Prognostic significance of the combination of preoperative hemoglobin,albumin, lymphocyte and platelet in patients with gastric carcinoma: a retrospective cohort study

Nutritional and immune status is important to the prognosis of patients with gastric carcinoma (GC). Here, we evaluated the prognostic significance of the combination of preoperative hemoglobin, albumin, lymphocyte and platelet (HALP) in patients with GC. From January 2005 to December 2011, 1332 patients with GC who underwent gastrectomy were randomly divided into the training (n = 888) and the validation sets (n = 444) by X-tile according to the sample size ratio 2:1. The cut-point of HALP was 56.8 and the patients were subsequently subdivided into HALP < 56.8 and HALP ≥ 56.8 groups in both two sets. Multivariate analysis revealed that gender (p < 0.001, p < 0.001), tumor size (p = 0.003, p = 0.035) and T stage (p < 0.001, p = 0.044) were independently related to HALP both in the training and the validation sets. Kaplan-Meier (p < 0.001, p = 0.003) and Cox regression (p = 0.043, p = 0.042) showed that the prognosis of HALP ≥ 56.8 group was significantly better than that of HALP < 56.8 group both in two sets (p < 0.001, p < 0.001). Nomograms of these two sets based on HALP was more accurate in prognostic prediction than TNM stage alone. Our findings suggested that HALP was closely associated with clinicopathological features and was an independent prognostic factor in GC patients. Nomogram based on HALP could accurately predict the prognosis of GC patients.     

CD133 overexpression correlates with clinicopathological features of gastric cancer patients and its impact on survival: A systematic review and meta-analysis

Background

CD133 is one of the most commonly used markers of cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical and prognostic significance of CD133 in gastric cancer remains controversial. To clarify a precise determinant of the clinical significance of CD133, we conducted a systematic review and meta-analysis to elucidate the correlation of CD133 overexpression with prognosis and clinicopathological features of GC patients.

Methods

A search in the Cochrane Library, Pubmed, Medline, Web of Knowledge and Chinese CNKI, CBM (up to Jun 30, 2015) was performed using the following keywords gastric cancer, CD133, AC133, prominin-1, etc. Electronic searches were supplemented by hand searching reference lists, abstracts and proceedings from meetings. Outcomes included overall survival and various clinicopathological features. Two reviewers independently screened the literature according to the inclusion and exclusion criteria, extracted the data, and assessed the methodological quality of the included studies, and then RevMan 5.2.0 software was used for meta-analysis.

Results

A total of 603 gastric cancer patients from 8 studies were included. The results of the meta-analyses showed that, there were significant differences of CD133 expression in the following comparisons: gastric cancer tissues vs. normal esophageal tissue (OR = 3.49, 95% CI [2.48, 490], P < 0.00001), lymph node metastasis vs. non-lymph node metastasis (OR = 2.75, 95% CI [1.99, 3.81], P < 0.00001), distant metastasis vs. non-distant metastasis (OR = 2.38, 95%CI [1.47, 3.85], P < 0.0004), clinical stages III~IV vs. clinical stages I~II (OR = 2.83, 95% CI [2.13, 3.76], P < 0.00001), as well as the accumulative 5-year overall survival rates of CD133-positive vs. CD133-negative patients (OR = 0.23, 95% CI [0.16, 0.33], P < 0.00001).

Conclusion

Overexpression of CD133 is associated with lymph node metastasis, distant metastasis, poor TNM stage. Additionally, CD133-positive gastric cancer patients had worse prognosis. Our results indicate that CD133 may be involved in the carcinogenesis of gastric cancer. Evaluation of cytoplasmic CD133 overexpression in gastric cancer tissue sections may be useful in the future as a novel prognostic factor. Nevertheless, due to the poor quality and small sample size of included trials, more well-designed multi-center randomized controlled trials should be performed.     

