Extrahepatic Metastases Research Articles

The Efficacy and Safety of Hepatic Artery Infusion Chemotherapy Combined with Lenvatinib and Programmed Death (PD)-1 Inhibitors for Unresectable Intrahepatic Cholangiocarcinoma: A Retrospective Study

Objectives: Although systemic chemotherapy (SC) is the mainstay for treating unresectable intrahepatic cholangiocarcinoma (ICC), its efficacy is limited and it causes severe systemic side effects. This study focuses on evaluating the effectiveness and safety of hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib plus programmed death-1 (PD-1) inhibitors (HLP), compared to SC in combination with lenvatinib plus PD-1 inhibitors (SCLP) for unresectable ICC. Methods: We analyzed patients initially diagnosed with unresectable ICC at our center between March 2021 and December 2023, classifying them into HLP and SCLP groups according to treatment regimen. This study assessed and compared overall survival (OS), progression-free survival (PFS), tumor response, and safety outcomes across the two treatment groups. Results: This study enrolled 53 subjects in total; 25 were treated with HLP and 28 with SCLP. The two groups showed well-matched baseline characteristics. The HLP group reported an extended median OS (12.8 vs. 11.0 months, p = 0.310) and a prolonged median PFS (8.8 vs. 6.4 months, p = 0.043), compared to the SCLP group. The HLP group had a better objective response rate (ORR) (52% vs. 25%, p = 0.043) and disease control rate (DCR) (96% vs. 78.6%, p = 0.104). Based on OS (p = 0.019) and PFS (p = 0.032) results, those without extrahepatic metastasis seemed to benefit more significantly from the HLP regimen than from the SCLP regimen. The HLP group experienced fewer grade 3–4 adverse events (AEs) than the SCLP group. Conclusions: The HLP regimen for unresectable ICC is an effective and safe strategy and is potentially better suited for patients without extrahepatic metastases.

Real world study on combining local interventions with systemic therapy in unresectable hepatocellular carcinoma

Combining local interventions with tyrosine kinase inhibitors (TKIs) plus anti-PD-1 antibodies in a triple therapy has demonstrated remarkable anti-tumor efficacy and facilitated conversion resection in patients with initially unresectable hepatocellular carcinoma (HCC). However, the long-term survival outcomes remain largely unexplored. This study focused on a cohort of consecutive patients who underwent triple therapy for initially unresectable HCC at the authors’ hospital between January 2020 and December 2022. Specifically, patients who exhibited a positive response to triple therapy and fulfilled the criteria for hepatectomy were selected for liver resection. Additionally, investigation assessed association between clinical factors and successful achievement of conversion resection, as well as postoperative recurrence. The study cohort comprised 79 patients, among whom 20 individuals (25.3%) underwent R0 resection subsequent to the initiation of triple therapy. Notably, patients without extrahepatic disease and those who exhibited a radiographic response to triple therapy were more likely to be eligible for curative resection. Importantly, hepatectomy independently associated with a favorable overall survival (HR, 0.388; 95% CI, 0.177–0.847; P = 0.017). Other independent risk factors related to overall survival contained extrahepatic metastasis (HR, 2.152; 95% CI, 1.076–4.302; P = 0.030), tumor number ≥ 4 (HR, 2.058; 95% CI, 1.001–4.234; P = 0.049) and radiological remission (HR, 0.233; 95% CI, 0.071–0.768; P = 0.017). For the 20 patients who underwent surgery, 12-month recurrence-free survival and overall survival rates were respectively 43.3% and 66.6%. The triple therapy demonstrated favorable prognostic outcomes and manageable safety profiles in patients with initially unresectable HCC.

Retrospective comparative survival analysis of ablation plus systemic therapy versus systemic therapy alone for breast cancer liver metastases, stratified by extrahepatic metastases status.

Current decision-making for the treatment of breast cancer liver metastases (BCLM) using ablation lacks strong evidence, especially for patients combined with extrahepatic metastases. To assess whether ablation plus systemic therapy (AS) improves survival outcomes in patients with BCLM compared to systemic therapy alone. This retrospective study analyzed patients with BCLM who received either AS or systemic therapy alone. Propensity score matching (PSM) and survival analysis were performed, taking into account factors like the characteristics of primary breast cancer, liver metastases and systemic therapies received. The study included 1021 female patients, with a median follow-up of 39.6 months. Of these patients, 132 underwent AS and 836 received systemic therapy alone. After PSM, among patients with BCLM (≤3 tumors, each ≤3cm), the median overall survival (OS) for those treated with AS or systemic therapy alone was 65.5 and 40.4 months, respectively (HR=0.48, p=.003); in the subset of patients with extrahepatic metastases, the median OS for those treated with AS and systemic therapy alone was 46.4 and 40.8 months, respectively (HR=0.58, p=.047). Among patients with >3cm or >3 lesions, the median OS for those treated with AS or systemic therapy alone was 45.2 and 29 months, respectively (HR=0.67, p=.084). Among patients with BCLM (≤3 tumors, each ≤3cm), AS provide longer survival compared to systemic therapy alone, even with extrahepatic metastases. For patients with larger or more numerous metastases (>3cm or >3 lesions), AS may provide survival benefit, but further validation is needed.

