Abstract
Background and Aims
The American Association for the Study of Liver Diseases recommends regular surveillance with ultrasonography (US) and alpha-feto protein every 6 months for patients at high risk of hepatocellular carcinoma (HCC). However, US is considered to be less effective than cross-sectional imaging modalities like computed tomography and magnetic resonance imaging for detecting early HCC. Limited data exist on the overall survival and receipt of curative treatment for patients undergoing surveillance with different imaging modalities.
Methods
We retrospectively reviewed patients (n = 1954) diagnosed with HCC between January 2011 and June 2021. Patients who developed HCC while on strict semiannual surveillance were included in the study. We estimated survival using the Kaplan-Meier method and compared the outcomes on different modalities of imaging using the Log Rank test. We used univariate and multivariate Cox model to evaluate factors affecting survival.
Results
A total of 183 patients developed HCC on semiannual surveillance with Imaging (115 with contrast-enhanced magnetic resonance imaging, 34 with multiphasic computed tomography and 34 with US) and alpha-feto protein. No significant difference was noted in overall survival or transplant-free survival based on the imaging modality employed for surveillance for at-risk patients. No correlation was found between the type of imaging modality for surveillance and receipt of curative treatment.
Conclusion
Using surveillance program rigorously in at-risk patients, we did not find any association between the imaging modality and clinical outcomes in patients with HCC. It is likely that adherence to surveillance program irrespective of imaging modalities is more effective to influence the outcome, but it needs further studies.
Keywords: HCC, Liver transplantation, MRI, racial disparities, Surveillance, survival, US
Introduction
Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and is the third most common cause of cancer mortality globally (8.3%) after lung (18%) and colorectal carcinoma (9.4%).1 In the United States, the American Cancer Society estimates that HCC is the sixth most common cancer nationally with an annual incidence of 8.6 HCC cases per 100,000 individuals. Mortality due to HCC has increased over the past decade with an annual percent increase in mortality by 1.3% (P < .05) per year from 2010 to 2019.2
If left untreated, patients with HCC have a very poor prognosis. The overall median survival for patients with untreated HCC is 9 months with the major cause of mortality being tumor progression.3 However, curative treatments for HCC have increased the survival rate significantly. Tumor resection is associated with a 60% 5-year survival rate and liver transplantation (LT) is associated with a 60%–80% 5-year survival rate. These curative treatments are viable options for patients who are diagnosed at an early stage. Therefore, surveillance programs that aim to diagnose HCC at an early stage may increase the likelihood of receiving a curative treatment and thus improve survival outcomes in patients with HCC.4
Cirrhosis, regardless of etiology, is a major risk factor for HCC and is associated with more than 80% of newly diagnosed HCC cases.5 The American Association for the Study of Liver Diseases recommends that all patients with Child A-B cirrhosis, or Child C cirrhosis who are currently listed for LT, and most patients with chronic Hepatitis B without cirrhosis to undergo regular HCC surveillance with Ultrasonography (US) with alpha-feto protein (AFP) every 6 months.6
However, multiple studies have shown that US has a limited efficacy in detecting HCC when compared with contrast-enhanced multiphasic computed tomography (CT) or magnetic resonance imaging (MRI). A meta-analysis showed that the pooled sensitivity of US to detect HCC was 45% (95% confidence interval [CI] 30%–62%) without AFP and 63% (95% CI 48%–75%) when combined with AFP.7 Another study revealed a superior sensitivity of MRI in detecting HCC with a range between 61.5% and 86.1% and a specificity between 92.7% and 97.9%.8 However, the higher cost, less accessibility and other factors associated with contrast enhanced CT and MRI have hindered their adoption in HCC surveillance. MRI frequently detects vascular benign lesions, such as arteriovenous shunts, leading to unnecessary surveillance. A previous study indicated that CT surveillance is less cost-effective compared to US, and MRI was noted to be cost-effective for surveillance in a high risk-population in another study.9,10 However, there are limited data comparing the efficacy of various imaging modalities used for HCC surveillance regarding the likelihood of receiving curative treatment and overall survival (OS).
In this study, we aimed to assess the association between the radiologic surveillance modality employed for HCC detection and the outcomes of patients with HCC with regards to utilization of curative treatment and OS.
