Leukotriene B4 receptor knockdown affects PI3K/AKT/mTOR signaling and apoptotic responses in colorectal cancer.

Colorectal cancer (CRC) presents a landscape of intricate molecular dynamics. In this study, we focused on the role of the leukotriene B4 receptor (LTB4R) in CRC, exploring its significance in the disease's progression and potential therapeutic approaches. Using bioinformatics analysis of the GSE164191 and the Cancer Genome Atlas-colorectal adenocarcinoma (TCGA-COAD) datasets, we identified LTB4R as a hub gene influencing CRC prognosis. Subsequently, we examined the relationship between LTB4R expression, apoptosis, and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway through cellular and mice experiments. Our findings revealed that LTB4R is highly expressed in CRC samples and is pivotal for determining prognosis. In vitro experiments demonstrated that silencing LTB4R significantly impeded CRC cell viability, migration, invasion, and colony formation. Correspondingly, in vivo tests indicated that LTB4R knockdown led to markedly slower tumor growth in mice models. Further in-depth investigation revealed that LTB4R knockdown significantly amplified the apoptosis in CRC cells and upregulated the expression of apoptosis-related proteins, such as caspase-3 and caspase-9, while diminishing p53 expression. Interestingly, silencing LTB4R also resulted in a significant downregulation of the PI3K/AKT/mTOR signaling pathway. Moreover, pretreatment with the PI3K activator 740Y-P only partially attenuated the effects of LTB4R knockdown on CRC cell behavior, emphasizing LTB4R's dominant influence in CRC cell dynamics and signaling pathways. LTB4R stands out as a critical factor in CRC progression, profoundly affecting cellular behavior, apoptotic responses, and the PI3K/AKT/mTOR signaling pathway. These findings not only shed light on LTB4R's role in CRC but also establish it as a potential diagnostic biomarker and a promising target for therapeutic intervention.

Circulating tumor cells participate in the formation of microvascular invasion and impact on clinical outcomes in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide. Although the treatment strategies have been improved in recent years, the long-term prognosis of HCC is far from satisfactory mainly due to high postoperative recurrence and metastasis rate. Vascular tumor thrombus, including microvascular invasion (MVI) and portal vein tumor thrombus (PVTT), affects the outcome of hepatectomy and liver transplantation. If vascular invasion could be found preoperatively, especially the risk of MVI, more reasonable surgical selection will be chosen to reduce the risk of postoperative recurrence and metastasis. However, there is a lack of reliable prediction methods, and the formation mechanism of MVI/PVTT is still unclear. At present, there is no study to explore the possibility of tumor thrombus formation from a single circulating tumor cell (CTC) of HCC, nor any related study to describe the possible leading role and molecular mechanism of HCC CTCs as an important component of MVI/PVTT. In this study, we review the current understanding of MVI and possible mechanisms, discuss the function of CTCs in the formation of MVI and interaction with immune cells in the circulation. In conclusion, we discuss implications for potential therapeutic targets and the prospect of clinical treatment of HCC.

Thymosin ß4, a potential marker of malignancy and prognosis in hepatocellular carcinoma.

BACKGROUND: The lack of effective early diagnostic markers is an obstacle in clinical diagnosis and treatment of hepatocellular carcinoma (HCC). Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is an increasing popular approach for identification of clinically relevant parameters including biomarkers. PATIENTS AND METHODS: 540 subjects, including 274 HCC, 119 liver cirrhosis, 89 hepatitis, and 58 healthy volunteers were enrolled. MALDI-TOF MS was used to select potential novel biomarkers from serum of HCC patients. Its clinical application was evaluated by experiments and clinical data analysis. RESULTS: We identified Thymosin ß4 (Tß4) in serum by MALDI-TOF MS. The expression of Tß4 was detected up-regulating in HCC cells and tissues which enhanced motility of HCC cells. More important, the level of serum Tß4 was significantly elevated in HCC patients. The AUROC showed the optimum diagnostic cut-off was 1063.6 ng/mL, ROC and 95% CI of Tß4 (0.908; 0.880-0.935) were larger than that of serum AFP (0.712; 0.662-0.762; p < 0.001). The sensitivity (91.3% vs 83.1%) and specificity (81.2% vs 20.3%) of serum Tß4 were higher than alpha-fetoprotein (AFP). In AFP-negative HCC, the sensitivity could reach to 80.5%. ROC analysis showed serum Tß4 had a better performance compared with AFP in distinguishing early-stage and small HCC. Tß4 is correlated with TNM stage (p = 0.016) and vascular invasion (p = 0.005). Survival analysis indicated the survival time of Tß4 positive patients was shorter (p < 0.001). Cox analysis suggested Tß4 could be an independent factor for HCC prognosis. CONCLUSION: Tß4 may serve as a novel biomarker for HCC diagnosis and prognosis.