Development and validation of the SPEAR scoring model and predicting overall survival in unresectable hepatocellular carcinoma patients treated with TACE, molecular targeted therapies, and immune checkpoint inhibitors.

533 Background: To develop and validate a predictive model to identify hepatocellular carcinoma (HCC) patients likely to benefit from combined treatment of transarterial chemoembolization (TACE), molecular targeted therapies (MTTs), and immune checkpoint inhibitors (ICIs). Methods: Data from 500 patients with unresectable HCC treated with TACE, MTTs, and ICIs (2019-2023) were analyzed. Patients were divided into a training set (241 from Nanfang Hospital) and a validation set (259 from various hospitals). Key prognostic variables were identified using random forest survival analysis, and the top five were used to construct a Cox proportional hazards model. Model performance was assessed using time-dependent AUC values, calibration curves, clinical decision curves (DCA), and net reclassification improvement (NRI) indices. Risk scores and optimal cut-off values for risk stratification were determined and validated. Results: Five key survival variables were identified: serum alpha-fetoprotein (AFP), red cell distribution width coefficient of variation (RDW-CV), aspartate aminotransferase (AST), platelet-to-lymphocyte ratio (PLR), and extrahepatic metastasis (EHM). The Cox model had a C-index of 0.694 in the training and 0.691 in the validation set. The training set's 1-year, 2-year, 2.5-year, and 3-year AUC values were 0.77, 0.73, 0.73, and 0.72, respectively, and 0.74, 0.74, 0.76, and 0.66 in the validation set. The ARAPE model demonstrated a more significant net benefit than existing models. Median overall survival (mOS) was 33.9 months for low-risk, 20.4 months for intermediate-risk, and 14.2 months for high-risk groups in the training set; in the validation set, mOS was 30.8, 18.7, and 10.5 months, respectively. Conclusions: The SPEAR model (Serum AFP, PLR, EHM, AST, and RDW-CV) model effectively stratifies risk for HCC patients receiving TACE combined with MTTs and ICIs, aiding in personalized treatment decisions.

Final analysis of modified (m)-FOLFOXIRI plus cetuximab versus bevacizumab for RAS wild-type and left-sided metastatic colorectal cancer: The DEEPER trial (JACCRO CC-13).

17 Background: The DEEPER trial (NCT02515734), which evaluated m-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², 5-FU 2400 mg/m²) plus cetuximab (cet) vs. bevacizumab (bev) as initial therapy in terms of depth of response (DpR) as the primary endpoint in RAS wild-type metastatic colorectal cancer (mCRC), has demonstrated a significantly better DpR in the cet arm (ASCO 2021). Moreover, favorable progression-free survival (PFS) was reported in the cet arm for patients (pts) with RAS / BRAF wild-type and left-sided tumors (ESMO 2023). Due to the small number of overall survival (OS) events, it was decided to extend the observation period, and the final survival analysis was performed at the cutoff date of August 2024. Methods: Survival analysis was pre-planned in the per-protocol set (PPS), which consisted of pts evaluable for the DpR by an external review board. The clinical outcomes were evaluated according to clinical factors including primary tumor sidedness, liver metastasis status, and BRAF status using a log-rank test. All statistical tests were two-sided, and P values ≤ 0.05 were considered significant. Results: 321 of 359 enrolled pts were defined as PPS (median age 65 years, 64% male, performance status [PS] 0/1: 91%/9%, left/right primary: 84%/16%). In RAS wild-type and left-sided tumors, median PFS and OS were 13.9 months vs. 12.1 months (HR 0.81, 95% CI 0.63-1.05) and 45.3 months vs. 41.9 months (HR 0.85, 95% CI 0.64-1.12) in the cet vs. bev arm, respectively. BRAF status was available in 234 (73%) of the 321 pts in the PPS. An exploratory analysis showed that PFS was significantly better in the cet arm compared to the bev arm (median 14.8 months vs. 11.9 months, HR 0.71, 95% CI 0.52-0.97) in 178 pts with RAS / BRAF wild-type and left-sided tumors. Additionally, OS was 50.2 months vs. 40.2 months (HR 0.74, 95% CI 0.53-1.05). Moreover, according to liver disease status, m-FOLFOXIRI plus cet was associated with longer PFS and OS in pts with RAS / BRAF wild-type and left-sided mCRC with extra-hepatic metastases (median 15.1 months vs. 11.4 months, HR 0.66, 95% CI 0.46-0.95 and 50.2 months vs. 38.6 months, HR 0.60, 95% CI 0.40-0.90), but not liver-limited disease (median 14.5 months vs. 15.5 months, HR 0.79, 95% CI 0.44-1.42 and 52.2 months vs. 49.9 months, HR 1.17, 95% CI 0.61-2.24). Conclusions: The final survival analysis of the DEEPER trial demonstrated favorable PFS and OS with m-FOLFOXIRI plus cet in pts with RAS / BRAF wild-type and left-sided mCRC. The m-FOLFOXIRI plus cet regimen may be a good option for initial therapy, offering longer survival times in pts with extra-hepatic metastases. Clinical trial information: jRCTs061180022 .