Materials and Methods
The study was approved by the Baylor College of Medicine Institutional Review Board (H-40333) and a waiver of informed consent was granted. We adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for cohort studies.11
Patient Population
We reviewed all patients diagnosed with HCC at Baylor St. Luke’s Medical Center Hospital between January 2011 and June 2021. Patients diagnosed with HCC were identified by searching the HCC codes using the International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision in the electronic medical records system. Each patient’s diagnosis was confirmed using imaging with Liver Imaging Reporting and Data System–5 by an expert radiologist in a multidisciplinary tumor board; patients with hepatic lesions of 1 cm or greater in its largest dimension were included in the study. Based on these criteria, we identified 1954 patients who were diagnosed with HCC during this timeframe. Distribution of patients is highlighted in Figure 1 with summary of inclusion and exclusion criteria. Within the same period, 9973 patients were identified with one or more International Classification of Diseases, Ninth Revision, or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes associated with liver cirrhosis or hepatitis B and eligible for surveillance.
Figure 1.
Patients’ selection with inclusion and exclusion criteria.
To be considered as having received surveillance prior to HCC detection and included in the study, (1) patients had to have at least one negative imaging scan performed 6 months prior the date of their HCC detection. HCC detection was defined as any lesion > 1cm detected on surveillance scan and subsequently confirmed as HCC based on American Association for the Study of Liver Diseases guidelines. (2) The imaging done for the purpose of surveillance, as outlined in the clinical note, (3) Surveillance scans had to be of the same imaging modality as the first detection scan (contrast-enhanced liver specific MRI, CT, or US) and (4) serum AFP must be available with each imaging. No patients were excluded for missing AFP measurements as all patients who underwent radiologic surveillance also had an accompanying AFP measurement. Any two consecutive surveillance scans that were more than 9 months apart were excluded. Lesions that were initially detected by US had contrast-enhanced MRI or multiphase CT scan for establishing the diagnosis. Out of the 1954 HCC diagnoses, 197 patients were included in the study based on strict surveillance criteria outlined. Fourteen patients were lost to follow up after HCC diagnosis and were not considered for this study.
We classified patients based on the type of surveillance imaging modality (MRI, CT, or US). The surveillance period was defined as the number of months from the first imaging scan recorded in our electronic medical record to the detection.
Data Collection
Clinical, laboratory, and imaging parameters were collected by retrospective chart review. Patient demographic data (date of birth, sex, race, and ethnicity), predetection data (primary and secondary etiology of liver disease, alcohol, body mass index, human immunodeficiency virus, transjugular intrahepatic portosystemic shunt, surveillance modality, date of first surveillance examination, and date of diagnostic surveillance examination), diagnostic imaging scan data (total tumor size, largest tumor dimension, macrovascular invasion, presence of metastatic deposits), clinical data at time of HCC detection (ascites, hepatic encephalopathy, presence and grade of varices, performance status), laboratory data at time of detection (hemoglobin, albumin, bilirubin, international normalized ratio (INR), creatinine, sodium), comorbid diseases (diabetes mellitus, hypertension, cardiac diseases, chronic kidney disease, cerebrovascular accidents), baseline treatment were documented.
We defined curative treatments as surgical resection or LT. Noncurative treatments were defined as local ablation, TACE, transarterial radioembolization, radiation, systemic therapy, and supportive care only. Early HCC was defined as a single tumor that is 2 cm or less at its largest dimension with no vascular invasion or metastasis at time of detection.
Outcomes of Interest
The OS or transplant-free survival was calculated for each patient group based on the type of surveillance imaging modality (MRI, CT, or US). Type of initial treatment was compared between patients’ groups. Furthermore, we evaluated the ability of imaging modalities to detect early HCC.
