Primary gastric and liver cancers rank among the most prevalent malignant tumors of the digestive tract. Despite their serious implications for health, the global age-standardized incidence remains relatively low, at ~11.1 per 100,000 for primary gastric cancer and ~8.657 per 100,000 for primary liver cancer. Although the occurrence of multiple primary malignancies is not uncommon in clinical practice, reports of synchronous primary gastric and liver cancer are exceedingly rare. The present study describes a case involving a 60-year-old man diagnosed with synchronous primary gastric and liver cancer. The patient underwent endoscopic submucosal dissection for lesions located at the gastric angle, followed by laparoscopic resection of a small liver tumor. Pathological examinations revealed moderately differentiated intramucosal adenocarcinoma at the gastric angle and well-differentiated hepatocellular carcinoma in the liver. Following a 3-year follow-up, the patient remained in good health, with no evidence of disease recurrence. In conclusion, clinicians should exercise caution in patients presenting with distinct lesions to ensure that subtle malignancies are not overlooked, particularly in those with confirmed cancer. For patients with multiple cancers, it is crucial to ascertain whether the malignancies are primary, as this determination influences treatment strategies.

To examine incidence trends and patterns for early- and late-onset liver cancer.

Liver and intrahepatic bile duct (IBD) cancers diagnosed between 2000 and 2019 were acquired from 22 SEER registries. Variables included early-onset (20-49) vs. late-onset (50+), anatomic subsite, histologic type (hepatocellular carcinoma [HCC] and IBD cholangiocarcinoma [ICC]), sex, and race/ethnicity. Age-standardized incidence rates were calculated using SEER*Stat. Jointpoint regression analysis was employed to estimate the annual percent change (APC) and the average APC (AAPC) with pairwise comparisons for trend by sex and by race/ethnicity stratified by age and subsite.

Liver cancer incidence decreased among early-onset (AAPC [95% CI] - 2.39 [- 2.74, - 2.07]) but increased among late-onset patients (2.85 [2.71, 3.01]), primarily driven by HCC (3.60 [3.50, 3.71]). IBD incidence increased for both ages with ICC incidence annually increasing 7.92% (6.84, 9.26) for early-onset and 6.32% (5.46, 8.86) for late-onset patients. Early-onset liver cancer displayed comparable trends across racial/ethnic groups; however, late-onset liver cancer showed more variation, particularly among American Indian/Alaska Native/Asian Pacific Islander (AI/AN/API) populations, which experienced a significant decrease in incidence, thereby narrowing the gap with other racial/ethnic groups. For IBD, an identical pattern of early-onset IBD among non-Hispanic Blacks (NHBs) compared to Hispanics was showed with coincidence test p = 0.1522, and a parallel pattern was observed among late-onset patients for both sexes (p = 0.5087).

Late-onset HCC continues to rise, except for NHB and AI/AN/API, where incidence rates have started to decrease over the past 4-5 years. Early and late-onset ICC incidence continues to increase across all racial/ethnic groups.

Monoclonal antibodies against claudin (CLDN) 18.2 (a component of tight junctions) in gastric epithelial cells are an emerging therapeutic option for patients with advanced gastric and esophageal adenocarcinoma. Phase 2 and 3 trials have shown clinical efficacy in patients whose tumors show high expression of CLDN18 by immunohistochemistry, and the US Food and Drug Administration has recently approved a drug for patients with advanced gastric and gastroesophageal adenocarcinoma and high CLDN18 expression. Adenocarcinoma of the bile ducts, a.k.a. cholangiocarcinoma (CCA), may share morphologic and immunophenotypic qualities with gastric adenocarcinoma, and are lethal tumors with limited therapeutic options. The purpose of this study was to determine if primary tumors of the bile ducts show expression of CLDN18 with the use of a monoclonal antibody to CLDN18, and if so, if the extent of expression is similar to that seen in the gastric and esophageal tumors of patients who responded to anti-CLDN18.2 therapeutics.

