145 Background: Given that Deficient Mismatch Repair (dMMR) colon cancer patients respond poorly to conventional chemotherapy but immunotherapy significantly improves pCR rates in this population, this study aims to explore whether neoadjuvant immunotherapy can increase the rate of R0 resection with preservation of adjacent organs in dMMR T4 colon cancer patients and investigate the optimal regimen of immunotherapy. Methods: This single-arm, open-label, phase II trial was conducted at Peking Union Medical College Hospital in China. Patients were eligible for enrollment if they had immunohistochemically confirmed colon adenocarcinoma with confirmation of dMMR and clinical T 4 stage (defined as a tumor has invaded the serosal surface [cT 4a ] or has invaded or adhered to adjacent organs or structures [cT 4b ]). All patients are planned to receive three cycles of camrelizumab (200mg intravenously administered at the beginning of each cycle every 3 weeks) followed by radical surgery. Surgery was scheduled 2–4 weeks after three cycles. The primary endpoint of this study was the R0 resection rate in all patients who received surgery (defined as resection with a microscopic negative margin). Secondary endpoints included the rate of pCR (defined as no residual viable tumor in either the tumor bed or the lymph nodes), tumor regression grade (TRG), the incidence of adverse event (AE) during neoadjuvant immunotherapy. Results: A total of 18 patients with clinical T 4 stage and dMMR colon cancers were deemed eligible for enrollment and 17 patients were included in per-protocol set analysis from April 2024 to July 2025. The primary endpoint was evaluable in 17 patients, with 16 patients having R0 resection of 94.1%. Pathological response was observed in 14 of 16 patients, including 11 with pathological complete response. The pCR associated with a decreased trend density of PD-L1+ cells [139.3 (99.0, 272.6) cells/mm 2 vs 323.1 (114.3, 528.2) cells/mm 2 , P =0.157]. All patients experienced treatment-related AEs (100%) during neoadjuvant immunotherapy. Sixteen patients (94.1%) had Grade 1-2 AEs, while 1 patients had Grade 3 AE. Conclusions: Three cycles of mono-immunotherapy appear to be a regimen for patients with dMMR T 4 colon cancer with acceptable surgical efficacy and safety. Clinical trial information: NCT06215677 .

BACKGROUND:The tumor microenvironment, particularly the tumor stroma, plays a critical role in tumor progression, immune evasion, and therapeutic resistance. However, its interaction with the immune landscape in rectal cancer (RC) remains incompletely understood. This study aimed to comprehensively characterize the stromal-immune ecosystem associated with the tumor stroma ratio (TSR) in RC and to evaluate its clinical and therapeutic relevance. METHODS:We analyzed a multicenter cohort of 498 patients with treatment-naïve RC in whom TSR was assessed on H&E-stained sections. Integrative multi-omics analyses were performed, including bulk RNA sequencing (n=118) and single-cell RNA/T-cell receptor (TCR) sequencing (n=10). Key findings were validated by immunohistochemistry (n=114) and multiplex immunofluorescence (n=20). Survival analyses and statistical comparisons were conducted to evaluate clinical associations and treatment responses. RESULTS:High TSR was an independent predictor of unfavorable disease-free survival and cancer-specific survival and was associated with aggressive clinicopathological features. Single-cell analyses revealed that TSR-high tumors exhibited a profoundly immunosuppressive microenvironment, characterized by clonally expanded terminally exhausted CD8+ T cells (CD8+ Tex-CXCL13) and activated CD4+ regulatory T cells (CD4+ Treg-TNFRSF4). Two LRRC15+ cancer-associated fibroblast (CAF) subsets (mCAF-CTHRC1 and mCAF-FAP) were enriched in TSR-high tumors. Among them, mCAF-CTHRC1 was associated with increased Treg abundance and activation features, with predicted interactions with CD4+ Treg-TNFRSF4 cells through the LGALS9-CD44 signaling axis. In addition, SPP1-expressing monocytes (Mon-SPP1) and malignant epithelial cells were prominent in TSR-high tumors and showed a predicted SPP1-CD44 interaction with T-cell subsets, suggesting potential involvement in immunosuppressive stromal-immune interactions. In patients receiving neoadjuvant therapy, pretreatment TSR-low tumors showed improved pathological response and survival outcomes compared with TSR-high tumors. In the neoadjuvant chemoradiotherapy plus immunotherapy cohort, TSR-low tumors were associated with a significantly higher major pathological response rate, whereas pathological complete response showed a non-significant trend in the same direction. CONCLUSIONS:High TSR identifies a clinically aggressive subtype of RC characterized by a profoundly immunosuppressive stromal-immune ecosystem enriched for exhausted T cells, immunosuppressive CAF programs, and SPP1-associated stromal-myeloid interactions. These findings highlight LGALS9-, LRRC15-, and SPP1-related stromal-immune pathways as candidate stromal-immune therapeutic vulnerabilities that warrant further mechanistic and preclinical validation.

