Publications by authors named "Amit G Singal"

342 Publications

Persistent Disparities in Colorectal Cancer Screening: A Tell-Tale Sign for Implementing New Guidelines in Younger Adults.

Cancer Epidemiol Biomarkers Prev 2022 Jun 23:OF1-OF9. Epub 2022 Jun 23.

School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas.

Background: In May 2021, the U.S. Preventive Services Task Force began recommending initiating colorectal cancer screening at age 45 (vs. 50) years.

Methods: We estimated prevalence of colorectal cancer screening (by colonoscopy, sigmoidoscopy, CT colonography, or stool-based tests) in adults ages 50 to 75 years using data from the National Health Interview Survey in 2000, 2003, 2005, 2008, 2010, 2013, 2015, and 2018. For each survey year, we estimated prevalence by age, race/ethnicity, educational attainment, family income, and health insurance. We also compared increases in prevalence of screening from 2000 to 2018 in 5-year age groups (50-54, 55-59, 60-64, 65-69, and 70-75 years).

Results: Overall, prevalence of colorectal cancer screening increased from 36.7% in 2000 to 66.1% in 2018. Screening prevalence in 2018 was lowest for age 50 to 54 years (47.6%), Hispanics (56.5%), Asians (57.1%), and participants with less than a high school degree (53.6%), from low-income families (56.6%), or without insurance (39.7%). Increases in prevalence over time differed by five-year age group. For example, prevalence increased from 28.2% in 2000 to 47.6% in 2018 (+19.4%; 95% CI, 13.1-25.6) for age 50 to 54 years but from 46.4% to 78.0% (+31.6%; 95% CI, 25.4%-37.7%) for age 70 to 75 years. This pattern was consistent across race/ethnicity, educational attainment, family income, and health insurance.

Conclusions: Prevalence of colorectal cancer screening remains low in adults ages 50 to 54 years.

Impact: As new guidelines are implemented, care must be taken to ensure screening benefits are realized equally by all population groups, particularly newly eligible adults ages 45 to 49 years.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-1330DOI Listing
June 2022

Ethnic disparities in early-onset gastric cancer: a population-based study in Texas and California.

Cancer Epidemiol Biomarkers Prev 2022 Jun 22. Epub 2022 Jun 22.

The University of Texas Southwestern Medical Center, Dallas, United States.

Background: Incidence rates of gastric cancer are increasing in young adults (age <50 years), particularly among Hispanic persons. We estimated incidence rates of early-onset gastric cancer (EOGC) among Hispanic and non-Hispanic White persons by census tract poverty level and county-level metro/non-metro residence.

Methods: We used population-based data from the California and Texas Cancer Registries from 1995-2016 to estimate age-adjusted incidence rates of EOGC among Hispanic and non-Hispanic White persons by year, sex, tumor stage, census tract poverty level, metro vs. non-metro county, and state. We used logistic regression models to identify factors associated with distant stage diagnosis.

Results: Of 3047 persons diagnosed with EOGC, 73.2% were Hispanic White. Incidence rates were 1.29 (95% CI 1.24, 1.35) and 0.31 (95% CI 0.29, 0.33) per 100,000 Hispanic White and non-Hispanic White persons, respectively, with consistently higher incidence rates among Hispanic persons at all levels of poverty. There was no statistically significant associations between ethnicity and distant stage diagnosis in adjusted analysis.

Conclusion: There are ethnic disparities in EOGC incidence rates that persist across poverty levels.

Impact: EOGC incidence rates vary by ethnicity and poverty; these factors should be considered when assessing disease risk and targeting prevention efforts.
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http://dx.doi.org/10.1158/1055-9965.EPI-22-0210DOI Listing
June 2022

Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease.

Sci Transl Med 2022 Jun 22;14(650):eabo4474. Epub 2022 Jun 22.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1 dendritic cells and dysfunctional CD8 T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.
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http://dx.doi.org/10.1126/scitranslmed.abo4474DOI Listing
June 2022

No increase in colorectal cancer screening in 2019 after American Cancer Society recommends starting screening at age 45.

Clin Gastroenterol Hepatol 2022 Jun 11. Epub 2022 Jun 11.

School of Public Health, University of Texas Health Science Center at Houston, Houston, TX.

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http://dx.doi.org/10.1016/j.cgh.2022.05.030DOI Listing
June 2022

Survival of cancer survivors with a new pancreatic cancer diagnosis.

Cancer Med 2022 Jun 8. Epub 2022 Jun 8.

School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.

Background: Persons newly diagnosed with pancreas cancer and who have survived a previous cancer are often excluded from clinical trials, despite limited evidence about their prognosis. We examined the association between previous cancer and overall survival.

Methods: This US population-based cohort study included older adults (aged ≥66 years) diagnosed with pancreas cancer between 2005 and 2015 in the linked Surveillance, Epidemiology, and End Results-Medicare data. We used Cox proportional hazards models to estimate stage-specific effects of previous cancer on overall survival, adjusting for sociodemographic, treatment, and tumor characteristics.

