Article

Predictive Significance of Preoperative Serum VEGF-C and VEGF-D, Independently and Combined With Ca19-9, for the Presence of Malignancy and Lymph Node Metastasis in Patients With Gastric Cancer

Authors:
  • Saint Savvas General Oncology Hospital of Athens
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Abstract

Cumulative evidence demonstrate that lymphangiogenic vascular endothelial growth factors (VEGF)-C and -D are over-expressed and associated to lymph node metastasis (LNM) in gastric cancer. The aim of this study is to investigate whether preoperative serum levels of VEGF-C and VEGF-D could be useful tumor markers in patients with operable gastric adenocarcinoma. We prospectively examined serum samples from 40 patients and 40 non-cancer controls using enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was implemented. VEGF-C and VEGF-D were studied independently and in combination with Ca19-9. In gastric cancer patients, preoperative VEGF-C was significantly lower as compared to controls and to postoperative VEGF-C (P < 0.001); preoperative VEGF-D was significantly higher as compared to controls and to postoperative VEGF-D (P < 0.001). ROC curve analysis identified a VEGF-C/VEGF-D cut-off value of < 2.7 for the presence of gastric cancer, with 83% sensitivity and 75% specificity (P < 0.001). Backward stepwise selection modeling including sex, age, VEGF-D and Ca19-9, predicted the presence of LNM with 86% sensitivity and 82% specificity (P < 0.001). Circulating levels of VEGF-C and VEGF-D could play a role as biomarkers for serological detection and staging in gastric cancer.

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... Among the VEGF family members, VEGF-A plays an essential role in angiogenesis. However, the significance of serum levels of other VEGF members (VEGF-C and -D) has been reported [1][2][3]. ...
... Recently, I have read with great interest an article by Tsirlis et al. [3] that evaluated circulating VEGF-C and -D levels in gastric carcinoma. Serum VEGF-C and -D levels were significant predictors for the presence of gastric cancer however, their study failed to show the relationship between the circulating VEGF-C and -D levels and tumor characteristics such as lymph node metastasis (LNM), tumor size (T) status, and stage. ...
... Serum VEGF-C and -D levels were significant predictors for the presence of gastric cancer however, their study failed to show the relationship between the circulating VEGF-C and -D levels and tumor characteristics such as lymph node metastasis (LNM), tumor size (T) status, and stage. Although some studies have indicated that overexpression of VEGF is an independent prognostic factor in gastric cancer [1,6], studies on circulating levels of VEGF-C and -D have shown contradictory results [1][2][3]. In contrast to the study by Tsirlis et al., Wang et al. [1] showed that increased levels of VEGF were positively correlated to LNM. ...
... Preoperative CA19-9 was found to be a statistically significant indicator of micrometastasis and hematogenous spread within gastric cancer patients [12]. Furthermore, elevated levels of preoperative CA19-9 were also found to be predictive of lymph node metastasis (LNM) in gastric cancer [13,14]. Given the current findings within other GI cancers, the aim of this study was to further explore the relationship of preoperative levels of CA19-19 and number of positive LN within confirmed cases of periampullary carcinoma status post PD. ...
... This prospective cohort study was inclusive of all patients who were confirmed cases of periampullary carcinoma at King Faisal Specialist Hospital and Research Center in Jeddah, Saudi Arabia from October 2010 to October 2018. Periampullary carcinoma was diagnosed based upon criteria set forth by the International Classifications of Diseases for Oncology 3 rd edition [14]. Patients were excluded from this study if found to have unresectable disease. ...
... Furthermore, CA19-9 is also implicated in hematogenous spread of tumor cells. Tumor cells traverse the blood stream utilizing adhesion molecules expressed across the membrane [10][11][12][13][14][15][16][17][18][19][20][21][22][23]. CA19-9 plays a role in hematologic spread in pancreatic cancers, as CA19-9 adheres to E and P selectins expressed across cells lining the peritoneum. ...
Article
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Background: Periampullary tumors affect the head of the pancreas, second part of the duodenum, distal portion of the common bile duct (CBD) and the ampulla of Vater. The pancreas is the most common site of periampullary tumors and the incidence of pancreatic adenocarcinoma is on the rise. Current research on gastric and periampullary cancers has found preoperative levels of Carbohydrate 19-9 antigen (CA19-9) to be a significant indicator of patient survival. The goal of this study was to further explore the relationship of preoperative levels of CA19-19 and positive lymph nodes (LN) within confirmed cases of periampullary carcinoma status post pancreatoduodenectomy. Methods: This is a retrospective cohort study performed at King Faisal Specialist hospital and research center in Jeddah, Saudi Arabia included all confirmed periampullary cancer cases for the period October 2010 to October 2018 (N = 50). Individual biometric data was collected and Pearson Correlation Coefficients (PCC) were calculated. For this study, PCC were explored between CA19-9 and number of positive LN, CA19-9 and tumor size, and number of positive LN and tumor size. Results: Mean preoperative CA19-9 levels were significantly elevated at 701.8 U⋅mL-1 (SD = 2063.027 U⋅mL-1). There were 28 patients (56%) who had positive LN involvement following resection. The average tumor size was 3.386 cm (SD = 1.986 cm). PCC showed a moderately positive correlation between CA19-9 levels and number of positive LN (r = 0.585, p = < 0.001). There was no statistically significant correlation between CA19-9 and tumor size (r = 0.238, p = 0.095). A weakly positive correlation was found between number of positive lymph nodes and tumor size (r = 0.28, p = 0.049). Conclusion: This study found a moderately positive correlation between CA19-9 and number of involved lymph nodes in patients diagnosed with periampullary tumors. This suggests the increased prognostic value of preoperative CA19-9 as it is possible that these preoperative values can highlight patients at increased risk of lymph node metastasis and disease progression.
... Serum tumour markers have long been used for early detection and follow-up in patients with gastric cancer. [10][11][12][13][14][15] Elevated serum levels of carbohydrate antigen 19-9 (CA19-9; or the sialyl-Lewis A determinant) have been the focus of investigations because of the reported association of CA19-9 with lymph-node metastases. 14 CA19-9 is a tumour-associated carbohydrate determinant. ...
... 16 Patients who show high expressing levels of the CA19-9 antigen have been shown to be at greater risk of developing lymphnode and haematogenous metastases. 14,16 The use of CA19-9 to indicate lymph-node metastases is, however, still controversial. 10,12,13,17 The low sensitivity and specificity of CA19-9 does not allow for its use in the prediction of lymph-node metastases. ...
... Since the introduction of CA19-9 serum levels in clinical practice, numerous publications have confirmed that elevated CA19-9 serum levels are a predictor for lymph-node metastases and indicate worse prognosis for patients with advanced gastric cancer. [10][11][12][13][14][15] To the best of our knowledge, the preoperative CA19-9 serum levels have never been used to predict micrometastases in patients with gastric cancer. As the up-regulated sialyl-Lewis A determinant (i.e., the CA19-9 antigen) in tumour cells has been shown to predispose patients with adenocarcinoma and squamous cell carcinoma to haematogenous metastases 16 , it can be seen that patients with elevated CA19-9 serum levels are at greater risk for micrometastatic lymph-node involvement. ...
Article
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We explored the prognostic value of the up-regulated carbohydrate antigen (CA19-9) in node-negative patients with gastric cancer as a surrogate marker for micrometastases. Micrometastases were determined using reverse transcription quantitative polymerase chain reaction (RT-qPCR) for a subgroup of 30 node-negative patients. This group was used to determine the cut-off for preoperative CA19-9 serum levels as a surrogate marker for micrometastases. Then 187 node-negative T1 to T4 patients were selected to validate the predictive value of this CA19-9 threshold. Patients with micrometastases had significantly higher preoperative CA19-9 serum levels compared to patients without micrometastases ( Preoperative CA19-9 serum levels can be used to predict higher risk for haematogenous spread and micrometastases in node-negative patients. However, CA19-9 serum levels lack the necessary sensitivity and specificity to reliably predict micrometastases.
... In this context, circulating biomarkers could offer a valid contribution in the design of a predictive algorithm. For several different tumors such as breast (13), colon (14), ovarian (15), endometrial (16), cervical (33), bladder (34), thyroid (35), gastric (36), esophageal (37), and gallbladder (38) cancers, a strong association between an increased expression of VEGF-D and the presence of lymph node metastases has already been demonstrated by IHC (13)(14)(15)(16)33) or at serum level (34)(35)(36)(37)(38); however, investigations on this biomarker regarding VSCC are lacking. To the best of our knowledge, this is the first study investigating the role of sVEGF in VSCC. ...
... In this context, circulating biomarkers could offer a valid contribution in the design of a predictive algorithm. For several different tumors such as breast (13), colon (14), ovarian (15), endometrial (16), cervical (33), bladder (34), thyroid (35), gastric (36), esophageal (37), and gallbladder (38) cancers, a strong association between an increased expression of VEGF-D and the presence of lymph node metastases has already been demonstrated by IHC (13)(14)(15)(16)33) or at serum level (34)(35)(36)(37)(38); however, investigations on this biomarker regarding VSCC are lacking. To the best of our knowledge, this is the first study investigating the role of sVEGF in VSCC. ...
... Higher levels of sVEGF-D in cancer patients compared to healthy controls or benign pathologies have been detected for some tumor types (36)(37)(38) and not for others (34,35), but Results are reported as odds ratio (OR) and 95% confidence interval (CI). C-index was adjusted for optimism using bootstrap. ...
Article
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Background Radical surgical resection of the primary tumor with mono/bilateral inguinofemoral lymph node dissection is the standard treatment for invasive vulvar squamous cell carcinoma (VSCC) and is frequently related to severe morbidity. Tailoring surgical treatment is of paramount importance, and a comprehensive preoperative evaluation is mandatory. Vascular endothelial growth factor D (VEGF-D) is considered a regulator of lymphangiogenesis involved in tumor spread via lymphatic vessels. The aim of this study was to evaluate the potential of VEGF-D in the prediction of inguinofemoral lymph node metastasis. Methods We analyzed the preoperative levels of serum VEGF-D (sVEGF-D) from two independent cohorts of patients with VSCC by enzyme-linked immunosorbent assay and its protein expression on tumor tissue by immunohistochemistry. Logistic regression was performed to identify the independent risk factors for lymph node metastasis, and Cox proportional hazard model was used for survival analysis. Results High levels of sVEGF-D, but not tissue VEGF-D, significantly correlated with positive groin nodes and a more advanced International Federation of Gynecologists and Obstetricians (FIGO) stage. In multivariable analysis, a high sVEGF-D level was an independent predictor of lymph node metastasis and worse prognosis. A prediction model based on sVEGF-D, tumor grade assessed on biopsy, tumor diameter, and lymph node clinical evaluation was able to predict lymph node metastasis, reaching C-index values of 0.79 and 0.73 in the training and validation cohorts, respectively. Conclusions The preoperative sVEGF-D level might be a reliable biomarker for the prediction of lymph node metastasis and prognosis in patients with VSCC, supporting better clinical/surgical decision. Multicenter prospective studies are required to confirm our findings.