Tissue microarrays containing 41 intrahepatic cholangiocarcinomas, 36 hilar cholangiocarcinomas, and 28 distal bile duct cholangiocarcinomas were stained with a monoclonal antibody which detects CLDN18 (Ventana 43-14A). The percentage of tumor cells staining and intensity was recorded for each case with tumors with 75% of cells showing moderate to strong intensity being considered high expressers.

High expression was seen in 14.63% of intrahepatic, 8.3% of hilar, and 17.8% of distal bile duct cholangiocarcinomas. Overall, 13.33% of CCAs expressed CLDN18 to an extent which would qualify for treatment in the gastric and esophageal trials.

Given the poor prognosis and current lack of therapeutic options, trials of anti-CLDN18.2 inhibitors could be considered in patients with CCA and high expression of CLDN18 by immunohistochemistry.

Primary liver cancer (PLC) is projected to be the third leading cause of cancer mortality in the United States in 2040. We examine the burden of PLC in the United States, stratified by sex, state and aetiological risk factors.

Data on PLC prevalence, incidence, death and disability-adjusted life years (DALYs) were extracted from the Global Burden of Disease Study 2021. Changes in these parameters were calculated using the Joinpoint regression model.

There were 47,970 cases, 31,450 incident cases, 24,770 deaths and 576,920 DALYs from PLC in the United States. The highest prevalence (16,980), incidence (12,040), death (9840) and DALYs (213,410) from PLC were due to chronic hepatitis C virus infection. From 2000 to 2021, PLC incidences increased by 141%, and PLC deaths increased by 136%. Age-standardised incidence rates (ASIRs) and death rates (ASDRs) per 100,000 population for PLC increased, primarily driven by alcohol-related liver disease (ALD) (ASIR: annual percent change [APC]: +2.40%; ASDR: APC: +2.22%) and metabolic dysfunction-associated steatotic liver disease (MASLD) (ASIR: APC: +2.32%; ASDR: APC: +2.04%).

The burden of PLC in the United States has risen in the past two decades, driven mainly by ALD and followed by MASLD. These findings offer policymakers an accurate assessment of the PLC burden and emphasise the need for targeted risk factor mitigation, especially regarding alcohol related policy.

While prior data showed an increasing incidence of hepatocellular carcinoma (HCC) in the United States, there are limited comprehensive and comparative data on the geographical variations of HCC trends in different demographic-specific populations.

To evaluate sex and age-specific incidence rates and time trends in different geographical regions in the United States.

Age-adjusted HCC incidence rates were collected from the United States Cancer Statistics (USCS) database which covers approximately 98% of the population in the United States. HCC rates were stratified by sex, age, and geographical region. annual percentage change (APC) and average APC (AAPC) were estimated using Joinpoint Regression. A pairwise comparison was conducted between sex-specific trends.

There were 467344 patients diagnosed with HCC in the United States in the USCS database between 2001 and 2020. The rates and trends varied by geographical region. When looking at the West region (115336 patients), incidence rates of HCC were overall increasing and also increasing in older adults. However, when evaluating younger adults, HCC incidence rates decreased in men but not in women with a sex-specific absolute AAPC-difference of 2.15 (P = 0.005). When evaluating the Midwest region (84612 patients), similar results were seen. While incidence rates were increasing in the overall population and in older adults as well, they were decreasing in younger men but not in women with a sex-specific absolute AAPC-difference of 1.61 (P < 0.001). For the Northeast region (87259 patients), the analysis showed similar results with decreasing HCC incidence rates in younger men but not counterpart women (Sex-specific AAPC-difference = 3.26, P < 0.001). Lastly, when evaluating the south (180137 patients), the results were also decreasing in younger men but not in women (Sex-specific AAPC-difference = 2.55, P < 0.001).

Nationwide analysis covering around 98% of the United States population shows an increasing incidence of HCC across all geographical regions, most notably in the South. While younger men experienced decreasing HCC incidence, younger women had a stable trend and this was noted across all regions as well. Our study offers insight into the epidemiology of HCC in different demographic groups across various United States geographical regions. While the reasons contributing to our findings are unclear, they can be related to sex and regional disparities in healthcare access and utilization. Future research is warranted to characterize the temporal change in HCC risk factors across different United States regions.