Results: Of 32,783 patients, 18.7% were previously diagnosed with another cancer. The most common previous cancers included prostate (29.0%), breast (18.9%), or colorectal (9.7%) cancer. More than half of previous cancers (53.9%) were diagnosed 5 or more years prior to pancreas cancer diagnosis or at an in situ or localized stage (47.8%). The proportions of patients surviving 1, 3, and 5 years after pancreas cancer were nearly identical for those with and without previous cancer. Median survival in months was as follows for those with and without previous cancer respectively: 7 versus 8 (Stage 0/I), 10 versus 10 (Stage II), 7 versus 7 (Stage III), and 3 versus 2 (Stage IV). Cox models indicated that patients with previous cancer had very similar or statistically equivalent survival to those with no previous cancer.

Conclusions: Given nearly equivalent survival compared to those without previous cancer, cancer survivors newly diagnosed with pancreas cancer should be considered for inclusion in pancreas cancer clinical trials.
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http://dx.doi.org/10.1002/cam4.4903DOI Listing
June 2022

Patient Navigation Increases Linkage to Care and Receipt of Direct-acting Antiviral Therapy in Patients with Hepatitis C.

Clin Gastroenterol Hepatol 2022 May 14. Epub 2022 May 14.

Parkland Health and Hospital System, Dallas, Texas; Department of Internal Medicine, Division of Infectious Disease and Geographic Medicine, UT Southwestern Medical Center, Dallas, Texas. Electronic address:

Background & Aims: Patient navigation interventions can improve health outcomes in underserved, low-income, and racial and ethnic minority groups, who often experience health disparities. We examined the effectiveness of patient navigation to improve linkage to hepatitis C virus (HCV) treatment receipt in a socioeconomically disadvantaged, racially diverse patient population.

Methods: We performed a pre-post analysis evaluating the effectiveness of a patient navigation program among baby boomers who tested positive for HCV in a safety-net health system. The usual care group (June 2013 to May 2015) and patient navigation group (January 2016 to December 2017) were balanced using a stabilized inverse probability of treatment weighting approach. We used logistic regression analyses to evaluate associations between patient navigation and linkage to care for HCV treatment evaluation, treatment initiation, and sustained virologic response.

Results: Among 1353 patients (62% black, 61% uninsured, 16% homeless), 769 were in the usual care group, and 584 were in the patient navigation group. The patient navigation group had significantly higher odds of linkage to care (odds ratio [OR], 3.7; 95% confidence interval [CI], 2.9-4.8) and treatment initiation (OR, 3.2; 95% CI, 2.3-4.2) within 6 months. The patient navigation group continued to have increased linkage to care (OR, 3.4; 95% CI, 2.7-4.3) and treatment initiation (OR 2.3; 95% CI, 1.7-3.0) at 12 months. However, there was no significant difference in sustained virologic response between the groups (86.9% vs 86.1%; P = .78).

Conclusions: Patient navigation was associated with significantly increased linkage to care and treatment initiation among patients with HCV infection. Patient navigation programs can be used to promote HCV elimination among traditionally difficult-to-reach patient populations.
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http://dx.doi.org/10.1016/j.cgh.2022.04.031DOI Listing
May 2022

Early detection of hepatocellular carcinoma: roadmap for improvement.

Expert Rev Anticancer Ther 2022 Jun 10;22(6):621-632. Epub 2022 May 10.

Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, US.

Introduction: Hepatocellular carcinoma (HCC) has a poor prognosis, related, in part, to frequent late-stage diagnosis. Improved implementation of effective HCC surveillance is critical to reduce HCC mortality.

Areas Covered: We performed a targeted literature review to identify intervention targets for improving HCC surveillance effectiveness, including enriched risk stratification tools, improved surveillance tools with higher accuracy for early HCC detection, and increasing surveillance adherence.

Expert Opinion: HCC surveillance has been demonstrated to be efficacious in several cohort studies but has lower surveillance effectiveness in clinical practice. HCC surveillance is currently recommended in all patients with cirrhosis, and improved risk stratification using clinical risk scores, genetic scores, and novel biomarkers are important to move from a 'one-size-fits-all' strategy to one more aligned with values of precision medicine. Current surveillance modalities, ultrasound, and AFP, miss over one-third of HCC at an early stage and are associated with potential surveillance harms, underscoring a need for alternative surveillance strategies with higher accuracy. MRI- and biomarker-based surveillance strategies have promising early data in phase II studies but require validation in phase III cohorts before routine use in practice. Finally, surveillance is underused in clinical practice, highlighting a need for intervention strategies to increase utilization.
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http://dx.doi.org/10.1080/14737140.2022.2074404DOI Listing
June 2022

Racial and ethnic disparities in early treatment with immunotherapy for advanced HCC in the United States.

Hepatology 2022 Apr 16. Epub 2022 Apr 16.

Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Background And Aims: Immunotherapy has emerged as an effective treatment for patients with advanced-stage HCC. We aimed to investigate the efficacy of immunotherapy for advanced HCC in a nationwide cohort and racial and ethnic disparities in access to immunotherapy.