Quantitative difference of oral pathogen between individuals with gastric cancer and individuals without cancer

The loss of teeth and lack of oral hygiene have been associated with the risk of developing gastric cancer (GC) in several populations evidenced in epidemiological studies. In this study, we quantitatively compared the proportion of oral pathogens in individuals with gastric cancer and individuals without cancer in a referral hospital in the city of Belém, Brazil. This study evaluated 192 patients with GC and 192 patients without cancer. Periodontal clinical examination was performed, and all individuals were submitted to the collection of salivary and dental biofilms. When comparing the median periodontal indexes in the gastric and cancer-free groups, it was statistically significant (p < 0.001) in the gastric cancer group compared to the probing depth of the periodontal pocket. Levels of bacterial DNA were observed in saliva and dental plaque, with a statistically significant difference (p < 0.001) between individuals with cancer and without neoplasia in all the bacteria surveyed. Significant relationships (p < 0.001) between biological agents and GC have been found in bacterial species that cause high rates of periodontal pathology and caries. The results suggest a different quantitative association in the presence of oral pathogens between individuals without cancer and patients with GC. As noted, it cannot be said that the bacteria present in the oral cavity increase the risk of gastric cancer or are aggravating factors of the disease. However, it is worth mentioning that, as it is part of the digestive system, the lack of care for the oral cavity can negatively affect the treatment of patients with gastric cancer.     

Analysis of the HNF4A isoform-regulated transcriptome identifies CCL15 as a downstream target in gastric carcinogenesis

Objective:Hepatocyte nuclear factor 4α (HNF4A) has been demonstrated to be an oncogene in gastric cancer (GC). However, the roles of different HNF4A isoforms derived from the 2 different promoters (P1 and P2) and the underlying mechanisms remain obscure.Methods:The expression and prognostic values of P1- and P2-HNF4A were evaluated in The Cancer Genome Atlas (TCGA) databases and GC tissues. Then, functional assays of P1- and P2-HNF4A were conducted both in vivo and in vitro. High-throughput RNA-seq was employed to profile downstream pathways in P1- and P2-HNF4A-overexpressing GC cells. The expression and gene regulation network of the candidate target genes identified by RNA-seq were characterized based on data mining and functional assays.Results:HNF4A amplification was a key characteristic of GC in TCGA databases, especially for the intestinal type and early stage. Moreover, P1-HNF4A expression was significantly higher in tumor tissues than in adjacent non-tumor tissues (P < 0.05), but no significant differences were found in P2-HNF4A expression (P > 0.05). High P1-HNF4A expression indicated poor prognoses in GC patients (P < 0.01). Furthermore, P1-HNF4A overexpression significantly promoted SGC7901 and BGC823 cell proliferation, invasion and migration in vitro (P < 0.01). Murine xenograft experiments showed that P1-HNF4A overexpression promoted tumor growth (P < 0.05). Mechanistically, RNA-seq showed that the cytokine-cytokine receptor interactions pathway was mostly enriched in P1-HNF4A-overexpressing GC cells. Finally, chemokine (C-C motif) ligand 15 was identified as a direct target of P1-HNF4A in GC tissues.Conclusions:P1-HNF4A was the main oncogene during GC progression. The cytokine-cytokine receptor interaction pathway played a pivotal role and may be a promising therapeutic target.     

Decreased albumin-to-alkaline phosphatase ratio predicted poor survival of resectable gastric cancer patients

BackgroundThe albumin-to-alkaline phosphatase ratio (AAPR) is an innovative prognostic index for various cancer patients, the clinical significance of the AAPR in patients with GC is unknown.MethodsWe retrospectively reviewed 227 resectable GC patients in our center. The Kaplan–Meier method and the Cox proportional hazards model were used to analyze the disease-free survival (DFS) and overall survival (OS). The Likelihood Ratio Test (LRT) and Akaike information criterion (AIC) were used to compare the prognostic abilities of the TNM and AAPR-TNM staging systems in DFS and OS predictionResultsThe AAPR was significantly decreased in GC patients, and the optimal cut-off value for resectable and benign gastric disease was 0.437 as determined by the receiver operating characteristic (ROC) curve. The correlation analysis revealed that decreased AAPR in GC was associated with T stage (P=0.004) and TNM stage (P=0.013). Decreased preoperative AAPR correlated with both unfavorable disease-free survival (DFS) and overall survival (OS). Cox regression analysis showed that the TNM stage (DFS: P=0.001, OS: P=0.002) and differential levels of AAPR (DFS: P<0.001, OS: P<0.001) were independent risk factors of DFS and OS. ROC analysis showed that the AAPR-TNM system was more superior than the TNM staging system for DFS (z=1.91, P=0.028) and OS (z=1.937, P=0.026) prediction. The likelihood ratio test (LRT) analysis indicated that the AAPR-TNM system had a significantly larger χ² for both DFS (35.58 vs. 34.51, P<0.001) and OS (32.92 vs. 30.07, P<0.001), and a lower Akaike information criterion (AIC) value both for DFS (1,032 vs. 1,065, P<0.001) and OS (869 vs. 898, P<0.001) compared to the TNM system.ConclusionsThe AAPR level significantly decreased in patients with GC, and impacted the prognosis of patients.     

