Background: Although the recommended minimal examined lymph node (ELN) number in rectal cancer (RC) is 12, this standard remains controversial because of insufficient evidence. We aimed to refine this definition by quantifying the relationship between ELN number, stage migration and long-term survival in RC. Methods: Data from a Chinese multi-institutional registry (2009-2018) and the Surveillance, Epidemiology, and End Results (SEER) database (2008-2017) on stages I–III resected RC were analysed to determine the relationship between ELN count, stage migration, and overall survival (OS) using multivariable models. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a Locally Weighted Scatterplot Smoothing (LOWESS) smoother, and structural breakpoints were determined using the Chow test. The relationship between ELN and survival was evaluated on a continuous scale using restricted cubic splines (RCS). Results: The distribution of ELN count between the Chinese registry (n=7694) and SEER database (n=21 332) was similar. With increasing ELN count, both cohorts exhibited significant proportional increases from node-negative to node-positive disease (SEER, OR, 1.012, P<0.001; Chinese registry, OR, 1.016, P=0.014) and serial improvements in OS (SEER: HR, 0.982; Chinese registry: HR, 0.975; both P<0.001) after controlling for confounders. Cut-point analysis showed an optimal threshold ELN count of 15, which was validated in the two cohorts, with the ability to properly discriminate probabilities of survival. Conclusions: A higher ELN count is associated with more precise nodal staging and better survival. Our results robustly conclude that 15 ELNs are the optimal cut-off point for evaluating the quality of lymph node examination and stratification of prognosis.

GADD45B acts as a member of the growth arrest DNA damage-inducible gene family, which has demonstrated to play critical roles in DNA damage repair, cell growth, and apoptosis. This study aimed to explore the potential relationship between GADD45B expression and tumor progression and evaluate the clinical value of GADD45B in stage II colorectal cancer (CRC). The expression patterns and prognostic value of GADD45B in CRC were analyzed based on The Cancer Genomic Atlas (TCGA). GADD45B expression features of 306 patients with stage II CRC and 201 patients with liver metastasis of CRC were investigated using immunochemical staining on tissue microarrays. Afterward, survival analysis and stratification analysis were performed in stage II to explore the prognostic and predictive significance of GADD45B. Overexpressed GADD45B is associated with poorer prognosis for CRC patients both in overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p = 0.001) based on the TCGA database. Analysis results according to the stage II CRC cohort and the liver metastatic CRC cohort revealed that GADD45B was gradually upregulated in normal mucosa including primary colorectal cancer (PCC). Colorectal liver metastases (CLM) tissues were arranged in order (normal tissue vs. PCC p = 0.005 and PCC vs. CLM p = 0.001). The low GADD45B group had a significantly longer five-year OS (p = 0.001) and progression-free survival (PFS) (p < 0.001) than the high GADD45B group for the stage II patients. The multivariate Cox regression analysis results proved that the expression level of GADD45B was an independent prognostic factor for stage II after radical surgery (OS: Hazard Ratio (HR) 0.479, [95% confidence interval (CI) 0.305–0.753] and PFS:HR 0.490, [95% CI 0.336–0.714]). In high GADD45B expression subgroup of stage II cohort, the patients who underwent adjuvant chemotherapy had longer PFS than those who did not (p = 0.008). High expression levels of GADD45B is an independent prognostic factor of decreased OS and PFS in stage II CRC patients. The stage II CRC patients with high GADD45B expression might benefit from adjuvant chemotherapy.

Background Immune checkpoint inhibitors have traditionally been understood to exert their effects primarily within the tumor microenvironment, particularly targeting CD8 + T cells. However, recent studies have highlighted a pivotal role of tumor-draining lymph nodes in mediating responses to immune checkpoint inhibitor therapy. This study aimed to elucidate the specific mechanisms by which tumor-draining lymph nodes respond to immune checkpoint inhibitor therapy and regulate the tumor microenvironment in human colorectal cancer. Methods We performed single-cell RNA sequencing and T cell receptor sequencing on tumor-draining lymph nodes and tumor tissues from patients with colorectal cancer. Through in-depth analysis of the single-cell data, we established the connection between TDLNs and tumor, and explored the impact of immune checkpoint inhibitor therapy on the immune microenvironment of tumor-draining lymph nodes. In addition, we conducted animal experiments to validate these findings. Results Our findings revealed that immune checkpoint inhibitor treatment induced the expansion of tumor-specific CD8 + effector memory T cells within tumor-draining lymph nodes, which may serve as a source for the progenitor-exhausted CD8 + T cells in the tumor microenvironment. Moreover, conventional dendritic cells type 1 and macrophages within tumor-draining lymph nodes facilitated this process. We also observed that immune checkpoint inhibitor therapy promoted the expansion of tumor-specific CD4 + follicular helper T cells in tumor-draining lymph nodes, which may explain the increase of CD4 + follicular helper T cells in the tumor microenvironment after immune checkpoint inhibitor therapy. These hypotheses were corroborated through experiments in mice. Conclusions Our findings delineate the critical regulatory function of tumor-draining lymph nodes in modulating the tumor microenvironment during Immune checkpoint inhibitor therapy.

