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1.
J Cell Physiol ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32026471

RESUMO

The expression pattern and role of circular RNAs (circRNAs) in the pathogenesis of gastric cancer (GC) and their underlying mechanisms remain unresolved. In this study, we identified differentially expressed circRNAs by a circRNA microarray and verified the results by quantitative reverse transcription-polymerase chain reaction using 117 clinical samples. Cell Counting Kit-8, wound healing, Transwell, and tumorsphere formation assays were conducted to assess the effects of circ-CEP85L on cell proliferation and invasion in vitro. Mouse intraperitoneal injection models were used to assess the functions of circ-CEP85L in vivo. Luciferase reporter assays, fluorescence in situ hybridization, and rescue experiments were performed to elucidate the underlying mechanism of circ-CEP85L. We found that circ-CEP85L, which has not been studied in GC, was significantly downregulated in GC tissues and that decreased circ-CEP85L expression correlated significantly with a worse prognosis. The knockdown of circ-CEP85L promoted the proliferation and invasion of GC cells, which was reversed by overexpression of circ-CEP85L. Furthermore, inhibition of circ-CEP85L promoted tumor growth in vivo. Mechanistically, circ-CEP85L was confirmed to be a direct target of miR-942-5p. In addition, rescue experiments indicated that circ-CEP85L is able to inhibit the proliferation and invasion of GC cells by sponging miR-942-5p. Finally, western blot assays verified that the downregulation of miR-942-5p efficiently reversed the inhibition of NFKBIA induced by circ-CEP85L overexpression. Therefore, we conclude that circ-CEP85L promotes NFKBIA expression by acting as a sponge of miR-942-5p; thus, inhibiting GC proliferation and invasion. circ-CEP85L is a potential target in the treatment of GC.

2.
Eur J Surg Oncol ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-32044202

RESUMO

BACKGROUND: and purpose: For gastric cancer patients with peritoneal metastasis (GCPM), there is no universally accepted prognostic staging system. This study aimed to validate the predictive ability of the 15th peritoneal metastasis staging system (P1abc) of the Japanese Classification of Gastric Carcinoma (JCGC). METHODS: The data of 309 GCPM patients from July 2007 to July 2017 were retrospectively analyzed. This study compared the prognosis prediction performances of P1abc, the previous JCGC PM staging (P123) and Gilly staging systems. RESULTS: The survival curve revealed a significant difference in overall survival (OS) predicted by P1abc, P123 and Gilly staging (all P < 0.05), and the survival of the two adjacent substages were well distinguished by P1abc but not by P123 and Gilly staging. Both P123 and Gilly staging were substituted with P1abc staging in a 2-step multivariate analysis. The results showed that P1abc staging was superior to both P123 and Gilly staging in its discriminatory ability (C-index), predictive accuracy (AIC) and predictive homogeneity (likelihood ratio chi-square). A stratified analysis by different therapies indicated that for the P1a and P1b patients, OS following palliative resection combined with palliative chemotherapy (PRCPC) was better than that after palliative resection (PR) or palliative chemotherapy (PC) alone (P < 0.05). For the P1c patients, OS after receiving PC was significantly superior to that after receiving PRCPC or PR (P = 0.021). CONCLUSION: P1abc staging is superior to P123 and Gilly staging in predicting the survival of GCPM patients. Surgeons can provide these patients with appropriate treatment options according to the corresponding substages within P1abc.

3.
J Gastrointest Surg ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32016671

RESUMO

BACKGROUND: Whether the change of the pre- and postoperative systemic inflammatory response (SIR) levels will affect the prognosis of gastric cancer (GC) is unclear. We aimed to investigate the dynamic changes in the pre- and postoperative SIR and their prognostic value for GC. METHODS: The clinicopathological data from 2257 patients who underwent radical gastrectomy between January 2009 and December 2014 at Fujian Medical University Union Hospital (FMUUH) were analyzed. Perioperative SIR changes were reported as changes in the lymphocyte-monocyte ratio (LMR), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). RESULTS: The SIR levels showed different trends from postoperative months 1 to 12. Multivariate analysis showed that preoperative (pre)-LMR was an independent predictor for the prognosis (P = 0.024). The postoperative 12-month (post-12-month) LMR predicted the 5-year overall survival (OS) rate with the highest accuracy (areas under the curve [AUC] 0.717). Patients were divided into four groups according to the optimal cutoff of the preoperative and post-12-month LMR: high pre-LMR to high postoperative (post)-LMR group, high pre-LMR to low post-LMR group, low pre-LMR to high post-LMR group, and low pre-LMR to low post-LMR group. The survival analysis showed 5-year OS rate was significantly higher in patients with high post-12-month LMR than in patients with low post-12-month LMR, regardless of pre-LMR levels (81.6% vs. 44.2%, P < 0.001). The prognostic accuracy was significantly improved by incorporating the post-12-month LMR in the tumor-node-metastasis (TNM) staging system (P = 0.003). CONCLUSIONS: The remeasurement of LMR at post-12-month is helpful in predicting the long-term survival of GC.