Selective internal radiation therapy with yttrium-90 resin microspheres followed by lenvatinib plus PD-1 inhibitor for large or huge advanced-stage hepatocellular carcinoma: A retrospective cohort study from China.

581 Background: Yttrium-90 resin microspheres have been introduced into China in recent years, but the efficacy or safety on Chinese patients are rarely reported. This study aimed to evaluate the efficacy and safety of selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres followed by lenvatinib and PD-1 inhibitor in Chinese patients with large (5.1–10.0 cm in diameter) or huge (>10.0 cm) advanced-stage hepatocellular carcinoma (HCC). Methods: Data of large or huge Barcelona Clinic Liver Cancer stage C HCC patients treated with SIRT followed by lenvatinib plus PD-1 inhibitor from November 2022 to October 2023 were prospectively collected and retrospectively analyzed. Key endpoints included overall survival (OS), progression-free survival (PFS), complete response rate (CRR), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors, and adverse events (AEs) graded based on Common Terminology Criteria for Adverse Events v5.0. Risk factors affecting PFS were analyzed using univariate and multivariate Cox regression models. Results: A total of 30 patients (27 males, 3 females; mean age 54 ± 11 years) were included. The mean longest diameter of the tumor was 9.6 ± 4.2 cm (range: 5.2–17.6 cm). Nineteen (63.3%) patients had more than three intrahepatic lesions, 15 (50.0%) had vascular invasion, and 13 (43.3%) had extrahepatic metastasis. Sixteen (53.3%) patients had undergone prior anticancer therapies. Two patients received two SIRT procedures, and the rest had one. Lenvatinib and PD-1 inhibitor treatment was initiated 3–7 days after the initial SIRT procedure. CRR was 20.0%, ORR was 73.3%, and DCR was 90.0%. Median PFS was 8.0 months (95% CI, 5.6–10.4), and median OS was not reached. OS rates at 6, 12, and 18 months were 93%, 74%, and 74%, respectively. Univariate and multivariate analysis indicated that baseline alpha-fetoprotein levels, baseline eosinophil count, and neutrophil-to-lymphocyte ratio at 1 month after SIRT were independent risk factors for PFS. AEs of any grade occurred in 86.7% of patients, with grade 3 AEs in 23.3%, and no grade 4/5 AEs were recorded. Conclusions: SIRT followed by lenvatinib and PD-1 inhibitor demonstrates promising efficacy and a favorable safety profile in Chinese patients with large or huge advanced-stage HCC.

Regorafenib combined with immunotherapy and prognosis of unresectable hepatocellular carcinoma.

541 Background: To investigate the prognosis and influencing factors of patients with unresectable hepatocellular carcinoma (uHCC) receiving regorafenib in different treatment modes. Methods: A total of 227 patients with uHCC who received at least 2 cycles of regorafenib treatment in the Affiliated Hospital of Qingdao University between June 2018 and August 2022 were retrospectively collected through the Hospital Information System (HIS). 204 patients were finally enrolled by inclusion and exclusion criteria after screening. Results: The median follow-up was 25.9 (4.5-69.7) months. The median overall survival (OS) of 204 patients with uHCC was 27.7 (95%CI 21.98-33.42) months. The 1, 2, 3 and 5-year OS were 80.9%, 55.9%, 41.4% and 26.7%, respectively. Univariate analysis showed that combination with immune checkpoint inhibitor (ICI) and metabolic-associated complications were independent factors for survival benefit of regorafenib, while the Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) scale = 2, undecreased Alpha-fetoprotein (AFP), macrovascular invasion and extrahepatic metastasis were independent risk factors for poor prognosis (P<0.05). Compared with 60 patients receiving regorafenib alone, 144 patients receiving regorafenib combined with ICI had a significant survival benefit (median OS, 16.9 vs. 31.5 months, respectively, P=0.006). The median OS of 153 patients receiving second-line therapy with regorafenib was 30.3 months. Among 51 patients receiving third or more lines of therapy with regorafenib, compared with 4 patients receiving regorafenib alone, 47 patients receiving regorafenib combined with ICI had a significant survival benefit (median OS, 9.4 vs. 24.1 months, respectively, P=0.000). Among 148 patients receiving local treatment, the median OS of patients with regorafenib combined with ICI (n=115) or without ICI (n=33) was 33.2 and 16.5 months, respectively (P=0.005). Conclusions: Regorafenib has a good prognosis in second-line treatment of uHCC. The OS of patients with regorafenib combined with ICI were significantly better than that of patients without ICI. The OS benefit of regorafenib combined with ICI was also equivalent in patients with third or more lines. The benefit of regorafenib combined with ICI was better for patients receiving local treatment.

Nivolumab plus ipilimumab in advanced hepatocellular carcinoma with Child-Pugh B: A multicenter retrospective study.