Intrahepatic cholangiocarcinoma (iCCA) was considered a contraindication for liver transplantation. However, recent studies have shown that highly selected cases of patients with a good response to neoadjuvant therapy may achieve acceptable survival rates when following liver transplantation.

To present two cases of patients with iCCA, without extrahepatic disease, who underwent living donor liver transplantation after receiving neoadjuvant chemotherapy.

Two cases of patients with histopathological diagnosis of locally advanced iCCA, ineligible for resection and without evidence of extrahepatic disease, are presented.

These patients underwent at least nine sessions of neoadjuvant chemotherapy, including Gemcitabine and Cisplatin, with or without the addition of immunobiological agents, resulting in a radiological tumor response. They subsequently underwent living donor liver transplantation. The average follow-up time was 15 months, with no clinical or radiological signs of disease.

In well-selected patients without extrahepatic disease, living donor liver transplantation represents a potential therapeutic option for iCCA.

The cancer atlas edited by several countries is the main resource for the analysis of the geographic variation of cancer risk. Correlating the observed spatial patterns with known or hypothesized risk factors is time-consuming work for epidemiologists who need to deal with each cancer separately, breaking down the patterns according to sex and race. The recent literature has proposed to study more than one cancer simultaneously looking for common spatial risk factors. However, this previous work has two constraints: they consider only a very small (2-4) number of cancers previously known to share risk factors. In this article, we propose an exploratory method to search for latent spatial risk factors of a large number of supposedly unrelated cancers. The method is based on the singular value decomposition and nonnegative matrix factorization, it is computationally efficient, scaling easily with the number of regions and cancers. We carried out a simulation study to evaluate the method's performance and apply it to cancer atlas from the USA, England, France, Australia, Spain, and Brazil. We conclude that with very few latent maps, which can represent a reduction of up to 90% of atlas maps, most of the spatial variability is conserved. By concentrating on the epidemiological analysis of these few latent maps a substantial amount of work is saved and, at the same time, high-level explanations affecting many cancers simultaneously can be reached.

Background: There is an observed variation in the burden of hepatocellular carcinoma (HCC) across different US populations. Our study aims to comprehensively assess variations in HCC incidence and mortality rates across different regions of the US. Understanding these geographical differences is crucial, given prior evidence indicating variations in the incidence of viral hepatitis and metabolic dysfunction-associated steatotic liver disease and varying access to curative HCC treatment among states. Methods: HCC age-adjusted incidence rates between 2001 and 2021 were obtained from the United States Cancer Statistics (USCS) database (which covers approximately 98% of the US population). HCC age-adjusted mortality rates between 2000 and 2022 were obtained from the National Center of Health Statistics (NCHS) database (covering approximately 100% of the US population). The rates were categorized by US geographical region into West, Midwest, Northeast, and South. Incidence rates were also categorized by race/ethnicity. Time trends [annual percentage change (APC) and average APC (AAPC)] were estimated by using Joinpoint Regression via the weighted Bayesian Information Criteria (p < 0.05). Results: Between 2001 and 2021, there were 491,039 patients diagnosed with HCC in the US (74.2% males). The highest incidence rate per 100,000 population was noted in the West (7.38), followed by the South (6.85). Overall incidence rates increased between 2001 and 2015 and then significantly decreased until 2021 (APC = -2.29). Most cases were in the South (38.8%), which also had the greatest increase in incidence (AAPC = 2.74). All four geographical regions exhibited an overall similar trend with an increase in incidence over the first 10-15 years followed by stable or decreasing rates. While stratification of the trends by race/ethnicity showed slight variations among the regions and groups, the findings are largely similar to all race/ethnic groups combined. Between 2000 and 2022, there were 370,450 patients whose death was attributed to HCC in the US (71.6% males). The highest mortality rate per 100,000 population was noted in the South (5.02), followed by the West (4.99). Overall mortality rates significantly increased between 2000 and 2013 (APC = 1.90), then stabilized between 2013 and 2016, and then significantly decreased till 2022 (APC = -1.59). Most deaths occurred in the South (35.8%), which also had the greatest increase in mortality (AAPC = 1.33). All four geographical regions followed an overall similar trend, with an increase in mortality over the first 10-15 years, followed by stable or decreasing rates. Conclusions: Our analysis, capturing about 98% of the US population, demonstrates an increase in HCC incidence and mortality rates in all geographical regions from 2000 to around 2014-2016, followed by stabilizing and decreasing incidence and mortality rates. We observed regional variations, with the highest incidence and mortality rates noted in the West and South regions and the fastest increase in both incidence and mortality noted in the South. Our findings are likely attributable to the introduction of antiviral therapy. Furthermore, demographic, socioeconomic, and comorbid variability across geographical regions in the US might also play a role in the observed trends. We provide important epidemiologic data for HCC in the US, prompting further studies to investigate the underlying factors responsible for the observed regional variations in HCC incidence and mortality.