4.
Surg Endosc ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953725

RESUMO

BACKGROUND: Numerous studies have shown that the short-term efficacy of three-dimensional (3D) laparoscopic radical gastrectomy (LG) is comparable to that of two-dimensional (2D)-LG. Whether 3D-LG affects the recurrence patterns of gastric cancer (GC) patients has not been investigated. METHODS: From January 2015 to April 2016, a total of 419 patients were recruited for a phase III clinical trial (NCT02327481), which compared the short-term outcomes between the 2D and 3D groups. The long-term efficacy including recurrence patterns was compared between the 2D and 3D groups in this retrospective study. Multivariate analyses were performed to determine whether 3D-LG affects the recurrence patterns. RESULTS: Ultimately, 401 patients were analyzed (197 in the 2D-LG group and 204 in the 3D-LG group), and no differences were observed in the clinicopathological data between the two groups. There were no significant differences between the two groups in the recurrence types, first recurrence time or recurrence-free survival (RFS) (all p > 0.05). According to the 7th American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system, both groups were stratified into pathological stages I, II, and III. The stratified analysis showed no significant differences in RFS or overall survival (OS) among patients in each subgroup (all p > 0.05). The multivariate analysis of RFS showed that tumor diameter, pTNM stage, lymphovascular invasion, and adjuvant chemotherapy were independent factors (all p < 0.05). The multivariate analysis of post-recurrence survival (PRS) showed that adjuvant chemotherapy was an independent protective factor (p = 0.043). CONCLUSIONS: 3D-LG for GC did not differ significantly from 2D-LG in the effects on 3-year recurrence patterns, RFS and OS, which provides more tumor-related evidence for 3D technology. And due to the technological similarity, it may have certain reference value for robotic-assisted gastrectomy. Further multicenter, large-scale clinical trials are warranted.

5.
BMC Cancer ; 20(1): 11, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906893

RESUMO

BACKGROUND: We sought to investigate the prognostic value of complete blood count (CBC)-based biomarkers for patients with resectable gastric cancer (GC). METHODS: Patients with GC who underwent primary surgical resection between December 2008 and December 2013 were included. The estimated area under the curve (AUC) and multivariate Cox regression models were used to identify the best CBC-based biomarker. Time-dependent receiver operating characteristic (t-ROC) curve analysis was used to predict overall survival and compare the prognostic impact. RESULTS: In the 1810 patients analyzed, the median follow-up period was 51.0 months (range 1-101 months). Based on multivariate analysis, the lymphocyte-monocyte ratio (LMR) and hemoglobin (Hb) level were independent prognostic factors (both P < 0.05). Based on the LMR and Hb level, we established the CBC-based inflammatory score (CBCS). A higher CBCS was associated with older age, female sex, higher American Society of Anesthesiologists (ASA) score, proximal tumor location, larger tumor size, later stage and vascular involvement (all P < 0.05). Univariate analyses showed that a higher CBCS was also associated with worse overall survival (OS), which was consistent in each stage (all P < 0.05). Multivariate analysis revealed that the CBCS was a significant independent biomarker (P < 0.05). The AUC for the CBCS (0.627) was significantly higher than the AUCs for the LMR (0.573) and Hb level (0.605) (both P < 0.05). Furthermore, the t-ROC curve of the CBCS was superior to that of the prognostic nutritional index (PNI), systemic immune-inflammation index (SII), modified Glasgow prognostic score (mGPS) and C-reactive protein/albumin ratio (CRP/Alb) throughout the observation period. CONCLUSION: The preoperative LMR and Hb level were optimal CBC-based biomarkers for predicting OS in GC patients after curative resection. Based on the LMR and Hb, we developed a novel and easily obtainable prognostic score called the CBCS, which may improve the prediction of clinical outcomes.

