Personalized prediction of postoperative complication and survival among Colorectal Liver Metastases Patients Receiving Simultaneous Resection using machine learning approaches: A multi-center study.

BACKGROUND: To predict clinical important outcomes for colorectal liver metastases (CRLM) patients receiving colorectal resection with simultaneous liver resection by integrating demographic, clinical, laboratory, and genetic data. METHODS: Random forest (RF) models were developed to predict postoperative complications and major complications (binary outcomes), as well as progression-free survival (PFS) and overall survival (OS) (time-to-event outcomes) of the CRLM patients based on data from two hospitals. The models were validated on an external dataset from an independent hospital. The clinical utility of the models was assessed via decision curve analyses (DCA). RESULTS: There were 1067 patients included in survival prediction analyses and 1070 patients included in postoperative complication prediction analyses. The RF models provided an assessment of the model contributions of features for outcomes and suggested KRAS, BRAF, and MMR status were salient for the PFS or OS predictions. RF model of PFS showed that the Brier scores at 1-, 3-, and 5-year PFS were 0.213, 0.202 and 0.188; and the AUCs of 1-, 3- and 5-year PFS were 0.702, 0.720 and 0.743. RF model of OS revealed that Brier scores of 1-,3-, and 5-year OS were 0.040, 0.183 and 0.211; and the AUCs of 1-, 3- and 5-year OS were 0.737, 0.706 and 0.719. RF model for postoperative complication resulted in an AUC of 0.716 and a Brier score of 0.196. DCA curves clearly demonstrated that the RF models for these outcomes exhibited a superior net benefit across a wide range of threshold probabilities, signifying their favorable clinical utility. The RF models consistently exhibited robust performance in both internal cross-validation and external validation. The individualized risk profile predicted by the models closely aligned with the actual survival outcomes observed for the patients. A web-based tool (https://kanli.shinyapps.io/CRLMRF/) was provided to demonstrate the practical use of the prediction models for new patients in the clinical setting. CONCLUSION: The predictive models and a web-based tool for personalized prediction demonstrated a moderate predictive performance and favorable clinical utilities on several key clinical outcomes of CRLM patients receiving simultaneous resection, which could facilitate the clinical decision-making and inform future interventions for CRLM patients.

Pre-hepatectomy dynamic circulating tumor DNA to predict pathologic response to preoperative chemotherapy and post-hepatectomy recurrence in patients with colorectal liver metastases.

OBJECTIVE: To evaluate the predictive value of pre-hepatectomy dynamic circulating tumor DNA (ctDNA) on pathologic response to preoperative chemotherapy and recurrence after liver resection for colorectal liver metastases (CRLM). BACKGROUND: Pathologic response is a predictor of clinical outcomes for patients undergoing hepatectomy for CRLM. Postoperative ctDNA has been proven to be sensitive for recurrence detection. However, few studies investigate the impact of pre-hepatectomy ctDNA on pathologic response and recurrence. METHODS: Patients with potential resectable CRLM underwent preoperative chemotherapy and hepatectomy between 2018 and 2021 was considered for inclusion. Plasma ctDNA was collected before and after preoperative chemotherapy. Pathologic response was analyzed for all patients after liver resection. Recurrence free survival was compared between patients with different ctDNA status and different pathologic response. The relation between ctDNA and pathologic response was also analyzed. RESULTS: A total of 114 patients were included. ctDNA was detectable in 108 of 114 patients (94.7%) before chemotherapy, in 56 of 114 patients (49.1%) after chemotherapy. Patients with ctDNA positive at baseline and negative after chemotherapy had significantly longer RFS (median RFS 17 vs 7 months, p = 0.001) and HRFS (median HRFS unreached vs 8 months, p < 0.001) than those with ctDNA persistently positive after chemotherapy. Two patients (1.6%) had a pathologic complete response and 56 patients (45.2%) had a pathologic major response. Post-chemotherapy ctDNA- was associated with improved major pathologic response (53.4% vs 32.1%, p = 0.011). In the multivariable analysis, ctDNA- after chemotherapy (HR 0.51, 95% CI 0.28-0.93), major pathologic response (HR 0.34, 95% CI 0.19-0.62) and surgery combined with radiofrequency ablation (HR 2.62, 95% CI 1.38-5.00) were independently associated with RFS (all p < 0.05). CONCLUSIONS: Pre-hepatectomy dynamic monitoring of ctDNA could predict pathologic response to preoperative chemotherapy and post-hepatectomy recurrence in CRLM patients. Negative ctDNA after preoperative chemotherapy was associated with better tumor regression grade and recurrence-free survival, which might be used to guide pre-hepatectomy chemotherapy and predict prognosis.

