Distinguishing characteristics have been found in the left-sided and right-sided colorectal cancer (CRC), which have different embryonic origins, molecular and clinical features. These result in differences in the efficacy of targeted therapy and immunotherapy. Multi-omics characterization, predicated upon tumor laterality, may facilitate a more precise and personalized approach to the treatment of patients with CRC. Encompassing whole-exome, proteomics, and phosphoproteomics sequencing, we conducted a comprehensive investigation of tumor and matched normal adjacent tissues from a total of 80 pairs of patients with CRC. Results revealed that the pathogenesis of left-sided CRC was predominantly associated with chromosomal instability, while right-sided CRC was primarily linked to microsatellite instability. Regarding the tumor microenvironment, left-sided CRC exhibited predominant microvascular endothelial cell proliferation, while right-sided CRC displayed enhanced MHC Class II-associated antigen presentation mediated by M1 macrophages. Additionally, the proportion of deficient mismatch repair that developed into microsatellite instability-high was observed to be lower in the left-sided CRC compared to the right-sided, indicating divergent DNA damage repair systems between laterality subtypes that contribute to differential immunotherapy efficacy. This integrated proteogenomic study provides a comprehensive and nuanced understanding of the molecular heterogeneity between left- and right-sided CRC, offering opportunities for optimizing these patients' treatment outcomes through tailored therapeutic strategies.

e16309 Background: Neuroendocrine Tumor Liver Metastases (NETLM) represent the most critical prognostic factor in patients with disseminated neuroendocrine tumors, frequently leading to significant morbidity and mortality. For patients with unresectable NETLM, locoregional therapies targeting the liver are essential for disease management and symptom palliation. Transarterial embolization (TAE) and transarterial chemoembolization (TACE) are established locoregional therapies for unresectable neuroendocrine tumor liver metastases (NETLM). The potential survival benefit of adding hepatic arterial infusion chemotherapy (HAIC) to these therapies remains unclear. This study aimed to compare the efficacy and safety of TAE/TACE alone versus TAE/TACE combined with HAIC (TAE/TACE+HAIC) in patients with unresectable NETLM. Methods: A retrospective analysis was conducted on 101 patients with unresectable NETLM treated at Peking University Cancer Hospital between February 2012 and November 2024. Of these, 67 patients received TAE/TACE alone and 34 patients received TAE/TACE+HAIC. Propensity score matching (PSM) was employed to minimize selection bias. The primary endpoint was progression-free survival (PFS) and secondary endpoints included hepatic progression-free survival (hPFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: PSM resulted in 21 patient pairs with comparable baseline characteristics between TAE/TACE and TAE/TACE+HAIC cohorts. Among these patients, 5 were classified as G1, 33 as G2, and 4 as G3. TAE/TACE matched cohort exhibited a higher median OS compared with the TAE/TACE+HAIC cohort(71.3 months vs. 34.2 months; P = 0.01), while hPFS (15.8 months vs. 14.9 months; P = 0.7) and PFS (11.7 months vs. 11.2 months; P = 0.9) were similar. ORR and DCR did not differ significantly (ORR: 42.9% vs. 57.1%, P = 0.54; DCR: 100% vs. 95.2%, P = 1.0). The patients underwent a total of 233 treatments. No treatment-related deaths occurred and serious adverse events were comparable, except for higher rates of elevated transaminases (14.5% vs. 4.5%; P = 0.02) and hyperbilirubinemia (5.3% vs. 0%; P = 0.01) in the combined group. Conclusions: TAE/TACE alone was associated with superior survival outcomes and a more favorable safety profile in patients with unresectable NETLM. These findings suggest that TAE/TACE alone may be a more effective and safer treatment approach for this patient population. The combination therapy should be approached with caution due to unimproved survival outcomes and increased liver-related toxicities.

We present a real-time denoising method for laser speckle contrast imaging (LSCI) that combines a logarithmic homomorphic transform with wavelet decomposition and adaptive thresholding. Experimental results on flow phantoms demonstrate improved linearity between the blood-flow index (BFI) and true velocity, while in vivo data show superior performance in enhancing image quality (higher Peak Signal-to-Noise Ratio/Mean Structural Similarity Index) and stabilizing BFI estimates, as well as reduced noise fluctuations compared to temporal-contrast, non-local means, Block-Matching and 3D Filtering, and variational mode decomposition. The method effectively suppresses high-frequency noise while preserving microvascular details, achieving higher PSNR/MSSIM and lower Root Mean Square Error. It processes a 4 K frame in 50 milliseconds with GPU acceleration, meeting real-time requirements. With fixed hyperparameters and adaptive thresholding, the method avoids the need for scene-specific tuning, offering robustness across varying noise levels and imaging conditions, making it a promising candidate for clinical LSCI applications.