6.
Cancer Lett ; 471: 38-48, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-31811909

RESUMO

The biological functions of circular RNAs (circRNAs) in gastric cancer (GC) remain largely unexplored. Here, we identified that circ-RanGAP1 was significantly upregulated in both GC tissues and exosomes from the plasma of GC patients. High circ-RanGAP1 expression was closely associated with an advanced TNM stage, lymph node metastases, and worse survival. Inhibition of circ-RanGAP1 decreased GC cell invasion and migration in vitro. Overexpression of circ-RanGAP1 had the opposite effect. Additionally, circ-RanGAP1 silencing remarkably suppressed tumor growth and metastasis of GC in vivo. Mechanistically, circ-RanGAP1 sponged miR-877-3p to upregulate VEGFA expression. Overexpression of miR-877-3p reversed the biological functions mediated by circ-RanGAP1 in GC cells. Interestingly, we demonstrated that circ-RanGAP1 was upregulated in plasma exosomes from preoperative GC patients. More importantly, the plasma exosomes derived from these patients enhanced the migration and invasion potential of GC cells. Overall, the circ-RanGAP1-mediated miR-877-3p/VEGFA axis promotes GC progression. Our findings suggest that circ-RanGAP1 might act as a potential prognostic biomarker and therapeutic target for GC treatment.

7.
Gastric Cancer ; 23(1): 184-194, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31300914

RESUMO

BACKGROUND: Increasing number of clinical studies have shown that laparoscopic distal gastrectomy (LDG) with D2 lymph node (LN) dissection is an effective method for the treatment of advanced gastric cancer (AGC). However, reports on the technical feasibility and oncology efficacy of laparoscopic total gastrectomy (LTG) in the treatment of AGC are rare. METHODS: A retrospective analysis of the clinicopathologic data of 1313 patients with clinical stage of cT2-4aN0-3M0 undergoing laparoscopic radical gastrectomy with D2 LN dissection from June 2007 to December 2013 was performed. Noncompliance was defined as patients with more than one LN station absence as described in the protocol for D2 lymphadenectomy in the Japanese Gastric Cancer Association (JGCA). According to the literature, it was subdivided into LN compliance group (all LN stations were detected), minor LN noncompliance group (1-2 LN stations were not detected), major LN noncompliance group (more than 2 LN stations were not detected). Based on the LN noncompliance, the surgical indications of LTG were analyzed with LDG as control. RESULTS: Among the 1313 patients, 197 (39.20%) patients and 321(39.71%) patients in the LDG group and the LTG group had minor LN noncompliance, 59(11.70%) patients and 163(20.10%) patients had major LN noncompliance. The difference in the extent of LN noncompliance between the two groups was statistically significant (p < 0.001). COX proportional hazards regression analysis elucidated that the LN noncompliance was an independent prognostic factor for overall survival (OS). BMI ≥ 25 kg/m2 and the history of previous abdominal surgery (PAS) were independent risk factors for major LN noncompliance in LTG group (p < 0.05), with which patients were defined as a LN noncompliance high-risk group. With the exception of LN noncompliance high-risk group, the difference in the extent of LN noncompliance between LTG group and LDG group was still statistically significant (p = 0.008). Tumor diameter > 60 mm is a preoperative risk factor for station #5 LN noncompliance, and no preoperative risk factors for station #6 LN noncompliance were found, with which patients were defined as LN noncompliance middle-risk group. CONCLUSION: LN noncompliance is an independent prognostic factor for poor prognosis in patients after LTG. Based on this finding, patients with BMI ≥ 25 kg/m2, history of PAS and tumor diameter > 60 mm in the advanced stage of upper-middle gastric cancer represent high/middle-risk groups with LN noncompliance in LTG surgery, which should be carefully selected.

8.
BMC Gastroenterol ; 19(1): 205, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791240

RESUMO

PURPOSE: To determine the indications for adjuvant chemotherapy (AC) in patients with stage IIa gastric cancer (T3N0M0 and T1N2M0) according to the 7th American Joint Committee on Cancer (AJCC). METHODS: A total of 1593 patients with T3N0M0 or T1N2M0 stage gastric cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) database for the period 1988.1-2012.12. Cox multiple regression, nomogram and decision curve analyses were performed. External validation was performed using databases of the Fujian Medical University Union Hospital (FJUUH) (n = 241) and Italy IMIGASTRIC center (n = 45). RESULTS: Cox multiple regression analysis showed that the risk factors that affected OS in patients receiving AC were age > 65 years old, T1N2M0, LN dissection number ≤ 15, tumor size > 20 mm, and nonadenocarcinoma. A nomogram was constructed to predict 5-year OS, and the patients were divided into those predicted to receive a high benefit (points ≤ 188) or a low benefit from AC (points > 188) according to a recursive partitioning analysis. OS was significantly higher for the high-benefit patients in the SEER database and the FJUUH dataset than in the non-AC patients (Log-rank < 0.05), and there was no significant difference in OS between the low-benefit patients and non-AC patients in any of the three centers (Log-rank = 0.154, 0.470, and 0.434, respectively). The decision curve indicated that the best clinical effect can be obtained when the threshold probability is 0-92%. CONCLUSION: Regarding the controversy over whether T3N0M0 and T1N2M0 gastric cancer patients should be treated with AC, this study presents a predictive model that provides concise and accurate indications. These data show that high-benefit patients should receive AC.

