Postoperative Recurrence In Stage Research Articles

A novel 9-gene signature for the prediction of postoperative recurrence in stage II/III colorectal cancer.

Background: Individualized recurrence risk prediction in patients with stage II/III colorectal cancer (CRC) is crucial for making postoperative treatment decisions. However, there is still a lack of effective approaches for identifying patients with stage II and III CRC at a high risk of recurrence. In this study, we aimed to establish a credible gene model for improving the risk assessment of patients with stage II/III CRC. Methods: Recurrence-free survival (RFS)-related genes were screened using Univariate Cox regression analysis in GSE17538, GSE39582, and GSE161158 cohorts. Common prognostic genes were identified by Venn diagram and subsequently subjected to least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox regression analysis for signature construction. Kaplan-Meier (K-M), calibration, and receiver operating characteristic (ROC) curves were used to assess the predictive accuracy and superiority of our risk model. Single-sample gene set enrichment analysis (ssGSEA) was employed to investigate the relationship between the infiltrative abundances of immune cells and risk scores. Genes significantly associated with the risk scores were identified to explore the biological implications of the 9-gene signature. Results: Survival analysis identified 347 RFS-related genes. Using these genes, a 9-gene signature was constructed, which was composed of MRPL41, FGD3, RBM38, SPINK1, DKK1, GAL3ST4, INHBB, CTB-113P19.1, and FAM214B. K-M curves verified the survival differences between the low- and high-risk groups classified by the 9-gene signature. The area under the curve (AUC) values of this signature were close to or no less than the previously reported prognostic signatures and clinical factors, suggesting that this model could provide improved RFS prediction. The ssGSEA algorithm estimated that eight immune cells, including regulatory T cells, were aberrantly infiltrated in the high-risk group. Furthermore, the signature was associated with multiple oncogenic pathways, including cell adhesion and angiogenesis. Conclusion: A novel RFS prediction model for patients with stage II/III CRC was constructed using multicohort validation. The proposed signature may help clinicians better manage patients with stage II/III CRC.

The Combination of Prognostic Nutritional Indicator and Serum Carcinoembryonic Antigen is Useful in Predicting Postoperative Recurrence in Stage II Colorectal Cancer.

The efficacy of adjuvant chemotherapy in stage II colorectal cancer (CRC) patients has not been clearly demonstrated. Therefore, identification of robust prognostic factors is crucial for the assessment of recurrence risk in stage II CRC and appropriate adjuvant treatment, in clinical practice. We enrolled 135 colorectal adenocarcinoma patients who underwent proctocolectomies and had histologically diagnosed stage II CRC. Receiver operating characteristic (ROC) analysis, to evaluate the predictive ability of certain serum factors for CRC recurrence, indicated that the prognostic nutritional indicator (PNI), followed by serum carcinoembryonic antigen (CEA) level, were the strongest predictive metrics. Based on cutoff values from ROC analyses, patients were divided as follows; CEAHigh (≥ 4.55 ng/mL), CEALow (< 4.55 ng/mL), PNIHigh (≥ 47.72), and PNILow (< 47.72). The recurrence rates of patients with CEAHigh and PNILow, CEAHigh and PNIHigh, CEALow and PNILow, and CEALow and PNIHigh were 34.3%, 0%, 6.8%, and 2.6%, respectively (a significant difference at P < 0.0001). Logistic regression analysis revealed that the combination of serum CEA level and PNI was an independent predictive indicator of tumor recurrence after operation in stage II CRC patients. The 5-year disease specific survival rates of patients with CEALowPNIHigh, CEAHighPNIHigh, CEALowPNILow, CEAHighPNILow were 100%, 100%, 97.4%, and 77.5%, respectively (P < 0.0001). The combination of CEA and PNI was useful in predicting postoperative recurrence in stage II CRC patients.

Multi-kinase framework promotes proliferation and invasion of lung adenocarcinoma through activation of dynamin-related protein 1.