Hepatocellular carcinoma remains a leading cause of cancer mortality worldwide, with peritumoral microenvironment interactions playing a critical role in disease progression. This multi-omics study employed artificial intelligence-pathology, single-nucleus multi-omics, spatial transcriptomics, and metabolomics to characterize peritumoral ductular reactions. Ductular reaction scores strongly predicted poor clinical outcomes and correlated with cirrhosis severity. We identified three functionally distinct cholangiocyte subpopulations, with Small_duct_type_Cho exhibiting robust fibroblast interactions that promote stromal remodeling. Metabolomic profiling revealed tumor margin enrichment of cholic acid, which induced CD8+ T cell dysfunction via NR1H4-dependent PD1 upregulation. Importantly, NR1H4 inhibition synergized with anti-PD1 therapy in murine models, significantly suppressing tumor growth. These results position ductular reactions as both a prognostic biomarker and therapeutic target, with cholic acid/NR1H4 pathway inhibition representing a promising immunotherapeutic strategy for hepatocellular carcinoma patients.

The histological heterogeneity of primary tumors across the pan-cancer spectrum poses a formidable barrier to accurate lymph node metastasis assessment, often causing AI systems to make “overconfident errors” on rare variants that lead to missed diagnoses. To address this, we present UPATHLN, a unified diagnostic platform that synergizes a pathology foundation model-based encoder with a decoupled uncertainty estimation mechanism. We developed and validated the system using a large-scale multicentre dataset of 26,229 lymph nodes from 14 distinct primary origins. In internal validation, UPATHLN achieved an area under the curve (AUC) of 0.986. Crucially, the uncertainty module functioned as a decisive fail-safe: by flagging potential false-negative predictions for mandatory pathologist review, it intercepted all missed diagnoses, securing 100% conditional sensitivity across both the development and independent test cohorts—even for tumors from seven unseen primary origins. Concurrently, this mechanism reduced the review burden on negative lymph nodes by 73.2%. Ultimately, UPATHLN sets a new benchmark for safety-critical AI, demonstrating that explicitly modeling uncertainty is key to unlocking reliable, workload-efficient diagnostics at the pan-cancer scale.

Annotated pathology datasets are the cornerstone for developing computational pathology. However, the intrinsic complexity of pathology data often results in a scarcity of large, manually annotated datasets. To address this challenge, a rapid, accurate, and automatic method for annotating tumor cells is essential for advancing the field of computational pathology. Here, we introduce a novel annotation technology. In our approach, Hematoxylin-eosin (H&E) slides were first digitized and preserved. These H&E slides were then faded and re-stained using multiple biological technologies (MBT) to identify specific biomarkers. The re-stained MBT slides were subsequently scanned again to create new digital images. The original and re-stained digital images underwent a registration and segmentation process to ensure that all minute structures in both images aligned perfectly. The staining results from the MBT slides, referred to as2 label maps, were extracted and transferred back onto the H&E slides, and the data were merged. This method allows for precise and efficient annotation of all tumor cells, including those expressing specific biomarkers, as well as the components of the tumor microenvironment. By rapidly generating high-quality, high-volume datasets, this innovative method significantly enhances the ability of AI approaches to analyze and interpret pathology data. Consequently, it supports the development of highly accurate diagnostic, prognostic, and predictive decision-making systems in the field of computational pathology.

