Oncogenic and immunological role of EDIL3 in human tumours: From pan-cancer analysis to validation in gastric cancer.

Background: Epidermal growth factor-like repeats and discoidin I-like domains 3 (EDIL3) is a secreted extracellular matrix protein implicated in diverse physiological and pathological processes including embryonic development, angiogenesis, and anti-inflammatory responses. Recent reports have indicated that EDIL3 play critical roles in carcinogenesis and progression of many cancers. Herein, we performed a pan-cancer investigation to study the potential functions of EDIL3 in various cancers and experimentally validate its function in gastric cancer (GC). Methods: We analysed EDIL3 expression profiles in different tumours using The Cancer Genome Atlas database. The Kaplan-Meier Plotter was used to investigate the prognostic value of EDIL3, while receiver operating characteristic curve was performed to analyze its diagnostic efficacy. Several bioinformatics tools were used to study the association between EDIL3 and promoter methylation, gene enrichment analysis, immune infiltration, immune-related genes, and drug sensitivity. Molecular biology experiments were conducted to validate the tumorigenic effects of EDIL3. Results: EDIL3 is variably expressed in different cancers and is closely associated with clinical outcomes. An inverse correlation between EDIL3 and DNA methylation has been observed in 13 cancers. Enrichment analysis indicated that EDIL3 is correlated with many cellular pathways such as extracellular matrix receptor interactions and focal adhesion. EDIL3 was tightly associated with immune infiltration and immune checkpoints. EDIL3 knockdown can promote GC calls apoptosis while preventing proliferation, migration, and invasion in vitro. Conclusion: EDIL3 is a promising prognostic, diagnostic, and immunological biomarker in various cancers, which could be applied as a new target for cancer therapy.

CLEC4D as a Novel Prognostic Marker Boosts the Proliferation and Migration of Gastric Cancer via the NF-κB/AKT Signaling Pathway.

Purpose: The functions of C-type lectin domain family 4 member D (CLEC4D), one member of the C-type lectin/C-type lectin-like domain superfamily, in immunity have been well described, but its roles in cancer biology remain largely unknown. Patients and Methods: This study aims to explore the role of CLEC4D in gastric cancer (GC). Bioinformatics preliminarily analyzed the expression of CLEC4D in gastric cancer. Immunohistochemical staining was used to detect the expression level and clinical pathological characteristics of CLEC4D in gastric cancer. The biological function of CLEC4D in gastric cancer cell lines was verified through in vitro and in vivo experiments. Results: In this study, CLEC4D expression was found to be markedly increased in gastric cancer (GC) tissues compared with matched normal gastric tissues, and high CLEC4D expression independently predicted unfavorable overall survival in patients with GC. Knockdown of CLEC4D markedly inhibited GC cell proliferation and migration. Mechanistically, CLEC4D knockdown deactivated the Akt and NF-κB signaling pathways in GC cells. Conclusion: Together, these results demonstrate that aberrantly increased CLEC4D expression promotes cancer phenotypes via the Akt and NF-κB signaling pathways in GC cells.

Case Report: sintilimab-induced Stevens-Johnson Syndrome in a patient with advanced lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have been widely applicated in clinical therapy in recent years. Skin-related adverse reaction is one of the most common adverse events for ICIs. Stevens-Johnson syndrome (SJS) is one of the serious cutaneous reactions threatening the life. Here, we reported a case of 76-year-old male patient with poorly differentiated metastatic lung adenocarcinoma, after 9 weeks exposure of sintilimab (3 doses) combined with paclitaxel liposome after concurrent chemotherapy/radiotherapy, experienced Stevens-Johnson syndrome involving limbs, trunk, lip and the oral mucosa. Biopsy of the skin tissue showed infiltration of CD4 and CD8 positive T lymphocytes. We also found PD-L1 expression in the glands and the basal layer of the skin. This finding is distinct from the previously reported expression of PD-L1 on the surface of epidermal keratinocytes in patients with SJS due to immunotherapy.

EDIL3 is a potential prognostic biomarker that correlates with immune infiltrates in gastric cancer.