9.
World J Gastroenterol ; 25(43): 6451-6464, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31798281

RESUMO

BACKGROUND: Because of the powerful abilities of self-learning and handling complex biological information, artificial neural network (ANN) models have been widely applied to disease diagnosis, imaging analysis, and prognosis prediction. However, there has been no trained preoperative ANN (preope-ANN) model to preoperatively predict the prognosis of patients with gastric cancer (GC). AIM: To establish a neural network model that can predict long-term survival of GC patients before surgery to evaluate the tumor condition before the operation. METHODS: The clinicopathological data of 1608 GC patients treated from January 2011 to April 2015 at the Department of Gastric Surgery, Fujian Medical University Union Hospital were analyzed retrospectively. The patients were randomly divided into a training set (70%) for establishing a preope-ANN model and a testing set (30%). The prognostic evaluation ability of the preope-ANN model was compared with that of the American Joint Commission on Cancer (8th edition) clinical TNM (cTNM) and pathological TNM (pTNM) staging through the receiver operating characteristic curve, Akaike information criterion index, Harrell's C index, and likelihood ratio chi-square. RESULTS: We used the variables that were statistically significant factors for the 3-year overall survival as input-layer variables to develop a preope-ANN in the training set. The survival curves within each score of the preope-ANN had good discrimination (P < 0.05). Comparing the preope-ANN model, cTNM, and pTNM in both the training and testing sets, the preope-ANN model was superior to cTNM in predictive discrimination (C index), predictive homogeneity (likelihood ratio chi-square), and prediction accuracy (area under the curve). The prediction efficiency of the preope-ANN model is similar to that of pTNM. CONCLUSION: The preope-ANN model can accurately predict the long-term survival of GC patients, and its predictive efficiency is not inferior to that of pTNM stage.

10.
World J Gastroenterol ; 25(41): 6258-6272, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31749596

RESUMO

BACKGROUND: Increasing numbers of laboratory blood parameters (BPM) have been reported to greatly affect the long-term outcomes of gastric cancer (GC) patients. However, the existing prognostic models do not comprehensively analyze these predictors. AIM: To construct a new prognostic tool, based on all the prognostic BPM, to achieve more accurate prognosis prediction for GC. METHODS: We retrospectively assessed 850 consecutive patients who underwent curative resection for stage II-III GC from January 2010 to April 2013. The patients were classified into developing (n = 567) and validation (n = 283) cohorts using computer-generated random numbers. A scoring system, namely BPM score, was then constructed using least absolute shrinkage and selection operator (LASSO) Cox regression model in the developing cohort, and validated in the validation cohort. A nomogram consisting of BPM score and tumor-lymph node-metastasis (TNM) stage was further created. The discrimination and calibration of the nomogram were evaluated via Harrell's C-statistic and the Hosmer-Lemeshow test. RESULTS: Using the LASSO model, we established the BPM score based on five BPM: Albumin, lymphocyte-to-monocyte ratio, neutrophil-to-lymphocyte ratio, carcinoembryonic antigen, and carbohydrate antigen 19-9. The BPM scores were divided into high- and low-BPM groups based on a cut-off value of -0.93. High-BPM patients were significantly older and had more advanced, larger tumors. In the developing cohort, significant differences were found in 5-year overall survival (OS) and 5-year disease-specific survival between the high-BPM and low-BPM patients. Similar results were found in the validation group. Multivariable analysis showed that the BPM score was an independent predictor of OS. High-BPM patients had a poorer 5-year OS for each subgroup. Furthermore, a nomogram that combined the BPM score and TNM stage had significantly better prognostic value compared with TNM stage alone. CONCLUSION: The BPM score provides more accurate prognosis prediction in stage II-III GC patients and is an effective complement to the TNM staging system.