Association of preoperative aspartate aminotransferase to platelet ratio index with outcomes and tumour microenvironment among colorectal cancer with liver metastases.

This study aims to investigate applicable robust biomarkers that can improve prognostic predictions for colorectal liver metastasis (CRLM) patients receiving simultaneous resection. A total of 1323 CRLM patients from multiple centres were included. The preoperative aspartate aminotransferase to platelet ratio index (APRI) level from blood of patients were obtained. Patients were stratified into a high APRI group and a low APRI group, and comparisons were conducted by analyzing progression-free survival (PFS), overall survival (OS) and postoperative early recurrence. Tumour samples of CRLM were collected to perform single-cell RNA sequencing and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) to investigate the association of APRI levels and the tumour microenvironment of CRLM. Compared with APRI <0.33, PFS disadvantage (IPTW-adjusted HR = 1.240, P = 0.015) and OS disadvantage (IPTW- adjusted HR = 1.507, P = 0.002) of APRI ≥0.33 were preserved in the IPTW-adjusted Cox hazards regression analyses. An APRI ≥0.25 was associated with a significantly increased risk of postoperative early recurrence after adjustment (IPTW-adjusted OR = 1.486, P = 0.001). The external validation showed consistent results with the training cohort. In the high APRI group, the single-cell RNA sequencing results revealed a heightened malignancy of epithelial cells, the enrichment of inflammatory-like cancer-associated fibroblasts and SPP1+ macrophages associated with activation of malignant cells and fibrotic microenvironment, and a more suppressed-function T cells; mIHC/IF showed that PD1+ CD4+ T cells, FOXP3+ CD4+ T cells, PD1+ CD8+ T cells, FOXP3+ CD8+ T cells, SPP1+ macrophages and iCAFs were significantly increased in the intratumoral region and peritumoral region. This study contributed valuable evidence regarding preoperative APRI for predicting prognoses among CRLM patients receiving simultaneous resection and provided underlying clues supporting the association between APRI and clinical outcomes by single-cell sequencing bioinformatics analysis and mIHC/IF.

Prediction of Clinical Precision Chemotherapy by Patient-Derived 3D Bioprinting Models of Colorectal Cancer and Its Liver Metastases.

Methods accurately predicting the responses of colorectal cancer (CRC) and colorectal cancer liver metastasis (CRLM) to personalized chemotherapy remain limited due to tumor heterogeneity. This study introduces an innovative patient-derived CRC and CRLM tumor model for preclinical investigation, utilizing 3d-bioprinting (3DP) technology. Efficient construction of homogeneous in vitro 3D models of CRC/CRLM is achieved through the application of patient-derived primary tumor cells and 3D bioprinting with bioink. Genomic and histological analyses affirm that the CRC/CRLM 3DP tumor models effectively retain parental tumor biomarkers and mutation profiles. In vitro tests evaluating chemotherapeutic drug sensitivities reveal substantial tumor heterogeneity in chemotherapy responses within the 3DP CRC/CRLM models. Furthermore, a robust correlation is evident between the drug response in the CRLM 3DP model and the clinical outcomes of neoadjuvant chemotherapy. These findings imply a significant potential for the application of patient-derived 3DP cancer models in precision chemotherapy prediction and preclinical research for CRC/CRLM.

Prognoses of Patients Treated With Surgical Therapy Versus Continuation of Local-Plus-Systemic Therapy Following Successful Down-Staging of Intermediate-Advanced Hepatocellular Carcinoma: A Multicenter Real-World Study.

