Risk factors for lymph node metastasis in patients with pancreatic neuroendocrine neoplasms

BACKGROUND Although PNENs generally have a better prognosis than pancreatic cancers,some PNENs display malignant behavior including lymph node(LN)metastasis.Complete tumor resection can be the only potentially curative treatment for patients with resectable PNENs.However,the indications for LN dissection are still controversial.Over the last decade,minimally invasive surgery such as laparoscopic pancreatic surgery(LPS)has been increasingly performed for pancreatic tumors including PNENs.AIM To investigate the risk factors for LN metastasis in PNENs and to select appropriate patients for limited surgery by LPS.METHODS From April 2001 to December 2019,92 patients underwent pancreatic resection for PNENs at Kumamoto University Hospital.Finally,82 patients were enrolled in this study.Using perioperative factors,we examined the predictive factors for LN metastasis in PNENs.RESULTS Among the 82 patients,the percentage of LN metastasis according to the pathological findings was 12%(10/82 cases).The median tumor size was 12 mm(range:5-90 mm).The median tumor size in the LN-positive group(37 mm)was significantly larger than that in the LN-negative group(12 mm)(P=0.0001).Multivariate analyses revealed that larger tumor size(≥20 mm)was an independent risk factor for LN metastasis(odds ratio 16.8,P=0.0062).In patients with small tumors(≤10 mm),LN metastasis was not found.CONCLUSION Larger tumor size(≥20 mm)is an independent risk factor for LN metastasis in PNENs.In smaller PNENs(≤10 mm),we may be able to choose limited surgery without LN dissection.

Prediction of risk factors for lymph node metastasis in early gastric cancer

AIM:To explore risk factors for lymph node metastases in early gastric cancer(EGC) and to confirm the appropriate range of lymph node dissection.METHODS:A total of 202 patients with EGC who underwent curative gastrectomy with lymphadenectomy in the Department of Surgery,Xinhua Hospital and Ruijin Hospital of Shanghai Jiaotong University Medical School between November 2003 and July 2009,were retrospectively reviewed.Both the surgical procedure and the extent of lymph node dissection were based on the recommendations of the Japanese gastric cancer treatment guidelines.The macroscopic type was classified as elevated(type Ⅰ or Ⅱa),flat(Ⅱb),or depressed(Ⅱc or Ⅲ).Histopathologically,papillary and tubular adenocarcinomas were grouped together as differentiated adenocarcinomas,and poorly differentiated and signet-ring cell adenocarcinomas were regarded as undifferentiated adenocarcinomas.Univariate and multivariate analyses of lymph node metastases and patient and tumor characteristics were undertaken.RESULTS:The lymph node metastases rate in patients with EGC was 14.4%.Among these,the rate for mucosal cancer was 5.4%,and 8.9% for submucosal cancer.Univariate analysis showed an obvious correlation between lymph node metastases and tumor location,depth of invasion,morphological classification and venous invasion(χ 2 = 122.901,P = 0.001;χ 2 = 7.14,P = 0.008;χ 2 = 79.523,P = 0.001;χ 2 = 8.687,P = 0.003,respectively).In patients with submucosal cancers,the lymph node metastases rate in patients with venous invasion(60%,3/5) was higher than in those without invasion(20%,15/75)(χ 2 = 4.301,P = 0.038).Multivariate logistic regression analysis revealed that the depth of invasion was the only independent risk factor for lymph node metastases in EGC [P = 0.018,Exp(B) = 2.744].Among the patients with lymph node metastases,29 cases(14.4%) were at N1,seven cases were at N2(3.5%),and two cases were at N3(1.0%).Univariate analysis of variance revealed a close relationship between the depth of invasion and lymph node metastases at pN 1(P = 0.008).CONCLUSION:The depth of invasion was the only independent risk factor for lymph node metastases.Risk factors for metastases should be considered when choosing surgery for EGC.

Study on the risk factors of lymphatic metastasis and the indications of less invasive operations in early gastric cancer

The principle of surgical treatment for gastric cancer is the radical resectioning although the suitable resecting range for different cases of gastric cancer is still being argued upon[1-9]. However, the diagnostic accuracy of early gastric cancer (EGC) without lymphatic metastasis has obviously improved with an improvement in the diagnostic technique and due to the accumulation of knowledge on the biological profiles of EG C[10-17]. The D2 lymph node excision was used as a regular operation to treat the EGC previously. But the concept for the EGC without lymphatic metastasis has gradually changed and the less invasive resections has been applied in some cases[18-20]. This study aimed at investigating the risk factors of lymphatic metastasis in EGC in order to find out the proofs for the suitable indications for less invasive operations such as endoscopic mucosal resectioning (EMR), laparoscopic and laparotomic resectioning.