11.
World J Clin Cases ; 7(21): 3419-3435, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31750326

RESUMO

BACKGROUND: The incidence of proximal gastric cancer (GC) is increasing, and methods for the prediction of the long-term survival of proximal GC patients have not been well established. AIM: To develop nomograms for the prediction of long-term survival among proximal GC patients. METHODS: Between January 2007 and June 2013, we prospectively collected and retrospectively analyzed the medical records of 746 patients with proximal GC, who were divided into a training set (n = 560, 75%) and a validation set (n = 186, 25%). A Cox regression analysis was used to identify the preoperative and postoperative risk factors for overall survival (OS). RESULTS: Among the 746 patients examined, the 3- and 5-year OS rates were 66.1% and 58.4%, respectively. In the training set, preoperative T stage (cT), N stage (cN), CA19-9, tumor size, ASA core, and 3- to 6-mo weight loss were incorporated into the preoperative nomogram to predict the OS. In addition to these variables, lymphatic vascular infiltration (LVI), postoperative tumor size, T stage, N stage, blood transfusions, and complications were incorporated into the postoperative nomogram. All calibration curves used to determine the OS probability fit well. In the training set, the preoperative nomogram achieved a C-index of 0.751 [95% confidence interval (CI): 0.732-0.770] in predicting OS and accurately stratified the patients into four prognostic subgroups (5-year OS rates: 86.8%, 73.0%, 43.72%, and 20.9%, P < 0.001). The postoperative nomogram had a C-index of 0.758 in predicting OS and accurately stratified the patients into four prognostic subgroups (5-year OS rates: 82.6%, 74.3%, 45.9%, and 18.9%, P < 0.001). CONCLUSION: The nomograms accurately predicted the pre- and postoperative long-term survival of proximal GC patients.

12.
BMC Cancer ; 19(1): 1127, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752770

RESUMO

BACKGROUND: The platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and neutrophil to lymphocyte ratio (NLR) reflect the systematic inflammatory response, with some evidence revealing that they are associated with poorer survival in patients with gastric cancer. However, the effect of the white blood cell to hemoglobin ratio (WHR) on the long-term prognosis of patients with gastric cancer has not been reported. Therefore, we sought to characterize the effect of WHR on long-term survival after radical gastrectomy and compare its value with that of other preoperative inflammation-based prognostic scores (PIPS). METHODS: Data from 924 patients with a diagnosis of nonmetastatic gastric adenocarcinoma who underwent surgical resection between December 2009 and May 2013 were included in this study. RESULTS: The optimal cutoff values for the WHR, PLR, LMR, and NLR were 2.855, 133.03, 3.405, and 2.61, respectively. Patients with an increased WHR (53% vs. 88.1%, p < 0.001), PLR (60.9% vs 75.6%, p < 0.001) and NLR (56.7% vs 72.8%, p < 0.001) and a decreased LMR (54% vs 74.5%, p < 0.001) had a significantly decreased 5-year OS. However, the stratified analysis showed that only the WHR predicted a significant 5-year survival rate difference at each stage as follows: stage I (82.7% vs 94.3%, p = 0.005), stage II (71.3% vs 90.2%, p = 0.001) and stage III (38.2% vs 58.1%, p < 0.001). The time-ROC curve showed that the predictive value of the WHR was superior to that of the PLR, LMR, and NLR during follow-up. The WHR (0.624) C-index was significantly greater than the PLR (0.569), LMR (0.584), and NLR C-indexes (0.56) (all P < 0.001). CONCLUSION: Compared with other PIPS, the WHR had the most powerful predictive ability when used for the prognosis of patients with gastric adenocarcinoma.

13.
Surg Endosc ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31720795

RESUMO

BACKGROUND: Well-designed retrospective studies (RSs) and small-sample prospective studies (PSs) evaluating the efficacy of interventions have received much attention. This study was designed to evaluate the differences between well-designed RSs and small-sample randomized controlled trials based on the efficacy of laparoscopic distal gastrectomy (LDG) and open distal gastrectomy (ODG) for advanced gastric cancer (GC). METHODS: The clinicopathological data of 1360 patients with GC who underwent DG were analysed. After propensity score matching (1:1), 380 cases (ODG = 190, LDG = 190) were finally selected in a RS. Meanwhile, data from 120 patients (ODG = 60, LDG = 60) who enrolled in a PS were analysed. RESULTS: In the PS, the LDG group had less intraoperative blood loss, shorter time to first flatus, and shorter time to fluid diet than the ODG group. In the RS, the LDG group had less intraoperative blood loss, and a shorter postoperative hospital stay than the ODG group. In the PS, the 3-year overall survival (OS) rate was 83.3% in the LDG group and 83.2% in the ODG group (p = 0.877). In the RS, the 3-year OS rate was 68.7% in the LDG group and 66.6% in the ODG group (p = 0.752). No significant interactions were observed between the two groups and any of the variables examined, either in the PS or RS. The recurrence patterns were similar in the two groups. Furthermore, Cox regression analysis showed that surgical method (LDG/ODG) was not a prognostic factor affecting OS or DFS, either prospectively or retrospectively. CONCLUSIONS: The oncologic efficacy of laparoscopic and open distal gastrectomy for advanced GC is comparable. Well-designed RSs can be similar to small sample of PSs in assessing long-term oncologic outcomes of surgical interventions, but the short-term outcomes obtained should be treated with caution.