e16308 Background: Neuroendocrine carcinoma (NEC) is an aggressive malignancy characterized by rapid progression and high metastatic potential, leading to a dismal median overall survival (OS) of only 11–12 months in patients with metastatic disease. Platinum-based chemotherapy with etoposide plus cisplatin or carboplatin remains the standard first-line treatment; however, its clinical benefit is modest, with an objective response rate (ORR) of approximately 31% and a median progression-free survival (PFS) of merely 4 months, and no established second-line therapy is currently available, underscoring a substantial unmet clinical need. Although intra-arterial liver-directed therapies (IALT) are routinely used to treat liver metastases from well-differentiated neuroendocrine tumors, their efficacy and safety in poorly differentiated and highly proliferative neuroendocrine carcinoma liver metastases (NECLM) remain largely undefined. This study aimed to evaluate the clinical outcomes and safety of IALT in patients with NECLM. Methods: 30 patients with pathologically confirmed NECLM who underwent IALT at Peking University Cancer Hospital from February 2012 to November 2024 were retrospectively analyzed. Treatment modalities included transarterial chemoembolization (TACE) alone (n = 5), transarterial embolization (TAE) alone (n = 2), hepatic arterial infusion chemotherapy (HAIC) alone (n = 1), TACE combined with HAIC (n = 20) and TAE combined with HAIC (n = 2). The primary endpoint was PFS while secondary endpoints included hepatic PFS (hPFS), OS, ORR, disease control rate (DCR) and safety. Results: The study cohort exhibited a substantial disease burden, with 83.3% of patients presenting with synchronous liver metastases and 76.7% with extrahepatic disease; moreover, 86.7% had received prior systemic therapy. The intervention achieved an ORR of 36.7% and a DCR of 70.0%. Median OS was 8.35 months, while median hPFS and PFS were 5.1 months and 4.5 months, respectively. No treatment-related deaths occurred. Grade ≥3 adverse events were generally manageable and most commonly consisted of transaminase elevation (18.9%), abdominal pain (17.0%) and hyperbilirubinemia (7.5%). Conclusions: IALT demonstrated acceptable safety and modest efficacy in the high-risk NECLM patients with aggressive disease and limited therapeutic options. These results indicate that IALT may serve as a feasible locoregional treatment strategy for NECLM, warranting further investigation to refine patient selection and optimize treatment approaches.

3139 Background: The detection of minimal residual disease (MRD) in colorectal cancer (CRC) is crucial for predicting postoperative recurrence, particularly liver metastasis. While peripheral blood (PB) liquid biopsy is widely used, portal vein blood (PVB) may offer higher sensitivity due to direct drainage of the hepatic circulation. Methods: We prospectively enrolled 297 CRC patients undergoing curative surgery. Intraoperative portal vein blood (PVB) and matched preoperative peripheral blood (PB) samples were collected simultaneously. Cell-free DNA was sequenced using a targeted 689-gene panel (1.5 Mb). Variants were filtered to retain only those with increased allele frequency (AF) in PVB relative to PB or exclusive detection in PVB (AF ≥1%), followed by stringent germline and noise removal. Binary mutation matrices were constructed for both blood sources. Machine learning (random forest, SVM, logistic regression, gradient boosting) was used to identify predictive gene signatures separately for PVB and PB. Model performance was compared using five-fold cross-validation. Results: PVB-derived ctDNA detected a significantly higher number of tumor-specific mutations compared to PB (mean 3.2 vs. 1.4 mutations per patient, p<0.001). PVB contained significantly higher ctDNA concentration (median 8.4 ng/mL vs 2.1 ng/mL in PB, p<0.001). A 20-gene panel selected from PVB data demonstrated superior predictive accuracy for liver metastasis compared to PB-derived markers. When validated in the same cohort, the PVB panel achieved an AUC of 0.849 (95% CI: 0.802–0.891) versus 0.714 (95% CI: 0.653–0.771) for PB-based prediction (p=0.003). Sensitivity for predicting liver metastasis was 70.0% for PVB versus 48.5% for PB. The PVB panel identified 26.6% of mutation carriers as high-risk, with 100% specificity (no recurrence in mutation-negative patients). In contrast, the PB model failed to achieve comparable risk stratification, with lower positive predictive value and higher false-negative rates. Conclusions: Portal vein blood ctDNA analysis is significantly more sensitive and accurate than peripheral blood in predicting postoperative liver metastasis in CRC. PVB-based liquid biopsy provides superior risk stratification, which could better inform adjuvant therapy decisions—identifying high-risk patients for intensified surveillance or treatment, while reducing overtreatment in low-risk patients. These findings support the clinical integration of PVB sampling for MRD detection in CRC surgical practice.

