Extrahepatic Cancer Research Articles

S1012 Outcomes of Liver Transplantation in Patients With Pre-Existing Extra-Hepatic Malignancies: A Systematic Review

INTRODUCTION: Liver transplantation (LT) is rarely carried out in patients with pre-existing extra-hepatic cancers, and little is known about patient survival and cancer recurrence in patients with a history of extra-hepatic cancer who undergo LT. METHODS: A systematic review of Medline and Embase was conducted from inception-March 2020 to identify studies reporting outcomes in patients with pre-existing extra-hepatic malignancies who underwent LT. Case reports and series were included in the systemic review due to the expected scarcity of data. Descriptive statistics were employed to report findings; results were reported as proportions. RESULTS: Overall, 112 cases were identified, 61 of which were extracted from 4 case series. Females constituted 50% of the cohort. The prevalence of solid tumors and hematological malignancies was 52.6% and 47.3%, respectively. The most commonly reported solid tumor and hematological malignancy was colorectal cancer (18.6%) and Hodgkin’s Lymphoma (24.5%), respectively. The most common indication for LT was HBV/HCV associated liver disease (22.3%), followed by sclerosing cholangitis (16.1%), and Budd-Chiari syndrome (15.2%). When stratified according to cancer type, HBV/HCV associated liver disease and Budd-Chiari syndrome were the most common indications for LT among patients with solid tumors and hematological malignancies, respectively. Additionally, 6 (5.4%) patients with hematological malignancies underwent LT due to acute liver failure (ALF) from HBV reactivation. The mean time from malignancy diagnosis to LT was 12.61 months (SD 14.74). T-cell antibody induction regimens were used in only two cases. The most used immunosuppressants were corticosteroids (36.6%), followed by cyclosporine (32.1%). Acute graft rejection was reported in 50 (44.6%) of patients. Nine (8%) patients experienced recurrent or progressive malignancy (4 solid tumors, 5 hematological malignancies/MPD). 86.6% of patients were alive over a mean follow-up period of 39 months. CONCLUSION: Liver transplantation can be offered in select patients with a history of extrahepatic malignancies and has an acceptable survival at three years. This literature review suggests a higher rate of rejection in these patients, which is likely reflective of a lower degree of immunosuppression.Table 1

Impact of hepatitis C virus treatment on the risk of non-hepatic cancers among hepatitis C virus-infected patients in the US.

Hepatitis C virus (HCV) infection is associated with with an increased risk of non-hepatic cancers, but the impact of HCV treatment on non-hepatic cancer is unclear. To assess if HCV treatment reduced the incidence of non-hepatic cancers among patients with chronic HCV infection in the US. We conducted a retrospective cohort study in MarketScan Databases from January 2005 to December 2016. Multivariable, time-varying Cox proportional-hazards models were used to determine hazard ratios (HRs) of incident non-hepatic cancers in treated and untreated patients with HCV infection. We conduscted subgroup analyses for sex, age, and presence of cirrhosis or diabetes. Among 62078 patients with newly diagnosed HCV infection, 17302 (28%) initiated HCV treatment, among whom 15322 completed 8-16weeks treatment (minimally effective treatment). Patients who initiated HCV treatment had an 11% decreased risk of developing an incident non-hepatic cancer compared to untreated patients (HR=0.89, 95% confidence interval (Cl) = 0.82-0.96). The reduction was slightly higher when patients completed a minimally effective treatment (HR=0.87; 95% Cl=0.80 - 0.95). This was observed in most subgroup analyses for those who had a minimally effective treatment including patients with cirrhosis. When we stratified cancer or therapy subtypes, the association remained consistent for pancreatic and lung cancers, and dual HCV therapy. HCV treatment led to a significantly reduced incidence of non-hepatic cancers among patients with HCV infection. Despite discrepancies between cancer or HCV therapy subtypes, our findings suggest that treating HCV infection can decrease the extrahepatic cancer burden associated with chronic HCV infection.

History of Nonalcoholic Fatty Liver Disease.