551 Background: The phase 3 CheckMate 9DW trial proposed that nivolumab plus ipilimumab (Nivo/Ipi) significantly improved the survival of patients with advanced hepatocellular carcinoma (aHCC) compared with sorafenib or lenvatinib as first-line treatment, but it only included patients with Child-Pugh A. Given the limited treatment options for patients with poor liver function, we aimed to assess the efficacy and safety of Nivo/Ipi in aHCC patients, stratified by liver function. Methods: This study included patients with aHCC who received Nivo/Ipi treatment at three referral hospitals between March 2020 and September 2023. Patients received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks (four doses), followed by nivolumab (240 mg) every 2 weeks. Results: Of 106 patients treated with Nivo/Ipi, 96 evaluable patients were included in the final analysis. Among them, 76 patients had Child-Pugh A, while 20 had Child-Pugh B. The baseline characteristics were generally comparable between the two groups, except for a significantly higher rate of extrahepatic metastasis in patients with Child-Pugh A (86.8% vs. 65.0%, p = 0.043) and a higher incidence of macrovascular invasion in patients with Child-Pugh B (55.0% vs. 27.6%, p = 0.032). The objective response rate (ORR) was 28.9% (22/76, 4 complete responses [CR] and 18 partial responses [PR]) in the Child-Pugh A group and 10.0% (2/20; 0 CR and 2 PR) in the Child-Pugh B group. Disease control rates were 42.1% in the Child-Pugh A group and 25.0% in the Child-Pugh B group. In a median follow-up duration of 29.3 months (95% confidence interval [CI], 28.8-29.8), the median overall survival (OS) was 8.9 months (95% CI, 5.5-17.6) in the Child-Pugh A group and 3.9 months (95% CI, 2.1-4.8) in the Child-Pugh B group (p < 0.001). The median progression-free survival (PFS) was 1.6 months (95% CI, 1.2-3.5) in the Child-Pugh A group and 1.2 months (95% CI, 0.8-2.1) in the Child-Pugh B group (p = 0.003). Adverse events of any grade occurred at a comparable rate between the two groups, although immune-related adverse events were significantly more frequent in the Child-Pugh A group. Multivariable analysis indicated that Child-Pugh B was consistently associated with a worse PFS and OS, while prior exposure to immune checkpoint inhibitors (ICIs) was associated with a poorer PFS. Notably, both responders with Child-Pugh B were both ICI naïve. Conclusions: While Nivo/Ipi treatment showed reduced efficacy in patients with Child-Pugh B, identifying potential responders beyond the current clinical trial criteria may offer opportunities to improve outcomes in this challenging population.

Exploring the efficacy of fluorouracil and platinum based chemotherapy in advanced hepatocellular carcinoma to bridge the treatment gap in resource limited settings

Advanced hepatocellular carcinoma (HCC) poses treatment challenges, especially where access to multi-kinase inhibitors and ICIs is limited by high costs and lack of insurance. This study evaluates the effectiveness of 5-fluorouracil (5-FU) plus platinum-based chemotherapy as an alternative systemic treatment for advanced HCC. A retrospective analysis of advanced HCC patients treated with 5-FU plus platinum-based chemotherapy was conducted. The Kaplan-Meier method determined median progression-free survival (PFS) and overall survival (OS). From April 2009 to October 2023, 48 patients with advanced HCC were included in the study. Nearly all patients (97.9%) had extrahepatic metastasis and stable liver function, with three-quarters previously treated with sorafenib. At a median follow-up of 7.8 months, the median PFS was 4.2 months (95% CI, 1.3–7.1), and the median OS was 8.2 months (95% CI, 2.5–13.9). A high pretreatment neutrophil-to-lymphocyte ratio (≥ 3.0) adversely affected both PFS (HR = 1.79; 95% CI, 0.99–3.25; p = 0.034) and OS (HR = 2.02; 95% CI, 1.10–3.69; p = 0.011). Hematologic toxicities related to the treatment were substantial, with 62.5% of patients experiencing grade 3 or 4 events, primarily neutropenia, which affected 60.4% of them. Our findings suggest that 5-FU combined with platinum-based chemotherapy is a viable, cost-effective alternative for advanced HCC treatment in resource-limited settings, particularly compared to ICIs and multi-kinase inhibitors, with significant implications for developing countries.

Prognostic value of clinical complete response for patients with initially unresectable hepatocellular carcinoma after conversion with triple therapy

Introduction: Accurately predicting the outcomes of conversion therapy among patients with initially unresectable hepatocellular carcinoma (uHCC) remains a challenge. Clinical complete response (cCR) has been proposed as a predictor of prognosis. However, information on its prognostic value in these patients is limited. We aimed to explore the prognostic value of cCR in patients with uHCC following conversion therapy and identify predictors of cCR. Methods: We included 241 patients with uHCC who underwent transcatheter arterial chemoembolization combined with lenvatinib and PD-1 inhibitors (triple therapy) as first-line treatment. The prognostic value of cCR, predictive factors of cCR, and the relationship between cCR and pathological complete response (pCR) were analyzed. Results: The cCR rate of the 241 patients included was 17.4%. Patients with cCR showed better overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) than those without. cCR was an independent risk factor for OS (hazard ratio [HR]: 0.11, 95% confidence interval [CI]: 0.03–0.42, p = 0.001) and PFS (HR: 0.29, 95% CI: 0.15–0.56, p < 0.001). Serum α-fetoprotein levels ≥400 ng/mL (odds ratio [OR]: 0.47, 95% CI: 0.22–0.95, p = 0.040) and extrahepatic metastasis (OR: 0.13, 95% CI: 0.01–0.62, p = 0.046) were independent negative predictors of cCR. A total of 107 patients (44.4%) underwent conversion surgery. Among these patients, cCR was associated with better OS (p =0.009) and recurrence-free survival (p = 0.007). cCR was significantly correlated with pCR (Φ = 0.61, p < 0.001). Albumin levels ≥35 g/L (OR: 0.12, 95% CI: 0.02–0.69, p = 0.018) and cCR (OR: 30.32, 95% CI: 9.19–128.00, p < 0.001) were independent predictors of pCR. Conclusion: cCR after triple therapy has an excellent long-term survival advantage and is significantly related to pCR. cCR may be a surrogate marker for predicting prognosis and pCR in patients with uHCC receiving triple therapy.

