Hepatocellular carcinoma (HCC) is the sixth most common malignancy globally and remains one of the leading causes of cancer-related mortality. Its incidence continues to rise worldwide, and it is currently the fastest-growing cancer by incidence in the United States. HCC most often arises in the context of chronic liver disease, particularly cirrhosis. While chronic viral hepatitis (hepatitis B and C) has traditionally been the primary etiologic factor, recent advances in antiviral therapies and prevention strategies have shifted the epidemiological landscape. Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease are increasingly prominent risk factors, especially in Western populations. This shift underscores the need for targeted risk factor modification, improved early detection, and enhanced surveillance protocols. The management of HCC necessitates a multidisciplinary approach, incorporating locoregional therapies, surgical resection, liver transplantation, and systemic therapies for advanced-stage disease. Recent advances in systemic treatments, including immune checkpoint inhibitors and combination therapies, have transformed the therapeutic landscape. Despite these developments, significant challenges persist in optimizing treatment, identifying predictive biomarkers, and personalizing therapy. Ongoing research is focused on refining molecular classifications and advancing precision medicine strategies to improve outcomes. This review provides a comprehensive overview of the etiology, surveillance strategies, diagnostic approaches, molecular features, and current treatment modalities for HCC.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly prescribed for the management of type 2 diabetes mellitus (T2DM). However, the potential connection between GLP-1 RAs and the risk of pancreatitis presents a complex and nuanced issue. Although these drugs are effective in improving blood sugar control and cardiovascular health, their association with pancreatitis remains an area of concern. Our study aims to evaluate the association between the use of GLP-1 RAs, considered as a single class, and the risk of pancreatitis in a comorbidity-free subgroup of patients with type 2 diabetes mellitus (T2DM) in the United States. Methods: Data were retrieved from the TriNetX research database using the US Collaborative Network, which included information from 61 healthcare organizations within the U.S. Patients diagnosed with T2DM were categorized into two cohorts: one consisting of the patients prescribed with GLP-1 RAs and the other comprising patients who did not receive GLP-1 RAs. Of this class of medications, the agents analyzed were dulaglutide, lixisenatide, exenatide, liraglutide, and semaglutide. Using a 1:1 propensity score matching (PSM) model, we matched patients of both cohorts based on baseline demographics, comorbidities (hypertensive disorders, ischemic heart disease, gallstones, annular pancreas, alcohol use disorders, hypertriglyceridemia, hypercalcemia, cystic fibrosis, and cannabis use), medications known to cause drug-related pancreatitis, and laboratory values. Results: Of 969,240 patients with T2DM, 9.7% (93,608) were on GLP-1 RA, and 90.3% (875,632) were not. After PSM, the sample included 81,872 patients in each cohort. The risk of pancreatitis between the two groups was not statistically different between the two cohorts at 6 months at (0.1% vs. 0.1%, p = 0.04), and remained without significant increase with time; at 1 year (0.1% vs. 0.2%, p = 0.02), 3 years (0.2% vs. 0.3%, p = 0.001), and 5 years (0.3% vs. 0.4%, p < 0.001). The lifetime risk of developing pancreatitis in patients on GLP-1 RA was lower (0.3% vs. 0.4%, p < 0.001). Conclusions: In our comorbidity-free U.S.-based population with T2DM, the use of GLP-1 RAs did not increase their risk of pancreatitis. Their use was associated with a lower lifetime risk of pancreatitis.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are becoming more popular in managing type 2 diabetes mellitus (T2DM). Concerns linger over potential links to malignancies like pancreatic and thyroid cancers, requiring more research to clarify their safety profiles. Additionally, evidence suggests GLP-1 RAs may lower colorectal and pancreatic cancer risk, especially in obese and overweight individuals, indicating a protective effect beyond weight loss. Current studies leave a gap in comprehensively understanding cancer risks associated with GLP-1 RAs, which prompts further research to enhance our understanding of their overall safety. Methods: We queried the US Collaborative Network (63 health care organizations) of the TriNetX research database. Patients with T2DM were identified and divided into two cohorts: patients on GLP-1 RAs and patients not on GLP-1 RAs. We excluded tobacco use and alcohol use disorders, obese patients with a body mass index (BMI) of >25 kg/m², and those with a family history of gastrointestinal malignancy, infectious mononucleosis, chronic gastritis, pernicious anemia, helicobacter pylori infection, or gastroesophageal reflux disease (GERD). We used a 1:1 propensity score matching (PSM) model using patients’ baseline characteristics, medications, labs, and genetics. We compared the rate of gastric cancer and esophageal cancer at the seven-year mark. Results: A total of 2,748,431 patients with T2DM were identified. Of those, 6% (n = 167,077) were on a GLP-1 RA and 94% (n = 2,581,354) were not on a GLP-1 RA. After PSM, both cohorts included 146,277 patients. Patients with T2DM who were on a GLP-1 RA, compared to those who were not, had a statistically significant lower risk of both gastric cancer (0.05% vs. 0.13%, p < 0.0001) and esophageal cancer (0.04% vs. 0.13%, p < 0.0001) at the seven-year mark. Conclusion: The use of GLP-1 RAs in patients with T2DM does not significantly increase the risk of gastric or esophageal cancer. This finding supports the continued use of GLP-1 analogues as a therapeutic option in managing T2DM, considering their well-established benefits and low risk of complications. Based on the study results, these medications may even have a protective effect against these malignancies.