Based on the assumption that characterizing the history of a disease will help in improving practice while offering a clue to research, this article aims at reviewing the history of nonalcoholic fatty liver disease (NAFLD) in adults and children. To this end, we address the history of NAFLD histopathology, which begins in 1980 with Ludwig’s seminal studies, although previous studies date back to the 19th century. Moreover, the principal milestones in the definition of genetic NAFLD are summarized. Next, a specific account is given of the evolution, over time, of our understanding of the association of NAFLD with metabolic syndrome, spanning from the outdated concept of “NAFLD as a manifestation of the Metabolic Syndrome”, to the more appropriate consideration that NAFLD has, with metabolic syndrome, a mutual and bi-directional relationship. In addition, we also report on the evolution from first intuitions to more recent studies, supporting NAFLD as an independent risk factor for cardiovascular disease. This association probably has deep roots, going back to ancient Middle Eastern cultures, wherein the liver had a significance similar to that which the heart holds in contemporary society. Conversely, the notions that NAFLD is a forerunner of hepatocellular carcinoma and extra-hepatic cancers is definitely more modern. Interestingly, guidelines issued by hepatological societies have lagged behind the identification of NAFLD by decades. A comparative analysis of these documents defines both shared attitudes (e.g., ultrasonography and lifestyle changes as the first approaches) and diverging key points (e.g., the threshold of alcohol consumption, screening methods, optimal non-invasive assessment of liver fibrosis and drug treatment options). Finally, the principal historical steps in the general, cellular and molecular pathogenesis of NAFLD are reviewed. We conclude that an in-depth understanding of the history of the disease permits us to better comprehend the disease itself, as well as to anticipate the lines of development of future NAFLD research.

Abstract 4746: Genomic alterations and clinical correlations of Chinese hepatoid adenocarcinoma patients

Abstract Background: In recent years, hepatoid adenocarcinoma (HAC), a rare tumor subtype, has attracted more and more attention because of its malignant nature, especially its poor prognosis due to frequent liver metastasis. HAC, recognized as an extrahepatic cancer that resembles hepatocellular carcinoma (HCC), is characterized by the solid sheet-like growth structures of hepatoid differentiation and excessive production of alpha-fetoprotein (AFP). Hepatoid adenocarcinoma of the stomach (HAS) is the most common site of HAC, however, the differences between HAS and HAC of other organs are unknown. Methods: Our Chinese HAC cohort consisted of 31 samples (25 HAS patients and 6 HAC of other organs patients) that were collected in the form of formalin-fixed, paraffin-embedded (FFPE) tumor tissues at Zhongshan Hospital from July 2013 to August 2017 for whole exome sequencing (WES) (OrigiMed, Shanghai). Results: A total of 31 patients with HAC had surgical treatment, 25 patients with HAS (median age 66.5 years, range 48-82) and 6 patients with HAC of other organs (median age 62.5 years, range 52-67). Most HAS patients were male (18/25, 72%), and most HAC of other organs patients were female (4/6, 66.7%). Survival analysis revealed that compared with patients with HAS, patients with HAC of other organs had a significantly poorer overall survival (OS) (p=0.0081) and disease-free survival (DFS) (p=0.0011). The most frequently mutated genes in the HAS tumor samples were TP53 (42%), MUC19 (35%), and TTN (35%). The substitution mutations of CDK4, KRT34 and GOLGA6L3 were only found in HAC from other organs samples but not from HAS samples. Copy number variations (CNVs) of CCNE1, VSTM2B, PLEKHF1 and POP4 were only identified in HAS samples. Interestingly, these 4 genes were located at chr19 and were co-mutated in 5 patients who had a significantly poorer OS than those without these CNVs (11.1 months vs. 19.3 months, respectively, p=0.045). The tumor mutational burden (TMB) of HAS was significantly higher compared with HAC of other organs was also significantly different (4 muts/Mb vs. 1.2 muts/Mb, respectively, p=0.012). Conclusions: Our study revealed the genomic profiling of Chinese HAC patients. Compared to patients with HAS, patients with HAC of other organs had a significantly poorer OS and DFS. The origin for HAC was associated with specific gene mutations and the TMB value. Patients with CNVs in chr19 were significantly associated with a poorer OS. Citation Format: Tianshu Liu, Erbao Chen, Chen Xu, Wei Li, Mengling Liu, Yichou Wei, Yiyi Yu, Yuehong Cui, Qian Li, Shuirong Zhang, Lujia Huang, Yueting Qu. Genomic alterations and clinical correlations of Chinese hepatoid adenocarcinoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4746.