The role of adjuvant chemotherapy (ACT) in patients with locally advanced rectal cancer (LARC) who achieve pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) remains controversial, and it is unclear whether pCR represents a uniformly low-risk state with respect to long-term outcomes. We retrospectively analyzed consecutive LARC patients who achieved pCR following nCRT and radical surgery between 2017 and 2022. Survival outcomes were assessed according to postoperative ACT administration, treatment adequacy (≥ 4 cycles vs. < 4 cycles), and baseline risk features. Among 1069 patients treated with nCRT and surgery, 251 (23.5%) achieved pCR. After a median follow-up of 49 months, no statistically significant differences in overall survival (OS) or disease-free survival (DFS) were observed between patients who received ACT and those who did not. In contrast, patients who completed an adequate course of ACT (≥ 4 cycles) demonstrated improved 4-year OS and DFS compared with those receiving fewer cycles or no ACT. This association was largely confined to patients with baseline high-risk features, while no significant survival differences were observed between different ACT regimens. These findings suggest that pCR does not represent a biologically homogeneous or uniformly low-risk condition in LARC. Adequate postoperative chemotherapy may confer survival benefit in selected high-risk patients. A risk-adapted approach to ACT warrants further investigation and prospective validation.

BackgroundPostoperative recurrence remains a major cause of treatment failure and death in patients with locally advanced rectal cancer (LARC), despite advances in neoadjuvant chemoradiotherapy (NCRT) and radical surgery. This study evaluated the prognostic value of initial recurrence patterns on post-recurrence survival (PRS) and examined clinicopathological factors associated with recurrence-free survival (RFS).MethodsThis retrospective study included 437 patients with LARC who underwent NCRT followed by surgery. In the cohort without preoperative metastasis, RFS was analyzed using the Kaplan–Meier method and Cox proportional hazards regression models. Among patients who developed postoperative recurrence, initial recurrence patterns were categorized as isolated lung metastasis, isolated liver metastasis, or complex recurrence based on the first site of recurrence. PRS was analyzed with the Kaplan–Meier method, and prognostic factors were identified through Cox proportional hazards regression models. A 2-year landmark analysis was conducted to assess subsequent overall survival (OS) according to recurrence status within 2 years after surgery.ResultsAmong the 437 patients, 347 remained recurrence-free, 28 had preoperative metastasis, and 62 developed postoperative recurrence. In the curative-intent cohort, multivariable Cox regression analysis indicated that pathological tumor deposit (pTD) positivity (HR, 2.37; P = 0.006) and ypTNM stage II–III (HR, 1.923; P = 0.012) were independently associated with shorter RFS. Multivariable Cox regression analysis showed that the initial recurrence pattern was independently associated with PRS. Compared with isolated lung metastasis, complex recurrence was consistently associated with poorer PRS, whereas isolated liver metastasis showed an intermediate prognosis. Kaplan–Meier analysis further revealed notable differences in PRS among recurrence patterns, with isolated lung metastasis having the most favorable outcome and complex recurrence the poorest prognosis. Additionally, recurrence within 2 years after surgery was linked to significantly lower subsequent OS in the 2-year landmark analysis.ConclusionsThe initial postoperative recurrence pattern was independently associated with PRS in patients with LARC following NCRT and surgery. Isolated lung metastasis was associated with relatively better outcomes, while complex recurrence indicated a poorer prognosis. In the curative-intent group, higher ypTNM stage and pTD positivity were independently associated with worse RFS. These findings may help improve postoperative risk stratification and support personalized surveillance and management.