BACKGROUND:While partial splenic artery embolization (PSE) has been effectively employed in treating portal hypertension, cirrhosis, and idiopathic thrombocytopenia, its combination with hepatic artery infusion chemotherapy (HAIC) for the management of chemotherapy-induced hypersplenism (CIH) has not been previously explored. This retrospective study aims to provide clinical insights into this potential therapeutic approach. MATERIALS AND METHODS:We conducted a retrospective analysis involving patients with colorectal cancer liver metastases (CRLM) who received PSE in conjunction with HAIC (utilizing the FOLFOX regimen) to manage thrombocytopenia due to hypersplenism. Tumor response assessment followed the response evaluation criteria in solid tumors, while adverse reactions were categorized using the Common Terminology Criteria for Adverse Events (version 5.0). The primary objective was to attain a platelet (PLT) count of 100 × 10 9 /L, with secondary objectives encompassing evaluation of adverse events related to the combined therapy and its efficacy against liver metastases. RESULTS:From January 2018 to May 2023, 20 patients with CRLM and CIH were consecutively enrolled in this investigation, each undergoing PSE and HAIC. In total, PSE was performed 25 times. Median pre- and post-PSE PLT counts were 51 × 10 9 /L and 116 × 10 9 /L, respectively, with 80% of participants reaching the primary endpoint of a PLT count of ≥100 × 10 9 /L. Abdominal pain emerged as the most frequent postoperative complication, affecting 11 patients (44%). The objective response rate stood at 25%, while the disease-control rate was reported at 80%. The median progression-free survival was measured at 3.9 months, with a median overall survival of 13.8 months. CONCLUSION:The combination of PSE and HAIC (FOLFOX regimen) represents a safe and effective strategy for managing CIH and CRLM, demonstrating favorable outcomes in PLT count restoration and disease control.

4132 Background: Patients with advanced hepatocellular carcinoma (HCC) characterized by high tumor burden (beyond up-to-seven criteria) and portal vein tumor thrombus (PVTT) have a median overall survival (OS) of lower than 4 months without intervention. Global guidelines rely on Phase III trials that often under-represented this high-risk subgroup, creating a therapeutic gap. While systemic combinations are standard, they may lack the rapid cytoreductive potency required to prevent liver failure in this subgroup. We emulated a target trial to evaluate if adding hepatic arterial infusion chemotherapy (HAIC) to lenvatinib and PD-1 inhibitors (H+L+P) improves outcomes compared to lenvatinib and PD-1 inhibitors (L+P) alone. Methods: Using multicenter data from 22 centers in the Chinese Liver Cancer Clinical Study Alliance (CHANCE) registry, we compared first-line H+L+P (n = 127) vs. L+P (n = 117) in patients with advanced HCC (BCLC stage C without extrahepatic spread) and PVTT (Vp1-4). To minimize selection and immortal time biases, we employed stabilized inverse probability of treatment weighting (sIPTW) and a cloning-censoring-weighting framework. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), site-specific PFS, objective response rate (ORR), and safety. Results: Baseline covariates were well-balanced after weighting (SMD < 0.1). After sIPTW adjustment, H+L+P demonstrated a significant survival benefit: median OS was 25.6 months (95% CI: 22.0–33.7) vs. 15.9 months (95% CI: 12.6–21.3) for L+P (adjusted HR, 0.60; 95% CI: 0.43–0.82; p = 0.0015). Crucially, a favorable survival trend was preserved even in the high-risk Vp3-4 subgroup (HR 0.77). Median PFS (RECIST v1.1) was 13.0 vs. 6.8 months (adjusted HR, 0.58; p = 0.0002). H+L+P significantly delayed progression in intrahepatic lesions (median 14.8 vs. 7.8 months; p = 0.0006) and PVTT (median 24.9 vs. 15.5 months; p = 0.0183). Intrahepatic ORR (mRECIST) was 87.4% for H+L+P vs. 28.9% for L+P (p < 0.0001), with a PVTT response rate of 81.6% vs. 22.1% (p < 0.0001). Grade ≥3 adverse events (AEs) occurred in 37.0% of the H+L+P group vs. 9.4% in the L+P group. Common Grade ≥3 AEs in the H+L+P arm included abdominal pain (20.5%) and leukopenia (5.5%); no treatment-related deaths occurred in the H+L+P group. Conclusions: In this target trial emulation, adding HAIC to lenvatinib and PD-1 inhibitors significantly improved OS and PFS in patients with high-risk HCC and PVTT. The survival advantage was driven by rapid and profound locoregional control, particularly of the tumor thrombus, with a manageable safety profile. Clinical trial information: NCT06631326 .