Thermal ablation versus surgical resection of small-size colorectal liver metastases (COLLISION): an international, randomised, controlled, phase 3 non-inferiority trial.

For patients with small-size colorectal liver metastases, growing evidence suggests thermal ablation to be associated with fewer adverse events and faster recovery than resection while also challenging resection in terms of local control and overall survival. This study assessed the potential non-inferiority of thermal ablation compared with surgical resection in patients with small-size resectable colorectal liver metastases. Adult patients (aged ≥18 years) from 14 centres in the Netherlands, Belgium, and Italy with ten or fewer small-size (≤3 cm) colorectal liver metastases, no extrahepatic metastases, and an Eastern Cooperative Oncology Group performance status of 0-2, were stratified per centre, and according to their disease burden, into low, intermediate, and high disease burden subgroups and randomly assigned 1:1 to receive either thermal ablation (experimental group) or surgical resection (control group) of all target colorectal liver metastases using the web-based module Castor electronic data capture with variable block sizes of 4, 6, and 8. Although at the operator's discretion, a minimally invasive approach in both treatment groups was recommended. The primary endpoint was overall survival, assessed in the intention-to-treat population. A hazard ratio (HR) of 1·30 was considered the upper limit of non-inferiority for the primary endpoint. A preplanned interim analysis with predefined stopping rules for futility (conditional power to prove the null hypothesis <20%) and early benefit (conditional power >90%, superior safety outcomes for the experimental group, and no difference or superiority regarding local control for the experimental group) was done 12 months after enrolment of 50% of the planned sample size. Safety was assessed per treatment group. This trial is registered with ClinicalTrials.gov, NCT03088150. Between Aug 7, 2017, and Feb 14, 2024, 300 patients were randomly assigned to the experimental group (n=148, 100 male [68%] and 48 female [32%]; median age 67·9 years [IQR 29·2-85·7]) or to the control group (n=148, 107 male [72%] and 41 female [28%]; median age 65·1 [IQR 31·4-87·4]); four patients (two in each treatment group) were excluded after randomisation because they were found to have other disease pathology. Median follow-up at the prespecified interim analysis was 28·9 months (IQR 0·3-77·8). The trial was stopped early for meeting the predefined stopping rules: (1) a conditional likelihood to prove non-inferiority for overall survival of 90·5% (median overall survival not reached in both groups; HR 1·05; 95% CI 0·69-1·58; p=0·83), (2) a non-inferior local control (median local control not reached in both groups; HR 0·13, 95% CI 0·02-1·06; p=0·057), and (3) a superior safety profile for the experimental group. Patients in the experimental group had fewer adverse events than those in the control group (28 [19%] vs 67 [46%]; p<0·0001). Serious adverse events occurred in 11 (7%) of 148 patients in the experimental group and 29 (20%) of 146 in the control group, mostly periprocedural haemorrhage requiring intervention (one [1%] vs eight [5%]), and infectious complications requiring intervention (six [4%] vs 11 [8%]). There were no treatment-related deaths in the experimental group and three treatment-related deaths (2%) in the control group (two due to postoperative cardiac complications and one due to sepsis and liver failure). The assumption that thermal ablation should be reserved for unresectable colorectal liver metastases requires re-evaluation and the preferred treatment should be individualised and based on clinical characteristics and available expertise. Medtronic-Covidien.

A novel nomogram on predicting extrahepatic metastasis in colorectal cancer with liver metastasis for selective application of 18F-FDG PET/CT.

Background: A more accurate assessment of extrahepatic metastases (EHMs) with colorectal cancer liver metastases (CRLMs) improve patient prognosis without unnecessary surgery and economic burden. At present, PET-CT can only be used as a second-line modality. We aimed to construct a predictive model for EHMs, and provide guidance for the selective application of 18F-FDG PET/CT. Methods: The clinical data of patients with CRLMs between December 2018 and February 2023 were retrospectively retrieved from the medical records of three large-capacity hospitals. Moreover, we explored the need for 18F-FDG PET/CT to be used selectively for detecting EHMs with CRLMs. Results: A total of 471 patients from two hospitals were included in the training set, 174 of whom had CRLMs and EHMs. Notably, the percentages of patients with positive serum CEA, CA19-9 and CA-125 levels were significantly greater in patients with CRLMs and EHMs than in those with liver-limited metastases. Univariate and multivariate logistic regression analyses revealed that the serum levels of CEA and CA-125 and multiple liver metastases were independent risk factors for EHMs. Additionally, we recruited 190 patients with CRLMs from one of the hospitals as the validation set. The nomogram model achieved stable and accurate prediction results in the training and validation sets (AUC = 0.768 and 0.733), and was significantly superior to CEA and CA19-9. Moreover, the sensitivity and specificity of 18F-FDG PET/CT for the diagnosis of EHMs were 100% and 88%, respectively. Conclusions: We constructed and validated a nomogram on predicting the risk of EHMs in patients with CRLMs, which can guide clinicians to selective application of 18F-FDG PET/CT.