Approach And Results: We used the US National Cancer Database to identify patients with tumor-node-metastasis stage 3 or 4 HCC between 2017 and 2018. We performed multivariable Cox regression to identify factors associated with overall survival (OS) and logistic regression to identify factors associated with receipt of immunotherapy. Of the 3,990 patients treated for advanced HCC, 3,248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR: 0.76, 95% CI: 0.65-0.88) after adjusting for covariates. There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted OR [aOR]: 0.63, 95% CI: 0.46-0.83) and Black patients (aOR: 0.71, 95% CI: 0.54-0.89) less likely to receive immunotherapy compared with White patients. There was a significant interaction between race-ethnicity and facility type, with higher disparity observed in nonacademic centers (interaction p = 0.004).

Conclusions: Immunotherapy was associated with improved OS compared with chemotherapy in advanced HCC. There are significant disparities in early access to immunotherapy, likely due to differential access to clinical trials and experimental therapies. A comprehensive approach to monitoring and eliminating racial-ethnic disparities in the management of advanced HCC is urgently needed.
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http://dx.doi.org/10.1002/hep.32527DOI Listing
April 2022

Clinical Outcomes of Patients with Suspicious (LI-RADS 4) Liver Observations.

Clin Gastroenterol Hepatol 2022 Apr 9. Epub 2022 Apr 9.

Department of Internal Medicine, UT Southwestern Medical Center, Department of Internal Medicine, Parkland Health and Hospital System, Dallas, Texas. Electronic address:

Hepatocellular cancer (HCC) surveillance is associated with increased curative treatment and improved survival, underscoring its importance in patients with cirrhosis. Surveillance is 1 step in a larger HCC screening continuum, and those with abnormal screening results must undergo diagnostic evaluation with multiphase computed tomography (CT) or magnetic resonance imaging (MRI). The Liver Imaging Reporting and Data System (LI-RADS) classifies liver observations in at-risk patients based on risk of malignancy and HCC, with LR-5 observations having a positive predictive value exceeding 95% for HCC. However, indeterminate liver nodules (ie, LR-3 or LR-4) are commonly observed in clinical practice, associated with heterogenous HCC risk, and have large variations in practice management. We previously reported the natural history of LR-3 observations in a multicenter cohort of patients with cirrhosis, demonstrating a high annual incidence for HCC development of 8.4 cases per 100 person-years; however, the natural history of LR-4 observations remains uncertain. Herein, we aimed to characterize clinical outcomes in patients with LR-4 observations in a multicenter cohort.
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http://dx.doi.org/10.1016/j.cgh.2022.03.038DOI Listing
April 2022

A Fucosylated Glycopeptide as a Candidate Biomarker for Early Diagnosis of NASH Hepatocellular Carcinoma Using a Stepped HCD Method and PRM Evaluation.

Front Oncol 2022 17;12:818001. Epub 2022 Mar 17.

Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States.

Aberrant specific N-glycosylation, especially the increase in fucosylation on specific peptide sites of serum proteins have been investigated as potential markers for diagnosis of nonalcoholic steatohepatitis (NASH)-related HCC. We have combined a workflow involving broad scale marker discovery in serum followed by targeted marker evaluation of these fucosylated glycopeptides. This workflow involved an LC-Stepped HCD-DDA-MS/MS method coupled with offline peptide fractionation for large-scale identification of -glycopeptides directly from pooled serum samples (each n=10) as well as differential determination of N-glycosylation changes between disease states. We then evaluated the fucosylation level of the glycoprotein ceruloplasmin among 62 patient samples (35 cirrhosis, 27 early-stage NASH HCC) by LC-Stepped HCD-PRM-MS/MS to quantitatively analyze 18 targeted glycopeptides. Of these targets, we found the ratio of fucosylation of a tri-antennary glycopeptide from site N762, involving N762_ HexNAc(5)Hex(6)Fuc(2)NeuAc(3) (P=0.0486), increased significantly from cirrhosis to early HCC. This fucosylation ratio of a tri-antennary glycopeptide in CERU could be a potential biomarker for further validation in a larger sample set and could be a promising candidate for early detection of NASH HCC.
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http://dx.doi.org/10.3389/fonc.2022.818001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970044PMC
March 2022

Systematic review with meta-analysis: incidence of variceal hemorrhage in patients with cirrhosis undergoing transesophageal echocardiography.

Aliment Pharmacol Ther 2022 05 28;55(9):1088-1098. Epub 2022 Mar 28.

Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA.

Background: The presence of esophageal varices is considered a relative contraindication to transesophageal echocardiography (TEE) by cardiology professional societies, so gastroenterologists are often consulted to perform upper endoscopy prior to TEE in patients with cirrhosis.

Aim: To perform a systematic review to quantify the risk of bleeding complications in patients with cirrhosis following TEE.

Methods: Two reviewers searched Ovid MEDLINE, MEDLINE In-Process and EMBASE databases from January 1992 to May 2021 for studies reporting bleeding complications from TEE in patients with cirrhosis. We calculated the pooled incidence rate of bleeding events using the metaprop command with a random effect model.