... Currently, preoperative staging relies on imaging studies, but these modalities cannot confirm or exclude the presence of metastatic lymph nodes. This is a very important issue in determining the ideal treatment for an individual, such as the choice of gastrectomy vs. submucosal resection [10,11]. ...
... VEGF-C and VEGF-D are both ligands for VEGFR-3 on the surface of lymphatic endothelial cells and act as regulators of lymphangiogenesis; these had been reported to be important factors in stimulating lymphangiogenesis and lymphatic metastasis [12]. Similarly, Tsirlis et al. [11] verified that in the preoperative period, VEGF-C levels were lower and VEGF-D levels were higher in patients with cancer when compared with controls (P<0.001). In the postoperative period, VEGF-C levels increased and VEGF-D levels decreased compared with the preoperative level (P<0.001). ...
Article
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Gastric cancer (GC) has high mortality owing to its aggressive nature. Tumor angiogenesis plays an essential role in the growth, invasion, and metastatic spread of GC. The aim of this work was to review the angiogenic biomarkers related to the behavior of GC, documented in the literature. A search of the PubMed database was conducted with the MeSH terms: “Stomach neoplasms/blood [MeSH] or stomach neoplasms/blood supply [MeSH] and angiogenic proteins/blood [Major]”. A total of 30 articles were initially collected, and 4 were subsequently excluded. Among the 26 articles collected, 16 examined the role of vascular endothelial growth factor (VEGF), 4 studied endostatin, 3 investigated angiopoietin (Ang)-2, 2 studied the Ang-like protein 2 (ANGTPL2), and 1 each examined interleukin (IL)-12, IL-8, and hypoxia inducible factor. Regarding VEGF, 6 articles concluded that the protein was related to lymph node metastasis or distant metastases. Five articles concluded that VEGF levels were elevated in the presence of GC and decreased following tumor regression, suggesting that VEGF levels could be a predictor of recurrence. Four articles concluded that high VEGF levels were correlated with poor prognosis and lower survival rates. Ang-2 and ANGTPL2 were elevated in GC and associated with more aggressive disease. Endostatin was associated with intestinal GC. VEGF is the most extensively studied angiogenic factor. It is associated with the presence of neoplastic disease and lymph node metastasis. It appears to be a good biomarker for disease progression and remission, but not for diagnosis. The data regarding other biomarkers are inconclusive.
... High VEGF-C levels were associated with poorly differentiated cancers, advanced stages, a higher density of lymphatic vessels in the tumor, and the presence of metastases to regional lymph nodes and distant organs [149,150]. In addition, high levels of the marker predicted a decrease in the survival rate of GC patients [148,149], especially in Caucasian patients [151]. However, in contrast, some authors noted lower serum levels of VEGF-C in patients with GC than in the control group [152]. ...
Article
Gastric cancer (GC) remains a serious oncological problem, ranking third in the structure of mortality from malignant neoplasms. Improving treatment outcomes for this pathology largely depends on understanding the pathogenesis and biological characteristics of GC, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers. It is known that the main cause of death from malignant neoplasms and GC, in particular, is tumor metastasis. Given that angiogenesis is a critical process for tumor growth and metastasis, it is now considered an important marker of disease prognosis and sensitivity to anticancer therapy. In the presented review, modern concepts of the mechanisms of tumor vessel formation and the peculiarities of their morphology are considered; data on numerous factors influencing the formation of tumor microvessels and their role in GC progression are summarized; and various approaches to the classification of tumor vessels, as well as the methods for assessing angiogenesis activity in a tumor, are highlighted. Here, results from studies on the prognostic and predictive significance of tumor microvessels in GC are also discussed, and a new classification of tumor microvessels in GC, based on their morphology and clinical significance, is proposed for consideration.
... As previously mentioned, the VEGF molecules also play a crucial role in metastasis. The VEGF-C and VEGF-D molecules have diagnostic potential because they are found under and overexpressed in GC patients, respectively (P<0.001) [65]. VEGF molecules also predict a reduction in overall survival time (P=0.040) ...
Article
Gastric cancer is the fourth most common type of cancer worldwide and the second most lethal. Gastric cancer biomarkers can be used for diagnosis, prediction of sensitivity to treatment, and prognosis. The following search terms were applied to PubMed as of December 2020: 'gastric cancer classification', 'gastric cancer epidemiology', 'cancer metastasis' and 'gastric cancer biomarker'. Only experimental studies were reported in the 'biomarkers' section. Some biomarkers can serve as therapeutic targets for antitumoral drugs. The genes analyzed include E-cadherin, RPRM, XAF1, MINT25, TFF1, p16 and p53. The miRNAs analyzed include miR-18a, miR185-5p, miR-125b and miR-21. Some molecules were associated with metastasis of gastric cancer, specifically those involved with EMT process and tissue degradation.
... Serum VEGF-D was reported to be elevated in some type of cancers and regarded as a biomarker of metastasis. 20,21 However, serum levels of VEGF-D in cancer and their potential role have not been systemically investigated. Nevertheless, cancer from different origins should be considered in differential diagnosis when we use VEGF-D in diagnosis of LAM. ...
Article
Background: Definite diagnosis of lymphangioleiomyomatosis (LAM) depends on either transbronchial lung biopsy or video-assisted thoracic surgery, unless there is a history of chylothorax, kidney angiomyolipoma (AML), or tuberous sclerosis complex (TSC). Vascular endothelial growth factor-D (VEGF-D) was recently considered as a novel diagnostic marker for LAM. Herein, we evaluated diagnostic value of serum VEGF-D in LAM patients. Methods: Serum samples were obtained from 78 cases of LAM (50 definite and 28 probable LAM based on European Respiratory Society guidelines), and 40 healthy female volunteers. VEGF-D was measured using enzyme-linked immunosorbant assay according to product instruction (R&D). Results: Serum VEGF-D was significantly increased in definite LAM group, compared with that of health control (median: 3841.9 pg/mL vs 405.5 pg/mL respectively, p < 0.001). The optimal cut-off point for definite LAM diagnosis was 850.7 pg/mL. In probable LAM group, the majority of patients (92.9%) had serum VEGF-D level over 850.7 pg/mL. The serum levels of VEGF-D in LAM patients with pulmonary cystic lesions only were lower than that in patients with any of evidences of AML, chylous effusions, adenopathy, lymphangioleiomyomas, or TSC, but higher than that in the health control. In addition, VEGF-D levels were correlated with disease severity measured as LAM CT grade, and presentations of chylous effusions and/or lymphatic involvement (p < 0.05). Conclusion: Serum VEGF-D should be added to the current diagnosis algorithm to enhance definitive diagnosis for LAM.
... Among the VEGF family members, VEGF-A played an essential role in angiogenesis. However, the significant value of serum levels of other VEGF members (VEGF-C and VEGF-d) has been reported [16][17][18]. However, previous studies on serum VEGF-C and VEGF-D in gastric cancer patients have presented with contradictory results. ...
Article
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Background To investigate the expression of chemokine ligand 2 (CCL2), chemokine ligand 18 (CCL18), and vascular endothelial growth factor (VEGF) in peripheral blood of patients with gastric cancer and their correlation with presence of malignancy and disease progression. Methods Sixty patients with pathological proved gastric cancer were prospectively included into study. The levels of CCL2, CCL18, and VEGF in peripheral blood were examined by enzyme-linked immunosorbentassay (ELISA). Peripheral blood from 20 healthy people was examined as control. Results The preoperative serum levels of CCL2, CCL18 and VEGF in gastric cancer patients were significantly higher than that of controls (P <0.001, P <0.001, and P <0.001, respectively). ROC curve analysis showed that with a cut-off value of ≥1272.8, the VEGF*CCL2 predicted the presence of gastric cancer with 83% sensitivity and 80% specificity. Preoperative serum CCL2 was significantly correlated to N stage (P =0.040); CCL18 associated with N stage (P =0.002), and TNM stage (P =0.002); VEGF correlated to T stage (P =0.000), N stage (P =0.015), and TNM stage (P =0.000). Conclusion Preoperative serum levels of CCL2 and VEGF could play a crucial role in predicting the presence and progression of gastric cancer.
... The occurrence and development of tumor are complex biological process, malignant invasive tumor growth and metastasis are the main cause of treatment failure [7] . Its growth and metastasis depends on angiogenesis, new blood vessels not only provide nutrition for their growth, also provide channels for transfer. ...
Article
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Objective To investigate the effect of vascular endothelial growth factor (VEGF), P53 and telomerase on angiogenesis in gastric carcinoma tissue. Methods A total of 95 surgical resection samples of gastric cancer tissue after pathological diagnosis are collected to observe the VEGF, P53 and telomerase expression using immunohistochemical methods. Relationship between their expression and its influence on angiogenesis in gastric carcinoma tissue were analyzed. Results Microvascular density (MVD) and the expression of VEGF, P53 and telomerase were positively correlated. Expression of VEGF and P53 protein were related to tumor type and lymph metastasis, and also a correlation was observed between P53 and VEGF. The telomerase expression had no correlation with VEGF, and P53. Conclusions VEGF angiogenesis has a angiogenesis promoting effect on gastric cancer tissue development and plays an important role in tumor generation and metastasis. Mutant P53 promotes the tumor angiogenesis generation by adjusting VEGF. Telomerase has a certain role in promoting activity of angiogenesis through different way rather than P53.
... The correlation between VEGF-C/LVD and prognosis in tumor differentiation, T stage, lymph node metastasis, and distant metastasis were also confirmed [20]. Another study further suggested using the combination of VEGF-C/-D and CA199 to predict lymphatic vessel metastasis [21]. Given that Akt/mTOR pathway and VEGF-C/-D play a vital role in lymphatic metastasis and prognosis, our study aims to explore the relationship between two pathways and further promote the mechanism of lymphangiogenesis and metastasis. ...