53 Background: Liver metastases are the main cause of death in colorectal cancer (CRC), yet only ~20% of patients qualify for surgery. For unresectable colorectal liver metastases (CRCLM), hepatic arterial infusion chemotherapy (HAIC) and drug-eluting bead transarterial chemoembolization (DEB-TACE) are common treatments. This study assesses the efficacy and safety of combining DEB-TACE with HAIC using FOLFOX or FOLFIRI. Methods: This retrospective study included 221 CRCLM patients treated at Peking University Cancer Hospital from 2018 to 2023. Of these, 182 received DEB-TACE with HAIC-FOLFOX and 39 with HAIC-FOLFIRI. Propensity score matching (PSM) minimized selection bias. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), hepatic PFS (hPFS), objective response rate (ORR), disease control rate (DCR), and treatment-related safety. Results: Propensity matching resulted in 38 pairs, achieving comparable baseline between DEB-TACE-HAIC-FOLFOX and DEB-TACE-HAIC-FOLFIRI cohorts. Of these pairs, 45 were male and 31 were female. Around 65.8% patients were younger than 65 years. The original locations of CRC in 67.1% of patients were on the left side. The middle to high grades of tumor were dominant (88.2%). Notably, 56.6% of patients harbored mutations in KRAS, NRAS or BRAF and extrahepatic metastasis occurred in 78.9% patients. Additionally, 75% patients were refractory to second line systemic therapy. Median hepatic progression-free survival (hPFS), progression-free survival (PFS), and overall survival (OS) were all slightly better in the matched DEB-TACE-HAIC-FOLFOX cohort, but not statistically significant (median hPFS: 8.6 vs. 5.8 months, P=0.206; median PFS: 6.4 vs. 4 months, P=0.062; median OS: 11.8 vs. 10.8 months, P=0.249). The objective response rate (ORR) was 36.8% in the DEB-TACE-HAIC-FOLFOX group and 39.5% in the DEB-TACE-HAIC-FOLFIRI group, with disease control rates (DCR) of 71.1% and 76.3%, respectively. These patients received 224 DEB-TACE plus HAIC treatments. There were no treatment-related deaths. Serious adverse events were comparable between the two groups, except for elevated transaminase. However, transaminase elevation was actually due to drug-eluting beads difference during DEB-TACE. With the further analysis of drug-eluting beads’ effect on adverse events, transaminase elevation, nausea, vomiting and pain occurred much frequently with DCB drug-eluting bead than HepaSphere drug-eluting bead; these differences were statistically significant. Conclusions: The combination of DEB-TACE with FOLFOX or FOLFIRI HAIC shows promising efficacy and tolerable safety for unresectable CRCLM. The FOLFIRI-based regimen is a viable alternative, especially for oxaliplatin-intolerant patients.

Background: Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of cancer-related mortality worldwide. The liver is the primary metastatic site, and the prognosis of gastric cancer with liver metastasis (GCLM) remains poor. While transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) are used for liver cancer, their roles in GCLM remain underexplored. Objectives: This study aimed to evaluate the efficacy and safety of drug-eluting bead TACE (DEB-TACE) combined with HAIC in patients with unresectable GCLM. Design: This was a retrospective, single-center cohort study. Methods: We retrospectively analyzed 62 patients with GCLM treated at Peking University Cancer Hospital between July 2018 and June 2023. Patients underwent 135 sessions using either HepaSphere beads plus HAIC-FOLFOX (HEPA-HAIC, n = 33) or DC bead plus HAIC-FOLFOX (DCB-HAIC, n = 29). The primary endpoint was median overall survival (mOS); secondary endpoints included median hepatic progression-free survival (mhPFS), median progression-free survival (mPFS), tumor response, and safety. Results: Among the patients (53 male, 9 female), 75.8% had intestinal-type cancer. Over 95% underwent prior treatments. The mOS was 10.7 months in both groups. The HEPA-HAIC cohort achieved longer mhPFS (8.6 vs 7.6 months) and mPFS (5.7 vs 4.4 months), though not statistically significant. Objective response rate and disease control rate were similar (30.3%/75.8% vs 31.0%/75.9%). Propensity score matching confirmed these findings. Univariate Cox regression suggested primary tumor location and carcinoembryonic antigen were prognostic for hPFS and OS, respectively. No treatment-related deaths occurred. Common adverse events (AEs) were transaminase elevation and pain. Nausea, vomiting, and severe pain were significantly less frequent with HEPA-HAIC (5.6% vs 31.7%, p = 0.001; 4.2% vs 31.7%, p < 0.001; 8.3% vs 22.2%, p = 0.01). Conclusion: DEB-TACE plus HAIC was feasible and demonstrated intrahepatic disease control with acceptable tolerability in unresectable GCLM; HEPA-HAIC showed a favorable safety profile.

