Perioperative blood transfusion is associated with poorer survival in patients with gastric cancer

The putative prognostic significance of perioperative blood transfusions on gastric cancers is controversial and the published results are contradictory. The aim of this study was to evaluate the prognostic influence of transfusion on Chinese gastric cancer surgery. Six hundreds and seventy-six patients who underwent curative gastrectomy for gastric cancer from 2000 to 2004 were retrospectively reviewed. Uni- and multivariate analyses of the incidence and amount of transfusion, and a comparison of the clinicopathological features were performed. Subgroup analyses of prognosis according to stage, tumor size, and pretreatment anemia were carried out. Blood transfusion was significantly associated with older age (>60 year), larger tumor (>6 cm), upper and middle location, surgical margin status, and pretreatment anemia. In addition, tumors in the transfused group were more advanced in depth of invasion, nodal stage, and TNM stage. No significant relationship was found between the amount of transfused blood and prognosis. Subgroup analyses of prognosis according to stage showed significant differences in stages II and III, between the transfused and nontransfused groups. Significant difference between the transfused and nontransfused groups could be observed in two subgroups of tumor size. Patients with or without anemia in the nontransfused group both had a longer survival time than those in the transfused group. On multivariate analysis, transfusion was shown to be an independent risk factor for poor prognosis. This study suggests that perioperative blood transfusion is associated with a significantly worse prognosis following gastric cancer surgery. The parameters such as advanced stage, tumor size, and anemia do not affect its prognostic value.     

Netrin-1 concentrations in patients with advanced gastric cancer and its relation with treatment

Context: Netrin-1 is found to be elevated and usable as a diagnostic biomarker in many human cancers.

Objectives: We evaluated serum Netrin-1 concentrations in patients with advanced gastric cancer compared with those in a healthy group.

Material and methods: Thirty patients with advanced gastric cancer and thirty healthy people were included in the study. Serum netrin-1 concentrations were measured by quantitative ELISA method in both groups.

Results: The mean serum Netrin-1 concentrations were found to be significantly higher in patients with gastric cancer than in healthy controls. The mean serum Netrin-1 concentrations were found to be significantly higher in patients with gastric cancer before the beginning of chemotherapy when compared after the completion of third cycle.

Discussion and conclusion: Our results indicated that netrin-1 concentrations elevated in advanced gastric cancer compared to a healthy control group and netrin-1 concentrations decreased with chemotherapy.     

Association of perioperative allogeneic blood transfusion with postoperative survival of patients with gastric cancer after curative gastrectomy

To explore the association of perioperative allogeneic blood transfusion (PABT) and postoperative survival rates in patients with gastric cancer (GC). In total, 186 patients with gastric cancer accepted curative gastrectomy were divided into three groups, the PABT <2 U group, the PABT > 2 U group, and the no blood transfusion group. The relationships between PABT and clinical pathological parameters were analyzed and their effects on the postoperative survival of patients with GC were studied. Multivariable COX regression results showed that PABT and tumor size are the important factors influencing the postoperative survival of patients with GC (P<0.05). When comparing with the no blood transfusion group and the PABT < 2 U group, the patient’s risk of death in the PABT > 2 U group rises to 3.282 and 2.130 times (95%CI: 1.731-4.886 and 1.194-3.797) (P<0.05), respectively. This study suggests that PABT is significantly associated with postoperative survival after curative gastrectomy in patients with GC.     

Identification of a novel cell cycle-related gene signature predicting survival in patients with gastric cancer

Gastric cancer (GC) is one of the most fatal cancers in the world. Thousands of biomarkers have been explored that might be related to survival and prognosis via database mining. However, the prediction effect of single gene biomarkers is not specific enough. Increasing evidence suggests that gene signatures are emerging as a possible better alternative. We aimed to develop a novel gene signature to improve the prognosis prediction of GC. Using the messenger RNA (mRNA)-mining approach, we performed mRNA expression profiling in a large GC cohort (n = 375) from The Cancer Genome Atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) was performed, and we recovered genes related to the G2/M checkpoint, which we identified with a Cox proportional regression model. We identified a set of five genes (MARCKS, CCNF, MAPK14, INCENP, and CHAF1A), which were significantly associated with overall survival (OS) in the test series. Based on this five-gene signature, the test series patients could be classified into high-risk or low-risk subgroups. Multivariate Cox regression analysis indicated that the prognostic power of this five-gene signature was independent of clinical features. In conclusion, we developed a five-gene signature related to the cell cycle that can predict survival for GC. Our findings provide novel insight that is useful for understanding cell cycle mechanisms and for identifying patients with GC with poor prognoses.     