Elevated intratumoral immune inflammation prior to treatment is typically associated with better outcomes in hot tumors treated with immune checkpoint inhibitors (ICIs). However, we observed a paradox in pMMR/MSS locally advanced rectal cancer (LARC) patients, where a subset with elevated baseline immune inflammation exhibited worse outcomes after combined radiotherapy and ICI treatment compared with patients with minimal immune inflammation. To investigate this counterintuitive finding, we performed paired scRNA-seq and scTCR-seq on longitudinally collected samples, including tumor biopsies (pre-treatment, post-radiotherapy, and post-immunotherapy) and peripheral blood mononuclear cells (pre-treatment and post-immunotherapy), from 20 pMMR/MSS LARC patients treated with sequential radiotherapy and ICI therapy (NCT06493240). We propose the concept of clonal entrapment to explain this phenomenon. Specifically, our profiling results reveal that increased HLA-DQA2 expression in dendritic cells and upregulated GDF15 expression in treatment-resistant tumor cells correlate with the restricted expansion of novel tumor-reactive TCR clonotypes. Consequently, the immune response is limited primarily by pre-existing TCR clonotypes within the tumor, especially those partially expanded under chronic inflammation, leading to the expansion of TCR clonotypes derived mainly from pre-treatment CD8+ T cell pools following ICI therapy. By identifying this feature of the pMMR/MSS LARC microenvironment, our study provides a high-resolution framework for understanding resistance to sequential radiotherapy and ICI therapy.

The Tianhe Procedure is a functional sphincter-preserving surgical approach developed for patients with rectal cancer following radiotherapy. This technique involves proximal extended resection of the colon beyond the pelvic cavity, followed by anastomosis of the non-irradiated proximal colon to the distal rectum or anal canal. This strategy aims to reduce the incidence of anastomotic complications and postoperative bowel dysfunction. However, there is currently a lack of standardized practice guidelines for implementing the Tianhe Procedure in China. Therefore, the Chinese Radiation Intestinal Injury Research Group, the Colorectal Surgery Group of Surgery Branch of the Chinese Medical Association, the Anorectal Branch of Chinese Medical Doctor Association, the Colorectal Cancer Committee of the Chinese Medical Doctor Association, the Colorectal Cancer Committee of China Anti-cancer Association, and the Gastrointestinal Surgical Branch of Guangdong Medical Doctor Association have jointly convened a panel of national experts to discuss and establish this standardized surgical procedure. This standard, based on the latest evidence from literature, research advancements, and expert experience, focuses on key aspects of the Tianhe Procedure, including its precise definition, indications, critical procedural steps, postoperative complications, and functional rehabilitation strategies. It aims to promote standardized implementation and broader clinical adoption of this innovative surgical technique.

Objective To investigate the clinical efficacy of neoadjuvant imatinib in the treatment of rectal gastrointestinal stromal tumor(GIST).Methods Patients with rectal GIST who underwent surgery at Peking Union Medical College Hospital from January 2015 to January 2025 were included.Clinical data were retrospectively analyzed.Patients were divided into the neoadjuvant therapy group(received preoperative ima-tinib)and the control group(underwent direct surgery without preoperative imatinib).Clinical outcomes and recurrence rates were compared between the two groups.Results A total of 74 patients meeting the inclusion criteria were included,with 43 included in the neoadjuvant therapy group and 31 included in the control group.Baseline evaluation showed that the median tumor diameter was significantly larger in the neoadjuvant therapy group than that in the control group[5.0(2.9,7.1)cm vs.2.0(0.8,3.2)cm,P＜0.001].After treat-ment with imatinib,the median tumor diameter in the neoadjuvant group decreased significantly from 5.0(2.9,7.1)cm to 2.3(1.0,4.0)cm(P=0.003).There were no significant differences between the two groups in positive surgical margin rate,anal sphincter preservation rate,5-year disease-free survival,hospi-tal stay,or recurrence rate.Conclusions Neoadjuvant therapy with imatinib can effectively reduce tumor vol-ume in patients with rectal GIST.However,its therapeutic benefit still needs to be further validated by prospec-tive,large-sample clinical studies with long-term follow-up.