The Clinical Characteristics, Patterns of Recurrence, and Long-Term Survival Outcomes of Dual-Phenotype Hepatocellular Carcinoma After Curative Liver Resection.

Dual-phenotype hepatocellular carcinoma (DPHCC) is discernible from classical HCC (CHCC) in its morphology and is characterized by the co-expression of both CHCC and cholangiocyte markers. This study aimed to clarify the difference between DPHCC and CHCC after surgery. Patients with HCC after surgery were collected. The clinical characteristics, patterns of recurrence, and survival outcomes of patients with DPHCC and CHCC were compared. Multivariate analyses were used to determine the independent risk factors that influence the prognosis of patients. Patients with DPHCC (n = 141) account for 26% of the total patients (n = 541). Compared to patients with CHCC, patients with DPHCC are significantly associated with incomplete capsules, microvascular invasion, and poor differentiation (all P < 0.05). Compared to patients with CHCC, the 5-year overall survival (OS) (56% vs 43%) and recurrence-free survival (RFS) (35% vs 28%) are lower in patients with DPHCC. Meanwhile, among patients with tumor recurrence after surgery, patients with DPHCC have a higher proportion of advanced-stage tumors, and extrahepatic metastasis (all P < 0.05). Moreover, multivariate analysis showed that DPHCC is an independent risk factor for both OS (HR 1.399, 95% CI 1.061-1.845, P = 0.017) and RFS (HR 1.313, 95% CI 1.033-1.669, P = 0.026). DPHCC, an aggressive HCC subtype with poor differentiation and high invasiveness, shows inferior RFS and OS post-liver resection compared to CHCC. Clinicians' recognition and addressing of its unique challenges can improve DPHCC patients' prognosis and QoL.

Hepatic arterial infusion chemotherapy enhances the efficacy of lenvatinib and PD-1 inhibitors for advanced hepatocellular carcinoma: A meta-analysis and trial sequential analysis.

Hepatic arterial infusion chemotherapy (HAIC) was an effective treatment for advanced hepatocellular carcinoma (HCC), and its effectiveness in combination with targeted immunotherapy regimens was controversial. This meta-analysis was performed to evaluate the efficacy of adding HAIC to lenvatinib in combination with programmed death-1 (PD-1) inhibitors. Literature related to the efficacy of HAIC in combination with lenvatinib plus PD-1 inhibitors in the treatment of advanced HCC was searched through PubMed, Cochrane Library, Embase, and Web of Science databases. TSA was used to control for the risk of random error and assess whether the meta-analysis evidence was conclusive. Eight relevant papers with a total of 1244 patients. Compared with the L-P treatment group, the H-L-P treatment group significantly prolonged OS (hazard ratio [HR] 2.11 [95% confidence interval (CI) 1.82-2.44]; p<0.001) and PFS (HR 1.91 [95% CI 1.67-2.17]; p<0.001) and improved ORR (risk ratio [RR] 2.20 [95% CI 1.74-2.78]; p<0.001) and DCR (RR 1.28 [95% CI 1.15-1.42]; p<0.001) in patients with advanced HCC. TSA analysis indicated that further trials were unnecessary, preliminary positive results were promptly obtained. Prognostic factor analysis demonstrated that extrahepatic metastasis were common independent risk factor for OS and PFS. The rate of adverse events (AEs) was higher in the H-L-P treatment group than in the L-P treatment group. HAIC combined with lenvatinib plus PD-1 inhibitors markedly extended OS and PFS, particularly in patients without extrahepatic metastases. Furthermore, it markedly enhanced ORR and DCR in patients with HCC.

The Prognostic Value of CRP/Alb Ratio in Predicting Overall Survival for Hepatocellular Carcinoma Treated with Transcatheter Intra-Arterial Therapy Combined with Molecular-Targeted Agents and PD-1/PD-L1 Inhibitors.

