Joshua Norman

All Publications

• Enhancing the prognostic accuracy of the RETREAT score with AFP-L3 and DCP tumor markers. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Norman, J. S., Li, P. J., Kotwani, P., Yao, F. Y., Pham, S., Gamez, J., Mehta, N. 2024

  Abstract

  BACKGROUND: The RETREAT (Risk Estimation of Tumor Recurrence after Transplant) Score is a validated tool to predict post-transplant HCC recurrence risk. AFP bound to Lens culinaris agglutinin (AFP-L3) and des-gamma-carboxyprothrombin (DCP) measured at transplant predict worse post-LT survival and may improve the RETREAT score.RESULTS: Our cohort comprised 284 patients transplanted for HCC who were within or downstaged to Milan, with 23 (8.1%) experiencing HCC recurrence. The modified RETREAT (mRETREAT) score assigns AFP-L3 ≥15% 2 points and DCP ≥ 7.5ng/mL 3 points. Patients with a modified RETREAT score ≥4 showed a 3-year recurrence-free survival (RFS) of 73.2%, versus 97.8% RFS if <4. In comparison, the original RETREAT score had a 3-year RFS of 80.0% if ≥2 versus 98.0% if <2. mRETREAT demonstrated a superior AUC of 0.86, compared to original RETREAT's 0.82, and enhanced calibration and accuracy with a lower Brier score (0.04).CONCLUSION: The integration of AFP-L3 and DCP into the RETREAT score appears to enhance prediction of post-LT HCC recurrence. Given these promising results, further study in a larger multi-center cohort is warranted for empiric derivation and validation of a modified RETREAT score including AFP-L3 and DCP.

  View details for DOI 10.1097/LVT.0000000000000551

  View details for PubMedID 39661334

• Multi-HCC: A practical model to prioritize patients with hepatocellular carcinoma on the liver transplant waiting list. Gastroenterology Norman, J., Mehta, N., Kim, W. R., Liang, J. W., Biggins, S. W., Asrani, S. K., Heimbach, J., Charu, V., Kwong, A. J. 2024

  Abstract

  Currently, patients with hepatocellular carcinoma (HCC) in the United States are assigned a uniform score relative to the median MELD at transplant (MMaT-3) after a minimum 6-month waiting period. Here, we develop a risk stratification model for patients with HCC, using the available and objective variables at time of listing.We identified adult liver transplant candidates with approved HCC exception in the OPTN database from 2015-2022. Cox regression analysis, as well as machine learning models (random survival forest and neural network), were used to develop models predicting waitlist dropout. Predicted waitlist dropout for patients with HCC was scaled to patients without exception using MELD 3.0.18,273 patients with HCC were listed for liver transplant with a median MELD 3.0 of 11 (IQR 8-15) and AFP 6 (IQR 4-17). Since all models performed similarly, a parsimonious Cox-based model comprised of MELD 3.0, AFP, and tumor burden, Multi-HCC (Model for Urgency for Liver Transplantation in HCC), was selected, with a c-statistic of 0.71 (95% CI 0.69-0.74) for 6-month dropout in the validation set, outperforming previous models, including HALT-HCC, deMELD, and MELD-Eq.An urgency-based priority system for patients with HCC, similar to MELD for patients with chronic liver disease, is achievable with a parsimonious model incorporating AFP, MELD 3.0, and tumor size. This approach can be applied to the liver allocation system to prioritize patients with HCC and can inform decision-making regarding urgency weights for exception cases in the upcoming continuous distribution system.

  View details for DOI 10.1053/j.gastro.2024.11.015

  View details for PubMedID 39622302

• CALIBRATING EXCEPTION POINTS FOR CONTINUOUS DISTRIBUTION: WHY MATCHING HCC TO NON-HCC WAITLIST DROPOUT FALLS SHORT Norman, J., Liang, J., Mehta, N., Charu, V., Kwong, A. LIPPINCOTT WILLIAMS & WILKINS. 2024: S998-S999

  View details for Web of Science ID 001366004002365

• Development and validation of a biomarker index for HCC treatment response. Hepatology communications Liang, J., Li, P. Y., Norman, J., Lauzon, M., Yeo, Y. H., Trivedi, H., Ayoub, W. S., Kuo, A., Friedman, M. L., Sankar, K., Gong, J., Osipov, A., Hendifar, A., Todo, T., Kim, I., Voidonikolas, G., Brennan, T. V., Wisel, S. A., Steggarda, J., Kosari, K., Saouaf, R., Nissen, N., Yao, F., Mehta, N., Yang, J. D. 2024; 8 (7)