Sequential expression of putative stem cell markers in gastric carcinogenesis

Background:

Gastric carcinogenesis has been well documented in the step-wise histopathological model, known as Correa pathway. Several biomarkers including CD44, Musashi-1 and CD133 have been reported as putative stem cell (PSC) markers.

Methods:

We investigated expression of PSC markers CD44, Musashi-1 and CD133 in relation to gastric carcinogenesis and prognosis and chemoresponse. Immunohistochemistry staining was performed in gastric cancer (GC) clinical specimens representing different steps of the Correa pathway. Gastric cancer samples taken before and after neoadjuvant chemotherapy with docetaxel, cisplatin and capecitabine (DCX) were also evaluated for PSC marker expression.

Results:

We showed that the expression of three PSC markers was significantly elevated in GC relative to normal gastric mucosa (P<0.001 for each marker). Precancerous lesions, including intestinal metaplasia and dysplasia, demonstrated increased expression of CD44 and Musashi-1. CD133 was predominantly expressed along the border between intramucosal carcinoma and connective tissue at later stages. High CD44 and CD133 expression showed prognostic value for worse patient survival (P=0.014 and P=0.019, respectively). A small number of tumours with high expression of CD44 and CD133 showed pathological response to DCX-based neoadjuvant chemotherapy.

Conclusion:

CD44 and Musashi-1 are frequently expressed in both premalignant gastric lesions and invasive GC, whereas CD133 expression is restricted mainly to neoplastic tissues.     

High expression of S100P is associated with unfavorable prognosis and tumor progression in patients with epithelial ovarian cancer

Accumulating evidence has demonstrated that S100P is involved in the tumorigenesis and progression of multiple cancers. In the current study, we evaluated the expression of S100P in epithelial ovarian cancer and assessed its relevance to clinicopathological characteristics. Moreover, we investigated the biological effects of S100P using A2780 and SKOV3 cells. S100P expression was significantly increased in epithelial ovarian cancer specimens compared with fallopian tube tissues and normal ovary tissues. And high expression of S100P in epithelial ovarian cancer samples was significantly associated with tumor stage (P<0.001), serum CA125 level (P=0.026), residual tumor (P<0.001), ascites (P<0.001) and lymph nodes metastasis (P<0.001). Multivariate Cox analysis showed that S100P expression was an independent prognostic factor of overall survival (OS) and progression free survival (PFS) (P=0.017 and 0.031, respectively). Functional assays showed that overexpression of S100P promoted cell proliferation and cell cycle progression but did not affect cell migration and invasion in A2780 and SKOV3 cells. These data suggest that S100P may contribute to tumor development in epithelial ovarian cancer and could be a useful marker for the prognosis of epithelial ovarian cancer patients.     

Decreased expression of prenyl diphosphate synthase subunit 2 correlates with reduced survival of patients with gastric cancer

Background

Identification of novel molecular biomarkers will improve the management of patients with gastric cancer (GC). Prenyl diphosphate synthase subunit 2 (PDSS2) is required for coenzyme Q10 biosynthesis and acts as a tumor suppressor; however, the role and regulatory mechanisms of PDSS2 in GC are not understood. The aim of this study was to determine expression status and regulatory mechanisms of PDSS2 in GC.

Methods

Associations between expression and methylation of PDSS2 were evaluated using GC cell lines. The clinical significance of PDSS2 expression was evaluated using 238 pairs of surgically resected gastric tissues with subgroup analysis based on GC subtypes.

Results

The expression of PDSS2 mRNA was decreased in 73% of GC cell lines compared with the control non-cancerous cell. The PDSS2 promoter was hypermethylated in cells with decreased PDSS2 expression, and treating these cells with a methylation inhibitor reactivated PDSS2 expression. GC tissues expressed significantly lower mean levels of PDSS2 mRNA compared with adjacent normal tissues (P <0.001). The expression pattern of PDSS2 protein was consistent with that of its mRNA. The decrease of PDSS2 mRNA expression in GC tissues (less than half the level of expression detected in the corresponding normal adjacent tissues) correlated significantly with elevated levels of carbohydrate antigen 19-9 (P = 0.015), lymph node metastasis (P = 0.022), and shorter recurrence-free survival after curative resection (P = 0.022). Further, multivariate analysis identified PDSS2 mRNA expression as an independent prognostic factor (hazard ratio 1.95, 95% confidence interval 1.22–3.09, P = 0.005), and its expression pattern and prognostic significance were similar among three GC subtypes.