This study aimed to evaluate the prognostic value of C-reactive protein to albumin (CRP/Alb) ratio in hepatocellular carcinoma (HCC) treated with transcatheter intra-arterial therapy combined with molecular targeted agents (MTAs) and programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors. Medical records of 271 consecutive patients with HCC receiving this combination therapy in China between 2019 and 2023 were retrospectively analyzed. Prognostic factors for progression-free survival (PFS) and overall survival (OS) were identified using univariate and multivariate Cox regression analyses. The discriminatory capability of inflammation-based prognostic scores-including the CRP/Alb ratio, C-reactive protein and alpha-fetoprotein in immunotherapy (CRAFITY) score, modified Glasgow prognostic score (mGPS), platelet-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)-was assessed using the area under the curve (AUC). A total of 133 patients met the inclusion criteria. The optimal cutoff value for the binary classification of CRP/Alb ratio in predicting OS, as determined using X-tile software, was 0.02. Multivariate analysis identified the CRP/Alb ratio (hazard ratio [HR] = 2.61, p < 0.001), tumor size (HR = 2.45, p = 0.018), and extrahepatic metastases (HR = 1.93, p = 0.015) as independent predictors of OS. For PFS, significant factors included Eastern Cooperative Oncology Group Performance Status (HR = 1.55, p = 0.033) and macrovascular invasion (HR = 1.48, p = 0.046). Patients with higher CRP/Alb ratios were more likely to experience fever and fatigue. The CRP/Alb ratio demonstrated significantly higher AUCs than PLR and SII at 24 months (all p < 0.05) and showed comparable AUCs to CRAFITY score and mGPS at 12, 24, and 36 months. The CRP/Alb ratio is a valuable prognostic marker for predicting OS and treatment-related adverse events in HCC patients receiving transcatheter intra-arterial therapy combined with MTAs and PD-1/PD-L1 inhibitors. This ratio can be used as a simple and reliable biomarker for assessing prognosis and guiding patient selection in clinical practice.

Fully Covered Stent-TIPS for Advanced HCC Patients with Portal Vein Tumor Thrombus-Related Severe Symptomatic Portal Hypertension.

Portal vein tumor thrombus (PVTT)-related severe symptomatic portal hypertension (SPH) leads to a poor prognosis in patients with advanced hepatocellular carcinoma (HCC). Traditional transjugular intrahepatic portosystemic shunt (TIPS) using covered plus bare stent can effectively relieve SPH, however, the bare segment is susceptible to obstruction due to PVTT invasion. This study aimed to evaluate the safety and efficacy of fully covered stent-TIPS (FCS-TIPS) for treatment of PVTT-related SPH in advanced HCC patients. This retrospective study enrolled 25 patients with advanced HCC who underwent FCS-TIPS for PVTT-related severe SPH from June 2018 to January 2024. The evaluated outcomes included overall survival (OS), technical success rate, reduction in portal venous pressure gradient (PPG), stent patency rate, SPH control rate, liver function and complications. The technical success rate was 100% without perioperative deaths or severe procedure-related adverse events. The average PPG decreased by 13.4±4.6mmHg. The overall symptom control rate of SPH was 96.0%. Variceal bleeding, ascites/hydrothorax, and enteropathy control rates were 100%, 95.0%, and 100%, respectively. Liver function showed mild improvement one month after TIPS. One patient (4.0%) experienced overt hepatic encephalopathy (OHE) and three (12.0%) patients developed shunt dysfunction during the follow-up period. None of the patients experienced shunt-induced extrahepatic metastasis. The median OS was 6.0 months and the cumulative survival rates at 3, 6, 12 months were 80.0%, 52.0% and 21.3%. FCS-TIPS is safe and effective for treating PVTT-related severe SPH and can serve as a bridging therapy for advanced HCC.

Robotic Subtotal Caudate Lobe Hepatic Resection for Paracaval Colorectal Metastasis: Technique of Inferior Vena Cava Dissection and Handling.

Minimally invasive technique for surgical management of colorectal metastasis is becoming the standard practice in the United States. Paracaval colorectal metastasis is a technically challenging tumor to resect due to its location.1-4 Abutment of the inferior vena cava (IVC) often requires advanced technique for vascular dissection and potential need for partial venous resection. The authors describe their technique of robotic subtotal caudate lobe resection for paracaval tumor requiring tangential IVC resection. A 76-year-old man after partial nonanatomic liver resection of colorectal metastases in segments 2, 4, and 8 presented with a new paracaval caudate tumor. A positron emission tomography (PET) scan showed a 3-cm FDG avid tumor with a standard uptake value (SUV) of 8.3 without extrahepatic metastasis. After a diagnostic laparoscopy, subtotal caudate lobe resection was undertaken. Short hepatic veins were divided to fully mobilize the Spiegel and paracaval portion. Liver transection was performed along the right side of the IVC. Upon the final IVC dissection, vascular abutment by the dorsal aspect of the tumor was encountered. Meticulous vascular dissection, performed with partial tangential IVC resection, was completed to gain complete tumor resection. The operation time was 3.5h, with 100ml of blood loss. The postoperative course was uneventful, and the patient was discharged home on postoperative day 2. The pathology results showed a moderately differentiated metastatic adenocarcinoma (3.8 × 3 × 1.8 cm) with a histologically negative vascular margin. The patient currently is 2 years from the operation without recurrence of disease. The authors describe a safe and feasible technique of robotic subtotal caudate lobe hepatic resection with partial IVC resection, which can be useful to practicing hepatobiliary surgeons.