BACKGROUND: The difference in the prognoses between treatment with surgical therapy and continuation of local-plus-systemic therapy following successful down-staging of intermediate-advanced hepatocellular carcinoma (HCC) remains unclear. METHODS: Data of 405 patients with intermediate-advanced HCC treated at 30 hospitals across China from January 2017 to July 2022 were retrospectively reviewed. All patients received local-plus-systemic therapy and were divided into the surgical (n = 100) and nonsurgical groups (n = 305) according to whether they received surgical therapy. The differences between long-term prognoses of the 2 groups were compared. Subgroup analysis was performed in 173 HCC patients who met the criteria for surgical resection following down-staging. RESULTS: Multivariable analysis of all patients showed that surgical therapy, hazard ratio (HR): 0.289, 95% confidence interval, CI, 0.136-0.613) was a protective factor for overall survival (OS), but not for event-free survival (EFS). Multivariable analysis of 173 intermediate-advanced HCC patients who met the criteria for surgical resection after conversion therapy showed that surgical therapy (HR: 0.282, 95% CI, 0.121-0.655) was a protective factor for OS, but not for EFS. Similar results were obtained after propensity score matching. For patients with Barcelona Clinic Liver Cancer stage B (HR: 0.171, 95% CI, 0.039-0.751) and C (HR: 0.269, 95% CI, 0.085-0.854), surgical therapy was also a protective factor for OS. CONCLUSIONS: Overall, for patients with intermediate-advanced HCC who underwent local-plus-systemic therapies, surgical therapy is a protective factor for long-term prognosis and can prolong OS, and for those who met the surgical resection criteria after conversion therapy, surgical therapy is recommended.

Deep learning-derived spatial organization features on histology images predicts prognosis in colorectal liver metastasis patients after hepatectomy.

Histopathological images of colorectal liver metastases (CRLM) contain rich morphometric information that may predict patients' outcomes. However, to our knowledge, no study has reported any practical deep learning framework based on the histology images of CRLM, and their direct association with prognosis remains largely unknown. In this study, we developed a deep learning-based framework for fully automated tissue classification and quantification of clinically relevant spatial organization features (SOFs) in H&E-stained images of CRLM. The SOFs based risk-scoring system demonstrated a strong and robust prognostic value that is independent of the current clinical risk score (CRS) system in independent clinical cohorts. Our framework enables fully automated tissue classification of H&E images of CRLM, which could significantly reduce assessment subjectivity and the workload of pathologists. The risk-scoring system provides a time- and cost-efficient tool to assist clinical decision-making for patients with CRLM, which could potentially be implemented in clinical practice.

Tumor attachment to Major intrahepatic vascular for Colorectal liver metastases.

BACKGROUND: Colorectal liver metastases attached major intrahepatic vessels has been considered to be a risk factor for survival outcome after liver resection. The present study aimed to clarify the outcomes of R1 surgery (margin < 1 mm) in CRLM patients, distinguishing parenchymal margin R1 and attached to major intrahepatic vessels R1. METHODS: In present study, 283 CRLM patients who were evaluated to be attached to major intrahepatic vessels initially and underwent liver resection following preoperative chemotherapy. They were assigned to two following groups: R0 (n = 167), R1 parenchymal (n = 58) and R1 vascular (n = 58). The survival outcomes and local recurrence rates were analyzed in each group. RESULTS: Overall, 3- and 5-year overall survival rates after liver resection were 53.0% and 38.2% (median overall survival 37 months). Five-year overall survival was higher in patients with R0 than parenchymal R1 (44.9%% vs. 26.3%, p = 0.009), whereas there was no significant difference from patients with vascular R1 (34.3%, p = 0.752). In the multivariable analysis, preoperative chemotherapy > 4 cycles, clinical risk score 3-5, RAS mutation, parenchymal R1 and CA199 > 100 IU/ml were identified as independent predictive factors of overall survival (p < 0.05). There was no significant difference for local recurrence among three groups. CONCLUSION: Parenchymal R1 resection was independent risk factor for CRLM. Vascular R1 surgery achieved survival outcomes equivalent to R0 resection. Non-anatomic liver resection for CRLM attached to intrahepatic vessels might be pursued to increase patient resectability by preoperative chemotherapy.

Combined ablation and resection (CARe) for resectable colorectal cancer liver Metastases-A propensity score matching study.