Article
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Lymphangiogenesis plays a significant role in metastasis and recurrence of gastric cancer. There is no report yet focusing on the modulation of VEGF pathway and lymphangiogenesis of gastric cancer by targeting Akt/mTOR pathway. This study aims to demonstrate the relationship between Akt/mTOR pathway and VEGF-C/-D in gastric cancer. We collected surgically resected gastric adenocarcinoma specimens from 55 consented patients. Immunohistochemistry staining of p-Akt, p-mTOR, VEGF-C, VEGF-D were performed and scored by two independent pathologists. The results were presented as staining intensity and positive staining cell rate. We also measured lymphatic vessel density (LVD) by D2-40 staining. Different dosages of p-Akt inhibitor LY294002 (12.5 μM, 25 μM, 50 μM) and p-mTOR inhibitor Rapamycin (25 nM, 50 nM, 100 nM) were given to gastric cancer cell line SGC-7901 in vitro. The inhibition rate of cell growth was tested by MTT at 24 h, 48 h and 72 h, respectively and protein expressions of Akt, p-Akt, mTOR, p-mTOR, VEGF-C and VEGF-D were examined by Western blot. The positive staining rates of p-Akt, p-mTOR, VEGF-C and VEGF-D in 55 gastric cancer clinical specimens were 74.54%, 85.45%, 72.73% and 58.18%. p-Akt and p-mTOR were positively correlated with VEGF-C and VEGF-D (p < 0.01). The LVD increased with incremental tendency of staining intensity of p-Akt, p-mTOR, VEGF-C and VEGF-D. LY294002 or Rapamycin significantly suppressed SGC-7901 cell growth and the inhibition rate was dose and time dependent (p < 0.001). In addition, the protein expression of p-Akt and p-mTOR were positively correlated with that of VEGF-C and VEGF-D (p < 0.05). The level of LVD in gastric cancer specimens was significant higher than that of normal gastric tissue and was positively correlated with p-Akt, p-mTOR, VEGF-C and VEGF-D. Inhibition of p-Akt and p-mTOR, in vitro, decreased tumor cell VEGF-C and VEGF-D significantly. Therefore, we concluded that lymphangiogenesis of gastric cancer might be related to Akt/mTOR-VEGF-C/VEGF-D axis.
... However, several studies in gastric cancer patients have reported conflicting results. Tsirlis et al. [15] from Greece observed that the preoperative sVEGF-C level was significantly lower than that observed in controls but that the preoperative sVEGF-D level was significantly higher than that in controls. In contrast, Al-Moundhri et al. [16] from Oman demonstrated that there were no significant differences in the serum VEGF-C levels between gastric adenocarcinoma patients and controls, whereas the serum levels of VEGF-D were significantly higher in control subjects than in gastric adenocarcinoma patients. ...
Article
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Gallbladder carcinoma (GBC) is the most common cancer of the biliary tract. Lymph node metastasis (LNM) is the major diffusion route of GBC and is a prognosis factor. The aim of study was to assess the potential of the serum VEGF-C and VEGF-D (sVEGF-C/D) levels to predict the presence of LNM and the survival of GBC patients. The preoperative sVEGF-C/D levels of 31 patients with GBC, 10 patients with cholesterol polyps, and 10 healthy volunteers were measured by enzyme-linked immunoadsorbent assay (ELISA). The sVEGF-C/D levels of patients with GBC were significantly higher than those of people with healthy gallbladders (p < 0.001 and p = 0.001, respectively) and cholesterol polyp (p = 0.032 and p = 0.004, respectively). In GBC, the sVEGF-C levels were associated with LNM (p = 0.011), distant metastasis (p = 0.018), and stage (p = 0.045), but the sVEGF-D levels had a significant association with the tumor depth (p = 0.001), LNM (p = 0.001), distant metastasis (p = 0.047), and stage (p = 0.002). The sVEGF-C/D diagnostic values for the presence of GBC were sensitivity of 71.0 and 74.2 % and specificity of 80.0 and 85.0 %, respectively. With respect to the diagnosis of LNM, the diagnostic values of sVEGF-C/D were as follows: sensitivity 81.2 and 87.5 % and specificity 73.3 and 80.0 %, respectively. The mean survival time with high sVEGF-C was significantly shorter than that with low sVEGF-C (p < 0.001), which was also true for low sVEGF-D (p = 0.032). The preoperative sVEGF-C/D levels might be reliable biomarkers for the presence of disease and LNM in patients with GBC. The sVEGF-C/D levels may be prognosis factors that can predict a poor outcome for GBC patients.
... Además, los altos niveles del marcador, predice una disminución en la tasa de supervivencia de los pacientes con CG [148,149], especialmente en pacientes caucásicos [151]. Sin embargo, en contraste, algunos autores notaron niveles séricos más bajos de FCEV-C en pacientes con CG que en el grupo control [152]. ...
Article
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El cáncer gástrico (CG) continúa siendo un grave problema oncológico, ocupando el tercer lugar en la estructura de mortalidad por neoplasias malignas. Mejorar los resultados del tratamiento para esta patología, depende en gran medida, de la comprensión de la patogenia y de las características biológicas del CG; incluida la identificación y caracterización de los biomarcadores de diagnóstico, pronóstico, predicción y biomarcadores terapéuticos. Se conoce que la principal causa de muerte por neoplasias malignas y CG, en particular, es la metástasis tumoral. Dado que la angiogénesis es un proceso crítico para el crecimiento tumoral y la metástasis, ahora se considera un marcador importante del pronóstico de la enfermedad y la sensibilidad a la terapia contra el cáncer. En la revisión presentada, se consideran los conceptos modernos de los mecanismos de formación de vasos tumorales y las peculiaridades de su morfología; se resumen datos sobre numerosos factores que influyen en la formación de microvasos tumorales y su papel en la progresión de GC; y se destacan varios enfoques para la clasificación de los vasos tumorales, así como los métodos para evaluar la actividad de la angiogénesis en un tumor. Aquí, también se discuten los resultados de los estudios sobre el significado pronóstico y predictivo de los microvasos tumorales en GC, y se propone para su consideración, una nueva clasificación de microvasos tumorales en GC, basada en su morfología y significado clínico.
... Similarly, Tsirlis et al. observed lower VEGF-C levels in the preoperative period in a patient group, while VEGF-D levels were higher, and that VEGF-C levels increased while VEGF-D levels decreased in the postoperative period. Those authors describedserum VEGF-C and VEGF-D levels as statistically significant determinants of the presence of gastric cancer and showed that the VEGF-C/VEGF-D ration was a powerful determinant of malignancy (Tsirlis et al., 2010). Vidal et al., (2009) observed significantly higher preoperative serum VEGF levels in patients with gastric cancer compared to a control group. ...
Article
Introduction and aim: The purpose of this study was to determine the value, in terms of diagnosis, resectability and prognosis of pentraxin-3 (PTX3), interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) in cases of gastric adenocarcinoma, an important condition both worldwide and in Turkey, and to determine their levels in order to contribute to elucidating the pathogenesis of the disease. Materials and methods: Serum was separated from blood specimens collected from 45 patients diagnosed with gastric adenocarcinoma and from a 30-member healthy control group. Serum PTX3, IL-8 and VEGF levels were studied by ELISA method. Results: Serum PTX3 values differed significantly between the patient group and the control group (p <0.05). Serum IL-8 values also differed significantly between the patient group and the control group (p <0.05). A significant difference was also observed between serum VEGF values in the patient group and the control group (p <0.05). Significant correlation was determined between serum PTX3 and VEGF (p <0.01; r=0.833), between serum PTX3 and IL-8 (p <0.01; r=0.818), and between serum VEGF and IL-8 (p <0.01; r=0.803), measurements when the entire study population was evaluated irrespectively of groups. Conclusion: Serum PTX3, IL-8 and VEGF levels decreased in cases of gastric adenocarcinoma compared to the control group, and their levels affected one another. .
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Dickkopf-3 (DKK3) may act as a tumor suppressor as it is down-regulated in various types of cancer. This study assessed the DKK3 protein expression in gastric cancer and its potential value as a prognostic marker. DKK3 expression was evaluated by immunohistochemistry in 158 gastric cancer samples from patients who underwent gastrectomy from 2002 to 2008. Clinicopathological parameters and survival data were analyzed. Loss of DKK3 expression was found in 64 of 158 (40.5 %) samples, and it was associated with advanced T stage (p < 0.001), lymph node metastasis (p < 0.001), UICC TNM stage (p < 0.001), tumor location (p = 0.029), lymphovascular invasion (p = 0.035), and perineural invasion (p = 0.032). Patients without DKK3 expression in tumor cells had a significantly worse disease-free and overall survival than those with DKK3 expression (p < 0.001, and p = 0.001, respectively). TNM stage (p = 0.028 and p < 0.001, respectively) and residual tumor (p < 0.001 and p = 0.003, respectively) were independent predictors of disease-free and overall survival. Based on the preoperative clinical stage assessed by computed tomography (CT), loss of DKK3 expression was predominantly associated with worse prognosis in patients with clinically node-negative advanced gastric cancer (AGC). The combination of DKK3 expression status and CT increased the accuracy of CT staging for predicting lymph node involvement from 71.5 to 80.0 % in AGC patients. Loss of DKK3 protein expression was significantly associated with poor survival in patients with gastric cancer and was strongly correlated with the TNM stage. DKK3 might be a potential biomarker of lymph node involvement that can improve the predictive power of CT.
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Gastric carcinogenesis is one of the most commonly occurring malignant neoplasms in China, and early diagnosis and treatment are crucial to improving the quality of life and reducing mortality rates for patients with gastric cancer. Serum-based detection methods allow for a standardized and non-invasive approach to monitoring progression of gastric cancer. We therefore summarize four serum-based biomarkers (E-cadherin, Runx3, hGC-1 and 3 subtypes of VEGF family) for gastric cancer, categorized into groups of genes and proteins, and evaluate their individual values in detecting gastric cancer, surveillance and evaluating prognosis of patients with gastric cancer.
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Lymph node metastasis is one of the predictive factors associated with poor prognosis of epithelial ovarian cancer. To clarify the role of CD34 and vascular endothelial growth factor receptor-3-positive (CD34+/VEGFR3+) lymphatic/vascular endothelial progenitor cells (LVEPC) in patients with lymph node metastasis and epithelial ovarian cancer progression, the levels of circulating CD34+/VEGFR3+ LVEPC in epithelial ovarian cancer patients were detected. We also tested the plasma protein levels of VEGF and stromal cell-derived factor to find out their possible relationships with lymph node metastasis in our epithelial ovarian cancer cohort. Peripheral blood samples were collected from 54 patients diagnosed as epithelial ovarian cancer, and 31 normal samples as control. The circulating levels of LVEPC were carried out by flow cytometry, and blood protein levels of biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). The level of circulating LVEPC was significantly higher in patients with ovarian cancer compared with that of healthy controls. There was also a statistically significant correlation between LVEPC levels and surgical staging of epithelial ovarian cancer (P < 0.01). The circulating levels of bone marrow-derived LVEPC are significantly increased in epithelial ovarian cancer patients and these levels correlate with lymph node metastasis too.