Factors related to lymph node metastasis and surgical strategy used to treat early gastric carcinoma

AIM:The prognosis of early gastric carcinoma (EGC) is generally excellent after surgery. The presence or absence of lymph node metastasis in EGC is an important prognostic factor. The survival and recurrence rates of node-negative EGC are much better than those of node-positive EGC. This study examined the factors related to lymph node metastasis in EGC to determine the appropriate treatment for EGC.METHODS: We investigated 748 patients with EGC who underwent surgery between January 1985 and December 1999 at the Division of Gastroenterologic Surgery, Department of Surgery, Chonnam National University Hospital. Several clinicopathologic factors were investigated to analyze their relationship to lymph node metastasis: age, sex, tumor location, tumor size, gross type, histologic type, depth of invasion, extent of lymph node dissection, type of operation,and DNA ploidy.RESULTS:Lymph node metastases were found in 75 patients (10.0%). Univariate analysis showed that male sex, tumor size larger than 2.0cm, submucosal invasion of tumor, histologic differentiation, and DNA ploidy pattern were risk factors for regional lymph node metastasis in EGC patients. However, a multivariate analysis showed that three risk factors were associated with lymph node metastasis:large tumor size, undifferentiated histologic type and submucosal invasion. No statistical relationship was found for age, sex, tumor location, gross type, or DNA ploidy in multivariate analysis. The 5-year survival rate was 94.2% for those without lymph node metastasis and 87.3% for those with lymph node metastasis, and the difference was significant (P<0.05).CONCLUSION: In patients with EGC, the survival rate of patients with positive lymph nodes is significantly worse than that of patients with no lymph node metastasis. Therefore,a standard D2 lymphadenectomy should be performed in patients at high risk of lymph node metastasis: large tumor size, undifferentiated histologic type and submucosal invasion.

Expression of connective tissue growth factor in tumor tissues is an independent predictor of poor prognosis in patients with gastric cancer

AIM: To examine the expression of connective tissue growth factor (CTGF), also known as CCN2, in gastric carcinoma (GC), and the correlation between the expression of CTGF, clinicopathologic features and clinical outcomes of patients with GC. METHODS: One hundred and twenty-two GC patients were included in the present study. All patients were followed up for at least 5 years. Proteins of CTGF were detected using the Powervision two-step immunostaining method. RESULTS: Of the specimens from 122 GC patients analyzed for CTGF expression, 58 (58/122, 47.5%) had a high CTGF expression in cytoplasm of gastric carcinoma cells and 64 (64/122, 52.5%) had a low CTGF expression. Patients with a high CTGF expression showed a higher incidence of lymph node metastasis than those with a low CTGF expression (P = 0.032). Patients with a high CTGF expression had significantly lower 5-year survival rate than those with a low CTGF expression (27.6% vs 46.9%, P = 0.0178), especially those staging Ⅰ+Ⅱ+Ⅲ (35.7% vs 65.2%, P = 0.0027). CONCLUSION: GC patients with an elevated CTGF expression have more lymph node metastases and a shorter survival time. CTGF seems to be an independent prognostic factor for the successful differentiation of high-risk GC patients staging Ⅰ+Ⅱ+Ⅲ. Over-expression of CTGF in human GC cells results in an increased aggressive ability.

Analysis of lymph node metastasis and survival prognosis in early gastric cancer patients: A retrospective study