In the past 5 years, clinical trials on immune checkpoint inhibitors (ICIs) for the treatment of locally advanced rectal cancer (LARC) have flourished globally, and China has become one of the leading regions in this field. In response to the breakthrough progress and accumulation of evidence from key clinical trials, the Chinese Society of Colorectal Surgery has recognised the need for updated consensus guidance on the development of perioperative and organ-preserving treatment strategies for LARC. This expert consensus guidance provided unified standards for the indications, medication regimens, efficacy evaluations and follow-up of ICIs in this population, with a focus mainly on perioperative management and organ-sparing strategies. The diagnostic part of this consensus guidance is based on the internationally recognised definition of mismatch repair/microsatellite instability detection and emphasises the importance of multidisciplinary teams in treatment decision-making. In terms of treatment, based on the results of key trials that have changed clinical practice in the past 5 years, this expert consensus provides graded recommendations for the duration of preoperative immunotherapy and the necessity of postoperative adjuvant therapy, local resection and organ preservation strategies. Moreover, we refined the management process for the safety of perioperative immunotherapy. This document aims to provide a reference for surgeons; internal medicine, radiation therapy, pathology and imaging physicians; patients and nursing staff involved in the treatment of LARC, as well as health policy makers.

BACKGROUND Total mesorectal excision is the standard surgery for locally advanced rectal cancer (LARC) after neoadjuvant chemoradiotherapy (nCRT), but it may lead to high complication rates and poor quality of life. This study evaluates whether transanal endoscopic microsurgery (TEM), as a partial resection procedure, can enhance quality of life for clinical complete response (cCR) or near-cCR patients without compromising survival. METHODS Between May 2017 to September 2021, 80 patients with T3-4N0M0 or TanyN+M0 mid-low rectal cancer achieving cCR or near-cCR post-nCRT were prospectively included at 6 Chinese centers. Patients underwent either TEM (Group A, n=38) or radical surgery (Group B, n=41). Clinicopathological, oncological, and functional outcomes were analyzed. RESULTS Postoperative histology revealed 22 ypT0 (57.9%), 5 ypT1 (13.2%), 10 ypT2 (26.3%), and 1 ypT3 (2.6%) cases in group A and 20 pCR (48.8%), 1 T0N1 (2.4%), 5 T1N0 (12.2%), 12 T2-3N0 (29.3%), 3 T2-3N1 (7.3%) cases in group B. After a 60-month median follow-up, local recurrence occurred in 2 patients (5.26%) in Group A and none in Group B. Distant metastases occurred in 8 patients (21.05%) in group A and 7 (17.07%) in group B. There was no significant difference between the two groups in 5-year disease-free survival (P=0.658) or 5-year overall survival (P=0.465). Group A showed significantly faster recovery (P<0.001) and better sphincter function per Wexner (1 vs. 4, P=0.001) and LARS (0 vs. 17, P<0.001) scores than Group B. CONCLUSION TEM may be an effective approach for assessing residual tumors in LARC patients with cCR or near-cCR. This approach offers an option for those requiring sphincter preservation, with no significant compromise in long-term oncological outcomes observed in our study.

