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Despite advances in pharmacogenomics that have led to innovative therapeutic strategies, substantial interindividual variability in drug efficacy and toxicity persists. Both endogenous and exogenous factors contribute to this unexplained variation, resulting in suboptimal treatment effectiveness, unnecessary healthcare costs, preventable mortality, and significant human suffering. The emerging field of exposomics is aimed at addressing the complex exposures that impact human health and offers an opportunity to interrogate how these exposures influence drug actions and outcomes. Here, we introduce pharmacoexposomics as a complementary framework that systematically quantifies the body's metabolic response to drug and environmental exposures using high-resolution mass spectrometry. We then present IndiPHARM (Individualized Pharmacology), a multi-institution, Advanced Research Projects Agency for Health–supported platform designed to integrate population-scale pharmacoexposomics with pharmacogenomics and clinical data to elucidate interindividual variability in drug response, identify adverse reactions, and inform tailored, effective treatment strategies that advance precision medicine.

Abstract Objectives Fibronodular hepatocellular carcinoma (FN-HCC) is a newly described variant of hepatocellular carcinoma (HCC), with only 29 cases reported. Histologically, it is divided into multiple smaller, well-defined tumor nodules by extensive fibrosis. Its differential diagnosis includes other HCC variants characterized by fibrous stroma, such as fibrolamellar hepatocellular carcinoma and scirrhous hepatocellular carcinoma. Fibronodular hyperplasia may also be considered in the differential diagnosis. We are reporting 7 cases to help better understand this entity. Methods We retrospectively identified 7 cases of FN-HCC and analyzed the clinical and histologic features of each tumor, as well as disease progression and patient prognosis. Results The FN-HCC cases were diagnosed at a median age of 58 years (range, 40-75 years), with a male predilection (n = 6, 86%). Most patients were White (n = 6, 86%), and 1 was African American (n = 1, 14%). Tumors had a mean size of 3.15 cm (range, 1-9 cm) and were mainly located in the right lobe (n = 5, 71%). Background liver was cirrhotic in 6 cases (86%). Five patients were hepatitis C positive (71%). All tumors were surgically removed, with a free resection margin. Among 3 patients with evident vascular invasion, 1 had a positive lymph node. This patient had tumor metastasis 6 years later; otherwise, all patients were disease free on follow-up. Conclusions Our cohort was concordant with published data showing a male predilection, hepatitis C association, and good prognosis when the disease is discovered before metastasis and is surgically excised with negative margins. However, it contradicts the published literature that associates FN-HCC with the absence of advanced fibrosis/cirrhosis.

Importance Adjuvant radiotherapy can improve locoregional control and survival in patients with olfactory neuroblastoma (ONB), particularly with advanced-stage and histologic-grade disease. Standard radiotherapy treatment is with intensity-modulated radiotherapy (IMRT). Proton beam radiotherapy (PBRT) provides theoretical advantages in greater sparing of dose to uninvolved organs at risk. Objective To investigate if there are differences in the effectiveness and radiation treatment–related adverse events (RTAEs) between adjuvant IMRT and PBRT for patients with ONB. Design, Setting, and Participants This propensity score–matched cohort study included patients with ONB treated between February 2005 and April 2021 with either IMRT or PBRT at 9 academic tertiary care centers in North America. Patients were matched 1:2 based on age, modified Kadish stage, and Hyams grade. Data were analyzed from July 2024 to January 2025. Exposure Adjuvant IMRT or adjuvant PBRT. Main Outcomes and Measures Local recurrence-free survival (RFS), any RFS, and overall survival (OS). RTAEs, ie, grade 2 events or higher based on Common Terminology Criteria for Adverse Events, were recorded for both modalities. Results Of 54 included patients, 27 (50%) were female, and the mean (SD) age was 46.2 (15.4) years. A total of 18 were treated with PBRT and 36 were treated with IMRT. Most patients had modified Kadish stage C disease (33 of 54 [61%]), and 24 patients (44%) had Hyams grade III or IV disease. The RTAE rate was 20% (8 of 40); IMRT had a rate of 21% (6 of 29), and PBRT had a rate of 18% (2 of 11). The difference in the point estimates for 10-year RFS showed a potential clinical benefit favoring IMRT, although the wide confidence interval indicates uncertainty (10-year RFS: IMRT, 63.3%; 95% CI, 44.6-89.8; PBRT, 37.8%; 95% CI, 14.2-100; difference, 25.5 percentage points; 95% CI, −17.6 to 68.6). There were no clinically meaningful differences in 10-year local RFS (IMRT, 75.6%; 95% CI, 59.8-95.4; PBRT, 72.7%; 95% CI, 45.2-100; difference, 2.9 percentage points; 95% CI, −35.9 to 41.7) or 10-year OS (IMRT, 61.8%; 95% CI, 42.8-89.1; PBRT, 57.1%; 95% CI, 24.3-100; difference, 4.7 percentage points; 95% CI, −49.2 to 58.6), although wide confidence intervals indicate considerable uncertainty. Conclusions and Relevance Due to the imprecision of estimates, no definitive conclusions can be made regarding the comparative effectiveness of IMRT vs PBRT for patients with ONB. These preliminary data may inform the design of appropriately powered prospective studies evaluating the efficacy of PBRT vs IMRT in this population.

