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Different approaches are available after progression of disease (PD) to immune checkpoint inhibitors (ICI) for hepatocellular carcinoma (HCC), including continuation of ICI, treatment switching to tyrosine kinase inhibitors (TKIs) and cessation of anticancer therapy. We sought to characterise the relationship between radiologic patterns of progression and survival post-ICI, also appraising treatment strategies.We screened 604 HCC patients treated with ICIs, including only those who experienced PD by data cut-off. We evaluated post-progression survival (PPS) according to treatment strategy at PD and verified its relationship with radiologic patterns of progression: intrahepatic growth (IHG), new intrahepatic lesion (NIH), extrahepatic growth (EHG), new extrahepatic lesion (NEH) and new vascular invasion (nVI).Of 604 patients, 364 (60.3%) experienced PD during observation. Median PPS was 5.3 months (95%CI: 4.4-6.9; 271 events). At data cut-off, 165 patients (45%) received no post-progression anticancer therapy; 64 patients (17.6%) continued ICI beyond PD. IHG (HR 1.64 [95%CI:1.21-2.22]; p=0.0013) and nVI (HR 2.15 [95%CI:1.38-3.35]; p=0.0007) were associated with shorter PPS. Multivariate models adjusted for progression patterns, treatment line, and ALBI grade and ECOG-PS at PD confirmed receipt of ICI beyond PD with (HR 0.17, 95%CI 0.09-0.32; p0.0001), or without subsequent TKI (HR 0.39, 95%CI 0.26-0.58; p0.0001) as predictors of prolonged PPS versus no anticancer therapy.ICI-TKI sequencing is a consolidated option in advanced HCC. nVI and IHG predict poorer prognosis. Despite lack of recommendation, continuation of ICI beyond progression in HCC is adopted clinically: future efforts should appraise which patients benefit from this approach.

Simple Summary The investigation of predictive and prognostic markers is pivotal in patients affected by hepatocellular carcinoma treated with immune-checkpoint-inhibitors. Inflammation has a central role in hepatocellular carcinoma development and progression; however, its role in influencing outcomes in the context of immunotherapy has not been fully elucidated yet. In the following study, we investigated the prognostic role of bloods derived inflammatory markers and we found that they predict survival and response of patients treated with immunotherapy for advanced hepatocellular carcinoma. Abstract Systemic inflammation is a hallmark of cancer, and it has a pivotal role in hepatocellular carcinoma (HCC) development and progression. We conducted a retrospective study including 362 patients receiving immune check-point inhibitors (ICIs) across three continents, evaluating the influence of neutrophiles to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), and prognostic nutritional index (PNI) on overall (OS), progression free survival (PFS), and radiologic responses. In our 362 patients treated with immunotherapy, median OS and PFS were 9 and 3.5 months, respectively. Amongst tested inflammatory biomarkers, patients with NLR ≥ 5 had shorter OS (7.7 vs. 17.6 months, p < 0.0001), PFS (2.1 vs. 3.8 months, p = 0.025), and lower objective response rate (ORR) (12% vs. 22%, p = 0.034); similarly, patients with PLR ≥ 300 reported shorter OS (6.4 vs. 16.5 months, p < 0.0001) and PFS (1.8 vs. 3.7 months, p = 0.0006). NLR emerged as independent prognostic factors for OS in univariate and multivariate analysis (HR 1.95, 95%CI 1.45–2.64, p < 0.001; HR 1.73, 95%CI 1.23–2.42, p = 0.002) and PLR remained an independent prognostic factor for both OS and PFS in multivariate analysis (HR 1.60, 95%CI 1.6–2.40, p = 0.020; HR 1.99, 95%CI 1.11–3.49, p = 0.021). Systemic inflammation measured by NLR and PLR is an independent negative prognostic factor in HCC patients undergoing ICI therapy. Further studies are required to understand the biological mechanisms underlying this association and to investigate the predictive significance of circulating inflammatory biomarkers in HCC patients treated with ICIs.

Background and Rationale: Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC. Methods: In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within −30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria. Results: Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494). Conclusions: Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation.

