While thousands of AI prediction models are published annually, few are adopted into routine practice, partly because improved statistical performance does not necessarily translate into meaningful impact on clinical decision-making. We conducted a prospective randomized multi-reader multi-case study to evaluate how a machine learning-based prognostic tool influences clinician performance in colorectal liver metastases (CRLM). In a prospective, randomized multi-reader multi-case trial (NCT07027605; Registration Date: January 1, 2025), 12 surgical oncologists assessed 166 retrospective CRLM cases with and without tool assistance in a crossed design with a 5-week washout. The primary endpoint was the difference in AUC for predicting 3-year mortality. Between January and July 2025, 12 readers completed 3984 assessments. Model assistance significantly improved the AUC for 3-year mortality prediction (mean difference 0.091; 95% CI 0.001-0.181; P = 0.048) and consistently improved accuracy across secondary prognostic endpoints. It also reduced decision time (2.53 vs. 3.04 minutes) and increased reader confidence. Benefits were greatest for junior to mid-level surgical oncologists. This exploratory study demonstrates that a machine learning prognostic tool can significantly improve accuracy, efficiency, and confidence in CRLM evaluation.

Phenotypic screening has played an important role in discovering innovative small-molecule drugs and clinical candidates with unique molecular mechanisms of action. However, conducting cell-based high-throughput screening from vast compound libraries is extremely time-consuming and expensive. Fortunately, deep learning has provided a new paradigm for identifying compounds with specific phenotypic properties. Herein, we developed a data-driven classification-generation cascade model to discover new chemotype antitumor drugs. Through wet-lab validation, WJ0976 and WJ0909 were identified as tetrahydrocarbazole derivatives and displayed potent broad-spectrum antitumor activity as well as growth inhibitory properties against multidrug-resistant cancer cells. Furthermore, the R-(−)-WJ0909 (WJ0909B), demonstrated optimal antitumor efficacy in vitro and ex vivo patient-derived organoids (PDOs). Further investigations revealed that WJ0909B upregulates p53 expression and cause mitochondria-dependent endogenous apoptosis. Moreover, WJ0909B and the click-activated prodrug WJ0909B-TCO potently inhibited tumor growth in cell-derived xenograft models. This research highlights the significant potential of deep learning-guided approach to phenotypic drug discovery for anticancer drugs and the strategy of click-activated prodrug for targeted cancer therapy.

Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies.

Background:Early-onset colorectal cancer (EO-CRC), defined as being diagnosed before the age of 50 years, is becoming increasingly prevalent. Among these patients, synchronous early-onset colorectal liver metastases (EO-CRLM) have emerged as a leading cause of mortality. This study aims to investigate the epidemiology, clinicopathological characteristics, and survival outcomes related to synchronous EO-CRLM to provide a clearer understanding of the challenges faced by patients with synchronous EO-CRLM. Methods:The National Cancer Database was queried for patients with synchronous CRLM diagnosed from 2010 to 2019. Patients were then stratified by age of onset: EO-CRLM (younger than 50 years old) and late-onset colorectal liver metastases (LO-CRLM) (50 years old or older). The incidence, limited-duration prevalence rates (over a 10-year period), clinicopathological characteristics and overall survival (OS) were assessed. Results:Among 115,422 patients with CRLM, EO-CRLM and LO-CRLM were observed in 17,536 (15.2%) patients and in 97,886 (84.8%) patients, respectively. The annual age-adjusted incidence of EO-CRLM increased from 0.48 to 0.69 per 100,000 population from 2010 to 2019 [average annual percentage change (AAPC): 5.1, 95% confidence interval (CI): 4.1 to 6.1], significantly faster than that of LO-CRLM (AAPC difference: 3.5, 95% CI: 2.5 to 4.5; P<0.001). The 10-year limited-duration prevalence for EO-CRLM increased from 0.0004% in 2010 to 0.0020% in 2019 (AAPC: 15.7, 95% CI: 10.2 to 21.5). A comparison of the clinicopathological features revealed that, compared with LO-CRLM, EO-CRLM patients were more likely to reside in urban areas, have higher rates of high school completion, have higher income, and be covered by private insurance/managed care. Genetic analysis revealed EO-CRLM with microsatellite instability (MSI)-high had the largest increase of AAPC of 28.7 (95% CI: 13.1 to 46.3) compared to MSI-low and microsatellite stability (MSS) (P<0.001). Similarly, EO-CRLM patients had a rapid rise in Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations with AAPC of 10.6 (95% CI: 8.8 to 12.5). Compared with LO-CRLM, EO-CRLM was associated with improved OS in inverse probability of treatment weighting-adjusted Cox proportional hazards regression analysis (hazard ratio: 0.876, 95% CI: 0.838 to 0.915; P<0.001). Conclusions:The incidence of EO-CRLM has increased rapidly, and represents a distinct population in terms of socioeconomic and clinicopathological characteristics. Among this cohort, the prognosis of patients with EO-CRLM was favorable compared to that of patients with LO-CRLM.

