Abstract
Introduction
Circulating inflammatory cytokines play critical roles in tumor-associated inflammation and immune responses. Recent data have suggested that several interleukins (ILs) mediate carcinogenesis in hepatocellular carcinoma (HCC). However, the predictive and prognostic value of circulating ILs is yet to be validated. Our study aimed to evaluate the association of the serum ILs with overall survival (OS) and clinicopathologic features in a large cohort of HCC patients.
Methods
We prospectively collected data and serum samples from 767 HCC patients treated at the University of Texas MD Anderson Cancer Center between 2001 and 2014, with a median follow-up of 67.4 months (95% confidence interval [CI]: 52.5, 83.3). Biomarker association with OS was evaluated by the log-rank method.
Results
The median OS in this cohort was 14.2 months (95% CI: 12, 16.1 months). Clinicopathologic features were more advanced, and OS was significantly inferior in patients with high circulating levels of IL1-R1, IL-6, IL-8, IL-10, IL-15, IL-16, and IL-18.
Conclusion
Our study shows that several serum IL levels are valid prognostic biomarker candidates and potential targets for therapy in HCC.
Keywords: Interleukins, Biomarker, Hepatocellular carcinoma, Overall survival, Prognosis
Introduction
Hepatocellular carcinoma (HCC) is the most common liver cancer that usually develops in the setting of chronic liver inflammation and disease [1]. It is the third leading cause of cancer-related deaths worldwide, with around 830,000 deaths in 2020 [2].
Alpha-fetoprotein (AFP) is the most commonly used serum marker for HCC screening, diagnosis, prognostication, and follow-up [3]. High AFP levels in patients with chronic liver disease denote an increased risk for HCC [3]. However, when using a cutoff level of 20 ng/mL, AFP only has a sensitivity of 60 percent and specificity of 80 percent in diagnosing HCC [4]. Moreover, serum AFP level was not shown to be a strong independent prognostic factor for HCC [5]. Given the abovementioned limitations of AFP, exploring other non-invasive biomarkers to assist in HCC prognosis, such as the cytokines from the interleukin (IL) family, is warranted. ILs are inflammatory cytokines and growth factors that play a role in inflammation and immune responses in cancer and may be associated with prognosis in patients with HCC [6]. Prior small studies have proposed the potential use of ILs as reliable biomarkers for prognosis [6–14], diagnosis [8, 15–24], and treatment resistance in HCC [11, 12, 25–32]. Specifically, several ILs have been reported to be elevated in patients with HCC, and some were associated with worse overall survival (OS). However, further prospective validation of the clinical and prognostic value of ILs in large cohorts is lacking. This study aimed to evaluate the OS distribution between high and low biomarker levels for a panel of ILs in a large HCC patient cohort and correlate IL level with clinicopathologic features.
Materials and Methods
Patients and Specimens
This cohort study enrolled treatment-naïve HCC patients treated at MD Anderson Cancer Center between 2001 and 2014. The clinicopathologic data and serum samples were collected prospectively. The study was approved by the Institutional Review Board (IRB) of the University of Texas MD Anderson Cancer Center. Written consent was obtained from all patients.
Biopsy and pathologic examination, or typical characteristics of contrast-enhanced cross-sectional imaging in cirrhotic patients, were the two accepted means for diagnosing HCC in our cohort. Several patient characteristics were recorded during blood collection, such as HCC risk factors (hepatitis B or C infection, cirrhosis, alcohol consumption), treatment modalities received, and the presence of metastasis.
IL Measurement
Twenty-seven IL biomarkers were measured in samples from the 767 HCC patients. They were measured by Myriad RBM (Austin, TX, USA), a Clinical Laboratory Improvement Amendments (CLIA) – certified biomarker testing laboratory. A multiplexed immunoassay panel (DiscoveryMAP v.3.3; Myriad RBM) was used to quantitate IL levels on an automated, Luminex xMAP-based platform (Austin, TX, USA).