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Background This study aimed to investigate the relationships between serum vascular endothelial growth factor (VEGF)‐A or VEGF‐C levels and lymph node metastasis (LNM) status in patients with papillary thyroid carcinoma (PTC). Methods The study enrolled 150 patients with pathologically proven PTC who underwent surgery: PTC without LNM, PTC with central neck metastasis, and PTC with lateral neck metastasis. Results Preoperative serum VEGF‐A levels were 300.12 ± 80.80 pg/mL overall and were not correlated with the presence of LNM. Preoperative serum VEGF‐C levels were 132.41 ± 48.48 pg/mL overall and were significantly correlated with the presence of LNM. Serum VEGF‐C levels were further increased in patients with lateral neck metastasis and positively correlated with the number of metastatic LNs (rho = 0.252, P = 0.002). Serum VEGF‐C, but not VEGF‐A, was identified as a significant predictor of lateral neck metastasis. Conclusion Serum VEGF‐C might be a clinically relevant biomarker of lateral neck metastasis in patients with PTC.
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To investigate whether serum vascular endothelial growth factor-C (SVEGF-C) and multi-detector computed tomography (MDCT) can predict lymph node metastasis (LNM) in gastric cancer (GC). The SVEGF-C level of 80 patients with GC was examined by enzyme linked immunosorbent assay. An MDCT scan of the abdomen was performed. Kaplan - Meier survival analysis was used to analyse survival. In patients with GC, a higher level of SVEGF-C was found in the LNM group (650.9 ± 198.6 vs 451.0 ± 115.5 pg/mL, P = 0.000) and in patients with distant metastases (834.3 ± 80.0 pg/mL vs 557.9 ± 187.0 pg/mL, P = 0.000). With a cut-off value of 542.5 pg/mL, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of SVEGF-C for predicating LNM were 82.8, 81.8, 82.5, 92.3 and 64.3%, respectively. MDCT could not be employed to detect the LNM. When SVEGF-C associated with MDCT was employed to determine LNM in GC, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 91.4, 86.4, 90.0, 94.6 and 79.2%, respectively. No difference of SVEGF-C level was found among N1, N2 and N3 groups (P > 0.05). The 5-year overall survival was 47.5%. A shorter mean survival time were found in patients with SVEGF-C >834.3 pg/ml (43.3 ± 2.8 months vs 67.4 ± 2.5 months, P = 0.000) and in patients who were MDCT-positive (42.7 ± 3.8 months vs 60.8 ± 2.2 months, P = 0.0034). SVEGF-C may be a biomarker for a preoperative diagnosis of LNM. In conjunction with MDCT, SVEGF-C can improve the accuracy of a diagnosis of LNM in GC. A higher SVEGF-C level and an MDCT-positive finding could predict the poorer prognosis of GC.
To evaluate the role of serum vascular endothelial growth factor (VEGF) and urine basic fibroblast growth factor (bFGF) in the differential diagnosis of vascular anomalies by receiver operating characteristic curve. Using the method of enzyme linked immunosorbent assay (ELISA), 364 cases of various vascular anomalies (proliferating hemangiomas, n = 146; hemangiomas, n = 106; vascular malformations, n = 112) and 440 cases of various vascular anomalies (proliferating hemangiomas, n = 154; involuting hemangiomas, n = 148; vascular malformations, n = 138) subjects were examined for the serum levels of VEGF and the urine bFGF respectively. Nonparametric statistical tests were used for data analysis. The VEGF levels of proliferating hemangioma, involuting hemangioma, vascular malformation and control groups were analyzed by the Kruskal-Wallis test. When there was significance (P < 0.05), a subgroup analysis was performed by the Mann-Whitney U test. A receiver operator characteristic (ROC) curve was constructed for both the serum levels of VEGF and urine bFGF to determine the optimal diagnostic cut-off to differentiate proliferating hemangioma from involuting hemangioma, vascular malformation and controls. The serum level of VEGF and the urine bFGF in proliferating hemangiomas were significantly higher than those in involuting hemangiomas, vascular malformations and negative controls (P < 0.01). And the differences among the latter three groups were not statistically significant (P > 0.05). The optimal diagnostic cut-off point of serum VEGF and urine bFGF to differentiate proliferating hemangioma from involuting hemangioma, vascular malformation and controls was 99.6 pg/mg and 0.16 ng/mmol respectively. The area under ROC curve, the sensitivity and specificity were 99.7%, 99.3%, 99.7% and 91.9%, 98.7%, 71.1% respectively. The differences of the area under ROC curve of serum VEGF and urine bFGF showed no statistical significance (P > 0.05). Serum VEGF and urine bFGF are helpful for differentiating proliferating hemangioma from involuting hemangioma, vascular malformation and controls. Both parameters have higher values of clinical application.
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Gastric and gastro-esophageal junction adenocarcinoma (GEA) remains a considerable major public health problem worldwide, being the fifth most common cancer with a fatality-to-case ratio that stands still at 70%. Angiogenesis, which is a well-established cancer hallmark, exerts a fundamental role in cancer initiation and progression and its targeting has been actively pursued as a promising therapeutic strategy in GEA. A wealth of clinical trials has been conducted, investigating anti-angiogenic agents including VEGF-directed monoclonal antibodies, small molecules tyrosine kinase inhibitors and VEGF-Trap agents both in the resectable and advanced setting, reporting controversial results. While phase III randomized trials testing the anti-VEGFR-2 antibody Ramucirumab and the selective VEGFR-2 tyrosine kinase inhibitor Apatinib demonstrated a significant survival benefit in later lines, the shift of angiogenesis inhibitors in the perioperative and first-line setting failed to improve patients’ outcome in GEAs. The molecular landscape of disease, together with novel combinatorial strategies and biomarker-selected approaches are under investigation as key elements to the success of angiogenesis blockade in GEA. In this article, we critically review the existing literature on the biological rationale and clinical development of antiangiogenic agents in GEA, discussing major achievements, limitations and future developments, aiming at fully realizing the potential of this therapeutic approach.
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The vascular endothelial growth factor family has recently been expanded by the isolation of two new VEGF-related factors, VEGF-B and VEGF-C. The physiological functions of these factors are largely unknown. Here we report the cloning and characterization of mouse VEGF-C, which is produced as a disulfide-linked dimer of 415 amino acid residue polypeptides, sharing an 85% identity with the human VEGF-C amino acid sequence. The recombinant mouse VEGF-C protein was secreted from transfected cells as VEGFR-3 (Flt4) binding polypeptides of 30-32x10(3) Mr and 22-23x10(3) Mr which preferentially stimulated the autophosphorylation of VEGFR-3 in comparison with VEGFR-2 (KDR). In in situ hybridization, mouse VEGF-C mRNA expression was detected in mesenchymal cells of postimplantation mouse embryos, particularly in the regions where the lymphatic vessels undergo sprouting from embryonic veins, such as the perimetanephric, axillary and jugular regions. In addition, the developing mesenterium, which is rich in lymphatic vessels, showed strong VEGF-C expression. VEGF-C was also highly expressed in adult mouse lung, heart and kidney, where VEGFR-3 was also prominent. The pattern of expression of VEGF-C in relation to its major receptor VEGFR-3 during the sprouting of the lymphatic endothelium in embryos suggests a paracrine mode of action and that one of the functions of VEGF-C may be in the regulation of angiogenesis of the lymphatic vasculature.
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We have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs.
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Background. This clinicopathological study evaluated the utility of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 as predictors of locoregional recurrence and long-term disease-free survival in patients with gastric cancer. Methods. During the period January 1989 to December 1994, 485 patients with primary gastric cancer were evaluated. Gastrectomies were performed in 434 patients. Prognostic factors were analyzed by the Kaplan-Meier method and multivariate analysis, using Cox regression. Results. Elevated serum CEA and CA19-9 levels were observed in 92 of the 485 patients (19.0%), and in 95 of the 435 patients (21.8%), respectively, and both markers were elevated in 29 of these 435 patients (6.7%). Elevated serum CEA and CA19-9 levels correlated well with lymph node metastasis, lymphatic invasion, vessel invasion, stage grouping, depth of invasion, and curability. Patients with elevated serum CEA levels were at significantly higher risk of having all recurrence factors than were those with normal serum CEA levels. Patients with elevated serum CA19-9 levels were at significantly higher risk of having peritoneal metastases and distant metastases than were those with normal serum CA19-9 levels. A significant difference in the cumulative survival curves of patients was demonstrated between those with elevated and those with normal serum CEA or CA19-9 levels, even for patients at the same disease stage (stage III). Patients with elevated levels of both markers had a significantly worse prognosis than patients in whom the levels of both markers were normal. In patients who underwent gastrectomy, elevated serum CEA levels either preoperatively or within 3 weeks after gastrectomy were associated with significantly worse prognosis than were normal levels. When the cutoff level of serum CEA was increased to 10 ng/ml, serum CEA, age, lymph node metastasis, and surgical stage grouping were selected as independent prognostic factors by multivariate analysis of 14 prognostic factors, using Cox regression. Conclusion. Serum CEA and CA19-9 levels provide additional prognostic information in patients with primary gastric cancer. In particular, an elevated serum CEA level provides additional prognostic information and is a useful indicator of curability in patients who undergo gastrectomy. Serum CEA level is an independent prognostic factor in patients with primary gastric cancer.
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Lymphangiogenic growth factors vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to promote lymphatic metastasis by inducing tumor-associated lymphangiogenesis. In this study, we have investigated how tumor cells gain access into lymphatic vessels and at what stage tumor cells initiate metastasis. We show that VEGF-C produced by tumor cells induced extensive lymphatic sprouting towards the tumor cells as well as dilation of the draining lymphatic vessels, suggesting an active role of lymphatic endothelial cells in lymphatic metastasis. A significant increase in lymphatic vessel growth occurred between 2 and 3 weeks after tumor xenotransplantation, and lymph node metastasis occurred at the same stage. These processes were blocked dose-dependently by inhibition of VEGF receptor 3 (VEGFR-3) signaling by systemic delivery of a soluble VEGFR-3-immunoglobulin (Ig) fusion protein via adenoviral or adeno-associated viral vectors. However, VEGFR-3-Ig did not suppress lymph node metastasis when the treatment was started at a later stage after the tumor cells had already spread out, suggesting that tumor cell entry into lymphatic vessels is a key step during tumor dissemination via the lymphatics. Whereas lymphangiogenesis and lymph node metastasis were significantly inhibited by VEGFR-3-Ig, some tumor cells were still detected in the lymph nodes in some of the treated mice. This indicates that complete blockade of lymphatic metastasis may require the targeting of both tumor lymphangiogenesis and tumor cell invasion.