This phase II clinical trial aimed to evaluate the efficacy and safety of neoadjuvant long-course chemoradiotherapy combined with sintilimab in mismatch repair-proficient (pMMR)/microsatellite-stable (MSS) locally advanced rectal cancer (LARC) patients with a PD-L1 tumor proportion score (TPS) ≥1% or combined positive score (CPS) ≥1. The primary endpoint was pathological complete response (pCR), and safety was assessed. This trial was registered on ClinicalTrials.gov (identifying number: NCT04833387) with the registration date of April 4, 2021. Although the target pCR rate was not fully achieved, a notable improvement was observed, with 7/20 (35.0%) patients achieving pCR in the intention-to-treat analysis. A trend toward higher pCR rates was observed in patients with PD-L1 CPS ≥ 5 than in those with CPS < 5 (50.0% vs. 27.3%, P = 0.311). Treatment-related adverse events occurred in 12 patients (60.0%), with no grade 4 events. Biomarker analysis revealed that higher CD3 (P < 0.001) and CD8 (P = 0.018) expression, along with lower TIM-3 (P = 0.017) expression in the stroma, was associated with higher pCR rates.

Colorectal cancer (CRC) diagnosis is challenging due to generalized symptoms. Various biomarker models exist, but their clinical application is limited by low sensitivity and heterogeneous cutoff values. This study aimed to develop and validate a diagnostic model for CRC. Data from 489 patients-337 with CRC and 152 with benign disease-were included. Patients were randomly assigned to training (n = 342) and validation (n = 147) cohorts. Logistic regression identified age (OR 1.06), CA153 (OR 0.26), CEA (OR 4.49), CYFRA 21-1 (OR 5.88), ferritin (OR 0.15), and hs-CRP (OR 0.05) as independent risk factors. Sensitivity and specificity were 88.61% and 82.86% in the training cohort and 90.00% and 76.60% in the validation cohort. Cutoff values for the biomarkers were: CA199, 9.809 U/mL; CA125, 7.743 U/mL; CA153, 6.295 U/mL; CEA, 3.982 ng/mL; CYFRA 21-1, 1.769 ng/mL; ferritin, 163.361 mg/L; hs-CRP, 0.196 mg/L; and serum albumin, 55.966 g/L. The model showed higher sensitivity for early-stage CRC (95.45%, 95% CI 87.2-98.6%) than late-stage CRC (87.27%, 95% CI 76.4-93.5%; P = 0.08). AUCs were 0.907 (training) and 0.872 (validation). The model demonstrated higher sensitivity for early-stage CRC (95.45%) than late-stage CRC (87.27%), underscoring its utility in early detection.