Conclusions

PDSS2 encodes a putative tumor suppressor, and we show here that its expression was regulated by hypermethylation of its promoter in GC cells. Inhibition of PDSS2 mRNA expression may serve as a novel biomarker of all types of GC.

Electronic supplementary material

The online version of this article (doi:10.1186/s13046-014-0088-3) contains supplementary material, which is available to authorized users.     

Down regulation of lactate dehydrogenase initiates apoptosis in HeLa and MCF-7 cancer cells through increased voltage-dependent anion channel protein and inhibition of BCL2

Malignant cells commonly use aerobic glycolysis for ATP production; this is known as the Warburg effect, where pyruvate is converted to lactate, by enzyme lactate dehydrogenase A (LDH-A). In this study, we have investigated the effect of inhibition of LDH-A on cells viability and identifying the mechanism of cell death in HeLa and MCF-7 cancer cells.Human cervical cancer HeLa cell line and breast cancer MCF-7 cell line were used to investigate the effect of inhibition of LDH-A by sodium oxamate on cell survival and proliferation using western blot, spectrophotometry, and immunofluorescent study.There was significant reduction in LDH-A (P < 0.001) and cell viability (P < 0.001) in a dose-dependent mode in both HeLa and MCF-7 SO-treated cancer cells. The voltage-dependent anion channel (VDAC) protein was significantly increased (P < 0.001) in association with decreased LDH-A. The proapoptotic proteins; cytochrome C (P < 0.001), BAX (P < 0.001), cleaved caspase-3 (P < 0.001), cleaved caspase-8 (P < 0.001), and cleaved caspase-9 (P < 0.001) were significantly increased in association with decreased LDH-A. While, the anti-apoptotic protein Bcl2 was significantly decreased (P < 0.001) in association with decreased LDH-A.We conclude that Inhibition of LDH-A can decrease cells viability through activation of intrinsic apoptotic pathway via increased VDAC protein and inhibition of Bcl2 as well as activation of the extrinsic apoptotic pathway through activation of caspase-8.     

The roles of BTG3 expression in gastric cancer: a potential marker for carcinogenesis and a target molecule for gene therapy

BTG (B-cell translocation gene) can inhibit cell proliferation, metastasis and angiogenesis, cell cycle progression, and induce differentiation in various cells. Here, we found that BTG3 overexpression inhibited proliferation, induced S/G2 arrest, differentiation, autophagy, apoptosis, suppressed migration and invasion in MKN28 and MGC803 cells (p < 0.05). BTG3 transfectants showed a higher mRNA expression of p27, Bax, 14-3-3, Caspase-3, Caspase-9, Beclin 1, NF-κB, IL-1, -2, -4, -10 and -17, but a lower mRNA expression of p21, MMP-9 and VEGF than the control and mock (p < 0.05). At protein level, BTG3 overexpression increased the expression of CDK4, AIF, LC-3B, Beclin 1 and p38 (p < 0.05), but decreased the expression of p21 and β-catenin in both transfectants (p < 0.05). After treated with cisplatin, MG132, paclitaxel and SAHA, both BTG3 transfectants showed lower viability and higher apoptosis than the control in both time- and dose-dependent manners (p < 0.05). BTG3 expression was restored after 5-aza-2′-deoxycytidine or MG132 treatment in gastric cancer cells. BTG3 expression was decreased in gastric cancer in comparison to the adjacent mucosa (p < 0.05), and positively correlated with venous invasion and dedifferentiation of cancer (p < 0.05). It was suggested that BTG3 expression might contribute to gastric carcinogenesis. BTG3 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of gastric cancer.     

