BRAFV600-mutant metastatic colorectal cancer comprises a biologically distinct and clinically aggressive subset of metastatic colorectal cancer. Early attempts to apply single-agent BRAFV600 inhibition failed because of rapid acquired resistance and reactivation of mitogen-activated protein kinase signaling. Over the last decade, rational combinations (BRAF inhibitors and epidermal growth factor receptor inhibitors with or without mitogen-activated protein kinase kinase inhibitors) have become the standard of care in the refractory setting and are now being evaluated upfront, whereas a wave of next-generation approaches (extracellular signal-regulated kinase and SHP2 inhibitors, receptor tyrosine kinase-targeted agents, and immunotherapy combinations) aims to prevent or overcome resistance. The objective of this comprehensive review was to summarize historic therapeutic approaches, current standards, and the mechanistic rationale and clinical development of next-generation strategies to combat resistance in BRAFV600-mutant metastatic colorectal cancer.

While immune checkpoint blockade (ICB) has transformed cancer treatment, only a minority of hepatocellular carcinoma (HCC) patients achieve durable responses. Studies have demonstrated the gut microbiome as an important modulator of anti-tumor immunity, yet its influence on tumorigenesis and ICB response in HCC remains incompletely characterized. We analyzed fecal microbiome composition via 16S rRNA sequencing from 17 patients with resectable HCC (stage Ib, II, and IIIb) receiving anti-PD-1 (NCT03916627). Treatment response was radiographically assessed (RECIST 1.1). Gut microbiota samples were collected pre-treatment and during therapy. To investigate the microbiome’s causal link with HCC tumorigenesis, we employed an immunogenic murine HCC model generated via hydrodynamic tail-vein delivery of MYC-lucOS and CTNNB1 plasmids. Ex-germ-free mice received fecal microbiota transplantation (FMT) from either (i) a clinical non-responder with high Bacteroidetes abundance (44.7%), or (ii) a responder with low Bacteroidetes abundance (0.89%). Overall response rate was 26.3% (5 responders, 14 non-responders). Microbiome profiling revealed no significant difference in alpha diversity between responders and non-responders. Longitudinal analysis between pre- and during-treatment stools showed minimal change in alpha diversity. Taxonomic comparisons between responders and non-responders revealed significant Bacteroidetes phylum enrichment in non-responders (p<0.05). In the murine model, FMT from the non-responder donor markedly accelerated tumor progression and reduced median survival compared with responder-derived FMT (p<0.05). Integrating clinical microbiome profiling with a humanized HCC mouse model, we identify Bacteroidetes enrichment as a contributor to HCC tumor progression. FMT from a non-responder stool with high Bacteroidetes accelerated tumorigenesis and reduced survival relative to responder-derived microbiota with low Bacteroidetes. Because mechanistic microbiome studies in liver cancer have long been limited by the absence of models that faithfully reflect patient tumor biology and immune evasion, we developed a genetically engineered, immunogenic HCC model that enabled us to also investigate the microbiome signatures observed in patients. Together, these findings support Bacteroidetes-targeted microbial modulation as a potential therapeutic strategy to abrogate tumor progression and enhance ICB efficacy in HCC. Joan Shang, Marina Barcena-Varela, Illaria Mogno, Anthony Lozano, Ian Liebling, Kai Mead, Zhihua Li, Lauren Grinspan, Katherine Lindblad, Marina Ruiz de Galarreta, Romain Donne, Sacha Gnjatic, Miriam Merad, Tomi Jun, Celina Ang, Thomas Marron, Jeremiah Faith, Amaia Lujambio. Bacteroidetes Enrichment Associated with Immune Checkpoint Blockade Resistance and Promotes Tumorigenesis in Hepatocellular Carcinoma [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C063.