BACKGROUND Early gastric cancer(EGC)is a common malignant tumor of the digestive system,and its lymph node metastasis and survival prognosis have been concerning.By retrospectively analyzing the clinical data of EGC patients,we can better under-stand the status of lymph node metastasis and its impact on survival and prog-nosis.AIM To evaluate the prognosis of EGC patients and the factors that affect lymph node METHODS The clinicopathological data of 1011 patients with EGC admitted to our hospital between January 2015 and December 2023 were collected in a retrospective cohort study.There were 561 males and 450 females.The mean age was 58±11 years.The patient underwent radical gastrectomy.The status of lymph node metastasis in each group was determined according to the pathological examination results of surgical specimens.The outcomes were as follows:(1)Lymph node metastasis in EGC patients;(2)Analysis of influencing factors of lymph node metastasis in EGC;and(3)Analysis of prognostic factors in patients with EGC.Normally distributed measurement data are expressed as mean±SD,and a t test was used for comparisons between groups.The data are expressed as absolute numbers or percentages,and the chi-square test was used for comparisons between groups.Rank data were compared using a nonparametric rank sum test.A log-rank test and a logistic regression model were used for univariate analysis.A logistic stepwise regression model and a Cox stepwise regression model were used for multivariate analysis.The Kaplan-Meier method was used to calculate the survival rate and construct survival curves.A log-rank test was used for survival analysis.RESULTS Analysis of influencing factors of lymph node metastasis in EGC.The results of the multifactor analysis showed that tumor length and diameter,tumor site,tumor invasion depth,vascular thrombus,and tumor differentiation degree were independent influencing factors for lymph node metastasis in patients with EGC(odds ratios=1.80,1.49,2.65,5.76,and 0.60;95%CI:1.29–2.50,1.11–2.00,1.81–3.88,3.87-8.59,and 0.48-0.76,respectively;P<0.05).Analysis of prognostic factors in patients with EGC.All 1011 patients with EGC were followed up for 43(0–13)months.The 3-year overall survival rate was 97.32%.Multivariate analysis revealed that age>60 years and lymph node metastasis were independent risk factors for prognosis in patients with EGC(hazard ratio=9.50,2.20;95%CI:3.31-27.29,1.00-4.87;P<0.05).Further analysis revealed that the 3-year overall survival rates of gastric cancer patients aged>60 years and≤60 years were 99.37%and 94.66%,respectively,and the difference was statistically significant(P<0.05).The 3-year overall survival rates of patients with and without lymph node metastasis were 95.42%and 97.92%,respectively,and the difference was statistically significant(P<0.05).CONCLUSION The lymph node metastasis rate of EGC patients was 23.64%.Tumor length,tumor site,tumor infiltration depth,vascular cancer thrombin,and tumor differentiation degree were found to be independent factors affecting lymph node metastasis in EGC patients.Age>60 years and lymph node metastasis are independent risk factors for EGC prognosis.

Lymph node metastasis in gastric cardiac adenocarcinoma in male patients

AIM:To reveal the clinicopathological features and risk factors for lymph node metastases in gastric cardiac adenocarcinoma of male patients.METHODS:We retrospective reviewed a total of 146male and female patients with gastric cardiac adenocarcinoma who had undergone curative gastrectomy with lymphadenectomy in the Department of Surgery,Xin Hua Hospital and Rui Jin Hospital of Shanghai Jiaotong University Medical School between November2001 and May 2012.Both the surgical procedure and extent of lymph node dissection were based on the recommendations of Japanese gastric cancer treatment guidelines.Univariate and multivariate analyses of lymph node metastases and the clinicopathological features were undertaken.RESULTS:The rate of lymph node metastases in male patients with gastric cardiac adenocarcinoma was72.1%.Univariate analysis showed an obvious correlation between lymph node metastases and tumor size,gross appearance,differentiation,pathological tumor depth,and lymphatic invasion in male patients.Multivariate logistic regression analysis revealed that tumor differentiation and pathological tumor depth were the independent risk factors for lymph node metastases in male patients.There was an obvious relationship between lymph node metastases and tumor size,gross appearance,differentiation,pathological tumor depth,lymphatic invasion at pN1and pN2,and nerve invasion at pN3in male patients.There were no significant differences in clinicopathological features or lymph node metastases between female and male patients.CONCLUSION:Tumor differentiation and tumor depth were risk factors for lymph node metastases in male patients with gastric cardiac adenocarcinoma and should be considered when choosing surgery.

FEASIBILITY OF WHOLE BODY DIFFUSION WEIGHTED IMAGING IN DETECTING BONE METASTASIS ON 3.0T MR SCANNER

Objective To evaluate the feasibility of whole body diffusion weighted imaging (DWI) in bone metastasis detection using bone scintigraphy as comparison. Methods Forty-five patients with malignancy history were enrolled in our study. All the patients received the whole body DWI and bone scintigraphy scan within 1 week. The magnetic resonance (MR) examination was performed on 3.0T MR scanner using embedded body coil. The images were reviewed separately by two radiologists and two nuclear medicine physicians, who were blinded to the results of the other imaging modality. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the two techniques for detecting bone metastasis were analyzed. Results A total of 181 metastatic lesions in 77 regions of 34 patients were detected by whole body DWI, and 167 metastatic lesions in 76 regions of 31 patients were identified by bone scintigraphy. The patient-based sensitivity and PPV of whole body DWI and bone scintigraphy were similar (89.5% vs. 81.6%, 97.1% vs. 91.2%), whereas, the patient-based specificity and NPV of whole body DWI were obviously higher than those of bone scintigraphy (85.7% vs. 57.1%, 60.0% vs. 36.4%). Ten regions negative in scintigraphy but positive in whole body DWI, mainly located in spine, pelvis, and femur; nine regions only detected by scintigraphy, mainly located in skull, sternum, clavicle, and scapula. The region-based sensitivity and specificity of whole body DWI were slightly higher than those of bone scintigraphy (89.5% vs. 88.4%, 95.6% vs. 87.6%). Conclusion Whole body DWI reveals excellent concordance with bone scintigraphy regarding detection of bone metastasis, and the two techniques are complementary for each other.