Statistical Analysis
IL markers were summarized using descriptive statistics as continuous variables. Each marker was dichotomized by its median as high (>median value) and low (<=median value). Log-rank test was applied to evaluate the association of IL markers and OS. Wilcoxon rank sum test/Kruskal-Wallis test by ranks was used to compare IL-6, IL-8, and IL-10 levels between subgroups of patients’ clinical factors.
A p value ≤0.05 was considered statistically significant. R software 4.1.1 was used for analysis.
Results
Our study included 767 HCC patients, of which 766 had OS data available for analysis with a median follow-up of 67.4 months (95% CI: 52.5, 83.3). Table 1 summarizes the patients’ risk factors and demographic and clinicopathological characteristics. Most patients were males over 60 years old, consistent with the demographics of HCC. Two-thirds of the patients were white. Most patients (65.2%) had either hepatitis B virus, hepatitis C virus (HCV), or both, and 63.7% of patients had cirrhosis. An AFP level ≥400 was seen in 32.7% of our patients, with a quarter of patients having distant metastasis and over three quarters having advanced Barcelona Clinic Liver Cancer scores. The median OS was 14.2 months (95% CI: [12, 16.1]), with 586/766 patients having passed away at the time of analysis.
Table 1.
Demographic characteristics, risk factors, and clinicopathological characteristics of 767 HCC patients
| Variables | HCC patients (n = 767) | |
|---|---|---|
| patients, n | % | |
| Age at diagnosis | ||
| ≤60 years | 327 | 42.6 |
| >60 years | 440 | 57.4 |
| Gender | ||
| Male | 567 | 73.9 |
| Female | 200 | 26.1 |
| Race | ||
| White | 514 | 67.0 |
| Non-white | 253 | 33.0 |
| Hepatitis status | ||
| HCV only | 301 | 39.2 |
| HBV only | 88 | 11.5 |
| HCV and HBV | 111 | 14.5 |
| History of cigarette smoking | 498 | 64.9 |
| History of alcohol consumption | 560 | 73.0 |
| History of diabetes | 271 | 35.3 |
| AFP level ≥20 ng/dL | 453 | 59.1 |
| AFP level ≥400 ng/dL | 251 | 32.7 |
| Presence of vascular invasion | 241 | 31 |
| Presence of vascular thrombosis | 172 | 22.4 |
| >50% tumor involvement | 180 | 23.5 |
| Distant metastasis | 189 | 24.6 |
| Lymph node metastasis | 157 | 20.4 |
| Adjacent organ invasion | 27 | 3.5 |
| Multi-nodularity | 474 | 61.8 |
| Tumor differentiation | ||
| Well-differentiated | 193 | 25.2 |
| Moderately differentiated | 211 | 27.5 |
| Poorly differentiated | 120 | 13.0 |
| Fibrolamellar | 13 | 1.6 |
| Clear cell | 7 | 0.9 |
| Presence of cirrhosis | 489 | 63.7 |
| Child-Pugh class | ||
| A | 412 | 53.7 |
| B | 299 | 39.0 |
| C | 56 | 7.3 |
| CLIP staging | ||
| Stage 0–2 | 485 | 63.2 |
| Stage 3–6 | 282 | 36.8 |
| BCLC staging | ||
| Stage 0–B | 172 | 22.4 |
| Stage C–D | 588 | 76.6 |
| TNM staging | ||
| Stage I–II | 253 | 33.0 |
| Stage IIIA–IIIB | 225 | 29.3 |
| Stage IIIC–IVB | 266 | 34.7 |
CLIP, Cancer of the Liver Italian Program; BCLC, Barcelona Clinic Liver Cancer; TNM, tumor, node, metastasis; HBV, hepatitis B virus.