  Abstract

  Serum AFP-L3%, AFP, and DCP are useful biomarkers for HCC detection, but their utility in assessing treatment response remains unknown. We aim to evaluate the accuracy of a biomarker model in the detection of posttreatment viable tumors.For model derivation, recipients with HCC undergoing liver transplant from 2018 to 2022 who had biomarkers collected within 3 months before transplant were included. We developed a generalized linear model for detecting posttreatment viable tumors with the 3 biomarkers as covariates, which we termed the "LAD Score." An independent cohort of 117 patients with HCC was used for external validation.Among 205 recipients of transplant, 70.2% had evidence of viable tumor on explant. The median LAD score was higher among patients with viable versus nonviable tumors (1.06 vs. 0.465, p < 0.001). The LAD score had a sensitivity of 55.6% and a specificity of 85.1% at the cutoff of 0.927, which was more accurate than imaging for detecting posttreatment viable tumors (AUROC 0.736 vs. 0.643, respectively; p = 0.045). The superior performance of the LAD score over imaging is primarily driven by its greater accuracy in detecting tumors <2 cm in diameter (AUROC of the LAD score 0.721 vs. imaging 0.595, p = 0.02). In the validation data set, the LAD score had an AUROC of 0.832 (95% CI: 0.753, 0.911) with a sensitivity of 72.5% and a specificity of 89.4% at the cutoff of 0.927.Our findings suggest the utility of LAD score in treatment response assessment after locoregional therapy for HCC, particularly in detecting small tumors. A larger prospective study is in progress to validate its accuracy and evaluate its performance in recurrence monitoring.

  View details for DOI 10.1097/HC9.0000000000000466

  View details for PubMedID 38896084

  View details for PubMedCentralID PMC11186807

• Dual Positivity for AFP-L3 and DCP Identifies Patients at Exceptionally High Risk for Post-LT HCC Recurrence. Journal of hepatology Norman, J. S., Mehta, N. 2024

  View details for DOI 10.1016/j.jhep.2024.02.006

  View details for PubMedID 38346579

• Management of ascites and volume overload in patients with cirrhosis. Clinical liver disease Kwong, A. J., Norman, J., Biggins, S. W. 2024; 23 (1): e0115

  View details for DOI 10.1097/CLD.0000000000000115

  View details for PubMedID 38343635

  View details for PubMedCentralID PMC10857675

• Reply to: Incorporating AFP-L3 and DCP in selecting patients with hepatocellular carcinoma for liver transplantation: what are the optimal criteria? Journal of hepatology Norman, J. S., Mehta, N. 2023

  View details for DOI 10.1016/j.jhep.2023.12.017

  View details for PubMedID 38154740

• A NOVEL HCC WAITLIST DROPOUT SCORE: BIOMARKER INTEGRATED DROPOUT GRADIENT ESTIMATION (BRIDGE) Li, J., Liang, J., Agopian, V. G., Nunez, K., Norman, J., Kim, N., Yum, J., Gumate, S., Cohen, A. J., Kosari, K., Nissen, N., Yao, F., Thevenot, P., Yang, J., Mehta, N. LIPPINCOTT WILLIAMS & WILKINS. 2023: S354

  View details for Web of Science ID 001094865400370

• Author Spotlight: Joshua Norman. Digestive diseases and sciences Norman, J. 2023

  View details for DOI 10.1007/s10620-023-08109-7

  View details for PubMedID 37713039

• AFP-L3 and DCP Strongly Predict Early Hepatocellular Carcinoma Recurrence After Liver Transplantation. Journal of hepatology Norman, J. S., Li, P. J., Kotwani, P., Shui, A. M., Yao, F., Mehta, N. 2023

  Abstract

  BACKGROUND & AIMS: Alpha-fetoprotein (AFP) predicts hepatocellular carcinoma (HCC) recurrence after liver transplant (LT) but remains an imperfect biomarker. The role of DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) in predicting HCC recurrence remains incompletely characterized. AFP-L3 and DCP could identify patients at high risk of post-transplant HCC recurrence and serve as liver transplant exclusion criteria to defer transplant until patients receive additional risk-reducing pre-transplant local regional therapy.METHODS: This prospective cohort study included consecutive HCC patients who underwent LT (within or down-staged to Milan criteria) between 2017 and 2022. Pre-transplant AFP, AFP-L3, and DCP measurements were obtained. The primary endpoint was the ability of biomarkers to predict HCC recurrence-free survival.RESULTS: This cohort included 285 patients with a median age of 67 (IQR 63-71). At LT, median biomarker values were AFP 5.0ng/mL (IQR 3.0-12.1), AFP-L3 6.7% (0.5-13.2), and DCP 1.0ng/mL (0.3-2.8). Most (94.7%) patients received pre-LT local regional therapy (LRT). After a median post-LT follow-up of 3.1 years, HCC recurrence was observed in 18 (6.3%) patients. AFP-L3 and DCP outperformed AFP with C-statistics of 0.81 and 0.86 respectively, compared with 0.74 for AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted 61.1% of HCC recurrences whereas among 265 patients not meeting this threshold, only 7 (2.6%) recurred. The Kaplan-Meier recurrence-free survival at 3 years post-LT was 43.7% for patients with dual-positive biomarkers compared to 97.0% for all others (p<0.001).CONCLUSIONS: Dual-positivity for AFP-L3 ≥15% and DCP ≥7.5 strongly predicted post-LT HCC recurrence. This model could refine LT selection criteria and identify high-risk HCC patients to receive additional LRT with LT on hold until biomarker reduction is achieved.

