Michael P. McRae

Background/Objectives: Oral potentially malignant disorders (OPMDs) require accurate risk stratification to identify patients at the highest risk for severe oral epithelial dysplasia (OED) or oral squamous cell carcinoma (OSCC). We developed and internally validated the oral cancer numerical index (OCNI), a quantitative risk score derived from clinical features and deep learning-based brush cytology measurements. Methods: This retrospective model development and internal validation study was conducted using data from the multicenter Grand Opportunity study. Prospectively recruited subjects with OPMD with complete data were divided at the subject level into a training set (n = 384) and a holdout test set (n = 164) using a 70:30 diagnosis-stratified split. The primary endpoint was severe OED or OSCC versus benign diagnoses, and mild and moderate OED. Predictors included age, sex, tobacco history, lesion color, lesion size, multiple lesions, ulcerative morphology, and the percentages of differentiated squamous epithelial and small round cells derived from deep learning-based cytology. Prespecified rule-out and rule-in thresholds were selected in the training set to target 90% sensitivity and 90% specificity, respectively, and then applied to the holdout test set. Results: At the prespecified rule-out threshold (OCNI ≤ 37.6), sensitivity was 92% and negative predictive value was 97%. At the rule-in threshold (OCNI > 60.0), specificity was 89% and positive predictive value was 67%. Calibration was good in the holdout set (intercept, −0.07; slope, 1.13; Hosmer–Lemeshow p = 0.36), and OCNI increased significantly with worsening histopathologic severity. Conclusions: OCNI provided an objective, clinically interpretable estimate of risk for severe OED or OSCC, with strong rule-out and rule-in performance and good calibration. These findings support further external validation of OCNI as an adjunctive tool for oral lesion risk stratification.

INTRODUCTION: Factors associated with decline of hepatic function and increase in portal-systemic shunting, which herald clinical outcome in persons with compensated cirrhosis, are poorly characterized. We used cholate challenge to evaluate the associations of liver disease etiology, concomitant diabetes, and maintenance drug therapy, with the degree of hepatic dysfunction and portal-systemic shunting. METHODS: In the SHUNT-V study, there were 255 subjects with compensated (Child-Pugh class A) cirrhosis who underwent cholate challenge, involving oral administration of [2,2,4,4- ² H] cholate and measurement of its serum concentrations at 20 and 60 minutes. Test outputs included a disease severity index (DSI) to assess global liver function and SHUNT% to assess portal systemic shunting. RESULTS: Eighty-seven percent of subjects were overweight, 65% were obese, 48% had metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), 51% had type 2 diabetes mellitus, 49% were taking anti-diabetic drugs, and 45% were taking lipid-lowering drugs. Laboratory values and clinical scores of MASLD/MASH subjects were similar to subjects with other etiologies for liver disease. In univariable regression, MASLD/MASH, diabetes mellitus, metformin, and statins were associated with lower DSI and SHUNT%. In multivariable regression, lower DSI was attributable to statins ( P = 0.0354) and metformin ( P = 0.0561). The combined use of lipid-lowering and anti-diabetic drugs, compared with no use, was associated with 19% reduction in DSI. CONCLUSION: Concomitant use of statins alone or in combination with metformin was independently associated with preserved hepatic function (DSI) and reduced portal-systemic shunting (SHUNT%).

Background/Objectives: Compensated advanced chronic liver disease (cACLD) affects millions and carries risk for portal hypertension, large varices, and clinical decompensation. The HepQuant DuO^® test provides a blood-based assessment of liver function and physiology, generating a disease severity index (DSI) validated for risk stratification. A retrospective, real-world, observational analysis was conducted to evaluate the utility of HepQuant DuO’s DSI cutpoint (18.3) in guiding endoscopy and clinical management decisions for patients with cACLD in the United States. Methods: De-identified data from 87 cases with cACLD were extracted from physician-provided Statements of Medical Necessity documenting the reasons for the HepQuant DuO test. The primary endpoint was concordance of endoscopy decisions with DSI ≤ 18.3 (avoid) or >18.3 (proceed). The secondary endpoint was concordance of clinical management intensity with the same cutpoint. Results: Among the 55 cases analyzed for endoscopy decisions, overall concordance with DSI 18.3 was 93% (p < 0.001 by Fisher’s exact test): 96% of cases with DSI ≤ 18.3 avoided endoscopy, and 90% with DSI > 18.3 underwent endoscopy. For the 45 cases assessing management intensity, overall concordance was 89% (p < 0.001): 90% of cases with DSI ≤ 18.3 had reduced follow-up, and 89% with DSI > 18.3 had intensified management. The cohort exhibited broad functional heterogeneity not captured by standard labs or elastography. Conclusions: HepQuant DuO’s DSI cutpoint 18.3 demonstrated strong concordance with real-world clinical decisions, supporting its utility for risk stratification, optimizing endoscopy use, and tailoring management in cACLD.