e15545 Background: The prognosis of microsatellite-stable (MSS) colorectal cancer liver metastasis (CRCLM) refractory to systemic therapy is dismal. Previous studies had showed the efficacy of hepatic arterial infusion chemotherapy (HAIC) for CRCLM. Thus, this trial assesses the proof-of-concept for combining genotype-directed targeted therapy, HAIC, and tislelizumab in heavily pretreated MSS-CRCLM. Methods: This prospective, open-label, single-center trial screened participants with MSS-CRCLM refractory to multiple-line systemic therapy. Participants received the combination therapy of HAIC, tislelizumab (200 mg intravenously before HAIC on day 1), and targeted therapy every 4 weeks. The targeted therapy was determined based on genotype: fruquintinib (3 mg/day on day 3 - 21) was used for KRAS/NRAS/BRAF/EGFR mutation-type or failure of cetuximab in past 3 months (Arm A), while cetuximab (500 mg/m 2 ) was used for KRAS/NRAS/BRAF/EGFR wile-type without the usage of cetuximab in past 3 months (Arm B). The primary endpoint was 6-month progression-free survival (PFS) rate. PFS, overall survival (OS), hepatic PFS (HPFS), objective response rate (ORR), disease control rate (DCR), and safety were also investigated. Results: Between February 2024 and October 2025, 59 participants (57.4 ± 9.2 years old, 39 male) were enrolled (37 in Arm A and 22 in Arm B). The 6-months PFS rate was 51.7% (Arm A: 39.7%, Arm B: 67.5%), with the median PFS of 6.1 months (95% confidence interval [CI]: 5.524 – 6.676). The median OS and HPFS were 17 (95% CI: 14.969 – 19.031) and 8.1 months (95% CI: 7.402 – 8.798), respectively. The ORR was 64.4% (mRECIST)/47.5% (RECIST1.1), with a DCR of 96.6%. The incidence of ≥ grade 3 adverse events (AEs) was 25.4%. The most common ≥ grade 3 AEs in Arm A was elevated alanine transaminase (3/37, 8.1%), hyperbilirubinemia (3/37, 8.1%), and abdominal pain (3/37, 8.1%); and the most common ≥ grade 3 AEs in Arm B was thrombocytopenia (2/22, 9.1%). Conclusions: These interim results provided clinical proof-of-concept for the genotype-directed combination of targeted therapy, HAIC, and tislelizumab as a viable salvage strategy for heavily pretreated MSS-CRCLM. The trial is still ongoing, and the results will be updated in the future. Clinical trial information: NCT06199232 . Endpoints in Arm A and Arm B. Total Arm AFruq+HAIC+Tisl Arm BCet+HAIC+Tisl 6-month PFS rate 51.7% 39.7% 67.5% PFS 6.1 months(95% CI: 5.524 – 6.676) 5.7 months (95% CI: 5.037 – 6.363) 7.4 months (95% CI: 4.799 – 10.001) OS 17 months(95% CI: 14.969 – 19.031) 15.7 months (95% CI: 7.983 – 23.417) Not reach HPFS 8.1 months(95% CI: 7.402 – 8.798) 7.8 months (95% CI: 5.566 – 10.034) 8.2 months(95% CI: 7.094 – 9.306) ORR (mRECIST/RECIST1.1) 64.4% /47.5% 62.2% /37.8% 68.2% /63.6% DCR 96.6% 97.3% 95.5% Incidence of ≥ grade 3 AEs 25.4% 29.7% 18.2%

Phenotypic plasticity is a hallmark feature driving cancer progression, metastasis, and therapy resistance. Fetal-like transcriptional programs have been increasingly implicated in promoting plastic cell states, yet their roles remain difficult to study due to limitations of existing culture models. Here, we establish a chemically defined patient-derived organoid system that enables long-term expansion of colorectal cancer (CRC) cells while preserving fetal-like features associated with phenotypic plasticity. Using this model, we identify an oncofetal state (OnFS) that is enriched in advanced tumors and linked to key features of plasticity, including epithelial-mesenchymal plasticity, as well as increased metastasis and treatment resistance. Mechanistically, we show that FGF2-AP-1 signaling maintains the OnFS program and associated phenotypic plasticity in CRC. This model offers a powerful platform for studying the fetal-like features underlying cancer cell plasticity and their role in tumor progression and treatment resistance in CRC.