Background: EDIL3, which contains epidermal growth factor-like repeats and discoidin I-like domains, is a secretory protein that plays an important role in embryonic development and various illnesses. However, the biological function of EDIL3 in gastric cancer (GC) is still unclear. The objective of this research was to explore the role and potential mechanism of EDIL3 in GC. Methods: In this study, we used the GEPIA, HPA, MethSurv, SMART, STRING, GeneMANIA, LinkedOmics TIMER, TIMER2.0, TISIDB, and RNAactDrug databases to comprehensively analyze the roles of EDIL3 in GC. To validate the in silico findings, EDIL3 expression was measured in our collected GC tissues. Meanwhile, several in vitro experiments were performed to test the function of EDIL3 in GC. Results: We found that EDIL3 was highly expressed in GC and associated with adverse clinical features. In vitro assays revealed that EDIL3 promoted the proliferation, migration, and invasion of GC cells. The functions of EDIL3 and co-expression genes were significantly associated with extracellular structure organization and matrix receptor interaction. EDIL3 expression was positively associated with numerous tumor-infiltrating immune cells and their biomarkers. Conclusion: This study determined that EDIL3 may function as an oncogene and is associated with immune infiltration in GC. EDIL3 could be used as a potential therapeutic target for GC.

Evaluating smoking cessation service at an emergency department clinical observation unit.

OBJECTIVES: To evaluate the effectiveness of a pilot smoking cessation service in an emergency department (ED) clinical observation unit. STUDY DESIGN: A descriptive case series review was undertaken of smoking cessation service patients in the short-stay unit of an acute hospital in Singapore from July 1, 2018, to December 31, 2019. METHODS: Upon admission, ED nurses screen all patients regarding their current smoking status and implement the 5 A's framework, which involves the steps of Ask-Advise-Assess-Assist-Arrange. Patients in the "contemplation" and "preparation" stages were offered the following components: (1) a bedside counseling session by a pharmacist and (2) a follow-up appointment at an outpatient smoking cessation clinic. Postdischarge follow-up telephone calls at 1, 6, and 12 months were carried out as part of the study data collection to obtain abstinence information. RESULTS: Forty-seven patients were included in the study; the majority were male (n = 41; 87.2%). The median numbers of cigarettes smoked per day at baseline, 1 month, 6 months, and 12 months were 14, 5, 3, and 5, respectively. The overall point-prevalence abstinence rates over the same follow-up time points were 26.5%, 38.7%, and 31.3%, respectively. The proportions of patients lost to follow-up at 1 month, 6 months, and 12 months were 27.7%, 34.0%, and 31.9%, respectively. CONCLUSIONS: Given the small sample and high number of uncontactable patients, more research is needed to assess whether the trend toward increasing point-prevalence abstinence rate over time and the trend toward decreasing median number of cigarettes smoked are observed in a larger sample.

Detection of Pathogenic Isoforms of IKZF1 in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15.

Leukemia-associated alternative splicing of IKZF1 can result in proteins with loss of one to four copies of its N-terminal zinc finger domains (N-ZnF). The best characterized pathogenic splice isoforms, Ik-6 and Ik-8, have been commonly found in BCR-ABL1+ acute lymphoblastic leukemia (ALL) and a subset of BCR-ABL1-like ALL. Infantile and childhood ALL that express these pathogenic IKZF1 isoforms have shown inferior clinical outcomes and can be resistant to tyrosine kinase inhibitors. Using ALL cell lines, we designed and validated a method to detect abnormal IKZF1 transcripts. In the SUP-B15 leukemia cell line, we noted novel IKZF1 transcripts that include both an Ik-6 splice and a transcript with a 14 base pair insertion at the C-terminus. There was also increased IKZF2 protein in SUP-B15 as compared to other ALL lines. Expression of Ik-6 could be suppressed by treatment with the pro-apoptotic type II histone deacetylase inhibitor givinostat. In 17 adult ALL samples, we noted the Ik-6 isoforms in 6 of 15 BCR-ABL1-, and 1 of 2 BCR-ABL1+ cases, with Ik-8 also expressed in one case. Cases with Ik-6 expression showed inferior survival as well as older age at presentation, lower expression of CD10 and more commonly a diploid karyotype.

Ablation of the Brca1-Palb2 Interaction Phenocopies Fanconi Anemia in Mice.