PURPOSE:Locally advanced pancreatic cancer (LAPC) accounts for 30% of pancreatic cancers. We assessed the efficacy and safety of a novel extended-release siRNA targeting KRASG12D/V mutations (siG12D-LODER) combined with chemotherapy in LAPC. PATIENTS AND METHODS:This two-cohort, phase II multicenter, open-label study (NCT01676259) evaluated siG12D-LODER with chemotherapy in patients with LAPC, regardless of KRAS status. In cohort 1, patients were randomized to siG12D-LODER plus gemcitabine/nab-paclitaxel (arm 1) or gemcitabine/nab-paclitaxel alone (arm 2). In cohort 2, patients with LAPC or borderline resectable disease received siG12D-LODER plus standard chemotherapy (modified FOLFIRINOX or gemcitabine/nab-paclitaxel) in a single-arm, nonrandomized design. Primary endpoints were overall survival (OS) for cohort 1 and objective response rate (ORR) for cohort 2. Secondary endpoints included progression-free survival, duration of response, OS (cohort 2), and ORR (cohort 1). RESULTS:Across two cohorts, 59 patients were enrolled. In cohort 1, the median OS in the modified intent-to-treat (mITT) population unselected for KRAS status was 22.7 months for siG12D-LODER + gemcitabine/nab-paclitaxel versus 21.9 months for chemotherapy alone (P > 0.05). Among patients with KRASG12D/V mutations, OS was 22.7 versus 13.5 months [HR, 0.59; 95% confidence interval (CI), 0.18-1.96; P = 0.39]. In cohort 2, ORR was 31.6% (95% CI, 0.13-0.57) in the mITT (unselected for KRAS); in the G12D/V subgroup, ORR was 57.1%, similar to 63.6% in cohort 1. Treatment-emergent adverse events were mainly procedure related, including grade 1/2 gastrointestinal events and higher infection rates in the intervention arm. CONCLUSIONS:siG12D-LODER plus chemotherapy is safe, tolerable, and warrants further investigation in KRASG12D/V-mutant LAPC.

BACKGROUND:Combination immune checkpoint inhibitors are recommended as first-line therapy for advanced hepatocellular carcinoma. However, only a third of patients respond to treatment, and improved approaches to predict response are required. Using baseline clinical data, we aimed to use advanced machine learning models to predict overall survival and progression-free survival in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab. METHODS:This retrospective cohort study was conducted at 24 centres across eight countries. Patients aged 18 years and older with a histological or radiological diagnosis of advanced hepatocellular carcinoma were included; those who had received previous systemic therapy for hepatocellular carcinoma were excluded. All patients received intravenous atezolizumab 1200 mg plus bevacizumab 15 mg/kg once every 3 weeks until disease progression. Seven supervised machine learning models, in combination with 13 feature selection techniques, were trained on 44 baseline clinical variables for the prediction of overall survival and progression-free survival. The three best-performing models, combined with their optimum feature selection techniques, were used to develop ensemble machine learning models for the prediction of overall survival and progression-free survival. The primary outcomes of the study were the predictions of overall survival, progression-free survival, and immunotherapy response using advanced machine learning. k-means clustering was used to stratify patients into two groups: those at low risk and those at high risk of either death (in the overall survival model) or disease progression (in the progression-free survival model). FINDINGS:934 patients who received immunotherapy from May 1, 2018 and were followed up until Oct 1, 2023 were screened, of whom 160 were excluded and 774 were included in the final study. Patients were divided into training (n=339), internal validation (n=146) and external validation (n=289) cohorts. Support vector machine, neural network, and naive Bayes algorithms had the best performance in the prediction of overall survival; for progression-free survival, the highest-performing algorithms were ridge regression, naive Bayes, and logistic regression. In the external validation cohort, the ensemble model for the prediction of overall survival (area under the receiver operating characteristic curve 0·75 [95% CI 0·69-0·81]) significantly outperformed all eight of the tested clinical benchmark variables: Barcelona Clinic Liver Cancer (BCLC) stage (0·54 [0·48-0·61]; p<0·0001), α-fetoprotein (AFP) concentration (0·60 [0·54-0·67]; p=0·0007), albumin-bilirubin (ALBI) grade (0·64 [0·58-0·71]; p=0·0003), neutrophil-to-lymphocyte ratio (0·56 [0·49-0·62]; p<0·0001), platelet-to-lymphocyte ratio (0·51 [0·44-0·58]; p<0·0001), combined ALBI grade and BCLC stage (0·67 [0·60-0·73]; p=0·0074), and two BCLC subclassifications (0·62 [0·55-0·69]; p=0·0007 and 0·61 [0·55-0·68]; p=0·0018). The ensemble model for the prediction of progression-free survival (0·64 [0·59-0·70]) outperformed five of the eight clinical predictors: BCLC stage (0·52 [0·46-0·58]; p<0·0001), neutrophil-to-lymphocyte ratio (0·53 [0·47-0·59]; p=0·0069), platelet-to-lymphocyte ratio (0·54 [0·48-0·60]; p=0·016), and two BCLC subclassifications (0·57 [0·50-0·64]; p=0·020 and 0·55 [0·49-0·62]; p=0·0091); the model did not outperform AFP concentration (0·59 [0·53-0·64]; p=0·14), ALBI grade (0·62 [0·56-0·67]; p=0·44), or combined ALBI grade and BCLC stage (0·59 [0·53-0·66]; p=0·12). For the overall survival model, patients stratified into the low-risk group had significantly longer median overall survival (16·4 months [95% CI 14·2-21·6]) than those in the high-risk group (4·8 months [3·0-6·9]; p<0·0001); similarly, patients stratified by the progression-free survival model into the low-risk group had significantly longer median progression-free survival (8·9 months [7·3-11·1]) than those in the high-risk group (3·7 months [2·9-5·6]; p=0·0021). INTERPRETATION:Our advanced machine learning models, which use routinely collected baseline clinical variables, are robust and externally validated and outperform established clinical biomarkers for predicting clinical outcomes with atezolizumab plus bevacizumab. These data-driven models could be used to stratify patients with hepatocellular carcinoma for personalised treatment strategies. FUNDING:None.

