Idiopathic pulmonary fibrosis (IPF) is sustained by a self-amplifying pathological circuit involving senescence-associated epithelial injury and fibroblast activation, which together drive persistent inflammatory signaling, excessive extracellular matrix deposition, and progressive loss of lung function. Although proteolysis-targeting chimeras (PROTACs) offer a powerful approach to eliminate disease-driving proteins, their application in fibrotic lung disease remains limited by inefficient pulmonary delivery, poor lesion retention, and insufficient intervention in multicellular profibrotic networks. Herein, we develop an inhalable enzyme-activated polymeric PROTAC nanococktail that enables concurrent degradation of two key profibrotic signaling regulators in fibrotic lungs. The nanococktail consists of GAL@SD and FAP@BD, two disease-microenvironment-responsive nanoparticles carrying distinct PROTAC cargos. GAL@SD responds to elevated senescence-associated β-galactosidase activity in fibrotic lungs and releases a stimulator of interferon genes (STING)-degrading PROTACs to suppress senescence-associated inflammatory signaling linked to impaired alveolar epithelial repair. FAP@BD is activated by fibroblast activation protein-α enriched in activated fibroblast-dominated fibrotic regions, delivering a bromodomain-containing protein 4 (BRD4)-degrading PROTAC to inhibit myofibroblast activation and extracellular matrix production. After inhalation, both nanoparticles exhibit efficient mucus penetration, improved pulmonary retention, and preferential accumulation in fibrotic lesions, enabling localized degradation of STING and BRD4. In a bleomycin-induced mouse model of pulmonary fibrosis, the combined PROTAC nanococktail achieves superior therapeutic efficacy compared with either single PROTAC nanoparticle, as demonstrated by restored lung architecture, improved respiratory function, reduced collagen deposition, and reversal of fibrosis-associated transcriptional programs. These results demonstrate an inhaled dual-PROTAC nanotherapeutic strategy for simultaneously attenuating epithelial senescence-associated inflammation and fibroblast-driven matrix remodeling.

Tumor-associated macrophages (TAMs) polarized toward an M2-like phenotype are critical drivers of immunosuppression in colorectal cancer (CRC). While Vasorin (VASN) is implicated in poor prognosis, its specific role in orchestrating the tumor immune microenvironment remains elusive. VASN expression and immune infiltration were analyzed using TCGA transcriptomics and single-cell transcriptomics, validated via immunohistochemistry and immunofluorescence in CRC patient cohorts. In vitro Transwell co-cultures and ELISA were utilized to assess cytokine secretion. In vivo VASN functions were evaluated using syngeneic mouse models alongside clodronate liposome-mediated macrophage depletion. Molecular interactions were delineated utilizing chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays, and genetic rescue strategies. VASN was significantly upregulated in CRC tissues and correlated with M2-like macrophage abundance and reduced survival. In vivo, VASN promoted tumor growth and suppressed CD8+ T cell effector function; crucially, these effects were significantly attenuated by macrophage depletion. Mechanistically, VASN activated the Hippo-YAP pathway, facilitating the YAP/TEAD4 complex to directly activate MYL9 transcription. This VASN–YAP–MYL9 axis triggered the paracrine secretion of IL-4 and IL-13 from tumor cells, driving neighboring macrophages toward an M2-like phenotype. This polarization subsequently impaired cytotoxic surveillance, facilitating immune evasion. This study identifies a novel VASN–YAP–MYL9 axis that reprograms macrophages to mediate immune escape. These findings broaden our understanding of CRC immune evasion and provide a rational framework for targeting VASN to remodel the immunosuppressive microenvironment and augment therapeutic efficacy.