Heterozygous mutations in the BRCA1 gene predispose women to breast and ovarian cancer, while biallelic BRCA1 mutations are a cause of Fanconi anemia (FA), a rare genetic disorder characterized by developmental abnormalities, early-onset bone marrow failure, increased risk of cancers, and hypersensitivity to DNA-crosslinking agents. BRCA1 is critical for homologous recombination of DNA double-strand breaks (DSB). Through its coiled-coil domain, BRCA1 interacts with an essential partner, PALB2, recruiting BRCA2 and RAD51 to sites of DNA damage. Missense mutations within the coiled-coil domain of BRCA1 (e.g., L1407P) that affect the interaction with PALB2 have been reported in familial breast cancer. We hypothesized that if PALB2 regulates or mediates BRCA1 tumor suppressor function, ablation of the BRCA1-PALB2 interaction may also elicit genomic instability and tumor susceptibility. We generated mice defective for the Brca1-Palb2 interaction (Brca1 L1363P in mice) and established MEF cells from these mice. Brca1 L1363P/L1363P MEF exhibited hypersensitivity to DNA-damaging agents and failed to recruit Rad51 to DSB. Brca1 L1363P/L1363P mice were viable but exhibited various FA symptoms including growth retardation, hyperpigmentation, skeletal abnormalities, and male/female infertility. Furthermore, all Brca1 L1363P/L1363P mice exhibited macrocytosis and died due to bone marrow failure or lymphoblastic lymphoma/leukemia with activating Notch1 mutations. These phenotypes closely recapitulate clinical features observed in patients with FA. Collectively, this model effectively demonstrates the significance of the BRCA1-PALB2 interaction in genome integrity and provides an FA model to investigate hematopoietic stem cells for mechanisms underlying progressive failure of hematopoiesis and associated development of leukemia/lymphoma, and other FA phenotypes. SIGNIFICANCE: A new Brca1 mouse model for Fanconi anemia (FA) complementation group S provides a system in which to study phenotypes observed in human FA patients including bone marrow failure.See related commentary by Her and Bunting, p. 4044.

Sonic Hedgehog/Gli1 Signaling Pathway Regulates Cell Migration and Invasion via Induction of Epithelial-to-mesenchymal Transition in Gastric Cancer.

Background: The aberrant activation of the Sonic hedgehog (Shh) signaling pathway is involved in progression of several types of cancer, including gastric cancer (GC). However, it remains uncertain whether it also plays a critical role in promoting cancer initiation and progression by inducing epithelial-to-mesenchymal transition (EMT) in GC. Thus, the aim of the present study was to determine whether the Shh pathway is involved in GC, and to investigate the function of the Shh pathway in the induction of EMT in GC. Materials and methods: The expression levels of Shh pathway members and EMT markers were examined in GC tissues by immunohistochemistry. The association between these factors and patient clinicopathological characteristics was analyzed. In addition, Gli-antagonist 61 (GANT61) was used to block Shh/Gli1 pathway activity, and recombinant Shh proteins (N-Shh) were used to activate the Shh pathway in GC cells. Wound healing and Transwell invasion and migration assays were performed to assess the effects of the Shh pathway on the migration and invasion of GC cells in vitro. Furthermore, western blot analysis was used to examine the changes in protein expression. Results: The results demonstrated that these Shh/Gli1 pathway members were upregulated in GC tissues, and that Gli1 upregulation was associated with tumor progression and a poor prognosis. Gli1 expression was negatively associated with E-cadherin (E-Cad) expression, and positively with Vimentin (VIM) expression in GC specimens. Further analysis revealed that when the Shh/Gli1 pathway was activated, the migratory and invasive abilities of GC cells were enhanced, and the expression levels of Gli1 and VIM were increased, while E-Cad expression was decreased. Opposite results were observed when the Shh/Gli1 pathway was blocked by GANT61. Conclusions: The present study indicated that the Shh/Gli1 pathway exhibits an abnormal activation pattern in GC with possible predictive and prognostic significance. The Shh/Gli1 pathway may promote the migratory and invasive potential of GC cells by inducing EMT. The Shh/Gli1 pathway can thus be considered as a potential therapeutic target for GC.

Clinical significance of Stathmin1 expression and epithelial-mesenchymal transition in curatively resected gastric cancer.