Objective The role of circulating tumor DNA (ctDNA) in management of patients with colorectal cancer is evolving, however, there are no data on ctDNA monitoring in patients with resected colorectal liver metastases (CRLM) who receive adjuvant hepatic artery (HAI) chemotherapy. We report our center’s initial experience with postoperative ctDNA monitoring in patients receiving adjuvant HAI chemotherapy. Summary Background Data Adjuvant HAI chemotherapy improves survival after CRLM resection. ctDNA has been shown to predict recurrence in patients with resected CRLM, however no ctDNA data are available in patients who receive adjuvant HAI chemotherapy. Methods All patients with CRLM who underwent surgical resection and HAI pump placement at our center were included in this study. Demographic, clinicopathologic, radiographic, and ctDNA data are reported. Results From 2019-2024, 13 patients with CRLM underwent surgical resection and HAI pump placement and had ctDNA testing. With median follow-up of 2.6 years (1.14-4.15), 11 (85%) patients experienced recurrence at a median of 7.9 months (2.3-22.5). In total, 10 (77%) patients were ctDNA-positive all of whom had radiographic evidence of recurrence. Three patients have died at the time of last follow-up. Conclusions After surgical resection and HAI chemotherapy, ctDNA was detectable in most patients, and was associated with radiographic recurrence in all ctDNA-positive patients. We report a high recurrence rate in this series of heavily-pretreated patients with known risk factors for recurrence.