Statistical Analysis
Descriptive statistics were used to summarize patient characteristics and curative treatment using counts and percentages for categorical data, median and interquartile range (IQR) for continuous data. To test for outcome difference between types of surveillance imaging modality, we used the chi-square test or Fisher’s exact test for categorical data, and the Kruskal-Wallis test for continuous data. OS was assessed using the Kaplan-Meier method and differences between groups were assessed by the log-rank test. Survival time was defined as the time from date of diagnosis to date of death or of last follow-up. Univariate and multivariate Cox regression models were performed to identify predictors that could be associated with survival. Following univariate analysis, variables identified with a P value less than 0.1 were entered into the multivariate Cox regression model. A backward stepwise elimination approach was used to determine the final model. Survival effect estimates are represented as hazard ratios (HRs) with the corresponding 95% CI. We accounted for LT as a competing risk by using the cumulative incidence function and Gray’s test. The Fine-Grey model was applied to perform multivariate analyses, taking into account the competing risk of LT. All reported P values are two-sided with P < .05 considered as statistically significant. A post hoc power analysis was performed; based on our calculations, with 85 per group, the study would have achieved 81% power at a two-sided significance level of 0.05 to detect a HR as small as 1.59 for CT or 0.65 for MRI when compared to the ultrasound, respectively. All statistical analysis was performed using Statistical Analysis System software (v 9.4; Statistical Analysis System Institute, Cary NC) and R (v 4.3.2; R Foundation for Statistical Computing, Vienna, Austria).
Results
Patient Characteristics
The cohort (N = 183) characteristics are described in Table 1. Most patients 115 (62.8%) had MR-based surveillance. The median age at HCC detection was 61 years (IQR: 57–67) and 120 (65.6%) patients were males. The ethnic distribution included 101 (56.1%) non-Hispanic Whites, 17 (9.4%) African Americans, and 45 (25%) Hispanics. More non-Hispanic White patients received MRI based surveillance (68.3%) compared to Hispanics (44.4%) and African Americans (17.6%). The primary etiologies of liver disease were Hepatitis C virus infection (n = 96, 52.4%), Metabolic dysfunction associated steatotic liver disease (n = 33, 18%), and alcohol-associated liver disease (n = 27, 14.7%). The median MELD score was 11 (8–16).
Table 1.
Baseline Characteristics of Patients
| All patients N = 183 | US surveillance N = 34 (18.6%) | CT surveillance N = 34 (18.6%) | MRI surveillance N = 115 (62.8%) | P value | |
|---|---|---|---|---|---|
| Median age at detection, median (IQR), y | 61 (57,67) | 62 (57,69) | 62.5 (58 66) | 60 (56, 66) | .229 |
| Sex, male, no. (%) | 120 (65.6%) | 22 (64.7%) | 19 (55.9%) | 79 (68.7%) | .394 |
| BMI, median (IQR), kg/m2 | 29 (26.2, 33.4) | 29.3 (26.6, 31.9) | 28.1 (24.5, 33) | 29 (26.5, 34.1) | .386 |
| Follow-up time (y, median (IQR)) | 4 (1.9–6.4) | 4.2 (1.3–5.9) | 3.1 (0.5–4.5) | 4.4 (2.5–7.2) | .02 |
| Liver disease etiology, no. (%) | |||||
| Hepatitis C virus | 96 (52.4%) | 18 (52.9%) | 18 (52.9%) | 60 (52.2%) | .993 |
| Hepatitis B virus | 13 (7.1%) | 3 (8.8%) | 1 (2.9%) | 9 (7.8%) | |
| ALD | 27 (14.7%) | 5 (14.7%) | 5 (14.7%) | 17 (14.8%) | |
| MASLD | 33 (18%) | 6 (17.6) | 7 (20.6%) | 20 (17.4%) | |
| Others | 14 (7.6%) | 2 (5.9%) | 3 (8.8%) | 9 (7.8%) | |
| Race-ethnicity | |||||
| Non-hispanic White | 101 (56.1) | 11 (33.3) | 12 (35.3) | 78 (69) | <.001 |
| African Americans | 17 (9.4) | 7 (21.2) | 7 (20.6) | 3 (2.7) | |
| Hispanic | 45 (25) | 10 (30.3) | 15 (44.1) | 20 (17.7) | |
| Other | 17 (9.4) | 5 (15.2) | . | 12 (10.6) | |
| Child-Pugh class, no. (%) | |||||
| A | 89 (46.8%) | 19 (55.9%) | 13 (38.2%) | 57 (49.6%) | .623 |
| B | 72 (39.3%) | 11 (32.4%) | 17 (50%) | 44 (38.3%) | |
| C | 22 (12%) | 4 (11.8%) | 4 (11.8%) | 14 (12.2%) | |
| MELD score, median (IQR) | 11 (8–16) | 10 [7–14] | 11.5 [8–17] | 11 [9–15] | .500 |
| AFP, median (IQR) | 6.4 (3.5, 19) | 6.7 (3.4, 19) | 12.5 (3.5–516) | 6.1 (3.6–13.1) | .141 |
| Tumor size (IQR) | 2.4 (1.7–3.5) | 2.6 (1.9–3.9) | 2.6 (1.7–3.6) | 2.3 (1.7–3.4) | .667 |
| BCLC stage, no. (%) | |||||
| Early (0/A) | 57 (31.1%) | 12 (35.3%) | 8 (23.5%) | 37 (32.2%) | .535 |
| Late (B/C/D) | 126 (68.9%) | 22 (64.7%) | 26 (76.5%) | 78 (67.8%) |
BMI, body mass index; ALD, alcohol-associated liver disease; MASLD, metabolic dysfunction associated steatotic liver disease.