Locally advanced rectal cancer (LARC) staged as mrT3 could be further subdivided into mrT3a to T3d based on depth of tumor invasion through the muscularis propria. Limited evidence exists to compare the differences across subgroups. Clinical data from patients between January 2018 and 2022 were collected. The study included patients with mrT3 LARC who received neoadjuvant chemoradiotherapy (NCRT). Based on depth of invasion through muscularis propria, patients were categorized into three groups: mrT3a (< 5 mm), mrT3b (5 10 mm), mrT3c d group (> 10 mm). The outcomes were disease-free survival (DFS), pathological complete response (pCR), tumor recurrence and metastasis. A total of 295 patients were identified, including 65 (22.0

3587 Background: Neoadjuvant chemoradiotherapy is currently the standard strategy for microsatellite stable (MSS) / mismatch repair-proficient (pMMR) locally advanced rectal cancer (LARC) patients. This study aimed to explore the safety and efficacy of combining specific (thymalfasin) and non-specific (tislelizumab) tumor immunotherapy with chemoradiotherapy in MSS/pMMR LARC. Methods: This trial is an open, prospective, multi-center, single-arm phase II clinical study assessing the efficacy and safety of neoadjuvant chemoradiotherapy combined with thymosin andtislelizumab in MSS/pMMR LARC. Stage II/III MSS/pMMR LARC patients (cT 3-4a N 0 M 0 and cT 1-4a N 1-2 M 0 ) with the tumor distal location ≤ 10 cm from anal verge at two centers in China were consecutively enrolled. Patients received chemoradiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week, 5 weeks; plus capecitabine 850-1000 mg/m 2 , bid, po, 5 days/week, day1-5), thymalfasin (4.8 mg, biw, ih, day 1 and day 4 from week 1-11) and three 21-day cycles tislelizumab (200 mg, iv.gtt, week 2, 5 and 8) as neoadjuvant therapy. Adjuvant therapies after neoadjuvant were nonuniformly specified and decided according to clinical experiences. The primary endpoint is the complete response (CR) rate, defined as the achievement of clinical complete response (cCR) after neoadjuvant therapy or pathological complete response (pCR) after total mesorectal excision (TME). Results: From Feb 2024 to Aug 2024, a total number of patients (n = 25) were enrolled and 3 patients were excluded because of T4b and dMMR. Finally, 2 patients were discontinued and 20 completed neoadjuvant therapy. The median age was 67.5 (from 36 to 74) years while the median tumor distal location was6.0 (from 3.5 to 8.5) cm. The CR, PD, and SD rate was 40.0% (8/20), 45.0% (9/20), and 15.0% (3/20) correspondingly, with the ORR rate of 85.0% (17/20). Grade 3 treatment-related adverse events (trAEs) including leukopenia and neutropenia were observed in 1 (5%) patient, while grade 1-2 trAEs were observed in 15(75.0%) patients. As for Dec 31, 2024, the EFS rate was 100% (20/20) with median follow-up time of 18.57 weeks (from 6.86 to 31.86). Conclusions: Neoadjuvant chemoradiotherapy plus thymalfasin and tislelizumab show promising anti-tumour activity in MSS/pMMR LARC patients, with manageable toxicities. This study suggests that such combination could be a promising therapeutic strategy for patients with MSS/pMMR LARC. Clinical trial information: NCT06056804 .

Patients with a tumor regression grade of 0 or 1 (CAP), are classified as well-responders after neoadjuvant chemoradiotherapy (NCRT). Although well-responders are expected to have superior prognosis, occurrences of recurrence and metastasis still exist. Clinical data of patients from January 2017 to 2022 were analyzed. Inclusion criteria: adenocarcinoma, cT3-4N0 or cTanyN+, receiving NCRT and surgery, CAP 0 1. The primary endpoint was three-year disease-free survival (3y-DFS). According to occurrence of DFS events, patients were divided into DFS (470, 91.8

