Serum VEGF-D Levels Research Articles

Association of proteinuria with improved prognosis in unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab, and the predictive role of serum vascular endothelial growth factorD levels: A multicenter retrospective study.

Atezolizumab/bevacizumab is a first-line therapy for unresectable hepatocellular carcinoma (HCC). Among several adverse events, grade ≥2 proteinuria is considered a significant adverse event that may cause bevacizumab interruption. Studies have shown that proteinuria might predict improved prognosis, although data are scarce and the association remains controversial, and the mechanisms and predictive factors remain unclear. We aimed to clarify these. In this multicenter retrospective study, we screened patients with HCC treated with atezolizumab/bevacizumab. The prognostic impact of grade ≥2 proteinuria was examined in patients with proper clinical data and preserved serum for growth factor analysis. For biomarker analysis predicting proteinuria, baseline serum vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D levels were analyzed. This study included 75 patients, and 32 (42.7%) experienced grade ≥2 proteinuria. No significant differences were observed between those with or without proteinuria, except for aspartate transaminase and alanine transaminase levels. Time-dependent Cox proportional hazards analysis revealed that grade ≥2 proteinuria was significantly associated with better prognosis (hazard ratio 0.221; 95% confidence interval 0.082-0.592; p=0.003). In biomarker analysis, low baseline serum VEGF-C and VEGF-D levels were significantly associated with proteinuria, and multivariate analysis demonstrated that baseline serum VEGF-D level was significantly associated with grade ≥2 proteinuria (hazard ratio 0.101; 95% confidence interval 0.029-0.357; p<0.001). Grade ≥2 proteinuria in patients with unresectable HCC treated with atezolizumab/bevacizumab indicates a better prognosis, and baseline serum VEGF-D levels can help predict its occurrence. These findings can help in managing adverse events and prognosis in advanced HCC treated with atezolizumab/bevacizumab.

Evaluation of maternal serum vascular endothelial growth factor C and D levels in intrahepatic cholestasis of pregnancy.

This study aimed to investigate maternal serum vascular endothelial growth factor (VEGF) C and D levels in patients with intrahepatic cholestasis of pregnancy (ICP). A total of 83 patients, including 41 patients with ICP and 42 healthy pregnant women, were included in the study. We first compared the maternal serum VEGF-C and VEGF-D levels between the ICP and control groups and then examined the correlation between the serum VEGF-C level and the bile acid level in patients with severe ICP. We observed statistically significantly higher serum VEGF-C levels and lower VEGF-D levels in the ICP group compared with the healthy controls (P < 0.001 and P = 0.015, respectively). According to receiver operating characteristic analysis, the optimal cutoff value for ICP was 147 ng/mL in the determination of the VEGF-C level (specificity and sensitivity: 76%). In patients with severe ICP, the serum VEGF-C statistically significantly correlated with the bile acid level (P = 0.019). This study showed that the maternal serum VEGF-C level was higher and the VEGF-D level was lower in patients with ICP compared with healthy pregnant women. We also found that the VEGF-C level was correlated with the serum bile acid level in patients with severe ICP. Serum VEGF-C level can be used in the diagnosis and follow-up of intrahepatic pregnancy cholestasis.

Changes in Serum Growth Factors during Resistance to Atezolizumab Plus Bevacizumab Treatment in Patients with Unresectable Hepatocellular Carcinoma.

The possible mechanisms of resistance to atezolizumab/bevacizumab for unresectable HCC, and the subsequent response to these therapies, remain underexplored. The sequential changes in serum growth factors, including VEGF-A, VEGF-C, VEGF-D, ANG-2, FGF-19, HGF, and EGF during atezolizumab/bevacizumab for unresectable HCC were evaluated in 46 patients. Patients who experienced PD after CR, PR, or SD to atezolizumab/bevacizumab were evaluated. A total of 4, 9, 19, and 14 patients showed CR, PR, SD, and PD, respectively. Of 32 patients with disease control, 28 experienced PD after CR, PR, or SD with atezolizumab/bevacizumab. Baseline growth factor levels were similar between patients with or without disease control and those with or without an objective response. Growth factor changes between the baseline and the best overall response points (BOR) for patients with disease control showed that FGF-19 significantly increased and ANG2 significantly decreased at the BOR. Growth factor changes between the BOR and the PD point in 28 patients who experienced PD after disease control showed that VEGF-D and ANG2 significantly increased at the PD point compared with that at the BOR. Summarily, increased serum VEGF-D and ANG-2 levels might contribute to developing resistance to atezolizumab/bevacizumab for unresectable HCC and might be target molecules in subsequent salvage therapies.

Serum VEGF-D level is correlated with renal dysfunction and proteinuria in patients with diabetic chronic kidney disease.