Alternating immunochemotherapy of advanced gastric carcinoma: A randomized comparison of carbazilquinone and PSK to carbazilquinone in patients with curative gastric resection

A total of 103 patients with advanced gastric carcinoma were randomized after curative surgery to receive an alternate administration of carbazilquinone (CQ and PSK (Krestin) or carbazilquinone alone. Each course of therapies started 1 week after the surgical operation and therapy schedules consisted of 9 courses. In each course of 6 weeks, CQ (2 mg/m²/week) was administered on day 0, 8, and 15. In combined immunochemotherapy group, PSK was given orally in 3-divided doses of 2 g/m²/day from the day of the third CQ administration for consecutive 4 weeks. Estimated survival rate and cumulative survival curve were compared utilizing the data up to 7 years after the operation. There was no overall significant difference in survival rates between the CQ plus PSK group and the CQ alone group, but a group of patients whose disease was classified as S₁ + S₂(N_1–2) survived significantly longer when treated with the combination of CQ and PSK. Neither in more advanced cases (> S₃ or > N₃) nor in cancers of early stages, the addition of PSK provided an additive effect. The favorable result obtained in one subgroup treated with PSK, suggests that the use of this agent in treating gastric cancers should be carefully evaluated in terms of serosal infiltration and nodal metastasis.     

Presence of cancer cells in gastric lavage of gastric cancer patients as an indicator of advanced disease,predictor of tumour aggressive phenotype and independent prognostic factor for poor survival: The endoluminal metastatic pathway of gastric cancer and GL0/GL1 classification

Objective

As of 2017, the pathobiology of gastric cancer (GC) is far from fully understood; consequently, new methods of basic and advanced research have been proposed and tested. The presence (GL1) vs absence (GL0) of malignant cells exfoliated in gastric lavage (GL) of GC patients was formerly evaluated with diagnostic intent but not for staging or prognostic assessment. We investigated this hitherto unreported application of cytopathology.

Methods

GL was preoperatively and prospectively collected from 80 GC patients and cytologically analysed. The results were compared with the classic clinicopathological features of GC and related to survival. The prognostic value of GL1 was assessed through univariate and multivariate analyses.

Results

GL1 was detected in 36 samples (45%) and correlated with advanced tumour depth (T3‐T4), lymphatic metastasis (N+), distant metastasis (M1) and lymphovascular invasion (LVI1; P=.0317, .0024, .003 and .0028, respectively). Overall survival (OS) was significantly shorter for GL1 (23 months) vs GL0 patients (42 months; P=.005) and GL1 vs GL0 T1 subjects (12.6 vs 47.8 months, P=.0029). Univariate analysis revealed that GL1, N+, M1, LVI1 and advanced stage were significantly associated with OS. Multivariate analysis assessed GL1 as the only independent prognostic factor for worse OS and progression‐free survival (P=.0013 and .0107).

Conclusions

In the present study, GL1 was correlated with advanced disease, aggressive tumour behaviour and poor prognosis. Although additional studies are needed to confirm these findings, the GL0/GL1 classification can be applied to GC patients to achieve higher accuracy in staging, prognostic stratification and treatment selection.     

A DCS-related lncRNA signature predicts the prognosis and chemotherapeutic response of patients with gastric cancer