Stress granules (SGs), which are phase-separating organelles that serve as protective cellular mechanisms in response to various harmful stimuli, have an unclear role in oxaliplatin resistance. Here, we establish a causal link between SG formation and oxaliplatin resistance in GC. Notably, we identify a key SG nucleator, namely, ubiquitin-associated protein 2-like (UBAP2L), as a previously unrecognized critical factor in mediating oxaliplatin resistance. UBAP2L-nucleated SG-mediated inhibition of apoptosis is associated with the recruitment of receptor of activated protein C kinase 1 (RACK1), a known promoter of apoptosis, to these entities. Transcriptional upregulation of UBAP2L is enhanced by oxaliplatin-induced phosphorylation and activation of heat shock factor protein 1 (HSF1) via AKT. Inhibiting either SG or HSF1 significantly overcomes oxaliplatin resistance in vivo. These findings demonstrate that UBAP2L-nucleated SGs play a vital role in mediating oxaliplatin resistance, with elevated SG levels emerging as a promising therapeutic target for overcoming this resistance.

This phase II clinical trial aimed to evaluate the efficacy and safety of neoadjuvant long-course chemoradiotherapy combined with sintilimab in mismatch repair-proficient (pMMR)/microsatellite-stable (MSS) locally advanced rectal cancer (LARC) patients with a PD-L1 tumor proportion score (TPS) ≥1

Importance:Current prognostic models for colorectal liver metastases (CRLM) primarily incorporate clinicopathologic features assessed at a single time point, resulting in a static risk assessment for individuals. Given that tumor progression is a dynamic process, especially for patients with CRLM, and patients' data are continuously collected during the follow-up visits, dynamic prediction is a natural model for risk assessments via reflecting the latest prognosis, whenever new marker measurements are available. Objective:To develop CRLM prognostic models and a clinical web-based tool to facilitate dynamic predictions. Design, Setting, and Participants:In this retrospective prognostic study, patients with CRLM who underwent resection between January 2014 and January 2021, were included in the training and validation cohorts. Clinicopathologic characteristics and preoperative and postoperative laboratory measurements taken within 12 months after surgery across 9 laboratory markers (carcinoembryonic antigen, carbohydrate antigen 19-9, γ-glutamyl transferase, red blood cell distribution width SD and coefficient of variance, aspartate aminotransferase to platelet ratio index, Fibrous-4 index, S-index, and neutrophil-to-lymphocyte ratio) were collected. Three prediction models for progression-free survival (PFS) and overall survival (OS) based on a functional random survival forest framework were constructed and compared: model A incorporated only clinicopathologic characteristics, model B included clinicopathologic characteristics and preoperative laboratory markers, and model C integrated clinicopathologic characteristics along with longitudinal laboratory markers. Data were analyzed from June 2024 to June 2025. Exposure:Resection in patients with CRLM. Main Outcomes and Measures:Performance metrics included area under the receiver operating characteristic curve (AUC) and Brier score (BS). Results:A total of 976 patients (median [IQR] age, 59 [51-65] years; 612 [62.7%] male) were eligible for this study, with 758 patients in the training cohort (median [IQR] age, 59 [52-66] years; 487 [64.2%] male) and 218 patients in the validation cohort (median [IQR] age, 58 [49-64] years; 125 [57.3%] male).The training cohort included a total of 24 992 longitudinal measurements, and the external validation cohort included 7198 longitudinal measurements. In the external validation cohort, model C demonstrated an improved prognostic capability compared with models A and B, with AUC values of 0.796 (95% CI, 0.740-0.848) for 1-year progression-free survival (PFS), 0.837 (95% CI, 0.768-0.899) for 3-year PFS, and 0.850 (95% CI, 0.780-0.914) for 5-year PFS. The corresponding BSs were 0.246 (95% CI, 0.236-0.261) for 1 year, 0.205 (95% CI, 0.193-0.218) for 3 years, and 0.142 (95% CI, 0.132-0.153) for 5 years. Model C consistently outperformed models A and B for overall survival (OS) prognosis, with AUCs of 0.849 (95% CI, 0.768-0.914) for 1 year, 0.741 (95% CI, 0.667-0.815) for 3 years, and 0.753 (95% CI: 0.656-0.849) for 5 years, alongside BS values of 0.047 (95% CI, 0.045-0.048) for 1 year, 0.178 (95% CI, 0.168-0.195) for 3 years, and 0.144 (95% CI, 0.133-0.165) for 5 years. Additionally, dynamic individualized risk profiles for PFS and OS were developed for patients. A web-based tool was created to facilitate the practical application of these dynamic prediction models for new patients in clinical environments. Conclusions and Relevance:In this retrospective prognostic study, the dynamic models, along with the web-based tool for personalized prediction, demonstrated improved performance by incorporating multiple longitudinal makers.