Results: We identified 21 studies comprising 4050 unique patients with cirrhosis; 9 studies (n = 3015) assessed the risk of intraoperative TEE during liver transplant (LT) and 12 studies (n = 1035) assessed bleeding risk in patients undergoing TEE for other indications. The pooled incidence of bleeding post-TEE was 0.37% (95% CI 0.04-0.94%) across all studies. Bleeding complications were low among patients undergoing TEE during LT as well as those undergoing TEE for other diagnostic reasons (0.97% vs. 0.004%) and among studies with mean MELD >18 compared to those with mean MELD <18 (0.43% vs. 0.08%). Few studies had a comparator arm, and data on patient-level factors impacting bleeding complications (including degree of liver dysfunction and coagulopathy) were limited across studies.

Conclusions: The risk of bleeding complications following TEE is low in patients with cirrhosis, suggesting TEE is safe and risk stratification with upper endoscopy may not be necessary.
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http://dx.doi.org/10.1111/apt.16860DOI Listing
May 2022

Correlation of LI-RADS 3 or 4 Observations with Histopathologic Diagnosis in Patients with Cirrhosis.

Clin Gastroenterol Hepatol 2022 Mar 17. Epub 2022 Mar 17.

Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas. Electronic address:

Patients with cirrhosis are high risk for developing hepatocellular carcinoma (HCC) and warrant surveillance using abdominal ultrasound and α-fetoprotein. Those with positive surveillance results should undergo diagnostic evaluation with multiphase computed tomography (CT) or magnetic resonance imaging (MRI). The LI-RADS system is an evidence-based system to classify observations on CT or MRI in at-risk patients, ranging from LR-1 (definite benign) to LR-5 (definite HCC), with LR-3 and LR-4 observations being intermediate risk for HCC. LR-3 and LR-4 observations are observed on CT or MRI in more than one-fourth of patients undergoing HCC surveillance and have a high, yet variable, risk for progression to HCC. Approximately one-third of patients with LR-3 observations and more than two-thirds of LR-4 observations develop HCC, and surveillance strategies vary widely in practice. Variation in radiographic appearance and natural history of these observations suggests that this may be a heterogeneous group of patients; however, their histopathology has not been well described. Herein, we correlated imaging findings and explant histopathology from liver transplant recipients with at least 1 LR-3 or LR-4 observation on CT or MRI within 6 months preceding transplantation.
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http://dx.doi.org/10.1016/j.cgh.2022.03.009DOI Listing
March 2022

Clinical Characteristics and Outcomes of Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma in the United States.

Clin Gastroenterol Hepatol 2022 Mar 17. Epub 2022 Mar 17.

Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California; Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, Los Angeles, California; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background & Aims: The extent to which nonalcoholic fatty liver disease (NAFLD) contributes to hepatocellular carcinoma (HCC) prevalence in contemporary practices and whether there are any etiologic differences in surveillance receipt, tumor stage, and overall survival (OS) remain unclear. We aimed to estimate the burden of NAFLD-related HCC and magnitude of associations with surveillance receipt, clinical presentation, and outcomes in a contemporary HCC cohort.

Methods: In a cohort of HCC patients from the Surveillance, Epidemiology and End Results-Medicare database between 2011 and 2015, we used multivariable logistic regression to identify factors associated with surveillance receipt, early-stage tumor detection, and curative treatment. Cox regression was used to identify factors associated with OS.

Results: Among 5098 HCC patients, NAFLD was the leading etiology, accounting for 1813 cases (35.6%). Compared with those with hepatitis C-related HCC, NAFLD was associated with lower HCC surveillance receipt (adjusted odds ratio, 0.22; 95% confidence interval [CI], 0.17-0.28), lower early-stage HCC detection (adjusted odds ratio, 0.49; 95% CI, 0.40-0.60), and modestly worse OS (adjusted hazard ratio, 1.20; 95% CI, 1.09-1.32). NAFLD subgroup analysis showed that early-stage HCC, absence of ascites/hepatic encephalopathy, surveillance, and curative treatment receipt were associated with improved OS. NAFLD patients with coexisting liver disease were more likely to have surveillance, early-stage detection, curative treatment, and improved OS than NAFLD patients without coexisting liver diseases.

Conclusions: NAFLD is the leading etiology of HCC among Medicare beneficiaries. Compared with other etiologies, NAFLD was associated with lower HCC surveillance receipt, early-stage detection, and modestly poorer survival. Multifaceted interventions for improving surveillance uptake are needed to improve prognosis of patients with NAFLD-related HCC.
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http://dx.doi.org/10.1016/j.cgh.2022.03.010DOI Listing
March 2022

Reply.

Hepatology 2022 Mar 18. Epub 2022 Mar 18.

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

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http://dx.doi.org/10.1002/hep.32462DOI Listing
March 2022

Gender, Age, Racial and Ethnic Disparities in Clinical Trial Enrollment for Primary Liver Cancer.

Gastroenterology 2022 Jul 12;163(1):14-20.e2. Epub 2022 Mar 12.

Division of Digestive and Liver Diseases, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.

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http://dx.doi.org/10.1053/j.gastro.2022.03.015DOI Listing
July 2022

Reinforcement learning evaluation of treatment policies for patients with hepatitis C virus.