Higher Levels of Fibrosis in a Cohort of Veterans with Chronic Viral Hepatitis are Associated with Extrahepatic Cancers

An estimated 2.4 million Americans, including more than 150,000 veterans, are chronically infected with hepatitis C virus (HCV). HCV is estimated to cause roughly 25% of all hepatocellular carcinoma. Although its mechanism is unknown, developing evidence suggests that chronic HCV infection is also associated with the development of extrahepatic cancers (EHCs). This paper aims to assess the relationship of hepatic fibrosis and chronic HCV with the risk of developing EHC. We conducted a single-center retrospective chart review of 1541 patients linked to the hepatitis clinic at the Veterans Affairs (VA) Maryland Health Care System who underwent transient elastography for evaluation and management of liver disease from 2014 to 2018. Liver fibrosis was measured using ultrasound and transient elastography. Extrahepatic cancer and site was identified by a retrospective chart review. In adjusted analysis of EHCs, advanced age (OR: 1.97, 95% CI: 1.30-3.04), and higher measured stiffness (OR 2.19, 95% CI: 1.32-3.64) were associated with an increased likelihood of developing EHC, controlling for HBV infection, HCV exposure, heavy alcohol use, and body mass index. We observed a significant association between increasing age and increasing levels of liver fibrosis with increased risk of EHC, notably prostate, head and neck squamous cell, lung, and hematologic cancers.

Synthesis of natural 3'-Prenylchalconaringenin and biological evaluation of ameliorating non-alcoholic fatty liver disease and metabolic syndrome.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and important risk factor for cardiac diseases, diabetes and extrahepatic cancers. Natural 3'-geranylchalconaringenin (GC) and desmethylxanthohumol (DX) from hop were synthesized using a regio-selective iodination and the Suzuki coupling reaction as key steps. GC and DX, along with their aglycone naringenin chalcone (NC) were investigated their decreasing the accumulation of cellular lipids. GC reduced lipid content and activated the AMP-activated protein kinase (AMPK) pathway in HepG2 and 3T3-L1 cells. In addition, GC had an obvious therapeutic effect on alleviating NAFLD and metabolic syndrome by activating the AMPK pathway invivo. In conclusion, GC may be potentially used as a candidate drug and functional food for treating NAFLD and metabolic syndrome.

Delivery of Tissue-Targeted Scalpels: Opportunities and Challenges for In Vivo CRISPR/Cas-Based Genome Editing.

CRISPR/Cas9-based genome editing has quickly emerged as a powerful breakthrough technology for use in diverse settings across biomedical research and therapeutic development. Recent efforts toward understanding gene modification methods in vitro have led to substantial improvements in ex vivo genome editing efficiency. Because disease targets for genomic correction are often localized in specific organs, realization of the full potential of genomic medicines will require delivery of CRISPR/Cas9 systems targeting specific tissues and cells directly in vivo. In this Perspective, we focus on progress toward in vivo delivery of CRISPR/Cas components. Viral and nonviral delivery systems are both promising for gene editing in diverse tissues via local injection and systemic injection. We describe the various viral vectors and synthetic nonviral materials used for in vivo gene editing and applications to research and therapeutic models, and summarize opportunities and progress to date for both methods. We also discuss challenges for viral delivery, including overcoming limited packaging capacity, immunogenicity associated with multiple dosing, and the potential for off-target effects, and nonviral delivery, including efforts to increase efficacy and to expand utility of nonviral carriers for use in extrahepatic tissues and cancer. Looking ahead, additional advances in the safety and efficiency of viral and nonviral delivery systems for tissue- and cell-type-specific gene editing will be required to enable broad clinical translation. We provide a summary of current delivery systems used for in vivo genome editing, organized with respect to route of administration, and highlight immediate opportunities for biomedical research and applications. Furthermore, we discuss current challenges for in vivo delivery of CRISPR/Cas9 systems to guide the development of future therapies.

Chronic Hepatitis C Virus Infection is Associated with an Increased Risk of Lung Cancer: A Systematic Review and Meta-analysis.

Chronic hepatitis C virus (HCV) infection is associated with increased risk of hepatocellular carcinoma. However, whether HCV infection also increases the risk of extra-hepatic cancer is still not well-established. This systematic review and meta-analysis was conducted in order to investigate the relationship between chronic HCV infection and lung cancer. A systematic review was performed using MEDLINE and EMBASE databases from inception to November 2019 with search strategy that included the terms for "hepatitis C virus" and "cancer". Eligible studies must be cohort studies that included patients with chronic HCV infection and comparators without HCV infection, then followed them for incident lung cancer. Relative risk, incidence rate ratio, standardized incidence ratio or hazard risk ratio of this association along with associated 95% confidence interval (CI) were extracted from each eligible study and combined for the calculation of the pooled effect estimate using the random effect, generic inverse variance method. A total of 20,459 articles were identified using the aforementioned search strategy. After two rounds of review, eight studies fulfilled the inclusion criteria and were included into the meta-analysis. Chronic HCV infection was significantly associated with an increased risk of lung cancer with the pooled relative risk of 1.94 (95% CI 1.56-2.42; I2 = 87%). Funnel plot was fairly symmetric and not suggestive of presence of publication bias. The current study demonstrated that chronic HCV infection is significantly associated with a 1.94-fold increased risk of developing lung cancer. However, further studies are still needed to investigate if this association is causative.