Endoscopic surveillance for patients with compensated advanced chronic liver disease (cACLD) is currently guided by the presence or size of esophageal varices. Current guidelines recommend repeat endoscopy every 2–3 years for patients with no varices and every 1–2 years for those with small varices, but these intervals are based largely on expert opinion rather than objective risk stratification. We evaluated the Disease Severity Index (DSI) from the oral cholate challenge test as a predictor of clinical outcomes in 195 patients from the Hepatitis C Anti-viral Long-term Treatment against Cirrhosis (HALT-C) Trial (ClinicalTrials.gov, NCT00006164) with cACLD with no or small esophageal varices. Subjects were stratified into four clinical risk categories based on DSI and platelet count: DSI ≤18.3 (low risk), DSI ≤24 with platelet count >135 nL⁻¹ (low-to-moderate risk), DSI ≤24 with platelet count ≤135 nL⁻¹ (moderate-to-high risk), and DSI >24 (high risk). Kaplan-Meier analysis demonstrated a stepwise increase in adverse outcomes (variceal hemorrhage, ascites, encephalopathy, Child-Pugh progression, transplant, and death) across these categories. In multivariable logistic regression, DSI was a highly significant predictor of clinical outcome (P<0.001), while categories of no or small esophageal varices was not (P=0.07). Based on these findings, we recommend integrating DSI into surveillance strategies to guide the timing of repeat endoscopy: later endoscopy (2–3 years) for lower-risk patients and earlier endoscopy (1–2 years) for higher-risk patients. We recommend repeat DSI testing every 2–3 years for low risk, 1.5–2 years for low-to-moderate risk, 1–1.5 years for moderate-to-higher risk, and <1 year for highest risk. These results suggest that DSI is a robust, noninvasive tool for refining timing of repeat endoscopy and optimizing resource utilization in cACLD, regardless of disease etiology.

Background: Fontan circulation (FC) in complex congenital heart disease is characterized by altered hemodynamics and associated with Fontan‐associated liver disease. Patients with FC may exhibit abnormalities in cholate clearance due to abnormal perfusion. We aimed to compare cholate clearance in adults with FC to healthy controls and explore associations between cholate clearance and clinical features. Methods and Results: This is a prospective cohort study of patients with FC ≥18 years of age between 2019 and 2022. Systemic and portal hepatic clearance of cholate was assessed using a dual cholate clearance assay (HepQuant Shunt), measuring systemic and portal hepatic filtration rates (HFRs). Systemic HFR/portal HFR ratio (SHUNT%) was calculated. Participants with FC and healthy controls were compared using the Fisher exact test and Wilcoxon test. Univariable regression and multivariable analyses determined associations with clinical variables. There were 35 participants with FC (54% women; median age 29.0 years [interquartile range, 24.0–36.0], 91% White) and 26 controls. In addition to lower platelet counts and higher aspartate aminotransferase to platelet ratio index, and Fibrosis‐4 indices, FC participants had lower systemic HFR and portal HFR. SHUNT% was comparable with controls but ranged from 8% to 76%, with 8 (23%) having SHUNT% >30%. In those with FC, increase in SHUNT% was associated with elevated Fontan pressure, higher aortopulmonary collateral flow, decreased oxygen saturation, elevated NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) levels, thrombocytopenia, and Fibrosis‐4 ≥1.45. Conclusions: Cholate clearance, as defined by systemic and portal HFR, is impaired in those with FC. Features of worse Fontan physiology correlate with higher SHUNT%, supporting the hypothesis that hemodynamic derangements play a role in progression of Fontan‐associated liver disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03726229.