Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related death. High recurrence rates after curative resection and the lack of specific biomarkers for intrahepatic metastases are ...major clinical problems. Recently, exosomal microRNAs (miRNAs) have been reported to have a role in the formation of the pre‐metastatic niche and as promising biomarkers in patients with malignancy. Here we aimed to clarify the molecular mechanisms of intrahepatic metastasis and to identify a novel biomarker miRNA in patients with HCC. A highly intrahepatic metastatic cell line (HuH‐7M) was established by in vivo selection. HuH‐7M showed increased proliferative ability and suppression of apoptosis and anoikis. HuH‐7M and the parental cell (HuH‐7P) showed the similar expression of epithelial‐mesenchymal transition markers and cancer stem cell markers. In vivo, mice treated with exosomes derived from HuH‐7M showed increased tumorigenesis of liver metastases. Exosomes from HuH‐7M downregulated endothelial cell expression of vascular endothelial‐cadherin (VE‐cadherin) and zonula occludens‐1 (ZO‐1) in non‐cancerous regions of liver and increased the permeability of FITC‐dextran through the monolayer of endothelial cells. The miRNAs (miR‐638, miR‐663a, miR‐3648, and miR‐4258) could attenuate endothelial junction integrity by inhibiting VE‐cadherin and ZO‐1 expression. In patients with HCC, higher serum exosomal miR‐638 expression was associated with tumor recurrence. In conclusion, the miRNAs secreted from a highly metastatic cancer cell can promote vascular permeability via downregulation of endothelial expression of VE‐cadherin and ZO‐1. Serum exosomal miR‐638 expression holds potential for serving as a significant and independent prognostic marker in HCC.
miR‐638, miR‐663a, miR‐3648, and miR‐4258 downregulate VE‐cadherin and ZO‐1 expression in HUVECs.
Malnutrition has been considered to be associated with the prognosis of cancer. The Geriatric Nutritional Risk Index (GNRI), based on serum albumin levels, present body weight, and ideal body weight, ...is a simple screening tool to predict the risk of nutrition-related morbidity and mortality in elderly patients. We aimed to evaluate whether preoperative GNRI was associated with postoperative complications and prognosis in elderly patients with colorectal cancer (CRC). We retrospectively enrolled 313 CRC patients aged ≥65 years after curative surgery and classified them into an all-risk GNRI (≤98) group and a no-risk GNRI (>98) group. Kaplan-Meier analysis showed overall survival was significantly worse in the all-risk GNRI group than in the no-risk GNRI group (P = 0.009). Multivariable analyses showed low GNRI (≤98) was an independent risk factor for postoperative complications (P = 0.048) and overall survival (P = 0.001) in the patients. Among the complications, the incidence of surgical site infection, in particular, was significantly higher in the all-risk GNRI group (P = 0.008). In conclusion, low preoperative GNRI (≤98) was associated with increased postoperative complications and poor prognosis. Preoperative GNRI can be used as an identifier for potential high-risk group of morbidity and mortality in elderly CRC patients.
Predictive factors of nivolumab treatment response in patients with gastric cancer (GC) remain unclear.
In this retrospective cohort study, tissue specimens of patients with unresectable or recurrent ...GC and prior or scheduled treatment with nivolumab as third-line or higher therapy between September 2017 and February 2019 were collected from 23 institutions. The tumour-positive score (TPS) and combined positive score (CPS) of PD-L1 expression and mismatch repair (MMR) were analysed by immunohistochemistry. Associations between clinicopathological factors and tumour-response rate, hyperprogressive disease (HPD) rate and survival were assessed.
Of 200 eligible patients, 143 had measurable lesions. The response and HPD rates were 17.5% and 22.1%, respectively. The response rate was significantly higher in patients with performance status (PS) 0-1 (P = 0.026), non-peritoneal metastasis (P = 0.021), PD-L1 TPS ≥ 1 (P = 0.012), CPS ≥ 5 (P = 0.007) or ≥ 10 (P < 0.001) or MMR deficiency (P < 0.001). The HPD rate was significantly higher in patients with PS 2-3 (P = 0.026), liver metastasis (P < 0.001) and CPS < 10 (P = 0.048). Multivariate analysis revealed that CPS (P = 0.001) and MMR (P = 0.002) were independent prognostic factors of progression-free survival, as well as liver metastasis (P < 0.001), peritoneal metastasis (P = 0.004) and CRP (P < 0.001).
PD-L1 CPS and MMR could be useful biomarkers for nivolumab treatment efficacy in GC.
UMIN000032164.
N6-methyladenosine (m6A) is the most abundant epitranscriptome modification in mammalian mRNA. Recent years have seen substantial progress in m6A epitranscriptomics, indicating its crucial roles in ...the initiation and progression of cancer through regulation of RNA stabilities, mRNA splicing, microRNA processing and mRNA translation. However, by what means m6A is dynamically regulated or written by enzymatic components represented by methyltransferase-like 3 (METTL3) and how m6A is significant for each of the numerous genes remain unclear. We focused on METTL3 in pancreatic cancer, the prognosis of which is not satisfactory despite the development of multidisciplinary therapies. We established METTL3-knockdown pancreatic cancer cell line using short hairpin RNA. Although morphologic and proliferative changes were unaffected, METTL3-depleted cells showed higher sensitivity to anticancer reagents such as gemcitabine, 5-fluorouracil, cisplatin and irradiation. Our data suggest that METTL3 is a potent target for enhancing therapeutic efficacy in patients with pancreatic cancer. In addition, we performed cDNA expression analysis followed by Gene Ontology and protein-protein interaction analysis using the Database for Annotation, Visualization, and Integrated Discovery and Search Tool for the Retrieval of Interacting Genes/Proteins databases, respectively. The results demonstrate that METTL3 was associated with mitogen-activated protein kinase cascades, ubiquitin-dependent process and RNA splicing and regulation of cellular process, suggesting functional roles and targets of METTL3.