BACKGROUND:Hepatocellular carcinoma (HCC) ranks as the sixth most common cancer and the third- leading cause of cancer-related deaths worldwide. The multidisciplinary tumor board (MDTB) has been recognized for improving outcomes in cancer management, but its role in patients with HCC undergoing liver transplantation (LT) remains underexplored. AIM:To evaluate the impact of an MDTB on survival outcomes in patients with HCC undergoing LT. METHODS:We retrospectively analyzed 393 patients with HCC who underwent LT at our institution from October 2015 to October 2021. Patients were categorized into the MDTB and non-MDTB groups. We compared preoperative and postoperative characteristics, overall survival (OS), and disease-free survival (DFS) between the two groups. RESULTS:Within the University of California, San Francisco (UCSF) criteria, no significant differences in OS and DFS were noted between the MDTB and non-MDTB groups. However, for patients who exceeded the UCSF criteria, the MDTB group exhibited a substantial improvement in both OS and DFS. The 1-year, 3-year, and 5-year OS rates for the MDTB group in this subgroup were 88.68%, 75.29%, and 61.78%, respectively, compared to 83.02%, 64.07%, and 38.25%, respectively in the non-MDTB group. Similarly, DFS rates were 89.47%, 71.35%, and 63.52%, respectively, vs 82.18%, 53.78%, and 34.04%, respectively. CONCLUSION:The MDTB approach was particularly beneficial for patients with HCC exceeding the UCSF criteria, significantly improving OS and DFS. These findings advocate for integrating MDTB into clinical practice for optimizing the management of high-risk patients with HCC undergoing LT.

8601 Background: RET alterations occur in non-small cell lung cancer (NSCLC, 2%), thyroid cancer (TC, 10%–20%) and a range of tumor types (<1%). RET inhibitors substantially improved the clinical outcomes of pts with RET-altered solid tumors. BYS10 is a highly potent and RET-specific inhibitor that overcomes RET V804 and G810 mutations, and exhibits high selectivity for RET over KDR. This study is to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of BYS10 in Chinese pts with RET-altered solid tumors. Methods: In phase Ⅰ, following an accelerated titration and BOIN design, eligible pts were treated with BYS10 at 25 to 600 mg daily dose. Primary endpoints included safety, tolerability, MTD and DLTs. Secondary endpoints included PK and preliminary antitumor activity. Results: As of 10 July, 2024, a total of 51 pts were enrolled in dose escalation cohorts at 25/50 mg QD (n = 1/1) and 50/100/200/250/300 mg BID (n = 3/12/12/9/13). The MTD was not reached. Treatment related adverse events (TRAEs) occurred in all subjects, the most common TRAE were elevated AST (64.7%), elevated ALT (58.8%), elevated TBIL (45.1%), decreased WBCs (43.1%), decreased NEUT (33.3%), hyperuricaemia (31.4%), hypertension (29.4%), hypoalbuminemia (25.5%), Elevated SCr (23.5%) and headaches (23.5%). Grade 3 to 4 TRAEs >5% included elevated AST (25.5%), elevated ALT (13.7%) and hypertension (9.8%) reported at 100 to 300 mg BID doses. Serious adverse events were recorded in 7 pts. Exposure of BYS10 increased in a dose-dependent manner from 25 to 600 mg. In 40 evaluable pts, the confirmed overall response rate (ORR) and disease control rate (DCR) by independent review committee per RECIST v1.1 were 62.5% and 85%, In pts with RET-fusion NSCLC (n=30), RET-fusion thyroid cancer (TC, n=6) and RET-mutant medullary thyroid cancer (MTC, n=4), the ORR/DCR were 60%/80%, 83.3%/100% and 50%/100%, respectively. Intracranial antitumor activity was observed by investigators in 4 pts with at least 1 measurable intracranial lesion (one intracranial complete response). The ORR/DCR by IRC in 200 mg and 300 mg BID cohorts were 66.7%/100% and 75%/91.7%, respectively. Conclusions: BYS10 was well tolerated and showed dose-dependent exposure. Preliminary antitumor activity was observed in pts with RET-altered NSCLC, TC and MTC. The study is still ongoing. Clinical trial information: ChiCTR2400085264 .