ABSTRACT We report the first known use of a trans-sigmoidal endoscopic ultrasound-guided biopsy in a patient with a simultaneous pancreas-kidney transplant, following failed conventional percutaneous biopsy methods. A 50-year-old man with a simultaneous pancreas-kidney transplant was suspected of graft dysfunction. Multiple percutaneous biopsies were unsuccessful due to anatomical barriers. After a multidisciplinary review, a trans-sigmoidal endoscopic ultrasound approach was attempted, yielding sufficient tissue for histopathology without complications. Histology revealed no evidence of acute rejection. This novel technique expands the potential for biopsy in complex transplant anatomies and should be considered in highly selected cases within specialized centers.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Introduction. Increased steatosis on preimplant liver frozen section is associated with delayed graft function and primary nonfunction. Efforts to standardize histologic assessment have proven difficult. Frozen section artifact and lipopeliosis complicate the detection of steatosis. We aimed to develop and validate an AI model to recognize large droplet fat and fat induced artifact (FIA)/lipopeliosis on preimplantation frozen section and to correlate the AI results with post-transplant clinical parameters. Methods. The model was applied to 161 consecutive liver transplant specimens with preimplant slides. Results were correlated with traditional and Banff histologic assessment and clinical parameters. Results. By traditional assessment, steatosis ranged from 0%–40%. The AI model identified a range of 0 to 15.9% steatosis. There was no difference in patient survival by any measures of steatosis. AI steatosis correlated with increased risk of early allograft dysfunction (OR = 1.63, P < .001), respiratory failure (OR = 1.21, P = .003), and more advanced fibrosis (OR = 1.18, P = .030), but was not correlated with graft or patient survival. FIA/lipopeliosis were identified in a range of 0 to 6.42%. In univariate analysis the percentage of FIA/lipopeliosis correlated with both graft and patient survival ( P = .044 and P = .009, respectively), but was not associated with increased risk of early allograft dysfunction, respiratory failure, or advanced fibrosis. Conclusions. We developed an AI model that quantitates large droplet fat and FIA/lipopeliosis on frozen section slides and found a correlation with post-transplant outcomes. Further studies on larger, multi-institutional cohorts with higher fat containing donors are necessary to determine the role this model may have in organ acceptance decisions.

Ectopic liver is a rare congenital anomaly characterized by the presence of liver tissue outside the normal liver without any direct connection to it. These lesions are usually detected incidentally during clinical evaluation for other issues. However, they sometimes mimic neoplastic lesions both clinically and radiologically, which poses diagnostic challenges. Here, we present 5 patients with ectopic liver, 4 of which mimicked neoplastic lesions. The first was a 54-year-old woman diagnosed with multiple liver lesions and an enlarged gastro-hepatic lymph node, suspected to be a primary hepatic neoplasm with metastasis. Upon resection, it was found to be a hepatocellular adenoma in the liver and intraabdominal ectopic liver tissue with a small hepatocellular adenoma. Patient 2 was a 36-year-old woman presenting with palpitations and shortness of breath. An echocardiogram revealed a right atrial mass, which was identified as ectopic liver upon microscopic examination. The third patient was a 57-year-old woman with intermittent abdominal pain who underwent cholecystectomy. Microscopy revealed ectopic liver tissue on the gallbladder's serosal surface, along with chronic cholecystitis. The fourth was a 36-year-old woman with a gallbladder polyp, which on microscopy revealed ectopic liver tissue with no other abnormalities in the gallbladder. The fifth patient was a 57-year-old woman presenting with shortness of breath, weakness, and right atrial mass, which was confirmed as ectopic liver. These patients illustrate varied presentations of ectopic liver, sometimes mimicking neoplasia. Hepatocellular adenomas arising in ectopic liver and ectopic liver in intracardiac locations are extremely rare and can be a diagnostic pitfall, as they can clinically, radiologically, and pathologically mimic serious conditions like neoplasia.