BACKGROUND: The efficacy of combining ablation and resection (CARe) in treating unresectable colorectal cancer liver metastases (CRLM) was well established. This study aimed to investigate the surgical and oncological outcomes of CARe strategy focusing on initially resectable CRLM. PATIENTS AND METHODS: A total of 971 patients with resectable CRLM from a retrospective database of 1414 CRLM patients were enrolled, including 120 in the CARe group and 851 in the hepatectomy alone group. Short- and long-term outcomes were compared between groups using propensity score matching analysis. RESULTS: After propensity score matching, 96 matched pairs of patients from each group were included. General characteristics of primary tumour and liver metastases were not statistically different between the CARe group and hepatectomy alone group. Disease-free survival (p = 0.257), intrahepatic recurrence-free survival (p = 0.329), and overall survival (p = 0.358) were similar between the two groups. Patients in CARe group had significantly reduced rate of major hepatectomy (5.2% vs. 21.9%, p = 0.001), lower incidence of postoperative hepatic insufficiency (0.0% vs. 5.2%, p = 0.023), and shortened postoperative hospital stay (7 d vs. 8 d, p = 0.019). Multivariate analysis showed that surgical approach did not affect oncologic outcome; liver metastasis with diameter >3 cm was an independent prognostic factor for hepatic recurrence-free and disease-free survival, and RAS status and lymph node metastasis at the primary site were independent prognostic factors for overall survival. CONCLUSION: For patients with resectable CRLM, CARe may be a better treatment strategy than hepatectomy alone, as it could avoid major hepatectomy and get better surgical outcomes, while providing the similar oncologic results.

miR-424-3p promotes metastasis of hepatocellular carcinoma via targeting the SRF-STAT1/2 axis.

Although emerging evidence has established the roles of miRNAs in hepatocellular carcinoma (HCC), the global functional implication of miRNAs in this malignancy remains largely uncharacterized. Here, we aim to systematically identify novel miRNAs involved in HCC and clarify the function and mechanism of specific novel candidate miRNA(s) in this malignancy. Through an integrative omics approach, we identified ten HCC-associated functional modules and a collection of candidate miRNAs. Among them, we demonstrated that miR-424-3p, exhibiting strong associations with extracellular matrix (ECM), promotes HCC cells migration and invasion in vitro and facilitates HCC metastasis in vivo. We further demonstrated that SRF is a direct functional target of miR-424-3p, and is required for the oncogenic activity of miR-424-3p. Finally, we found that miR-424-3p reduces the interferon pathway by attenuating the transactivation of SRF on STAT1/2 and IRF9 genes, which in turn enhances the matrix metalloproteinases (MMPs)-mediated ECM remodeling. This study provides comprehensive functional relevance of miRNAs in HCC by an integrative omics analysis, and further clarifies that miR-424-3p in ECM functional module plays an oncogenic role via reducing the SRF-STAT1/2 axis in this malignancy.

Systemic therapy with or without transcatheter intra-arterial therapies for unresectable hepatocellular carcinoma: a real-world, multi-center study.

Background: Systemic therapy is the standard care of unresectable hepatocellular carcinoma (uHCC), while transcatheter intra-arterial therapies (TRITs) were also widely applied to uHCC patients in Chinese practice. However, the benefit of additional TRIT in these patients is unclear. This study investigated the survival benefit of concurrent TRIT and systemic therapy used as first-line treatment for patients with uHCC. Methods: This real-world, multi-center retrospective study included consecutive patients treated at 11 centers accross China between September 2018 and April 2022. Eligible patients had uHCC of China liver cancer stages IIb to IIIb (Barcelona clinic liver cancer B or C stage), and received first-line systemic therapy with or without concurrent TRIT. Of 289 patients included, 146 received combination therapy and 143 received systemic therapy alone. The overall survival (OS), as primary outcomes, was compared between patients who received systemic therapy plus TRIT (combination group) or systemic therapy alone (systemic-only group) using survival analysis and Cox regression. Imbalances in baseline clinical features between the two groups were adjusted through propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Moreover, subgroup analysis was conducted based on the different tumor characteristics of enrolled uHCC patients. Results: The median OS was significantly longer in the combination group than the systemic-only group before adjustment [not reached vs. 23.9 months; hazard ratio (HR), 0.561; 95% confidence interval (CI), 0.366 to 0.861; P = 0.008], after PSM (HR, 0.612; 95% CI, 0.390 to 0.958; P = 0.031) and after IPTW (HR, 0.539; 95% CI, 0.116 to 0.961; P = 0.008). Subgroup analyses suggested the benefit of combining TRIT with systemic therapy was greatest in patients with liver tumors exceeding the up-to-seven criteria, with an absence of extrahepatic metastasis, or with alfa-fetoprotein ≥ 400 ng/ml. Conclusion: Concurrent TRIT with systemic therapy was associated with improved survival compared with systemic therapy alone as first-line treatment for uHCC, especially for patients with high-intrahepatic tumor load and no extrahepatic metastasis.