Patients with low expression of serum IL-1 receptor type 1 (IL-1R1) had a median OS of 21.98 months (95% CI: 19.55, 27.83), which was significantly higher than those in the high-expression group, who had a median OS of 7 months (95% CI: 6.18, 9.43) (p < 0.0001) (Table 2). Similar results were seen for serum IL-1 receptor type 2 (Table 2). IL-2 receptor alpha (IL-2Rα) was elevated in half the patients (Table 3). Patients with high levels of IL-2Rα had a median OS of 8.25 months (95% CI: 6.54, 10.09), which was significantly lower than patients with low levels of IL-2Rα, who had a median OS of 21.55 months (95% CI: 18.37, 25.86). Circulating IL-6 was elevated in 49.7% of HCC patients (Table 3). Additionally, patients with high levels of IL-6 had a median OS of 7.62 months (95% CI: 6.14, 9.69), which was significantly lower than those with low levels of IL-6, who had a median OS of 21.09 months (95% CI: 18.37, 25.79) (p < 0.0001). The same association was found for serum IL-8, IL-10, and IL-16; high levels of these biomarkers were associated with a significantly shorter OS (Table 2). Additionally, compared to their counterparts, patients with an elevated Eastern Cooperative Oncology Group (ECOG) score, a higher AFP score (≥400), higher Barcelona Clinic Liver Cancer score, as well as lymph node invasion and metastasis, had significantly higher IL-6 levels (Table 4). IL-8 and IL-10 showed similar results (Table 4). In addition, there was a non-significant trend for a difference in OS between the high IL-17 group and low IL-17 groups (p = 0.086). However, only 21 patients had elevated IL-17 (Table 2). In contrast, circulating IL-18 was elevated in 382 patients (Table 3). Patients with high IL-18 had a median OS of 10.71 months (95% CI: 8.8, 13.17) which was significantly shorter compared to 14.46 months (95% CI: 12.16, 16.39) in patients with low IL-18 (p < 0.0001) (Table 2). Serum IL-22 was elevated in 325 patients, and in these patients, the median OS was 10.71 (95% CI: [8.8, 14.85), which was shorter compared to the OS of 15.74 months (95% CI: 13.17, 17.87) in patients with low IL-22 but did not reach statistical significance (p = 0.055) (Table 2). We did not find any trend for an association between OS and serum IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-7, or IL-13 (Table 2).
Table 2.
ILs associated with poor OS
| Variable | Level | N | Deaths | Median OS (95% CI) (M) | p value |
|---|---|---|---|---|---|
| All patients | 766 | 586 | 14.19 (11.96, 16.13) | ||
| IL-1R1 | H | 383 | 325 | 7 (6.18, 9.43) | <0.0001 |
| L | 383 | 261 | 21.98 (19.55, 27.83) | ||
| IL-1R2 | H | 375 | 297 | 9.26 (7.36, 11.76) | <0.0001 |
| L | 391 | 289 | 18.89 (16.07, 21.98) | ||
| IL-2Rα | H | 382 | 324 | 8.25 (6.54, 10.09) | <0.0001 |
| L | 384 | 262 | 21.55 (18.37, 25.86) | ||
| IL-5 | H | 12 | 10 | 5.06 (2.5, NA) | 0.0052 |
| L | 754 | 576 | 14.19 (12.06, 16.23) | ||
| IL-6 | H | 381 | 318 | 7.62 (6.14, 9.69) | <0.0001 |
| L | 385 | 268 | 21.09 (18.37, 25.79) | ||
| IL-6 receptor subunit beta | H | 382 | 314 | 7.85 (6.41, 9.43) | <0.0001 |
| L | 384 | 272 | 21.55 (18.86, 25.13) | ||
| IL-8 | H | 382 | 299 | 7.72 (6.41, 9.79) | <0.0001 |
| L | 384 | 287 | 20.47 (17.74, 23) | ||
| IL-10 | H | 306 | 252 | 8.87 (6.67, 10.71) | <0.0001 |
| L | 460 | 334 | 17.41 (15.51, 20.53) | ||
| IL-15 | H | 79 | 68 | 8.34 (5.82, 17.35) | 0.0017 |
| L | 687 | 518 | 14.85 (12.39, 16.49) | ||
| IL-16 | H | 382 | 307 | 11.73 (9.79, 15.11) | 0.0048 |
| L | 384 | 279 | 16.13 (13.31, 20.17) | ||
| IL-17 | H | 21 | 19 | 7.1 (4.34, 26.38) | 0.0855 |
| L | 745 | 567 | 14.46 (12.16, 16.39) | ||
| IL-18 | H | 382 | 310 | 10.71 (8.8, 13.17) | <0.0001 |
| L | 384 | 276 | 17.41 (15.08, 21.26) | ||
| IL-18 binding protein | H | 369 | 311 | 7.23 (6.14, 9.26) | <0.0001 |
| L | 397 | 275 | 20.47 (17.35, 23.46) | ||
| IL-22 | H | 325 | 260 | 11.53 (8.8, 14.85) | 0.0552 |
| L | 441 | 326 | 15.74 (13.17, 17.87) |
IL-1R2, IL-1 receptor type 2.