Characteristics of Hepatocellular Carcinoma (HCC) at Time of Detection
The median time between starting surveillance and detection of HCC was 28 months (IQR: 15–51). Most patients (75.4%) were diagnosed with solitary hepatic lesions. The median total tumor size at the time of detection was 2.4 cm (IQR: 1.7–3.5), median total tumor size for lesions detected by MRI was 2.3 cm (IQR 1.7–3.4), CT 2.6 cm (IQR 1.7–3.6) and US 2.6 cm (IQR 1.9–3.9) with (P value = .67). Median AFP at time of detection was 6.4 ng/dl (IQR: 3.5–19). Macrovascular invasion at time of presentation was observed in only 6% of patients.
Cross-sectional imaging and ultrasound (US) did not differ significantly in detecting early-stage disease, as defined by the Barcelona Clinic Liver Cancer (BCLC) staging system. Figure 2 highlights the early/late stage BCLC tumors at time of detection. All imaging modalities detected more (n = 126, 68.9%) late stage BCLC; however, this difference was not statistically significant.
Figure 2.
Early/late BCLC tumors at time of detection.
Receipt of Curative Treatment
Multiple treatment approaches were utilized in the study cohort, among which transarterial chemoembolization (TACE) was the most utilized in 64.5% of cases. Overall, 9.3% of patients received supportive care only.
Of the 183 HCC patients, 98 (53.6%) received curative treatment (97 patients received LT, 1 received liver resection) either initially (n = 16) or following noncurative treatment (n = 82). There was no statistically significant relationship between the type of radiological scan used and the receipt of curative treatment (P value = .561) (Figure 3).
Figure 3.
Receipt of curative treatment.
Patients undergoing surveillance with US were more likely to receive TACE as the initial treatment (US 79.4%, MRI 65.2%, CT 47.1%, P value = .02). The choice between other therapeutic options, including hepatic resection, radio frequency ablation, LT, transarterial radioembolization, and systemic therapy, were not influenced significantly by the surveillance modality.
Race and ethnicity were not significantly associated with the receiving curative treatment for the patients in this study. Among all patients, 53% received curative treatment. When broken down by race and ethnicity, 56.4% of non-Hispanic Whites received curative treatment, compared to 47.1% of African Americans and 46.7% of Hispanics. The difference in the receipt of curative treatment among these groups was not statistically significant (P value = .684) after adjusting for other variables.
Overall Survival
During the follow up, 78 patients (42.6%) died, with a median follow-up duration of 4 years (IQR: 1.9–6.4). Univariate analysis using the log-rank test and KM curves indicated that Child Pugh score, hemoglobin level, albumin, bilirubin, INR, sodium levels, MELD score, and total tumor size at time of detection had statistically significant effect on survival outcomes (P values < 0.05) (Table A1). In Kaplan Meier (Figure 4), there were no statistically significant differences for survival for MRI (HR: 0.70, 95% CI: 0.39–1.24), P value = .22) or for CT (HR: 1.41, 95% CI: 0.72–2.78), P value = .31) compared to those using US.
Figure 4.
Kaplan-Meier curves for survival US vs CT and US vs MRI.
In the multivariate analysis using the Cox model with race and ethnicity, and modality, race and ethnicity had statistically significant association with survival. Non-Hispanic Whites and African Americans were associated with better survival rates compared to Hispanics (HR: 0.48, P value = .011) and (HR: 0.34, P value = .012) respectively after adjusting for other variables including treatment modalities. However, there were no statistically significant differences for survival between patients who received surveillance using MRI (HR: 0.91, 95% CI: 0.48–1.71), P value = .768) or CT (HR: 1.93, 95% CI: 0.96–3.89, P value = .067) compared to those using US. These results are highlighted in Table 2.