Background:Chemotherapy combined with immune checkpoint inhibitor have prolonged survival of patients with advanced biliary tract cancers (BTCs), and the previous studies showed the synergistic anti-tumor effect of chemotherapy, anti-angiogenesis therapy, and immunotherapy. Hepatic arterial infusion chemotherapy (HAIC) achieved a higher tumor response and survival benefit in previous phase II studies for advanced BTCs. Thus, we conducted this phase II trial to evaluate the efficacy and safety of HAIC combined with bevacizumab and toripalimab for advanced BTCs. Methods:Treatment-naïve participants with advanced BTCs were recruited for this phase II trial. Combination therapy, comprising HAIC with bevacizumab (300 mg, day 1), oxaliplatin (40 mg/m2, 2 h, days 1-3), and 5-fluorouracil (800 mg/m2, 22 h, days 1-3) plus intravenous toripalimab (240 mg, day 1 before HAIC), was repeated every 4 weeks for a maximum of six consecutive cycles. Intravenous toripalimab (240 mg) and bevacizumab (300 mg) were administered every 4 weeks as maintenance treatment. The primary endpoint was objective response rate (ORR) according to Immune-Modified Response Evaluation Criteria in Solid Tumors criteria, and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Olink proximity extension assay with a Target 96 Immuno-Oncology panel was exploratory investigated. Results:Between July 2020 and January 2022, 32 participants were enrolled. The ORR was 84.38%, and the disease control rate was 96.88%. Median PFS and OS were 13.20 months [95% confidence interval (CI): 8.93-17.47] and 19.0 months (95% CI: 12.22-25.78), respectively. Grade 3 or higher adverse events (AEs) were observed in 10 participants (31.25%), and the most frequent grade 3 or higher AEs were elevated ALT/AST (4/32, 12.50%), elevated total bilirubin (3/32, 9.38%), and neutropenia (3/32, 9.38%). In exploratory analysis, Child-Pugh B [hazard ratio (HR): 22.65, 95% CI: 3.66-140.08, P=0.001] and high level of macrophage metalloproteinase-12 (HR: 5.99, 95% CI: 1.60-22.37, P=0.008) were indicated as the risk factors related to worse PFS. Conclusions:HAIC combined with bevacizumab and toripalimab may serve as an improved first-line treatment for advanced BTCs, which require a randomized control trial for verification. Trial Registration:This trial is registered at ClinicalTrail.gov (NCT04217954).

Sonodynamic therapy (SDT) is a viable alternative to traditional photodynamic therapy owing to its ability to penetrate tissue. However, the therapeutic efficacy of a single SDT treatment is constrained by the prolonged hypoxia of the tumor, rendering SDT ineffective for treating disease. SDT was used in conjunction with nitric oxide (NO) gas in this study to induce apoptosis and ferroptosis in hepatocellular carcinoma (HCC) cells for treating cancer treatment. We synthesized 5,10,15,20-tetra (4-aminophenyl) porphyrin nanobubbles (TAPP@NBs) for the SDT treatment. S-nitroso glutathione (GSNO) was used as an NO gas donor. Thein vitroanticancer effect of the combined treatment was examined using HepG2 and HUH7 hepatoma cell lines. Reactive oxygen species and NO were examined using 2,7-dichlorodihydrofluorescein diacetate and 3-amino,4-aminomethyl-2',7'-difluorescein diacetate staining, respectively. Cell proliferation and apoptosis were analyzed using CCK-8 and flow cytometry, respectively. Ferroptosis was evidenced using glutathione and malondialdehyde assays. The cellular migratory capacity was assessed using a Transwell assay. TAPP@NBs can serve as a sonosensitizer for the SDT. GSNO serves as an NO donor under ultrasound and contributes to gas treatment, considerably increasing SDT efficacy. HCC cell proliferation and migration were considerably lower after combined SDT and NO gas therapy. Combined SDT and NO gas therapy induced apoptosis and ferroptosis in HCC cells. This paper describes a novel approach for optimizing tumor treatment.

Generating high-quality meshes for CAD models is a crucial preprocessing task for numerical simulation. Although mesh generation techniques are well-established, automatic hexahedral meshing remains challenging, particularly for complex geometries. Conventional methods often require manual intervention to decompose solid models into simpler, meshable blocks, which is labor-intensive and demands expert knowledge. To address the challenge of automating the block decomposition of solid models for hexahedral meshing, we propose a novel reinforcement learning (RL) framework. This framework enables an agent to learn optimal decomposition strategies by interacting with a CAD modeling environment. Key contributions include a network-friendly method for representing and learning the environment's state and the agent's actions-3D geometric shapes and the corresponding block decomposition operations; a two-step training strategy that integrates imitation learning with reinforcement learning to improve training efficiency. Experimental results demonstrate that our RL-based method achieves amore effective automatic block decomposition of complex 3D solid models for generating high-quality hexahedral meshes.