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The availability of immune checkpoint inhibitors (ICIs) for the management of advanced hepatocellular cancer (HCC) has changed the treatment paradigm. There are emerging questions regarding the efficacy of subsequent anticancer therapies. The primary aim of this retrospective, multicenter study was to examine the types of anticancer treatment received after ICIs and to assess the impact on post-ICI survival. We established an international consortium of 11 tertiary-care referral centers located in the USA (n = 249), Europe (n = 74), and Asia (n = 97), and described patterns of care following ICI therapy. The impact of subsequent therapy on overall survival (OS) was estimated using the Kaplan–Meier method and presented with a 95% confidence interval (CI). A total of 420 patients were treated with ICIs for advanced HCC after one line of systemic therapy (n = 371, 88.8%): 31 (8.8%) had died, 152 (36.2%) received best supportive care (BSC) following ICIs, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKIs, n = 132, 80.9%), in particular sorafenib (n = 49, 30.0%), were the most common post-ICI therapy followed by external beam radiotherapy (n = 28, 17.2%), further immunotherapy (n = 21, 12.9%), locoregional therapy (n = 23, 14.1%), chemotherapy (n = 9, 5.5%), and surgery (n = 6, 3.6%). Receipt of post-ICI therapy was associated with longer median OS compared with those who had received BSC (12.1 vs. 3.3 months; hazard ratio [HR]: 0.4 (95% CI: 2.7–5.0). No difference in OS was noted in those patients who received TKI before ICIs compared with those who received ICIs followed by TKI. Conclusion: Post-ICI therapy is associated with OS in excess of 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICIs.

Purpose The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). Patients and methods We derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association. Results In the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25–0.75) and PFS (HR 0.48; 95% CI: 0.31–0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46–0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32–0.95) in the multi-institutional dataset. Conclusion Development of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response.

INTRODUCTION: We assessed the influence of a best practice alert (BPA) embedded within the electronic medical record on improving hepatitis C virus (HCV) birth-cohort screening by primary care physicians (PCPs). METHODS: Screening by 155 PCPs was monitored during 2 consecutive 9-month periods before and after implementation of the BPA. All tests were reviewed to differentiate true screening from other testing indications. RESULTS: Of 155 PCPs, 131 placed screening orders before and after BPA. Twenty-two PCPs started testing after BPA (P = 0.02). The number of tests placed and screening rates per PCP increased from 16 to 84 and from 3.3% to 13.2%, respectively (P < 0.0001). Before BPA, most PCPs rarely ordered screening HCV tests, whereas a small group of physicians generated most tests, indicative of an underlying power-law distribution. After the BPA, a new group of high-performing PCPs emerged, whose screening patterns were again characterized by a power-law distribution. However, pre-BPA test rates of individual PCPs were not predictive of their post-BPA rates. Overall, the introduction of the BPA narrowed the gap between low- and high-performing testers, indicating that modest increases in testing by a large number of low-performing PCPs could drive substantial improvement in program implementation. DISCUSSION: HCV birth-cohort screening by PCPs was shaped by an underlying power-law distribution. This distribution was preserved after the implementation of a BPA, although pre-BPA test rates were not predictive of post-BPA rates. Increases in test rates by high- and low-performing PCPs both contributed to the overall success of the BPA.

Medical-refractory severe alcoholic hepatitis (AH) has a high mortality. The national frequency, longer term outcomes and regional practices of AH liver transplantation (LT) in the United States are not well described, despite the increasing mortality from alcohol-associated liver disease. We analyzed the trends in frequency and outcomes of UNOS data on 39 455 adult patients who underwent LT from 2014 to 2019, including AH LT recipients. LTs for AH increased 5-fold, from 28 in 2014 to 138 in 2019, varying 8-fold between UNOS regions. Three transplant centers accounted for 50%-90% of AH LTs within each region. The number of transplant centers performing AH LTs increased from 14 in 2014 to 47 in 2019. AH patients were younger (mean = 39.4 years), had higher MELD scores (mean = 36.8), and were more often on dialysis (46.0%) and in ICU (38.4%), compared to other indications (all P