Table 3.
ILs elevated in HCC patients
| Variable | Level | N | % | Deaths |
|---|---|---|---|---|
| All patients | 766 | 586 | ||
| IL-1 receptor antagonist | H | 372 | 48.56 | 285 |
| L | 394 | 51.44 | 301 | |
| IL-1R1 | H | 383 | 50 | 325 |
| L | 383 | 50 | 261 | |
| IL-1R2 | H | 375 | 48.95 | 297 |
| L | 391 | 51.05 | 289 | |
| IL-2Rα | H | 382 | 49.87 | 324 |
| L | 384 | 50.13 | 262 | |
| IL-6 | H | 381 | 49.73 | 318 |
| L | 385 | 50.27 | 268 | |
| IL-6 receptor | H | 360 | 47.0 | 274 |
| L | 406 | 53.0 | 312 | |
| IL-6 receptor subunit beta | H | 382 | 49.87 | 314 |
| L | 384 | 50.13 | 272 | |
| IL-8 | H | 382 | 49.87 | 299 |
| L | 384 | 50.13 | 287 | |
| IL-10 | H | 306 | 40.0 | 252 |
| L | 460 | 60.0 | 334 | |
| IL-12 subunit p40 | H | 376 | 49.09 | 291 |
| L | 390 | 50.91 | 295 | |
| IL-16 | H | 382 | 49.87 | 307 |
| L | 384 | 50.13 | 279 | |
| IL-18 | H | 382 | 49.87 | 310 |
| L | 384 | 50.13 | 276 | |
| IL-18 binding protein | H | 369 | 48.17 | 311 |
| L | 397 | 51.83 | 275 | |
| IL-22 | H | 325 | 42.42 | 260 |
| L | 441 | 57.68 | 326 | |
| IL-23 | H | 344 | 44.90 | 263 |
| L | 422 | 55.10 | 323 |
IL-1R2, IL-1 receptor type 2.
Table 4.
Association of expression of ILs with clinical factors
| Covariate | ECOG | n | Mean ± SD, median (range) | p value |
|---|---|---|---|---|
| By ECOG | ||||
| IL-6 | 0–1 | 665 | 74.252 ± 599.735, 5.2 (4.5, 13,000) | <0.0001 |
| 2+ | 102 | 160.015 ± 1,288.347, 13 (4.5, 13,000) | ||
| IL-8 | 0–1 | 665 | 559.086 ± 1,494.586, 65 (2.9, 7,050) | 0.0515 |
| 2+ | 102 | 659.748 ± 1,622.803, 90 (6.5, 7,050) | ||
| IL-10 | 0–1 | 665 | 8.867 ± 12.925, 6.8 (6.8, 306) | <0.0001 |
| 2+ | 102 | 13.846 ± 21.645, 9.35 (6.8, 203) | ||
| Covariate | Vascular invasion | N | Mean ± SD, median (range) | p value |
|---|---|---|---|---|
| By metastasis | ||||
| IL-6 | None | 576 | 79.677 ± 639.761, 5.2 (4.5, 13,000) | 0.0023 |
| Present | 189 | 104.476 ± 955.625, 7.5 (4.5, 13,000) | ||
| IL-8 | None | 576 | 548.48 ± 1,494.166, 63 (2.9, 7,050) | 0.0047 |
| Present | 189 | 641.792 ± 1,572.095, 95 (3.5, 7,050) | ||
| IL-10 | None | 576 | 8.792 ± 9.501, 6.8 (6.8, 203) | <0.0001 |
| Present | 189 | 11.789 ± 23.884, 7.2 (6.8, 306) | ||
