Size and number of lymph nodes were risk factors of recurrence in stage II colorectal cancer.

BACKGROUND: Size and number of lymph nodes (LNs) were reported to be associated with the prognosis of stage II colorectal cancer (CRC). The purpose of this study was to determine the prognostic role of the size of LNs (SLNs) measured by computer tomography (CT) and the number of retrieved LNs (NLNs) in the relapse-free survival (RFS) and overall survival (OS) among stage II CRC patients. METHODS: Consecutive patients diagnosed with stage II CRC at Fudan University Shanghai Cancer Center (FUSCC) from January 2011 to December 2015 were reviewed, and 351 patients were randomly divided into two cohorts for cross-validation. The optimal cut-off values were obtained using X-tile program. Kaplan-Meier curves and Cox regression analyses were conducted for the two cohorts. RESULTS: Data from 351 stage II CRC patients were analyzed. The cut-off values for SLNs and NLNs were 5.8 mm and 22, respectively, determined by the X-tile in the training cohort. In the validation cohort, Kaplan-Meier curves demonstrated SLNs (P = 0.0034) and NLNs (P = 0.0451) were positively correlated with RFS but not with OS. The median follow-up time in the training cohort and the validation cohort were 60.8 months and 61.0 months respectively. Univariate and multivariate analysis revealed that both SLNs (training cohort: Hazard Ratio (HR) = 2.361, 95% Confidence interval (CI): 1.044-5.338, P = 0.039; validation cohort: HR = 2.979, 95%CI: 1.435-5.184, P = 0.003) and NLNs (training cohort: HR = 0.335, 95%CI: 0.113-0.994, P = 0.049; validation cohort: HR = 0.375, 95%CI: 0.156-0.900, P = 0.021) were independent prognostic factors for RFS whereas not for OS. CONCLUSION: SLNs and NLNs are independent prognostic factors for patients with stage II CRC. Patients with SLNs > 5.8 mm and NLNs ≤ 22 are apt to have higher risk of recurrence.

Association of preoperative and recurrent serum carcinoembryonic antigen and outcome of colorectal cancer patients with metastatic relapse.

Background: Seldom have the associations of preoperative CEA (p-CEA) and recurrent CEA (r-CEA) levels as well as changes in p-CEA and r-CEA with survival in patients with stage I-III colorectal cancer (CRC) who have experienced metastatic relapse, been thoroughly examined. Methods: 241 consecutive patients with stage I-III CRC who experienced metastatic relapse at Fudan University Shanghai Cancer Center (FUSCC) between January 2008 and January 2016 were investigated. The influence of p-CEA, r-CEA and CEA alteration on the overall survival (OS) and relapse-to-death survival (RDS) was evaluated. The restricted cubic spline regression model was employed to explore the optimal cut-off value of CEA. Results: All 241 patients were categorized into four groups built on their CEA alteration patterns as follows: A, patients presenting elevated p-CEA levels but normal r-CEA levels (P-N); B, patients displaying normal levels of both p-CEA and r-CEA (N-N); C, patients exhibiting elevated levels of both p-CEA and r-CEA (P-P); D, patients with normal p-CEA levels but elevated r-CEA levels (N-P). The correlation between p-CEA and OS (P = 0.3266) and RDS (P = 0.2263) was insignificant. However, r-CEA exhibited a significant association with both OS (P = 0.0005) and RDS (P = 0.0002). Group A demonstrated the longest OS and RDS, whereas group D exhibited the poorest OS and RDS outcomes. For both OS and RDS, the CEA alteration groups served as an independent prognostic indicator. The optimal cut-off threshold for CEA was determined to be 5.1 ng/ml via the restricted cubic spline regression model. Conclusion: r-CEA has a stronger correlation with OS and RDS in individuals with stage I-III CRC who have experienced metastatic relapse.The change between p-CEA and r-CEA could further indicate post-relapse survival, thereby facilitating the assessment of mortality risk stratification in stage I-III CRC patients experiencing metastatic relapse.

Personalized circulating tumor DNA monitoring improves recurrence surveillance and management after curative resection of colorectal liver metastases: a prospective cohort study.

