Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2–5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.

Liver cancer is an emerging global health issue, with rising incidence in both the United States and the economically developing world. Although Guatemala experiences the highest rates of this disease in the Western hemisphere and a unique 1:1 distribution in men and women, few studies have focused on this population. Thus, we determined the prevalence and correlates of aflatoxin B₁ (AFB₁) exposure and hepatitis virus infection in Guatemalan adults. Healthy men and women aged ≥40 years (n = 461), residing in five departments of Guatemala, were enrolled in a cross-sectional study from May—October of 2016. Serum AFB₁-albumin adducts were quantified using isotope dilution mass spectrometry. Multivariate linear regression was used to assess relationships between AFB₁-albumin adduct levels and demographic factors. Biomarkers of hepatitis B virus and hepatitis C virus infection were assessed by immunoassay and analyzed by Fisher’s exact test. AFB₁-albumin adducts were detected in 100% of participants, with a median of 8.4 pg/mg albumin (range, 0.2–814.8). Exposure was significantly higher (p<0.05) in male, rural, low-income, and less-educated participants than in female, urban, and higher socioeconomic status participants. Hepatitis B and C seropositivity was low (0.9% and 0.5%, respectively). Substantial AFB₁ exposure exists in Guatemalan adults, concurrent with low prevalence of hepatitis virus seropositivity. Quantitatively, AFB₁ exposures are similar to those previously found to increase risk for liver cancer in Asia and Africa. Mitigation of AFB₁ exposure may reduce liver cancer incidence and mortality in Guatemala, warranting further investigation.

Liver cancer, the sixth most frequently occurring cancer in the world and the third most common cause of cancer mortality, has wide geographical variation in both incidence and mortality rates. At the end of the 20th century, incidence rates began declining in some high-rate areas and increasing in some lower-rate areas. These trends were undoubtedly driven by the shifting contributions of both well-established and more novel risk factors. While notable strides have been made in combating some major risk factors, such as hepatitis B virus and hepatitis C virus, the emergence of metabolic conditions as important drivers of liver cancer risk indicates that much work remains to be done in prevention. As liver cancer is strongly associated with economic and social deprivation, research, early-diagnosis, and treatment among disadvantaged populations are of paramount importance.

Airborne pollutants have collectively been classified as a known human carcinogen and, more broadly, affect the health of hundreds of millions of people worldwide. Benzene is a frequent component of air pollution, and strategies to protect individuals against unavoidable exposure to this and other airborne carcinogens could improve the public's health. Earlier clinical trials in Qidong, China, demonstrated efficacy in enhancing the detoxication of benzene using a broccoli sprout beverage. A randomized, placebo-controlled, multidose trial of a broccoli sprout beverage was designed to determine the lowest effective concentration that enhances benzene detoxication adjudged by enhanced excretion of the urinary biomarker, S-phenylmercapturic acid (SPMA). Following informed consent, 170 subjects were randomly assigned in 5 blocks of 34 each to drink either a placebo beverage (n = 55) or 1 of 3 graded concentrations of a broccoli sprout beverage [full (n = 25), one-half (n = 35), and one-fifth (n = 55)] for 10 consecutive days. Concentrations of SPMA arising through induced benzene conjugation with glutathione were quantified by MS in sequential 12-h overnight urine collections during the intervention. MS was also used to quantify urinary sulforaphane metabolites in each dosing regimen that resulted in a median 24-h urinary output of 24.6, 10.3, and 4.3 µmol, respectively, confirming a dose-dependent de-escalation of the inducing principle within the beverage. A statistically significant increase in benzene mercapturic acids in urine was found for the high-dose group (+63.2%) during the 10-d period. The one-half dose (+11.3%) and one-fifth dose groups (−6.4%) were not significantly different from placebo controls. An intervention with a broccoli sprout beverage enhanced the detoxication of benzene, an important airborne pollutant, when dosed at a concentration evoking a urinary elimination of ∼25 µmol sulforaphane metabolites per day, and it portends a practical and frugal population-based strategy to attenuate associated long-term health risks of air pollution. This trial was registered at clinicaltrials.gov as NCT02656420.

During the 60 years since the first scientific reports about a relation between aflatoxin exposure and adverse health consequences, both in animals and humans, there has been a remarkable number of basic, clinical and population science studies characterising the impact of this mycotoxin on diseases such as liver cancer. Many of these human investigations to date have focused on populations residing in Asia and Africa due to the high incidence of liver cancer and high exposures to aflatoxin. These studies formed the basis for the International Agency for Research on Cancer to classify the aflatoxins as Group 1 known human carcinogens. In addition, aflatoxin contamination levels have been used in international commodity trade to set the price of various staples such as maize and groundnuts. While there have been many case-control and prospective cohort studies of liver cancer risk over the years there have been remarkably few investigations focused on liver cancer in Latin America. Our interdisciplinary and multiple institutional collaborative has been developing a long-term strategy to characterise the role of aflatoxin and other mycotoxins as health risk factors in Guatemala and neighbouring countries. This paper summarises a number of the investigations to date and provides a roadmap of our strategies for the near term to discern the emergent aetiology of liver cancer in this region. With these data in hand public health-based prevention strategies could be strategically implemented and conducted to lower the impact of these mycotoxins on human health.

Aflatoxin B1 (AFB1) is a known human hepatocarcinogen and a recent study reported elevated AFB1 levels, measured by serum albumin biomarkers, among Guatemalan adults. While AFB1 can contaminate a variety of foodstuffs, including maize, Guatemala's main dietary staple, the relationship of maize intake to serum AFB1-albumin adducts levels in Guatemala has not been previously examined. As a result, a cross-sectional study was conducted among 461 Guatemalan adults living in five geographically distinct departments of the country. Participants provided a serum sample and completed a semi-quantitative food frequency questionnaire and a sociodemographic questionnaire. Multiple linear regression analysis was used to estimate the least square means (LSQ) and 95% confidence intervals (95% CI) of log-transformed AFB1-albumin adducts by quintiles of maize consumption in crude and adjusted models. Additionally, analyses of tortilla consumption and levels of maize processing were conducted. The median maize intake was 344.3 g per day [Interquartile Range (IQR): 252.2, 500.8], and the median serum AFB1-albumin adduct level was 8.4 pg/mg albumin (IQR: 3.8, 22.3). In adjusted analyses, there was no association between overall maize consumption and serum AFB1-albumin levels. However, there was a statistically significant association between tortilla consumption and AFB1-albumin levels (ptrend = 0.01). The LSM of AFB1-albumin was higher in the highest quintile of tortilla consumption compared to the lowest quintile [LSM:9.03 95%CI: 7.03,11.70 vs 6.23, 95%CI: 4.95,8.17, respectively]. These findings indicate that tortilla may be an important source of AFB1 exposure in the Guatemalan population. Therefore, efforts to control or mitigate AFB1 levels in contaminated maize used for tortillas may reduce overall exposure in this population.