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Vascular endothelial growth factor (VEGF)-D and its homolog VEGF-C influence lymphangiogenesis through activation of VEGF receptor 3 (VEGFR-3), and have been implicated in lymphatic tumor spread. Nodal dissemination of gastric adenocarcinomas critically determines clinical outcome and therapeutic options of affected patients. Therefore, we analyzed expression and prognostic significance of VEGF-D along with VEGF-C, and VEGFR-3 in gastric adenocarcinomas. VEGF-C, VEGF-D, and VEGFR-3 were analyzed in 91 R(0)-resected primary gastric adenocarcinomas, corresponding noncancerous gastric mucosa, and lymph node metastases employing immunohistochemistry and/or in situ hybridization. Blood and lymph vessel densities were assessed after staining with CD31 and LYVE-1-specific antibodies. VEGF-D and VEGF-C were detected in 67.0% and 50.5% of gastric cancers, respectively. Healthy gastric mucosa was negative for VEGF-C and in 12.5% positive for VEGF-D. Presence of VEGF-D (P = .005) or VEGF-C (P = .006) was correlated with lymphatic metastases and decreased survival (VEGF-D, P < .05; VEGF-C, P < .05). VEGFR-3 was correlated with reduced carcinoma-specific survival (P < .05), and Cox multivariate regression analysis qualified VEGF-D and VEGFR-3, but not VEGF-C, as independent prognostic parameters. In lymph node-positive gastric cancers, presence of VEGF-D/VEGFR-3 was associated with poor survival, whereas absence of VEGF-D/VEGFR-3 defined a subgroup of patients with clearly favorable prognosis. VEGF-D and VEGFR-3 are novel independent prognostic marker molecules aiding to identify patients with poor prognosis after curative resection of gastric adenocarcinomas. Combined analysis of the VEGF-C/VEGF-D/VEGFR-3 system can be useful to identify patients with unfavorable clinical outcome and thereby may help to refine therapeutic decisions in gastric cancer.
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Both vascular endothelial growth factor (VEGF)-C and (VEGF)-D are ligands of VEGF receptor (VEGFR)-3 (Flt-4) and VEGFR-2 (KDR/FLK-1) and are supposed to participate in lymphangiogenesis. The purpose of this study was to clarify the clinical significance of the expression of these factors and to evaluate their relationship with prognosis in patients with gastric carcinoma. Fifty pairs of normal mucosa and cancer specimens were obtained from patients who had undergone gastrectomy for primary gastric carcinoma and subjected to reverse transcriptase-polymerase chain reaction for VEGF-C, VEGF-D, and VEGFR-3. Both VEGF-C and VEGF-D mRNA expression significantly correlated with lymphatic invasion (P < 0.05). Although VEGF-C and -D were concomitantly expressed in most cases, only VEGF-C expression was related to lymph node metastasis. VEGFR-3 expression was associated both with VEGF-C and VEGF-D expression, but not with lymph node metastasis. Tumors expressing these mRNAs tended to correlate with poorer prognosis, but the relationships were not statistically significant. Our study suggests that both VEGF-C and VEGF-D are involved in lymphatic spreading of gastric cancer cells, which is clinically useful for the evaluation of lymphatic invasion in patients with gastric carcinoma.
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A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer. We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival. ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P=0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P<0.001). In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival. (Current Controlled Trials number, ISRCTN93793971 [controlled-trials.com].).
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Clinical decisions for the treatment of localized gastric cancer have become much more sophisticated and complicated than ever. Two recent large-scale trials published in NEJM for East Asian 1 and Western patients 2 strongly support the routine use of adjuvant chemotherapy. However, differences in design, extent of surgery, kind of chemotherapy timing of administration, and survival results in the two trials as well as potential differences in genetic background of Asian and Western gastric caner patients raise critical questions and grow confusion and uncertainty. Which is the optimum update treatment for Western patients? Is the Japanese model with standardized D2 surgery followed by one year S-1 chemotherapy applicable in the West and can it produce similar excellent results or should treatment decisions be based on Western patients data from the UK MAGIC trial 2 and the USA INT-0116 trial? 3 This editorial approaches this critical question towards a live-saving decision. Emphasis is given to current advances in network biology, 4 cancer genome and functional studies 5–10 as well as a current comprehensive benchto-bedside genomic-based protocol for biomarkersbased personalized treatment of gastric cancer. 11 The landmark ACTS-GC Japanese study demonstrated excellent survival results with primary standardized D2 surgery followed by S-1 chemotherapy for advanced stages II and III. 1 Most patients (89%) had node-positive disease; these advanced tumor stages are associated with poor prognosis in the West. 12 Despite this advanced disease, the overall 3year survival rate was 70% after D2 surgery alone and 80% in the S-1 chemotherapy group. The hazard ratio for death in the S-1 group, as compared with the surgery-only group, was 0.68 (95% CI, 0.52–0.87; p = 0.003). Because of this significant survival difference the trial was stopped. Local control is now increasingly recognized to have a crucial role in the treatment strategy not only of gastric cancer 13–15 but also for many other solid tumor including breast cancer despite the use of adjuvant treatment. 16,17 Appropriate surgery alone
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Metastasis is the principal cause of cancer mortality, with the lymphatic system being the first route of tumor dissemination. The glycoproteins VEGF-C and VEGF-D are members of the vascular endothelial growth factor (VEGF) family, whose role has been recently recognized as lymphatic system regulators during embryogenesis and in pathological processes such as inflammation, lymphatic system disorders and malignant tumor metastasis. They are ligands for the VEGFR-3 receptor on the membrane of the lymphatic endothelial cell, resulting in dilatation of existing lymphatic vessels as well as in vegetation of new ones (lymphangiogenesis). Their determination is feasible in the circulating blood by immunoabsorption and in the tissue specimen by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Experimental and clinicopathological studies have linked the VEGF-C, VEGF-D/VEGFR3 axis to lymphatic spread as well as to the clinical outcome in several human solid tumors. The majority of these data are derived from surgical specimens and malignant cell series, rendering their clinical application questionable, due to subjectivity factors and post-treatment quantification. In an effort to overcome these drawbacks, an alternative method of immunodetection of the circulating levels of these molecules has been used in studies on gastric, esophageal and colorectal cancer. Their results denote that quantification of VEGF-C and VEGF-D in blood samples could serve as lymph node metastasis predictive biomarkers and contribute to preoperative staging of gastrointestinal malignancies.
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To analyze the serum levels and prognostic significance of vascular endothelial growth factor (VEGF) -A, -C, and -D, and their receptors, VEGFR-1 and -2 in gastric adenocarcinomas. The serum levels of VEGF family members were measured in 76 control subjects and 76 patients with gastric adenocarcinoma using an enzyme-linked immunosorbent assay (ELISA). These measurements were correlated with clinco-pathological features and survival rates. The serum levels of VEGF-A and its receptor, VEGFR-1, were significantly higher in patients with gastric cancer than in healthy donors (t = 2.3, P = 0.02 and t = 4.2, P < 0.0001, respectively). In contrast, the serum levels of VEGF-D were significantly higher in control subjects than in patients (t = 2.9, P = 0.004). There was no significant difference in serum levels of VEGF-C and VEGFR-2 between patients and controls. VEGF-C was associated with advanced tumor stage and presence of metastasis. VEGFR-1 was associated with metastasis, advanced overall stage, tumor differentiation and survival. VEGFR-2 levels were associated with poor tumor differentiation. There was no significant prognostic value for any of the VEGF family members or their receptors except for VEGFR-1 where high levels were associated with a poor overall survival. Serum VEGF levels vary significantly in the same cohort of patients with variable clinico-pathological features and prognostic values. The simultaneous measurement of VEGF receptors levels in sera may overcome the limitations of a single biomarker assay.
Article
Metastasis is the principal cause of cancer mortality, with the lymphatic system being the first route of tumor dissemination. The glycoproteins VEGF-C and VEGF-D are members of the vascular endothelial growth factor (VEGF) family, whose role has been recently recognized as lymphatic system regulators during embryogenesis and in pathological processes such as inflammation, lymphatic system disorders and malignant tumor metastasis. They are ligands for the VEGFR-3 receptor on the membrane of the lymphatic endothelial cell, resulting in dilatation of existing lymphatic vessels as well as in vegetation of new ones (lymphangiogenesis). Their determination is feasible in the circulating blood by immunoabsorption and in the tissue specimen by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Experimental and clinicopathological studies have linked the VEGF-C, VEGF-D/VEGFR3 axis to lymphatic spread as well as to the clinical outcome in several human solid tumors. The majority of these data are derived from surgical specimens and malignant cell series, rendering their clinical application questionable, due to subjectivity factors and post-treatment quantification. In an effort to overcome these drawbacks, an alternative method of immunodetection of the circulating levels of these molecules has been used in studies on gastric, esophageal and colorectal cancer. Their results denote that quantification of VEGF-C and VEGF-D in blood samples could serve as lymph node metastasis predictive biomarkers and contribute to preoperative staging of gastrointestinal malignancies.