Establishment and validation of a nomogram to predict the risk of ovarian metastasis in gastric cancer: Based on a large cohort

BACKGROUND Ovarian metastasis is a special type of distant metastasis unique to female patients with gastric cancer.The pathogenesis of ovarian metastasis is incompletely understood,and the treatment options are controversial.Few studies have predicted the risk of ovarian metastasis.It is not clear which type of gastric cancer is more likely to metastasize to the ovary.A prediction model based on risk factors is needed to improve the rate of detection and diagnosis.AIM To analyze risk factors of ovarian metastasis in female patients with gastric cancer and establish a nomogram to predict the probability of occurrence based on different clinicopathological features.METHODS A retrospective cohort of 1696 female patients with gastric cancer between January 2006 and December 2017 were included in a single center,and patients with distant metastasis other than ovary and peritoneum metastasis were excluded.Potential risk factors for ovarian metastasis were analyzed using univariate and multivariable logistic regression.Independent risk factors were chosen to construct a nomogram which received internal validation.RESULTS Ovarian metastasis occurred in 83 of 1696 female patients.Univariate analysis showed that age,Lauren type,whether the primary lesion contained signet-ring cells,vascular tumor emboli,T stage,N stage,the expression of estrogen receptor,the expression of progesterone receptor,serum carbohydrate antigen 125 and the neutrophil-to-lymphocyte ratio were risk factors for ovarian metastasis of gastric cancer(all P<0.05).Multivariate analysis showed that age<50 years,Lauren typing of non-intestinal,gastric cancer lesions containing signet-ring cell components,N stage>N2,positive expression of estrogen receptor,serum carbohydrate antigen 125>35 U/mL,and a neutrophil-to-lymphocyte ratio>2.16 were independent risk factors(all P<0.05).The independent risk factors were constructed into a nomogram model using R language software.The consistency index after continuous correction was 0.840[95%confidence interval:(0.7740.906)].After the internal self-sampling(Bootstrap)test,the calibration curve of the model was obtained with an average absolute error of 0.007.The receiver operating characteristic curve of the obtained model was drawn.The area under the curve was 0.867,the maximal Youden index was 0.613,the corresponding sensitivity was 0.794,and the specificity was 0.819.CONCLUSION The nomogram model performed well in the prediction of ovarian metastasis.Attention should be paid to the possibility of ovarian metastasis in high-risk populations during re-examination,to ensure early detection and treatment.

The Expression of VEGF-C and It’s Receptor VEGFR-3 Correlates with Lymph Node Metastasis in Gastric Cancer

Background: Regional lymph node invasion and metastasis may happen early during the progres-sion of gastric cancer. The lymphadenectomy is still the key method to treat lymph nodemetastasis. In the recent years, scientists have found some growth factors and receptors that can promote angiogenesis which also play an important role in adjusting the formation of the new lymph vessel, and lymphangiogenesis may play a key role in the process of lymph node metastasis. Objectives: This study aims to explore the correlation between the expression of vascular endothelial growth factor-C (VEGF-C), vascular endothelial growth factor receptor 3 (VEGFR-3) and lymph node me-tastasis (LNM), and its impact on prognosis of patients with gastric cancer. Methods: The samples were collected from gastric cancer database of Sichuan Provincial People’s Hospital from 2005 to 2007, which were registered and followed up. The samples were divided into two groups according to situation whether there is lymph node metastasis, which is lymph node metastasis N(+) and without lymph node metastasis N(﹣). The expression of VEGF-C, VEGFR-3 and CD34 were measured by immuno histochemistry staining with monoclonal antibody (anti-VEGF-C, anti-VEGFR-3, and anti-CD34). Kaplan-meier, logistic and Cox regression was performed to explore their impact on the prognosis of patients with gastric cancer. Results: In total 186 cases were collected, 96 cases in N(+) group and 90 cases in N(﹣) group. The percentage of VEGF-C expression is 54.83% (102/186) in all groups, 73.9% (71/96) in N(+) group, and 34.44% (31/90) in N(﹣) group (p = 0.001). The percentage of VEGFR-3 expression is 33.33% (62/186) in all groups, 44.78% (43/96) in N(+) group, and 21.11% (19/90) in N(﹣) group (p = 0.001). There are no statistical differences in microvessel density (MVD) between N(﹣) and N(+) group. The average lymphatic vessel density (LVD) was significant different between N(+) and N(﹣) group (26.23 ± 8.2 and 18.46 ± 7.4, t = ﹣2.427, p = 0.016). The five-year overall survival rate of N(+) group is 31% and the N(﹣) group is 66%;there are statistical differences between the two groups (Log rank = 27.15, p = 0.001). The five-year overall survival rates of VEGF-C positive group and VEGF-C negative group are 36% and 59%, with the statistical differences (Log rank = 27.15, p = 0.001). And the five-year overall survival rates of VEGFR-3 positive group and VEGFR-3 negative group are 31% and 43%, also with the statistical differences (Log rank = 5.241, p = 0.041). Conclusions: The expressions of VEGF-C, VEGFR-3 in cell plasma of gastric cancer tissue not only correlate with lymphatic vessel density and lymph node metastasis (LNM), but also are important factors which impact prognosis of gastric cancer patients.