BACKGROUND: Approximately 60% of patients with colorectal liver metastases (CRLM) experience relapse within 2 years after radical resection, previous studies have proven that repeat local treatment (LT) could prolong survival, however, it is difficult to seize the window for LT due to the lack of a high-sensitive surveillance method. In this study, the authors aim to examine the value of longitudinal circulating tumor DNA (ctDNA) in guiding adjuvant chemotherapy, optimizing clinical surveillance strategy, and thereby improving CRLM outcomes. MATERIALS AND METHODS: The authors conducted a prospective clinical trial using a personalized, tumor-informed ctDNA assay to monitor 60 CRLM patients undergoing resection with curative intent. Formalin-fixed paraffin-embedded tumor samples were collected after surgery. Blood samples were collected before surgery, 30 days after surgery (post-OP), and every third month until relapse or up to 2 years. RESULTS: A total of 394 plasma samples from 60 eligible patients were analyzed, with a median follow-up time of 31.3 months. Landmark analyses revealed that detectable ctDNA at post-OP (HR, 4.8), postadjuvant chemotherapy (HR, 6.0), and end-of-treatment (HR, 5.6) were associated with higher recurrence risk ( P <0.001). Post-OP ctDNA positivity served as the only independent prognostic marker in the multivariant analysis (HR, 5.1; P <0.001). Longitudinal ctDNA analysis identified relapsed patients at both sensitivity and specificity of 100%. Most (75%) patients were found with radiological relapse within 6 months after the first detectable ctDNA with a median lead time of 3.5 months. In relapsed patients, 73.2% had oligometastatic disease and 61% were liver-restricted, of which 72.0% received repeat LTs, and 60.0% achieved a secondary no evidence of disease status. CONCLUSIONS: Longitudinal ctDNA monitoring assists in early prediction of relapse, and thereby improves survival of CRLM patients by increased secondary resection rate and secondary no evidence of disease rate.

Tumor-associated Macrophage-derived Interleukin-23 Interlinks Kidney Cancer Glutamine Addiction with Immune Evasion.

BACKGROUND: Glutamine addiction is a hallmark of clear cell renal cell carcinoma (ccRCC); yet whether glutamine metabolism impacts local immune surveillance is unclear. This knowledge may yield novel immunotherapeutic opportunities. OBJECTIVE: To seek a potential therapeutic target in glutamine-addicted ccRCC. DESIGN, SETTING, AND PARTICIPANTS: Tumors from ccRCC patients from a Shanghai cohort and ccRCC tumor data from The Cancer Genome Atlas (TCGA) cohort were analyzed. In vivo and in vitro studies were conducted with fresh human ccRCC tumors and murine tumor cells. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Immune cell numbers and functions were analyzed by flow cytometry. Glutamine and cytokine concentrations were determined. Survival was compared between different subpopulations of patients using Kaplan-Meier and Cox regression analyses. RESULTS AND LIMITATIONS: We found that in ccRCC, high interleukin (IL)-23 expression was significantly associated with poor survival in both TCGA (overall survival [OS] hazard ratio [HR]=2.04, cancer-specific survival [CSS] HR=2.95; all p<0.001) and Shanghai (OS HR=2.07, CSS HR=3.92; all p<0.001) cohorts. IL-23 blockade prolongs the survival of tumor-bearing mice, promotes T-cell cytotoxicity in in vitro cultures of human ccRCC tumors, and augments the therapeutic benefits of anti-PD-1 antibodies. Mechanistically, glutamine consumption by ccRCC tumor cells results in the local deprivation of extracellular glutamine, which induces IL-23 secretion by tumor-infiltrating macrophages via the activation of hypoxia-inducible factor 1α (HIF1α). IL-23 activates regulatory T-cell proliferation and promotes IL-10 and transforming growth factor ß expression, thereby suppressing tumor cell killing by cytotoxic lymphocytes. The positive correlations between glutamine metabolism, IL-23 levels, and Treg responses are confirmed in both TCGA cohort and tumors from Shanghai ccRCC patients. Study limitations include the unclear impacts of glutamine deprivation and IL-23 on other immune cells. CONCLUSIONS: Macrophage-secreted IL-23 enhanced Treg functions in glutamine-addicted tumors; thus, IL-23 is a promising target for immunotherapy in ccRCC. PATIENT SUMMARY: In this study, we analyzed the immune components in glutamine-addicted clear cell renal cell carcinoma (ccRCC) tumors from two patient cohorts and conducted both in vitro and in vivo studies. We found that ccRCC tumor cell-intrinsic glutamine metabolism orchestrates immune evasion via interleukin (IL)-23, and IL-23-high patients had significantly poorer survival than IL-23-low patients. IL-23 should thus be considered a therapeutic target in ccRCC, either alone or in combination with immune checkpoint inhibitors.