Intraluminal Brachytherapy in Unresectable Extrahepatic Biliary Duct Cancer: An Italian Pooled Analysis.

To evaluate the outcome of patients with unresectable extrahepatic cholangiocarcinoma (CC) treated with external-beam radiotherapy (EBRT) and concurrent chemotherapy (CT) with or without intraluminal brachytherapy (ILBT) boost or with definitive ILBT. A pooled analysis of patients with non-metastatic unresectable CC was performed. They were treated in three different institution with EBRT plus CT with or without an ILBT boost. Some patients received only ILBT with curative dose. Seventy-three patients were included in the analysis. Thirty-nine patients (53%) received EBRT treatment with ILBT boost (18 patients with CT during EBRT), while 28 patients (38%) were treated with EBRT (CT in 26 patients) and 6 patients (8.2%) with definitive ILBT (2 patients with CT). CT was administered including either the use of gemcitabine or 5-fluorouracil. With a median follow-up of 16 month (range=1-94 months), median overall survival (OS) was 16 months. Overall median LC was 16 months and patients who underwent ILBT had a better local control (LC) (p=0.018). The role of ILBT in unresectable CC is not yet supported by robust evidence in the literature. However, within this limit, preliminary results seem to suggest an improved local control in patients treated with ILBT, almost comparable to the ones of standard chemo-radiotherapy (CRT).

Association between nonalcoholic fatty liver disease and extrahepatic cancers: a systematic review and meta-analysis

BackgroundNAFLD is tightly associated with various diseases such as diabetes, cardiovascular disease, kidney disease, and cancer. Previous studies had investigated the association between NAFLD and various extrahepatic cancers, but the available data to date is not conclusive. The aim of this study was to investigate the association between NAFLD and various extrahepatic cancers comprehensively.MethodsSearches were conducted of various electronic databases (PubMed, EMBASE, Medline, and the Cochrane Library) to identify observational studies published between 1996 and January 2020 which investigated the association between NAFLD and extrahepatic cancers. The pooled OR/HR/IRR of the association between NAFLD and various extrahepatic cancers were analyzed.ResultsA total of 26 studies were included to investigate the association between NAFLD and various extrahepatic cancers. As the results shown, the pooled OR values of the risk of colorectal cancer and adenomas in patients with NAFLD were 1.72 (95%CI: 1.40–2.11) and 1.37 (95%CI: 1.29–1.46), respectively. The pooled OR values of the risk of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma in patients with NAFLD were 2.46 (95%CI: 1.77–3.44) and 2.24 (95%CI: 1.58–3.17), respectively. The pooled OR value of the risk of breast cancer in patients with NAFLD was 1.69 (95%CI: 1.44–1.99). In addition, NAFLD was also tightly associatied with the risk of gastric cancer, pancreatic cancer, prostate cancer, and esophageal cancer.ConclusionsNAFLD could significantly increase the development risk of colorectal adenomas and cancer, intrahepatic and extrahepatic cholangiocarcinoma, breast, gastric, pancreatic, prostate, and esophageal cancer. NAFLD could be considered as one of the influencing factors during the clinical diagnosis and treatment for the extrahepatic cancers.

The Association Between Nonalcoholic Fatty Liver Disease and Risk of Cardiovascular Disease, Stroke, and Extrahepatic Cancers

Although primarily a disease with liver-specific complications, nonalcoholic fatty liver disease (NAFLD) is a systemic disease with extrahepatic complications. We aim to evaluate the association between NAFLD and cardiovascular disease (CVD), stroke and cerebrovascular disease, and extrahepatic cancers. We searched MEDLINE, EMBASE, and Cochrane Systematic Review Database from January 1, 2000 to July 1, 2019 to identify peer-reviewed English language literature using predefined keywords for NAFLD, CVD, stroke and cerebrovascular disease, and extrahepatic cancers among adults. Two reviewers independently selected studies for inclusion. Measures of association between NAFLD and CVD, stroke and cerebrovascular disease, and extrahepatic cancers were extracted. Quality assessed using Newcastle-Ottawa scale and Grading of Recommendations Assessment, Development and Evaluation (GRADE). Thirty studies were included evaluating CVD, 16 studies evaluating stroke or cerebrovascular disease, and 13 studies evaluating extrahepatic cancers. On pooled meta-analysis assessment, NAFLD was associated with increased risk of CVD (risk ratio [RR]: 1.78; 95% confidence interval [CI]: 1.52-2.08) and stroke or cerebrovascular disease (RR: 2.08, 95% CI: 1.72-2.51). Significant heterogeneity in assessing extrahepatic cancers prevented applying meta-analysis methods, but NAFLD seemed to be associated with increased risk of breast and colorectal cancers. Overall level of quality of studies were very low by GRADE. NAFLD is associated with increased risks of CVD and stroke or cerebrovascular disease among adults. There appears to be increased risk of breast and colorectal cancers. Given low quality of evidence, it is premature to make any strong conclusions to modify CVD, stroke, or cancer screening policies in patients with NAFLD.