Recurrence Prediction by Circulating Tumor DNA in the Patient with Colorectal Liver Metastases After Hepatectomy: A Prospective Biomarker Study.

BACKGROUND: The recurrence rate after hepatic resection of colorectal liver metastases (CRLM) remains high. This study aimed to investigate postoperative circulating tumor DNA (ctDNA) based on ultra-deep next-generation sequencing (NGS) to predict patient recurrence and survival. METHODS: Using the high-throughput NGS method tagged with a dual-indexed unique molecular identifier, named the CRLM-specific 25-gene panel (J25), this study sequenced ctDNA in peripheral blood samples collected from 134 CRLM patients who underwent hepatectomy after postoperative day 6. RESULTS: Of 134 samples, 42 (31.3%) were shown to be ctDNA-positive, and 37 resulted in recurrence. Kaplan-Meier survival analysis showed that disease-free survival (DFS) in the ctDNA-positive subgroup was significantly shorter than in the ctDNA-negative subgroup (hazard ratio [HR], 2.96; 95% confidence interval [CI], 1.91-4.6; p < 0.05). When the 42 ctDNA-positive samples were further divided by the median of the mean allele frequency (AF, 0.1034%), the subgroup with higher AFs showed a significantly shorter DFS than the subgroup with lower AFs (HR, 1.98; 95% CI, 1.02-3.85; p < 0.05). The ctDNA-positive patients who received adjuvant chemotherapy longer than 2 months showed a significantly longer DFS than those who received treatment for 2 months or less (HR, 0.377; 95% CI, 0.189-0.751; p < 0.05). Uni- and multivariable Cox regression indicated two factors independently correlated with prognosis: ctDNA positivity and no preoperative chemotherapy. CONCLUSION: The study demonstrated that ctDNA status 6 days postoperatively could sensitively and accurately predict recurrence for patients with CRLM using the J25 panel.

In-Depth Serum Proteomics Reveals the Trajectory of Hallmarks of Cancer in Hepatitis B Virus-Related Liver Diseases.

Hepatocellular carcinoma (HCC) is a prevalent cancer in China, with chronic hepatitis B (CHB) and liver cirrhosis (LC) being high-risk factors for developing HCC. Here, we determined the serum proteomes (762 proteins) of 125 healthy controls and Hepatitis B virus-infected CHB, LC, and HCC patients and constructed the first cancerous trajectory of liver diseases. The results not only reveal that the majority of altered biological processes were involved in the hallmarks of cancer (inflammation, metastasis, metabolism, vasculature, and coagulation) but also identify potential therapeutic targets in cancerous pathways (i.e., IL17 signaling pathway). Notably, the biomarker panels for detecting HCC in CHB and LC high-risk populations were further developed using machine learning in two cohorts comprised of 200 samples (discovery cohort = 125 and validation cohort = 75). The protein signatures significantly improved the area under the receiver operating characteristic curve of HCC (CHB discovery and validation cohort = 0.953 and 0.891, respectively; LC discovery and validation cohort = 0.966 and 0.818, respectively) compared to using the traditional biomarker, alpha-fetoprotein, alone. Finally, selected biomarkers were validated with parallel reaction monitoring mass spectrometry in an additional cohort (n = 120). Altogether, our results provide fundamental insights into the continuous changes of cancer biology processes in liver diseases and identify candidate protein targets for early detection and intervention.

Effect of vessels that encapsulate tumor clusters (VETC) on the prognosis of different stages of hepatocellular carcinoma after hepatectomy.

