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Abstract Background The prognostic value of Albumin and D-dimer has been established for multiple tumor types, indicating their potential for predicting tumor development. Nevertheless, the predictive capability of the DDI-to-albumin ratio (DAR) in locally advanced rectal cancer (LARC) remains uncertain. Purpose The objective of this study was to investigate the prognostic significance of the DAR in LARC. Methods A total of 513 patients who underwent neoadjuvant chemoradiotherapy (nCRT) prior to total mesorectal excision (TME) between March 2013 to October 2019 were included in this study. Patients were divided into high-level DAR (> 0.016) or low-level DAR (≤ 0.016) groups based on ROC curve analysis optimum cut-off value. The prognostic value of the DAR in LARC was analyzed. Results The study enrolled 513 patients. Patients were stratified into high-level DAR (> 0.016) and low-level DAR (≤ 0.016) cohorts according to the optimal cut-off value determined by ROC curve analysis. The 5-year overall survival (OS) rates for patients in the low DAR group (≤ 0.016) and the high DAR group (> 0.016) were 89.4% and 80.9%, respectively (p = 0.013). The 5-year disease-free survival (DFS) rates were 85.7% and 77.4% (p = 0.027). Multivariate analyses demonstrated that DAR were independent prognostic factors for OS (p = 0.02) and DFS (0.025). Predictive nomograms that included the DAR score group (C-index: OS-0.743, DFS-0.705) were superior to those without DAR scores (C-index: OS-0.721, DFS-0.697). Conclusion The DAR demonstrates high usability and prognostic value in predicting OS and DFS outcomes among patients diagnosed with LARC who undergo nCRT.

Abstract Otopetrin 1 (OTOP1) is a proton-activated channel crucial for animals’ perception of sour taste. Despite its significance, the gating mechanism of OTOP1 remains poorly understood. Here, we demonstrate that carvacrol activates the mouse OTOP1 (mOTOP1) channel under neutral and acidic conditions. Functional analysis showed that carvacrol enhances pH fluorescence signals in OTOP1-expressing cells, with reduced efficacy at lower pH levels. Carvacrol selectively activates mOTOP1, while mOTOP2, mOTOP3, and Chelonia mydas OTOP1 (CmOTOP1) are insensitive to carvacrol activation under neutral pH. Through chimera and point mutation experiments, swapping S134 in transmembrane segment 3 (TM3) and T247 in the TM5-6 linker abolished carvacrol activation of mOTOP1 and conferred activation on CmOTOP1, suggesting these two residues are critical for carvacrol sensitivity. These findings highlight TM3 and TM5-6 linker as pivotal gating apparatus of OTOP1 channels and potential docking sites for drug design.

ABSTRACT Background The hiatal ligament, as the anatomical landmark for the completion of total mesorectal excision (TME) for ultra‐low rectal cancer, represents a continuation of the longitudinal muscle of the rectum. It receives vascular supply from the median sacral artery and contains lymphatic vessels. In cases where ultra‐low rectal cancer is located in the posterior rectal wall, the hiatal ligament may theoretically serve as an anatomical region susceptible to direct tumor cell spread or distant metastasis. Objective To evaluate the effect of circumferential tumor location (CTL) on postoperative survival of low rectal cancer and to determine the effect of total hiatal ligament excision (THLE) on the prognosis of patients with posterior rectal cancer. Methods Patients with ultra‐low rectal cancer who underwent laparoscopic surgery between March 2014 and October 2021 were enrolled in this study. Propensity score matching (PSM) analysis was used to compare the clinicopathological characteristics and prognosis of patients in the posterior group and the non‐posterior group. Prognostic factors were identified using COX regression. PSM analysis was also used in the posterior tumor subgroup to compare the clinicopathological characteristics and prognosis of patients in the hiatal ligament traditional transection (HLTT) and THLE groups. Results After PSM, OS, and DFS were comparable between the posterior and non‐posterior groups. Similarly, no difference was noted in the local recurrence rate between the two groups (p = 0.23). The prognosis of ultra‐low rectal cancer was not affected by CTL. However, the local recurrence rate was significantly lower in the THLE group compared with the HLTT group (p = 0.023). Multivariate analysis of the posterior group identified CRM, TNM stage III, and HLTT as independent risk factors for local recurrence‐free survival. Conclusions CTL is not a prognostic risk factor for low rectal cancer. In posterior wall tumors, THLE significantly reduces the local recurrence rate for low rectal cancer.