Genomic alterations and clinical correlations of Chinese patients with hepatoid adenocarcinoma of the stomach/alpha-fetoprotein gastric cancer.

e13514 Background: Hepatoid adenocarcinoma of stomach (HAS) is a rare subtype of gastric cancer (GC) with poor prognosis due to frequent liver metastasis. HAS, recognized as an extrahepatic cancer that resembles hepatocellular carcinoma (HCC), is characterized by solid sheet-like growth structures with hepatoid differentiation and excessive production of alpha-fetoprotein (AFP). This HAS subtype of GC (AFPGC) is genetically distinct compared to other common GC but requires more evidences for better characterization. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were collected from 25 HAS and 9 AFPGC patients at Zhongshan Hospital from July 2013 to August 2017 for whole exome sequencing (WES) test. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: Our cohort included 25 males and 9 females who had undergone surgical treatment. The 25 HAS patients had a median age of 66.5 years (range 48-82) and the 9 AFPGC patients had a median age of 64 years (range 52-76). Patients with AFP>20 had a significantly better overall survival (OS) compared with patients with AFP≤20. The most frequently mutated genes were TP53 (44%), TTN (44%), and MUC19 (30%) in HAS tumor samples and CDC27 (44%), NKX2-3 (44%), and TTN (44%) in AFPGC samples. Patients with URI1 or POP4 alterations had a significantly poorer OS than patients without those genes mutations (7.6 months vs. 19.8 months, p = 0.016, and 10.9 months vs. 19.7 months, p = 0.038, respectively). However, patients with SPTA1 alterations had a significantly better OS compared to patients without SPTA1 alterations (27.6 months vs. 15.8 months, p = 0.042). Patients with higher tumor mutational burden (TMB) (≥3.9 muts/Mb) had a significantly better OS compared with patients with lower TMB (<3.9 muts/Mb), which indicated TMB may be an independent prognostic factor (HR: 0.032, 95%CI: 0.003-0.33, p = 0.004). Conclusions: Our study revealed the genomic profile of HAS/AFPGC patients. The most frequently mutated genes in HAS and AFPGC were different, which helps to better characterize these tumors. AFP and TMB may be potential biomarkers for predicting patients’ prognosis.

Association of chronic hepatitis C virus infection with an increased risk of lung cancer: A systematic review and meta-analysis.

e13562 Background: Chronic hepatitis C virus (HCV) infection is associated with increased risk of multiple types of extrahepatic cancer, such as lymphomas, thyroid cancer and renal cancer. However, whether HCV infection also increases the risk of lung cancer is still inconclusive. This systematic review and meta-analysis was performed in order to determine the relationship between chronic HCV infection and lung cancer. Methods: A systematic review was performed using EMBASE and MEDLINE databases from inception to November 2019 with search strategy that represents “hepatitis C virus” and “cancer”. Eligible studies must be cohort studies which include patients with chronic HCV infection and comparators without HCV infection, then follow them for incident lung cancer. Relative risk, incidence rate ratio (IRR), standardized incidence ratio, or hazard risk ratio of this association along with associated 95% confidence interval (CI) from each study were extracted and combined for the calculation of the pooled effect estimate using the random effect, generic inverse variance. Results: 20,459 articles were discovered using the aforementioned search strategy. After two rounds of review, eight studies fulfilled the inclusion criteria and were included into the meta-analysis. Chronic HCV infection was significantly associated with increased risk of lung cancer with the pooled relative risk of 1.94 (95% CI, 1.56 – 2.42; I2 = 87%). Funnel plot was fairly symmetric and not suggestive of presence of publication bias. Conclusions: Chronic HCV infection is significantly associated with a 1.94-fold increased risk in the development of lung cancer compared to no infection.