  View details for DOI 10.1016/j.jhep.2023.08.020

  View details for PubMedID 37683735

• Milky Way: Management of Primary Intestinal Lymphangiectasia. Digestive diseases and sciences Norman, J. S., Testa, S., Wang, C. X., Savage, T. 2023

  View details for DOI 10.1007/s10620-023-08077-y

  View details for PubMedID 37634185

  View details for PubMedCentralID 7789053

• Optimizing liver transplant prioritization for hepatocellular carcinoma through risk stratification. Current opinion in organ transplantation Norman, J., Mehta, N., Kwong, A. 2023

  Abstract

  In the United States, candidates with hepatocellular carcinoma (HCC) meeting standardized qualifying criteria receive similar priority on the liver transplant waiting list through Model for End-Stage Liver Disease exception points, without consideration of the dropout risk or relative expected benefit from liver transplantation. A more nuanced allocation scheme for HCC is needed to better represent the individual urgency for liver transplant and optimize organ utility. In this review, we discuss the development of HCC risk prediction models for practical use in liver allocation.HCC is a heterogenous disease that requires improved risk stratification for patients who fall within current transplant eligibility criteria. Several models have been proposed, though none have been adopted in clinical practice or liver allocation to date, due to various limitations.Improved HCC risk stratification for liver transplant candidates is needed to more accurately represent their urgency for transplant, with continued attention to the potential impact on post-liver transplant outcomes. Plans to implement a continuous distribution model for liver allocation in the United States may provide an opportunity to re-consider a more equitable allocation scheme for patients with HCC.

  View details for DOI 10.1097/MOT.0000000000001080

  View details for PubMedID 37339511

• A MODIFIED RETREAT SCORE INCORPORATING AFP-L3 AND DCP BIOMARKERS IMPROVES POST-LIVER TRANSPLANT HCC RECURRENCE RISK PROGNOSTICATION Norman, J., Kotwani, P., Shui, A., Dodge, J. L., Yao, F., Mehta, N. WILEY. 2022: S58-S59

  View details for Web of Science ID 000870796600065

• Social Determinants of Mental Health and Physician Aid-in-Dying: The Real Moral Crisis AMERICAN JOURNAL OF BIOETHICS Ho, A., Norman, J. S. 2019; 19 (10): 52-54

  View details for DOI 10.1080/15265161.2019.1654025

  View details for Web of Science ID 000487986000019

  View details for PubMedID 31566494

• Opposing roles of Toll-like receptor and cytosolic DNA-STING signaling pathways for <i>Staphylococcus aureus</i> cutaneous host defense PLOS PATHOGENS Scumpia, P. O., Botten, G. A., Norman, J. S., Kelly-Scumpia, K. M., Spreafico, R., Ruccia, A. R., Purbey, P. K., Thomas, B. J., Modlin, R. L., Smale, S. T. 2017; 13 (7): e1006496

  Abstract

  Successful host defense against pathogens requires innate immune recognition of the correct pathogen associated molecular patterns (PAMPs) by pathogen recognition receptors (PRRs) to trigger the appropriate gene program tailored to the pathogen. While many PRR pathways contribute to the innate immune response to specific pathogens, the relative importance of each pathway for the complete transcriptional program elicited has not been examined in detail. Herein, we used RNA-sequencing with wildtype and mutant macrophages to delineate the innate immune pathways contributing to the early transcriptional response to Staphylococcus aureus, a ubiquitous microorganism that can activate a wide variety of PRRs. Unexpectedly, two PRR pathways-the Toll-like receptor (TLR) and Stimulator of Interferon Gene (STING) pathways-were identified as dominant regulators of approximately 95% of the genes that were potently induced within the first four hours of macrophage infection with live S. aureus. TLR signaling predominantly activated a pro-inflammatory program while STING signaling activated an antiviral/type I interferon response with live but not killed S. aureus. This STING response was largely dependent on the cytosolic DNA sensor cyclic guanosine-adenosine synthase (cGAS). Using a cutaneous infection model, we found that the TLR and STING pathways played opposite roles in host defense to S. aureus. TLR signaling was required for host defense, with its absence reducing interleukin (IL)-1β production and neutrophil recruitment, resulting in increased bacterial growth. In contrast, absence of STING signaling had the opposite effect, enhancing the ability to restrict the infection. These results provide novel insights into the complex interplay of innate immune signaling pathways triggered by S. aureus and uncover opposing roles of TLR and STING in cutaneous host defense to S. aureus.

  View details for DOI 10.1371/journal.ppat.1006496

  View details for Web of Science ID 000406623700031

  View details for PubMedID 28704551

  View details for PubMedCentralID PMC5526579