Relationship between Lymphatic Vessel Density and Lymph Node Metastasis of Invasive Micropapillary Carcinoma of the Breast

OBJECTIVE To investigate the relationship between lymphatic vessel density and lymph node metastasis of invasive micropapillary carcinoma (IMPC) of the breast. METHODS The immunohistochemical study for vascular endothelial growth factor-c (VEGF-C), VEGF Receptor-3 (VEGFR-3) and lymphatic vessel density of 51 cases of IMPC were performed, and lymph node metastases were examined by microscopic analysis of these cases. RESULTS In IMPC, VEGF-C was expressed in the cytoplasm and/or on the membrane of the tumor cells, and the expression of VEGF-C showed a positive correlation with lymph node metastasis (P<0.01). Lymphatic vessel density was determined by the number of micro-lymphatic vessels with VEGFR-3 positive staining. Lymphatic vessel density was positively correlated with VEGF-C expression (P<0.01) and lymph node metastasis (P<0.01). The percentage of IMPC in the tumor was not associated with the incidence of lymph node metastasis. The metastatic foci in lymph nodes were either pure or predominant micropapillary carcinoma. CONCLUSION The results suggested that VEGF-C overexpression stimulated tumor lymphangiogenesis, and the increased lymphatic vessel density may be the key factor that influenced lymph node metastasis of IMPC.

Expression of splice variants of CD44 in tumor－adjacent tissue of human primary liver cancer

The expression of metastasis-associated splice variants of CD44 in tumor-adjacent tissue was studied in 31 patients with primary liver cancer. In the patients with more metastatic evidence of liver cancer, the expression of splice variants of CD44 was found higher in tumor-adjacent tissue than in tumor tissue itself, suggesting that the expression of splice variants of CD44 in tumor-adjacent tissue may be a more useful indicator than that in turnor tissue itself for evaluating metastatic potential of primary liver cancer.

Role of tissue factor in hepatocellular carcinoma genesis, invasion and metastasis

Background Numerous studies indicate that tissue factor （TF）, namely tissue thromboplastin, has a close relationship with malignant tumor genesis and progress. It contributes to blood coagulation as well as the regulation of cellular differentiation, the formation of blood vessels, and also tumor recurrence and metastasis. The present study aimed to detect TF expression in hepatocellular carcinoma （HCC） patients and to elucidate its association with prognosis and clinical features of the disease. Methods The plasma TF levels of 50 HCC patients and 30 controls were assayed by ELISA. The expressions of TF mRNA and protein in HCC tissues, adjacent tissues and normal tissues were detected by reverse transcription- polymerase chain reaction （RT-PCR） and Western blotting. The acquired data were analyzed with related clinic-pathological documents. The patients were followed up for five years, and the relationship between TF and prognosis was analyzed. Results The plasma TF levels were significantly increased in HCC compared to the controls （P 〈0.05）, presenting a close relationship with differentiation level, tumor size and hepatocirrhosis occurrence （P 〈0.05）. There were remarkably higher values in cases of lymphatic metastasis, extrahepatic metastasis and portal tumor thrombus （PTT） （P 〈0.05） compared to non-metastasis or non-tumor thrombus, but no significant difference with different focus number or envelope （P 〉0.05）. The positive rates and the relative expression of TF mRNA in HCC tissue were 63.0% （17/27） and 0.567±0.268, respectively, significantly higher than that in adjacent tissues or normal tissues （P 〈0.05）. In the patients with positive results, the relative expression intensity varied significantly with different tumor size and index of local invasion and metastasis （P 〈0.05）. The positive rates and the relative expression intensities of TF protein in HCC tissue were 74.1% （20/27） and 4.093±1.256, respectively, significantly higher than those in adjacent tissue or normal tissue （P 〈0.05）. In the patients with positive results, the relative expression intensity showed significant difference in different tumor size, differentiation level, and index of local invasion and metastasis （P 〈0.05）. Conclusions The TF levels were significantly higher in plasma and tissues of HCC patients, presenting a close relationship with the index of invasion and metastasis. It indicated that TF might be related to differentiation and metastasis of HCC.