Incidence of extrahepatic cancers among individuals with chronic hepatitis B or C virus infection: A nationwide cohort study.

This study examined the association between chronic HBV or HCV infection and the risk of extrahepatic cancers. A total of 537103 adults aged ≥20years without history of cancer were identified from the Korean National Health Insurance Service-National Sample Cohort between 2003 and 2013. The difference in cancer incidence was compared between those with and without chronic HBV or HCV infection. During 3854130 person-years of follow-up (median follow-up: 8.0years), 19089 participants developed cancer. After adjusting for sex, body mass index, smoking, drinking, income percentile, residential area and comorbidities, hazard ratios (HRs) for incident extrahepatic cancer were significantly higher in participants with chronic HBV infection (HR: 1.27, 95% confidence interval [CI]: 1.20-1.35), HCV infection (HR: 1.31, 95% CI: 1.16-1.48) or HBV/HCV dual infection (HR: 1.41, 95% CI: 1.31-1.72) compared to participants without HBV or HCV infection. In chronic HBV infection, the cancer risk was higher for haematologic malignancy [HR (95% CI)=2.46 (1.92-3.15)], gallbladder [1.55 (1.05-2.29)], pancreas [1.52 (1.07-2.15)], stomach [1.39 (1.22-1.58)], lung [1.27 (1.04-1.55)], colorectum [1.21 (1.03-1.42)] and thyroid cancer [1.20 (1.05-1.36)]. In chronic HCV infection, the cancer risk was higher for testis [10.34 (1.35-79.78)], gallbladder [2.90 (1.62-5.18)], prostate [2.51 (1.65-3.82)] and thyroid cancer [1.46 (1.10-1.93)]. In conclusion, chronic HBV or HCV infection was not only associated with an increased risk of liver cancer, but also associated with an increased risk of multiple extrahepatic cancers.

Associations Between Nonalcoholic Fatty Liver Disease and Cancers in a Large Cohort in China

The relationship between nonalcoholic fatty liver disease (NAFLD) and cancer, especially extrahepatic cancers, has not been fully clarified. We analyzed data from a large prospective cohort study to determine the relationship between NAFLD and development of cancers in men. We collected data from the Kailuan cohort, a community-based cohort of 54,187 adult men in China, from June 2006 through October 2007. NAFLD was diagnosed by ultrasonography after excluding other causes related to chronic liver disease. Fine and Gray competing risk regression model was used to evaluate associations between NAFLD (without cirrhosis) and cancers. The prevalence of NAFLD was 32.3%. NAFLD was associated with increased risk of all cancers (hazard ratio [HR], 1.22; 95% CI, 1.10-1.36; P= .0001), thyroid cancer (HR, 2.79; 95% CI, 1.25-6.21; P= .01), and lung cancer (HR, 1.23; 95% CI, 1.02-1.49; P= .03). The association between NAFLD and risk of thyroid cancer increased with level of alanine aminotransferase (ALT). In men with NAFLD, level of ALT 80 U/L or more was associated with hepatocellular carcinoma (HR, 8.08; 95% CI, 2.46-26.56; P= .0006). NAFLD increased risk of colorectal cancer (HR, 1.96; 95% CI, 1.17-3.27) and lung cancer (HR, 1.38; 95% CI, 1.03-1.84) only in smokers. An association between NAFLD and kidney cancer (HR, 1.57; 95% CI, 1.03-2.40) was only observed in men without diabetes. A cohort study from China found that men with NAFLD have a higher risk of extrahepatic cancers, including thyroid and lung cancer. In men with NAFLD, higher levels of ALT were associated with higher risk of thyroid and hepatocellular cancer. NAFLD increased risk of colorectal and lung cancer only in smokers, and increased risk of kidney cancer in men without diabetes.

PNPLA3 Gene Polymorphism and Liver- and Extrahepatic Cancer–Related Mortality in the United States

The palatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 G allele is associated with nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma,1 and all-cause or cardiovascular mortality in the general population.2 One recent Italian study reported an association between PNPLA3 polymorphism and liver-related events and mortality in biopsy-confirmed NAFLD.3 Regarding extrahepatic cancer-related mortality, one study showed that only women carrying the G allele without hepatic steatosis had a 60% lower risk for cancer-related mortality.4 However, owing to insufficient follow-up and selected populations, the results from these studies cannot generalize about the association between PNPLA3 polymorphism and liver- and extrahepatic cancer-related mortality at a population level. Thus, we investigated the association between PNPLA3 polymorphism and liver- and extrahepatic cancer-related mortality based on the presence of NAFLD in the U.S. general population.