Prospective analysis of the effects of RAS mutation on local tumor progression and overall survival after radiofrequency ablation for colorectal liver metastases

Objectives To investigate the effects of RAS mutation on local tumor progression (LTP) and overall survival (OS) after radiofrequency ablation (RFA) for colorectal liver metastases (CRLMs). Methods This prospective study consecutively enrolled patients with CRLM who underwent ultrasound-guided RFA between June 2020 and July 2022. RAS mutation status was analyzed via the amplification refractory mutation system PCR method. The safety margin was measured via an anatomic landmark-based manual assessment method. Factors associated with time-to-LTP and OS were assessed via univariate and multivariate analyses. Results A total of 163 patients with 284 ablated tumors were included. Sixty-nine patients (42.3%) had RAS mutations. Compared with the RAS-wild-type group, the RAS-mutant group had a higher 2-year cumulative LTP rate (20.0% vs. 9.8%, p = 0.016) and a worse 2-year OS rate (55.7% vs. 79.8%, p < 0.001). Compared with RAS-wild-type tumors, RAS-mutant tumors had a significantly greater 2-year cumulative LTP rate in the subgroups with safety margins <5 mm (47.6% vs. 24.9%, p = 0.034) and ≥5 mm (8.6% vs. 1.9%, p = 0.045). In the multivariate Fine–Gray analysis, RAS mutation (SHR, 2.42; p = 0.007) and a safety margin <5 mm (SHR, 7.94; p < 0.001) were found to be independent predictors of the time-to-LTP. According to the multivariate Cox analysis, RAS mutation (HR, 2.13; p = 0.010), CEA >5 ng/mL (HR, 2.29; p = 0.017), and extrahepatic metastases (HR, 2.04; p = 0.016) were independent predictors of shorter OS. Conclusions RAS mutation was an independent predictor of LTP and OS after RFA for patients with CRLM. RAS-mutant tumors require wider safety margins.

Predictive value of gemstone spectral imaging for chemotherapy response in colorectal cancer liver metastases: A retrospective study.

Accurate and timely assessment of tumor response after chemotherapy is crucial in clinical settings. The aim of this study was to explore the feasibility of Gemstone Spectral Imaging (GSI) for early assessment of chemotherapy responses in patients with colorectal cancer liver metastasis (CRCLM). From October 2012 to October 2018, 46 patients (28 males and 18 females) with CRCLM received GSI followed by chemotherapy were retrospectively reviewed. The patients were divided into a response group (n = 32) and a nonresponse group (n = 14) according to the tumor response to chemotherapy. The iodine concentration images and virtual monoenergetic images (VMIs) with an optimal contrast-to-noise ratio at the arterial phase (AP) and portal venous phase (PVP) were obtained by GSI viewer. The iodine concentration value and computed tomography (CT) value on VMIs and slope of spectral attenuation curves of all lesions were compared. A logistic regression analysis was used to determine the predictor of chemotherapy response. The difference of extrahepatic metastasis (P = 0.001), CT value on 68 keV VMIs at the AP (P = 0.005) and PVP (P = 0.001), slope of CT value attenuation curves at the AP (P = 0.013) and PVP (P = 0.001), and iodine concentration value at PVP (P = 0.003) between the response and nonresponse groups were statistically significant. The CT value of the 68 keV VMIs (OR: 1.206; 95% confidence interval [CI]: 1.021-1.425, P = 0.027) and the iodine concentration value at PVP (OR: 1.952; 95% CI: 1.034-3.684, P = 0.039) were independent prognostic factors for predicting chemotherapy response. Baseline GSI may help predict the response to chemotherapy and provide a good tumor-response indicator through single-energy CT value of 68 keV at the PVP and iodine concentration.

Robotic Total Anatomical Left Hepatectomy with En Bloc Caudate Resection and Systematic Portal Lymphadenectomy for Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma is the second most common primary liver cancer with an aggressive behavior and poor prognosis.1,2 The only potential curative option is radical resection, traditionally undertaken via an open operation.3,4 Reports on minimally invasive approach are sparse and limited. In this video, we described our technique for robotic total anatomical left hepatectomy with en bloc caudate resection for an intrahepatic cholangiocarcinoma involving segment 1 and dorsal aspect of segment.4 METHODS: A 78-year-old man presented to our office with a caudate lobe mass infiltrating dorsal aspect of left hepatic lobe. CT scan of abdomen/pelvis showed a large caudate lobe mass, consistent with an intrahepatic cholangiocarcinoma. No evidence of extrahepatic metastasis was seen. The operation was undertaken by using a robotic platform with 5 ports. An intraoperative ultrasound was used to mark the location of the middle hepatic vein to be preserved while securing R-0 parenchymal margins. Operation time was 4.5 hours with 100 cc blood loss. The postoperative course was uneventful, and the patient was discharged home on postoperative day 6. Pathological results showed moderately differentiated cholangiocarcinoma of Caudate lobe (6.7 cm) with two additional satellite lesions in the left hepatic lobe (0.5 cm, 0.7 cm). Background liver tissue showed congested sinusoids and minimal macrovesicular steatosis negative for significant cholestasis, inflammation, or fibrosis. 1/13 hilar lymph nodes was involved by carcinoma. We demonstrated a safe, feasible, and reproducible technique of robotic total anatomical left hepatectomy with en bloc caudate resection and portal lymphadenectomy for intrahepatic cholangiocarcinoma.