Background
Microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) are candidate predictors for the response to immune checkpoint inhibitors, and may predict chemotherapy sensitivity. ...We investigated the simultaneous expression of mutL homolog 1 (MLH1), a mismatch repair gene, and PD-L1 in gastric cancers.
Methods
We examined MLH1 and PD-L1 expression in surgical specimens from 285 gastric cancer patients treated with or without preoperative chemotherapy, and assessed the relation between expression results and both histological response and recurrence-free survival (RFS).
Results
Of 285 patients, 28 (9.8%) and 70 (24.6%) exhibited negative MLH1 and high PD-L1 expression, respectively. Most MLH1-negative tumors (85.7%) showed high MSI, and these tumors exhibited high PD-L1 expression more frequently than MLH1-positive tumors (57.1% vs. 21.0%,
P
< 0.001). MLH1-negative patients were significantly less likely to respond to preoperative chemotherapy than MLH1-positive patients (16.7% vs. 61.2%,
P
= 0.005), whereas there was no significant difference between high- and low-PD-L1 expression patients (55.9% vs. 56.6%,
P
= 0.95). RFS in patients without preoperative chemotherapy was significantly longer in the MLH1-negative group than in the MLH1-positive group (HR 0.30; 95% CI 0.09–0.95;
P
= 0.030), whereas in patients with preoperative chemotherapy there was no significant difference in RFS between the two groups (HR 0.70; 95% CI 0.30–1.63;
P
= 0.41). PD-L1 expression was not associated with RFS in patients with or without chemotherapy.
Conclusions
Loss of MLH1 was associated with chemoresistance and did not prolong survival following neoadjuvant chemotherapy. The strong association between MLH1 and MSI status suggests that immune checkpoint inhibitors may be preferable to conventional chemotherapy for MLH1-negative gastric cancer.
Background
Several studies have shown that postoperative complications worsen the prognosis of patients with malignancies. However, our previous study showed that C-reactive protein (CRP) elevation ...over 12 mg/dL was a more reliable prognostic indicator than complication occurrence. This large-scale, multicenter validation study aimed to confirm the prognostic value of postoperative CRP elevation in resectable gastric cancer.
Methods
Data of 1456 patients with pT2–T4 gastric cancer who underwent R0 resection were collected from 21 institutions. The prognostic value of the highest postoperative serum level of CRP (CRP
max
) during hospitalization was evaluated using the Kaplan–Meier method. The prognostic independence of CRP
max
with assessed with a Cox multivariate analysis of recurrence-free survival (RFS).
Results
RFS in the high CRP
max
(≥ 12 mg/dL) group was significantly worse than that in the low CRP
max
(< 12 mg/dL) group (log-rank
P
= 0.002). The recurrence pattern showed that liver metastasis occurred more frequently in the high CRP
max
group (9.2%) than in the low CRP
max
group (4.7%) (
P
= 0.001). In patients without intra-abdominal infectious complications, the high CRP
max
group showed significantly worse RFS than the low CRP
max
group (log-rank
P
= 0.026). In patients with intra-abdominal infectious complications, the high CRP
max
group had worse RFS than the low CRP
max
group, but this difference was not significant (log-rank
P
= 0.075). Cox multivariate analysis with 13 covariables showed that CRP
max
(
P
= 0.043) was an independent prognostic factor, but postoperative complications were not (
P
= 0.387).
Conclusion
Postoperative CRP elevation was a better predictor of prognosis in patients with gastric cancer than the occurrence of intra-abdominal infectious complications.
Dickkopf1 (DKK1) is overexpressed in various cancers and promotes cancer cell proliferation by binding to cytoskeleton-associated protein 4 (CKAP4). However, the mechanisms underlying DKK1 expression ...are poorly understood. RNA sequence analysis revealed that expression of the transcription factor forkhead box M1 (FOXM1) and its target genes concordantly fluctuated with expression of DKK1 in pancreatic ductal adenocarcinoma (PDAC) cells. DKK1 knockdown decreased FOXM1 expression and vice versa in PDAC and esophageal squamous cell carcinoma (ESCC) cells. Inhibition of either the DKK1-CKAP4-AKT pathway or the ERK pathway suppressed FOXM1 expression, and simultaneous inhibition of both pathways showed synergistic effects. A FOXM1 binding site was identified in the 5'-untranslated region of the DKK1 gene, and its depletion decreased DKK1 expression and cancer cell proliferation. Clinicopathological and database analysis revealed that PDAC and ESCC patients who simultaneously express DKK1 and FOXM1 have a poorer prognosis. Multivariate analysis demonstrated that expression of both DKK1 and FOXM1 is the independent prognostic factor in ESCC patients. Although it has been reported that FOXM1 enhances Wnt signaling, FOXM1 induced DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. These results suggest that DKK1 and FOXM1 create a positive feedback loop to promote cancer cell proliferation.
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