| Covariate | Lymph node | n | Mean ± SD, median (range) | p value |
|---|---|---|---|---|
| By lymph node invasion | ||||
| IL-6 | None | 608 | 75.995 ± 616.805, 5.2 (4.5, 13,000) | 0.0021 |
| Present | 157 | 123.79 ± 1,061.866, 7.5 (4.5, 13,000) | ||
| IL-8 | None | 608 | 551.333 ± 1,493.668, 62 (2.9, 7,050) | 0.0024 |
| Present | 157 | 649.764 ± 1,589.489, 96 (3.5, 7,050) | ||
| IL-10 | None | 608 | 9.44 ± 15.561, 6.8 (6.8, 306) | 0.0012 |
| Present | 157 | 9.889 ± 9.28, 6.8 (6.8, 112) | ||
| Covariate | AFP_CLIP | n | Mean ± SD, median (range) | p value |
|---|---|---|---|---|
| By AFP | ||||
| IL-6 | <400 | 516 | 79.068 ± 641.484, 5.2 (4.5, 13,000) | 0.0376 |
| ≥400 | 251 | 99.204 ± 883.473, 6.7 (4.5, 13,000) | ||
| IL-8 | <400 | 516 | 497.529 ± 1,332.533, 85 (3.7, 7,050) | 0.0196 |
| ≥400 | 251 | 608.927 ± 1,591.303, 63 (2.9, 7,050) | ||
| IL-10 | <400 | 516 | 8.921 ± 9.862, 6.8 (6.8, 203) | 0.0023 |
| ≥400 | 251 | 10.778 ± 20.954, 6.8 (6.8, 306) | ||
| Covariate | BCLC | n | Mean ± SD, median (range) | p value |
|---|---|---|---|---|
| By BCLC | ||||
| IL-6 | Stage 0–B | 172 | 82.885 ± 501.73, 4.5 (4.5, 4,500) | <0.0001 |
| Stage C–D | 588 | 87.391 ± 787.499, 6.7 (4.5, 13,000) | ||
| IL-8 | Stage 0–B | 172 | 479.935 ± 1,349.906, 52.5 (2.9, 7,050) | 0.0003 |
| Stage C–D | 588 | 603.799 ± 1,563.405, 74 (3.5, 7,050) | ||
| IL-10 | Stage 0–B | 172 | 7.723 ± 3.756, 6.8 (6.8, 50) | <0.0001 |
| Stage C–D | 588 | 10.085 ± 16.367, 6.8 (6.8, 306) | ||
ECOG, Eastern Cooperative Oncology Group; AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer.
Discussion
To our knowledge, this is the largest ever-reported prospective study that investigated the association between several circulating IL family members and OS in patients with HCC. Consistent with prior studies which suggested the role of ILs as potential prognostic biomarkers for HCC (6–14), our study showed that elevated levels of IL-R1, IL-6, IL-8, IL-10, IL-16, and IL-18 were associated with a significantly shorter median OS in those patients compared to those with low levels. Additionally, several ILs were elevated in more than half of patients with HCC, indicating the potential role of ILs in diagnosing HCC (8, 15–24).