Background:Tumor location affects rectal cancer management, but no consensus exists on criteria. The anterior peritoneal reflection (aPR), an anatomical landmark, shows potential for defining tumor location but requires clinical validation. This study evaluated the utility of aPR in guiding neoadjuvant chemoradiotherapy (nCRT) decisions and predicting lateral lymph node (LLN)/distant metastasis patterns. Methods:This single-center retrospective cohort analyzed data from Peking Union Medical College Hospital (Beijing, China) between January 2016 and August 2022. Magnetic resonance imaging (MRI)-measured aPR parameters were pathologically validated. Patients were stratified by aPR-based definition and tumor height (10 cm). Kaplan-Meier survival curves, log-rank tests, and Cox regression were used for prognostic analysis. Results:Among 588 patients (439 tumors ≥5 cm from the anal verge), MRI identified aPR with an accuracy of 95.4%. For tumors ≥5 cm, aPR-defined middle-to-low rectal cancer showed lower 3-year disease-free survival (DFS) rate than the upper rectal cancer (P = 0.010), while their 3-year overall survival (OS) rates were comparable. Conversely, 10-cm-defined classification showed no DFS or OS differences (both P > 0.2). Cox regression confirmed aPR-defined classification as an independent DFS predictor (HR = 3.19, P = 0.014), while 10-cm classification was non-predictive. nCRT with tumor regression grade (TRG) 0-1 trended toward improved DFS compared with direct surgery (HR = 0.56, P = 0.072). The independent protective effect of nCRT with TRG 0-1 for DFS was exclusive to the aPR-defined middle-to-low rectal cancer subgroup (HR = 0.45, P = 0.026) and not observed in the 10-cm subgroup. aPR-defined classification was independently associated with LLNs on MRI and postoperative pulmonary metastasis. Conclusion:aPR may guide nCRT decision-making and predict LLN metastasis and postoperative distant organ metastasis.

Radiotherapy displays unique antitumor synergism with immune checkpoint inhibitors, which is indicated by high pathological complete response (pCR) rates from single-arm trials of locally advanced rectal cancer (LARC). Here we test the efficacy and safety of the radiation–immune checkpoint inhibitor combination in patients with LARC in a phase 2, randomized trial conducted in eight major colorectal cancer centers in Beijing. In total, 186 eligible all-comer (proficient mismatch repair and deficient mismatch repair) participants were enrolled. The patients were randomly assigned to receive neoadjuvant chemoradiation + concurrent/sequential PD-1 blockade (experiment groups A/B) or neoadjuvant chemoradiation alone (control group). Radical surgeries were scheduled after neoadjuvant treatments. The primary endpoint was the pCR rate. The pCR rates were 27.1 NCT05245474 ). In a multicenter, open-label, randomized phase 2 trial, neoadjuvant chemoradiation with PD-1 blockade elicited a pathological complete response rate superior to that with neoadjuvant chemoradiation alone in patients with locally advanced rectal cancer.

BackgroundThe evolving neoadjuvant therapy regime is revolutionizing the management of local advanced rectal cancer (LARC). Total neoadjuvant therapy (TNT) and neoadjuvant immunotherapy are currently the most prominent strategies. However, existing studies predominantly evaluate these approaches in isolation, leaving their comparative efficacy unresolved.MethodsA three-arm retrospective study was conducted including a total of 160 consecutive patients pathologically diagnosed as adenocarcinoma with pMMR or non-MSI-H and receiving neoadjuvant therapy followed by radical resection in Peking Union Medical College Hospital (PUMCH). Based on the neoadjuvant therapy regimen, patients were divided into three groups: the nCRT group (n=81), the TNT group (n=42), and the PD-1 group (n=37). The clinical data including baseline characteristics, treatment information, and MRI accuracy on rectal cancer restaging were analyzed. Considering the possible impact of gut microbiome on antitumor immunity, we also analyzed differences in gut microbiome between baseline stool samples from pCR and non-pCR patients in the PD-1 group.ResultsNo significant differences were found in baseline characteristics among the three groups. The rates of pathologic complete response (pCR, corresponding to pTRG 0) were 25.9% (21/81) in the nCRT group, 40.5% (17/42) in the TNT group, and 45.9% (17/37) in the PD-1 group (p=0.048). The accuracy of MRI for restaging rectal cancer T stage was not ideal, particularly in the TNT and PD-1 groups. Additionally, the α and β diversity of gut microbiome between baseline stool samples from pCR and non-pCR patients in the PD-1 group were similar.ConclusionsBoth TNT and PD-1 combination therapy demonstrated higher tumor regression and pCR rates compared with nCRT, suggesting enhanced local tumor control. However, improvements in rectal MRI accuracy and gut microbiome research are needed to enhance precision in diagnostics and therapy.