There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust.

ZLDI-8 is an A disintegrin and metalloproteinase domain 17 (ADAM17) inhibitor that suppresses the shedding of Notch1 to the Notch1 intracellular domain (NICD). In previous studies, we found that ZLDI-8 was able to sensitize HCC to sorafenib, but the mechanism of action remains unclear. The sensitizing effects of ZLDI-8 were tested both in vitro and in vivo. EMT-related factors, sorafenib sensitivity-related proteins and ECM-related gene expression were assessed using immunohistochemistry, RTPCR and Western blotting. Knockdown assays were conducted to determine the relationship between the Notch and Integrin pathways. CoIP assays, nuclear and cytoplasmic fractionation and immunofluorescence colocalization were applied to explore the interaction between the Notch and Integrin pathways. Appropriate statistical analysis methods were used to assess the significance of the experimental results and to ensure the scientific validity and reliability of the experimental design. We found that ECM- and EMT-related proteins were downregulated after ZLDI-8 treatment (P<0.05). ZLDI-8 significantly downregulated Integrinβ1 and Integrinβ3 in HCC in vitro and in vivo (P<0.05), possibly through Foxc2-dependent regulation. Mechanistically, interfering with the expression of both Integrin-linked kinase (ILK) and the NICD may downregulate the expression of proteins targeted by sorafenib, thereby sensitizing cells to sorafenib. The retroregulation of Integrinβ by ILK may occur through the interaction between the NICD and ILK and may be the result of the translocation of the complexus. Our study indicates that blocking the Notch pathway may affect Integrinβ through crosstalk between the Notch1 and Integrinβ/ILK signaling pathways, thus providing a potential therapeutic strategy for HCC.

Understanding how specific populations are affected by liver cancer is important for identifying priorities, policies, and interventions to mitigate health risks and reduce disparities. This study aims to provide comprehensive analysis of rates and trends in liver cancer mortality for different racial and ethnic populations in the USA nationally and at the county level from 2000 to 2019.

We applied small-area estimation methods to death registration data from the US National Vital Statistics System and population data from the US National Center for Health Statistics to estimate liver cancer mortality rates by county, racial and ethnic population, and year (2000-19) in the USA. Race and ethnicity were categorised as non-Latino and non-Hispanic American Indian or Alaska Native (AIAN), non-Latino and non-Hispanic Asian or Pacific Islander (Asian), non-Latino and non-Hispanic Black (Black), Latino or Hispanic (Latino), and non-Latino and non-Hispanic White (White). Estimates were adjusted using published misclassification ratios to correct for inaccuracies in race or ethnicity as recorded on death certificates, and then age-standardised. Mortality rate estimates are presented for all county and racial and ethnic population combinations with a mean annual population greater than 1000.

