The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAF V600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAF V600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAF V600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population. What's new?The prevalence of Lynch syndrome (LS) varies significantly in different ethnic populations. In this study, the authors screened more than 3000 Chinese colorectal cancer patients for mutations associated with LS, including mismatch repair (MMR) and BRAF V600E mutations. They found that, while the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of mutations is different, including many not previously reported. Older patients had a decreased risk of LS, suggesting that germline sequencing may not be necessary in this population.

Systemic inflammation was recognized as an essential factor contributing to the development of malignancies. This study aimed to investigate the prognostic value of pre-operative lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in patients with colorectal liver-only metastases (CLOM) undergoing hepatectomy. We retrospectively enrolled 150 consecutive patients with CLOM between 2000 and 2012. The optimal cutoff values of continuous LMR, NLR, and PLR were determined using the receiver operating characteristic curve analysis. Recurrence-free survival (RFS) and overall survival (OS) related to the LMR, NLR, and PLR were analyzed using both Kaplan–Meier and multivariate Cox regression methods. Elevated LMR (≥2.82) and lower NLR (<4.63) were significantly associated with better RFS and OS in patients with CLOM after hepatectomy, instead of lower PLR (<150.17). Multivariate Cox analysis identified elevated LMR as the only independent inflammatory factor for better RFS (hazard ratio, 0.591; 95% CI, 0.32–0.844; P=0.008) and OS (hazard ratio, 0.426; 95% CI, 0.254–0.716; P=0.001). In the subgroup analysis, elevated LMR was a significant favorable factor in both 5-year RFS and OS of patients with male gender, lymph node metastases, colon cancer, liver tumor with the largest diameter <5 cm, preoperative carcinoembryonic antigen level <200 ng/mL, negative hepatitis B virus infection, non-anatomic liver resection, postoperative chemotherapy, and non-preoperative chemotherapy. This study demonstrated that the preoperative LMR was an independent predictor of RFS and OS in patients with CLOM undergoing hepatic resection, and it appeared to be superior to the NLR and PLR.

BackgroundDickkopf 1 (DKK1) is associated with tumor progression. However, whether DKK1 influences the tumor response to programmed cell death protein 1 (PD-1) blockade in colorectal cancers (CRCs) with deficient mismatch repair (dMMR) or microsatellite instability (MSI) has never been clarified.MethodsTumor tissues from 80 patients with dMMR CRC were evaluated for DKK1 expression and immune status via immunohistochemistry. Serum DKK1 was measured in another set of 43 patients who received PD-1 blockade therapy. CT26 cells and dMMR CRC organoids were cocultured with T cells, and CT26-grafted BALB/c mice were also constructed. T-cell cytotoxicity was assessed by apoptosis assays and flow cytometry. The pathway through which DKK1 regulates CD8+ T cells was investigated using RNA sequencing, and chromatin immunoprecipitation and luciferase reporter assays were conducted to determine the downstream transcription factors of DKK1.ResultsElevated DKK1 expression was associated with recurrence and decreased CD8+ T-cell infiltration in dMMR CRCs, and patients with high-serum DKK1 had a poor response to PD-1 blockade. RNA interference or neutralization of DKK1 in CRC cells enhanced CD8+ T-cell cytotoxicity, while DKK1 decreased T-bet expression and activated GSK3β in CD8+ T cells. In addition, E2F1, a downstream transcription factor of GSK3β, directly upregulated T-bet expression. In organoid models, the proportion of apoptotic cells was elevated after individual neutralization of PD-1 or DKK1 and was further increased on combined neutralization of PD-1 and DKK1.ConclusionsDKK1 suppressed the antitumor immune reaction through the GSK3β/E2F1/T-bet axis in CD8+ T cells. Elevated serum DKK1 predicted poor tumor response to PD-1 blockade in dMMR/MSI CRCs, and DKK1 neutralization may restore sensitivity to PD-1 blockade.