In our previous study, it was demonstrated that the Stathmin1 (STMN1) is overexpressed in gastric cancer (GC) and that its high expression level is associated with tumor invasion and metastasis. Epithelial-mesenchymal transition (EMT) has also been shown to be critically involved in GC invasion and metastasis. Certain studies have indicated that STMN1 may serve an important role in the EMT process. However, the association between STMN1 expression and EMT-associated markers, as well as clinicopathological characteristics of patients with GC, remains unclear. The aim of the present study was to investigate the clinicopathological significance and prognostic value of STMN1 and EMT-associated markers in GC. The expression of STMN1 and the EMT-associated proteins E-cadherin (E-Cad) and vimentin (VIM) were analyzed by immunohistochemistry in GC and adjacent non-tumorous tissues. Associations between the expression of these markers and clinicopathological parameters were analyzed. The association between STMN1 expression and EMT-associated markers was investigated in the GC cell lines BGC-803 and SGC-7901. The results revealed that STMN1 was expressed in 63.5% of the 167 GC tissues, which was significantly higher than the percentage observed in the adjacent non-tumorous tissues (P=0.003). The STMN1 expression was demonstrated to be positively associated with the VIM levels (P=0.001) and negatively associated with the E-Cad levels (P=0.022) in GC tissues. The STMN1 expression was associated with Lauren's Classification, invasion depth, lymph node metastasis and pathological Tumor-Node-Metastasis (pTNM) stage (P<0.05). In the univariate analyses, the high E-Cad expression was a positive prognostic indicator for overall survival, whereas the high STMN1 and VIM expression was a negative indicator. COX multiple regression analysis demonstrated that the pTNM stage [hazard ratio (HR) 1.912, 95% confidence interval (CI): 1.282-2.851, P=0.001] and E-Cad expression (HR 0.403, 95% CI: 0.249-0.650, P=0.000) were independent prognostic factors. It was also revealed that the expression level of E-Cad decreased, while the expression level of VIM increased by depleting STMN1 levels in GC cells. The present results suggest that the aberrant expression of STMN1 may promote tumor progression through EMT in GC.

[Protective effects of genistein on Aß25₋35-induced PC12 cell injury via regulating CaM-CaMKIV signaling pathway].

Genistein is a kind of isoflavone compounds， also called phytoestrogens， with clinical effects on cardiovascular disease， cancer and postmenopausal-related gynecological diseases， and also has the potentiality in the prevention and treatment of Alzheimer's disease(AD). In this study， the protective effect of genistein on Aß25₋35-induced PC12 cell injury and effect on CaM-CaMKIV signaling pathway were observed to investigate its mechanism for AD. PC12 cells were cultured in vitro and then the safe concentration of genistein and the modeling concentration and optimal time point of administration of Aß25₋35 were screened by MTT assay. After being pretreated with different concentrations of genistein(25， 50， 100 µmol·L⁻¹) on PC12 cells， the AD model of PC12 cells was induced by Aß25₋35. Then the survival rate of cells was detected by MTT assay; morphological change of cells was observed under the inverted microscope， and apoptosis of cells was assessed by AO/EB fluorescence staining; the neuroprotective effects of genistein on AD cell model were observed and the optimal concentration of genistein was determined. Expressions of mRNA and protein levels of CaM， CaMKK， CaMKIV and tau were detected by qRT-PCR and Western blot assay， respectively. The results showed that as compared with the blank group， the cell survival rate was decreased; the cell damage and apoptosis were increased; and the expressions of mRNA and protein levels of CaM， CaMKK， CaMKIV and tau were increased in AD model group. Genistein could significantly improve the cell survival rate， reduce the cell damage and apoptosis of AD cell model， and significantly down-regulate the expressions of mRNA and protein levels of CaM， CaMKK， CaMKIV and tau of AD cell model. These results indicated that genistein has obviously neuroprotective effect on the AD cell model induced by Aß25₋35， and the mechanism may be related to the down-regulation of CaM-CaMKIV signaling pathway and Tau protein expression.

Potent induction of apoptosis by givinostat in BCR-ABL1-positive and BCR-ABL1-negative precursor B-cell acute lymphoblastic leukemia cell lines.