In previous studies, IL-1α level has been documented to be significantly higher in HCC patients compared to chronic HCV with cirrhosis patients [33]. We could not confirm this finding in our study, in which only 5 patients from our cohort had increased levels of IL-1α. Moreover, when assessing its prognostic potential, we found no significant difference in OS between the low and high IL-1α groups. Interestingly, IL-1R1, the receptor primarily responsible for transmitting the inflammatory effects of IL-1, was elevated in half the patients in our study and showed a significant association with OS. The reason for the disparity in the results between serum IL-1α and IL-1R1 is unclear. Future studies should assess the interplay between IL-1α and IL-1R1, the importance of the platform used for measurements, and their diagnostic and prognostic values. Importantly, we dichotomized our IL values by the median values. Although this method has been widely used in biomarker research, it is very challenging to compare results from different studies given the inherent heterogeneity between different patient populations. Therefore, future multicenter studies are warranted [10, 11, 13, 27, 28].
The literature has shown that high serum levels of IL-6 are associated with increased risk of HCC, independently of hepatitis virus infection, alcohol consumption, gender, BMI, and radiation exposure [21]. Serum IL-6 level was significantly higher in HCC patients than in HCV patients with peri-hepatic fibrosis, patients with hepatic cirrhosis, and control healthy individuals [7, 8, 15, 23]. In our study, 49.7% of patients with HCC had elevated levels of IL-6. When assessing the prognostic value of IL-6 in HCC patients (Table 4), IL-6 titers were significantly higher in patients with more advanced HCC staging, ECOG performance status, and AFP levels [15]. Thus, our results further support the value of serum IL-6 as a biomarker of poor survival. Importantly, circulating IL-6 may also be a biomarker of treatment resistance. Multiple studies assessed IL-6 in the context of antiangiogenic therapy and showed worse survival outcomes in HCC patients with elevated IL-6 who received sunitinib, sorafenib, or bevacizumab, alone or with atezolizumab immunotherapy [11, 25, 29]. These results warrant further evaluation of circulating IL-6 as a biomarker of resistance to antiangiogenic and immune checkpoint blockade therapy in patients with HCC.
Similarly, previous studies have also reported a significant elevation in circulating IL-8 in patients with HCC compared to control subjects [19, 20, 24]. In our study (Table 4), elevated IL-8 levels were seen in 50% of our patients. Consistent with published literature [9], our findings showed a poor prognosis for high circulating IL-8 levels in HCC patients, particularly in early-stage disease.
Serum IL-10 levels were reported to be significantly higher in HCC than in normal control groups [13, 16, 17, 23, 34]. In our study, 40% of HCC patients had elevated serum IL-10. Patients with high IL-10 were also reported to have a significantly worse disease-free survival [16, 22] and shorter OS [13, 30]. This was further highlighted in a study where serum IL-10 correlated to clinical outcomes in patients with resectable HCC, with tumor resection, resulting in decreased IL-10 levels [13]. Thus, our results are consistent with these prior reports and support the further evaluation of circulating IL-10 as a prognostic biomarker in HCC patients.
Notably, analysis of IL-17 as a biomarker for HCC has yielded varying results and dissonant findings. In one study, serum IL-17 levels were significantly higher in HCC patients than in the healthy control group [18]. However, Kim et al., [12] reported lower levels of IL-17 levels in HCC patients than in healthy adults. Our study also revealed that only a minority of patients (21) showed elevated IL-17. With regards to prognosis, patients with early HCC recurrence after curative hepatectomy had significantly higher pre-surgery serum IL-17 concentrations than patients without early recurrence [26]. Additionally, elevated serum levels of IL-17 were linked to better OS in HCC patients [26]. Nonetheless, our findings did not demonstrate a significant difference in median OS between patients with high and low IL-17.
Tangkijvanich et al. [14] reported that serum IL-18 levels in patients with HCC were significantly higher in patients with HCC compared to those of controls. In our study, 50% of our patients had elevated levels of IL-18. Furthermore, when evaluating its prognostic significance, Tangkijvanich et al. [14] found that IL-18 was a significant and independent prognostic factor of survival; patients with high serum IL-18 levels had a poorer median OS than those with low serum IL-18 levels. This finding is consistent with our results.
Finally, circulating IL-22 was elevated in 42% of patients in our study. It has been previously found to associate with worse OS and disease-free survival [35], as well as increased aggressiveness of HCC [36]. In our study, the difference in median OS between patients in the high IL-22 group and those in the low IL-22 group showed a similar but non-significant trend.