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BackgroundVoltage-gated sodium channel 1.5 (Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. The present study aimed to explore the associations of Nav1.5 expression with clinical outcomes and estrogen receptor-β (ER-β) expression in non-metastatic colon cancer patients receiving radical resection.MethodsA total of 269 consecutive patients with pathologically confirmed stages I–III colon cancer who underwent radical resection were selected. Nav1.5 and ER-β expression was detected by using immunohistochemistry (IHC) on tissue microarray constructed from paraffin-embedded specimens. IHC score was determined according to the percentage and intensity of positively stained cells. Statistical analysis was performed with the X-tile method, k coefficient, Chi square test or Fisher’s exact test, logistic regression, log-rank test, and Cox proportional hazards models.ResultsWe found that Nav1.5 was commonly expressed in tumor tissues with higher mean IHC score as compared with matched tumor-adjacent normal tissues (5.1 ± 3.5 vs. 3.5 ± 2.7, P < 0.001). The high expression of Nav1.5 in colon cancer tissues was associated with high preoperative carcinoembryonic antigen level [odds ratio (OR) = 2.980; 95% confidential interval (CI) 1.163–7.632; P = 0.023] and high ER-β expression (OR = 2.808; 95% CI 1.243–6.343; P = 0.013). Log-rank test results showed that high Nav1.5 expression contributed to a low 5-year disease-free survival (DFS) rate in colon cancer patients (77.2% vs. 92.1%, P = 0.048), especially in patients with high ER-β expression tumor (76.2% vs. 91.3%, P = 0.032). Analysis with Cox proportional hazards model demonstrated that high Nav1.5 expression [hazard ratio (HR) = 2.738; 95% CI 1.100–6.819; P = 0.030] and lymph node metastasis (HR = 2.633; 95% CI 1.632–4.248; P < 0.001) were prognostic factors for unfavorable DFS in colon cancer patients.ConclusionsHigh expression of Nav1.5 was associated with high expression of ER-β and indicated unfavorable oncologic prognosis in patients with non-metastatic colon cancer.

The data here, in addition to prove the heterogeneity of hUC-MSCs, confirmed that the stronger therapeutic effects of hUC-MSC1 were attributed to its stronger anti-apoptotic effect, paracrine of trophic factors and potential RPE cell differentiation capacity. Thus, the subset hUC-MSC1, not the other subset or the ungrouped hUC-MSCs should be used for effective treatment of RD.

BackgroundWe performed a systematic screening of colorectal cancer (CRC) tissues to investigate whether mismatch repair (MMR) status and ERCC1 protein expression could be predictive of clinical outcomes for these patients following the recommendation of The Evaluation of Genomic Applications in Practice of Prevention (EGAPP).MethodsThe expression of four MMR genes and ERCC1 were assessed by immunohistochemistry (IHC) from cancer tissue samples of 2233 consecutive CRC patients.ResultsWe observed that most CRC patients with a proficient MMR (pMMR) status tended to have simultaneous ERCC1 protein expression (P< 0.001). Stage III CRC patients with deficient MMR (dMMR) had higher prognoses than the same stage patients with pMMR (DFS: 74% vs 65%, P = 0.04; OS: 79% vs 69%, P = 0.04). Here, dMMR is also associated with poorer survival for stage II patients after chemotherapy (DFS: 66% vs 78%, P = 0.04). Stage II and III patients that were shown to express ERCC1 protein had higher DFS and OS than those that were deficient in expression (stage II, DFS: 83% vs 70%, P = 0.006; OS 85% vs 73%, P = 0.02. Stage III, DFS: 67% vs56%, P = 0.03; OS: 71% vs 57%, P = 0.04).ConclusionsOur results indicate that dMMR appeared to predictive of a survival benefit for stage III CRC patients. We also found the determination of ERCC1 expression to be useful for predicting DFS or OS for stage II and III CRC patients. In addition, the expression of MMR genes and ERCC1 showed a significant relationship.

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