Colorectal neuroendocrine tumors with liver metastases (CRNELM) are associated with a poorer prognosis compared to their nonmetastatic counterparts. A comprehensive understanding of the tumor microenvironment (TME) heterogeneity between primary lesions (PL) and liver metastases (LM) could provide crucial insights for enhancing clinical management strategies for these patients. We utilized single-cell RNA sequencing to analyze fresh tissue samples from CRNELM patients, aiming to elucidate the variations in TME between PL and LM. Complementary multidimensional validation was achieved through spatial transcriptomics, bulk RNA sequencing, and multiplex immunohistochemistry/immunofluorescence. Our single-cell RNA sequencing analysis revealed that LM harboured a higher proportion of CD8 + T cells, CD4 + T cells, NK cells, NKT cells, and B cells exhibiting a stress-like phenotype compared to PL. RGS5 + pericytes may play a role in the stress-like phenotype observed in immune cells within LM. MCs in PL (PL_MCs) and LM (LM_MCs) exhibit distinct activation of tumor-associated signaling pathways. Notably, COLEC11 + matrix cancer-associated fibroblasts (COLEC11_mCAFs) were found to be significantly associated with LM_MCs. Cell communication analysis unveiled potential targetable receptor-ligand interactions between COLEC11_mCAFs and LM_MCs. Multidimensional validation confirmed the prominence of the characteristic stress-like phenotypes, including HSPA6_CD8_Tstr, HSPA6_NK, and COLEC11_mCAFs in LM. Moreover, a higher abundance of COLEC11_mCAFs correlated with poorer survival rates in the neuroendocrine tumor patient cohort. Overall, our study provides the first single-cell analysis of the cellular and molecular differences between PL and LM in CRNELM patients. We identified distinct cell subsets and receptor-ligand interactions that may drive TME discrepancies and support metastatic tumor growth. These insights highlight potential therapeutic targets and inform strategies for better managing CRNELM patients.

BACKGROUND:Patients with synchronous colorectal cancer liver metastasis (CRLM) often face sub-optimal outcomes from systemic therapy or resection. This study investigates the prognostic value of the pre-treatment S-index, a reliable non-invasive marker for liver fibrosis, for outcomes in synchronous CRLM patients. METHODS:This study included two populations of patients with synchronous CRLM: one population undergoing resection and another population receiving systemic therapy for unresectable CRLM. Pre-treatment S-index levels were assessed from blood samples. Patients were categorized into high and low S-index groups, and comparisons were made regarding outcomes: progression-free survival (PFS), early post-operative recurrence and fibrosis in liver metastases in the resection population, and treatment response in the systemic therapy population. Multiplex immunohistochemistry/immunofluorescence (mIHC/IF) was used to investigate the distribution of immunosuppressive T-cell subsets in liver metastases. RESULTS:For synchronous CRLM patients receiving resection (n = 1000), patients with high preoperative S-index demonstrated significantly worse PFS both before (HR = 1.556, 95 % CI: 1.255-1.929; P < 0.001) and after IPTW-adjusted Cox proportional hazards regression analysis (IPTW-adjusted HR = 1.439, 95 % CI: 1.094-1.894; P = 0.036). High S-index patients also exhibited an elevated risk of early recurrence, both before and after adjustment (OR = 1.556, 95 % CI: 1.255-1.929, P < 0.001; IPTW-adjusted OR = 1.439, 95 % CI: 1.094-1.894, P = 0.009). For synchronous CRLM patients receiving system therapy (n = 123), a high pre-treatment S-index (OR = 34.691, P = 0.005) was a significant predictor of progression disease in multivariate analyses. Further, the S-index showed an AUC of 0.814 (95 %CI: 0.762-0.866, P < 0.001) for detecting fibrosis in liver metastases, with a specificity of 0.928. mIHC/IF analysis revealed that inhibitory T cells, especially CD4+PD1+ T cells and CD4+FOXP3+ T cells, were significantly elevated in the liver metastases of the high S-index group. CONCLUSION:This study contributed valuable evidence regarding pre-treatment S-index for association with outcomes among synchronous CRLM patients receiving resection or system therapy. Furthermore, it underscores a significant association between a high S-index and the presence of fibrosis in liver metastases, as well as more infiltration of immunosuppressive T cells in the tumor.