BACKGROUND: Vessels that encapsulate tumor clusters (VETC) is a newly discovered vascular pattern in hepatocellular carcinoma (HCC), representing high biological aggressiveness. However, it remains unclear whether the prognostic impact of VETC differs in patients with different staged HCC. This study aimed to evaluate the effect of VETC on the prognosis of patients with HCC at different stages after hepatectomy. METHODS: Patients who underwent hepatectomy for HCC between January 2005 and December 2019 were assessed, and stratified according to their Barcelona Clinic Liver Cancer (BCLC) stage. Overall survival (OS) and disease-free survival (DFS) were compared between patients with and without VETC. Independent risk factors of OS and DFS were determined by multivariable Cox regression analyses. RESULTS: A total of 837 consecutive patients undergoing curative hepatectomy were enrolled, and VETC pattern was found in 339 (40.5%) patients. The incidence of VETC in patients at BCLC-0, BCLC-A, BCLC-B and BCLC-C stage was 17.8%, 40.2%, 53.7% and 66.0%, respectively. In the entire patients, VETC+ patients had significantly lower OS and DFS than VETC- patients. After stratification of patients according to BCLC stage, VETC was associated with worse OS and DFS only in patients at BCLC-A and BCLC-B stages, but not in those at BCLC-0 and BCLC-C stages. Multivariable analyses also revealed that VETC was an independent risk factor for OS and DFS in both the patients at BCLC-A and BCLC-B stages. CONCLUSIONS: VETC is associated with poor OS and DFS in patients with HCC at BCLC-A and BCLC-B stage after hepatectomy, but it does not affect the survival of patients with HCC at BCLC-0 and BCLC-C stage after hepatectomy.

Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress.

BACKGROUND: Tumor cells display augmented capability to maintain endoplasmic reticulum (ER) homeostasis and hijack ER stress pathway for malignant phenotypes under microenvironmental stimuli. Metabolic reprogramming is a well-known hallmark for tumor cells to provide specific adaptive traits to the microenvironmental alterations. However, it's unknown how tumor cells orchestrate metabolic reprogramming and tumor progression in response to ER stress. Herein, we aimed to explore the pivotal roles of SEC63-mediated metabolic remodeling in hepatocellular carcinoma (HCC) cell metastasis after ER stress. METHODS: The expression levels of SEC63 in HCC tissues and adjacent non-cancerous tissues were determined by immunohistochemistry and western blot. The regulatory roles of SEC63 in HCC metastasis were investigated both in vitro and in vivo by RNA-sequencing, metabolites detection, immunofluorescence, and transwell migration/invasion analyses. GST pull-down, immunoprecipitation/mass spectrometry and in vivo ubiquitination/phosphorylation assay were conducted to elucidate the underlying molecular mechanisms. RESULTS: We identified SEC63 as a new regulator of HCC cell metabolism. Upon ER stress, the phosphorylation of SEC63 at T537 by IRE1α pathway contributed to SEC63 activation. Then, the stability of ACLY was upregulated by SEC63 to increase the supply of acetyl-CoA and lipid biosynthesis, which are beneficial for improving ER capacity. Meanwhile, SEC63 also entered into nucleus for increasing nuclear acetyl-CoA production to upregulate unfolded protein response targets to improve ER homeostasis. Importantly, SEC63 coordinated with ACLY to epigenetically modulate expression of Snail1 in the nucleus. Consequently, SEC63 promoted HCC cell metastasis and these effects were reversed by ACLY inhibition. Clinically, SEC63 expression was significantly upregulated in HCC tissue specimens and was positively correlated with ACLY expression. Importantly, high expression of SEC63 predicted unfavorable prognosis of HCC patients. CONCLUSIONS: Our findings revealed that SEC63-mediated metabolic reprogramming plays important roles in keeping ER homeostasis upon stimuli in HCC cells. Meanwhile, SEC63 coordinates with ACLY to upregulate the expression of Snail1, which further promotes HCC metastasis. Metastasis is crucial for helping cancer cells seek new settlements upon microenvironmental stimuli. Taken together, our findings highlight a cancer selective adaption to ER stress as well as reveal the potential roles of the IRE1α-SEC63-ACLY axis in HCC treatment.

Sintilimab plus Lenvatinib conversion therapy for intermediate/locally advanced hepatocellular carcinoma: A phase 2 study.