399 Background: Portal hypertension increases intestinal permeability, dysbiosis, and bacterial translocation, leading to a pro-inflammatory state, which can in turn promote progression of liver disease. However, multiple studies have shown that BB use in patients with cirrhosis can reduce the risk of developing HCC, and in patients with HCC, BB can improve overall survival (OS). In recent years, ICIs have become first-line therapy for patients with unresectable HCC, and we aimed to evaluate whether BB use conferred survival benefits in patients treated with ICIs using real-world data. Methods: We conducted a retrospective chart review of HCC patients treated with ICI from 2017 to 2019 at 13 institutions across North America, Europe, and Asia in order to evaluate the association between BB use and OS, as well as BB use and overall response rate (ORR). Univariable and multivariable logistic regression models were used to evaluate associations, and survival analyses were performed using the Kaplan-Meier method. Results: A total of 578 patients were evaluated. The median age of the cohort was 65 years, and 80% of patients were male. The majority of patients (70%) were cirrhotic. The causes of underlying liver disease were as follows: HBV (22%), HCV (36%), alcohol (20.8%), and NASH (13%). Most patients (73.5%) had Child Pugh (CP) class A liver disease, and good performance status with ECOG score either 0 (52%) or 1 (45%). The majority of patients (75%) treated with ICIs received a PD-1 inhibitor alone. There were 360 deaths (62% of patients) with a median follow-up of 30.8 months (Quartiles: 17.2-40.3 months). Two hundred and three (35%) patients had BB use at any point during ICI therapy. Fifty-one percent of these patients were on a nonselective BB whereas 49% were taking a cardio-selective BB. BB use was not significantly correlated with OS (hazard ratio, 1.12; 95% CI, 0.9-1.39; P = 0.298) or ORR (odds ratio, 0.84; 95% CI, 0.54-1.31; P = 0.451) in univariate or multivariate analyses. Conclusions: Patients who used BB while on immunotherapy for unresectable HCC did not have statistically significant differences in OS or ORR compared to patients who did not use BB. More studies are required to elucidate the effect of beta blockade on the microbiome, immune activation, and HCC.

Background: Immune checkpoint inhibition (ICI) is an expanding option in hepatocellular carcinoma (HCC). Antibiotics (ATB) have been shown to reduce response and survival after ICI in other cancers. Methods: Efficacy of ICI is described in patients (pt) from 11 centres (246 USA, 100 Asia, 68 Europe), with median overall (OS), progression-free survival (PFS) and best response (RECIST 1.1) compared between pt with and without ATB exposure in the early immunotherapy period (EIOP) of 30 days before and after ICI initiation. Results: Most of our 414 pt were cirrhotic (297, 71.7%) due to hepatitis C (162, 391.1%) with Barcelona Clinic Stage C (294, 71.0%), Child-Pugh class (CP) A (313, 76.3%) and AFP>400 IU/mL (158, 39.3%). OS was 15.4 mo (95%CI 13.1-17.7) and PFS was 5.3 months (95% CI 4.5-6.0). Most ICI was anti-PD-1 monotherapy (358, 86.5%) and given as 1st (173, 41.8%) or 2nd line (208, 50.2%). Best response to ICI was complete response in 27 pt (6.5%), partial response in 45 (10.9%), stable disease (SD) in 160 (38.6%) and progressive disease (PD) in 161 (38.9%). ATB was given to 167 pt (40.3%), prior to or early after (30 d) ICI initiation (EIOP, 157, 38.0%) or beyond 30 days (21, 5.1%), mostly as beta-lactams (27, 10.9%) or quinolones (26, 10.5%). ATB use was independent of CP class (p=0.76), ECOG performance status (p=0.58) and BCLC stage (p=0.60). mOS in the EIOP+ group was similar to the EIOP- group (13.1 vs 15.5 mo, p=0.92). mPFS in the EIOP+ group was significantly longer than the EIOP- group (7.9 vs 4.2 mo, p=0.004). Observations persisted when stratified by CP class (p=0.42) and ICI type (p=0.92). Partial response rate was higher in the EIOP+ group (17.3% vs 8.6%, p=0.01), although overall objective response and disease control rates were similar between EIOP groups (ORR: 22.7% vs 15.9%, p=0.10; DCR: 64.0% vs 56.6%, p=0.15). Pt in the EIOP+ group were not more likely to experience gastrointestinal AE (EIOP +/- 9.2%/5.4%, p=0.12) or hepatic AE (EIOP +/-, 17.9%/16.5%, p=0.92) of any grade, while severe liver AE (grade 2 or above) were less common in the EIOP+ group (EIOP+/- 2.8%/9.5%, p=0.01). Conclusions: ATB in the 30 d before or after ICI initiation in HCC is associated with prolonged PFS. This is contrary to findings in other solid tumors. Evaluation of the immune-microbiologic determinants of response to ICI in HCC a key research question. Citation Format: Petros Fessas, Muntaha Naeem, Thomas U. Marron, David Szafron, Elad Sharon, Anwar Saeed, Tomi Jun, Sirish Dharmapuri, Abdul R. Naqash, Thoetchai Peeraphatdit, Anuhya Gampa, Yinghong Wang, Uqba Khan, Mahvish Muzaffar, Musharraf Navaid, ChiehJu Lee, Pei-Chang Lee, Anushi Bulumulle, Bo Yu, Sonal Paul, Neil Nimkar, Dominik Bettinger, Hannah Hildebrand, Yehia I. Abugabal, Tiziana Pressiani, Nicola Personeni, Naoshi Nishida, Masatoshi Kudo, Ahmed Kaseb, Yi-Hsiang Huang, Celina Ang, Anjana Pillai, Lorenza Rimassa, David J. Pinato. Early antibiotic exposure delays disease progression following immune checkpoint inhibitor therapy for hepatocellular carcinoma: Evidence from an observational study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 485.