Novel multiplex stool-based assay for the detection of early-stage colon cancer in a Chinese population.

BACKGROUND: Stool DNA (sDNA) methylation analysis is a promising, noninvasive approach for colorectal cancer screening; however, reliable biomarkers for detecting early-stage colon cancer (ECC) are lacking, particularly in the Chinese population. AIM: To identify a novel stool-based assay that can improve the effectiveness of ECC screening. METHODS: A blinded case-control study was performed using archived stool samples from 125 ECC patients, and 125 control subjects with normal colonoscopy. The cohort was randomly divided into training and test sets at a 1.5:1 ratio. Targeted bisulfite sequencing (TBSeq) was conducted on five pairs of preoperative and postop-erative sDNA samples from ECC patients to identify DNA methylation biomarkers, which were validated using pyrosequencing. By logistic regression analysis, a multiplex stool-based assay was developed in the training set, and the detection performance was further assessed in the test set and combined set. The χ 2 test was used to investigate the association of detection sensitivity with clinico-pathological features. RESULTS: Following TBSeq, three hypermethylated cytosine-guanine sites were selected as biomarkers, including paired box 8, Ras-association domain family 1 and secreted frizzled-related protein 2, which differed between the groups and were involved in important cancer pathways. An sDNA panel containing the three biomarkers was constructed with a logistic model. Receiver operating characteristic (ROC) analysis revealed that this panel was superior to the fecal immunochemical test (FIT) or serum carcinoembryonic antigen for the detection of ECC. We further found that the combination of the sDNA panel with FIT could improve the screening effectiveness. In the combined set, the sensitivity, specificity and area under the ROC curve for this multiplex assay were 80.0%, 93.6% and 0.918, respectively, and the performance remained excellent in the subgroup analysis by tumor stage. In addition, the detection sensitivity did not differ with tumor site, tumor stage, histological differentiation, age or sex, but was significantly higher in T4 than in T1-3 stage tumors (P = 0.041). CONCLUSION: We identified a novel multiplex stool-based assay combining sDNA methylation biomarkers and FIT, which could detect ECC with high sensitivity and specificity throughout the colon, showing a promising application perspective.

N-mytistoyltransferase 1 and 2 are potential tumor suppressors and novel targets of miR-182 in human non-small cell lung carcinomas.

BACKGROUND & AIMS: Non-small cell lung cancer (NSCLC) accounts for about 80% of lung cancer diagnoses across the world. Despite recent appreciable improvements in treatment plans for patients with NSCLC, the prognosis for those with the cancer still remains poor. Recently, a growing number of studies have shown that N-myristoyltransferases (NMTs) may be critical in carcinogenesis, however, the functional and clinical significance of this pathway in NSCLC remains unclear and requires further research. METHODS: Initially, we evaluated the expression levels of NMT1 or NMT2 in a clinical cohort comprising of 303 paired primary NSCLC tissues and matched normal mucosae by using ELISA. We subsequently performed a tissue microarray analysis (TMA) to confirm its expression pattern in an independent validation cohort (n = 78). Then, we used a publicly available KM plotter database (n = 1921) to evaluate the prognostic impact of NMT1 and NMT2 in NSCLC. Lastly, a series of in-vitro molecular/cellular and animal experiments were performed for mechanistic understanding of the role of N-myristoyltransferases in NSCLC. RESULTS: Our ELISA data revealed that the expression level of NMT1 and NMT2 was down-regulated in tumor tissues (n = 303, P < 0.0001), which was confirmed in an independent validation cohort by TMA (n = 78, P = 0.014 for NMT1 and P < 0.0001 for NMT2). On the other hand, patients with low expression of NMT1 or NMT2 had shorter overall survival (P = 0.013, HR = 0.85 for NMT1; P = 0.00059, HR = 0.8, for NMT2). Mechanistically, we revealed that the interaction and co-localization of NMT1 and NMT2 in NSCLC, and N-terminus of NMT1 and NMT2 was observed to be crucial for their interaction as well as for their catalytic activity. Moreover, we found that NMT1 can significantly promote the expression of NMT2 by enhancing its stability. We corroborated these findings by performing functional assays in which the knockout of NMT1 and NMT2 resulted in enhanced cell proliferation, migration and invasion as well as increased tumorxenograftgrowth. In addition, we identified miR-182 as a novel regulator of both NMT1 and NMT2. More specifically, the overexpression or inhibition of miR-182 modulated globe N-myristoylation level, contributed to phenotypic alterations in NSCLS cells. CONCLUSIONS: NMT1 and NMT2 can act as potential tumor suppressors in NSCLC, and the inhibition of miR-182 expression or therapeutic NMTs replenishment may be a promising treatment option for patients with NSCLC.