Article
AIM: To investigate whether serum vascular endothelial growth factor-C (SVEGF-C), VEGF-C, and lymphatic vessel density (LVD) in tumor tissues are related to lymph node metastasis (LNM) and prognosis in gastric cancer. METHODS: SVEGF-C levels of 80 gastric cancer patients and 20 healthy donors were examined using ELISA. VEGF-C expression and LVD were examined using immunohistochemical staining. Kaplan-Meier survival analysis was performed to determine their influence on the prognosis of the patients. RESULTS: The SVEGF-C level in gastric cancer patients (595.9 ± 201.0 ng/L) was significantly higher (P = 0.000) than controls (360.0 ± 97.4 ng/L). Both SVEGF-C and LVD were significantly higher in poorly differentiated adenocarcinomas, T3 and T4, LNM, distant metastasis, and pTNM groups III and IV (P = 0.000). The sensitivity and specificity of SVEGF-C for predicting LNM were 82.8% and 81.8%, respectively (cut-off = 542.5 ng/L). The positive expression rate of VEGF-C was significantly higher in cancerous than in normal tissues (65% vs 20%; P = 0.001). VEGF-C expression up-regulation was significantly related to differentiation, depth of invasion, LNM, distant metastasis, and pTNM stage (P = 0.000). LVD was 10.7 ± 3.1/200 HP in the experimental group vs 4.9 ± 1.3/200 HP in controls (P = 0.000); LVD in cancerous tissues with and without LNM was 12.0 ± 2.7/200 HP vs 7.6 ± 0.5/200 HP, respectively (P = 0.000). SVEGF-C and LVD were significantly higher in VEGF-C positive than in negative patients (P = 0.000); SVEGF-C level was related to LVD (P = 0.000). Kaplan-Meier survival analysis factors predicating poor prognosis were: SVEGF-C level (P = 0.001), VEGF-C expression and LVD (both P = 0.000). CONCLUSION: SVEGF-C level, VEGF-C and LVD are related to LNM and poor prognosis of patients with gastric cancer. SVEGF-C may be a biomarker for LNM in gastric cancer.
Article
Lymph node metastasis is a major prognostic factor for patients with breast cancer. Vascular endothelial growth factors (VEGF)-C and VEGF-D are capable of stimulating lymphangiogenesis, and VEGF-C enhances lymphatic metastasis. The aim of the present study was to determine whether VEGF-C and VEGF-D messenger RNA (mRNA) expression is correlated with lymphatic invasion and lymph node metastasis in patients with breast cancer. Total RNAs were isolated from 33 surgical specimens of breast cancer tissue and 7 samples of normal breast tissue. VEGF-C and VEGF-D mRNA expression was measured by quantitative reverse transcription—polymerase chain reaction analysis. There was no correlation between VEGF-C mRNA expression and lymphatic invasion or lymph node metastasis. However, VEGF-D mRNA expression was decreased in cancer tissue, and it was inversely correlated with lymphatic invasion and the number of metastatic lymph nodes. An increased VEGF-C/VEGF-D ratio was also correlated with lymph node metastasis and the number of metastatic lymph nodes. Our results suggest that a decrease in VEGF-D mRNA or an increase in the VEGF-C/VEGF-D ratio may have an association with tumorigenesis and/or lymph node metastasis in breast cancer.
Article
Although serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are commonly measured before surgery for gastric carcinoma, this clinical significance is not fully understood. We evaluated a total of 549 patients with gastric cancer who underwent gastrectomy. Levels of CEA and CA19-9 were measured preoperatively in all patients. We retrospectively analyzed correlations between CEA or CA19-9 and clinicopathologic features, and estimated the prognostic utility of the tumor markers by analyzing clinicopathologic characteristics of the carcinoma as a function of seropositivity or negativity of the antigens in combination or by raising the levels. The positivity rates of CEA (≥5 ng/mL) and CA19-9 (≥37 U/mL) were 19.5% and 18%, respectively. Serum CEA and CA19-9 positivity significantly correlated with depth of invasion, hepatic metastasis, and curativity. Forty-nine patients positive for both CEA and CA19-9 had significantly higher frequencies of lymph node metastasis, deeper invasion by the tumor, lower rates of curative resection (p < 0.01), and higher rates of hepatic metastasis (p < 0.05) than 377 patients with normal levels of CEA and CA19-9. Surgical outcomes of patients who were CEA-and CA19-9-positive were poorer than those of patients with normal CEA and CA19-9 levels (p < 0.01). Significant correlation was found between serum CEA and CA19-9 level (p < 0.001, r = 0.24). Doubling the threshold level of serum positivity to 10 ng/mL (CEA) and 74 U/mL (CA19-9) improved the prognostic value of these factors. However, multivariate analysis using Cox's hazards model revealed that only CEA positivity using the doubled threshold value (10 ng/mL) (p = 0.04, hazard ratio =1.7), nodal involvement (p = 0.01, hazard ratio = 1.9), and depth of invasion (p = 0.02 hazard ratio =1.5) significantly predicted prognosis. Carcinoembryonic antigen positivity using the doubled threshold level (10 ng/mL) was an important prognostic factor in patients with gastric cancer.
Article
EUS is an integral part of the pretherapeutic evaluation program for patients with upper GI cancer. To evaluate the impact of EUS-guided FNA on the clinical management of patients with gastric cancer. The study included patients with confirmed gastric carcinoma who were referred to the Department of Surgical Gastroenterology, Gentofte Hospital, Copenhagen University, Copenhagen, Denmark, during a 6-year period (2001-2007). The patients underwent standard pretherapeutic evaluation. If no signs of incurability were detected, the patients were offered EUS and EUS-guided FNA. EUS-guided FNA was performed when lymph nodes or lesions were considered to be distant metastases. A board of surgeons was asked to evaluate the management of the patients after the results obtained by EUS-guided FNA were revealed. This study involved 234 patients with gastric carcinoma. EUS-guided FNA. Number of patients with distant metastasis diagnosed by EUS-guided FNA, with the avoidance of unnecessary surgery. A total of 81 consecutive patients underwent EUS-guided FNA. Ninety-nine lesions were targeted, and 61 (62%) of these lesions were found to be malignant. In 38 of 81 patients (42%) distant metastases were confirmed by EUS-guided FNA. As judged by the board of surgeons, EUS-guided FNA changed the management plan in 34 of 234 patients (15%). The positive EUS-guided FNA diagnoses were not surgically verified. EUS-guided FNA is a very important modality and should be integrated as a routine procedure in the preoperative staging algorithm of gastric cancer.
Article
Accurate assessment of lymph node status is of crucial importance for appropriate treatment planning and determining prognosis in patients with gastric cancer. The aim of this study was to systematically review the current role of imaging in assessing lymph node (LN) status in gastric cancer. A systematic literature search was performed in the PubMed/MEDLINE and Embase databases. The methodological quality and diagnostic performance of the included studies was assessed. Six abdominal ultrasonography (AUS) studies, 30 endoscopic ultrasonography (EUS) studies, 10 multidetectorrow computed tomography (MDCT) studies, 3 conventional magnetic resonance imaging (MRI) studies, 4 (18)F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) studies, and 1 FDG-PET/CT fusion study were included. In general, the included studies had moderate methodological quality. The sensitivity and specificity of AUS varied between 12.2% and 80.0% (median, 39.9%) and 56.3% and 100% (median, 81.8%). The sensitivity and specificity of EUS varied between 16.7% and 95.3% (median, 70.8%) and 48.4% and 100% (median, 84.6%). The sensitivity and specificity of MDCT varied between 62.5% and 91.9% (median, 80.0%) and 50.0% and 87.9% (median, 77.8%). The sensitivity and specificity of MRI varied between 54.6% and 85.3% (median, 68.8%) and 50.0% and 100% (median, 75.0%). The sensitivity and specificity of FDG-PET varied between 33.3% and 64.6% (median, 34.3%) and 85.7% and 97.0% (median, 93.2%). The sensitivity and specificity of the FDG-PET/CT fusion study were 54.7% and 92.2%. For all the imaging modalities, there were no significant differences between the mean sensitivities and specificities of high- and low-quality studies. AUS, EUS, MDCT, conventional MRI, and FDG-PET cannot reliably be used to confirm or exclude the presence of LN metastasis. The performance of highresolution PET/CT fusion and functional MRI techniques still has to be determined.
Article
The proliferation of lymphatic endothelial cells (LECs) occurs not only in tumor and inflamed tissues, but also in regional draining lymph nodes (LNs). The lymph node lymphangiogenesis (LNLG) has recently emerged as a prominent area in biomedical research, because it is involved in the pathogenesis of several human diseases. The LEC functional features and lymphatic remodeling regulated by lymphangiogenic factors actively promote tumor metastasis and the inflammation process. VEGF-A/VEGFR-2 and VEGF-C/-D/VEGFR-3 have been implicated as the prime mediators in inflammation- or tumor-induced LNLG. This knowledge may provide a foundation for further understanding of specific modification in the gene expression, cell migration, and differentiation of LECs and other cells in lymphatic-associated diseases. Importantly, it should be taken into consideration that inflammation and lymphangiogenesis are strongly linked in the formation and metastasis of cancer when designing therapeutic strategies.
Article
Vascular endothelial growth factors (VEGF)-C and -D play an important role in lymphangiogenesis, and the expressions of these factors are related to lymphatic invasion and lymph node metastasis in various malignant neoplasms. The present study investigates the expression of VEGF-C and -D in early gastric cancer and analyzes its relationship to lymph node micrometastasis determined by reverse transcription-polymerase chain reaction (RT-PCR). We examined 1,828 lymph nodes obtained from 80 patients with node-negative early gastric cancer. All dissected lymph nodes were examined by RT-PCR for CEA mRNA in addition to hematoxylin-eosin staining. The resected primary specimens were immunostained using anti-VEGF-C and -D polyclonal antibodies. The incidence of lymph node micrometastasis determined by RT-PCR was 23.8% (19/80). The high expression of VEGF-C and -D was found in 27.5% (22/80) and in 21.3% (17/80), respectively. The expression of VEGF-C and -D was closely related to lymph node micrometastasis (P = 0.0390 and 0.0213, respectively). We demonstrated a close relationship between micrometastasis and VEGF-C and -D expression of the primary tumor. Thus, levels of VEGF-C and -D expression might be useful for predicting micrometastasis in patients with early gastric cancer.
Article
Vascular endothelial growth factor-C (VEGF-C) is one of the most potent lymphangiogenic members of the VEGF family that has been associated with lymph node metastasis and poor prognosis in patients with colorectal cancer (CRC). In this study, we evaluated the relationship of preoperative serum VEGF-C (sVEGF-C) and survival in CRC patients. sVEGF-C levels were determined, prior to resection, in a cohort of 120 newly presenting patients with CRC by quantitative ELISA. Patients who had positive lymph node involvement and higher Dukes' staging (C&D) were associated with shorter time to metastases as expected (p = 0.002 and 0.001, respectively). Patients with distant metastasis had significantly lower levels of sVEGF-C than those without histopathologically proven disease (p = 0.004). However, there was no significant difference in the median sVEGF-C level in patients with or without lymph node metastatic involvement (91 pg/ml vs. 124 pg/ml; p = 0.81). Patients with a sVEGF-C concentration less than the median value (103 pg/ml) showed a poorer overall survival than patients with sVEGF-C levels greater than the median; but this was not statistically significant. In this study, low sVEGF-C levels are associated with distant metastasis; hence, preoperative levels may aid in the selection of CRC patients who require further investigation.