BACKGROUND:The efficacy of neoadjuvant chemotherapy combined with dual immune checkpoint blockade in proficient mismatch repair/microsatellite-stable (pMMR/MSS) locally advanced colorectal cancer (LACRC) remains uncertain. METHODS:In this open-label, randomized phase 2 trial (ClinicalTrials.gov: NCT05571644), eligible patients were randomly assigned (1:1:1) to receive 6 cycles of neoadjuvant mFOLFOXIRI plus cadonilimab, mFOLFOXIRI, or mFOLFOX6, followed by surgery and adjuvant chemotherapy. The primary endpoint was pathological complete response (pCR) in the intention-to-treat population. Secondary endpoints included major pathological response (MPR), safety, locoregional recurrence, disease-free survival, and overall survival. FINDINGS:Between July 2023 and August 2024, 123 patients were randomly assigned (41 per group). Neoadjuvant mFOLFOXIRI plus cadonilimab significantly improved pCR compared with mFOLFOX6 (26.8% versus 9.8%; odds ratio [OR], 3.4; 95% confidence interval [CI], 1.04 to 13.24; p = 0.046), whereas mFOLFOXIRI alone did not (14.6% versus 9.8%; OR, 1.6; 95% CI, 0.4 to 6.7; p = 0.50). MPR rates were 68.3%, 46.3%, and 43.9%, respectively, and were significantly higher with mFOLFOXIRI plus cadonilimab than with mFOLFOX6 (p = 0.026). Downstaging to ypStage 0-I occurred in 66%, 45%, and 41% of patients in the three groups, respectively, and was significantly higher in the mFOLFOXIRI plus cadonilimab group (p = 0.027). Grade ≥3 adverse events were manageable, with liver enzyme elevation and neutropenia being the most common. CONCLUSIONS:Neoadjuvant mFOLFOXIRI plus cadonilimab significantly improved pCR compared with mFOLFOX6 in LACRC, with a manageable safety profile, supporting further investigation. FUNDING:This work was funded by the National Science Fund for Distinguished Young Scholars (82425045) and the National Natural Science Foundation of China (82272800).

IntroductionAlthough TNM staging is the standard framework for prognostic assessment in colorectal cancer (CRC), patients within the same stage can have heterogeneous outcomes. This study aimed to extract tumor-tissue features from whole-slide images (WSIs), develop an image-derived prognostic model for stage II–III CRC, and conduct an exploratory evaluation of its performance.MethodsA transfer-learning tissue classifier was used to identify tumor regions in CRC WSIs. Self-supervised contrastive learning was used to extract tumor features, which were summarized by patient-level K-Means clustering. An attention-based survival model generated a locked image-derived Risk Score. The actual analyzed population comprised 335 patients with locally advanced CRC: 318 patients recorded as stage III and 17 patients with T4N0 disease (high-risk stage II by AJCC eighth-edition anatomic staging). The 265-patient TCGA cohort was randomly divided 8:2 into a training set and an internal holdout set; 70 SAHSYU patients formed a single-center exploratory cohort. Discrimination was quantified with patient-level bootstrap confidence intervals. Cox regression, Kaplan–Meier analysis, one-year calibration, and exploratory decision-curve analysis were performed. A sensitivity analysis excluded all N0 patients without retraining or changing the locked Risk Score.ResultsThe C-index was 0.704 (95% bootstrap CI 0.637–0.768) in training, 0.663 (0.544–0.776) in the internal holdout set, and 0.706 (0.533–0.859) in SAHSYU. Per one training-set standard deviation, the Risk Score was associated with PFS internally (HR 1.688, 95% CI 1.080–2.640; Wald p=0.022) and exploratorily in SAHSYU (HR 6.010, 95% CI 1.170–30.877; p=0.032). In the sensitivity analysis excluding all N0 records without retraining, the C-index remained 0.647 internally and 0.705 in SAHSYU; fixed-threshold log-rank p values were 0.014 and 0.027, respectively.ConclusionThe image-derived Risk Score showed preliminary PFS discrimination and risk-stratification potential in stage II–III CRC. These findings require validation in larger multicenter cohorts with more events, longer follow-up, formal calibration, and clinical-utility assessment before treatment decisions can be informed.

