We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. In the discovery cohort, clinical benefit 6 months (CB_6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB_6m than in those with CB_6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8⁺ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8⁺ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Introduction: Atezolizumab and bevacizumab (Ate/Bev) combination has become the new first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). Although several studies reported thyroid dysfunction after treatment with immune checkpoint inhibitors, the clinical and immunological significance of thyroid dysfunction in patients treated with Ate/Bev has not been comprehensively addressed. We aimed to comprehensively evaluate the clinical and immunological implications of thyroid dysfunction in unresectable HCC patients treated with Ate/Bev. Methods: We enrolled 208 patients with unresectable HCC treated with Ate/Bev from three Korean cancer centers. Thyroid adverse events (AEs) were reviewed, and cytokines and T cells in the blood samples were analyzed at baseline. For external validation, we analyzed clinical outcomes according to thyroid AEs in patients treated with Ate/Bev in the IMbrave150 study. Results: Forty-one (19.7%) out of 208 patients experienced thyroid dysfunction (hypothyroidism [17.3%] and thyrotoxicosis [5.8%]) after Ate/Bev treatment. Median time to onset of hypothyroidism and thyrotoxicosis after Ate/Bev treatment was 3.5 and 1.3 months, respectively. Patients with thyroid AEs demonstrated significantly better progression-free survival, overall survival, and objective response rate than those without thyroid AEs. These findings were still consistent even after adjusting for confounding factors. Furthermore, favorable survival outcomes in patients with thyroid AEs were also validated in a cohort of IMbrave150 patients. While patients with thyrotoxicosis showed a significantly lower level of baseline IL-6, those with hypothyroidism did not show significant differences in circulating cytokine levels and CD8+ T-cell fractions. Conclusions: A fraction of patients with HCC treated with Ate/Bev experienced thyroid dysfunction, and the development of thyroid AEs was associated with favorable clinical outcomes.

Background and Aims: Anti‐programmed death 1 (PD‐1) monotherapy triggers various responses by each organ. In advanced hepatocellular carcinoma (HCC), while extrahepatic lesions demonstrate objective response rates (ORR) of 20%–40%, only 10% of intrahepatic lesions respond. Although first‐line atezolizumab/bevacizumab has shown survival benefits in advanced HCC, organ‐specific responses remain unexplored. Therefore, we aimed to assess organ‐specific responses in patients with advanced HCC receiving atezolizumab/bevacizumab. Methods: This retrospective, multicenter, observational study included patients who received first‐line atezolizumab/bevacizumab for advanced HCC. Patients with Child‐Pugh class A, measurable tumour lesions and serial imaging available for response evaluation were eligible. Results: Between May 2020 and June 2021, 131 patients (median age: 62) from three cancer referral institutions were included. Ninety‐one had hepatitis B (69.5%), 108 were at Barcelona clinic liver cancer stage C (82.4%), and 78 had extrahepatic metastasis (59.5%). After a median follow‐up of 10.1 months, median progression‐free survival was 6.8 months (95% confidence interval [CI], 4.6–9.2), median overall survival remained unreached (95% CI, range unavailable) and the ORR was 29.0%. Among 270 individual tumour lesions, the liver was the most commonly involved organ ( n = 158). Atezolizumab/bevacizumab induced ORR of 27.8%, 42.2%, 29.1% and 21.0% for liver, lymph nodes, lungs and other sites, respectively. The organ‐specific response rate for intrahepatic tumours decreased with increasing size (35.6%: <5 cm, 15.0%: ≥ 5 cm). Conclusions: Unlike anti‐PD‐1 monotherapy, atezolizumab/bevacizumab demonstrated favourable responses in intrahepatic lesions, comparable to those in extrahepatic lesions, and may potentially overcome the immune‐tolerant hepatic microenvironment in patients with advanced HCC.