Introduction: Patients with intermediate or locally advanced hepatocellular carcinoma (HCC) who are not eligible for radical treatment typically have a poor overall prognosis. Treatment strategies that can convert unresectable HCC into resectable HCC may improve patient survival. We conducted a single arm phase 2 trial to evaluate the efficacy and safety of Sintilimab plus Lenvatinib as conversion therapy for HCC. Methods: A single-arm, single-center study conducted in China (NCT04042805). Adults (≥18 years) with Barcelona Clinic Liver Cancer (BCLC) Stage B or C HCC ineligible for radical surgery with no distant/lymph node metastasis received Sintilimab 200 mg IV on day 1 of a 21-day cycle plus Lenvatinib 12 mg (body weight ≥60 kg) or 8 mg (body weight <60 kg) orally once daily. Resectability was based on imaging and liver function. The primary endpoint was objective response rate (ORR), assessed using RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), event-free survival (EFS) in patients who underwent resection, surgical conversion rate, and safety. Results: Overall, 36 patients were treated between August 1, 2018, and November 25, 2021; the median age was 58 years (range, 30-79), and 86% were male. The ORR (RECIST v1.1) was 36.1% (95% CI, 20.4-51.8) and the DCR was 94.4% (95% CI, 86.9-99.9). Eleven patients underwent radical surgery and one received radiofrequency ablation and stereotactic body radiotherapy; after a median follow up of 15.9 months, all 12 were alive and four had recurrence, median EFS was not reached. Median PFS among 24 patients who did not undergo surgery was 14.3 months (95% CI, 6.3-26.5). Treatment was generally well tolerated; two patients had serious adverse events; there were no treatment-related deaths. Conclusions: Sintilimab plus Lenvatinib is safe and feasible for the conversion treatment of intermediate to locally advanced HCC initially unsuitable for surgical resection.

Five-year survival post hepatectomy for colorectal liver metastases in a real-world Chinese cohort: Recurrence patterns and prediction for potential cure.

BACKGROUND: Patients with a 5-year recurrence-free survival post liver resection for colorectal cancer liver metastases (CRLM) are considered to be potentially cured. However, there is a deficit of data on long-term follow-up and the recurrence status among these patients in the Chinese population. We analyzed real-world follow-up data of patients with CRLM who underwent hepatectomy, explored the recurrence patterns, and established a prediction model for a potential cure scenario. METHODS: Patients who underwent radical hepatic resection for CRLM during 2000-2016, with actual follow-up data for at least 5 years, were enrolled. The observed survival rate was calculated and compared among the groups with different recurrence patterns. The predictive factors for 5-year non-recurrence were determined using logistic regression analysis; a recurrence-free survival model was developed to predict long-term survival. RESULTS: A total of 433 patients were included, of whom 113 patients were found non-recurrence after 5 years follow-up, with a potential cure rate of 26.1%. Patients with late recurrence (>5 months) and lung relapse showed significantly superior survival. Repeated localized treatment significantly improved the long-term survival of patients with intrahepatic or extrahepatic recurrences. Multivariate analysis showed that RAS wild-type CRC, preoperative CEA <10 ng/ml, and liver metastases ≤3 were independent factors for a 5-year disease-free recurrence. A cure model was developed based on the above factors, achieving good performance in predicting long-term survival. CONCLUSIONS: About one quarter patients with CRLM could achieve potential cure with non-recurrence at 5-year after surgery. The recurrence-free cure model could well distinguish the long-term survival, which would aid clinicians in determining the treatment strategy.

Prediction of hepatic lymph node metastases based on magnetic resonance imaging before and after preoperative chemotherapy in patients with colorectal liver metastases underwent surgical resection.