The combination of docetaxel, cisplatin, and S-1 (DCS) is a common chemotherapy regimen for patients with gastric cancer (GC). However, studies on long noncoding RNAs (lncRNAs) associated with the chemotherapeutic response to and prognosis after DCS remain lacking. The aim of the present study was to identify DCS mRNAs-lncRNAs associated with chemotherapy response and prognosis in GC patients. In the present study, we identified 548 lncRNAs associated with these 16 mRNAs in the TCGA and {"type":"entrez-geo","attrs":{"text":"GSE31811","term_id":"31811"}}GSE31811 datasets. Eleven lncRNAs were used to construct a prognostic signature by least absolute shrinkage and selection operator (LASSO) regression. A model including the 11 lncRNAs (LINC02532, {"type":"entrez-nucleotide","attrs":{"text":"AC007277.1","term_id":"4580503","term_text":"AC007277.1"}}AC007277.1, AC005324.4, {"type":"entrez-nucleotide","attrs":{"text":"AL512506.1","term_id":"12044702","term_text":"AL512506.1"}}AL512506.1, {"type":"entrez-nucleotide","attrs":{"text":"AC068790.7","term_id":"8571647","term_text":"AC068790.7"}}AC068790.7, {"type":"entrez-nucleotide","attrs":{"text":"AC022509.2","term_id":"6938434","term_text":"AC022509.2"}}AC022509.2, {"type":"entrez-nucleotide","attrs":{"text":"AC113139.1","term_id":"18875234","term_text":"AC113139.1"}}AC113139.1, LINC00106, {"type":"entrez-nucleotide","attrs":{"text":"AC005165.1","term_id":"3242748","term_text":"AC005165.1"}}AC005165.1, MIR100HG, and UBE2R2-AS1) associated with the prognosis of GC was constructed. The signature was validated in the TCGA database, model comparison, and qRT-PCR experiments. The results showed that the risk signature was a more effective prognostic factor for GC patients. Furthermore, the results showed that this model can well predicting chemotherapy drug response and immune infiltration of GC patients. In addition, our experimental results indicated that lower expression levels of LINC00106 and UBE2R2-AS1 predicted worse drug resistance in AGS/DDP cells. The experimental results agreed with the predictions. Furthermore, knockdown of LINC00106 or UBE2R2-AS1 can significantly enhanced the proliferation and migration of GC AGS cells in vitro. In conclusion, a novel DCS therapy-related lncRNA signature may become a new strategy to predict chemotherapy response and prognosis in GC patients. LINC00106 and UBE2R2-AS1 may exhibit a tumor suppressive function in GC.     

Adoptive transfer of natural killer cells in combination with chemotherapy improves outcomes of patients with locally advanced colon carcinoma

Background

Despite the availability of multiple treatment strategies, patients with advanced colon carcinoma (CC) have poor prognoses. The aim of this study was to evaluate the efficacy and safety of natural killer (NK) cell therapy in combination with chemotherapy in patients with locally advanced CC.

High LIMP2 expression serves as a predictor for improved clinical outcomes in gastric cancer patients

Lysosomal integral membrane protein-2 (LIMP2) is an important component of innate immunity. However, its role in the anti-tumor response remains unknown. Here, we found that the level of LIMP2 mRNA was frequently upregulated in gastric cancer (GC) tissues according to the TCGA, which was confirmed by immunohistochemistry in 329 cases. LIMP2 expression was significantly associated with Lauren classification (P=0.042), depth of invasion (P=0.016), lymph node metastasis (P=0.039) and TNM stage (P=0.027). LIMP2 expression (P<0.001), differentiation (P<0.001), TNM stage (P<0.001) and preoperative CEA (P=0.018) can be used as independent prognostic factors. GC patients with higher levels of LIMP2 mRNA experienced improved clinical outcomes. Mechanically, the TGF-β signaling pathway, the ERBB signaling pathway, and Toll-like receptor signaling were enriched in proteins with higher LIMP2. Moreover, LIMP2 expression was positively related with M1 tumor-associated macrophages (TAMs) in TCGA data, which was verified by capturing LIMP2 and CD86 co-expression in GC samples. The study suggests that LIMP2 expression in GC would pr edict improved outcomes with M1 TAMs infiltration.     

Helicobacter pylori strain and the pattern of gastritis among first-degree relatives of patients with gastric carcinoma

Background. Relatives of gastric cancer patients have an increased risk of gastric cancer, possibly related to genetically‐related strains of Helicobacter pylori or a common environment. Methods. The pattern of gastritis and H. pylori from gastric cancer patients and their first‐degree relatives were compared using detailed DNA fingerprints and vacA, cagA, and iceA genotyping. Results. Sixteen index cases from Korea, the US, or Colombia and their 38 first‐degree relatives (brothers, sisters, sons and daughters) were studied. No definite, or consistent, relationship between the pattern of gastritis and the relatedness of the H. pylori strain was observed (i.e. relatives could have an identical or a totally different pattern of gastritis regardless if they were infected with identical or highly similar organisms). For example, three elderly siblings of an index case with atrophic pangastritis had identical H. pylori isolates and environments in childhood and yet two had antral predominant nonatrophic gastritis, which is typically associated with duodenal ulcer instead of gastric cancer. Conclusions. The results of this study are not consistent with the hypothesis that specific virulence factors or similar H. pylori strains correlate with a specific histologic pattern or outcome even among those sharing the same environment in childhood.     