14.
Cancer Cell Int ; 19: 282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31728130

RESUMO

Background: Angiogenesis plays critical roles in the progression and metastasis of malignant tumors. Gastric neuroendocrine carcinoma is an uncommon stomach cancer that is rich in blood vessels and exhibits highly malignant biological behavior with a poor prognosis. The role of CDK5RAP3 in GNEC has not been reported to date. Methods: Immunohistochemistry was used to assess the expression of CDK5RAP3 in GNEC tissues and adjacent non-tumor tissues. Cell lines with stable overexpression or knockdown of CDK5RAP3 were constructed using lentiviral transfection. Wound-healing assays, invasion and metastasis assays, tube formation assays, and tumor xenograft transplantation assays were performed to evaluate the effect of CDK5RAP3 on GNEC angiogenesis in vitro and in vivo. Real-time PCR, ELISA, western blot analysis, and confocal-immunofluorescence staining were used to explore the molecular mechanism of CDK5RAP3's effect on angiogenesis. Results: Compared with their respective adjacent non-tumor tissues, protein levels of CDK5RAP3 were significantly decreased in GNEC tissues. Furthermore, low expression of CDK5RAP3 was correlated with more advanced TNM stage, increased tumor microvessel density, and poor prognosis. Functionally, we found that GNEC cells with CDK5RAP3 knockdown promoted human umbilical vein endothelial cells migration and tube formation via activation of AKT/HIF-1α/VEGFA signaling, resulting in increased levels of VEGFA in GNEC cell supernatant. In addition, CDK5RAP3 overexpression in GNEC cells caused the opposing effect. Consistent with these results, nude mouse tumorigenicity assays showed that CDK5RAP3 expression downregulated angiogenesis in vivo. Lastly, patients with low CDK5RAP3 expression and high VEGFA expression exhibited the worst prognosis. Conclusions: This study demonstrated that CDK5RAP3 inhibits angiogenesis by downregulating AKT/HIF-1α/VEGFA signaling in GNEC and improves patient prognosis, suggesting that CDK5RAP3 could be a potential therapeutic target for GNEC.

15.
Cancer Sci ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31710406

RESUMO

The present study was designed to evaluate the dynamic survival and recurrence of remnant gastric cancer (RGC) after radical resection and to provide a reference for the development of personalized follow-up strategies. A total of 298 patients were analyzed for their 3-year conditional overall survival (COS3), 3-year conditional disease-specific survival (CDSS3), corresponding recurrence and pattern changes, and associated risk factors. The 5-year overall survival (OS) and the 5-year disease-specific survival (DSS) of the entire cohort were 41.2% and 45.8%, respectively. The COS3 and CDDS3 of RGC patients who survived for 5 years were 84.0% and 89.8%, respectively. The conditional survival in patients with unfavorable prognostic characteristics showed greater growth over time than in those with favorable prognostic characteristics (eg, COS3, ≥T3: 46.4%-83.0%, Δ36.6% vs ≤T2: 82.4%-85.7%, Δ3.3%; P < 0.001). Most recurrences (93.5%) occurred in the first 3 years after surgery. The American Joint Committee on Cancer (AJCC) stage was the only factor that affected recurrence. Time-dependent Cox regression showed that for both OS and DSS, after 4 years of survival, the common prognostic factors that were initially judged lost their ability to predict survival (P > 0.05). Time-dependent logistic regression analysis showed that the AJCC stage independently affected recurrence within 2 years after surgery (P < 0.05). A postoperative follow-up model was developed for RGC patients. In conclusion, patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow-up model for RGC patients of different stages, which may affect the design of future clinical trials.