BMC Med Inform Decis Mak 2022 03 11;22(1):63. Epub 2022 Mar 11.

Health Services Research and Development Center of Clinical Management Research, VA Ann Arbor Healthcare System, 2215 Fuller Road, Gastroenterology 111D, Ann Arbor, MI, 48105, USA.

Background: Evaluation of new treatment policies is often costly and challenging in complex conditions, such as hepatitis C virus (HCV) treatment, or in limited-resource settings. We sought to identify hypothetical policies for HCV treatment that could best balance the prevention of cirrhosis while preserving resources (financial or otherwise).

Methods: The cohort consisted of 3792 HCV-infected patients without a history of cirrhosis or hepatocellular carcinoma at baseline from the national Veterans Health Administration from 2015 to 2019. To estimate the efficacy of hypothetical treatment policies, we utilized historical data and reinforcement learning to allow for greater flexibility when constructing new HCV treatment strategies. We tested and compared four new treatment policies: a simple stepwise policy based on Aspartate Aminotransferase to Platelet Ratio Index (APRI), a logistic regression based on APRI, a logistic regression on multiple longitudinal and demographic indicators that were prespecified for clinical significance, and a treatment policy based on a risk model developed for HCV infection.

Results: The risk-based hypothetical treatment policy achieved the lowest overall risk with a score of 0.016 (90% CI 0.016, 0.019) while treating the most high-risk (346.4 ± 1.4) and the fewest low-risk (361.0 ± 20.1) patients. Compared to hypothetical treatment policies that treated approximately the same number of patients (1843.7 vs. 1914.4 patients), the risk-based policy had more untreated time per patient (7968.4 vs. 7742.9 patient visits), signaling cost reduction for the healthcare system.

Conclusions: Off-policy evaluation strategies are useful to evaluate hypothetical treatment policies without implementation. If a quality risk model is available, risk-based treatment strategies can reduce overall risk and prioritize patients while reducing healthcare system costs.
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http://dx.doi.org/10.1186/s12911-022-01789-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8913329PMC
March 2022

Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials.

Clin Cancer Res 2022 Jun;28(11):2297-2305

Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Purpose: Ramucirumab is an effective treatment for patients with advanced hepatocellular carcinoma (aHCC) and baseline alpha-fetoprotein (AFP) ≥400 ng/mL. We aimed to identify prognostic and predictive factors of response to ramucirumab in patients with aHCC with AFP ≥400 ng/mL from the phase III REACH and REACH-2 randomized trials.

Patients And Methods: Patients with aHCC, Child-Pugh class A with prior sorafenib treatment were randomized in REACH and REACH-2 (ramucirumab 8 mg/kg or placebo, biweekly). Meta-analysis of individual patient-level data (pooled population) from REACH (AFP ≥400 ng/mL) and REACH-2 was performed. A drug exposure analysis was conducted for those with evaluable pharmacokinetic data. To identify potential prognostic factors for overall survival (OS), multivariate analyses were performed using a Cox proportional hazards regression model. To define predictors of ramucirumab benefit, subgroup-by-treatment interaction terms were evaluated.

Results: Of 542 patients (316 ramucirumab, 226 placebo) analyzed, eight variables had independent prognostic value associated with poor outcome (geographical region, Eastern Cooperative Oncology Group performance score ≥1, AFP >1,000 ng/mL, Child-Pugh >A5, extrahepatic spread, high neutrophil-to-lymphocyte ratio, high alkaline phosphatase and aspartate aminotransferase). Ramucirumab survival benefit was present across all subgroups, including patients with very aggressive HCC [above median AFP; HR: 0.64; 95% confidence interval (CI): 0.49-0.84] and nonviral aHCC (HR: 0.56; 95% CI: 0.40-0.79). While no baseline factor was predictive of a differential OS benefit with ramucirumab, analyses demonstrated an association between high drug exposure, treatment-emergent hypertension (grade ≥3), and increased ramucirumab benefit.

Conclusions: Ramucirumab provided a survival benefit irrespective of baseline prognostic covariates, and this benefit was greatest in patients with high ramucirumab drug exposure and/or those with treatment-related hypertension.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-4000DOI Listing
June 2022

Risk factors for HCC in contemporary cohorts of patients with cirrhosis.

Hepatology 2022 Mar 1. Epub 2022 Mar 1.

Sections of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA.

Background And Aims: Etiological risk factors for cirrhosis have changed in the last decade. It remains unclear to what extent these trends in cirrhosis risk factors have changed HCC risk.