Squalene synthase predicts poor prognosis in stage I-III colon adenocarcinoma and synergizes squalene epoxidase to promote tumor progression.

Colon adenocarcinoma (COAD) is one of the most prevalent malignancies, with poor prognosis and lack of effective treatment targets. Squalene synthase (FDFT1) is an upstream enzyme of squalene epoxidase (SQLE) in cholesterol biosynthesis. In a previous study, we revealed that SQLE promotes colon cancer cell proliferation in vitro and in vivo. Here, we investigate the prognostic value of FDFT1 in stage I-III COAD and explore the potential underlying mechanisms. Squalene synthase was significantly upregulated in stage I-III COAD and positively correlated with poor differentiation and advanced tumor stage. High expression of FDFT1 was an independent predictor of overall and relapse-free survival, and the nomograms based on FDFT1 could effectively identify patients at high risk of poor outcome. Squalene synthase accelerated colon cancer cell proliferation and promoted tumor growth. Lack of FDFT1 resulted in accumulating NAT8 and D-pantethine to lower reactive oxygen species levels and inhibit colon cancer cell proliferation. Moreover, the combined inhibition of FDFT1 and SQLE induced a greater suppressive effect on cell proliferation and tumor growth than single inhibition. Taken together, these results indicate that FDFT1 predicts poor prognosis in stage I-III COAD and has the tumor-promoting effect on COAD through regulating NAT8 and D-pantethine. Targeting both FDFT1 and SQLE is a more promising therapy than their single inhibition for stage I-III COAD.

Serum Levels of ITGBL1 as an Early Diagnostic Biomarker for Hepatocellular Carcinoma with Hepatitis B Virus Infection.

PURPOSE: Early diagnostic biomarkers of hepatocellular carcinoma (HCC) are needed to distinguish hepatitis B virus (HBV) associated HCC (HBV-HCC) patients from at-risk patients. We assessed the diagnostic values of serum Integrin beta-like 1 (ITGBL1) for early-stage HBV-HCC. PATIENTS AND METHODS: We recruited 716 participators including 299 in the training and 417 in the validation stage, (HBV-HCC, chronic hepatitis B (CHB), HBV-related liver cirrhosis (HBV-LC), and healthy controls) between 2017 and 2020 from three centers. Serum ITGBL1 was measured by ELISA. Receiver operating characteristic (ROC) was used to calculate diagnostic accuracy. RESULTS: The serum levels of ITGBL1 in HBV-HCC patients were significantly lower than those in CHB and HBV-LC patients. This result was confirmed in the follow-up patients who progressed from HBV-LC to HCC. The optimum diagnostic cutoff value of serum ITGBL1 was 47.93ng/mL for detection of early-stage HBV-HCC. The serum ITGBL1 has higher diagnostic accuracy than AFP20 in differentiating the early-stage HBV-HCC from the at-risk patients (area under curve [AUC] 0.787 vs 0.638, p<0.05). For AFP-negative (<20ng/mL) HBV-HCC patients, serum ITGBL1 maintained diagnostic accuracy (training cohort: AUC 0.756, 95% confidence interval [CI] 0.683-0.819, sensitivity 68.18%, and specificity 68.85%; validation cohort: 0.744, 0.686-0.796, 81.13%, and 55.88%). Combination ITGBL1 with AFP20 significantly increased diagnostic accuracy in differentiating the HBV-HCC from at-risk patients (AUC 0.840; 0.868) than ITGBL1 (AUC 0.773, p<0.05; 0.732, p<0.0001) or AFP20 (AUC 0.705, p<0.0001; 0.773, p<0.0001) alone. CONCLUSION: The serum level of ITGBL1 improved identification of AFP-negative HBV-HCC patients, and increased diagnostic accuracy with AFP20 together in the early detection of HBV-HCC.