Correlation of integrin β3 mRNA and vascular endothelial growth factor protein expression profiles with the clinicopathological features and prognosis of gastric carcinoma

AIM： To investigate integrin β3 mRNA and vascular endothelial growth factor （VEGF） protein expression in gastric carcinoma, and its correlation with microvascular density, growth-pattern, invasion, metastasis and prognosis. METHODS： In situ hybridization（ISH） of integrin β3 mRNA and immunohistochemistry of VEGF and CD34 protein were performed on samples from 118 patients with gastric cancer. RESULTS： The positive rate of integrin β3 mRNA in non-tumor gastric mucosa （20%） was significantly lower than that of the gastric cancer tissue （52.5%, X^2 = 10.20, P 〈 0.01）. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the positive expression rates of integrin β3 mRNA were significantly higher than those in patients of expanding type （P 〈 0.01）, stage T1-T2 （P 〈 0.01）, non-vessel invasion （P 〈 0.01）, without lymphatic metastasis （P 〈 0.01）, without hepatic and peritoneal metastasis （P 〈 0.01）, respectively. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the positive expression rates of VEGF protein were significantly higher than those in patients of expanding type （P 〈 0.01）, stage T1-T2 （P 〈 0.01）, non-vessel invasion （P 〈 0.01）, without lymphatic metastasis （P 〈 0.01）, without hepatic and peritoneal metastasis （P 〈 0.01）, respectively. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the mean MVD were significantly higher than those in patients of expanding type （P 〈 0.01）, stage T1-T2 （P 〈 0.01）, non-vessel invasion （P 〈 0.01）, without lymphatic metastasis （P 〈 0.01）, without hepatic and peritoneal metastasis （P 〈 0.01）, respectively. It was found that the positive expression rate of integrin β3 mRNA was positively related to that of VEGF protein （P 〈 0.01） and MVD （P 〈 0.05）, meanwhile the positive expression rate of VEGF protein was positively related to MVD （P 〈 0.05）. The mean survival period in patients with positive expression of integrin β3 mRNA and VEGF, and MVD ≥54.9/mm^2 was significantly shorter than that in patients with negative expression of integrin β3 mRNA （P 〈 0.05） and VEGF （P 〈 0.01）, and MVD 〈 54.9/mm^2 （P 〈 0.01）. Five-year survival rate in patients with positive expression of integrin β3 mRNA and VEGF, and MVD ≥54.9/mm^2 was significantly lower than those with negative expression of integrin β3 mRNA （P 〈 0.05）, VEGF （P 〈 0.05）, and MVD 〈 54.9/mm^2 （P 〈 0.01）. CONCLUSION： Integrin β3 and VEGF expression can synergistically enhance tumor angiogenesis, and may play a crucial role in invasion and metastasis of gastric carcinoma. Therefore, they may be prognostic biomarkers and novel molecular therapeutic targets.

Expression of Vascular Endothelial Growth Factor-C and Vascular Endothelial Growth Factor Receptor-3 in Ovarian Epithelial Tumors

Objective： To explore the role of vascular endothelial growth factor-C （VEGF-C） in the process of angiogenesis, lymphangiogenesis and lymphatic metastasis in epithelial ovarian tumors. Methods： In situ hybridization and immunohistochemical staining for VEGF-C were performed in 30 epithelial ovarian carcinomas, 9 borderline tumors and 26 benign tumors. Endothelial cells were immunostained with anti-VEGFR-3 pAb and anti-CD31 mAb, and VEGFR-3 positive vessels and microvessel density （MVD） were assessed by image analysis. Results： VEGF-C mRNA and protein expression were detected in cytoplasm of carcinoma cells. VEGF-C mRNA and protein expression in ovarian epithelial carcinomas were significantly higher than those in borderline tumors and benign tumors （P〈0.05 or P〈0.01）. In ovarian epithelial carcinomas, VEGF-C protein expression, VEGFR-3 positive vessels and MVD were significantly higher in the cases of clinical stage Ⅲ-Ⅳ and with lymph node metastasis than those of clinical stage Ⅰ-Ⅱ and without lymph node metastasis respectively （P〈0.05 or P〈0.01）. VEGFR-3 positive vessels and MVD were significantly higher in VEGF-C protein positive tumors than negative tumors （P〈0.05）. VEGFR-3 positive vessels was significantly correlated with MVD（P〈0.01）. Conclusion： VEGF-C might play a role in lymphatic metastasis via lymphangiogenesis and angiogenesis in epithelial ovarian tumors, and VBEGF-C could be used as a biologic marker of metastasis in ovarian epithelial tumors.

