Systemic inflammation and immune dysfunction has been proved to be significantly associated with cancer progression and metastasis in many cancer types, including colorectal cancer. We examined the prognostic significance of the systemic immune-inflammation index (SII) in patients with metastatic colorectal cancer (mCRC) and the relationship between the lymphocytic response to the tumor and this index. This retrospective study evaluated 240 consecutive patients with newly diagnosed stage IV mCRC who underwent surgical resection. The SII values were calculated based on preoperative laboratory data regarding platelet, neutrophil, and lymphocyte counts. Tumor-infiltrating lymphocytes were evaluated using the surgical specimens. The overall survival and their 95% confidence interval (95% CI) were estimated by regression analyses and the Kaplan–Meier method. After a mean follow-up of 26.7 (1.1–92.4) months, 146 patients (60.8%) died. In the univariate analysis, a high SII was significantly associated with poor overall survival (P = 0.009). The multivariable analysis also confirmed that a high SII was independently associated with poor overall survival (hazard ratio: 1.462, 95% confidence interval 1.049–2.038, P = 0.025). The SII value was significantly correlated with the TILs value at the tumor’s center (P = 0.04), but not at the invasive margin (P = 0.39). When we evaluated overall survival for groupings of the tumor-infiltrating lymphocytes and SII values, we identified three distinct prognostic groups. The group with low tumor-infiltrating lymphocyte values and high SII values had the worst prognosis. A high SII value independently predicts poor clinical outcomes among patients with mCRC. In addition, combining the lymphocytic response to the tumor and SII could further enhance prognostication for mCRC.

Significance: CRC patients with KRAS mutations are confronted with limited targeted therapeutic options. In this study, we have shown that the median survival time for KRAS -mutation mCRC patients with diabetes on metformin is 37.8 mo longer than those treated with other hypoglycemic drugs in combination with standard systemic therapy. Metformin is preferentially accumulated in KRAS -mutation CRC cells in both primary cell cultures and patient-derived xenografts. The promising therapeutic activity of metformin has a negative correlation with MATE1 expression, which is proven to eliminate metformin from CRC cells. These findings indicate that KRAS -mutation mCRC patients could benefit from metformin treatment, and somatic KRAS status or MATE1 expression should be recommended to predict the therapeutic response of metformin in CRC.

We aimed to determine the prognostic values of 39 circulating cytokines in Chinese patients with metastatic colorectal cancer (CRC) and to develop a novel cytokine‐based prognostic classifier (CBPC) for prognostic prediction. A total of 176 patients were divided into two cohorts based on the date of first‐line chemotherapy. The first 99 cases were assigned to the training cohort, and the remaining 77 cases were assigned to the validation cohort. Thirty‐nine cytokines were simultaneously analyzed in the patient serum samples using multiplex bead‐based Luminex technology. We used support vector machine‐based methods and Cox proportional hazards models to develop a CBPC from the training cohort, which we then validated using the second patient cohort. Univariate analysis showed that FGF‐2, TGFα, Flt‐3L, GM‐CSF, INFα2, GRO, IL‐10, MCP‐3, MDC, sIL‐2Rα, IL‐2, IL‐7, IL‐8, MCP‐1, MIP‐1β, TNFα and VEGF were significant risk factors affecting the overall survival (OS) of both the training cohort and the validation cohort. We developed a CBPC to predict the OS of metastatic CRC patients using these 17 cytokines (sensitivity, 0.835; specificity, 0.800). In the validation cohort, the CBPC was found to have significant power in predicting the OS of metastatic CRC patients. Our study showed that there were significant associations between cytokine expression and prognosis of the patients with metastatic CRC. The CBPC that we developed includes multiple circulating cytokines and may serve as a novel screening tool for identifying metastatic CRC patients with a high risk of short OS. These high‐risk individuals may also be suitable for cytokine‐targeted therapies.

The consensus is that a minimum of 12 lymph nodes should be analyzed at colectomy for colon cancer. However, right colon cancer and left colon cancer have different characteristics, and this threshold value for total number of lymph nodes retrieved may not be universally applicable. The data of 63,243 patients with colon cancer treated between 2004 and 2012 were retrieved from the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. Multivariate Cox regression analysis was used to determine the predictive value of total number of lymph nodes for survival after adjusting for lymph nodes ratio. The predictive value in left-sided colon cancer and right-sided colon cancer was compared. The optimal total number of lymph nodes cutoff value for prediction of overall survival was identified using the online tool Cutoff Finder. Survival of patients with high total number of lymph nodes (≥12) and low total number of lymph nodes (< 12) was compared by Kaplan–Meier analysis. After stratifying by lymph nodes ratio status, total number of lymph nodes≥12 remained an independent predictor of survival in the whole cohort and in right-sided colon cancer, but not in left-sided colon cancer. The optimal cutoff value for total number of lymph nodes was determined to be 11. Low total number of lymph nodes (< 11) was associated with significantly poorer survival after adjusting for lymph nodes ratio in all subgroups except in the subgroup with high lymph nodes ratio (0.5–1.0). Previous reports of the prognostic significance of total number of lymph nodes on node-positive colon cancer were confounded by lymph nodes ratio. The 12-node standard for total number of lymph nodes may not be equally applicable in right-sided colon cancer and left-sided colon cancer.

Background: The prognostic nutritional index (PNI) and systemic immune-inflammation index (SII) are indicators of nutritional immune status. They have been reported associated with clinical outcomes of various solid tumors. However, it is unclear whether they can serve as predictors for patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) receiving immunotherapy. Our objective was to study the prognostic value of PNI and SII in these patients.Methods: Seventy-five MSI-H mCRC patients were enrolled in our study. Logistic regression analysis was used to identify features that influenced immunotherapy response. Survival differences between groups of mCRC patients were compared using the Kaplan–Meier method and log-rank test. The independent risk parameters for progression-free survival (PFS) and overall survival (OS) of patients with MSI-H mCRC were established by Cox proportional risk regression analysis.Results: The optimal SII and PNI cutoff values were 409.6 and 51.35. Higher PNI (p = 0.012) and lower high-density lipoprotein cholesterol (HDLC, p = 0.012) were associated with a better immunotherapy response. SII (p = 0.031), cholesterol (CHO) (p = 0.007) and aspartate aminotransferase (AST) (p = 0.031) were independent prognostic factors correlated with OS. Higher PNI (p = 0.012) and lower AST (p = 0.049) were negative predictors of PFS. In addition, patients suffered from immune-related adverse events (irAEs) had a lower SII level (p = 0.04).Conclusion: Higher AST and SII, and lower PNI predict worse outcomes in MSI-H mCRC patients undergoing immunotherapy. Moreover, patients with lower SII before immunotherapy suffered from irAEs more often.