Approach And Results: We used data from two contemporary, prospective multiethnic cohorts of patients with cirrhosis: the Texas Hepatocellular Carcinoma Consortium Cohort and the Houston Veterans Administration Cirrhosis Surveillance Cohort. Patients with cirrhosis were enrolled from seven US centers and followed until HCC diagnosis, transplant, death, or June 30, 2021. We calculated the annual incidence rates for HCC and examined the effects of etiology, demographic, clinical, and lifestyle factors on the risk of HCC. We included 2733 patients with cirrhosis (mean age 60.1 years, 31.3% women). At enrollment, 19.0% had active HCV, 23.3% had cured HCV, 16.1% had alcoholic liver disease, and 30.1% had NAFLD. During 7406 person-years of follow-up, 135 patients developed HCC at an annual incidence rate of 1.82% (95% CI, 1.51-2.13). The annual HCC incidence rate was 1.71% in patients with cured HCV, 1.32% in patients with alcoholic liver disease, and 1.24% in patients with NAFLD cirrhosis. Compared to patients with NAFLD, the risk of progression to HCC was 2-fold higher in patients with cured HCV (HR, 2.04; 95% CI, 1.24-3.35). Current smoking (HR, 1.63; 95% CI, 1.01-2.63) and overweight/obesity (HR, 1.79; 95% CI, 1.08-2.95) were also associated with HCC risk.

Conclusions: HCC incidence among patients with cirrhosis was lower than previously reported. HCC risk was variable across etiologies, with higher risk in patients with HCV cirrhosis and lower risk in those with NAFLD cirrhosis. Current smoking and overweight/obesity increased HCC risk across etiologies.
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http://dx.doi.org/10.1002/hep.32434DOI Listing
March 2022

Hypervascular transformation of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement on gadoxetic acid-enhanced MRI: long-term follow-up in a surveillance cohort.

Eur Radiol 2022 Feb 28. Epub 2022 Feb 28.

Liver Cancer Center, Asan Medical Center, Seoul, Republic of Korea.

Objectives: With the increasing use of gadoxetic acid-enhanced MRI for HCC surveillance, hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) are frequently encountered. We investigated the rate of these nodules with hypervascular transformation, which suggests hepatocarcinogenesis, by using a prospectively collected longitudinal surveillance cohort data.

Methods: This study included 382 prospectively enrolled patients at high risk for developing HCC who underwent 1-3 rounds of bi-annual surveillance gadoxetic acid-enhanced MRI. MRI was analyzed to detect HBP hypointense nodules without APHE. Follow-up dynamic CTs and MRIs were evaluated to detect hypervascular transformation of the nodules. Cox proportional hazards regression analyses were used to find predictors for hypervascular transformation.

Results: A total of 76 HBP hypointense nodules without APHE were found in 48 patients, giving a prevalence of 12.6% (48/382). The mean nodule size was 10.8 mm, with 43.4% (33/76) being ≥ 10 mm. Over a median follow-up of 78.6 months, 19 nodules (25.0%) showed hypervascular transformation, all of which demonstrated typical imaging features of HCC. On multivariable Cox-regression analysis, size (≥ 10 mm) was the only independent predictor of hypervascular transformation (hazard ratio, 3.31; 95% confidence interval, 1.21-9.05). The cumulative incidence of hypervascular transformation at 12 and 60 months of nodules ≥ 10 mm was 12.3% and 50.4%, respectively, while that of nodules < 10 mm was 2.5% and 13.9%, respectively.

Conclusions: About half of the HBP hypointense nodules ≥ 10 mm without APHE transformed to HCC at 5 years of follow-up, indicating the necessity for cautious monitoring with an augmented and extended follow-up schedule for these nodules.

Key Points: • The prevalence of HBP hypointense nodules without APHE was 12.6% in a prospectively recruited population at high risk of developing HCC. • Nodule size ≥ 10 mm was significantly associated with hypervascular transformation, and approximately half of the HBP hypointense nodules ≥ 10 mm without APHE transformed to HCC during 5 years of follow-up. • Given the risk of malignant transformation, HBP hypointense nodules ≥ 10 mm without APHE should be closely monitored.
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http://dx.doi.org/10.1007/s00330-022-08623-8DOI Listing
February 2022

First-Line Immune Checkpoint Inhibitor-Based Sequential Therapies for Advanced Hepatocellular Carcinoma: Rationale for Future Trials.

Liver Cancer 2022 Jan 23;11(1):75-84. Epub 2021 Nov 23.

Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.

Introduction: Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies.

Methods: A Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences.

Results: ATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases.

Conclusion: Our simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC.
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http://dx.doi.org/10.1159/000520278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820155PMC
January 2022

The Practice of Retransplantation for Recurrent Alcohol-associated Liver Disease in the United States Is Uncommon With Acceptable Outcomes.

Transplant Direct 2022 Mar 11;8(3):e1297. Epub 2022 Feb 11.

Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX.

Alcohol-associated liver disease (ALD) is the leading indication for liver transplantation (LT) in the United States. Alcohol use disorder relapse can lead to graft failure and the need for liver retransplantation (re-LT). Despite the rising incidence of LT for ALD, the practice of re-LT for recurrent ALD is not well understood. We aimed to define the practice of re-LT for recurrent ALD during the last 20 y.

Methods: Using the US national transplant registry, adults who underwent re-LT for recurrent ALD were compared with LT recipients who died from recurrent ALD and propensity score-matched re-LT recipients with non-ALD indications. All groups had at least 1-y survival of their primary graft. Kaplan-Meier analysis was used to calculate 1- and 5-y survivals.