Table 2.
Multivariate Cox Regression Model for Overall Survival Comparing US vs Cross-sectional Imaging
| Variable (reference) | Hazard ratio for risk of death (95% CI) | P value |
|---|---|---|
| Race-ethnicity (Hispanic) | ||
| Non-Hispanic White | 0.48 (0.28, 0.85) | .011 |
| African Americans | 0.34 (0.15, 0.80) | .012 |
| Modality (US) | ||
| CT | 1.93 (0.96, 3.89) | .067 |
| MRI | 0.91 (0.48, 1.71) | .768 |
| MELD - Na | 1.11 (1.07, 1.16) | <.0001 |
| Total tumor size at time of detection | 1.40 (1.25, 1.56) | <.0001 |
Transplant-free Survival
During follow up period, 95 patients received LT, accounting for 52% of the total. As LT can be a competing event for OS since it could impact patient survival outcomes, we used the Gray’s test and Fine-Grey model with LT as a competing event for univariate and multivariate analyses. Similar to the OS analysis, univariate analysis shows that Child Pugh score, hemoglobin level, albumin, INR, sodium levels, MELD score, and total tumor size at time of detection had statistically significant effect on survival outcomes (P values < 0.05). (Table A2).
In the cumulative risk analysis (Figure 5) and multivariate analysis, there were no statistically significant differences for LT-free survival between patients who received surveillance using MRI (HR: 0.75, 95% CI: 0.39–1.44, P = .38) or CT (HR: 1.39, 95% CI: 0.65–3, P value = .39) compared to those using US. These results are highlighted in Table A3.
Figure 5.
Cumulative risk rate between imaging modalities.
Discussion
Our retrospective cohort study involving 183 patients with HCC detected following rigorous surveillance protocol showed no significant differences in OS or transplant-free survival based on the imaging modality employed. Furthermore, no correlation was found between the type of imaging modality and receipt of curative treatment. Most patients had a solitary hepatic lesion (75.4%) at detection. The median tumor size at the time of detection was 2.4 cm with 68.9% of the tumors detected at late stage BCLC (B/C/D). Curative treatment was administered to 53.6% of the patient population irrespective of modalities.
A meta-analysis by Singal, et al. found that HCC surveillance significantly improved rates of curative treatment (odds ratio 2.24, 95% CI 1.99–2.52) and extended survival (odds ratio 1.90, 95% CI: 1.67–2.17).12 However, data on survival outcomes among patients surveilled using different radiologic modalities are less clear. Our study results diverge from the results of a recent study that showed that surveillance by CT or MRI has a survival benefit compared to surveillance using US with or without AFP.13 Several factors may have contributed to these differences. In the referenced study, 34.8% had no imaging in the year before HCC diagnosis, and in the US group the annual surveillance rate was 72.1% and a semiannual surveillance rate dropped to 27.9%. Our study enrolled patients who rigorously adhered to semiannual surveillance mirroring published practice guidance, and each imaging scan was complemented by AFP, irrespective of modes for surveillance.6 Secondly, our study included patients who consistently underwent surveillance with a single modality leading up to HCC detection. Lastly, all patients received care from hepatology specialists. Our study represents the best-case scenario, where patients are linked to specialty care and adhere to a single surveillance modality. This contrasts with the earlier study where less than half (43.1%) of the individuals had undergone follow up by gastroenterologist or hepatologist in the 36 months prior to being diagnosed with HCC, while 14.9% had care provided with primary care during the same timeframe. These factors can account for the variations observed in terms of survial benefits and the likelihood of receiving curative treatment when comparing both studies.14,15 CT and MRI are increasingly utilized in HCC surveillance due to concerns of poor sensitivity of US, despite the lack of cost-effectiveness data.16 The same was reflected in our study population as 81% had surveillance using CT or MRI. Contrary to the widespread notion that more advanced imaging techniques, such as MRI and CT, offer superior outcomes, our study observed no statistically significant differences in OS between the groups surveilled with MRI, CT, or US. The lack of significant differences in survival outcomes across modalities may be attributable to a uniform treatment algorithm post-HCC diagnosis. Limitations of use of imaging in clinical practice include cost of testing, transportation of patients, inadequate referrals to specialists, and difficulty in scheduling the imaging test, with an overall pooled estimate of only 24% usage in a meta-analysis of 29 studies involving 118,799 subjects. Even in a tertiary care center, implementation of imaging-based surveillance was followed in less than 70% of eligible patients.17 The key to successful surveillance program is effective implementation of available resources that is cost-effective and easily accessible, and appropriate adherence.