Recent studies revealed the role of dynamin-related protein 1 (DRP1), encoded by the DNM1L gene, in regulating the growth of cancer cells of various origins. However, the regulation, function, and clinical significance of DRP1 remain undetermined in lung adenocarcinoma. Our study shows that the expression and activation of DRP1 are significantly correlated with proliferation and disease extent, as well as an increased risk of postoperative recurrence in stage I to stage IIIA lung adenocarcinoma. Loss of DRP1 in lung adenocarcinoma cell lines leads to an altered mitochondrial morphology, fewer copies of mitochondrial DNA, decreased respiratory complexes, and impaired oxidative phosphorylation. Additionally, the proliferation and invasion are both suppressed in DRP1-depleted lung adenocarcinoma cell lines. Our data further revealed that DRP1 activation through serine 616 phosphorylation is regulated by ERK/AKT and CDK2 in lung adenocarcinoma cell lines. Collectively, we propose the multikinase framework in activating DRP1 in lung adenocarcinoma to promote the malignant properties. Biomarkers related to mitochondrial reprogramming, such as DRP1, can be used to evaluate the risk of postoperative recurrence in early-stage lung adenocarcinoma.

Revealing Epigenetic Factors of circRNA Expression by Machine Learning in Various Cellular Contexts.

SummaryCircular RNAs (circRNAs) have been identified as naturally occurring RNAs that are highly represented in the eukaryotic transcriptome. Although a large number of circRNAs have been reported, the underlying regulatory mechanism of circRNAs biogenesis remains largely unknown. Here, we integrated in-depth multi-omics data including epigenome, transcriptome, and non-coding RNA and identified candidate circRNAs in six cellular contexts. Next, circRNAs were divided into two classes (high versus low) with different expression levels. Machine learning models were constructed that predicted circRNA expression levels based on 11 different histone modifications and host gene expression. We found that the models achieve great accuracy in predicting high versus low expressed circRNAs. Furthermore, the expression levels of host genes of circRNAs, H3k36me3, H3k79me2, and H4k20me1 contributed greatly to the classification models in six cellular contexts. In summary, all these results suggest that epigenetic modifications, particularly histone modifications, can effectively predict expression levels of circRNAs.

Left colon as a novel high-risk factor for postoperative recurrence of stage II colon cancer

BackgroundIt is not clear whether stage II colon and rectal cancer have the same risk factors for recurrence. Thus, the purpose of this study was to identify the risk factors for postoperative recurrence in stage II colorectal cancer.Patients and methodsWe retrospectively analyzed the data of 990 patients who had undergone radical surgery for stage II colorectal cancer. Patients’ pathological features and characteristics including age, sex, family history, body mass index, tumor diameter, gross type of tumor, infiltration degree (T3/T4), tumor grade, perineural invasion, vascular invasion, lymphatic invasion, pathologic examination of lymph node number, and preoperative carcinoembryonic assay (CEA) level was compared between patients with and without recurrence. Finally, the prediction of the left and right colons was analyzed.ResultsThe mean ages of the colon cancer and rectal cancer patients were 69.5 years and 66.4 years, respectively. In total, 508 (82.1%) and 285 (76.8%) patients were treated laparoscopically for colon cancer and rectal cancer, respectively, with median follow-up periods of 42.2 months and 41.8 months, respectively. Forty-four recurrences occurred in both the colon cancer (7.1%) and rectal cancer (11.9%) groups. The preoperative serum CEA level and T4 infiltration were significantly higher in recurrent colorectal cancer patients. The postoperative recurrence rate of left colon cancer (descending colon, sigmoid colon) was higher than that of right colon cancer (cecum, ascending colon, transverse colon) (OR 2.191, 95% CI 1.091–4.400, P = 0.027). In COX survival factor analysis of colon cancer, the left colon is one of the independent risk factors (risk ratio 5.377, 95% CI 0.216–0.88, P = 0.02). In disease-free survival (DFS), the left colon has a relatively poor prognosis (P = 0.05). However, in the COX analysis and prognosis analysis of OS, no difference was found between the left colon and the right colon.ConclusionPreoperative CEA and depth of infiltration (T4) are high-risk factors associated with recurrence and are prognostic factors in stage II colorectal cancer. Left colon is also a risk factor for postoperative recurrence of stage II colon cancer.

A circRNA signature predicts postoperative recurrence in stage II/III colon cancer.