Issue highlights

Issue highlights

Transarterial (chemo)embolisation versus no intervention or placebo for liver metastases.

The liver is affected by two of the most common groups of malignant tumours: primary liver tumours and liver metastases from colorectal carcinoma or other extrahepatic primary cancers. Liver metastases are significantly more common than primary liver cancer, and long-term survival rate after radical surgical treatment is approximately 50%. However, R0 resection (resection for cure) is not feasible in the majority of people; therefore, other treatments have to be considered. One possible option is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Transarterial chemoembolisation (TACE) of the hepatic artery can be achieved by administering a chemotherapeutic drug followed by vascular occlusive agents, and can lead to selective necrosis of the liver tumour while it may leave normal parenchyma virtually unaffected. This can also be performed without chemotherapy, which is called bland transarterial embolisation (TAE). To assess the beneficial and harmful effects of TAE or TACE compared with no intervention or placebo in people with liver metastases. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and four more databases (December 2019). We also searched two trials registers and the US Food and Drug Administration database (September 2019). Randomised clinical trials assessing beneficial and harmful effects of TAE or TACE compared with no intervention or placebo for liver metastases. We followed standard Cochrane methodological procedures. We extracted information on participant characteristics, interventions, study outcomes, study design, and trial methods. Two review authors independently extracted data and assessed risk of bias. We assessed the certainty of evidence with GRADE. We resolved disagreements by discussion. We included one randomised clinical trial with 61 participants (43 male and 18 female) with colorectal cancer with liver metastases: 22 received transarterial embolisation (TAE; hepatic artery embolisation), 19 received transarterial chemoembolisation (TACE; 5-fluorouracil hepatic artery infusion chemotherapy with degradable microspheres), and 20 received 'no active therapeutic intervention' as a control. Most tumours were synchronous, unresectable metastases involving up to 75% of the liver. Participants were followed for a minimum of seven months. The trial was at high risk of bias. Very-low-certainty evidence found inconclusive results for mortality at 44 months between the TAE and TACE versus no intervention groups (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.06; 61 participants). Local recurrence was reported in 10 participants without any details about the group allocation. Very-low-certainty evidence found little or no difference in mortality between the TAE and no intervention groups (RR 0.91, 95% CI 0.75 to 1.10; 42 participants). Median survival was 7 months from trial entry (range 2 to 44 months) in the TAE group and 7.9 months (range 1 to 26 months) in the control group, and 8.7 months after diagnosis (range 2 to 49 months) in the TAE group and 9.6 months (range 1 to 27 months) in the control group. The trial authors reported the differences were not statistically significant. There were no reported side effects in the control group. In the TAE group, 18 participants experienced short-term symptoms of 'post-embolisation syndrome', which were relieved with symptomatic treatment; one participant also had a local puncture site haematoma. Very-low-certainty evidence found little or no difference in mortality between the TACE and no intervention groups (RR 0.83, 95% CI 0.65 to 1.07; 39 participants). Median survival in the TACE group was 10.7 months (range 3 to 38 months) from trial entry, and 13.0 months (range 3 to 38 months) after diagnosis. The trial authors reported that differences between groups were not statistically significant. All participants experienced short-term nausea, with or without vomiting, immediately after treatment; one participant developed a wound infection, and one developed deep vein thrombosis. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health-related quality of life. Cancer Research Campaign, a non-profit organisation, provided a grant for the trial; Pharmacia Ltd. delivered the Port-a-Cath arterial delivery systems and degradable starch microspheres. We identified one ongoing trial comparing TACE plus chemotherapy versus chemotherapy alone in people with unresectable colorectal liver metastases who failed with first-line chemotherapy (NCT03783559). Based on one, small randomised trial at high risk of bias, the evidence is very uncertain about the effect of TAE or TACE versus no active therapeutic intervention on mortality for people with liver metastases as the true effect may be substantially different. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health-related quality of life. Short-term, minor adverse events were recorded in the intervention groups only. Large trials, following current standards of conduct and reporting, are required to explore the benefits and harms of TAE or TACE compared with no intervention or placebo in people with resectable and unresectable liver metastasis.

Percutaneous ethanol injection for liver metastases.

