Aiwen Wu

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.

Colorectal cancer is the third most common malignant tumor globally. The current clinical therapeutic outcome is often jeopardized by the complex pathological process that is highly heterogenous among individual patients. It becomes increasingly critical for successful treatments to have diverse valid therapeutic options in clinic, which urgently demands efficient preclinical animal model to develop new drug and screen effective and safe clinical interventions. Patient-derived xenograft (PDX) mouse models, created by implanting fresh tumor tissue into immunodeficient or humanized mice, serve as a crucial resource in translational cancer research. These models closely replicate the tissue, cellular, and genetic characteristics of the original tumors, supporting their use in precision medicine, drug discovery, biomarker research, and studies of drug resistance. However, repeated transplantation can introduce genomic instability, molecular shifts, and phenotype variability. This article explores the development, advantages, limitations, and future directions of PDX models in preclinical cancer research.

Peritoneal lavage cytology (PLC) is used to detect peritoneal micrometastases in gastrointestinal malignancies, but its prognostic value in colorectal canc

Background/Objectives: The metastatic patterns of apical lymph node (ALN) in rectal and sigmoid colon cancer are currently unclear, and there is no consensus on the indications for dissection of ALN. This study aimed to analyze the impact of ALN metastasis on prognosis, determine the metastatic patterns of ALN and provide evidence for indications of ALN dissection in rectal and sigmoid colon cancer. Methods: In this multicenter, retrospective cohort study, patients from five centers with stage I-III rectal or sigmoid colon cancer who underwent laparoscopic radical surgery with ALN dissection without neoadjuvant treatment from January 2015 to December 2019 were enrolled. Results: Among 2809 patients, the positive rate of ALN was 1.9%. The 5-year overall survival and cancer-specific survival rate for patients with metastatic ALN were 37.5% and 41.0%, respectively. ALN metastasis was the independent risk factor for poor prognosis. Tumor size ≥5 cm (OR = 2.32, 95% CI: 1.30–4.13, p = 0.004), signet ring cell cancer/mucinous adenocarcinoma (vs. poor differentiated adenocarcinoma, OR = 0.19, 95% CI: 0.08–0.45, p < 0.001; vs. moderate to well differentiated adenocarcinoma, OR = 0.22, 95% CI: 0.11–0.42, p < 0.001), T4 stage (OR = 1.93, 95% CI: 1.05–3.55, p = 0.034), N2 stage (OR = 8.86, 95% CI: 4.45–17.65, p < 0.001) and radiologic evidence of extramural venous invasion (OR = 1.88, 95% CI: 1.03–3.42, p = 0.040) were independent risk factors for ALN metastasis. The nomogram model developed by these factors achieved a good predictive performance. Conclusions: This research offered insights into the incidence, risk factors, and prognostic significance of apical lymph node metastasis in cases of rectal and sigmoid colon cancer. Additionally, the study furnished empirical support for the criteria guiding ALN dissection. Furthermore, a pragmatic risk assessment model was developed to predict ALN metastasis.

BACKGROUND Stoma creation is a common procedure in colorectal cancer surgery, however, stoma-related complications remain a significant concern. AIM To investigate the incidence, types, and risk factors of stoma-related complications in colorectal cancer patients who underwent stoma creation. METHODS Patients with stoma was prospectively recorded in the established stoma system. Data was collected from this stoma management system from November 2021 through May 2024. The rates of stoma-related complications were assessed, and potential risk factors were analyzed using univariate and multivariate logistic regression models. RESULTS A total of 734 patients were included in the analysis. The results showed that 12.3% of patients experienced stoma-related complications, with mucocutaneous separation, edema, and skin excoriation being the most common complications. The majority (90%) of complications were classified as grade 2 according to the Clavien-Dindo classification. Surgical factors, such as blood loss volume greater than 500 mL and open surgery, were significantly associated with stoma complications. Additionally, stoma features like location, shape, color, height, and edema were important factors in the association with complications. Body mass index over 30 kg/m² was also found to be a significant risk factor. CONCLUSION These findings highlight the need for a holistic approach to preventing and managing stoma complications, considering both patient-related and surgical factors.

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%, 32.7% and 14.0% for experiment groups A and B and the control group, respectively. The difference in pCR rates between experiment group B and the control group reached statistical significance (risk ratio 2.332, 95% confidence interval 1.106–4.916; P = 0.019). No substantial differences between either one of the experiment groups and the control group were observed regarding adverse reaction, surgical complication and disease progression. Our results show that adding PD-1 blockade after neoadjuvant chemoradiation increases the pCR rate for patients with LARC and raises no substantial safety concerns. Phase 3 trials with larger sample sizes are warranted (ClinicalTrials.gov identifier NCT05245474).