Accurate risk stratification for patients with stage II/III colon cancer is pivotal for postoperative treatment decisions. Here, we aimed to identify and validate a circRNA‐based signature that could improve postoperative prognostic stratification for these patients. In current retrospective analysis, we included 667 patients with R0 resected stage II/III colon cancer. Using RNA‐seq analysis of 20 paired frozen tissues collected postoperation, we profiled differential circRNA expression between patients with and without recurrence, followed by quantitative validation. With clinical information, we generated a four‐circRNA‐based cirScore to classify patients into high‐risk and low‐risk groups in the training cohort. The patients with high cirScores in the training cohort had a shorter disease‐free survival (DFS) and overall survival (OS) than patients with low cirScores. The prognostic capacity of the classifier was validated in the internal and external cohorts. Loss‐of‐function assays indicated that the selected circRNAs played functional roles in colon cancer progression. Overall, our four‐circRNA‐based classifier is a reliable prognostic tool for postoperative disease recurrence in patients with stage II/III colon cancer.

Combining fluorine-18 fluorodeoxyglucose positron emission tomography and pathological risk factors to predict postoperative recurrence in stage I lung adenocarcinoma.

The aim of this study was to investigate the predictive value of qualitative assessment of tumor fluorine-18 fluorodeoxyglucose (F-FDG) uptake on PET and pathological risk factors for postoperative tumor recurrence in patients with stage I lung adenocarcinoma. Eighty-seven patients with stage I lung adenocarcinoma who had undergone F-FDG-PET and sequential surgical treatment without adjuvant chemotherapy were enrolled into this retrospective study. Qualitative assessment visually compared tumor F-FDG uptake with liver uptake. Tumors with one or more risk factors of tumor size of at least 4 cm, poorly differentiated, visceral pleural invasion, and lymphovascular invasion were defined as pathological high-risk tumors. Patients with pathological high-risk tumors had a significantly (P=0.015) higher standardized uptake value. A multivariable Cox's proportional hazard analysis showed that tumor F-FDG uptake>liver uptake (adjusted hazard ratio: 3.54; 95% confidence interval: 1.36-9.21, P=0.010) and pathological high-risk tumors (adjusted hazard ratio: 2.34; 95% confidence interval: 1.13-4.87, P=0.023) were significant independent predictors of postoperative tumor recurrence. Patients with tumor F-FDG uptake>liver uptake and pathological high-risk tumors had significantly (P=0.001) worse 5-year disease-free survival (38.8%) and significantly (P=0.011) worse overall survival (68.5%). Tumor F-FDG uptake>liver uptake and pathological high-risk tumors were significant independent predictors of postoperative tumor recurrence in stage I lung adenocarcinoma. Combining the two factors improves the prediction of disease-free and overall survivals, which could offer a feasible prediction model for clinically recommending adjuvant chemotherapy.

Blood Vessel Invasion Is a Strong Predictor of Postoperative Recurrence in Endometrial Cancer.

Although lymphovascular space invasion is a prognostic factor for the recurrence of resectable endometrial cancer, the differential impacts of lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) on the recurrence of endometrial cancer are poorly described. We investigated the prognostic significance of LVI and BVI on the recurrence of endometrial cancer and their association with patterns of recurrence. We retrospectively reviewed 376 patients with stage I to III endometrial cancer who underwent surgery with curative intent at our institution between 2007 and 2015. The associations of the presence of lymphovascular space invasion or LVI and BVI with recurrence-free survival and patterns of recurrence were evaluated. Lymphovascular space invasion positivity was an independent prognostic factor for recurrence-free survival (hazards ratio [HR], 3.070; 95% confidence interval [CI], 1.404-6.824; P = 0.0048). However, when categorized by LVI versus BVI, the latter was a strong independent prognostic factor (HR, 2.697; CI, 1.288-5.798; P = 0.0081), whereas the former was not (HR, 1.740; CI, 0.795-3.721; P = 0.1637). Hematogenous metastasis was the most prevalent form of recurrence in endometrial cancer (24 [50%] of all 48 recurrent cases). Notably, 17 (19.5%) of 87 patients with BVI developed hematogenous metastases, compared with 7 (2.4%) of 289 without BVI (χ test, P < 0.0001). Blood vessel invasion rather than LVI was a strong predictor of postoperative recurrence in stage I to III endometrial cancer, probably due to its predisposition to hematogenous metastases.