Background: The National Quality Forum has endorsed at least 12 lymph node yield (LNY) as a surgical quality indicator in colorectal cancer (CRC), but the prognostic value of adequate lymphadenectomy has rarely been investigated for CRC patients with distant metastatic disease. Methods: 4575 CRC patients with synchronous liver metastasis who underwent primary tumor resection were identified from a Chinese registry and the Surveillance, Epidemiology, and End Results (SEER) database between 2010 to 2017. Kaplan-Meier methods and Cox regression models were performed to assess the correlations between LNY and 3-year cancer specific survival (CSS). Propensity score matching (PSM) were used to confirmed the survival comparison between patients with <12 and ≥12 LNY. Results: The retrieval of at least 12 LNY was identified in most CRC patients (SEER database, 3380/3899, 86.7%; Chinese cohort, 565/676, 83.6%). In both SEER database and Chinese cohort, the patients with LNY ≥12 was significantly associated with better CSS compared to patients with LNY <12 before and after PSM, with all P<0.05. After controlling for the confounders, multivariate analysis demonstrated that LNY was also an independent prognostic factor for patients with distant metastasis in both cohorts. In subgroup analysis, the CSS benefit for patients with LNY ≥12 was observed across most of subgroups. Conclusions: Clinical feasibility of the 12–node threshold as a guideline quality metric of cancer care for CRC patients is necessary, and an oncologically adequate lymphadenectomy is still a critical component of high-quality surgical standard in CRC patients with distant metastases.

Background: The impact of the timing of bone metastasis (BM) diagnosis on colorectal cancer (CRC) patients is unclear. Our study aimed to explore the differences in clinicopathological characteristics, treatments and prognosis between synchronous BM (SBM) and metachronous BM (MBM) from CRC. Methods: We retrospectively investigated clinical data of CRC patients with SBM or MBM from 2008 to 2017 at Chinese National Cancer Center. Cancer specific survival (CSS) after BM diagnosis was estimated using the Kaplan-Meier method. The multivariable COX regression model identified the prognostic factors of CSS. Results: Finally, 63 CRC patients with SBM and 138 CRC patients with MBM were identified. Compared to SBM from CRC, MBM significantly was more involving multiple bone lesions (63.0 vs. 7.9%; p < 0.001), and more frequently originated from rectal cancer (60.9 vs. 41.3%; p = 0.033). The therapeutic strategies in SBM and MBM group were contrasted including systemic treatment, bisphosphonates, radiotherapy and metastasectomy for BM. 85.5% of patients in MBM group and 25.4% of patients in SBM group underwent primary tumor resection at initial diagnosis (p < 0.001). The median CSS was 11 months in both SBM and MBM group (p = 0.556), yet MBM patients developed from CRC in early AJCC stage presented obviously longer survival than those from advanced stage. Furthermore, patients could have improved CSS from primary tumor resection while there might be no survival benefit from targeted therapy in both SBM and MBM groups. Bisphosphonates was associated with a better CSS for patients with SBM, while radiotherapy for BM was related to a better CSS for patients with MBM. Conclusion: The CRC patients in SBM and MBM group represented different clinicopathological characteristics and treatment modalities, which affected the prognosis in different ways. Distinct consideration for CRC patients with SBM and MBM in clinical decision making is required.

Objectives: To compare the value of tumor stroma ratio (TSR) and radiomic signature from baseline MRI for stratifying the risk of distant metastases (DM) in patients with locally advanced rectal cancer (LARC). Materials and methods: Data from 302 patients with LARC who underwent neoadjuvant chemoradiotherapy and total mesorectal excision in our hospital between 2015 and 2018 were retrospectively reviewed, and the patients were randomly allocated into the training and validation cohorts in a ratio of 7:3. Patients were followed-up for more than 3 years postoperatively with metachronous DM as the endpoint. Independent risk factors for DM-free survival (DMFS) were analyzed using Cox regression. The TSR of endoscopic biopsy specimens was scored automatically. Totally 1229 radiomic features of each tumor were extracted from baseline MRI, and the Radscore was calculated. Results: The median follow-up time was 54.3 (51.6–57.1) months, and the 3-year DMFS was 83.8%. The best cutoff value of the TSR to distinguish a patient’s DM risk was 0.477 (Sen=70.8%, Sep=78%, P <0.001). Increased TSR (HR=3.072, P =0.006) and Radscore (HR=719.231, P =0.023), advanced MR-evaluated T stage (HR=2.660, P =0.023) and ypN (HR=2.362, P =0.028) stage were independent risk factors for DMFS. The area under the curve of the combined model was significantly higher than that of the radiomic model ( P =0.013) but without a significant advantage over the TSR model ( P =0.086). Conclusion: TSR of colonoscopic biopsies can independently stratify DM risk in patients with LARC. The TSR model is the most convenient and efficient method for DM risk stratification in LARC.