We have previously shown that givinostat can induce potent apoptosis in the BCR-ABL1-positive, TP53-wild type B-cell acute lymphoblastic leukemia (B-ALL) cell line SUP-B15. We extend our studies here to two additional B-ALL cell lines, BCR-ABL1-negative CCRF-SB and p210 BCR-ABL1-positive NAML1. Givinostat induced significant cell growth inhibition in both cell lines, with an IC50 of 0.65±0.052µM and 0.25±0.028µM in CCRF-SB and NAML1, respectively. The key signal protein of the BCR-ABL1, Crk-L1, was significantly reduced by givinostat treatment in NAML1. As in SUP-B15, givinostat induced apoptosis in both cell lines but showed different levels of cleavage of the procaspase proteins Casp-3, Casp-7 and PARP. Levels of cell cycle-DNA repair regulator p21, CHK1 and FANCD2 levels were markedly affected by givinostat treatment. These data further enrich our understanding of the mechanisms of the antineoplastic effects of givinostat in B-ALL and provide a preclinical rationale for the inclusion of givinostat or similar agent in leukemia therapy.

microRNA-29 mediates a novel negative feedback loop to regulate SCAP/SREBP-1 and lipid metabolism.

The membrane-bound transcription factors, SREBPs (sterol regulatory element-binding proteins), play a central role in regulating lipid metabolism. The transcriptional activation of SREBPs requires the key protein SCAP (SREBP-cleavage activating protein) to translocate their precursors from the endoplasmic reticulum to the Golgi for subsequent proteolytic activation, a process tightly regulated by a cholesterol-mediated negative feedback loop. Our previous work showed that the SCAP/SREBP-1 pathway is significantly upregulated in human glioblastoma (GBM), the most deadly brain cancer, and that glucose-mediated N-glycosylation of SCAP is a prerequisite step for SCAP/SREBP trafficking. More recently, we demonstrated that microRNA-29 (miR-29) mediates a previously unrecognized negative feedback loop in SCAP/SREBP-1 signaling to control lipid metabolism. We found that SREBP-1, functioning as a transcription factor, promotes the expression of the miR-29 family members, miR-29a, -29b and -29c. In turn, the miR-29 isoforms reversely repress the expression of SCAP and SREBP-1. Moreover, treatment with miR-29 mimics effectively suppressed GBM tumor growth by inhibiting SCAP/SREBP-1 and de novo lipid synthesis. These findings, recently published in Cell Reports, strongly suggest that delivery of miR-29 in vivo may be a promising approach to treat cancer and metabolic diseases by suppressing SCAP/SREBP-1-regulated lipid metabolism.

Feedback Loop Regulation of SCAP/SREBP-1 by miR-29 Modulates EGFR Signaling-Driven Glioblastoma Growth.

Dysregulated lipid metabolism is a characteristic of malignancies. Sterol regulatory element binding protein 1 (SREBP-1), a transcription factor playing a central role in lipid metabolism, is highly activated in malignancies. Here, we unraveled a link between miR-29 and the SCAP (SREBP cleavage-activating protein)/SREBP-1 pathway in glioblastoma (GBM) growth. Epidermal growth factor receptor (EGFR) signaling enhances miR-29 expression in GBM cells via upregulation of SCAP/SREBP-1, and SREBP-1 activates miR-29 expression via binding to specific sites in its promoter. In turn, miR-29 inhibits SCAP and SREBP-1 expression by interacting with their 3' UTRs. miR-29 transfection suppressed lipid synthesis and GBM cell growth, which were rescued by the addition of fatty acids or N-terminal SREBP-1 expression. Xenograft studies showed that miR-29 mimics significantly inhibit GBM growth and prolong the survival of GBM-bearing mice. Our study reveals a previously unrecognized negative feedback loop in SCAP/SREBP-1 signaling mediated by miR-29 and suggests that miR-29 treatment may represent an effective means to target GBM.

Inhibition of SOAT1 Suppresses Glioblastoma Growth via Blocking SREBP-1-Mediated Lipogenesis.