The liver is affected by two of the most common groups of malignant tumours: primary liver tumours and liver metastases from colorectal carcinoma or other extrahepatic primary cancers. Liver metastases are significantly more common than primary liver cancer, and the reported long-term survival rate after radical surgical treatment is approximately 50%. However, R0 resection (resection for cure) is not feasible in the majority of patients; therefore, other treatments have to be considered. One of these is percutaneous ethanol injection (PEI), which causes dehydration and necrosis of tumour cells, accompanied by small-vessel thrombosis, leading to tumour ischaemia and destruction of the tumour. To assess the beneficial and harmful effects of percutaneous ethanol injection (PEI) compared with no intervention, other ablation methods, or systemic treatments in people with liver metastases. We searched the following databases up to 10 September 2019: the Cochrane Hepato-Biliary Group Controlled Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE Ovid; Embase Ovid; Science Citation Index Expanded; Conference Proceedings Citation Index - Science; Latin American Caribbean Health Sciences Literature (LILACS); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We also searched clinical trials registers such as ClinicalTrials.gov, the International Clinical Trials Registry Platform (ICTRP), and the US Food and Drug Administration (FDA) (17 September 2019). Randomised clinical trials assessing beneficial and harmful effects of percutaneous ethanol injection and its comparators (no intervention, other ablation methods, systemic treatments) for liver metastases. We followed standard methodological procedures as outlined by Cochrane. We extracted information on participant characteristics, interventions, study outcomes, study design, and trial methods. Two review authors performed data extraction and assessed risk of bias independently. We assessed the certainty of evidence by using GRADE. We resolved disagreements by discussion. We identified only one randomised clinical trial comparing percutaneous intratumour ethanol injection (PEI) in addition to transcatheter arterial chemoembolisation (TACE) versus TACE alone. The trial was conducted in China and included 48 trial participants with liver metastases: 25 received PEI plus TACE, and 23 received TACE alone. The trial included 37 male and 11 female participants. Mean participant age was 49.3 years. Sites of primary tumours included colon (27 cases), stomach (12 cases), pancreas (3 cases), lung (3 cases), breast (2 cases), and ovary (1 case). Seven participants had a single tumour, 15 had two tumours, and 26 had three or more tumours in the liver. The bulk diameter of the tumour on average was 3.9 cm, ranging from 1.2 cm to 7.6 cm. Participants were followed for 10 months to 43 months. The trial reported survival data after one, two, and three years. In the PEI + TACE group, 92%, 80%, and 64% of participants survived after one year, two years, and three years; in the TACE alone group, these percentages were 78.3%, 65.2%, and 47.8%, respectively. Upon conversion of these data to mortality rates, the calculated risk ratio (RR) for mortality at last follow-up when PEI plus TACE was compared with TACE alone was 0.69 (95% confidence interval (CI) 0.36 to 1.33; very low-certainty evidence) after three years of follow-up. Local recurrence was 16% in the PEI plus TACE group and 39.1% in the TACE group, resulting in an RR of 0.41 (95% CI 0.15 to 1.15; very low-certainty evidence). Forty-five out of a total of 68 tumours (66.2%) shrunk by at least 25% in the PEI plus TACE group versus 31 out of a total of 64 tumours (48.4%) in the TACE group. Trial authors reported some adverse events but provided very few details. We did not find data on time to mortality, failure to clear liver metastases, recurrence of liver metastases, health-related quality of life, or time to progression of liver metastases. The single included trial did not provide information on funding nor on conflict of interest. Evidence for the effectiveness of PEI plus TACE versus TACE in people with liver metastases is of very low certainty and is based on one small randomised clinical trial at high risk of bias. Currently, it cannot be determined whether adding PEI to TACE makes a difference in comparison to using TACE alone. Evidence for benefits or harms of PEI compared with no intervention, other ablation methods, or systemic treatments is lacking.

Complications, morbidity and mortality of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized public health problem, affecting up to a quarter of the world's adult population. The burden of NAFLD is influenced by the epidemics of obesity and type 2 diabetes mellitus (T2DM) and the prevalence of these conditions is not expected to decrease in the forthcoming decades. Consequently, the burden of NAFLD-related liver complications (non-alcoholic steatohepatitis [NASH], cirrhosis and hepatocellular carcinoma) and the need for life-saving liver transplantation are also expected to increase further in the near future. A large body of clinical evidence indicates that NAFLD is associated not only with increased liver-related morbidity and mortality, but also with an increased risk of developing other important extra-hepatic diseases, such as cardiovascular disease (that is the predominant cause of death in patients with NAFLD), extra-hepatic cancers (mainly colorectal cancers), T2DM and chronic kidney disease. Thus, NAFLD creates a considerable health and economic burden worldwide and often results in poor quality of life. This narrative review provides an overview of the current literature on main complications, morbidity and mortality of this common and burdensome liver disease.