Predictive Nomogram for Recurrence of Stage I Colorectal Cancer After Curative Resection

BackgroundPatients with stage I colorectal cancer (CRC) have excellent prognosis after curative surgery. However, approximately 5% to 10% of patients experience recurrence and have a poor prognosis. Because the incidence of stage I CRC is increasing with active screening programs worldwide, a more accurate and easy-to-use predictive tool for recurrence is becoming more important. This study aimed to develop a predictive nomogram for recurrence in stage I CRC. Patients and MethodsA total of 1538 patients who underwent curative surgery for stage I CRC were enrolled. Predictive factors for recurrence were determined by multivariate Cox regression model and were used to develop a predictive nomogram. This model was internally validated, and performance was evaluated through calibration plots. ResultsThe cumulative recurrence rate at 5 years after surgery for stage I CRC was 5.3%. In multivariate Cox analysis, independent predictors of recurrence were tumor location at rectum, pT2 stage, and presence of lymphovascular invasion. The 5-year recurrence rate was significantly different depending on the number of risk factors (0.7% for 0, 5.8% for 1, and 9.7% for ≥ 2 risk factors). On this basis, a nomogram for recurrence-free survival was developed and internally validated. The concordance index of the nomogram was 0.71, and the performance was acceptable. ConclusionWe developed and internally validated a nomogram that can predict postoperative recurrence in stage I CRC patients. This nomogram may be used to more accurately stratify the risk of recurrence and to perform personalized postoperative surveillance in stage I CRC patients.

Erratum to "Analysis of Postoperative Recurrence in Stage I-III Midgut Neuroendocrine Tumors".

Erratum to "Analysis of Postoperative Recurrence in Stage I-III Midgut Neuroendocrine Tumors".

Analysis of Postoperative Recurrence in Stage I-III Midgut Neuroendocrine Tumors.

Surgery represents the only curative treatment for stage I-III midgut neuroendocrine tumors (NETs). At present, there are very limited data on the risk of postoperative recurrence. The optimal modality, duration and frequency of surveillance have not been well established. In this work, we investigated the long-term risk of recurrence, peak timing of recurrence, and potential predictors of relapse in patients with stage I-III midgut NETs. We retrospectively evaluated 129 patients with stage I-III midgut NETs who were seen at the Moffitt Cancer Center between 2000 and 2010 following an R0/R1 resection. Disease-free survival (DFS) was estimated using the Kaplan-Meier method. Demographic, clinical, and pathological features were assessed as potential predictors of recurrence. All statistical tests were two-sided. After a median postoperative follow-up of 81 months (range = 1-295 months), recurrence was diagnosed in 40 out of 129 patients (31.0%, 95% confidence interval [CI] = 23.0% to 39.0%). Liver, mesentery, and pelvic lymph nodes were the main sites of relapse. The median DFS was 138 months (95% CI = 117 to 223 months). Resection of 17 or fewer lymph nodes predicted relapse (P = .01) and shorter DFS (P = .04). Among patients who relapsed, the cumulative risks of recurrence at one, five, and 10 years were 15.0% (95% CI = 3.9% to 26.1%), 50.0% (95% CI = 34.5% to 65.5%), and 85.0% (95% CI = 73.9% to 96.0%). No recurrence was observed among patients (n = 6) with stage I tumors, whereas similar rates of relapse were noted in patients with stage II or III NETs (n = 118). An annual surveillance interval may allow early detection of recurrence. Given the apparent decline in recurrence after eight years from surgery, a decade-long duration of active surveillance may be proposed.

Genetic variations associated with postoperative recurrence in stage I non-small cell lung cancer.

Postoperative recurrence in stage I non-small cell lung cancer (NSCLC) is the major cause of a poor prognosis. This study aims to identify genetic variants that are associated with the prognosis of early-stage NSCLCs. A genome-wide association study (GWAS) was conducted in 250 patients in stage I NSCLCs and the results were replicated in additional 308 patients. Results from an Affymetrix Genome-wide Human SNP array in 250 patients identified 94 SNPs with significant associations (P < 2 × 10(-4)), which were selected for replication in 308 additional patients. Pooled analysis of the 558 patients determined that rs1454694 in chromosome 4q34 was the most significant marker of lung cancer prognosis in the stage I patients (adjusted HR = 2.81; P = 5.91 × 10(-8)). After the candidate loci were mapped, an additional four markers at chromosome 4q34.3 were significantly associated with recurrence-free survival (RFS; P < 5 × 10(-5)). A haplotype of five SNPs in 4q34 also showed significant association with RFS (P = 4.29 × 10(-6)). A genetic polymorphism rs1454694 was identified as a novel genetic risk factor for RFS of stage I NSCLCs. This genome-wide study suggests that genetic markers in 4q34.3 contribute to predict the prognosis of Korean patients with stage I NSCLCs.