16.
BMC Cancer ; 19(1): 1048, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694573

RESUMO

BACKGROUND: Most lymph node metastasis (LNM) models for early gastric cancer (EGC) include lymphovascular invasion (LVI) as a predictor. However, LVI must be confirmed by postoperative pathology. In this study, we aimed to develop a model for predicting the risk of LNM/LVI in EGC using preoperative factors. METHODS: EGC patients who underwent radical gastrectomy at Fujian Medical University Union Hospital and Sun Yat-sen University Cancer Center (n = 1460) were selected as the training set. The risk factors of LNM/LVI were investigated. Data from the International study group on Minimally Invasive surgery for GASTRIc Cancer trial (n = 172) were selected as the validation set. RESULTS: In the training set, the incidence of LNM/LVI was 21.6%. The 5-year cancer-specific survival rates of patients with and without LNM/LVI were 92.4 and 95.0%, respectively, with significant difference (P = 0.030). Multivariable logistic regression analysis showed that the four independent risk factors for LNM/LVI were female, tumor larger than 20 mm, submucosal invasion and undifferentiated tumor histological type (all P <  0.05); the area under the curve (AUC) was 0.694 (95% confidence interval [CI]: 0.659-0.730). Patients were divided into low-risk, intermediate-risk, high-risk and extremely high-risk groups by recursive partitioning analysis; the incidences of LNM/LVI were 5.4, 12.6, 24.2 and 37.8%, respectively (P <  0.001). The AUC of the validation set was 0.796 (95%CI, 0.662-0.851) and the predictive performance of the LNM/LVI risk in the validation set was consistent with that in the training set. CONCLUSIONS: The risk of LNM/LVI in differentiated mucosal EGC is low, which indicated that endoscopic resection is a treatment option. The risk of LNM/LVI in undifferentiated mucosal EGC and submucosa EGC are high and gastrectomy with lymph node dissection is suggested.

17.
World J Gastroenterol ; 25(37): 5641-5654, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31602164

RESUMO

BACKGROUND: Robotic surgery has been considered to be significantly better than laparoscopic surgery for complicated procedures. AIM: To explore the short-term effect of robotic and laparoscopic spleen-preserving splenic hilar lymphadenectomy (SPSHL) for advanced gastric cancer (GC) by Huang's three-step maneuver. METHODS: A total of 643 patients who underwent SPSHL were recruited from April 2012 to July 2017, including 35 patients who underwent robotic SPSHL (RSPSHL) and 608 who underwent laparoscopic SPSHL (LSPSHL). One-to-four propensity score matching was used to analyze the differences in clinical data between patients who underwent robotic SPSHL and those who underwent laparoscopic SPSHL. RESULTS: In all, 175 patients were matched, including 35 patients who underwent RSPSHL and 140 who underwent LSPSHL. After matching, there were no significant differences detected in the baseline characteristics between the two groups. Significant differences in total operative time, estimated blood loss (EBL), splenic hilar blood loss (SHBL), splenic hilar dissection time (SHDT), and splenic trunk dissection time were evident between these groups (P < 0.05). Furthermore, no significant differences were observed between the two groups in the overall noncompliance rate of lymph node (LN) dissection (62.9% vs 60%, P = 0.757), number of retrieved No. 10 LNs (3.1 ± 1.4 vs 3.3 ± 2.5, P = 0.650), total number of examined LNs (37.8 ± 13.1 vs 40.6 ± 13.6, P = 0.274), and postoperative complications (14.3% vs 17.9%, P = 0.616). A stratified analysis that divided the patients receiving RSPSHL into an early group (EG) and a late group (LG) revealed that the LG experienced obvious improvements in SHDT and length of stay compared with the EG (P < 0.05). Logistic regression showed that robotic surgery was a significantly protective factor against both SHBL and SHDT (P < 0.05). CONCLUSION: RSPSHL is safe and feasible, especially after overcoming the early learning curve, as this procedure results in a radical curative effect equivalent to that of LSPSHL.

18.
Dis Markers ; 2019: 3863458, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565098

RESUMO

Objective: Circular RNAs (circRNAs) have been reported to be widely involved in pathological processes of various cancers. However, little is known about their diagnostic values in early gastric cancer (EGC). This study is aimed at exploring whether circulating circRNAs in plasma could act as biomarkers for EGC diagnosis. Materials and Methods: Mass spectrometry (MS) was performed to identify the proteins that at significantly aberrantly levels in gastric cancer (GC) tissues. The target circRNA was identified by bioinformatics analysis. A receiver operating characteristic (ROC) curve was generated to evaluate the diagnostic utility. Results: MS revealed that the ribosomal protein L6 (RPL6) expression was significantly downregulated only in EGC tissues vs. nontumorous tissues; this was validated by western blotting (n = 30, p = 0.0094). Bioinformatics analysis predicted that there is a hsa_circ_0006848/hsa_miR-329-5p/RPL6 axis in GC progression. The hsa_circ_0006848 expression was significantly downregulated in EGC tissues (vs. nontumorous tissues, n = 30, p = 0.0073) and plasma samples from EGC patients (vs. paired healthy volunteers, n = 30, p = 0.0089). In addition, the hsa_circ_0006848 plasma level in postoperative patients was significantly higher than that of preoperative patients (n = 30, p = 0.047). Furthermore, the decreased hsa_circ_0006848 expression in plasma was negatively correlated with poor differentiation (p = 0.037) and tumor size (p = 0.046). The area under the ROC curve (AUC) of hsa_circ_0006848 in plasma was 0.733, suggesting a good diagnostic value. The plasma hsa_circ_0006848 level combined with the carcinoembryonic antigen (CEA), carbohydrate-associated antigen 19-9 (CA19-9), and carbohydrate-associated antigen 72-4 (CA72-4) level increased the AUC to 0.825. Conclusion: Our results indicated that plasma hsa_circ_0006848 may be a novel noninvasive biomarker in EGC diagnosis.