Background: This study aimed to construct a nomogram based on CAF features to predict the cancer-specific survival (CSS) rates of locally advanced rectal cancer (LARC) patients. Methods: The EPIC algorithm was employed to calculate the proportion of CAFs. based on the differentially expressed genes between the high and low CAF proportion subgroups, prognostic genes were identified via LASSO and Cox regression analyses. They were then used to construct a prognostic risk signature. Moreover, the GSE39582 and GGSE38832 datasets were used for external validation. Lastly, the level of immune infiltration was evaluated using ssGSEA, ESTIMATE, CIBERSORTx, and TIMER. Results: A higher level of CAF infiltration was associated with a worse prognosis. Additionally, the number of metastasized lymph nodes and distant metastases, as well as the level of immune infiltration were higher in the high CAF proportion subgroup. Five prognostic genes (SMOC2, TUBAL3, C2CD4A, MAP1B, BMP8A) were identified and subsequently incorporated into the prognostic risk signature to predict the 1-, 3-, and 5-year CSS rates in the training and validation sets. Differences in survival rates were also determined in the external validation cohort. Furthermore, independent prognostic factors, including TNM stage and risk score, were combined to established a nomogram. Notably, our results revealed that the proportions of macrophages and neutrophils and the levels of cytokines secreted by M2 macrophages were higher in the high-risk subgroup. Finally, the prognostic genes were significantly associated with the level of immune cell infiltration. Conclusion: Herein, a nomogram based on CAF features was developed to predict the CSS rate of LARC patients. The risk model was capable of reflecting differences in the level of immune cell infiltration.

The prognosis of patients with locally advanced rectal cancer (LARC) has improved with the adoption of a multidisciplinary treatment approach combining neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME). Developing real-time, sensitive biomarkers to monitor systemic changes during nCRT is of paramount importance. Although the association between albumin-derived neutrophil-to-lymphocyte ratio (Alb-dNLR) and prognosis in various cancers is established, its prognostic value in LARC patients undergoing nCRT is not well-studied. This study enrolled a cohort of 618 LARC patients, stratifying them into two groups according to their change in Alb-dNLR (∆Alb-dNLR) values, using an optimal cut-off point: a low ∆Alb-dNLR group (≤ 0.90) and a high ∆Alb-dNLR group (> 0.90). The prognostic significance of ∆Alb-dNLR was evaluated using a Cox proportional hazards model. The 5-year overall survival (OS) rates were 75.2% in the low ∆Alb-dNLR group (≤ 0.90) and 85.9% in the high ∆Alb-dNLR group (>0.90) (P < 0.001). The 5-year disease-free survival (DFS) rates were 71.2% and 80.6%, respectively (P = 0.016). Multivariate analyses demonstrated that both ∆Alb-dNLR and pre-Alb-dNLR were independent prognostic factors for OS (P ≤ 0.001), while ∆Alb-dNLR was demonstrated as an independent prognostic factor for DFS (P = 0.016). A predictive nomogram, incorporating the ∆Alb-dNLR subgroup, demonstrated enhanced performance (concordance index [C-index] of 0.720 for OS and 0.690 for DFS) compared to the pre-treatment Alb-dNLR subgroup (C-index of 0.700 for OS and of 0.680 for DFS). Therefore, ∆Alb-dNLR shows significant potential as a usable and prognostic biomarker for predicting OS and DFS in LARC patients undergoing nCRT.

Abstract Purpose To evaluate the impact of the log odds of positive lymph nodes (LODDS) on cancer‐specific survival (CSS) in colon mucinous adenocarcinoma (MAC) patients, compared with pN stage and the lymph nodes ratio (LNR). Methods A total of 10,182 colon MAC patients from the Surveillance, Epidemiology, and End Results database were divided into the training group. The external validation group included 153 patients from Fujian Medical University Union Hospital. The Cox regression method was used to identify prognostic risk factors. Nomograms were evaluated by Harrell's concordance index (C‐index) and calibration curves. Recursive partitioning analysis (RPA) was used to develop a novel staging system. Results Time‐dependent receiver operating characteristic curves (ROC) to predict CSS showed the areas under the ROC curve of LODDS were always higher than pN stage and LNR. LNR and LODDS classifications can well distinguish the prognosis of patients with the same pN stage. Cox analyses indicated that age, tumor size, pT stage, pN stage, LNR, and LODDS were independent predictors of CSS (p