BACKGROUND: Patients with colorectal liver metastases (CRLM) combined with hepatic lymph node (HLN) metastases have a poor prognosis. In this study, we developed and validated a model using clinical and magnetic resonance imaging (MRI) parameters to predict HLN status before surgery. METHODS: A total of 104 CRLM patients undergoing hepatic lymphonodectomy with pathologically confirmed HLN status after preoperative chemotherapy were enrolled in this study. The patients were further divided into a training group (n = 52) and a validation group (n = 52). The apparent diffusion coefficient (ADC) values, including ADCmean and ADCmin of the largest HLN before and after treatment, were measured. rADC was calculated referring to the target liver metastases, spleen, and psoas major muscle (rADC-LM, rADC-SP, rADC-m). In addition, ADC change rate (Δ% ADC) was quantitatively calculated. A multivariate logistic regression model for predicting HLN status in CRLM patients was constructed using the training group and further tested in the validation group. RESULTS: In the training cohort, post-ADCmean (P = 0.018) and the short diameter of the largest lymph node after treatment (P = 0.001) were independent predictors for metastatic HLN in CRLM patients. The model's AUC was 0.859 (95% CI, 0.757-0.961) and 0.767 (95% CI 0.634-0.900) in the training and validation cohorts, respectively. Patients with metastatic HLN showed significantly worse overall survival (p = 0.035) and recurrence-free survival (p = 0.015) than patients with negative HLN. CONCLUSIONS: The developed model using MRI parameters could accurately predict HLN metastases in CRLM patients and could be used to preoperatively assess the HLN status and facilitate surgical treatment decisions in patients with CRLM.

Contrast-Enhanced Ultrasound With SonoVue and Sonazoid for the Diagnosis of Colorectal Liver Metastasis After Chemotherapy.

PURPOSE: To compare the diagnostic efficacy of SonoVue and Sonazoid contrast-enhanced ultrasound (CEUS) in correctly detecting and characterizing colorectal liver metastasis (CRLM) after chemotherapy. MATERIALS AND METHODS: Patients with CRLMs treated with chemotherapy and subsequently scheduled for hepatic resection were prospectively enrolled from April 2020 to January 2021. Lesions detected by SonoVue or Sonazoid CEUS were recorded as and characterized as metastases or non-metastatic lesions respectively. Histopathology or intraoperative ultrasound with MRI were the reference standard. RESULTS: A total of 348 focal liver lesions in 42 patients were investigated, including 297 CRLMs and 51 non-metastatic lesions. SonoVue showed significantly higher diagnostic accuracy (64.7% versus 54.0%; P < .001) and sensitivity (63.3% versus 50.5%; P < .001) in the diagnosis of CRLMs than Sonazoid, both methods presented with similar specificity (72.5% versus 74.5%; P = 1.0). Forty metastases appeared non-hypoenhancing (hyperenhancing or isoenhancing) in the late phase and postvascular phase of Sonazoid CEUS and were mischaracterized as benign lesions. CONCLUSION: SonoVue performed significantly better than Sonazoid in the diagnosis of CRLMs after chemotherapy.

Impacts of primary tumor location on outcomes in patients undergoing hepatectomy for colorectal liver metastasis vary according to tumor burden.

Purpose: The purpose of this study was to verify whether the prognostic value of primary tumor location (PTL) for patients undergoing resection for colorectal liver metastasis (CRLM) is affected by tumor burden. Methods: Patients who underwent a first curative-intent surgery for CRLM from 2006 to 2017 were enrolled. The imaging tumor burden score (TBS) was calculated as TBS2 = (maximum tumor diameter in cm)2 + (number of lesions)2. Then, the prognostic role of PTL was assessed in different TBS zones. Results: The patient population consisted of 524 left-sided (LS) and 118 right-sided (RS) primary tumors. The distribution of TBS in the patient cohort was: Zone1: TBS <3 [n = 161 (25.1%)], zone 2: TBS ≥3 to <7 [n = 343 (53.4%)], and zone 3: TBS ≥7 [n = 138 (21.5%)]. In the whole cohort, the 5-year overall survival (OS) in the RS group was worse than that in the LS group (35.6% vs. 45.4%). However, after adjustment for known prognostic confounders, the RS group was not independently associated with a poorer OS (HR 1.18, p = 0.247). Among patients with TBS <7, OS in the RS group was significantly shorter than that in the LS group in both univariate and multivariate analyses. The prognostic role of PTL remained significant after propensity score matching or excluding patients who received anti-EGFR agents. Conversely, the association between PTL and OS was no longer evident in patients with TBS ≥7. Conclusion: The current study demonstrates that the prognostic value of PTL varies by TBS, and RS tumors are only associated with shorter survival in patients with low or medium TBS.