PURPOSE: Elevated lipogenesis regulated by sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor playing a central role in lipid metabolism, is a novel characteristic of glioblastoma (GBM). The aim of this study was to identify effective approaches to suppress GBM growth by inhibition of SREBP-1. As SREBP activation is negatively regulated by endoplasmic reticulum (ER) cholesterol, we sought to determine whether suppression of sterol O-acyltransferase (SOAT), a key enzyme converting ER cholesterol to cholesterol esters (CE) to store in lipid droplets (LDs), effectively suppressed SREBP-1 and blocked GBM growth. EXPERIMENTAL DESIGN: The presence of LDs in glioma patient tumor tissues was analyzed using immunofluorescence, immunohistochemistry, and electronic microscopy. Western blotting and real-time PCR were performed to analyze protein levels and gene expression of GBM cells, respectively. Intracranial GBM xenografts were used to determine the effects of genetically silencing SOAT1 and SREBP-1 on tumor growth. RESULTS: Our study unraveled that cholesterol esterification and LD formation are signature of GBM, and human patients with glioma possess elevated LDs that correlate with GBM progression and poor survival. We revealed that SOAT1 is highly expressed in GBM and functions as a key player in controlling the cholesterol esterification and storage in GBM. Targeting SOAT1 suppresses GBM growth and prolongs survival in xenograft models via inhibition of SREBP-1-regulated lipid synthesis. CONCLUSIONS: Cholesterol esterification and storage in LDs are novel characteristics of GBM, and inhibiting SOAT1 to block cholesterol esterification is a promising therapeutic strategy to treat GBM by suppressing SREBP-1. Clin Cancer Res; 22(21); 5337-48. ©2016 AACR.

Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth.

Tumorigenesis is associated with increased glucose consumption and lipogenesis, but how these pathways are interlinked is unclear. Here, we delineate a pathway in which EGFR signaling, by increasing glucose uptake, promotes N-glycosylation of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and consequent activation of SREBP-1, an ER-bound transcription factor with central roles in lipid metabolism. Glycosylation stabilizes SCAP and reduces its association with Insig-1, allowing movement of SCAP/SREBP to the Golgi and consequent proteolytic activation of SREBP. Xenograft studies reveal that blocking SCAP N-glycosylation ameliorates EGFRvIII-driven glioblastoma growth. Thus, SCAP acts as key glucose-responsive protein linking oncogenic signaling and fuel availability to SREBP-dependent lipogenesis. Targeting SCAP N-glycosylation may provide a promising means of treating malignancies and metabolic diseases.

Evaluating the clinical feasibility: The direct bisulfite genomic sequencing for examination of methylated status of protocadherin10 (PCDH10) promoter to predict the prognosis of gastric cancer.

OBJECTIVE: To elucidate the clinical significance of the methylated status of CpG site count of PCDH10 promoter in the survival prediction in gastric cancer (GC). METHODS: In the previous study, we demonstrated that the methylated CpG site count was significantly associated with the overall survival (OS) of GC patients by using the bisulfite genomic sequencing (BGS) with no less than five clones per sample. It was so complex and expensive for patients to undergo the BGS clones. In this study, we detected the different CpG site counts (hypermethylated and hypomethylated) of PCDH10 DNA promoter in GC samples of 471 patients by directly bisulfite genomic sequencing (D-BGS) without any clone. Furthermore, we evaluated the relationships between the methylated status of PCDH10 promoter and OS. RESULTS: Two hundred and fifty-seven of 471 (54.6%) GC patients were identified to present with PCDH10 promoter methylation by D-BGS. Patients who presented with 5 or more methylated CpG site counts of PCDH10 promoter had significantly poorer prognosis than patients who with less than 5 methylated CpG site counts of PCDH10 promoter (p= 0.039). With the multivariate survival analysis, we demonstrated that T stage, N stage and the hypermethylated CpG site counts of PCDH10 DNA promoter were the independent predictors of OS of GC patients. In addition, the hypermethylated CpG site counts of PCDH10 DNA promoter had smaller Akaike information criterion (AIC) and Bayesian information criterion (BIC) values than the other two independent predictors of the OS, indicating the hypermethylated CpG site counts of PCDH10 DNA promoter as the best prognostic predictor of GC. CONCLUSIONS: Our present findings suggested that the hypermethylated CpG site counts of PCDH10 DNA promoter for evaluating the prognosis of GC was reasonable by using the D-BGS.

Prognostic nutritional index predicts postoperative complications and long-term outcomes of gastric cancer.