Article
Neogenesis of lymphatic vessel and lymphatic invasion is frequently found in the stroma of cancers, but the mechanisms of this phenomenon remain unclear. Vascular endothelial growth factor C (VEGF-C) is known to be the only growth factor for the lymphatic vascular system, and its receptor has been identified as Flt4. To clarify the mechanism of lymphatic invasion in cancer, we studied the expression of VEGF-C and flt4 genes in gastric cancer tissues. VEGF-C mRNA was mainly expressed in primary tumors (15 of 32; 47%), but the frequency of VEGF-C mRNA expression was low in normal mucosa (4 of 32; 13%). In primary tumors, there was a significant relationship between VEGF-C and flt4 mRNA expression. In contrast, Flt4 was mainly expressed on the lymphatic endothelial cells but not in cancer cells. A strong correlation was found between VEGF-C expression and lymph node status, lymphatic invasion, venous invasion, and tumor infiltrating patterns. Cancer cells in the lymphatic vessels frequently showed intracytoplasmic VEGF-C immunoreactivity. Furthermore, there was a close correlation between VEGF-C tissue status and the grade of lymph node metastasis. Patients with high expression of VEGF-C protein had a significantly poorer prognosis than did those in low VEGF-C expression group. By the Cox regression model, depth of wall invasion, lymph node metastasis, and VEGF-C tissue status emerged as independent prognostic parameters, and the VEGF-C tissue status was ranked third as an independent risk factor for death. These results strongly suggest that cancer cells producing VEGF-C may induce the proliferation and dilation of lymphatic vessels, resulting in the development of invasion of cancer cells into the lymphatic vessel and lymph node metastasis.
Article
Vascular endothelial growth factors (VEGFs) C and D are novel members of the VEGF family that show some selectivity toward lymphatic endothelial cells. Recent studies suggest that VEGF-C may be involved in lymphangiogenesis and spread of cancer cells via lymphatic vessels. However, whether other VEGF family members play a role in lymph node metastasis is largely unknown. The aim of the present study was to explore whether expressions of VEGF-A, VEGF-B, VEGF-C, and VEGF-D are correlated with lymph node status in lung adenocarcinoma. Total RNA was isolated from 60 surgical specimens of lung adenocarcinoma with (n = 27) or without (n = 33) lymph node metastasis. The relative mRNA abundance of VEGF-A, VEGF-B, VEGF-C, and VEGF-D was measured by real-time reverse transcription-PCR analysis based on TaqMan fluorescence methodology. We found that, as single factors, expression of none of the four VEGF family members clearly correlated with the presence of lymph node metastasis. The only tendency noted was for higher VEGF-B and VEGF-C and lower VEGF-D levels in the node-positive group. However, two-way scatterplot analysis revealed that tumors with lymph node metastasis were associated with a pattern of low VEGF-D and high VEGF-A, VEGF-B, or VEGF-C, such that the ratios of VEGF-D:VEGF-A, VEGF-D:VEGF-B, or VEGF-D:VEGF-C were significantly lower in the node-positive group. Strikingly, none of the 11 tumors with high VEGF-D levels metastasized to lymph nodes. Furthermore, a low VEGF-D:VEGF-C ratio correlated with the presence of lymphatic invasion, and six of seven tumors with a pattern of very high expression of VEGF-C and low expression of VEGF-D displayed lymph vessel invasion that extended along the bronchovascular tree beyond the main tumor. Finally, levels of VEGF-A, but not VEGF-B or VEGF-C, were higher in tumors with large nodal metastasis (> or = 1 cm) than in those with small (< 1 cm) nodal metastasis. These results support the hypothesis that two VEGF family members are involved in lymph node metastasis at two distinct steps; VEGF-C facilitates entry of cancer cells into the lymph vasculature, whereas VEGF-A promotes the growth of metastatic tumor through angiogenesis. The results also suggest that the balance between VEGF-C and VEGF-D could be important rather than the level of VEGF-C alone. Whether a low VEGF-D level plays a causative role in lymph node metastasis requires further investigation.
Article
The aim of this longitudinal study was to evaluate the effectiveness of the serum tumor markers CEA, CA 19-9, and CA 72-4 in the early diagnosis of recurrence of gastric cancer. One hundred and thirty-three patients who had undergone potentially curative surgery were considered. Serum samples were obtained preoperatively, 1 week after surgery, and at every follow-up examination. Mean follow-up time for the entire patient population was 41 +/- 33 months, and 71 +/- 27 months for patients classified as disease-free. Preoperative positivity was 16% for CEA, 35% for CA 19-9, and 20% for CA 72-4. Recurrence of disease was found in 75 patients (56%). Marker sensitivity in recurrent cases was 44% for CEA, 56% for CA 19-9, and 51% for CA 72-4; the combined use of the three markers increased sensitivity to 87%, which reached 100% in patients with positive preoperative levels. Marker specificity, evaluated in 58 disease-free patients, was 79% for CEA, 74% for CA 19-9, and 97% for CA 72-4. The combined assay of CEA, CA 19-9, and CA 72-4 may be useful for early diagnosis of recurrence of gastric cancer; however, only CA 72-4 positivity should be considered a specific predictor of tumor recurrence.
Article
Angiogenic factors play a major role in tumor growth and metastasis. The purpose of this study was to clarify the prognostic significance of the expression of vascular endothelial growth factor (VEGF) and VEGF-C in gastric carcinoma. Formalin-fixed and paraffin embedded sections of tumor tissue were obtained from 76 patients who underwent curative gastrectomy for gastric carcinoma. Immunohistochemical staining for VEGF and VEGF-C was performed. VEGF and VEGF-C were positively expressed in 39 and 45% of the patients, respectively. No correlation existed between VEGF and VEGF-C expressions. VEGF expression was significantly correlated with venous invasion. VEGF-C expression was significantly correlated with lymphatic and venous invasion. Patients with positive staining for VEGF showed a significantly lower survival rate than VEGF negative patients. After subdivision, according to the combination of VEGF and VEGF-C expression, VEGF-C expression had a significant unfavorable impact on prognosis among patients with negative staining for VEGF. The expression of VEGF and/or VEGF-C was independent prognostic determinant by the multivariate survival analysis. The positive expression for VEGF and/or VEGF-C was an important prognostic determinant after curative gastrectomy for gastric carcinoma. VEGF-C may stimulate the tumor progression in the absence of VEGF.
Article
Preoperative serum levels of sialyl Lewis(a) (CA19-9), sialyl Lewis(x) (SLX) and sialyl Tn (STN) antigens in 180 patients with gastric cancer were examined to establish predictive factors for serum levels of these antigens compared with carcinoembryonic antigen (CEA). The patients were divided into low and high antigen groups. Multivariate logistic regression analysis revealed the following independent predictive factors for high antigen levels [odds ratio]: liver metastasis for CA19-9 [4.40], SLX [9.90], STN [39.65] and CEA [5.14]; peritoneal dissemination for SLX [4.78] or STN [13.01]; venous invasion for CEA [3.56]; lymph node metastasis for CA19-9 [4.51]. In addition, high CA19-9 levels were independently related to lymph node metastasis in patients with stage I or II tumors. In conclusion, high serum levels of CA19-9, SLX and STN are associated with liver metastasis, while high serum levels of SLX and STN are associated with peritoneal dissemination. In addition, high serum CA19-9 levels may represent an independent predictor for lymph node metastasis.
Article
Lymph node metastasis is a major prognostic factor for patients with breast cancer. Vascular endothelial growth factors (VEGF)-C and VEGF-D are capable of stimulating lymphangiogenesis, and VEGF-C enhances lymphatic metastasis. The aim of the present study was to determine whether VEGF-C and VEGF-D messenger RNA (mRNA) expression is correlated with lymphatic invasion and lymph node metastasis in patients with breast cancer. Total RNAs were isolated from 33 surgical specimens of breast cancer tissue and 7 samples of normal breast tissue. VEGF-C and VEGF-D mRNA expression was measured by quantitative reverse transcription-polymerase chain reaction analysis. There was no correlation between VEGF-C mRNA expression and lymphatic invasion or lymph node metastasis. However, VEGF-D mRNA expression was decreased in cancer tissue, and it was inversely correlated with lymphatic invasion and the number of metastatic lymph nodes. An increased VEGF-C/VEGF-D ratio was also correlated with lymph node metastasis and the number of metastatic lymph nodes. Our results suggest that a decrease in VEGF-D mRNA or an increase in the VEGF-C/VEGF-D ratio may have an association with tumorigenesis and/or lymph node metastasis in breast cancer.
Article
Surgeons disagree about the merits and risks of radical lymph node clearance during gastrectomy for cancer. To evaluate survival and peri-operative mortality after limited or extended lymph node removal during gastrectomy for cancer. We searched MEDLINE, EMBASE, CancerLit, LILACS, Central Medical Journal Japanese Database and the Cochrane register, references from relevant articles and conference proceedings. We contacted known workers in the field. Studies published after 1970 which reported 5 year survival or postoperative mortality rates, and clearly defined the node dissection performed, were considered. We excluded studies which overtly included patients receiving perioperative chemotherapy, and comparisons with clear systematic treatment allocation bias. Randomised controlled trials (RCTs), non-randomised comparisons and observational studies were considered separately. Three reviewers selected trials for inclusion. Quality assessment and data extraction were performed independently by two reviewers. Results of trials of similar design were pooled. Meta-analysis was performed separately for randomised and non-randomised comparisons. Two randomised and two non-randomised comparisons of limited (D1) versus extended (D2) node dissection and 11 cohort studies of either D1 or D2 resection were analysed. Meta-analysis of randomised trials did not reveal any survival benefit for extended lymph node dissection (Risk ratio = 0.95 (95% CI 0.83 - 1.09), but showed increased postoperative mortality (RR 2.23, 95% CI 1.45 - 3.45). Pre-specified subgroup analysis suggested a possible benefit in stage T3+ tumours (RR = 0.68, 95% CI 0.42-1.10). Non-randomised comparisons showed no significant survival benefit for extended dissection (RR 0.92, 95% CI 0.83 -1.02), but decreased mortality (RR 0.65, 95% CI 0.45-0.93). Subgroup analysis showed apparent benefit in UICC stage II and IIIa. Observational studies of D2 resection reported much better mortality and survival than those of D1 surgery, but the settings were strikingly different. D2 dissection carries increased mortality risks associated with spleen and pancreas resection, and probably with inexperience and low case volumes. Randomised studies show no evidence of overall survival benefit, but possible benefit in T3+ tumours. These results may be confounded by surgical learning curves and poor surgeon compliance. Non-randomised comparisons suggest a possible survival benefit for D2 in intermediate UICC stages. Observational studies show high 5 year survival and low operative mortality after D2 dissection in experienced units, and poor results after D1 dissection in non-specialist units. Further studies, with precautions to eliminate learning curve effects, contamination and non-compliance, are needed to evaluate D2 dissection in intermediate stage gastric cancer.