Comparative mutational analysis of distal colon cancer with rectal cancer.

Distal colon and rectal cancer are associated with each other but display distinct clinical behavior; however, the genetic basis for these differences is poorly understood. In the present study, a systematic comparison of mutational profiles between 137 distal colon and 125 rectal cancer samples was performed based on the data from the Memorial Sloan Kettering Cancer Center. Tumor mutational burden analysis showed that distal colon and rectal cancer harbored a similar burden of ~5.9 mutations/megabase, irrespective of the mismatch repair status. Comparison of significantly mutated genes between the groups determined that B-Raf proto-oncogene serine/threonine kinase mutations were enriched in distal colon cancer, whilst RAS and SMAD family member 4 (SMAD4) mutations were significantly more frequent in rectal cancer. Furthermore, two novel and potentially targetable hotspot mutations (APC regulator of WNT signaling pathway R876* and SMAD4 R361) were identified, which were enriched in rectal cancer compared with distal colon cancer. Overall, the results of the present study showed that the mutation profiles of distal colon and rectal cancer were largely similar, but distinct in specific key genetic events, which may provide valuable information for improving the management of patients with the disease.

Prognostic significance of lymphovascular invasion in colorectal cancer and its association with genomic alterations.

BACKGROUND: Lymphovascular invasion (LVI) is suggested to be an early and important step in tumor progression toward metastasis, but its prognostic value and genetic mechanisms in colorectal cancer (CRC) have not been well investigated. AIM: To investigate the prognostic value of LVI in CRC and identify the associated genomic alterations. METHODS: We performed a retrospective analysis of 1219 CRC patients and evaluated the prognostic value of LVI for overall survival by the Kaplan-Meier method and multivariate Cox regression analysis. We also performed an array-based comparative genomic hybridization analysis of 47 fresh CRC samples to examine the genomic alterations associated with LVI. A decision tree model was applied to identify special DNA copy number alterations (DCNAs) for differentiating between CRCs with and without LVI. Functional enrichment and protein-protein interaction network analyses were conducted to explore the potential molecular mechanisms of LVI. RESULTS: LVI was detected in 150 (12.3%) of 1219 CRCs, and the presence was positively associated with higher histological grade and advanced tumor stage (both P < 0.001). Compared with the non-LVI group, the LVI group showed a 1.77-fold (95% confidence interval: 1.40-2.25, P < 0.001) increased risk of death and a significantly lower 5-year overall survival rate (P < 0.001). Based on the comparative genomic hybridization data, 184 DCNAs (105 gains and 79 losses) were identified to be significantly related to LVI (P < 0.05), and the majority were located at 22q, 17q, 10q, and 6q. We further constructed a decision tree classifier including seven special DCNAs, which could distinguish CRCs with LVI from those without it at an accuracy of 95.7%. Functional enrichment and protein-protein interaction network analyses revealed that the genomic alterations related to LVI were correlated with inflammation, epithelial-mesenchymal transition, angiogenesis, and matrix remodeling. CONCLUSION: LVI is an independent predictor for survival in CRC, and its development may correlate with inflammation, epithelial-mesenchymal transition, angiogenesis, and matrix remodeling.

Nomogram for Predicting Risk of Intestinal Complications After Colorectal Cancer Surgery.