甲状腺乳头状癌被膜侵犯患者中央区淋巴结转移风险因素列线图预测模型的建立及验证

目的探讨甲状腺乳头状癌(PTC)伴被膜侵犯时中央区淋巴结转移(centrallymphnodemetastasis,CLNM)的相关因素,并构建临床列线图预测模型,为临床诊治提供理论依据。方法回顾性分析2020年10月~2023年10月保定市第一中心医院普外科收治的PTC侵犯被膜患者的临床资料,包括性别、年龄、体重指数(BMI)、纵横比、肿瘤位置、多灶性、微钙化、合并桥本甲状腺炎(Hashimoto thyroiditis,HT)和肿瘤直径。根据是否出现CLNM分为正常组(107例)和转移组(108例),对数据进行单因素及多因素分析,构建可视化列线图预测模型,并绘制受试者工作特征(ROC)曲线评估模型诊断效能。采用重复抽样1000次的Bootstrap检验对列线图模型进行内部验证。一致性指数(consistency index,C-index)和校准曲线来表示模型的预测性能和预测准确度。最后绘制临床决策曲线(DCA)判断模型的临床应用能力。结果共纳入215例PTC伴被膜侵犯患者,其中108例(50.23%)发生CLNM。单因素分析显示CLNM发生与患者肿瘤直径、纵横比>1、肿瘤位于下极、多灶性和合并HT有关(P<0.05)。多因素回归分析显示,肿瘤直径、纵横比>1、肿瘤位于下极和多灶性是CLNM的独立危险因素(OR=1.401、1.875、2.291、2.303,P<0.05),合并HT是CLNM的保护因素(OR=0.501,P<0.05)。基于以上危险因素构建PTC伴被膜侵犯患者发生CLNM的列线图预测模型,ROC曲线显示:曲线下面积AUC为0.859,95%CI:0.792~0.925,约登指数为0.734,敏感度为0.878,特异度为0.856,模型有较高的预测价值。内部验证C-index=0.83(95%CI:0.748~0.959)。校正曲线显示预测值靠近理想曲线,有较好一致性,在DCA曲线中该模型在临床效能表现良好。结论当PTC伴被膜侵犯时,肿瘤较大、纵横比>1、肿瘤位于下极、多灶性提示发生CLNM的风险较高,而合并HT是发生CLNM的保护因素。基于以上危险因素构建的列线图模型有较高的区分度和校准度,有助于临床医师术前评估和术中探查,以便尽早对高危患者进行预防和治疗。

cN0级单侧甲状腺乳头状癌患者对侧气管旁淋巴结转移临床特征的Meta分析

目的分析临床淋巴结阴性(clinically node-negative,cN0)的单侧甲状腺乳头状癌(papillary thyroid cancer,PTC)患者发生对侧中央区淋巴结转移(contralateral central lymph node metastasis,CCLNM)临床危险因素,为预防性中央区淋巴结清扫(prophylactic central lymph node dissection,PCLND)的范围提供依据。方法检索PubMed、Cochrane Library、Web of Science、EMBASE、CNKI数据库中公开发表研究cN0单侧PTC患者CCLNM临床特征的相关文献,截至时间为2023年9月,采用RevMan5.4、Stata15.1软件进行数据分析。结果共纳入14篇文献,包括3532例患者。所有患者CCLNM发生率范围为3.9%~30.6%。分析结果提示:男性(OR=1.65,95%CI=1.28~2.11)、肿瘤直径≥1 cm(OR=2.88,95%CI=2.30~3.60)、年龄≤55岁(OR=2.10,95%CI=1.15~3.82)、包膜受累(OR=1.63,95%CI=1.04~2.57)、腺外侵犯(OR=1.76,95%CI=1.31~2.36)、脉管侵犯(OR=4.23,95%CI=2.25~7.98)、同侧中央区淋巴结转移(OR=10.83,95%CI=5.56~21.10)、喉前淋巴结转移(OR=4.32,95%CI=2.66~7.02)、气管前淋巴结转移(OR=6.67,95%CI=2.06~21.54)患者更容易发生CCLNM(P均<0.05)。而未发现肿瘤多灶性、桥本甲状腺炎、BRAF基因突变、MACIS≥6、超声回声、超声血流与CCLNM相关。结论男性、肿瘤直径≥1 cm、年龄≤55岁、包膜受累、腺外侵犯、脉管侵犯、同侧中央区淋巴结转移、喉前淋巴结转移、气管前淋巴结转移是发生CCLNM的重要危险因素,这些因素可作为cN0单侧PTC患者PCLND的程度指标。