Retracted: Vinculin promotes gastric cancer proliferation and migration and predicts poor prognosis in patients with gastric cancer

Vinculin is a highly conserved protein involved in cell proliferation, migration, and adhesion. However, the effects of vinculin on gastric cancer (GC) remain unclear. Therefore, we aimed to explore the functional role of vinculin in GC, as well as its underlying mechanism. Expression of vinculin in patients with GC was analyzed by real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry. Overall survival was evaluated by the Kaplan-Meier method with the log-rank test. The relationship between vinculin and clinicopathological characteristics of patients with GC was further identified. In addition, we assessed the expression of vinculin in GC cell lines. Besides, vinculin was suppressed or overexpressed by transfection with small interfering (si-vinculin) or pcDNA-vinculin and then cell viability, cell apoptosis, and/or migration was respectively examined by the 3-(4, 5-dimethylthiazole-2-yl)-2, 5-biphenyl tetrazolium bromide assay, flow cytometer, and scratch assay, respectively. Moreover, the cell cycle- and apoptosis-related proteins were detected by Western blot analysis. The expression of vinculin was significantly increased in the GC tissues and cells compared with the nontumor tissues or cells. Vinculin protein positive staining was mainly located in the cell membrane and cytoplasm. Moreover, vinculin was significantly associated with Tumor Node Metastasis (TNM) and poor differentiation. Patients with high vinculin levels had significantly worse overall survival than those with low levels. Suppression of vinculin significantly decreased cell viability and migration and promoted cell apoptosis. However, overexpression of vinculin statistically increased cell viability but had no effects on cell apoptosis. Vinculin promotes GC proliferation and migration and predicts poor prognosis in patients with GC.     

Development of a novel gene signature in patients without Helicobacter pylori infection gastric cancer

Gastric cancer (GC) is one of the most fatal common cancers in worldwide. Helicobacter pylori (H. pylori) infection is closely related to the development of GC, although the mechanism is still unclear. In our study, we aim to develop a robust messenger RNA (mRNA) signature associated with H. pylori (-) GC that can sensitively and efficiently predict the prognostic. The RNA-seq expression profile and corresponding clinical data of 598 gastric cancer samples and 63 normal samples obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database. Using gene set enrichment analysis H. pylori (+) GC and H. pylori (-) GC patients and normal samples to select certain genes for further analysis. Using univariate and multivariate Cox regression model to establish a gene signature for predicting the overall survival (OS). Finally, we identified G2/M related seven-mRNA signature (TGFB1, EGF, MKI67, ILF3, INCENP, TNPO2, and CHAF1A) closely related to the prognosis of patients with H. pylori (-) GC. The seven-mRNA signature was identified to act as an independent prognostic biomarker by stratified analysis and multivariate Cox regression analysis. It was also validated on two test groups from TCGA and GSE15460 and shown that patients with high-risk scores based on the expression of the seven mRNAs had significantly shorter survival times compared to patients with low-risk scores (P < .0001). In this study, we developed a seven-mRNA signature related to G2/M checkpoint from H. pylori (-) GCs that as an independent biomarker potentially with a good performance in predicting OS and might be valuable for the clinical management for patients with GC.     

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m² daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.     

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m² daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.     

精准营养联合生长抑素对胃癌根治术患者的临床疗效

目的 探讨生长抑素联合精准营养疗法对胃癌根治术患者术后营养指标水平和肠道菌群的影响。 方法 选取我院2017年10月至2019年1月收治并拟行胃癌根治术治疗的92例胃癌患者为研究对象,随机分为对照组(46例)和观察组(46例)。两组患者术后均给予常规处理。对照组患者同时给予生长抑素+常规肠外营养支持,观察组患者同时给予生长抑素+精准营养支持。于营养干预前后统计两组患者营养相关指标[体质量、血清白蛋白(ALB)、前白蛋白(PA)、淋巴细胞计数(LC)、肌酐(Ct)以及尿素氮(UN)]水平;对肠道菌群进行alpha分析,并计算肠杆菌、肠球菌、乳杆菌和双歧杆菌数量。 结果 营养干预前,两组患者营养相关指标水平以及肠道菌群相关指标水平之间差异无统计学意义(均P>0.05)。营养干预后,(1)观察组患者平均体质量以及血清ALB、PA、LC水平分别为(56.98±5.34)kg、(29.98±6.03)mg/L、(137.14±35.17)g/L、(1.15±0.26)×109,对照组分别为(53.29±5.18)kg、(26.12±5.29)mg/L、(104.53±27.66)g/L、(0.82±0.18)×109,两组之间差异有统计学意义(均P结论 胃癌根治术患者术后联合生长抑素和精准营养疗法能够显著改善患者的营养状况,保持肠道菌群丰度,平衡肠道菌群分布,值得临床研究和应用。     