Results: Between 2000 and 2020, 74 re-LTs were performed for recurrent ALD (1.0% of all re-LTs). There was an increase in recurrent ALD re-LT practice from 2017 to 2020 versus 2014 to 2016 (20 versus 2). At the time of re-LT, patients with recurrent ALD had a significant decrease in body mass index (median 25.1 versus 28.8 kg/m;  < 0.001) versus the index LT. Patient and graft survivals were similar between patients who underwent re-LT for ALD and non-ALD (56.4% versus 56.9% 5-y graft survival,  = 0.96; 62.8% versus 59.0% 5-y patient survival,  = 0.58).

Conclusions: The practice of re-LT for recurrent ALD is uncommon in the United States. Graft and patient survivals seem to be acceptable and support the occasional practice of re-LT for recurrent ALD should the patient be deemed an appropriate candidate.
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http://dx.doi.org/10.1097/TXD.0000000000001297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8843372PMC
March 2022

Association between ultrasound quality and test performance for HCC surveillance in patients with cirrhosis: a retrospective cohort study.

Aliment Pharmacol Ther 2022 03 15;55(6):683-690. Epub 2022 Feb 15.

Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.

Background: Ultrasound visualisation is limited in approximately 20% of patients with cirrhosis undergoing hepatocellular carcinoma (HCC) surveillance; however, it is unknown if impaired visualisation directly impacts test performance. We aimed to evaluate the association between ultrasound visualisation and surveillance test performance.

Methods: We performed a retrospective cohort study among patients with cirrhosis, with or without HCC, who underwent ultrasound-based surveillance at two large health systems between July 2016 and July 2019. Ultrasound visualisation assessment was recorded by interpreting radiologists using the ultrasound LI-RADS Visualisation score. We performed logistic regression analyses to evaluate the association between ultrasound visualisation and diagnostic test performance. We assessed sensitivity for HCC detection among ultrasounds performed in the year prior to HCC diagnoses and specificity using ultrasounds in those without HCC.

Results: Among 186 patients with HCC, severely limited visualisation (Vis Score C) on ultrasound prior to HCC diagnosis was associated with increased odds of false-negative results, that is lower sensitivity (OR 7.94, 95% CI 1.23-51.16) in multivariable analysis. Ultrasound sensitivity with visualisation scores A or B exceeded 75%, compared to only 27.3% with visualisation score C. Among 2052 cirrhosis patients without HCC, moderate visualisation limitations (Vis score B) were associated with increased odds of false-positive results (OR 1.60, 1.13-2.27), although specificity exceeded 95% across all visualisation scores.

Conclusions: Impaired ultrasound visualisation is associated with worse surveillance test performance. Alternative blood-based biomarkers and imaging strategies are needed for patients at risk for ultrasound-based surveillance failure.
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http://dx.doi.org/10.1111/apt.16779DOI Listing
March 2022

Understanding Compliance, Practice Patterns, and Barriers Among Gastroenterologists and Primary Care Providers Is Crucial for Developing Strategies to Improve Screening for Barrett's Esophagus.

Gastroenterology 2022 05 9;162(6):1568-1573.e4. Epub 2022 Feb 9.

Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

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http://dx.doi.org/10.1053/j.gastro.2022.02.003DOI Listing
May 2022

Cost Effectiveness of Mailed Outreach Programs for Colorectal Cancer Screening: Analysis of a Pragmatic, Randomized Trial.

Clin Gastroenterol Hepatol 2022 Feb 7. Epub 2022 Feb 7.

The Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas; Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas.

Background & Aims: Clinical guidelines for colorectal cancer (CRC) screening suggest use of either stool-based tests or colonoscopy - modalities that differ in recommended screening intervals, adherence, and costs. We know little about the long-term cost differences in population-health outreach strategies to promote these strategies.

Methods: We conducted a cost-effectiveness analysis to compare 2 mailed outreach strategies to increase CRC screening from a pragmatic, randomized clinical trial: mailed fecal immunochemical test (FIT) kits vs invitations to complete a screening colonoscopy. We built a 10-year Markov chain Monte Carlo microsimulation model to account for differences in screening intervals, adherence, and costs.

Results: Mailed FIT kits had a lower 10-year average per-person cost of screening relative to colonoscopy invitations ($1139 vs $1725) but with 10.89 fewer months of compliance and 60 fewer advanced neoplasia detected (37 advanced adenomas and 23 CRC). Incremental cost effectiveness ratios for colonoscopy invitations compared with mailed FIT kits were $55.23, $15.84, and $25.48 per additional covered month, advanced adenoma, and CRC, respectively. Although FIT was the preferred strategy at low willingness-to-pay thresholds, the 2 strategies were equal at a willingness-to-pay threshold of $41.31 per covered month gained.

Conclusion: Mailed FIT or colonoscopy invitations are both options to improve CRC screening completion and advanced neoplasia detection, and the choice of outreach strategy may differ by a health system's willingness-to-pay threshold. Mailed FIT kits are less expensive than colonoscopy invitations but result in fewer months of screening compliance and advanced neoplasia detected.
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http://dx.doi.org/10.1016/j.cgh.2022.01.054DOI Listing
February 2022

HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: A meta-analysis.

J Hepatol 2022 Jul 6;77(1):128-139. Epub 2022 Feb 6.

