significance of hypoxic and metabolic gene profiling in hepatocellular carcinoma","authors":"Fabiola Milosa,&nbsp;Rosina Maria Critelli,&nbsp;Simone Lasagni,&nbsp;Alessandra Pivetti,&nbsp;Lorenza Di Marco,&nbsp;Dante Romagnoli,&nbsp;Lucia Carulli,&nbsp;Francesco Dituri,&nbsp;Serena Mancarella,&nbsp;Gianluigi Giannelli,&nbsp;Maria-Luz Martinez-Chantar,&nbsp;Luca Fabris,&nbsp;Erica Villa","doi":"10.1002/lci2.23","DOIUrl":"10.1002/lci2.23","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background &amp; Aims</h3>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is characterized by high clinical and biological heterogeneity, depending on the extremely variable combinations of pathways, linked with immune mechanisms, neo-angiogenesis, ECM remodeling, metabolism and/or hypoxia. We recently identified a 5-genes neo-angiogenic transcriptomic signature (TS), able to discriminate between “aggressive” HCCs (TS-positive) from “bland” HCCs (TS negative), the former having extremely poor survival. The aim of this study was to compare gene expression of our HCC cohort with gene expression of well-characterized, published signatures, which have been related with several different functions potentially relevant in carcinogenesis (ie immune control, hypoxia, metabolism, vascular invasion). We also aimed to ascertain the prognostic power for survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The gene expression profile of a cohort of 78 HCC patients prospectively identified were analysed according to a series of published gene expression signatures related with hypoxia, metabolism and immunity and related with the ability of the signature to predict survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Only few genes described in the various immune-signatures analyzed were differentially expressed and were related with reduced survival in our prospective cohort, especially in TS-positive HCCs. Genes composing hypoxic, metabolic and vascular invasion signatures were instead much more deregulated both in aggressive or bland HCCs. For most of them, the level of expression related with reduced survival. This suggests their possible value as biomarker of tumor aggressiveness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Altogether, our data demonstrate that in HCC, and especially in aggressive TS-positive HCC, signaling pathways related with hypoxic and metabolic/glycolytic signatures are more relevant in determining a poorer outcome of HCC than immune-related pathways.</p>\u0000 </section>\u0000 </div>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"2 1","pages":"15-26"},"PeriodicalIF":0.0,"publicationDate":"2021-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/lci2.23","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46390923","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}

{"title":"Back to the basics: How the preclinical rationale shapes the immunotherapy landscape for hepatocellular carcinoma","authors":"Antonio D’Alessio,&nbsp;Lorenza Rimassa","doi":"10.1002/lci2.24","DOIUrl":"10.1002/lci2.24","url":null,"abstract":"<p>Few types of cancers have witnessed such a dramatic change of the treatment paradigm in the last year as hepatocellular carcinoma (HCC). 2020 has been a milestone year, establishing atezolizumab plus bevacizumab as the new standard of care for first-line treatment of unresectable HCC, based on the results of the phase III IMbrave150 trial.<span>^{1, 2}</span> The success of the combination of an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) and an antiangiogenic agent is the result of a strong preclinical rationale, which has been widely studied in HCC, paving the way for its widespread clinical application. The positive results of the IMbrave150 study are just the tip of the iceberg, with several immunotherapy combinations currently under investigation in phase I-III studies. Immune checkpoint inhibitors (ICIs) used as monotherapy have led to disappointing results in HCC, both in first line, with nivolumab failing to demonstrate any survival advantage over sorafenib in the CheckMate 459 trial,<span>³</span> and in second line, with pembrolizumab not confirming the promising results of the previous phase II trial in the KEYNOTE-240 trial.<span>⁴</span> For this reason, combining ICIs with other drug classes could overcome innate tumour resistance and eventually increase the number of patients benefitting from immunotherapy. The novel treatment strategies under the spotlight include PD-1/PD-L1 mAbs plus antivascular endothelial growth factor (VEGF) mAb, PD-1/PD-L1 mAbs plus multikinase inhibitors (MKIs) and ICI combinations (PD-1/PD-L1 mAbs plus cytotoxic T lymphocyte antigen [CTLA]-4 mAbs). In preclinical studies, these combinations have shown to enhance the efficacy of the single agents, thus suggesting a potential synergistic effect.</p><p>The use of anti-VEGF agents rests on the principle that HCC is a richly vascularized cancer, and several proangiogenic factors play a central role in tumour growth and distant spread. In addition, preclinical research unravelled a whole world of immunomodulatory effects of the VEGF pathway, thus suggesting the possible use of bevacizumab in combination with immunotherapy. Indeed, VEGF receptors and the downstream effectors induce an immunosuppressive microenvironment by acting on innate and adaptive immune response. VEGF pathway can enhance the action of immature dendritic cells, myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages, while at the same time increasing the percentage and the action of regulatory T cells (T-regs) in the tumour microenvironment.<span>⁵</span> In preclinical models, the use of bevacizumab has shown to revert these VEGF-induced immunosuppressive mechanisms, and, when bevacizumab is combined with an ICI, antitumor immune response induced by PD-1 blockade seems to be enhanced, even in ICI-resistant HCC models, thanks to an immunostimulatory T cell reprogramming.<span>⁶</span> Based on a sim","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"2 1","pages":"5-6"},"PeriodicalIF":0.0,"publicationDate":"2021-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/lci2.24","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49490296","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}

