Breast carcinoma is the most common cancer among women worldwide that consists of a heterogeneous group of subtype diseases. The whole-slide images (WSIs) can capture the cell-level heterogeneity, and are routinely used for cancer diagnosis by pathologists. However, key driver genetic mutations related to targeted therapies are identified by genomic analysis like high-throughput molecular profiling. In this study, we develop a deep-learning model to predict the genetic mutations and biological pathway activities directly from WSIs. Our study offers unique insights into WSI visual interactions between mutation and its related pathway, enabling a head-to-head comparison to reinforce our major findings. Using the histopathology images from the Genomic Data Commons Database, our model can predict the point mutations of six important genes (AUC 0.68–0.85) and copy number alteration of another six genes (AUC 0.69–0.79). Additionally, the trained models can predict the activities of three out of ten canonical pathways (AUC 0.65–0.79). Next, we visualized the weight maps of tumor tiles in WSI to understand the decision-making process of deep-learning models via a self-attention mechanism. We further validated our models on liver and lung cancers that are related to metastatic breast cancer. Our results provide insights into the association between pathological image features, molecular outcomes, and targeted therapies for breast cancer patients.

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and increased risk of cancer. The impacts of bariatric surgery on cancer risk in NAFLD patients are unknown. We investigated the effect of bariatric surgery on cancer risk in patients with NAFLD and severe obesity using the MarketScan database. Methods We conducted a retrospective cohort study of 18 to 64 years old newly diagnosed NAFLD patients with severe obesity between 2007 and 2017. We used Cox proportional hazard models to examine the association between bariatric surgery, modeled as a time-varying covariate, and the risks of any cancer and obesity-related cancer, while accounting for confounding using inverse probability of treatment weighting (IPTW). Results A total of 98,090 patients were included in the study, 33,435 (34.1%) received bariatric surgery. In those without surgery, 1898 incident cases of cancer occurred over 115,890.11 person-years of follow-up, compared with 925 cancer cases over 67,389.82 person-years among surgery patients (crude rate ratio, 0.84; 95% CI, 0.77- 0.91). The IPTW-adjusted risk of any cancer and obesity-related cancer was reduced by 18% (hazard ratio, 0.82; 95% CI, 0.76–0.89) and 25% (hazard ratio, 0.65; 95% CI, 0.56–0.75), respectively, in patients with versus without bariatric surgery. The adjusted risks of any cancer and obesity-related cancer were significantly lower in cirrhotic versus non-cirrhotic patients who underwent surgery. In cancer-specific models, bariatric surgery was associated with significant risk reductions for colorectal, pancreatic, endometrial, thyroid cancers, hepatocellular carcinoma, and multiple myeloma. Conclusion Bariatric surgery was associated with significant reductions in the risks of any cancer and obesity-related cancer in NAFLD patients with severe obesity.

Summary: Background/Aims: We examined the effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) initiation on long‐term Adverse Liver Outcomes (ALO) in patients with Metabolic Dysfunction‐Associated Steatotic Liver Disease (MASLD) cirrhosis and type 2 diabetes using real‐world data from the MarketScan database.Methods: We conducted a retrospective cohort study of patients with MASLD cirrhosis and type 2 diabetes between 2012 and 2020. Cox proportional hazard models examine the association between GLP‐1RAs initiation, modelled as time‐dependent, and the risk of ALO, a composite endpoint defined by the first occurrence of hepatic decompensation(s), portal hypertension, hepatocellular carcinoma (HCC) or liver transplantation (LT). We used Overlap Propensity Score Weighting (OPSW) to account for confounding. The study included 459 GLP‐1RAs and 4837 non‐GLP‐1RAs patients.Results: The non‐GLP‐1RAs patients presented with 1411 (29%) ALO over 7431.7 person years, while GLP‐1RAs patients had 32 (7%) ALO over 586.6 person years – risk rate difference 13.5 (95% CI: 11.4–15.7) per 100 person‐years. The OPSW‐adjusted risk of ALO was reduced by 36% (hazard ratio [HR]: 0.64; 95% CI: 0.54–0.76) in patients with vs. without GLP‐1RAs initiation. GLP‐1RAs initiation was associated with significant reductions in the adjusted risk of hepatic decompensation (HR: 0.74; 95% CI: 0.61–0.88), portal hypertension (HR: 0.73; 95% CI: 0.60–0.88), HCC (HR: 0.37; 95% CI: 0.20–0.63) and LT (HR: 0.24; 95% CI: 0.12–0.43).Conclusion: The use of GLP‐1RAs was associated with significant risk reductions in long‐term adverse liver outcomes, including hepatic decompensation, portal hypertension, HCC and LT, in MASLD cirrhosis patients with type 2 diabetes.

Acute kidney injury and hepatorenal syndrome in cirrhosis

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the US, affecting more than 30% of adults.¹ It is characterized by hepatic steatosis in the absence of substantial alcohol consumption, long-term use of steatogenic drugs, or genetic disorders.² The disease encompasses the full spectrum of fatty liver disease, including nonalcoholic fatty liver, nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis.^2,3 Although individuals with NAFLD are typically asymptomatic, NASH has been associated with increased risk of advanced fibrosis, NASH-related cirrhosis, and hepatocellular carcinoma.^4-6

The circadian clock and gut microbiome play integral roles in preserving metabolic homeostasis. Circadian rhythms represent an endogenous time-keeping system that regulates cell and organ functions and synchronizes physiology with external cues to establish metabolic homeostasis. A variety of functions throughout the gastrointestinal tract and liver are under circadian control, including nutrient transport, processing, and detoxification. The gut microbiota also plays an essential role in host metabolism, regulating processes such as digestion, inflammatory modulation, and bile acid metabolism. Both the circadian clock and the gut microbiota influence each other in a reciprocal fashion, as gut dysbiosis can precipitate circadian asynchrony, and vice-versa. Disruption of either system impacts homeostasis in a bidirectional manner and can contribute to metabolic dysfunction. Evidence suggests such disruptions can lead to the development of metabolic diseases, including obesity, diabetes, nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma. This review will provide a basic overview of the circadian and gut microbial systems, how they are intertwined, and their impact on the liver and gastrointestinal tract and in the development of metabolic disease. Particular areas of discussion include epigenetic regulation of circadian pathways as well as a mechanistic overview of microbial dysbiosis. In addition, therapeutic targets of these systems, including dietary modifications, behavioral modifications, and microbial-directed therapies, will be explored.