TPS271 Background: Locally advanced colorectal cancer (LACRC) is recommended to receive neoadjuvant chemotherapy(NCT) by the NCCN guidelines before surgery. NCT might reduce tumor size, achieve downstaging of the tumor and lymph nodes, improve R0 resection rate, enhance prognosis or even watch-and-wait. Previous studies have shown a 2.07% retrieval rate of lymph nodes beyond 5 cm along the bowel for cases classified as T≤3, with an even lower incidence of positive lymph nodes. Retrospective cohort comparison at our center showed that reducing the extent of bowel resection (3 cm of distal margin and 5 cm of proximal margin) after NCT did not affect the lymph node retrieval and the 1-year DFS. Extending the resection length of the bowel or expanding the scope of regional mesenteric lymph node dissection beyond 5 cm does not improve staging accuracy. Instead, it might increase the risk of complications . For LACRC with ycT≤3N0M0 (stage IIA or lower) after NCT, the optimal extent of bowel resection remains a subject for further investigation. Methods: This is a prospective, multicenter, randomized phase III-controlled trial conducted in collaboration with the Sixth Affiliated Hospital of Sun Yat-sen University and multiple domestic colorectal cancer centers. Patients with upper rectal or rectosigmoid junction tumors at a clinical stage of cT3-4N+M0 will be enrolled. For patients with pMMR/MSS status: Tumor downstaged to T≤3N0M0 after NCT or total neoadjuvant therapy (TNT). Chemotherapy regimens include, but are not limited to, FOLFOX6, CAPOX, or FOLFOXIRI. For patients with dMMR/MSI-H: Tumor downstaged to T≤3N0M0 after immunotherapy. The trial will compare conventional resection margins with reduced margins in patients who have met the ycT ≤3N0M0 regression criteria following NCT or TNT. Reduced resection margins refer to the surgical resection region including 5 cm bowel proximal to the tumor, 3 cm bowel distal to the tumor and lymph node dissection in the corresponding mesentery. Conventional resection margins refer to the surgical resection region including 10 cm bowel proximal to the tumor, 5 cm bowel distal to the tumor, and lymph node dissection in the corresponding mesentery. The goal of this clinical trial is to learn evaluate the safety and efficacy of reduced surgical resection margins in patients with ycT≤3N0M0 regression following NCT. The primary research objective is 3-year disease-free survival (DFS). The secondary research objectives include R0 resection rate, number of lymph nodes dissected, surgical safety metrics and other survival outcomes. This study plans to enroll 874 patients, with 10 patients enrolled as of August 30th, 2025. Registration with ClinicalTrials.gov (NCT 07038122) has been completed. Clinical trial information: NCT 07038122 .

TPS3646 Background: Immunotherapy has shown promising therapeutic effects in mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). However, for patients with mismatch repair-proficient or microsatellite stable (pMMR/MSS) CRC, the efficacy of single-agent PD-1 monoclonal antibody remains limited. Previous studies reported that combining anti-angiogenic drugs with PD-1 monoclonal antibody might improve the efficacy of immunotherapy. Our BASKETII study (NCT04895137) demonstrated that the neoadjuvant therapy regimen of mFOLFOX6 combined with Bevacizumab and sintilimab significantly enhanced the immunotherapy sensitivity of pMMR/MSS locally advanced CRC (LACRC), resulting in improved pathological complete response (pCR) rates and higher R0 resection rates. Methods: BASKETIII is a multicenter, randomized controlled, phase III study with a parallel design conducted in China. This trial aims to evaluate whether the neoadjuvant therapy regimen of mFOLFOX6 combined with Bevacizumab and sintilimab can further improve survival outcomes, and maintain the higher pCR rate and acceptable safety profile compared to mFOLFOX6 in pMMR/MSS LACRC patients. Eligible participants will be randomly assigned in a 1:1 ratio to either the experimental group or the control group. Participants in the experimental group will receive the neoadjuvant therapy regimen of mFOLFOX6 + Bevacizumab + sintilimab. The first five doses will follow the mFOLFOX6 combined with Bevacizumab and sintilimab regimen, and the sixth dose will receive only mFOLFOX6 and sintilimab but without Bevacizumab, in order to avoid delay of surgery. Participants in the control group will receive the neoadjuvant therapy regimen of mFOLFOX6 alone. Participants in both groups will undergo radical surgical treatment after neoadjuvant therapies. Participants who achieve pCR based on postoperative pathology will be regularly followed up. Participants who do not achieve pCR will receive adjuvant therapy with a maxim of six doses and will be regular followed up after the final dose of adjuvant therapy. The primary outcome of this study is to evaluate the 3-year disease-free survival (DFS). The key inclusion criteria include histologically confirmed adenocarcinoma of the colon or upper rectum; tumor biopsy immunohistochemical identified pMMR or MSS identified through next-generation sequencing or polymerase chain reaction; Clinical staging of cT4NxM0. The main exclusion criteria include evidence of distant metastasis beyond the pelvic region; history of pelvic or abdominal radiotherapy; multiple CRC or multiple primary tumors; history of immunotherapy and other malignancies within the past 5 years. A total of 122 patients are planned to be enrolled in this study. This study is registered with ClinicalTrials.gov (NCT06791512) and is recruiting. Clinical trial information: NCT06791512 .