BACKGROUND Intestinal complications are a major cause of morbidity after colorectal cancer surgery. This study aimed to develop an effective nomogram for predicting risk of intestinal complications following colorectal cancer surgery. MATERIAL AND METHODS We retrospectively analyzed 1876 patients who underwent colorectal cancer surgery at Yangpu and Zhuji hospitals from January 2013 to October 2018. Intestinal complications were defined as intestinal obstruction, leakage or bleeding, or peritonitis within 30 days after surgery. A logistic regression model was used to identify the risk factors associated with postoperative intestinal complications, and a nomogram for intestinal complications was established. The predictive accuracy of the nomogram was assessed using area under the receiver operating characteristic curve (AUC) and calibration plot. RESULTS A total of 164 patients (8.7%) developed intestinal complications after colorectal cancer surgery; 35 (21.3%) of whom died in the postoperative period. Multivariate logistic analysis showed that male gender, history of abdominal surgery, preoperative intestinal obstruction/perforation, metastatic cancer, and lower level of hemoglobin and prognostic nutrition index were independent risk factors (P<0.05 for all). A nomogram was then constructed, and it displayed good accuracy in predicting postoperative intestinal complications with an AUC of 0.76. The calibration plot also showed an excellent agreement between the predicted and observed probabilities. CONCLUSIONS We constructed a nomogram based on clinical variables, which could provide individual prediction of postoperative intestinal complications with good accuracy.

Correction: Development and validation of nomograms for predicting survival in patients with non-metastatic colorectal cancer.

[This corrects the article DOI: 10.18632/oncotarget.16167.].

PIK3CA and TP53 mutations predict overall survival of stage II/III colorectal cancer patients.

AIM: To investigate the predictive value of PIK3CA and TP53 mutation status in colorectal cancer (CRC) patients treated with 5-fluorouracil-based chemotherapy. METHODS: In this study, a total of 315 patients with histologically proven CRC were enrolled from Yangpu Hospital affiliated to Shanghai Tongji University between 2007 and 2011. Of these patients, 241 with stage II/III CRC received 5-fluorouracil-based adjuvant chemotherapy. Formalin-fixed paraffin-embedded lesion samples of the patients with curatively resected CRC were collected. Next-generation sequencing was performed to identify somatic gene mutations. The correlation of PIK3CA and TP53 mutation status with overall survival (OS) was analyzed using a Cox proportional hazard model and the Kaplan-Meier method. RESULTS: Among the 241 patients with stage II/III in this cohort, the PIK3CA and/or TP53 mutation was detected in 177 patients, among which 54 patients had PIK3CA and TP53 double mutations. The PIK3CA or TP53 mutation was not significantly correlated with OS in univariate and multivariate analyses. Compared with patients without PIK3CA and TP53 mutations, those with double PIK3CA-TP53 mutations showed a significantly worse survival (univariate HR = 2.21; 95%CI: 1.15-4.24; multivariate HR = 2.02; 95%CI: 1.04-3.91). The PIK3CA mutation located in the kinase domain showed a trend toward a shorter OS compared with wild-type tumors (multivariate HR = 1.56; 95%CI: 1.00-2.44; P = 0.052). The Kaplan-Meier curve showed that patients harboring the PIK3CA mutation located in the kinase domain had a worse clinical outcome than those with wild-type status (Log-rank P = 0.041). CONCLUSION: Double mutation of PIK3CA and TP53 is correlated with a shorter OS in stage II/III CRC patients treated with 5-fluorouracil-based therapy.

Increased p16 and p53 protein expression predicts poor prognosis in mucosal melanoma.

Primary mucosal melanoma (MM) is a rare, and aggressive, neoplasm with a poor prognosis. To date, few prognostic markers of MM have been well-defined. The aim of this study is to clarify the prognostic value of p53 and p16 proteins in predicting the clinical outcome of Chinese patients with MM. A total of 59 MM samples were contained from biopsy specimens, and, expressions of p53 and p16 proteins were assessed by immunohistochemistry. Cox regression analysis was performed to investigate the association of these proteins with the overall survival of MM patients. Increased p16 expression was significantly associated with reduced survival at three years (P=0.039). Increased p53 expression correlates with reduced one-year (P=0.025), and, two-year survival (P=0.037). Increased p53 and p16 protein expression may be helpful prognostic indicators for the management of these patients.

[Impact of neutrophil-to-lymphocyte ratio on the prognosis of patients with locally advanced colorectal cancer].