Abstract Background Immunotherapies targeting ligand-receptor interactions (LRIs) are advancing rapidly in the treatment of colorectal cancer (CRC), and LRIs also affect many aspects of CRC development. However, the pattern of LRIs in CRC and their effect on tumor microenvironment and clinical value are still unclear. Methods We delineated the pattern of LRIs in 55,539 single-cell RNA sequencing (scRNA-seq) samples from 29 patients with CRC and three bulk RNA-seq datasets containing data from 1411 CRC patients. Then the influence of tumor microenvironment, immunotherapy and prognosis of CRC patients were comprehensively investigated. Results We calculated the strength of 1893 ligand-receptor pairs between 25 cell types to reconstruct the spatial structure of CRC. We identified tumor subtypes based on LRIs, revealed the relationship between the subtypes and immunotherapy efficacy and explored the ligand-receptor pairs and specific targets affecting the abundance of tumor-infiltrating lymphocytes. Finally, a prognostic model based on ligand-receptor pairs was constructed and validated. Conclusion Overall, through the comprehensive and in-depth investigation of the existing ligand-receptor pairs, this study provides new ideas for CRC subtype classification, a new risk screening tool for CRC patients, and potential ligand-receptor pair targets and pathways for CRC therapy.

BackgroundIn the current tumor–lymph node–metastasis (TNM) staging system for colon neuroendocrine tumors, lymph node status is divided into N1 and N0. An assessment of the lymph node ratio (LNR) and a proposal for a modified mTNM staging system were the objectives of this study.MethodsSelecting the optimal cut-off value of LNR was done using X-tile. A Cox regression model and the Kaplan–Meier method were performed to calculate patient cancer-specific survival in the Surveillance, Epidemiology and End Results cohort. Recursive partitioning analysis was used to improve TNM staging.ResultsThe study included 674 patients. The current TNM staging system showed inadequate discriminatory power between stage I and stage II patients (p = 0.088). The optimal cut-off value was determined as 0.6 for LNR. Based on multivariate Cox regression analysis, the modified mN classification could be classified into mN 0 (LNR = 0.00), mN 1 (LNR = 0.01–0.60), and mN 2 (LNR > 0.60), and was found to be an independent factor affecting prognosis (p

While the prognosis of patients with partial SRCC (PSRCC) has been rarely reported, colorectal signet-ring cell carcinoma (SRCC) has been associated with poor prognosis. The aim of this study was to analyze the prognosis of patients with different SRCC composition and establish a prediction model. A total of 91 patients with SRC component were included in the study. These patients were divided into two groups: SRCC group (SRC composition > 50%; n=41) and partial SRCC (PSRCC) group (SRC composition ≤ 50%; n=50). COX regression model was used to identify independent prognostic factors for overall survival (OS). A predictive nomogram was established and compared with the 7th AJCC staging system. After a median follow-up of 16 months, no significant difference in OS was observed in either group. Preoperative carcinoembryonic antigen (CEA) level, pN stage, M stage, preoperative ileus, and adjuvant chemotherapy were independent prognostic risk factors for OS (p

PurposeThis study aimed to determine the probability and prognostic factors of colon cancer-specific mortality (CCSM) and noncancer-specific mortality (NCSM) for patients with stage I/II colon cancer and evaluate the association of age on cause-specific mortality.Materials and methodsFrom Surveillance, Epidemiology, and End Results (SEER) database, we identified 33152 patients with stage I/II colon cancer undergoing surgery between 2004 and 2011. The cumulative incidence of CCSM and NCSM was calculated, and competing risk analysis was performed to investigate prognostic factors for cause-specific mortality.ResultsIn patients 75 years of age, 5-year cumulative incidence of CCSM was 5.7%, 7.8%, and 16.1%, respectively (overall, 10.6%); 5-year cumulative incidence of NCSM was 2.2%, 7.1%, and 26.9%, respectively (overall, 13.8%). The probability of CCSM and NCSM increased with advanced age. The 5-year cumulative incidence of CCSM was higher than NCSM in patients 75 years of age. The probability of CCSM and NCSM was similar in patients 50-75 years of age. Competing-risk multivariable analysis demonstrated that increasing age was a strong predictor of CCSM (per year increase, SHR 1.03,95% confidence interval [CI]: 1.03-1.04). Age was most predictive of NCSM: (per year increase, SHR 1.08, 95% CI: 1.08-1.08).ConclusionAge was significantly associated with an increased cumulative incidence of CCSM and NCSM of patients with stage I/II colon cancer underwent surgery. NCSM was a significant competing event and should be adequately considered when performing survival analysis.