Blocking the C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signal offers the potential to induce immunogenic cell death (ICD) and enhance immunotherapy of glioblastoma (GBM). However, traditional intracellular targeted delivery strategies and adenosine-mediated tumor immunosuppression limit its therapeutic efficacy. Herein, we present an acidity-triggered self-assembly nanoplatform based on bioorthogonal reaction to potentiate GBM immunotherapy through dual regulation of metabolism and immune pathways. AMD3100 (CXCR4 antagonist) and CPI-444 (adenosine 2A receptor inhibitor) were formulated into micelles, denoted as AMD@iNPDBCO and CPI@iNPN3, respectively. Upon administration, the pH-sensitive poly(2azepane ethyl methacrylate) group of AMD@iNPDBCO responds to the acidic tumor microenvironment, exposing the DBCO moiety, resulting in highly efficient bioorthogonal reaction with azide group on CPI@iNPN3 to form large-sized aggregates, ensuring extracellular drug release. The combination of AMD3100 and CPI-444 contributes to ICD induction, dendritic cell maturation, and immunosuppressive milieu alleviation by reducing tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, leading to a robust antitumor response, thereby significantly prolonging survival in orthotopic GBM-bearing mice. Furthermore, the nanoplatform remarkably amplifies immuno-radiotherapy by potently evoking cytotoxic CD8+ T cell priming, and synergized with immune checkpoint blockade by delaying CD8+ T cell exhaustion. Our work highlights the potential of the in situ assembly nanoplatform tailored for delivery of extracellular-targeted therapeutic agents for boosting GBM immunotherapy.

The efficacy of checkpoint blockade immunotherapy for glioblastoma (GBM) is significantly influenced by the precise delivery of therapeutic agents that can penetrate the blood-brain barrier (BBB) and reprogram the tumor immune microenvironment. Conventional nanoscale carriers used for delivering immune checkpoint blockers are more likely to be internalized by tumor cells, leading to a loss of drug efficacy. This study presents a phosphatidylcholine (PC)-coated nanoparticle (PCNP) with an optimized PC ratio on its surface, achieving a balanced surface charge. This surface optimization minimizes nanoparticle-cell membrane interactions, reducing cellular uptake and thereby enhancing extracellular drug targeting efficacy. The constructed PC shell enabled PCNPs to penetrate the BBB mediated by choline transporters. The PC shell can attenuate interactions between PCNPs and cells, thereby preventing the internalization of PCNPs. Additionally, the poly-l-histidine core can undergo protonation in the acidic microenvironment, resulting in rapid disintegration of PCNPs and facilitating the quick release of the encapsulated CPI-444 (an extracellular adenosine receptor blocker) and temozolomide, inducing immunogenic cell death and blocking extracellular adenosine receptors to reverse the immunosuppressive feedback signaling pathway of the adenosinergic axis. This combination therapy has shown a novel therapeutic strategy for extracellular immune checkpoint blockade in GBM.

