Bahawal Victoria Hospital, Bahawalpur

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with its incidence rising due to the increasing prevalence of metabolic liver diseases. While chronic viral hepatitis has traditionally been the primary risk factor, non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), have emerged as significant contributors to hepatocarcinogenesis. The interplay between metabolic disorders, chronic inflammation, and liver fibrosis plays a crucial role in disease progression, necessitating further investigation into the impact of fatty liver disease on HCC development. Objective: This study aimed to evaluate the association between fatty liver disease, particularly NAFLD and NASH, and the development of HCC while identifying key metabolic risk factors that contribute to disease progression. Methods: A retrospective cohort study was conducted, analyzing the medical records of 147 patients diagnosed with HCC at a tertiary care hospital between 2018 and 2023. Patients were categorized into two groups: those with NAFLD/NASH (n = 78) and those with other liver disease etiologies, including viral hepatitis and alcohol-related liver disease (n = 69). Clinical and demographic data, metabolic risk factors, liver function tests, and imaging findings were collected. Statistical analysis, including chi-square tests, t-tests, and multivariate logistic regression, was performed using SPSS version 26 to determine independent risk factors for HCC. Results: Among 147 patients, 78 (53.1%) had NAFLD or NASH, while 69 (46.9%) had HCC secondary to other liver diseases. Metabolic risk factors were more prevalent in the NAFLD/NASH group, with obesity present in 54 (69.2%) and diabetes in 60 (76.9%) cases, significantly higher than in the non-NAFLD group (p < 0.01). NASH was identified in 56 (71.8%) of NAFLD patients, with 62 (79.5%) presenting with cirrhosis at the time of HCC diagnosis. Advanced fibrosis (stage 3 or 4) was observed in 73 (93.6%) NAFLD/NASH patients compared to 52 (75.4%) in the non-NAFLD group (p = 0.01). Multivariate analysis identified NASH (adjusted OR = 3.85, 95% CI 1.72–8.64, p = 0.01) and cirrhosis (adjusted OR = 5.32, 95% CI 2.11–13.39, p < 0.01) as independent predictors of HCC. Median survival was lower in the NAFLD/NASH group (18 months) than in those with viral hepatitis-related HCC (28 months, p = 0.04). Conclusion: NAFLD and NASH represent significant risk factors for HCC, highlighting the growing impact of metabolic liver disease on cancer development. The strong association between metabolic dysfunction and liver cancer progression underscores the need for early screening, lifestyle interventions, and targeted therapies to reduce the disease burden in high-risk populations.

This letter addresses the study "Effectiveness and Safety of Finerenone in the Treatment of IgA Nephropathy Patients" by Qingqing Gao, which investigates finerenone as adjunct therapy in IgA nephropathy. While the study offers promising insights, key methodological limitations-including lack of randomization, blinding, and small sample size-raise concerns regarding selection bias and external validity. Additionally, the omission of important clinical parameters such as blood pressure and inflammatory markers limits the scope of safety monitoring. The letter emphasizes the need for larger, multicenter, randomized controlled trials with improved monitoring strategies, including MEST-C scoring, to enhance diagnostic accuracy and outcome interpretation. Despite the study's strengths in reporting UACR reduction and stable eGFR, a more rigorous research design is essential to fully evaluate finerenone's long-term efficacy and safety in this patient population.

e12630 Background: Microbial metabolic pathways are known to influence immunotherapy resistance and these may similarly contribute to resistance in LA TNBC treated with NA ICIs. We previously reported differential microbial response predictors of treatment in this population. In this analysis, we are presenting updated data demonstrating differences in the expanded profile of microbiome, metabolites and cytokines. Methods: 35 patients who received NA pembrolizumab and chemotherapy for LA TNBC were identified at Moffitt Cancer Center and Tampa General Hospital between February 2022 to October 2023. Blood and stool samples were collected at initiation and completion of NA therapy and/or when the patients developed grade 3 or higher toxicity to therapy. The goal was to study the gut microbiome, composition and metabolites associated with pCR We conducted shotgun metagenomic sequencing on 59 stool samples, GC-MS sequencing in 59 stool and 56 plasma for metabolites and 25 serum cytokines. Patient characteristics were as follows: 26 Caucasian, 4 African-American, 2 Hispanic, 3 unknown, median age 52 years. 23 patients had stage II, while 12 patients had stage III, 17 patients were node negative while 18 were node positive disease. Results: Response was assessed in 34 patients, of which 12 had pCR (ypT0/is ypN0) while 22 had residual disease (RD), 5 (14%) patients had recurrence. At median follow up of 20.38 months, the percentage survival was 87.3% (95% CI: 69.3-95.1). One patient experienced disease progression while on NA therapy, and 6 developed grade 3-4 immune-related adverse events, resulting in treatment discontinuation, with one patient succumbing to these complications. Butyric acid is a known microbial metabolite associated with immunosuppressive effects. However, its role in TNBC role has not been explored. We report that lower butyric acid is associated with a significantly higher likelihood of pCR in LA TNBC,HR 0.9, p < 0.05. Meanwhile amino acid metabolites tyrosine and phenylalanine are associated with better pCR with HR 3.99 and HR 1.2, p < 0.05 respectively. No difference in alpha diversity at baseline or follow-up comparing patient pCR vs RD. Beta diversity at follow-up was statistically different between patients with pCR vs RD while no difference noted at baseline. Higher levels of CXCL5, CCL2 were noted in patients with RD. Conclusions: To our knowledge this is the first analysis in patients with LA TNBC treated with NA ICB showing differential immunosuppressive microbial metabolites, particularly Short Chain Fatty Acids which are associated with pCR. Biomarkers play a vital role in identifying patients who are most likely to respond to immune checkpoint blockade (ICB). The gut microbiome may act as a predictive biomarker for neoadjuvant ICB response in TNBC, necessitating validation in larger studies.