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.

OBJECTIVE:Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further. DESIGN:Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice. RESULTS:These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (TERT), 6q, 8p, 16q, 9p (CDKN2A/B), 17p (TP53) and 13q (RB1), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials. CONCLUSION:HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.

BACKGROUND:Early-onset colorectal cancer with synchronous liver metastasis (EO-CRLM) is a growing concern with a grim prognosis. METHODS:EO-CRLM patients were identified from the National Cancer Database. Random survival forest model and random forest (RF) model were developed for the prediction of overall survival (OS) and 6-month mortality, respectively. RESULTS:The variables with top contributions for random survival forest model of OS included primary tumor resection, chemotherapy and bone metastases. The AUCs of 1-, 3- and 5-year OS were 0.787, 0.763 and 0.761, respectively. The individualized risk profile predicted by the models closely aligned with the actual survival outcomes observed for the patients. The variables with top contributions for RF model for 6-month mortality included chemotherapy, Charlson-Deyo comorbidity score and presence of tumor deposits. RF model for 6-month mortality resulted in an AUC of 0.821 in training set, 0.828 in cross-validation and 0.852 in testing cohort. RF models for OS and 6-month mortality exhibited great net benefit with favorable clinical utility. CONCLUSION:The models generated in this study accurately identified EO-CRLM patients at risk of worse OS and short-term mortality, which may complement standard clinical assessment and aid in creation of advanced care planning.

BackgroundTo 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.MethodsRandom 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).ResultsThere 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.ConclusionThe 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.

BACKGROUND:Despite recommendations for primary tumor resection (PTR) with or without liver resection (LR) in the patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and isolated liver metastases, there are conflicting data for their impact on overall survival (OS). METHODS:2320 patients with GEP-NETs and isolated liver metastases were identified from NCDB. Multiple imputations were used to accommodate missing data, and inverse probability of treatment weighting (IPTW) was conducted to minimize bias. RESULTS:Patients with PTR had a greater OS than those without PTR (3-year rate of 88.6% vs. 69.9%, P < 0.001), which was preserved in the adjusted analysis (IPTW-adjusted HR = 0.387, 95% CI: 0.264-0.567; P < 0.001). Patients with LR had a greater OS than those without LR (3-year rate 87.7% vs. 75.2%, P = 0.003), which was also preserved in adjusted analysis (IPTW-adjusted HR = 0.450, 95% CI: 0.229-0.885; P = 0.021). Patients undergoing both PTR and LR had the greatest survival advantage than those with other surgical interventions (P < 0.001). CONCLUSIONS:Either PTR or LR is associated with improved survival for GEP-NET patients with isolated liver metastases. However, there remains significant selection bias in the current study, and caution should be exercised when selecting patients for resection.