OBJECTIVE: To investigate the impact of neutrophil-to-lymphocyte ratio(NLR) on the prognosis of patients with locally advanced colorectal cancer (LACRC). METHODS: Clinicopathological data of 684 patients with stage II(-III( CRC undergoing radical resection at Shanghai Ruijin Hospital from January 2008 to December 2010 were analyzed retrospectively. NLR was calculated from neutrophil and lymphocyte counts on routine blood tests prior to surgery. The optimal cutoff value of NLR for predicting 5-year overall survival (OS) was determined through receiver operating characteristic (ROC) curve analysis. According to the cut-off value, patients were divided into high NLR and low NLR groups. Clinicopathological characteristics and prognosis were compared between two groups. Univariate and multivariate analyses were performed with Cox proportional hazards model to evaluate the impact of clinical factors on prognosis. RESULTS: A total of 396 male and 288 female patients were included in the study, with a median age of 62 years(range 21-92).Among these patients, 335 had rectal cancers and 349 had colonic cancers; 328 were TNM stage II( and 356 were stage III(. The end of follow-up was January 2016. ROC curve showed that the optimal cut-off value of NLR was 3.0, then patients were divided into low NLR group (NLR≤3.0, n=481) and high NLR group (NLR>3.0, n=203). Compared with low NLR group, the high NLR group was more likely to be older (median 64 vs. 61, t=-2.412, P=0.016), presented higher ratio of colonic cancer [66.0%(134/203) vs. 44.7%(215/481), χ2=25.945, P=0.000] and stage III( tumor [60.1%(122/203) vs. 48.6%(234/481), χ2=7.499, P=0.007], but lower ratio of first-degree relative cancer history [8.9%(18/203) vs. 15.6%(75/481); χ2=5.496, P=0.020]. However, no significant differences were observed between two groups in gender, smoking and drinking history, tumor differentiation grade, vessel invasion and nerve invasion (all P>0.05). The median follow-up time was 67 months (range 3-92), and the 5-year OS rates of high NLR and low NLR group were 59.6% and 73.2% respectively, with significant difference (P=0.001). Cox multivariate analysis revealed that age >65 years (HR=2.07, 95%CI=1.59-2.70, P=0.000), no first-degree relative cancer history (HR=2.01, 95%CI=1.23-3.28, P=0.005), poor differentiation grade (HR=1.65, 95%CI=1.26-2.15, P=0.000), positive vessel or nerve invasion (HR=1.92, 95%CI=1.35-2.71, P=0.000), high TNM stage(HR=2.10, 95%CI=1.59-2.77, P=0.000) and preoperative NLR>3.0(HR=1.51, 95%CI=1.14-2.00, P=0.004) were independent risk factors of prognosis for patients with LACRC. CONCLUSIONS: Preoperative NLR can influence the prognosis of patients with LACRC receiving radical surgery. High NLR is associated with poor prognosis.

Development and validation of nomograms for predicting survival in patients with non-metastatic colorectal cancer.

BACKGROUND: This study aimed to develop nomograms for predicting survival in patients with non-metastatic colorectal cancer (CRC). RESULTS: On multivariate analyses of the derivation set, the nomograms for OS and CSS shared common significant prognostic factors: age, first-degree relative cancer history, differentiation grade, vessels/nerves invasion, TNM stage, CEA, CA19-9 and PNI. The nomograms displayed good accuracy in predicting OS and CSS, with C-indexes of 0.75 and 0.76, respectively. The calibration plots also showed an excellent agreement between the predicted and observed survival probabilities. Furthermore, the predictive accuracy of the nomograms was confirmed in the validation set, with C-indexes of 0.79 and 0.83 for OS and CSS, respectively. MATERIALS AND METHODS: On the basis of data from 822 patients with resected non-metastatic CRC, nomograms for predicting overall survival (OS) and cancer-specific survival (CSS) were established using Cox regression model. The predictive performance of the nomograms was assessed by concordance index (C-index) and calibration plot. An independent external cohort of 171 patients was used to validate the nomograms. CONCLUSIONS: We developed and validated two nomograms for patients with non-metastatic CRC, which could provide individual prediction of OS and CSS with high accuracy.

Prognostic Value of the Combination of Preoperative Hemoglobin, Lymphocyte, Albumin, and Neutrophil in Patients with Locally Advanced Colorectal Cancer.