Melatonin inhibits the migration of human gastric carcinoma cells at least in part by remodeling tight junction

The recurrence and metastasis is one of the major reasons for malignant tumor treatment failure. Melatonin, a naturally occuring hormone, could reduce the recurrence and metastasis of various tumors. However, the underlying molecular mechanisms of melatonin on tumor metastasis inhibition have not been fully elucidated. In the present study, we explored the impact of melatonin on the migratory capability of human gastric carcinoma cells using wound healing assay, and further investigated if the inhibition on migration ability of melatonin was embodied by relocating tight junction proteins zo-1 and occludin onto the cells surface to remodel tight junction structure. Immunofluorescence assay and Western blot analysis were performed to detect the expression and cell location of the tight junction proteins. The migration distance was decreased as the cells were treated with melatonin. And melatonin increased the membrane location of tight junction proteins, zo-1 and occludin, showed by immunofluorescence staining and Western blot analysis. The results we got show that melatonin makes tight junction proteins anchored more on the cells membrane to remodel cells tight junction, which increase cells adhesion and decrease motility, resulting in the inhibition of gastric cancer cells migration and metastasis ability.     

Genome-wide DNA methylation profiles in noncancerous gastric mucosae with regard to Helicobacter pylori infection and the presence of gastric cancer

Background and Aims: To determine genome‐wide DNA methylation profiles induced by Helicobacter pylori (H. pylori) infection and to identify methylation markers in H. pylori‐induced gastric carcinogenesis. Methods: Gastric mucosae obtained from controls (n = 20) and patients with gastric cancer (n = 28) were included. A wide panel of CpG sites in cancer‐related genes (1505 CpG sites in 807 genes) was analyzed using Illumina bead array technology. Validation of the results of Illumina bead array technique was performed using methylation‐specific PCR method for four genes (MOS, DCC, CRK, and PTPN6). Results: The Illumina bead array showed that a total of 359 CpG sites (269 genes) were identified as differentially methylated by H. pylori infection (p < .0001). The correlation between methylation‐specific PCR and bead array analysis was significant (p < .0001, Spearman coefficient = 0.5054). Methylation profiles in noncancerous gastric mucosae of the patients with gastric cancer showed quite distinct patterns according to the presence or absence of the current H. pylori infection; however, 10 CpG sites were identified to be hypermethylated and three hypomethylated in association with the presence of gastric cancer regardless of H. pylori infection (p < .01). Conclusions: Genome‐wide methylation profiles showed a number of genes differentially methylated by H. pylori infection. Methylation profiles in noncancerous gastric mucosae from the patients with gastric cancer can be affected by H. pylori‐induced gastritis. Differentially methylated CpG sites in this study needs to be validated in a larger population using quantitative methylation‐specific PCR method.     

经皮内镜下空肠造口术在胃癌术后胃排空障碍治疗中的应用

目的:报道经皮内镜下空肠造口术在胃癌术后胃排空障碍治疗中行胃减压及肠内营养支持的治疗效果。方法:28例胃癌术后胃排空障碍的病人在局麻或基础麻醉下行经皮內镜下空肠造口术,术后行胃减压及肠内营养支持?峁?28例患者均操作成功,平均操作时间为(19.5±4.6)min,无严重导管相关并发症。术后第2天开始通过空肠营养管进行肠内营养,平均术后(7.3土1.6)天完全摆脱肠外营养支持。术后平均(19.4土7.7)天恢复胃动力夹闭胃引流管。平均留置时间(35.8士11.8)天,拔管时营养状况较术前明显改善。结论:皮内镜下空肠造口术在胃癌术后胃排空障碍的治疗中能够起到有效的胃减压和营养支持,明显改善患者生活质量。