Our results showed that the cross-sectional imaging (contrast-enhanced multiphasic CT and MRI) had a similar rate of early BCLC stage at detection compared to US, in contrast to the results of other reports that showed that MRI surveillance was superior in early tumor detection.12,18,19 In our study, the median tumor size at detection was similar between the three modalities. Kim et al. showed that MRI outperformed US, with 86.0% early detection rate compared to US’s 27.9% (P < .001).20 Another meta-analysis revealed MRI’s overall sensitivity and specificity in detecting HCC nodules smaller than 2 cm to be 78% and 92%, respectively.21 Majority of research assessing the relationship between tumor size at detection and the surveillance modality used often rely on either BCLC classification or Milan criteria for defining early tumor.14,15 Consequently, the inference that cross-sectional imaging modalities can identify smaller tumor sizes with improved survival may be misleading due to presence of multiple confounding factors such as performance score, liver function or vascular invasion status included within these frameworks. The existing notion that ultrasound surveillance is associated with worse outcomes may not be accurate. US has limitations, being operator dependent and influenced by patients’ body habitus. Despite its lower sensitivity in detecting tumors smaller than 2 cm, US showed high sensitivity (pooled sensitivity of 94%, 95% CI: 83–98) for detecting HCC at any stage.22
The observation that non-Hispanic Whites and African Americans were associated with better survival compared to Hispanics despite similar size and stage at detection is consistent with the previous reports23, 24, 25, 26 and merits further investigation. This discrepancy may be attributed to disparities in post-HCC detection care. Investigating the causes of these disparities holds the potential to guide targeted interventions enhancing health-care equity.
Limitations of our study include its retrospective nature, lack of randomization in assigning surveillance modalities, and analyses of a small highly selective cohort which may have introduced selection bias. The findings of the post hoc power analysis suggests that the current sample sizes of our study may have been insufficient to detect smaller differences in outcomes. These limitations were mitigated by our robust inclusion and exclusion criteria analyzing a homogeneous group of patients who adhered to semiannual surveillance following guidelines. Serum AFP measurement with every imaging scan may have eliminated other confounders. HCC surveillance is difficult to implement as less than 30% of eligible patients undergo recommended semiannual surveillance with US and AFP in the best-case scenario,13 and hence we designed our study to compare its efficacy with contrast enhanced imaging studies that are considered superior but more expensive and not readily available. A multicenter study with randomization of imaging modalities in a larger patient population would be helpful to validate our findings. Analysis of racial disparities and their association with outcomes highlights the importance of appropriate postsurveillance follow-up.
In conclusion, using surveillance protocol rigorously, our study did not find any association between the imaging modality and clinical outcomes in patients with HCC. It emphasizes importance of access, implementation, and adherence to surveillance program, irrespective of the radiologic modality. Further studies are needed to explore the effectiveness of adherence to surveillance program to influence the outcome in this population.
Footnotes
Authors’ Contributions: Ahmed El Sabagh: Study Conception and Design, Data Collection and Management, Drafting of Manuscript, and Critical Revision of Manuscript. Islam Mohamed: Data Collection and Management, Drafting of Manuscript. Mazen El Sheikh: Data Collection and Management. Megha Bhongade: Data Collection and Management. Eunji Jo: Statistical Analysis. Susan G Hilsenbeck: Statistical Analysis. Fasiha Kanwal: Critical Revision of Manuscript. Prasun K Jalal: Study Conception and Design, Drafting of Manuscript, Critical Revision of Manuscript, Supervision, and Oversight.
Conflicts of Interest: The authors disclose no conflicts.
Funding: This study was funded by Dora Roberts Foundation.
Ethical Statement: The study was approved by the Baylor College of Medicine Institutional Review Board (H-40333) and a waiver of informed consent was granted.
Data Transparency Statement: All data and analytical methods will be made available after contacting the authors.
Reporting Guidelines: STROBE.
Material associated with this article can be found, in the online version, at https://doi.org/10.1016/j.gastha.2025.100704.
Supplementary Material
Supplementary Material
References
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