Aims Selective lateral pelvic lymph node (LPN) dissection (LPND) following neoadjuvant chemoradiotherapy (nCRT) for rectal cancer is widely recognized. This study aimed to determine the effects of nCRT before LPND on local control and prognosis of rectal cancer patients. Materials and methods Data were retrieved from a prospective database for rectal cancer patients with clinical LPN metastasis receiving total mesorectal excision and LPND at three institutions between January 2012 and December 2019. Selection bias was minimized using propensity score matching (PSM) and short-term and clinical outcomes were compared. Results Patients ( n = 213) were enrolled and grouped as either nCRT ( n = 97) or non-nCRT ( n = 116). PSM was used to identify 83 matched pairs. In the matched cohort, nCRT patients had a longer operation duration (310.6 vs. 265.0 min, P = 0.001), lower pathological LPN metastasis rate (32.5% vs. 48.2%, P = 0.040), and fewer harvested lymph nodes (22 vs. 25, P = 0.018) compared to the non-nCRT group. However, after PSM, the two groups had similar estimated overall 3-year survival (79.5% vs. 80.7%, P = 0.922), 3-year disease-free survival (66.1% vs. 65.5, P = 0.820), and 3-year local recurrence-free survival (88.6% vs. 89.7%, P = 0.927). Distant metastasis was the predominant recurrence pattern in the overall (45/58, 77.6%) and matched (33/44, 75.0%) cohorts. Conclusions LPND without nCRT is effective and sufficient in preventing local recurrence in patients with LPN metastases. Future prospective randomized controlled studies are warranted to confirm these findings. Since systemic metastasis is the predominant recurrence pattern in patients with LPN metastasis post-LPND, improved perioperative systemic chemotherapy is needed to prevent micrometastasis.

Liver metastasis remains the primary cause of mortality in patients with colon cancer. Identifying specific driver gene mutations that contribute to metastasis may offer viable therapeutic targets. To explore clonal evolution and genetic heterogeneity within the metastasis, we conducted single-cell exome sequencing on 150 single cells isolated from the primary tumor, liver metastasis, and lymphatic metastasis from a stage IV colon cancer patient. The genetic landscape of the tumor samples revealed that both lymphatic and liver metastases originated from the same region of the primary tumor. Notably, the liver metastasis was derived directly from the primary tumor, bypassing the lymph nodes. Comparative analysis of the sequencing data for individual cell pairs within different tumors demonstrated that the genetic heterogeneity of both liver and lymphatic metastases was also greater than that of the primary tumor. This finding indicates that liver and lymphatic metastases arose from clusters of circulating tumor cell (CTC) of a polyclonal origin, rather than from a single cell from the primary tumor. Single-cell transcriptome analysis suggested that higher EMT score and CNV scores were associated with more polyclonal metastasis. Additionally, a mutation in the TRPS1 (Transcriptional repressor GATA binding 1) gene, TRPS1 R544Q, was enriched in the single cells from the liver metastasis. The mutation significantly increased CRC invasion and migration both in vitro and in vivo through the TRPS1R544Q/ZEB1 axis. Further TRPS1 mutations were detected in additional colon cancer cases, correlating with advanced-stage disease and inferior prognosis. These results reveal polyclonal seeding and TRPS1 mutation as potential mechanisms driving the development of liver metastases in colon cancer.