The in situ local immune response,tumour senescence and proliferation in colorectal cancer

Background:

Immune cell infiltrates are important determinants of colorectal cancer (CRC) outcome. Their presence may be driven by tumour or host-specific factors. From previous studies in mice, senescence, a state of cell cycle arrest, may moderate tumour progression through upregulation of antitumour immune responses. The relationships between senescence and immune infiltrates have not previously been studied in humans. We explore whether a marker of senescence (p16^ink4a) in combination with low level expression of a proliferation marker (ki-67) relate to T cell infiltrates in CRC, and whether p16^ink4a, Ki-67 and immune infiltrates have similar prognostic value.

Methods:

Immunostaining of p16^inka and Ki-67 was performed within a CRC tissue microarray. Nuclear p16^inka and Ki-67 were categorised as high/low. T-cell markers, CD3, CD45RO, CD8 and FOXP3 were scored separately as high/low grade in three areas of the tumour: the invasive margin (IM), tumour stroma and cancer cell nests (CCNs).

Results:

Two hundred and thirty stage I–III cancers were studied. High nuclear p16^ink4a was expressed in 63% and high proliferation (Ki-67 >15%) in 61%. p16^ink4a expression was associated with reduced CD45RO+ cells at the IM (P<0.05) and within the stroma (P<0.05) and reduced CD8+ cells at the IM (P<0.01). A low Ki-67 proliferative index was associated with reduced density of CD3+ cells in CCNs (P<0.01), reduced CD45RO+ cells at the IM (P<0.05) and within the CCNs (P<0.001), reduced FOXP3+ cells at the IM (P<0.001), within the stroma (P=0.001) and within CCNs (P<0.001) and reduced CD8+ cells at the IM (P<0.05) and within the CCNs (P<0.05). Tumours with both a low proliferative index and expression of p16^ink4a demonstrated similar consistent relationships with reduced densities of T-cell infiltrates. On multivariate analysis, TNM stage (P<0.001), low CD3 cells at the IM (P=0.014), low CD8 cells at the IM (P=0.037), low proliferation (Ki-67; P=0.013) and low senescence (p16^ink4a; P=0.002) were independently associated with poorer cancer survival.

Conclusion:

Senescence, proliferation and immune cell infiltrates are independent prognostic factors in CRC. Although related to survival, p16^ink4a-associated senescence is not associated with an upregulation of antitumour T-cell responses.     

Hepatitis B virus (HBV) receptors: Deficiency in tumor results in scant HBV infection and overexpression in peritumor leads to higher recurrence risk

Hepatitis B virus (HBV) infection is a risk factor for hepatocarcinogenesis and recurrence. Here, we sought to characterize intratumoral and peritumoral expression of HBsAg and its specific receptors in HBsAg-positive hepatocellular carcinoma (HCC) patients and further examined their correlation with the recurrence-free survival (RFS). HCC tissue and adjacent normal tissue specimens were acquired from HBsAg-positive patients. The presence of HBsAg and receptors, as well as hepatic progenitor cells (HPCs) were detected by tissue microassay and immunohistochemistry. Necroinflammatory activity was evaluated by HE staining. The mean IOD of HBsAg and HBV DNA in the intratumoral tissues was markedly lower than that in the peritumoral tissues (P < 0.001). Pearson correlation analysis further showed a significant correlation between the expression of HBsAg and NTCP (r = 0.461, P < 0.001) or ASGPR (r = 0.506, P < 0.001) in peritumoral tissues. And the peritumoral HBsAg and receptors presented a positive association with necroinflammatory activity (P < 0.05). Inflammation induced by HBV infection presented a positive association with HPCs activation (P < 0.05). Additionally, due to lack of HBV receptors, HPCs was not preferentially infected with HBV, but activated HPCs had a significant correlation with HBsAg expression in peritumoral tissues, and the peritumoral HPCs activation was associated with RFS of HCC patients, therefore, the overexpression of HBsAg and receptors in peritumor were also with higher recurrence risk (P < 0.05). In conclusion, lack of HBV receptors resulted in scant HBV infection in tumor cells, and overexpression of HBsAg and receptors in peritumor was strongly associated with higher recurrence risk in HCC patients.     