Gene-Expression Signature Predicts Postoperative Recurrence in Stage I Non-Small Cell Lung Cancer Patients

About 30% stage I non-small cell lung cancer (NSCLC) patients undergoing resection will recur. Robust prognostic markers are required to better manage therapy options. The purpose of this study is to develop and validate a novel gene-expression signature that can predict tumor recurrence of stage I NSCLC patients. Cox proportional hazards regression analysis was performed to identify recurrence-related genes and a partial Cox regression model was used to generate a gene signature of recurrence in the training dataset −142 stage I lung adenocarcinomas without adjunctive therapy from the Director's Challenge Consortium. Four independent validation datasets, including GSE5843, GSE8894, and two other datasets provided by Mayo Clinic and Washington University, were used to assess the prediction accuracy by calculating the correlation between risk score estimated from gene expression and real recurrence-free survival time and AUC of time-dependent ROC analysis. Pathway-based survival analyses were also performed. 104 probesets correlated with recurrence in the training dataset. They are enriched in cell adhesion, apoptosis and regulation of cell proliferation. A 51-gene expression signature was identified to distinguish patients likely to develop tumor recurrence (Dxy = −0.83, P<1e-16) and this signature was validated in four independent datasets with AUC >85%. Multiple pathways including leukocyte transendothelial migration and cell adhesion were highly correlated with recurrence-free survival. The gene signature is highly predictive of recurrence in stage I NSCLC patients, which has important prognostic and therapeutic implications for the future management of these patients.

Clinical significance of UNC5B expression in colorectal cancer

The purpose of this study was to find a methylation-related gene that could become a biomarker or therapeutic target in colorectal carcinoma (CRC). We screened candidate genes suspected to be silenced by DNA methylation using cDNA microarray analysis. To investigate the clinical significance of one candidate gene (UNC5B), we analyzed the correlation between mRNA expression and clinicopathological features using clinical tissue samples. Moreover, methylation specific PCR analysis was performed to reveal whether the promoter region was methylated in CRC cell lines. We found 75 candidate genes that were potentially suppressed by DNA methylation in CRC. We focused on UNC5B, a possible tumor suppressor gene and regulator of apoptosis known to be inactivated in CRC. The mRNA expression analysis using tissue samples revealed that UNC5B mRNA was down-expressed in about 20% of CRC patients, and the patients with low-UNC5B-expression tumors showed a significantly higher recurrence rate after curative surgery. According to the univariate and multivariate analysis, low UNC5B expression was an independent risk factor for postoperative recurrence in stage I, II and III CRC patients. Furthermore, patients with low expression of UNC5B in tumors had significantly poorer prognosis than those with high expression of UNC5B. Although UNC5B mRNA expression was restored by the demethylation treatment in CRC cell lines, the promoter region of UNC5B was not methylated. UNC5B is a potential biomarker for the selection of patients with high risk of postoperative recurrence and worse prognosis in CRC.

CLINICAL SIGNIFICANCE OF THREE PARAMETERS, CD16, IAP AND CEA IN PATIENTS WITH STAGE IV GASTRIC CANCER

In order to find an index for early diagnosis of post operative recurrence in stage IV gastric cancer, we studied in serum CD16, IAP and CEA.Seventy operated patients with stage IV gastric cancer were divided into those survived for more than one year after the operation (group A; 29) and those died within one year (group B; 41), and compared for time-dependent changes in serum CD16, IAP and CEA. There was no significant difference in preoperative abnormal level in the 3 parameters between both groups. While, postoperative time-dependent changes were minimal in group A, but showed an increasing tendency in group B. In this study, recurrence-positive symptoms were designated in CD16 by more than 10% increase during 3 months; in IAP by more than 500μg/ml; and in CEA by more than 10 ng/ml. In 16 patients of group A who experienced clinical recurrence, 9 patients were CD 16-positive, 5 were IAP-positive, and 10 were CEA positive at the time of clinical manifestation of recurrence or before the manifestation. In addition, 15 patients had at least one positive symptom among of them at the time of or before recurrence. Recurrence-free cases did not show any such findings.These results suggest that estimation of these three parameters may be useful for early diagnosis of recurrence in patients with gastric cancer.