Background & Aims: Atezolizumab/bevacizumab (A/B) is now a standard first-line treatment for advanced hepatocellular carcinoma (HCC), but the optimal second-line regimen is not known. We evaluated real-world treatment patterns and outcomes to investigate factors associated with post-progression survival (PPS). Methods: In this multicenter, international, retrospective study, we examined clinical characteristics and outcomes of patients with advanced HCC who progressed on first-line A/B. The primary outcome of PPS was defined as time from first radiographic progression on A/B to death. Results: A total of 406 patients alive after progression on first-line A/B were included in the final analysis, of whom 45.3% (n =184) received best supportive treatment (BST) and 54.7% (n = 222) continued active systemic treatment. In the second line, 155 patients were treated with tyrosine kinase inhibitors (TKIs), 45 with immune checkpoint inhibitor (IO)-based regimens, and 3 had missing data. Median PPS of the whole cohort (mPPS) was 6.0 months (95% CI 5.2-7.2). On multivariate Cox regression analysis, absence of portal vein tumor thrombus, ECOG <2, and continued active treatment were predictors of better PPS. mPPS was significantly longer for patients who continued active treatment vs. BST (9.7 vs. 2.6 months; HR 0.41, p <0.001). In the second-line setting, patients treated with TKIs had a numerically shorter mPPS compared to those treated with IO (8.4 vs. 14.9 months; HR 1.37, p = 0.256). Conclusions: Continuation of active therapy after A/B progression was independently associated with better survival even after adjusting for baseline disease characteristics. mPPS with IO-based therapy exceeded a year, suggesting that IO continuation post-progression may retain benefit. The precise sequencing of TKI and IO regimens warrants further investigation. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background and Aims: Atezolizumab and bevacizumab (A+B) are recommended for treating unresectable hepatocellular carcinoma (HCC). Although highly effective, A+B can lead to potentially life-threatening adverse events including bleeding. We investigated whether albumin-bilirubin (ALBI) grade identifies patients with a higher risk of bleeding and its impact on prognosis than the Child-Pugh (CP) score. Methods: We performed a multicenter retrospective study of 15 tertiary referral centers that consecutively treated patients with A+B. We analyzed the association between the ALBI grade and gastrointestinal bleeding using the chi 2 test. Overall survival (OS) stratified by ALBI was estimated using the Kaplan-Meier method and the predictive value for the 6-months OS landmark with ROC curves. Results: Of the 368 patients included in the analysis, 163 (44.3%), 192 (52.2%) and 13 (3.5%) had ALBI 1, ALBI 2, and ALBI 3, respectively. ALBI grade was associated with a 3-fold increase in bleeding risk (3.1% in ALBI 1 vs 10.2% in ALBI 2/3, p=0.008). Among 192 patients with pre-treatment EGD, G2 and G3 varices were associated with an increased risk of bleeding, whereas G1 varices had a similar risk as no varices. Patients with ALBI 1 achieved a longer median OS (not reached; 95% CI, 24.9-33.7), than ALBI 2 (9.7 months; 95% CI, 7.0-12.3) or ALBI 3 (5.6 months; 95% CI, 0.1-12.0). ALBI outperformed the CP score for predicting 6-month OS with an AUC 0.79 of ALBI versus 0.71 for the CP score (p=0.01). Conclusion: A Higher ALBI grade was associated with an increased risk of gastrointestinal bleeding after receiving A+B, and outperformed the CP score in predicting worse survival.

Background and Aims:Growing evidence highlight the critical role of the gut microbiome in tumorigenesis and response to immunotherapies. However, the impact of gut microbes on hepatocellular carcinoma (HCC) progression and response to immune-checkpoint blockade (ICB) remains unclear due to the lack of combined preclinical and clinical studies. Approach & Results:We performed 16S rRNA of cross-cohort stool samples from 10 HCC responders (R) and 40 non-responders (NR) to ICB at baseline and on-treatment time-points. We identified an enrichment of Bacteroidetes in NR. To study the role of the microbiome in the cancer immune response, we generated an immunogenic mouse model of HCC via hydrodynamic tail-vein injection (HDTVI) of DNA plasmids mimicking common HCC alterations and immunogenicity by expressing model antigens (MYC-lucOS;CTNNB1 tumors). We found that antibiotic (ABX)-induced dysbiosis promoted a pro-tumorigenic effect in the MYC-lucOS;CTNNB1 HCC model by the expansion of a specific Bacteroidetes, Parabacteroides distasonis. Colonization of mice carrying MYC-lucOS;CTNNB1 HCCs with Parabacteroides distasonis confirmed its pro-tumorigenic effect in vivo. Furthermore, we explored the effects of colonizing with microbiotas from patients and showed that microbiota from a NR donor enriched in Bacteroidetes promoted faster tumorigenesis than microbiota from a R donor with reduced Bacteroidetes. We isolated 6 Bacteroidetes species from the NR donor, cultured them, and used them as a cocktail to colonize mice; similarly, mice transplanted with this cocktail showed increased tumorigenesis and reduced survival. Conclusions:This study identified Bacteroidetes enrichment as a potential biomarker of ICB resistance in HCC and, by using immunogenic mouse models, established that Bacteroidetes abundance influences tumor development.

Background & Aims Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 +/- 11 years), and 163 (19%) were female (mean age 67 +/- 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted.