Netrin-4 as a biomarker promotes cell proliferation and invasion in gastric cancer

Gastric cancer (GC) is the second most common cause of cancer-related death with limited serum biomarkers for diagnosis and prognosis. Netrin-4 (Ntn4) is a laminin-related secreted molecule found to regulate tumor progression and metastasis. However, it is completely unknown whether Ntn4 has roles in GC development. Here, we first reported Ntn4 knockdown significantly suppressed cell proliferation and motility, while overexpression or addition of exogenous Ntn4 reversed these effects. In addition, Ntn4 receptor, neogenin (Neo) was also found highly expressed in GC cells and mediated the Ntn4-induced cell proliferation and invasion. Moreover, Ntn4 or Neo silencing decreased the phosphorylation of Stat3, ERK, Akt and p38, indicating multi-oncogenic pathways (Jak/Stat, PI3K/Akt, and ERK/MAPK) were involved in Ntn4-induced effects on the GC cells. Importantly, Ntn4 level was significantly increased in 82 tumor tissues (p = 0.001) and 52 serum samples (p < 0.0001) from GC patients and positively correlated with Neo expression (p = 0.003). Ntn4 expression was negatively correlated with the survival period (p = 0.038), and positively associated with the severity of pathological stages of the tumors (p = 0.008). Taken together, Ntn4 promoted the proliferation and motility of GC cells which was mediated by its receptor Neo and through further activation of multi-oncogenic pathways. Elevated Ntn4 was detected in both tumor tissues and serum samples of GC patients and suggested a relatively poor survival, indicating Ntn4 may be used as a potential non-invasive biomarker for diagnosis and prognosis of GC.     

Neutropenia predicts better prognosis in patients with metastatic gastric cancer on a combined epirubicin,oxaliplatin and 5-fluorouracil regimen

Chemotherapy-induced neutropenia (CIN) reportedly indicated better prognosis for some cancers. We retrospectively analyzed 150 evaluable metastatic gastric cancer (MGC) patients who had received first-line EOF5 (combination regimen of epirubicin, oxaliplatin and 5-day continuous infusion of 5-fluorouracil) treatment. We divided patients into three groups according to the worst grade of CIN: absent group (grade 0), moderate group (grade 1–2) and severe group (grade 3–4). Multivariate analyses of overall survival (OS) proved moderate and severe CIN were important prognostic factors whether regarding CIN as a time-varying covariate (TVC) or not. Compared with absent CIN, hazard ratio (HR) for moderate and severe CIN were 0.31 (95% confidential interval (CI): 0.17–0.55; P < 0.001) and 0.36 (95% CI: 0.20–0.64; P = 0.001) respectively with TVC; and were 0.31 (95% CI: 0.17–0.56; P < 0.001) and 0.34 (95% CI: 0.19–0.61; P < 0.001) respectively without TVC. In progression-free survival (PFS) analyses, moderate and severe CIN showed similar results. In the landmark group (n = 122 patients) analyses with TVC, moderate and severe CIN remained prognostic factors for PFS, while only moderate CIN was prognostic factor for OS. CIN predicted longer OS and PFS in MGC patients treated with first-line EOF5 chemotherapy.     

Is adjuvant chemotherapy necessary for early gastric cancer?

Objective:To quantify the potential benefit of adjuvant chemotherapy (ACT) with respect to survival, and to identify factors for predicting prognoses in early gastric cancer patients.Methods:Patients with pT1 gastric cancer (GC) who underwent radical resection with D2 lymphadenectomy were retrospectively analyzed. Based on lymph node metastasis (LNM) status and treatment regimens, patients were classified into groups, and clinicopathological variables, overall survival (OS), and disease-specific survival (DSS) were compared.Results:Of 1,050 enrolled patients, 151 patients (14.4%) had a positive LNM status. Submucosal invasion, undifferentiated state, tumor size > 2 cm, ulceration, and lymphovascular invasion were independent risk factors for LNM using multivariate analyses. The 5-year OS of all patients was 96.4%. HER2 positive, perineural invasion, and LNM were independent factors for worse survival. Patients with pT1N3 GC had a worse 5-year OS and DSS than pT1N0, pT1N1, and pT1N2 patients (P < 0.001). The 5-year OS and DSS for pT1N1 patients showed no significant difference between ACT and surgery only patients. For pT1N2 patients, the 5-year OS and DSS showed no significant difference between S-1 and Xelox treatments. For pT1N3 patients, 7 (36.8%) received S-1, while 12 (63.2%) received Xelox treatment. Patients receiving Xelox treatment showed a better 5-year OS (75.0% vs. 14.3%) and DSS (81.8% vs. 20.0%) than patients receiving S-1 (P < 0.05).Conclusions:Curative surgery only was adequate for patients with pT1N0 and pT1N1. Xelox showed no survival benefits for pT1N2 patients. Therefore, S-1 is the optimal choice for pT1N2 patients, when considering adverse effects. Xelox is recommended for pT1N3 patients.     