PURPOSE:The clinical benefit of incorporating oxaliplatin into conventional neoadjuvant chemoradiotherapy (nCRT) for patients with high-risk locally advanced rectal cancer (LARC) remains controversial. METHODS AND MATERIALS:This multicenter, open-label, randomized controlled trial enrolled 505 patients with high-risk LARC, defined by the presence of at least 1 of the following adverse features: clinical T4 stage, clinical N2 stage, high tumor grade, extramural vascular invasion, involvement of the mesorectal fascia, or perianal musculature involvement. Enrollment took place between August 2017 and April 2022. Patients were randomly assigned to receive long-course radiation therapy combined with a 3-cycle chemotherapy regimen of capecitabine and oxaliplatin (CapeOX group; n = 248) or capecitabine alone (Cape group; n = 257). The primary endpoint was 3-year disease-free survival (3y-DFS). RESULTS:Following nCRT, radical surgery was performed in 91.5% of the CapeOX group and 92.2% in the Cape group (P = .778). Pathologic complete response rates were comparable between the CapeOX and Cape groups (25.5% vs 25.3%; P = .954). A significantly greater proportion of patients in the CapeOX group achieved marked tumor regression (College of American Pathologists (CAP 0-1)) compared with the Cape group (58.6% vs 46.8%; P = .011). The incidence of grade 3 to 4 treatment-related toxicities was similar between the groups (CapeOX: 14.1% vs Cape: 9.3%; P = .095). After a median follow-up of 37 months, 3y-DFS and 3-year overall survival rates were comparable between the groups (both P > .050). Overall, patients who achieved CAP 0 to 1 had significantly better 3y-DFS than those with CAP 2 to 3 (89.0% vs 80.9%; P = .018). CONCLUSIONS:The addition of oxaliplatin to conventional nCRT may enhance pathologic tumor regression in patients with high-risk LARC without a significant increase in severe adverse events. However, this intensified 3-cycle chemotherapy regimen did not translate into a long-term survival benefit.

BACKGROUND:Accurate risk stratification is essential to optimize neoadjuvant therapy for locally advanced rectal cancer (LARC) in the era of precision medicine. This study assessed the feasibility and safety of a circulating tumor DNA (ctDNA)-guided neoadjuvant strategy. METHODS:This interim analysis included patients with mid-low rectal adenocarcinoma (cT3-4N0M0 or cT1-4N1-2M0) from the multicenter, randomized CINTS-R trial using a 2:1 allocation to an experimental or control group. The control group received conventional nCRT (long-course radiotherapy with concurrent capecitabine followed by one XELOX cycle). In the experimental group, treatment was stratified as follows: (1) ctDNA-defined high-risk patients received TNT, consisting of the same nCRT followed by five additional XELOX cycles (six in total); (2) ctDNA-defined low-risk patients proceeded directly to surgery after nCRT; and (3) patients with dMMR/MSI-H/TMB-H tumors received neoadjuvant tislelizumab (≥6 cycles). The analysis focuses on feasibility and safety outcomes. RESULTS:Between February 2023 and September 2024, 349 patients were randomized and 316 included in analysis (experimental: 210; control: 106). Among the experimental group, 115 were ctDNA-high-risk and 89 ctDNA-low-risk. High-risk patients were significantly older and more often male, with larger tumors, longer tumor-to-anal verge distance, greater circumferential involvement, and higher EMVI rates (all p ＜0.05). Serious adverse events (SAEs, CTCAE v5.0, grade 3-4) occurred in 10.0 % vs. 6.6 % of patients in the experimental and control groups (p = 0.316). Notably, 15.7 % of TNT-treated patients discontinued chemotherapy due to SAEs, whereas all nCRT recipients completed treatment. CONCLUSION:This interim analysis demonstrates the feasibility and safety of a ctDNA-guided, risk-adapted neoadjuvant strategy for LARC. Final outcomes will further clarify its clinical efficacy. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT05601505.