442 Background: HIV-associated HCC is an incompletely characterized disease with poor prognosis. People living with HIV (PWH) are commonly excluded from clinical trials, leading to a paucity of high-level evidence for optimal management. Whether ICIs are tolerated and effective in HIV-associated uHCC remains unclear. Methods: Using data from the CATCH-IT consortium and from a global dataset recruiting patients with HCC from 14 centers in 3 continents, we selected patients with HIV-associated uHCC treated with ICIs and compared their outcomes with a matched cohort of HIV negative (HIV-) patients. Primary endpoints were overall (OS) and progression-free survival (PFS). Propensity score matching (PSM) between the two groups was performed for the following variables: age, sex, HCC aetiology, Child-Pugh class (CP-C), ECOG-PS, BCLC stage, alpha-fetoprotein (AFP) levels, treatment line, portal vein tumor thrombosis (PVTT), and extrahepatic spread (EHS). Restricted mean survival time (RMST) difference analyses stratified by HIV status were performed for OS and PFS at 3, 6 and 9 months. Results: We accrued 46 PWH and 400 HIV-, treated mostly in the first-line setting (58.7% vs. 43.7%) with either atezolizumab plus bevacizumab (28.3% vs 17.5%) or anti-PD-1 monotherapy. Median age at ICI start was 62 (38-76) and 64 (18-87); viral hepatitis (HCV: 58.7%; HBV: 34.8%) were the prevalent aetiologies in PWH, non-viral (46%) was the most common in HIV-; most patients had BCLC-C HCC (84.8% and 82.3%). In PWH, median CD4 count was 345 cells/mm3 (IQR: 200-465); viral load was undetectable in 45 patients, all were established on combined anti-retroviral therapy. Following PSM, 44 PWH and 117 HIV- were included. Median OS was 7.5 months (95%CI: 5.2-NR) in PWH and 10.8 months (95%CI: 7.3-19.5) in HIV- (HR: 0.89; 95%CI: 0.56-1.42; p=0.58). Presence of PVTT, AFP>400 ng/mL, and ECOG-PS=1 but not HIV status were associated with worse OS in uni- and multivariable models. Median PFS was 2.8 months (95%CI: 2.6-4.8) for PWH vs 3.0 months (95%CI: 2.4-5.3) for HIV- (HR: 0.83-95%CI:0.56-1.24 ;p=0.38); HIV status was not associated with worse PFS. RMST confirmed no OS or PFS differences based on HIV status. In matched cohorts, neither ORR (21% vs. 19.1%, p=0.97) nor DCR (44.7% vs. 55.4%, p=0.19) were associated with HIV status. All grade immune-related adverse events (irAEs) were more frequent in HIV (44.0% vs 21.7%, p=0.003), with similar incidence of grade ≥3 irAEs (22.2% vs 13.0%). PWH had lower incidence of dermatological toxicities (4.3% vs 22%, p=0.003) and a trend towards lower incidence of hepatotoxicity (6.5% vs 18%, p=0.059). Conclusions: This study provides practice-informing evidence to support the use of ICIs in PWH and uHCC. Our findings encourage the inclusion of patients with well-controlled HIV in prospective clinical trials.

IMPORTANCE Whether patients with Child-Pugh class B (CP-B) cancer with unresectable hepatocellular carcinoma (uHCC) benefit from active anticancer treatment vs best supportive care (BSC) is debated. OBJECTIVE To evaluate the association of immune checkpoint inhibitor (ICI)-based therapies vs BSC with overall survival (OS) of patients with uHCC and CP-B liver dysfunction. DESIGN, SETTING, AND PARTICIPAN This retrospective, multicenter, international clinical case series examined data of patients with CP-B with uHCC who were receiving first-line ICI-based regimens from September 2017 to December 2022 whose data were extracted from an international consortium and compared with a cohort of patients with CP-B receiving BSC. Patients were treated in tertiary care centers across Europe, US, and Asia in routine clinical practice. After applying the inclusion criteria, 187 and 156 patients were left in the ICI and BSC groups, respectively. The propensity score was calculated for the following variables: age, alpha-fetoprotein levels, Child-Pugh score, extrahepatic spread, portal vein tumor thrombosis, cirrhosis, ascites, and baseline Eastern Cooperative Oncology Group performance status. EXPOSURES Patients in the ICI group received first-line systemic therapy with either atezolizumab plus bevacizumab (A+B) (n = 141) or nivolumab (n = 46). MAIN OUTCOMES AND MEASURES OS in the inverse probability of treatment weighting (IPTW) populations was the main outcome, and it was estimated with Kaplan-Meier method; univariable Cox regression test was used to make comparisons between the 2 groups. RESULTS The median age was 66 (IQR, 61-72) and 73 (IQR, 66-81) years in the ICI (33 women [18%]) and BSC groups (41 women [26%]), respectively. In the IPTW populations, median OS was significantly longer in the ICI group (7.50 months; 95% CI, 5.62-11.15) compared with BSC (4.04 months; 95% CI, 3.03-5.03; hazard ratio, 0.59; 95% CI, 0.43-0.80; P < .001). Multivariable analysis confirmed that ICI exposure was associated with a reduction of approximately 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P < .001), and the presence of portal vein tumor thrombosis, an Eastern Cooperative Oncology Group performance score of greater than 1, and alpha-fetoprotein levels of 400 ng/mL or greater were associated with increased risk of death. CONCLUSIONS AND RELEVANCE The results of this case series provide comparative evidence of improved survival in association with ICI treatment compared with BSC in patients with uHCC with CP-B liver dysfunction.