The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer

Background:

The importance of lymphocyte subtypes in determining outcome in primary operable ductal invasive breast cancer remains unclear. The aim of present study was to examine the relationship between tumour lymphocyte subsets infiltrate and standard clinico-pathological factors and survival in patients with primary operable invasive ductal breast cancer.

Methods:

The analysis of the inflammatory cell infiltrate, including lymphocyte subtypes, was undertaken using immunohistochemical techniques and visual quantitative and semi-quantitative techniques in 338 patients with ductal breast cancer.

Results:

The majority (91%) of patients had high grade inflammatory cell infiltrate. The median follow-up of the survivors was 164 months. During this period, 65 died of their cancer. On univariate analysis, tumour inflammatory cell infiltrate, macrophages infiltrate (P<0.05), lymphocytic infiltrate (P<0.001) and CD8+ T-lymphocytic infiltrate (P<0.01) were associated with improved cancer-specific survival, whereas neutrophil (P<0.05) and CD138+ B-lymphocytic infiltrate (P<0.001) were associated with poorer cancer-specific survival. On multivariate analysis, tumour lymphocytic infiltrate (P<0.001), macrophage infiltrate (P<0.05), CD8+ T-lymphocytic infiltrate (P<0.01) and CD138+ B-lymphocytic infiltrate (P<0.001) were independently associated with cancer survival. When the significant inflammatory cell types were included with tumour-based factors in multivariate analysis only tumour size (Hazard ratios (HR): 2.55, 95% confidence interval (CI): 1.53–4.27, P<0.001), Ki-67 index (HR: 2.08, 95% CI: 1.08–4.00, P<0.05), lymphovascular invasion (HR: 4.40, 95% CI: 2.07–9.35, P<0.001), macrophage infiltrate (HR: 0.49, 95% CI: 0.33–0.73, P<0.001), lymphocytic infiltrate (HR: 0.11, 95% CI: 0.05–0.23, P<0.001), CD8+ T-lymphocytic infiltrate (HR: 0.57, 95% CI: 0.38–0.87, P<0.001) and CD138+ B-lymphocytic infiltrate (HR: 2.86, 95% CI: 1.79–4.56, P<0.001) were independently associated with cancer survival.

Conclusion:

The majority of patients with invasive ductal breast cancer had high-grade inflammatory cell infiltrate. In these patients, inflammatory cells including macrophage and lymphocytic infiltrate, and subsets CD8+ T-lymphocytic infiltrate and CD138+ B-lymphocytic infiltrate had superior prognostic value, compared with hormone status and lymph node involvement in patients with primary operable invasive ductal breast cancer.     

Tag SNPs in long non-coding RNA H19 contribute to susceptibility to gastric cancer in the Chinese Han population

Long non-coding RNA (lncRNA) H19 is involved in tumor development, progression, and metastasis. This case-control study assessed the association between H19 genetic variants and susceptibility to gastric cancer (GC) in a Chinese Han population. We genotyped four lncRNA H19 single nucleotide polymorphisms (SNPs) (rs217727 C > T, rs2839698 C > T, rs3741216 A > T, rs3741219 T > C) in 500 GC patients and 500 healthy controls. Carriers of variant rs217727T and rs2839698T alleles showed increased GC risk (P = 0.008 and 0.011, respectively). Compared with the common genotype, CT + TT rs217727 and CT + TT rs2839698 genotypes were associated with significantly increased GC risk (P = 0.040, adjusted odds ratio [OR] = 1.32, 95% confidence interval [CI] = 1.01–1.71; P = 0.033, adjusted OR = 1.31, 95% CI = 1.02–1.69, respectively). Further stratified analyses revealed that the association between GC risk and variant genotypes of rs217727 was more profound in younger individuals (≤59 years) and non-smokers, while the association between risk and the rare rs2839698 genotype persisted in men and rural subjects. rs2839698 CT and TT genotypes were also associated with higher serum H19 mRNA levels compared with the CC genotype. These findings suggest that lncRNA H19 SNPs may contribute to susceptibility to GC.     