In the original publication [...].

TPS3639 Background: Colorectal cancer liver metastasis (CRLM) significantly decreases colorectal cancer (CRC) patient prognosis, affecting 30-50% of CRC patients at diagnosis or thereafter. Notably, up to 70%-90% CRLM are diagnosed as unresectable. Standard treatments include systemic chemotargeted-therapies (CT). However, only 10-30% CRLM can be converse to resectable state by CT, with an objective response rate (ORR) of just 15%-20% and a median overall survival (OS) of approximately 20-30 months. Improving prognosis of CRLM patients remains challenging. Stereotactic body radiation therapy (SBRT) combined with immunotherapy might offer promising alternatives. SBRT provides high-dose tumor control while protecting surrounding tissues better than conventional radiotherapy. It also facilitates the release of tumor-associated antigens, reshaping the immune microenvironment and inducing stronger immune responses. The combination of SBRT and PD-1 antibodies might synergistically enhance the anti-tumor efficacy. Despite SBRT's demonstrated efficacy in unresectable CRLM with few adverse reactions, no prospective studies have explored its combination with PD-1 antibodies. Methods: This is a multicenter, open-label, single-arm, phase II trial conducted in China. Patients will receive SBRT at 8-12 Gy per fraction over 5 fractions, combined with 5-FU-based CT and PD-1 antibody therapy before and after SBRT. Eight weeks (±2 weeks) post SBRT, imaging assessments or multi-point liver biopsies will be performed. Multidisciplinary teams (MDT) will determine subsequent plans: cCR/pCR patients will undergo maintenance CT or enter a watch-and-wait phase; non-cCR/pCR patients will continue maintenance CT or exit the study. This is the first study exploring whether SBRT combined with PD-1 monoclonal antibody can improve ORR, OS, quality of life (QOL) and potentially achieve no evidence of disease (NED) status for unresectable CRLM. Key inclusion criteria: pMMR/MSS CRC, MDT-assessed unresectability due to main portal vein invasion, multiple hepatic vein invasion or lack of R0 resection/ablation feasibility. Main exclusion criteria encompass active hepatitis, cirrhosis, Child-Pugh B/C, checkpoint inhibitor therapies history and ECOG performance status ≥2. Twenty-four patients are planned for enrollment, with two already enrolled as of January 25, 2025. The study is registered with ClinicalTrials.gov (NCT06794086) and is ongoing. Clinical trial information: NCT06794086 .

Accurate prognostic assessment before neoadjuvant chemoradiotherapy remains challenging for locally advanced rectal cancer (LARC), limiting personalised treatment decisions. Here, we develop the Integrated Multimodal Prognostic Assessment for Locally Advanced Rectal Cancer Neoadjuvant Chemoradiotherapy (IMPACT), an artificial intelligence framework employing bidirectional multimodal attention mechanisms to capture cross-modal feature interactions and integrating pre-treatment pelvic magnetic resonance imaging, pathological biopsy whole slide images, and clinical information from 752 LARC patients across two independent centres. IMPACT achieves C-indexes of 0.805 for overall survival and 0.760 for disease-free survival, significantly outperforming the Guideline-based Imaging Risk Score (0.712 and 0.697, respectively). High-risk patients demonstrate 8.3-fold increased mortality risk and 6.5-fold increased recurrence risk compared to low-risk patients. External validation maintains robust performance with preserved risk stratification capability. Systematic ablation studies confirm the incremental value of trimodal fusion over single-modality approaches. IMPACT enables accurate pre-treatment prognostic stratification, facilitating evidence-based treatment intensification for high-risk patients and de-escalation strategies for low-risk cases in clinical practice.