Background & Aims: Nab-paclitaxel plus gemcitabine-cisplatin (Gem/Cis/nab-P) had promising efficacy in phase II trials for advanced biliary tract cancer (BTC) but failed to demonstrate superiority in phase III. We investigated Gem/Cis/nab-P efficacy and identified molecular subgroups with clinical benefit. Approach & Results: This prospective observational cohort study (NCT04871321) enrolled 119 patients with advanced BTC who received Gem/Cis/nab-P from July 2021 to December 2022. Of these, 108 were included in genomic and transcriptomic analyses of pretreatment tumor samples that met quality control criteria. Among 119 patients, 39.5% had intrahepatic cholangiocarcinoma, 37.0% extrahepatic cholangiocarcinoma, and 23.5% gallbladder cancer. Most patients had metastatic disease (68.9%). At a median follow-up of 23.7 months, the median progression-free survival was 8.3 months and median overall survival 19.8 months. Grade ≥3 treatment-related adverse events occurred in 70 patients (58.8%), and dose reduction was required in 99.2%. Frequent genetic alterations were TP53 (53.7%), KRAS (29.6%), and CDKN2A (20.4%), with TP53 mutations being significantly associated with worse outcomes. Transcriptomic analysis identified four molecular subtypes: cholangiocyte-like, stromal, metabolic, and inflammatory-proliferative. The cholangiocyte-like subtype, marked by increased cholangiocyte markers, had the most favorable prognosis. Stromal and metabolic subtypes showed moderate outcomes, characterized by a fibroblast-rich stroma with activated angiogenesis and enriched metabolic pathways, respectively. The inflammatory-proliferative subtype had the worst prognosis, with cell cycle and inflammatory activation, and an exhausted immune microenvironment. Conclusions: This study demonstrated the clinical activity of Gem/Cis/nab-P in advanced BTC and highlighted that biology-driven patient stratification based on genomic and transcriptomic features may provide important prognostic information.

Objectives To determine risk factors for catheter survival and complications after image-guided implantation of a totally implanted vascular access device (TIVAD). Methods A total of 2883 TIVADs (2735 patients, 63.5±13 years old, 1060 men, 1675 women) implanted under guidance by ultrasound and fluoroscopy in our institution from January 2010 to December 2019 were evaluated retrospectively. We used the log rank test and logistic regression to analyse risk factors associated with catheter survival and complications. Results Female patients (n=1778; 61.7%; mean catheter survival days: 780.6 days) and those with a haematological malignancy (n=277; 10.1%; mean catheter survival days: 1019 days) had significantly better catheter survival than male patients (n=1105; 38.3%; mean catheter survival days: 645.9 days) and those with a solid organ malignancy (n=2447; 89.5%; mean catheter survival days: 701 days) (p<0.001 and p=0.003). Patients with haematological malignancies and benign vascular inflammatory disease (n=11; 0.4%) were vulnerable to infection (n=96; 3.3%) (p<0.001 and p=0.004). Thrombotic malfunction (n=38; 1.3%) was significantly more common in females than males (p=0.005). Non-thrombotic malfunction (n=16; 0.6%) showed a significant association with left positioning of the TIVAD (n=410; 14.2%) (p=0.043). Wound dehiscence (n=3; 0.1%) was significantly more frequent in punctured veins other (n=23; 0.8%) than the internal jugular vein (p<0.001). Conclusions Increased attention should be paid to patients with an underlying haematological malignancy, underlying vascular inflammatory disease, female patients, older patients, those accessed via a vein other than the IJV, those with left positioning of the TIVAD system or those with a prolonged TIVAD maintenance.

Background: Immune checkpoint inhibitor (ICI) monotherapy elicits limited intrahepatic responses in patients with advanced hepatocellular carcinoma (HCC). Here, we investigate the organ‐specific objective response rate (OSORR) of nivolumab plus ipilimumab (Nivo/Ipi) combination treatment, considering prior ICI exposure, compared with nivolumab (Nivo) monotherapy.Methods: We analyzed 204 lesions from Nivo/Ipi‐treated and 305 lesions from Nivo‐treated patients with advanced HCC at five referral cancer centers in Korea. Organ‐specific response criteria were adopted from Response Evaluation Criteria in Solid Tumors 1.1, according to the indicated sites: the liver, lung, lymph nodes (LNs), and other metastatic sites.Results: Nivo/Ipi combination therapy showed OSORRs of 18.1% in the liver, 17.7% in the lungs, 30.0% in LNs, and 12.5% in other metastatic sites. Patients without prior ICI exposure had OSORRs of 29.0% in the liver, 31.3% in the lungs, 33.3% in LNs, and 23.1% in other metastatic sites (72 individual lesions). Conversely, patients with prior ICI exposure had OSORRs of 11.5% in the liver, 11.4% in the lung, 27.8% in LNs, and 7.4% in other metastatic sites (132 individual lesions). Furthermore, patients who achieved a response in the liver or the lung had longer progression‐free and overall survival, compared with those without responses. Nivo monotherapy yielded OSORRs of 13.5%, 25.3%, 39.3%, and 18.4% in the liver, lungs, LNs, and other metastatic sites, respectively.Conclusion: Nivo/Ipi combination therapy induced superior intrahepatic responses compared to Nivo monotherapy in patients with advanced HCC without prior ICI exposure, highlighting its potential to overcome liver‐specific immune tolerance.