{"title":"T-cell mediated responses against alpha-foetoprotein in hepatocellular carcinoma: Relationship with hepatitis C virus infection, tumour phenotype and patients’ survival","authors":"David J. Pinato,&nbsp;Petros Fessas,&nbsp;Antonello Gibbin,&nbsp;Giuseppa Occhino,&nbsp;Elisa Boccato,&nbsp;Carlo Smirne,&nbsp;Rosalba Minisini,&nbsp;Mario Pirisi","doi":"10.1002/lci2.22","DOIUrl":"10.1002/lci2.22","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alpha-foetoprotein (AFP) is a potential immunotherapeutic target in hepatocellular carcinoma (HCC). However, T-cell response (TR) to AFP is suppressed in HCC due to immune evasion. It is unknown whether HCV infection may pre-condition TR against AFP, or whether TR may influence the clinical course of HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We prospectively enrolled 18 HCV+ treatment-naïve patients with cirrhosis (CC), 18 HCV+ HCC cases and 17 HCV- HCC cases. TR was quantified by ELISPOT using assays specific to interleukin (IL) 2, IL10 and granulocyte-monocyte colony stimulating factor (GM-CSF) on ex-vivo peripheral blood mononuclear cells (PBMC) stimulated in vitro with AFP peptides. Cytokine ratios were compared between groups and with clinicopathological features of HCC, including overall survival (OS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The proportion of AFP-specific responses was not different across the studied groups for any of the assayed cytokines. AFP-specific IL-2 responses were increased in larger (<i>P</i> = .02), multifocal tumours (<i>P</i> = .01) and correlated with advanced disease (<i>P</i> = .01). TRs did not correlate with other clinicopathological factors and did not predict for OS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Tumour stage but not HCV infection is related to the emergence of anti-AFP TRs. These data enable formulation of a rationale for the further development of anti-AFP immunotherapy in HCC, facilitating optimal patient selection for future studies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"2 1","pages":"7-14"},"PeriodicalIF":0.0,"publicationDate":"2021-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/lci2.22","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47444442","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}

{"title":"Role of epigenetic alterations in aflatoxin-induced hepatocellular carcinoma","authors":"Sathish Kumar Mungamuri,&nbsp;Vijay Aditya Mavuduru","doi":"10.1002/lci2.20","DOIUrl":"10.1002/lci2.20","url":null,"abstract":"<p>Aflatoxins are produced by <i>Aspergillus flavus and Aspergillus parasiticus</i> and are toxic carcinogens. These ‘fungal molds’ grow on corn, groundnuts, cereals and other grains. Of all the aflatoxins, Aflatoxin-B1 (AFB1) is considered the most toxic. Long-term exposure of AFB1 forms DNA adducts causing many genetic mutations and epigenetic alterations, ultimately leading to hepatocellular carcinoma (HCC). The liver is the major site of Aflatoxin detoxification; wherein cytochrome P-450 (CYP450) enzymes process the AFB1 into its epoxide AFB1-Exo-8,9-Epoxy (ABFO) and other less toxic metabolites. ABFO, in turn, reacts with DNA, RNA and protein molecules forming AFB adducts. The AFB1-DNA adducts in turn will induce various mutations, mainly mediated by G→T transversions. Aflatoxins are also known to cause HCC cell proliferation, growth, and invasion as well as angiogenesis by various epigenetic mechanisms including DNA methylation, histone post-translational modifications and non-coding RNA deregulation, etc. In this review, we will be emphasizing on epigenetic mechanisms by which aflatoxins induce hepatocarcinogenesis. In the last section, we will also discuss various methodologies to control aflatoxin contamination and detoxification of aflatoxin adducts using natural substances that are potentially anti-aflatoxins.</p>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"1 2","pages":"41-50"},"PeriodicalIF":0.0,"publicationDate":"2020-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/lci2.20","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43580404","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}