AIM: To investigate the impact of prognostic nutritional index (PNI) on the postoperative complications and long-term outcomes in gastric cancer patients undergoing total gastrectomy. METHODS: The data for 386 patients with gastric cancer were extracted and analyzed between January 2003 and December 2008 in our center. The patients were divided into two groups according to the cutoff value of the PNI: those with a PNI ≥ 46 and those with a PNI < 46. Clinicopathological features were compared between the two groups and potential prognostic factors were analyzed. The relationship between postoperative complications and PNI was analyzed by logistic regression. The univariate and multivariate hazard ratios were calculated using the Cox proportional hazard model. RESULTS: The optimal cutoff value of the PNI was set at 46, and patients with a PNI ≥ 46 and those with a PNI < 46 were classified into PNI-high and PNI-low groups, respectively. Patients in the PNI-low group were more likely to have advanced tumor (T), node (N), and TNM stages than patients in the PNI-high group. The low PNI is an independent risk factor for the incidence of postoperative complications (OR = 2.223). The 5-year overall survival (OS) rates were 54.1% and 21.1% for patients with a PNI ≥ 46 and those with a PNI < 46, respectively. The OS rates were significantly lower in the PNI-low group than in the PNI-high group among patients with stages II (P = 0.001) and III (P < 0.001) disease. CONCLUSION: The PNI is a simple and useful marker not only to identify patients at increased risk for postoperative complications, but also to predict long-term survival after total gastrectomy. The PNI should be included in the routine assessment of advanced gastric cancer patients.

Prognostic value of the lymph node ratio in stage III gastric cancer patients undergoing radical resection.

OBJECTIVE: The aim of this study was to investigate the prognostic value of metastatic lymph node ratio (LNR) in patients having radical resection for stage III gastric cancer. METHODS: A total of 365 patients with stage III gastric cancer who underwent radical resection between 2002 and 2008 at Tianjin Medical University Cancer Institute and Hospital were analyzed. The cut-point survival analysis was adopted to determine the appropriate cutoffs for LNR. Kaplan-Meier survival curves and log-rank tests were used for the survival analysis. RESULTS: By cut-point survival analysis, the LNR staging system was generated using 0.25 and 0.50 as the cutoff values. Pearson's correlation test revealed that the LNR was related with metastatic lymph nodes but not related with total harvested lymph nodes. Cox regression analysis showed that depth of invasion and LNR were the independent predictors of survival (p<0.05). There was a significant difference in survival between each pN stages classified by the LNR staging, however no significant difference was found in survival rate between each LNR stages classified by the pN staging. CONCLUSIONS: The LNR is an independent prognostic factor for survival in stage III gastric cancer and is superior to the pN category in TNM staging. It may be considered as a prognostic variable in future staging system.

Prognostic value of number of examined lymph nodes in patients with node-negative gastric cancer.

AIM: To elucidate the potential impact of examined lymph nodes (eLNs) on long-term survival of node-negative gastric cancer patients after curative surgery. METHODS: A total of 497 node-negative gastric cancer patients who underwent curative gastrectomy between January 2000 and December 2008 in our center were enrolled in this study. Patients were divided into 4 groups according to eLNs through cut-point analysis. Clinicopathological features were compared between ≤ 15 eLNs group and > 15 eLNs group and potential prognostic factors were analyzed. The Log-rank test was used to assess statistical differences between the groups. Independent prognostic factors were identified using the Cox proportional hazards regression model. Stratified analysis was performed to investigate the impact of eLNs on patient survival in each stage. Overall survival was also compared among the four groups. Finally, we explored the recurrent sites associated with eLNs. RESULTS: Patients with eLNs > 15 had a better survival compared with those with eLNs ≤ 15 for the entire cohort. By the multivariate survival analysis, we found that the depth of invasion and the number of eLNs were the independent predictors of overall survival (OS) of patients with node-negative gastric cancer. According to the cut-point analysis, T2-T4 patients with 11-15 eLNs had a significantly longer mean OS than those with 4-10 eLNs or 1-3 eLNs. Patients with ≤ 15 eLNs were more likely to experience locoregional and peritoneal recurrence than those with > 15 eLNs. CONCLUSION: Number of eLNs could predict the prognosis of node-negative gastric cancer, and dissection of > 15 eLNs is recommended during lymphadenectomy so as to improve the long-term survival.