Liuwei Dihuang pill suppresses metastasis by regulating the wnt pathway and disrupting β-catenin/T cell factor interactions in a murine model of triple-negative breast cancer

OBJECTIVE:To investigate if the Liuwei Dihuang pill(LWDHP)can inhibit metastasis to the liver and lungs in mice bearing triple-negative breast cancer(TNBC),and the molecular mechanism underpinning this action.METHODS:Ninety-nine TNBC bearing-mice were distributed randomly to five groups:control(Con),paclitaxel(PTX),low-dose LWDHP(LLP,2.3 g·kg^-1·d^-1),middle-dose LWDHP(MLP,4.6 g·kg^-1·d^-1)and high-dose LWDHP(HLP,9.2 g·kg^-1·d^-1).The LWDHP were administered(p.o.)to the agonal stage.The morphology of BC cells was observed by hematoxylin&eosin staining.Expression of axin-2,β-catenin,T cell factor(TCF),cyclin-D1 and vascular endothelial growth factor(VEGF)was detected by western blotting or immunofluorescence.β-catenin/TCF-1 interaction was measured using a co-immunoprecipitation assay.RESULTS:After LWDHP treatment,metastasis of BC cells to the lungs and liver was inhibited,expression of axin-2 was increased,expression of TCF-1,β-catenin,cyclin-D1 and VEGF was decreased,andβ-catenin/TCF-1 interaction was disrupted.CONCLUSION:The LWDHP could inhibit metastasis of BC cells to the liver and lungs.The molecular mechanism underlying this action may be regulation of protein expression andβ-catenin/TCF-1 interactions in the Wnt pathway.

Extrahepatic synthesis of coagulation factor Ⅶ by colorectal cancer cells promotes tumor invasion and metastasis

Background Blood coagulation factor Ⅶ （FⅦ） is physiologically synthesized in the liver and released into the blood. Binding of FⅦ to tissue factor （TF） is related to the metastatic potential of tumor cells, also a significant risk factor in the development of hepatic metastasis in patients with colorectal cancer （CRC）. It has been found that some cancer cells can produce FⅦ extrahepatically. However, litte is known about FⅦ and CRC. We therefore hypothesized that CRC cells may synthese FⅦ, leading to tumor invasion and metastasis.Methods We detected the expression of FⅦ protein in 55 CRC specimens by immunohistochemical staining. The FⅦ mRNA in 45 of 55 CRC cases, 6 colon cancer cell lines and one hepatoma cell line was measured by real-time reverse transcription-PCR （RT-PCR）. Transwell invasion assays were performed to evaluate the changes of cell migration and invasion of LoVo cancer cells in vitro. We further observed the likely effectors regulated by the TF/FⅦa complex Western blotting assay.Results Extrahepatic synthesis of FⅦ was detected in the cytoplasm of 32 （58.2%） CRC specimens byimmunohistochemistry, but not in normal mucosa. Liver metastasis （P=0.003） and TNM staging （P=0.005） were significantly correlated with FⅦ antigen expression. The positive ratios in stages Ⅰ, Ⅱ, Ⅲ and Ⅳ were 33.3%, 40.0%,52.4% and 87.5%, respectively. The expression of FⅦ mRNA in CRC with hepatic metastasis was significantly higher than CRC without hepatic metastasis （5.33±2.88 vs. 1.47±0.51, P=0.03）. Ectopic FⅦa induced a slight increase （1.34-fold） in the number of migrating cells, which was inhibited by the specific TF antibody. The formation of TF/FⅦacomplex resulted in a marked increase in the expression of matrix metalloproteinases （MMP）-2 （3.5-fold） and MMP-9（4.7-fold） in a time-dependent and dose-dependent manner.Conclusions Extrahepatic synthesis of FⅦ by CRC cells may promote tumor invasion and metastasis. MMPs, as downstream effectors of TF/FⅦa signaling, facilitate the development of metastasis in colon cancer.