FUT2 is a gene for a fucosyltransferase that encodes expression of ABO blood group antigens found on gastrointestinal mucosa and secretions. We hypothesized that the fecal microbiomes of healthy subjects, with blood group antigens A, B, and O, have differing compositions. We analyzed 33 fecal and blood specimens from healthy subjects for FUT2 genotype, and the fecal microbiome was determined by 454 pyrosequencing. Our data show that being a blood group secretor is associated with less diversity at higher orders of taxonomy; and the presence of blood group A antigens in the secretor subjects are associated with an expansion families of bacteria within the gut. Furthermore, our study confirms the previous findings that secretors and nonsecretors have differing bacterial taxa. This extends the previous findings by demonstrating that the impact of being a nonsecretor is higher than that of individual blood group antigens. Additionally, we demonstrate that both secretor status and blood group antigen expression especially affect the Lachnospiraceae family of bacteria within the gut microbiome, with lower abundances noted in nonsecretors and higher abundances in secretors of various blood groups. We further note specific differences in blood group A-secretors demonstrating that the genus Blautia is lower in the group A-secretors compared with the non-A-secretors and that this reduction is accompanied by higher abundances of members of the Rikenellaceae, Peptostreptococcaceae, Clostridiales, and Turicibacter. This study offers a first insight into the relationship between the fecal microbiome and blood group antigens in secretors.

AIM: To determine the prevalence for hepatitis B virus (HBV) and HBV screening and vaccination practices for inflammatory bowel disease (IBD). METHODS: This study is a retrospective, cross-sectional observational study. A retrospective chart review was performed in 500 patients who have been consecutively treated for IBD between September 2008 and January 2013 at the Rush University Medical Center Gastroenterology section. The patients were identified through the electronic medical record with the criteria that they attended the gastroenterology clinic, and that they had a diagnosis of IBD at the time of visit discharge. Once identified, each record was analyzed to determine whether the subject had been infected with HBV in the past, already been vaccinated against HBV, or advised to get vaccinated and followed through with the recommended vaccination. RESULTS: About 254 out of 500 patients (51%) had HBV screening ordered. Among those ordered to have screening tests, 86% followed through with HBV serology. Gastroenterology physicians had significantly different screening ratios from each other (P < 0.001). There were no significant differences in the ratios of HBV screening when IBD specialists were compared to other gastroenterology physicians (0.505 ± 0.023 vs 0.536 ± 0.066, P = 0.66). Of those 220 patients screened, 51% of IBD patients were found not to be immune against HBV. Approximately 50% of gastroenterology physicians recommended HBV vaccinations to their patients in whom serology was negative for antibodies against HBV. IBD specialists recommended vaccinations to a higher percentage of their patients compared to other gastroenterology physicians (0.168 ± 0.019 vs 0.038 ± 0.026, P = 0.015). Present and/or past HBV infection was found in 3.6% of the patients who had serology checked. There was no statistically significant difference in the prevalence of hepatitis B surface antigen (HBsAg) between our study and that reported in previous studies done in Spain (4/220 vs 14/2076 respectively, P = 0.070); and in France (4/220 vs 3/315 respectively, P = 0.159). But, the prevalence of anti-HBcAb in this study was less than that reported in the study in Spain (7/220 vs 155/2076 respectively, P = 0.006); and was not significantly different from that reported in the study in France (7/220 vs 8/315 respectively, P = 0.313). CONCLUSION: The prevalence of HBsAg in our IBD patients was not higher than previously reported European studies. Most IBD patients are not routinely screened or vaccinated against HBV at a tertiary referral center in the United States.