Background: Due to the heterogeneity of colorectal cancer (CRC), models that can predict the chemotherapy response are needed to facilitate personalized treatment. Aim: To construct patient-derived tumor-like cell cluster (PTC) models in vitro drug sensitivity screening for CRC personalized chemotherapy. Methods: We collected 140 CRC tissues via surgical resection in three Chinese hospitals and establish PTC models which is highly similar to the original tumor tissue. The sensitivity to various chemotherapy drugs was assessed in these PTC models. We recorded the PTC model cultivation process and patients' clinical data and assessed the concordance between in vitro drug sensitivity and clinical outcomes. Results: PTC models were successfully established from 124 specimens, with a success rate of 88.6 %. The average culture time was 3.02 ± 1.56 days, and the median time to obtain drug sensitivity results was 11 days (10–13 days). Drug sensitivity testing revealed that the PTC models had variable responses to different chemotherapy regimens, with some patients showing unexpected sensitivity to regimens not typically considered first-line treatments. The median follow-up time for all patients was 19 months, and there was no significant difference in disease-free survival (DFS) between patients whose actual responses to clinical treatment regimens were consistent or inconsistent with the PTC model predictions. Conclusion: The PTC model for drug sensitivity testing has advantages of high success rate and rapid drug screening time. This study provides a promising tool for personalized chemotherapy sensitivity screening in patients with CRC and, after further clinical trials, may guide clinical treatment decision making.

Background and Purpose: Neoadjuvant immunotherapy currently significantly enhances treatment efficacy for locally advanced rectal cancer (LARC); However, clinical management of immune-related adverse events (irAEs) lacks robust evidence. This study aimed to investigate the characteristics, clinical management strategies, and outcomes of irAEs during neoadjuvant immunotherapy for rectal cancer, providing a basis for optimizing irAEs monitoring and intervention. Methods: We retrospectively analyzed clinical data from LARC patients who developed irAEs after receiving neoadjuvant immunotherapy at Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, between July 2022 and June 2024. Types of irAEs, severity, time of onset, management strategies, and outcomes were recorded. All patients underwent regular follow-up for at least 6 months. This study has been approved by Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (ethical approval number: I-24PJ0024). Descriptive statistics were used to summarize irAEs patterns and management approaches. Results: A total of 41 irAE episodes occurred among the 30 patients. Mild irAEs (Grade 1-2) accounted for 78.0% (32/41), while severe irAEs (Grade 3-4) constituted 22.0% (9/41). Five patients (16.7%) permanently discontinued treatment due to severe toxicity. Endocrine toxicities were most frequent (36.6%, 15/41), primarily characterized by progression from hyperthyroidism to hypothyroidism; 75.0% required thyroid hormone replacement therapy. One case of delayed-onset adrenal insufficiency was alleviated with glucocorticoid (GC) therapy. Among hepatotoxicities (19.5%, 8/41), 62.5% were Grade 3 injury, and 37.5% required GC intervention; two patients experienced recurrence during adjuvant chemotherapy. Three cases of severe myositis occurred, accompanied by asymptomatic myocardial injury (evidenced by markedly elevated creatine kinase and concurrent changes in cardiac biomarkers), all requiring high-dose GC pulse therapy combined with intravenous immunoglobulin or immunosuppressants (recovery period: 2-4 months). Nine dermatological reactions were managed with topical therapy. Two gastrointestinal events occurred, including one Grade 3 diarrhea treated with GCs. The overall GC usage rate was 31.7% (13/41), with 76.9% administered for Grade ≥3 irAEs. Conclusion: irAEs during neoadjuvant immunotherapy for LARC are predominantly mild-to-moderate and manageable with supportive care. However, some patients develop severe (Grade 3-4) irAEs requiring multidisciplinary management. GC usage is concentrated in higher-grade irAEs, with severe myositis and cardiac involvement necessitating intensive immunosuppressive therapy despite their rarity. Recurrence of irAEs during adjuvant chemotherapy in a minority of patients underscores the necessity for early recognition, graded intervention, and comprehensive management throughout the entire treatment cycle.