Department of Internal Medicine, University of Pennsylvania, Philadelphia PA, United States.

Background & Aims: There is controversy regarding the overall value of hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis given the lack of data from randomized-controlled trials. To address this issue, we conducted a systematic review and meta-analysis of cohort studies evaluating the benefits and harms of HCC surveillance in patients with cirrhosis.

Methods: We performed a search of the Medline and EMBASE databases and national meeting abstracts from January 2014 through July 2020 for studies reporting early-stage HCC detection, curative treatment receipt, or overall survival, stratified by HCC surveillance status, among patients with cirrhosis. Pooled risk ratios (RRs) and hazard ratios, according to HCC surveillance status, were calculated for each outcome using the DerSimonian and Laird method for random effects models.

Results: We identified 59 studies including 145,396 patients with HCC, which was detected by surveillance in 41,052 (28.2%) cases. HCC surveillance was associated with improved early-stage detection (RR 1.86, 95% CI 1.73-1.98; I = 82%), curative treatment receipt (RR 1.83, 95% CI 1.69-1.97; I = 75%), and overall survival (hazard ratio 0.67, 95% CI 0.61-0.72; I = 78%) after adjusting for lead-time bias; however, there was notable heterogeneity in all pooled estimates. Four studies examined surveillance-related physical harms due to false positive or indeterminate surveillance results, but no studies examined potential financial or psychological harms. The proportion of patients experiencing surveillance-related physical harms ranged from 8.8% to 27.5% across studies, although most harms were mild in severity.

Conclusion: HCC surveillance is associated with improved early detection, curative treatment receipt, and survival in patients with cirrhosis, although there was heterogeneity in pooled estimates. Available data suggest HCC surveillance is of high value in patients with cirrhosis, although continued rigorous studies evaluating benefits and harms are still needed.

Lay Summary: There has been ongoing debate about the overall value of hepatocellular carcinoma (HCC) screening in patients with cirrhosis given the lack of data from randomized-controlled trials. In a systematic review of contemporary cohort studies, we found that HCC screening is associated with improved early detection, curative treatment receipt, and survival in patients with cirrhosis, although there were fewer data quantifying potential screening-related harms. Available data suggest HCC screening is of high value in patients with cirrhosis, although continued studies evaluating benefits and harms are still needed.
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http://dx.doi.org/10.1016/j.jhep.2022.01.023DOI Listing
July 2022

Reply.

Clin Gastroenterol Hepatol 2022 Feb 4. Epub 2022 Feb 4.

Division of Digestive and Liver Diseases, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern, Dallas Texas.

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http://dx.doi.org/10.1016/j.cgh.2022.01.049DOI Listing
February 2022

Incidence of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.

Gastroenterology 2022 05 1;162(6):1772-1774. Epub 2022 Feb 1.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.

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http://dx.doi.org/10.1053/j.gastro.2022.01.037DOI Listing
May 2022

Deep learning in hepatocellular carcinoma: Current status and future perspectives.

World J Hepatol 2021 Dec;13(12):2039-2051

Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States.

Hepatocellular carcinoma (HCC) is among the leading causes of cancer incidence and death. Despite decades of research and development of new treatment options, the overall outcomes of patients with HCC continue to remain poor. There are areas of unmet need in risk prediction, early diagnosis, accurate prognostication, and individualized treatments for patients with HCC. Recent years have seen an explosive growth in the application of artificial intelligence (AI) technology in medical research, with the field of HCC being no exception. Among the various AI-based machine learning algorithms, deep learning algorithms are considered state-of-the-art techniques for handling and processing complex multimodal data ranging from routine clinical variables to high-resolution medical images. This article will provide a comprehensive review of the recently published studies that have applied deep learning for risk prediction, diagnosis, prognostication, and treatment planning for patients with HCC.
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http://dx.doi.org/10.4254/wjh.v13.i12.2039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8727204PMC
December 2021

Racial and Ethnic Disparities in Barriers to Care in Patients with Hepatocellular Carcinoma.

Clin Gastroenterol Hepatol 2021 Dec 26. Epub 2021 Dec 26.

Department of Internal Medicine, UT Southwestern Medical Center, Parkland Health & Hospital System, Dallas, Texas. Electronic address:

Hepatocellular carcinoma (HCC) is a leading cause of death in patients with cirrhosis and has a rising mortality rate in the United States. Racial and ethnic minorities experience a disproportionate burden of HCC, including higher incidence rates, more late-stage diagnoses, and worse survival. These disparities are complex in nature and can be attributed to many proximal, intermediate, and distal determinants, such as health literacy and behaviors, social support, social needs, social determinants of health, and access to health care. Prior studies have identified racial and ethnic differences in clinical factors, including receipt of HCC surveillance and tumor stage; however, few studies have examined differences in patient-reported barriers that may partly explain observed disparities. Understanding these data is essential to inform interventions to address and mitigate disparities. Therefore, we described patient-reported barriers to medical care and examined differences in barriers by race and ethnicity in a large, diverse population of patients newly diagnosed with HCC.
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http://dx.doi.org/10.1016/j.cgh.2021.12.027DOI Listing
December 2021
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