In conclusion, this study strongly supports the use of minimally invasive serum biomarkers such as serum IL-1R, IL-6, IL-8, IL-10, and IL-18 for the prognostication of HCC patients and their potential value as therapeutic targets to address resistance to systemic therapy. Therefore, future studies should assess IL levels and their association with OS and treatment outcomes in various stages and patient populations of HCC.
Statement of Ethics
This investigation was reviewed and approved by the University of Texas MD Anderson Cancer Center Institutional Review Board in 2000, protocol ID00-083. Written informed consent was obtained from each participant.
Conflict of Interest Statement
D.G.D. received consultant fees from Innocoll and research grants from Bayer, Surface Oncology, Exelixis, and BMS. No funding or reagent from these companies was used in this study. All other authors report no commercial associations (e.g., consultancies, stock ownership, equity interests, or patent-licensing arrangements) that might pose a conflict of interest in connection with the submitted article.
Funding Sources
The University of Texas MD Anderson Cancer Center, SPORE in HCC, Grant #NCI, P50 CA217674-01A1 (to AOK), NCI R01CA260872 (to AOK, HMA, DGD). D.G.D.’s research is also funded through NIH (Grant No. R01CA260857 and R01CA247441) and by Department of Defense PRCRP (Grant No. W81XWH-19–1-0284, W81XWH1910482, and W81XWH-21–1–0738). All other authors report no competing financial interests related to this work.
Author Contributions
Study concept, design, and supervision: Shadi Chamseddine and Ahmed O. Kaseb. Acquisition of data: Shadi Chamseddine, Lianchun Xiao, Ryan Sun, Yehia I. Mohamed, Jeffrey S. Morris, Rikita I. Hatia, Manal M. Hassan, and Ahmed O. Kaseb. Analysis and interpretation of data: Shadi Chamseddine, Lianchun Xiao, Ryan Sun, Yehia I. Mohamed, Rikita I. Hatia, Dan G. Duda, and Ahmed O. Kaseb. Drafting of the manuscript: Shadi Chamseddine, Yehia I. Mohamed, Dan G. Duda, Sunyoung Lee, Lianchun Xiao, Rikita I. Hatia, Sunyoung S. Lee, Jeffrey S. Morris, James Yao, Zishuo Ian Hu, Hesham M. Amin, Hop S. Tran Cao, Maria Diab, Amr Mohamed, Ahmed Nassar, and Ahmed O. Kaseb. Critical revision of the manuscript for important intellectual content: Shadi Chamseddine, Yehia I. Mohamed, Dan G. Duda, Sunyoung Lee, Lianchun Xiao, Rikita I. Hatia, Sunyoung S. Lee, Jeffrey S. Morris, James Yao, Zishuo Ian Hu, Hop S Tran Cao, Hesham M. Amin, Maria Diab, Amr Mohamed, Ahmed Nassar, and Ahmed O. Kaseb Statistical analysis: Shadi Chamseddine, Lianchun Xiao and Ryan Sun. Administrative, technical, or material support: Shadi Chamseddine, Yehia I. Mohamed, Dan G. Duda, Sunyoung S. Lee, Lianchun Xiao, Manal M. Hassan, Rikita I. Hatia, Jeffrey S. Morris, James Yao, Hesham M. Amin, Hop S. Tran Cao, Maria Diab, Amr Mohamed, Ahmed Nassar, Saumil Datar, and Ahmed O. Kaseb.
Funding Statement
The University of Texas MD Anderson Cancer Center, SPORE in HCC, Grant #NCI, P50 CA217674-01A1 (to AOK), NCI R01CA260872 (to AOK, HMA, DGD). D.G.D.’s research is also funded through NIH (Grant No. R01CA260857 and R01CA247441) and by Department of Defense PRCRP (Grant No. W81XWH-19–1-0284, W81XWH1910482, and W81XWH-21–1–0738). All other authors report no competing financial interests related to this work.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