e15645 Background: The integration of immunotherapy with chemoradiotherapy (CRT) represents a novel therapeutic strategy for pMMR/MSS rectal adenocarcinoma. However, no prospective studies have demonstrated whether long-course radiotherapy (LCRT) or short-course radiotherapy (SCRT) exhibits superior synergistic effects when combined with immunotherapy. This study aims to evaluate the efficacy of SCRT versus LCRT in combination with immunotherapy using real-world data from a single institution and to investigate the differential impact of the two radiotherapy modalities on immunotherapy sensitization. Methods: This retrospective, real-world efficacy study included patients with untreated pMMR/MSS rectal adenocarcinoma aged 18 to 75 years, with clinical stages II-III and no prior systemic or local anticancer treatment. Patients received either LCRT (GTV 50Gy/25 fractions) or SCRT (GTV 25Gy/5 fractions), alongside 5-FU-based chemotherapy and PD-1 antibody therapy. Primary endpoints were PCR and clinical complete response (CCR) rates, while secondary endpoints included the incidence of acute adverse reactions and postoperative complications. The study aimed to provide further evidence for future treatment strategies by comparing the efficacy differences between these two radiotherapy regimens in combination with immunotherapy. Results: From January 2021 to December 2024, a total of 129 patients were enrolled. Among the 129 patients, 9 (2 received SCRT and 7 received LCRT) patients underwent "watch and wait" strategy due to imaging assessment of CCR. Of the 129 evaluable patients, 36 received SCRT and 93 received LCRT. The median age was 59 years (range: 22-75), with 44 females (34.1%). Stage III patients accounted for 119 (92.2%). Among high-risk patients, 86 (66.7%) had tumors located ≤5 cm from the anus, 81 (62.8%) were MRF (+) status and 62 (48.1%) were EMVI (+) status. The 120 patients who underwent total mesorectal excision surgery showed a PCR rate of 44.1% in the SCRT group compared to that of 40.7% in the LCRT group (p = 0.732). The CCR rate was 41.7% in the SCRT group, which was higher than that of 30.1% in the LCRT group (p = 0.212). No significant differences in acute toxicities were observed between the two radiotherapy modalities. The most common treatment-related adverse events were mainly grade 1-2 hematologic toxicity (37.2%), gastrointestinal toxicity (25.2%), and neurotoxicity (14.7%), with no severe treatment-related adverse events reported. Conclusions: SCRT combined with immunotherapy appeared to show more favorable PCR/CCR rates than LCRT combined with immunotherapy in patients with pMMR/MSS rectal adenocarcinoma, suggesting it as a promising treatment option. Further follow-up is required to assess long-term survival outcomes, and prospective randomized controlled studies are needed to validate these findings.

Laparoscopic radical resection has become the most important treatment for resectable colorectal cancer (CRC). However, there is still a lack of researches on the efficacy and safety of reduced-port laparoscopic surgery (RPLS) versus conventional laparoscopic surgery (CLS) in the treatment of CRC. From January 2019 to July 2022, 698 patients with CRC received surgical treatment in the Sixth Affiliated Hospital of Sun Yat-sen University were enrolled in this retrospective cohort study. Patients were divided into RPLS group (n = 220) and CLS group (n = 478) according to their surgical procedures. Propensity score matching (PSM) was used to adjust the differences in baseline characteristics. The incidence of perioperative outcomes and survival rates related results were analyzed after PSM. Four hundred twenty-two patients were equally divided into RPLS group (n = 211) and CLS group (n = 211) after PSM. There were no statistically significant differences in overall survival (OS) and progression-free survival (PFS) between the two groups (P value was 0.773 and 0.579 respectively). The perioperative outcomes of patients between the two groups were comparable, except that patients in the RPLS group had a shorter postoperative hospital stay (P value < 0.001). For patients with CRC, both RPLS and CLS might be acceptable surgical options. No significant differences in perioperative outcomes, PFS rates and OS rates were observed between the two groups. For certain cases, RPLS was superior to CLS in terms of postoperative recovery.