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Background: Proton pump inhibitors (PPIs) are frequently used after endoscopic variceal ligation (EVL) to reduce post-procedural bleeding, though studies have shown mixed results regarding their efficacy. While some suggest benefits, others report no significant advantage and highlight potential risks, including infection, kidney injury, and hepatic complications in cirrhotic patients. This study utilizes the TriNetX global health research network to evaluate the outcomes of PPI use following elective EVL for primary prophylaxis. Methods: This retrospective cohort study was conducted using the TriNetX database to evaluate adult patients with cirrhosis and esophageal varices who underwent EVL for primary prophylaxis. Patients who received at least two weeks of PPI therapy following EVL were compared to those who did not receive PPI within one month post-procedure. Outcomes assessed included esophageal bleeding, adverse events such as acute kidney injury (AKI), pneumonia, spontaneous bacterial peritonitis (SBP), Clostridioides difficile infection, hepatic encephalopathy, and all-cause mortality at 4 weeks and 8 weeks. Results: Of 6196 patients with cirrhosis and esophageal varices who underwent EVL, 12% (n = 764) received adjuvant PPI post-procedure, while 88% (n = 5432) did not receive PPI. After 1:1 propensity score matching, two well-balanced cohorts of 618 patients each were analyzed. PPI use was not associated with a reduction in esophageal bleeding at either 4 weeks (1.8% vs. 1.7%, p = 0.89) or 8 weeks (2.3% vs. 1.9%, p = 0.60). However, the composite adverse event rate—including SBP, hepatic encephalopathy, pneumonia, C. difficile, and acute kidney injury (AKI)—was significantly higher in the PPI group at both 4 weeks (7.9% vs. 3.0%, p < 0.01) and 8 weeks (13.2% vs. 3.0%, p < 0.01). Subgroup analysis showed no significant differences in pneumonia, SBP, or C. difficile infection at either time point. Hepatic encephalopathy was significantly more frequent in the PPI group at 8 weeks (4.9% vs. 2.0%, p = 0.01), and AKI occurred more often at both 4 weeks (5.7% vs. 2.0%, p < 0.01) and 8 weeks (9.6% vs. 2.1%, p < 0.01). Mortality was similar at 4 weeks but significantly higher in the PPI group at 8 weeks (4.3% vs. 1.7%, p < 0.01). Conclusions: PPI use after prophylactic EVL did not reduce bleeding risk and was linked to higher rates of adverse events. These findings suggest routine use may not be beneficial and should be reconsidered in cirrhotic patients who undergo EVL for primary prophylaxis.

Background: Current guidelines advise against platelet transfusion prior to emergent esophageal variceal band ligation (EVL) in cirrhotic patients with platelet counts below 50 × 10³/μL. However, recommendations for elective EVL remain unclear. This study evaluates the outcomes of cirrhotic patients undergoing outpatient EVL. Methods: Adult patients aged 18 years and older diagnosed with cirrhosis, with or without significant thrombocytopenia (<50 × 10³/μL), were identified using the TriNetX database. Patients who received platelet transfusions within one week prior to or on the day of EVL were excluded. Cirrhotic patients with significant thrombocytopenia undergoing outpatient elective EVL were categorized into two cohorts: (1) those with platelet counts between 30 and 49 × 10³/μL and (2) those with platelet counts ≥50 × 10³/μL. Propensity score matching (PSM) was employed to compare rates of post-EVL esophageal variceal bleeding and 14-day mortality between the two cohorts. Results: A total of 16,718 cirrhotic patients undergoing outpatient EVL were included in the analysis. Of these, 17.2% (n = 2874) had significant thrombocytopenia, while 82.8% (n = 13,844) had platelet counts ≥50 × 10³/μL. Two well-matched cohorts (2864 patients each) were created using 1:1 PSM. No statistically significant differences were observed between the groups regarding 14-day post-EVL esophageal variceal bleeding (13.7% vs. 15.2%; p = 0.12), 14-day mortality (5.7% vs. 5.0%; p = 0.28), and 28-day mortality (8.4% vs. 7.5%; p = 0.20). Conclusions: Elective EVL appears to be safe in cirrhotic patients with platelet counts as low as 30 × 10³/μL, challenging the current threshold of 50 × 10³/μL for platelet transfusion.