Nationally, the age-standardised liver cancer mortality rate increased between the years 2000 (4·2 deaths per 100 000 population [95% uncertainty interval 4·1-4·3]) and 2016 (6·0 per 100 000 [5·9-6·1]), followed by a stabilisation in rates from 2016 to 2019 (6·1 per 100 000 [6·0-6·2]). Similar trends were observed across the AIAN, Black, Latino, and White populations, whereas the Asian population showed an overall decrease across the 20-year study period. Qualitatively similar trends were observed in most counties; however, the mortality rate and the rate of change varied substantially across counties, both within and across racial and ethnic populations. For the 2016-19 period, mortality continued to increase at a substantial rate in some counties even while it stabilised nationally. Nationally, the White population had the lowest mortality rate in all years, while the racial and ethnic population with the highest rate changed from the Asian population in 2000 to the AIAN population in 2019. Racial and ethnic disparities were substantial: in 2019, mortality was highest in the AIAN population (10·5 deaths per 100 000 [9·1-12·0]), notably lower for the Asian (7·5 per 100 000 [7·1-7·9]), Black (7·6 per 100 000 [7·3-7·8]), and Latino (7·7 per 100 000 [7·5-8·0]) populations, and lowest for the White population (5·5 [5·4-5·6]). These racial and ethnic disparities in mortality were prevalent throughout the country: in 2019, mortality was higher in minoritised racial and ethnic populations than in the White population living in the same county in 408 (87·7%) of 465 counties with unmasked estimates for the AIAN population, 604 (90·6%) of 667 counties for the Asian population, 1207 (81·2%) of 1486 counties for the Black population, and 1073 (73·0%) of 1469 counties for the Latino population.

Although the plateau in liver cancer mortality rates in recent years is encouraging, mortality remains too high in many locations throughout the USA, particularly for minoritised racial and ethnic populations. Addressing population-specific risk factors and differences in access to quality health care is essential for decreasing the burden and disparities in liver cancer mortality across racial and ethnic populations and locations.

US National Institutes of Health (Intramural Research Program, National Institute on Minority Health and Health Disparities; National Heart, Lung, and Blood Institute; Intramural Research Program, National Cancer Institute; National Institute on Aging; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Office of Disease Prevention; and Office of Behavioral and Social Sciences Research).

While the incidence rates of hepatocellular carcinoma (HCC) are increasing, there are limited comprehensive data on demographic-specific incidence and mortality trends in the USA. We aimed to evaluate recent trends in HCC incidence and mortality among different demographic groups in the USA.

Age-adjusted HCC incidence rates were calculated from the Centers for Disease Control's United States Cancer Statistics database, which combines incidence data on newly diagnosed cancer cases and covers approximately 98% of the population in the USA. Additionally, age-adjusted HCC mortality rates were obtained from the Centers for Disease Control's National Center for Health Statistics database, which offers comprehensive coverage spanning nearly 100% of deaths attributed to HCC in the USA. Rates were stratified by sex, age (older [≥55 years] and younger [<55 years] adults), race and ethnicity (Non-Hispanic White, Non-Hispanic Black, Hispanic, Non-Hispanic Asian/Pacific Islander, and Non-Hispanic American Indian/Alaska Native), and tumor stage at diagnosis (early and late). Annual and average annual percentage change (AAPC) were calculated using joinpoint regression. A sex-specific pairwise comparison was conducted.

Between 2001 and 2020, there were 467,346 patients diagnosed with HCC (26.0% women), with increasing incidence in both sexes without significant difference (p=0.65). In younger adults (78,169 patients), the incidence decreased in men but not in women (AAPC difference=-2.39, p=0.002). This was seen in various racial and ethnic groups, mostly driven by early-stage tumors (AAPC difference=-2.65, p=0.02). There were 329,973 deaths attributed to HCC between 2000 and 2020 (28.4% women). In younger adults (43,093 deaths), mortality decreased in men at a greater rate than in women (AAPC difference=1.61, p=0.007). This was seen in various racial and ethnic groups, most notably in non-Hispanic American Indian/Alaska Natives (AAPC difference=-4.51, p=0.01).

Nationwide USA data, covering nearly all HCC cases, show an increasing incidence and mortality over the last two decades. In younger adults, there was a decreasing incidence in men but not in women, due to early-stage tumors. Mortality improved in younger men at a greater rate than in women, especially in Non-Hispanic American Indian/Alaska Natives. Future studies are warranted to identify the risk factors associated with the occurrence and outcomes of HCC in demographic-specific populations, especially younger women.