19.
BMC Cancer ; 19(1): 920, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31521128

RESUMO

BACKGROUND: Tumor-infiltrating immune cells are present in various malignant tumors, but their clinical significance in gastric cancer (GC) remains unclear. This study aimed to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). METHODS: Using a prospective database containing 401 cases of GC, we evaluated TIL (cluster of differentiation 8 (CD8) expression) and TAM (cluster of differentiation 68 (CD68) expression) statuses via immunohistochemical staining. RESULTS: Compared with CD8+ TIL-negative cases (n = 196, 48.6%), CD8+ TIL-positive cases (n = 205, 51.1%) showed significantly better recurrence-free survival (RFS) [log-rank p<0.001; multivariate HR: 0.372; 95% confidence interval (CI): 0.239-0.579, p<0.001]. In contrast, compared with CD68+ TAM-negative cases (n = 217, 54.1%), CD68+ TAM-positive cases (n = 184, 45.9%) had significantly poor RFS [log-rank p<0.001; multivariate HR: 2.182; 95% CI: 1.435-3.318, p<0.001]. Thus, patients with a positive CD8+ TIL and negative CD68+ TAM status exhibited significantly increased RFS. Multivariate analysis demonstrated that CD8+ TILs and CD68+ TAMs may serve as independent prognostic markers for RFS. Incorporating CD8+ TIL and CD68+ TAM statuses into the AJCC TNM system generated a predictive model with better predictive accuracy for RFS. More importantly, patients with a positive TIL and negative TAM status showed a tendency of improved RFS after postoperative adjuvant chemotherapy (PAC). Similar results were obtained by overall survival (OS) analysis. CONCLUSIONS: CD8+ TIL and CD68+ TAM statuses were identified as independent prognostic factors that may be integrated into the current TNM staging system to refine risk stratification and to better predict the survival benefit from PAC in patients with GC. TRIAL REGISTRATION: The current controlled trial was registered at ClinicalTrials.gov (ID: NCT02327481 ) on December 30, 2014.

20.
J Exp Clin Cancer Res ; 38(1): 410, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533855

RESUMO

BACKGROUND: UFM1 has been found to be involved in the regulation of tumor development. This study aims to clarify the role and potential molecular mechanisms of UFM1 in the invasion and metastasis of gastric cancer. METHODS: Expression of UFM1 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was analyzed by Western blotting, immunohistochemistry, and realtime PCR. Its correlation with the clinicopathological characteristics and prognosis of gastric cancer patients was analyzed. The effects of UFM1 on the invasion and migration of gastric cancer cells were determined by the wound and trans-well assays, and the effect of UFM1 on subcutaneous tumor formation was verified in nude mice. The potential downstream targets of UFM1 and related molecular mechanisms were clarified by the human protein kinase assay and co-immunoprecipitation technique. RESULTS: Compared with the corresponding adjacent tissues, the transcription level and protein expression level of UFM1 in gastric cancer tissues were significantly downregulated (P < 0.05). The 5-year survival rate of gastric cancer patients with low UFM1 expression was significantly lower than the patients with high UFM1 expression (42.1% vs 63.0%, P < 0.05). The invasion and migration abilities of gastric cancer cells with stable UFM1 overexpression were significantly decreased, and the gastric cancer cells with UFM1 stable knockdown showed the opposite results; similar results were also obtained in the nude mouse model. Further studies have revealed that UFM1 could increase the ubiquitination level of PDK1 and decrease the expression of PDK1 at protein level, thereby inhibiting the phosphorylation level of AKT at Ser473. Additionally, the effect of UFM1 on gastric cancer cell function is dependent on the expression of PDK1. The expression level of UFM1 can improve the poor prognosis of PDK1 in patients with gastric cancer. CONCLUSION: UFM1 suppresses the invasion and metastasis of gastric cancer by increasing the ubiquitination of PDK1 through negatively regulating PI3K/AKT signaling.

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