BACKGROUND AND AIMS:Unlike other malignancies, hepatic functional reserve competes with tumor progression in determining the risk of mortality from hepatocellular carcinoma (HCC). However, the relative contribution of hepatic decompensation over tumor progression in influencing overall survival (OS) has not been assessed in combination immunotherapy recipients. APPROACH AND RESULTS:From the AB-real observational study (n = 898), we accrued 571 patients with advanced/unresectable hepatocellular carcinoma, Child-Pugh A class treated with frontline atezolizumab + bevacizumab (AB). Hepatic decompensation and tumor progression during follow-up were studied in relationship to patients' OS using a time-dependent Cox model. Baseline characteristics were evaluated as predictors of decompensation in competing risks analysis. During a median follow-up of 11.0 months (95% CI: 5.1-19.7), 293 patients (51.3%) developed tumor progression without decompensation, and 94 (16.5%) developed decompensation. In multivariable time-dependent analysis, decompensation (HR: 19.04, 95% CI: 9.75-37.19), hepatocellular carcinoma progression (HR: 9.91, 95% CI: 5.85-16.78), albumin-bilirubin (ALBI) grade 2/3 (HR: 2.16, 95% CI: 1.69-2.77), and number of nodules >3(HR: 1.63, 95% CI: 1.28-2.08) were independently associated with OS. Pretreatment ALBI grade 2/3 (subdistribution hazard ratio [sHR]: 3.35, 95% CI: 1.98-5.67) was independently associated with decompensation, whereas viral etiology was protective (sHR: 0.55, 95% CI: 0.34-0.87). Among patients with viral etiology, effective antiviral treatment was significantly associated with a lower risk of decompensation (sHR: 0.48, 95% CI: 0.25-0.93). CONCLUSIONS:Hepatic decompensation identifies patients with the worst prognosis following AB and is more common in patients with baseline ALBI >1 and nonviral etiology. Effective antiviral treatment may protect from decompensation, highlighting the prognostic disadvantage of patients with nonviral etiologies and the importance of multidisciplinary management to maximize OS.

Background and aimsPerianal fistulizing Crohn’s disease (PFCD)-associated anorectal and fistula cancers are rare but often devastating diagnoses. However, given the low incidence and consequent lack of data and clinical trials in the field, there is little to no guidance on screening and management of these cancers. To inform clinical practice, we developed consensus guidelines on PFCD-associated anorectal and fistula cancers by multidisciplinary experts from the international TOpClass consortium.MethodsWe conducted a systematic review by standard methodology, using the Newcastle-Ottawa Scale quality assessment tool. We subsequently developed consensus statements using a Delphi consensus approach.ResultsOf 561 articles identified, 110 were eligible, and 76 articles were included. The overall quality of evidence was low. The TOpClass consortium reached consensus on six structured statements addressing screening, risk assessment, and management of PFCD-associated anorectal and fistula cancers. Patients with longstanding (>10 years) PFCD should be considered at small but increased risk of developing perianal cancer, including squamous cell carcinoma of the anus(SCCA) and anorectal carcinoma. Risk factors for SCCA, notably human papilloma virus (HPV), should be considered. New, refractory, or progressive perianal symptoms should prompt evaluation for fistula cancer. There was no consensus on timing or frequency of screening in patients with asymptomatic perianal fistula. Multiple modalities may be required for diagnosis, including an exam under anesthesia (EUA) with biopsy. Multidisciplinary team efforts were deemed central to the management of fistula cancers.ConclusionInflammatory bowel disease (IBD) clinicians should be aware of the risk of PFCD-associated anorectal and fistula cancers in all patients with PFCD. The TOpClass consortium consensus statements outlined herein offer guidance in managing this challenging scenario.