Background: The aim of the study was to investigate the incidence and spectrum of adverse events in unresectable hepatocellular carcinoma (HCC) patients treated with immune checkpoint inhibitors (ICIs) or ICI-based combinations. Summary: The study protocol was prospectively registered on PROSPERO (CRD42022319255). We searched PubMed, EMBASE, and the Cochrane Library for published clinical trials from database inception to April 22, 2022. Studies that included at least one group of unresectable HCC patients treated with ICIs or ICI-based combinations and reported the incidence or spectrum of treatment-related adverse events (trAEs) or immune-related adverse events (irAEs) were eligible. The incidence and spectra of all-grade and grade ≥3 trAEs were the primary outcomes. The profiles of irAEs, the incidence of trAEs leading to treatment discontinuation, and treatment-related mortalities were additional outcomes. We applied random-effects models to pool the incidence and spectra of adverse events. Subgroup analyses and meta-regression were performed. The literature search identified 2,464 records. Twenty studies (4,146 participants with HCC) met the eligibility criteria. The pooled incidences of all-grade trAEs, grade ≥3 trAEs, all-grade irAEs, and grade ≥3 irAEs were 80.1% (95% CI: 73.8–85.2), 35.4% (95% CI: 27.2–44.6), 31.1% (95% CI: 21.0–43.5), and 6.6% (95% CI: 3.6–11.8), respectively. ICIs plus oral targeted agents (all-grade OR = 17.07, 95% CI: 6.05–48.16, p < 0.001; grade ≥3 OR = 9.35, 95% CI: 4.53–19.29, p < 0.001) and ICIs plus intravenous targeted agents (all-grade OR = 4.91, 95% CI: 1.80–13.42, p = 0.003; grade ≥3 OR = 4.21, 95% CI: 1.42–12.48, p = 0.012) were associated with increased trAEs compared with monotherapy. The all-grade trAEs with the highest pooled incidences were reactive capillary endothelial proliferation (49.2%, 95% CI: 26.3–72.3), neutropenia (34.6%, 95% CI: 17.1–57.5), and proteinuria (32.8%, 95% CI: 19.8–49.2). The grade ≥3 trAEs with the highest pooled incidences were hypertension (11.1%, 95% CI: 4.0–29.0), neutropenia (10.5%, 95% CI: 7.0–15.4), and increased aspartate aminotransferase (7.7%, 95% CI: 6.3–9.4). The pooled incidence of trAEs leading to treatment discontinuation was 8.0% (95% CI: 6.0–10.5), and the overall incidence of treatment-related mortalities was 1.1%. Key Messages: This study comprehensively summarized the incidence and spectrum of trAEs in unresectable HCC patients receiving ICIs or ICI-based combinations in clinical trials. The results from this study will provide a useful reference to guide clinical practice.

Objective:G1 and G2 colorectal neuroendocrine neoplasms (NENs) are a group of rare and indolent diseases. We aimed to delineate their genetic characteristics and explore their metastatic mechanisms.Methods:We used next-generation sequencing technology for targeted sequencing for 54 patients with G1 and G2 colorectal NENs. We delineated their genetic features and compared the genetic characteristics between metastatic NENs and nonmetastatic NENs. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was utilized to explore their abnormal pathways and study their potential metastatic mechanisms.Results:We collected 23 metastatic NENs and 31 nonmetastatic NENs. In the whole cohort, the common mutated genes were NCOR2, BRD4, MDC1, ARID1A, AXIN2, etc. The common copy number variations (CNVs) included amplification of HIST1H3D, amplification of HIST1H3E, and loss of PTEN. The KEGG enrichment analysis revealed that PI3K-Akt, MAPK, and Rap1 were the major abnormal pathways. There were significantly different genetic features between metastatic NENs and nonmetastatic NENs. The metastatic NENs shared only 47 (22.5%) mutated genes and 6 (13.3%) CNVs with nonmetastatic NENs. NCOR2, BRD4, CDKN1B, CYP3A5, and EIF1AX were the commonly mutated genes in metastatic NENs, while NCOR2, MDC1, AXIN2, PIK3C2G, and PTPRT were the commonly mutated genes in nonmetastatic NENs. Metastatic NENs presented a significantly higher proportion of abnormal pathways of cell senescence (56.5% vs 25.8%, P = .022) and lysine degradation (43.5% vs 16.1%, P = .027) than nonmetastatic NENs.Conclusion:G1 and G2 colorectal NENs are a group of heterogeneous diseases that might obtain an increased invasive ability through aberrant cell senescence and lysine degradation pathways.