Circulating IL-6 concentrations link tumour necrosis and systemic and local inflammatory responses in patients undergoing resection for colorectal cancer

Background:

Cancer-associated inflammation, in the form of local and systemic inflammatory responses, appear to be linked to tumour necrosis and have prognostic value in patients with colorectal cancer. However, their relationship with circulating biochemical mediators is unclear. The aim of the present study was to examine the interrelationships between circulating mediators, in particular interleukin-6 (IL-6) and tumour necrosis, and local and systemic inflammatory responses in patients undergoing resection for colorectal cancer.

Methods:

Data were collected from preoperative blood tests for 118 patients who underwent resection for colorectal cancer. Analysis of circulating IL-6, IL-10, vascular endothelial growth factor (VEGF), differential white cell count, C-reactive protein, and albumin were carried out. Routine pathology specimens were examined for tumour characteristics including necrosis and the extent of the inflammatory cell infiltrate. Body composition was examined using body mass index (BMI), total body fat, subcutaneous body fat, visceral fat, and skeletal muscle mass.

Results:

Circulating IL-6 concentrations were significantly associated with increased T stage (P<0.05), tumour necrosis (P<0.001), IL-10 (P<0.001), VEGF (P<0.001), modified Glasgow Prognostic Score (mGPS; P<0.001), white cell (P<0.01) and platelet (P<0.01) counts, and low skeletal muscle index (P<0.01). When normalised for T stage, tumour necrosis was associated with IL-6 (P<0.001), IL-10 (P<0.01), VEGF (P<0.001), mGPS (P<0.001), neutrophil–lymphocyte ratio (NLR; P<0.05), white cell (P<0.001), neutrophil (P<0.05), and platelet counts (P<0.005), and skeletal muscle index (P<0.001).

Conclusion:

The present study provides, for the first time, supportive evidence for the hypothesis that tumour necrosis, independent of T stage, is associated with elevated circulating IL-6 concentrations, thereby modulating both local and systemic inflammatory responses including angiogenesis that, in turn, may promote tumour progression and metastases.     

Chemotherapy vs supportive care alone for relapsed gastric,gastroesophageal junction,and oesophageal adenocarcinoma: a meta-analysis of patient-level data

Background:

Second-line chemotherapy treatment of patients with relapsed gastric and oesophageal cancers in comparison with supportive care (SC) alone has been supported by recent phase 3 clinical trials, but a meta-analysis of patient-level data is lacking.

Methods:

We searched Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and the Web of Science for phase 3 clinical trials that compared second-line chemotherapy with SC alone for gastric and oesophageal cancers. A meta-analysis of the comprehensive patient-level data from the three identified trials was performed.

Results:

A total of 410 patients with gastric (n=301), gastroesophageal junction (n=76), or oesophageal (n=33) adenocarcinoma were identified. In all, 154 patients received single-agent docetaxel and 84 patients received single-agent irinotecan, each with SC. SC alone was given to 172 patients. Chemotherapy significantly reduced the risk of death (hazard ratio (HR)=0.63, 95% confidence interval (CI)=0.51–0.77, P<0.0001). This effect was observed for treatment with docetaxel (HR=0.71, 95% CI=0.56–0.89, P=0.003) and irinotecan (HR=0.49, 95% CI=0.36–0.67, P<0.001). Overall survival (OS) benefit was greatest for patients who progressed 3–6 months following first-line chemotherapy (HR=0.39, 95% CI=0.26–0.59, P<0.0001). Performance status (PS) 0–1 compared with PS 2 (HR=0.66, 95% CI=0.46–0.94, P=0.02), locally advanced disease compared with metastatic disease (HR=0.41, 95% CI=0.25–0.67, P=0.0004) and older age (HR=0.94 per 5 years, 95% CI=0.90–0.99, P=0.01) were significant predictors of improved OS. Progression of disease during first-line treatment (HR=1.24, 95% CI=0.96–1.59) or within the first 3 months of completion of first-line treatment (HR=1.42, 95% CI=1.09–1.83) were predictors of an increased risk of death compared with progression between 3 and 6 months (P=0.03). Health-related quality of life outcomes were reported in only one of the three trials, precluding meta-analysis of these parameters.

Conclusions:

This meta-analysis of patient-level data confirms that second-line chemotherapy treatment results in significantly better OS compared with SC alone in patients with platinum and fluoropyrimidine refractory gastric and oesphageal adenocarcinoma. Health-related quality of life outcomes should be included in future trials in this setting.