LBA210 Background: Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is recommended for mismatch repair-proficient (pMMR) or microsatellite stability(MSS) LARC. Recent studies have shown that anti-PD-1/PD-L1 in combination with CRT can improve pathological complete response (pCR) compared to CRT in the neoadjuvant setting. This trial aims to investigate the efficacy and safety of SCRT followed by cadonilimab, a first-in-class anti-PD-1/CTLA-4 bispecific antibody, plus mFOLFOX6 in patients (pts) with LARC. Methods: Eligible pts aged 18-79 years with pMMR/MSS, nonmetastatic, stage cT3-4N0 or cT1-4N1-2 rectal adenocarcinoma located below the peritoneal reflection were enrolled and given SCRT (25Gy/5F) followed by 6 cycles of cadonilimab (6mg/kg, q2w) plus mFOLFOX6. The primary endpoint was pCR. Secondary endpoints included clinical complete response (cCR), major pathological response (MPR), disease-free survival (DFS), overall survival (OS), safety and quality of life. The exploratory endpoint explored potential biomarkers related to response. Results: From April 2023 to May 2024, 27 pts were enrolled and received at least 1 dose of treatment. As of data cutoff date of October 20, 2024,median follow-up was 9.7 months (IQR 5.4–18·8)，and all pts received study treatment, and 24/27(88.9%) underwent R0 resections (one delayed surgery due to chemotherapy-related pneumonia, while the other two were assessed unresectable). The primary endpoint was met with a pCR of 37%(10/27)(95% CI, 19.4%–57.6%) and MPR of 55.6%. A cCR of 22.2%(6/27) was observed, and among them, 83.3%(5/6) still received local excisions. The T downstaging was observed in 59.3%(16/27) while N downstaging in 66.7%(18/27). Grade 3–5 adverse events occurred in 5 (18.5%) of 27 pts; the most common were diarrhea (ten [37%]),nausea (ten [37%]) and fatigue (ten [37%]), and neutropenia (seven [26%]). Drug-related serious adverse events occurred in eight (30%) of 27 patients. No new safety signal was identified. Conclusions: In pts with pMMR/MSS LARC, neoadjuvant SCRT with cadonilimab plus mFOLFOX6 resulted in promising pCR rates with intolerable toxicities. Follow up continues. These data deserve further investigations in a phase III randomized trial. Clinical trial information: NCT05792735 .

LBA3555 Background: Radical laparoscopic resection is the mainstay of treatments for non-metastatic colorectal cancer (CRC). Reduced-port laparoscopic surgery (RPLS) has emerged with the concept of more minimal invasion on the basis of conventional laparoscopic surgery (CLS). RPLS has only 3 or 4 ports for surgeon and observer, which might increase the difficulty of the operation. The efficacy and safety of RPLS for CRC remains unclear. This study aims to evaluate the curative effect and safety of RPLS versus CLS for resectable CRC, which is registered with ClinicalTrials.gov (NCT05953662). Methods: From July 2023 to December 2024, a total of 500 patients with CRC received surgical treatment in the Sixth Affiliated Hospital of Sun Yat-sen University, Nanfang Hospital of Southern Medical University and Ruijin Hospital of Shanghai Jiao Tong University School of Medicine were enrolled in this prospective cohort study. The primary outcome measure is 1 year disease free survival (DFS). The secondary outcome measures are total operation time, intraoperative blood loss, postoperative hospital stays, complication rate, mortality, 3 years DFS and OS. Patients were randomized divided into RPLS group (n=250) and CLS group (n=250). The study has completed recruitment. Results: There were no significant differences of the clinical characteristics between the two groups. The RPLS group had significantly less intraoperative blood loss (26.23±22.33 ml vs 50.72±80.10 ml, P<0.001 ). The total operation time was also shorter for the RPLS group (147.89±52.40 min vs 189.77±67.79 min, P<0.001 ). The postoperative hospital stay was shorter for the RPLS group (7.63±4.45 days vs 8.22±3.61 days, P<0.001 ). Regarding postoperative complications, the RPLS group is comparable with CLS group in a total of grade I/II/III complication rate (6% vs 3.2%, P=0.154 ). Grade III complications were few in both groups, presenting in 0.4% of the RPLS group and 0.8% of the CLS group. The pTNM stage distribution was similar between the groups, with no significant differences ( P=0.59 ). The mean number of harvested lymph nodes was similar (22.25±13.72 vs 23.55±18.22, P=0.413 ), as well as the mean number of positive lymph nodes (1.04±2.54 vs 0.93±2.23, P=0.556 ). All of the participants were received a radical resection (R0 resection) with negative margin and circumferential resection margin. There was no mortality in 30 days postoperative. With a median follow-up of 10 months, 2 cases experienced metastasis in the RPLS group and 4 cases in the CLS group experienced postoperative recurrence and metastasis. Conclusion: RPLS demonstrated non-inferiority in surgical safety compared to CLS, with significantly less intraoperative blood loss, shorter operation time. Additionally, RPLS showed superior postoperative recovery, with a shorter hospital stay. We need a long-term follow-up to validate the oncology safety of the reduced-port approach. Clinical trial information: NCT05953662 .