Article
Vascular endothelial growth factor C (VEGF-C) and D (VEGF-D) are considered to be potentially lymphangiogenic and can selectively induce hyperplasia of the lymphatic vasculature. In this study, we aimed to clarify the relation between expression of VEGF-C and -D and lymphatic metastasis in early gastric cancers. Using the specific antibodies, we classified 105 cases which were treated as gastrectomy with standard lymphadenectomy at the First Department of Surgery, Tokyo University Hospital, between 1994 and 2001, into three groups (diffuse type, focal type and negative type) for VEGF-C and two groups (positive and negative) for VEGF-D. There was a significant correlation between the expression of VEGF-C and -D and lymphatic invasion but not with venous invasion. All of the 22 cases that were negative for VEGF-C and -D were histologically classified as adenocarcinoma of undifferentiated type and showed negative lymph node metastasis and also negative lymphatic invasion. VEGF-C was positive in all tumors of differentiated type, while its expression varied in tumors of undifferentiated type. The VEGF-D positive rate is much lower than that of VEGF-C. In undifferentiated tumors in particular, VEGF-D was positive only in 4/64 (6%) and three of these four had nodal metastasis. Therefore, in tumors of differentiated type, expression of VEGF-C and -D had no clinical relevance. In tumors of undifferentiated type, the negative expression of VEGF-C suggests lack of nodal metastasis, while the positive expression of VEGF-D suggests nodal metastasis. The lymph node metastasis was significantly related to the expression of VEGF-C and -D in adenocarcinomas of undifferentiated type but not in those of differentiated tumors. In early gastric cancers of histologically undifferentiated type with negative expression of VEGF-C and -D, limited surgery might be safely applied because the possibility of nodal metastasis is very low. These observations are based only on retrospective analysis of a small case series and further evaluation with a larger number of cases is necessary.
Article
Vascular endothelial growth factor (VEGF) and VEGF-C play a crucial role in the regulation of tumor growth and metastasis. The current study examined the significance of serum VEGF and VEGF-C levels in relation to conventional clinicopathologic parameters, response to treatment, and survival in patients with cervical carcinoma. Between December 1999 and March 2004, serum VEGF and VEGF-C levels were analyzed in 78 patients with cervical carcinoma undergoing primary treatment (primary surgery [n=40] and radiotherapy [n=38]), as well as in 30 healthy controls. Serum VEGF and VEGF-C levels were assessed by enzyme-linked immunosorbent assay before and within 2 weeks after treatment. Serum VEGF and VEGF-C levels were higher in patients with cervical carcinoma than in the healthy control (P=0.0002 and P=0.0007, respectively). Both VEGF and VEGF-C concentrations increased significantly in patients with squamous cell carcinoma (SCC vs. normal control: P<0.0001 and P=0.0001, respectively), but not in adenocarcinoma (vs. normal control: P=0.2982 and P=0.7766, respectively). In an analysis of SCC, the pretherapeutic serum levels of VEGF and VEGF-C correlated significantly with advanced International Federation of Gynecology and Obstetrics stage and large tumor size, but not with lymph node metastasis. The pretherapeutic serum level of VEGF-C also correlated significantly with disease recurrence or persistence after treatment. Both serum VEGF and VEGF-C levels decreased significantly after treatment. The serum levels of both VEGF and VEGF-C have potential usefulness as biologic markers of SCC of the uterine cervix.
Article
The spread of tumor cells to regional lymph nodes is an early event of gastric cancer metastasis. In our study, we assessed the expression of lymphangiogenic factors and lymphatic endothelial markers in gastric carcinoma tissues and compared expression levels with the status of lymph node metastasis. We also examined the correlation between lymphatic vessel density (LVD) in primary tumors and lymph node metastasis. Paired biopsy samples (tumor and corresponding normal mucosa) of gastric tissue were obtained from 39 patients with gastric carcinoma. The expression of VEGF-C, VEGF-D, VEGFR-3 and podoplanin mRNAs was assessed by real-time quantitative PCR. The expression of VEGF-C (but not of VEGF-D) was significantly greater in patients with lymph node metastasis than in those without metastasis. The expression of lymphatic endothelial markers VEGFR-3 and podoplanin was also significantly greater in the node-positive group. LVD, as assessed by immunohistochemistry for podoplanin, was correlated with lymph node metastasis. These results indicate that quantitative analysis of lymphangiogenic markers in gastric biopsy specimens may be useful in predicting metastasis of gastric cancer to regional lymph nodes.
Article
Vascular endothelial growth factor (VEGF)-C and VEGF-D are angiogenic and lymphangiogenic members of the VEGF family of growth factors. Increased VEGF-C or VEGF-D expression in human tumours may be associated with lymph-node metastasis and lymphatic invasion. Circulating plasma levels of VEGF-A, VEGF-C and VEGF-D were measured in patients with colorectal cancer, and assessed for their usefulness as a diagnostic tool for determining lymph-node metastasis. One hundred and twenty patients with colorectal cancer and 50 healthy control patients were included in the study. Plasma growth-factor levels were assessed by enzyme-linked immunosorbent assays. No significant differences in plasma VEGF-C or VEGF-D levels were seen between patients subgrouped by clinicopathological variables. In particular, there were no differences in median plasma VEGF-C or VEGF-D level in patients with and without lymph-node involvement (VEGF-C: 11.2 U/ml [range, 4.9-51.9] vs 9.9 U/ml [4.4-93.4 U/ml]; P = 0.90; VEGF-D: 335 pg/ml [113-1102] vs 316.5 pg/ml [0-1343]; P = 0.68). Circulating plasma levels of VEGF-C and VEGF-D do not allow pre-operative identification of lymph-node status in patients with colorectal cancer.
Article
The molecular mechanisms of lymphangiogenesis induced by vascular endothelial growth factor (VEGF)-C and VEGF-D in gastric cancer were studied. VEGF-C and VEGF-D gene expression vectors were transfected into the gastric cancer cell line KKLS, which did not originally express VEGF-C and VEGF-D, and stable transfectants (KKLS/VEGF-C and KKLS/VEGF-D) were established. The cell lines were inoculated into the subserosal layer of the stomach and subcutaneous tissue of nude mice. VEGF-C and VEGF-D expression in KKLS/VEGF-C and KKLS/VEGF-D cells was found by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. Expression of mouse VEGF receptor (VEGFR)-2 and mouse VEGFR-3 mRNA was detected in the KKLS/VEGF-C and KKLS/VEGF-D gastric tumors. Newly formed lymphatic vessels were detected not only in the periphery but also in the center of the tumors. The intratumor lymphatic vessels connected with the preexisting lymphatic vessels in the muscularis mucosa. The average numbers of lymphatic vessels in KKLS/VEGF-C (52.0 +/- 9.5) and KKLS/VEGF-D (16.4 +/- 0.6) gastric tumors were significantly higher than that in the KKLS/control vector tumors (4.0 +/- 1.4). VEGF-C and VEGF-D may induce neoformation of lymphatic vessels in experimental gastric tumors by the induction of VEGFR-3 expression.
Article
This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice and Economics Committee. The paper was approved by the Committee on April 22, 2005, and by the AGA Governing Board on October 6, 2005.
Article
Five-year survival of gastric cancer is 10% in Western countries compared with over 50% in Japan. This is because the disease is not identified in the West until later in its evolution. T1 cancer has an excellent prognosis, but most of the patients either have no symptoms or complain of long-standing, non-specific dyspepsia; alarm symptoms, when identified, usually indicate that the cancer is already inoperable. Early gastric cancer is infrequently diagnosed in the West because the low prevalence of gastric cancer means that endoscopists do not search with the same diligence as they do in Japan. A further barrier is the widespread prescription of proton pump inhibitors that heal malignant ulcers and diminish symptoms, thus rendering them more difficult to identify clinically and endoscopically. An improvement in diagnosis may be achieved by newer endoscopy technology which enables cancers to be identified more easily, or by an inexpensive screening test to select patients with extensive gastric atrophy, thereby identifying those at risk who can then be screened endoscopically.
Article
In August 2004, the United Kingdom Department of Health advisory body published dyspepsia referral guidelines for primary care practitioners. These guidelines advised empiric treatment with antisecretory medications and referral for endoscopy only in the presence of alarm symptoms. The current study aimed to evaluate the effect of these guidelines on the detection of esophagogastric cancer. The study reviewed a prospectively compiled database of 4,018 subjects who underwent open access gastroscopy during the years 1990 to 1998. The main outcome measures for the study were cancer detection rates, International Union Against Cancer (UICC) stage, and survival. Gastroscopy identified esophagogastric carcinoma in 123 (3%) of the 4,018 subjects. Of these 123 patients, 104 (85%) with esophagogastric cancer had "alarm" symptoms (anemia, mass, dysphagia, weight loss, vomiting) and would have satisfied the referral criteria. The remaining 15% would not have been referred for initial endoscopic assessment because their symptoms were those of uncomplicated "benign" dyspepsia. The patients with "alarm" symptoms had a significantly more advanced tumor stage (metastatic disease in 47% vs 11%; p < 0.001), were less likely to undergo surgical resection (50% vs 95%; p < 0.001), and had a poorer survival (median, 11 vs 39 months; p = 0.01) than their counterparts without such symptoms. The use of alarm symptoms to select dyspeptics for endoscopy identifies patients with advanced and usually incurable esophagogastric cancer. Patients with early curable cancers often have only dyspeptic symptoms, and their diagnosis will be delayed until the symptoms of advanced cancer develop.
Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer
  • Y Yonemura
  • Y Endo
  • H Fujita
Yonemura Y, Endo Y, Fujita H, et al.: Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer. Clin Cancer Res 1999;5:1823–1829.
Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma
  • Niki T S Iba
  • M Tokunou
Niki T, Iba S, Tokunou M, et al.: Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma. Clin Cancer Res 2000;6:2431–2439.
VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development
  • Kukk
Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma
  • Niki
Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer
  • Yonemura