BACKGROUND Systemic inflammatory response and nutritional status are important to the prognosis of patients with colorectal cancer (CRC). This study aimed to investigate the prognostic value of the combination of preoperative hemoglobin, lymphocyte, albumin, and neutrophil (HLAN) in patients with locally advanced CRC (LACRC). MATERIAL AND METHODS We performed a retrospective analysis in 536 LACRC patients undergoing radical surgery. The value of HLAN was defined as follow: HLAN=Hemoglobin (g/L)×Lymphocyte (/L)×Albumin (g/L)/Neutrophil (/L)/100. The X-tile program was used to determine the optimal cut-point of HLAN, and the prognostic value of HLAN for overall survival (OS) was evaluated with the Cox proportional hazard model. RESULTS The cut-point of HLAN was set at 19.5. Compared with the high-HLAN group, the low-HLAN group had a 1.50-fold (95% confidence interval 1.09-2.05) increased risk of death and a significantly lower OS rate (P<0.001). Furthermore, the risk stratification model based on HLAN (AUC=0.72) displayed better accuracy in OS prediction than the TNM system (AUC=0.61). CONCLUSIONS HLAN is a valuable prognostic marker for patients with LACRC.

Preoperative combined hemoglobin, albumin, lymphocyte and platelet levels predict survival in patients with locally advanced colorectal cancer.

More than 50% of patients with colorectal cancer (CRC) are initially diagnosed with locally advanced CRC (LACRC), and half of those patients develop recurrence or metastasis after resection. Here, we investigated whether the novel index HALP, which is a combination of preoperative hemoglobin, albumin, lymphocyte and platelet levels, correlates with survival in LACRC patients. A total of 820 patients with LACRC from two independent hospitals were included in our study. The correlations between HALP and overall and cancer-specific survival were calculated using training and validation sets. Lower HALP values correlated with an increased risk of death and cancer-related death in both sets. Moreover, the risk score based on HALP allowed stratification of patients into distinct prognostic groups with greater accuracy than previously proposed indexes. These results suggest that HALP may be useful as a clinical prognostic factor for patients with LACRC.

High-throughput RNAi screening of human kinases identifies predictors of clinical outcome in colorectal cancer patients treated with oxaliplatin.

The purpose of this study is to identify protein kinase genes that modulate oxaliplatin cytotoxicity in vitro and evaluate the roles of these genes in predicting clinical outcomes in CRC patients receiving oxaliplatin-based adjuvant chemotherapy. A high-throughput RNAi screening targeting 626 human kinase genes was performed to identify kinase genes whose inhibition potentiates oxaliplatin sensitivity in CRC cells. The associations between copy numbers of the candidate genes and recurrence-free survival and overall survival were analyzed in 142 stage III CRC patients receiving first-line oxaliplatin-based adjuvant chemotherapy who were enrolled from two independent hospitals. HT-RNAi screening identified 40 kinase genes whose inhibition potentiated oxaliplatin cytotoxicity in DLD1 cells. The relative copy number (RCN) of MAP4K1 and CDKL4 were associated with increased risks of both recurrence and death. Moreover, significant genes-based risk score and the ratios of RCN of different genes can further categorize patients into subgroups with distinctly differing outcomes. The estimated AUC for the prediction models including clinical variables plus kinase biomarkers was 0.77 for the recurrence and 0.82 for the survival models. The copy numbers of MAP4K1 and CDKL4 can predict clinical outcomes in CRC patients treated with oxaliplatin-based chemotherapy.

PIK3C2G copy number is associated with clinical outcomes of colorectal cancer patients treated with oxaliplatin.

PURPOSE: To investigate whether the copy number of PIK3C2G is associated with clinical outcomes for stage III colorectal cancer (CRC) patients treated with oxaliplatin-based chemotherapy. METHODS: A total of 142 CRC patients who received first-line oxaliplatin-based chemotherapy after curative surgery in Ruijin Hospital and The Tenth People's Hospital were recruited in this study. Patients were enrolled between June 2006 and December 2011, with follow-up to January 2014. Quantitative real-time PCR method was used to detect the copy number of PIK3C2G. Cox proportional hazards model and Kaplan-Meier curves were used to analyze the association between PIK3C2G copy number and clinical outcome. RESULTS: In patients with stage III disease, low copy number of PIK3C2G was associated with increased risk of both recurrence (HR, 2.44, 95% CI, 1.33-4.47, P=0.004) and death (HR, 2.89, 95% CI, 1.49-5.60, P=0.002). Multivariate analysis also indicated that low PIK3C2G copy number was a significant and independent predictor of OS and RFS of stage III CRC. CONCLUSIONS: PIK3C2G is capable of predicting the recurrence and overall survival of stage III CRC patients receiving oxaliplatin-based therapy.