BACKGROUND:Rectal cancer is a common cancer worldwide and lacks effective prognostic markers. The development of prognostic markers by computational pathology methods has attracted increasing attention. This paper aims to construct a prognostic signature from whole slide images for predicting progression-free survival (PFS) of rectal cancer through an unsupervised artificial intelligence algorithm. METHODS:A total of 238 patients with rectal cancer from two datasets were collected for the development and validation of the prognostic signature. A tumor detection model was built by transfer learning. Then, on the basis of the tumor patches recognized by the tumor detection model, a convolutional autoencoder model was built for decoding the tumor patches into deep latent features. Next, on the basis of the deep latent features, the tumor patches were divided into different clusters. The cluster number and other hyperparameters were optimized by a nested cross-validation method. The percentage of each cluster from the patient's tumor patches, which is hereafter called PCF, was calculated for prognostic signature construction. The prognostic signature was constructed by Cox proportional hazard regression with L2 regularization. Finally, bioinformatic analysis was performed to explore the underlying biological mechanisms of the PCFs. RESULTS:The accuracy of the tumor detection model in distinguishing tumor patches from non-tumor patches achieved 99.3%. The optimal cluster number was determined to be 9. Therfore, 9 PCFs were calculated to construct the prognostic signature. The prognostic signature achieved a concordance index of 0.701 in the validation cohort. The Kaplan-Meier survival curves showed the prognostic signature had good risk stratification ability. Through the bioinformatic analysis, several PCF-associated genes were identified. These genes were enriched in various gene ontology terms. CONCLUSION:The developed prognostic signature can effectively predict PFS in patients with rectal cancer and exploration of the underlying biological mechanisms may help to promote its clinical translation.

BackgroundTNM staging is the main reference standard for prognostic prediction of colorectal cancer (CRC), but the prognosis heterogeneity of patients with the same stage is still large. This study aimed to classify the tumor microenvironment of patients with stage III CRC and quantify the classified tumor tissues based on deep learning to explore the prognostic value of the developed tumor risk signature (TRS).MethodsA tissue classification model was developed to identify nine tissues (adipose, background, debris, lymphocytes, mucus, smooth muscle, normal mucosa, stroma, and tumor) in whole-slide images (WSIs) of stage III CRC patients. This model was used to extract tumor tissues from WSIs of 265 stage III CRC patients from The Cancer Genome Atlas and 70 stage III CRC patients from the Sixth Affiliated Hospital of Sun Yat-sen University. We used three different deep learning models for tumor feature extraction and applied a Cox model to establish the TRS. Survival analysis was conducted to explore the prognostic performance of TRS.ResultsThe tissue classification model achieved 94.4% accuracy in identifying nine tissue types. The TRS showed a Harrell's concordance index of 0.736, 0.716, and 0.711 in the internal training, internal validation, and external validation sets. Survival analysis showed that TRS had significant predictive ability (hazard ratio: 3.632, p=0.03) for prognostic prediction.ConclusionThe TRS is an independent and significant prognostic factor for PFS of stage III CRC patients and it contributes to risk stratification of patients with different clinical stages.