Biomarkers associated with chronic kidney disease (CKD) may play a crucial role in the early diagnosis of diabetic kidney disease. However, there have been few reports published on serum vascular endothelial cell growth factor (VEGF)-D in patients with diabetic CKD. We divided patients with diabetic CKD into two groups: CKD 3–4 and CKD 5. In total, 42 patients with diabetic kidney disease and seven healthy controls without diabetes mellitus were enrolled in this study. An observational study was conducted to evaluate the serum VEGF-D levels and other clinical parameters in each group and to assess the relationship among these factors. The serum levels of VEGF-D were higher in the CKD 3–4 group and CKD 5 group than in the control group. However, there was no significant difference in serum levels of VEGF-D between CKD stage 3–4 group and CKD stage 5 group. Correlation analysis showed that serum VEGF-D was negatively correlated with estimated glomerular filtration rate but positively correlated with serum creatinine, urine albumin-to-creatinine ratio, and urine protein-to-creatinine ratio. Serum VEGF-D was a good biomarker in receiver operating characteristic analysis and independently associated with CKD stages in multiple linear regression analysis. Circulating VEGF-D was positively correlated with blood growth/differentiation factor-15, endostatin, and chemokine (C-X-C motif) ligand 16 levels. Serum VEGF-D levels were correlated with renal dysfunction, albuminuria, and proteinuria in patients with diabetic kidney disease. Elucidation of the role of VEGF-D as a biomarker requires further study.

Serum vascular endothelial growth factors C and D as forecast tools for patients with gallbladder carcinoma.

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.

VEGF-D and A Preoperative Serum Levels Predict Nodal and Distant Metastases in Differentiated Thyroid Cancer Patients.

Preoperative tumor aggressiveness biomarkers may help surgeons decide the extent of an operation. However, whether serum angiogenetic factors can be used to predict the prognosis of patients with differentiated thyroid cancer is still unclear. Seventy-six DTC patients were prospectively recruited. Preoperative serum samples were collected and measured for Tie-2, Ang-1, Ang-2, VEGF-A, and VEGF-D levels. The potential correlations between their serum levels and clinicopathologic features as well as their prognoses were analyzed. Older age (>45 years old) and higher VEGF-A serum levels were independent predictors of extrathyroidal extension. The VEGF-D serum level was an independent factor for lymph node metastases and VEGF-A was an independent factor for distant metastases. None of these serum angiogenetic factors were significantly different between patients who were disease free and those with recurrences. The presence of lymph node metastases was the only independent factor for recurrence over the 2-year follow-up. Preoperative serum VEGF-A and VEGF-D levels were significantly elevated in DTC patients with distant and lymph node metastases. These findings, when combined with other clinicopathological factors, may help in surgical decisions.

Similar Trends in Serum VEGF-D Levels and Kidney Angiomyolipoma Responses with Longer Duration Sirolimus Treatment in Adults with Tuberous Sclerosis

ContextWe have previously shown that serum VEGF-D is elevated at baseline, correlates with kidney angiomyolipoma size at baseline and 12 months, and decreases with sirolimus treatment in adults with tuberous sclerosis complex (TSC). To further investigate the utility of serum VEGF-D for longer term monitoring of TSC kidney disease, we present VEGF-D level results with 24 month follow-up.ObjectiveTo compare 24 month VEGF-D levels in two subgroups of sirolimus treated patients (OFF SIROLIMUS AFTER 12 MONTHS or ON SIROLIMUS AFTER 12 MONTHS).Design and Intervention(s)Serum VEGF-D was measured in samples collected from subjects enrolled in a phase 2 multicenter trial evaluating sirolimus for the treatment of kidney angiomyolipomas associated with TSC or TSC/LAM. All participants were treated with sirolimus from 0–12 months. During months 12–24, sirolimus was discontinued in one subgroup. The other subgroup was treated with additional sirolimus.SettingAdult TSC participants were recruited from six clinical sites in the United States (comprehensive TSC clinics, 5; urology clinic, 1).PatientsThere were 28 TSC patients who completed all 24 months of the study and serum samples were available at 24 months from 18/28 patients.Main Outcome Measure(s)We compared the percent change in VEGF-D levels (baseline to 24 months) in patients from the two treatment subgroups.ResultsAt 24 months, VEGF-D levels decreased by 67% compared with baseline (to 787±426 pg/ml) in the ON SIROLIMUS AFTER 12 MONTHS group versus a 13% decrease (to 2971±4014 pg/ml) in the OFF SIROLIMUS AFTER 12 MONTHS group (p = 0.013, Mann-Whitney test). A similar trend was observed in kidney angiomyolipoma size but not in pulmonary function tests. Conclusions Serum VEGF-D may be useful for monitoring response to treatment with sirolimus and kidney angiomyolipoma size in patients with TSC, but confirmation is needed.Trial RegistrationClinical trials.gov NCT00126672.

Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease

BackgroundTuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.MethodsWe completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.Results36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1–2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).ConclusionsSirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.Trial RegistrationClinicaltrials.gov NCT00126672

Reduced serum VEGF-D levels in metastatic differentiated thyroid cancer

Reduced serum VEGF-D levels in metastatic differentiated thyroid cancer

Impaired lymphangiogenesis due to excess vascular endothelial growth factor-D/Flt-4 signalling in the skin of patients with systemic sclerosis

Vascular abnormalities are one of the primary pathological components of systemic sclerosis (SSc). However, it has not been determined if there are also abnormalities in the formation of lymphatic vessels in SSc. To evaluate lymphangiogenic activity in SSc skin. The numbers of D2-40-positive lymphatic vessels in skin specimens from healthy control subjects and patients with SSc were counted and compared. Quantitative real-time polymerase chain reaction (PCR) was performed to determine mRNA levels of vascular endothelial growth factor (VEGF)-D and Flt-4 (fms-related tyrosine kinase 4, VEGFR-3, one of the receptors for VEGF-D) in the skin. Serum VEGF-D levels were measured with specific enzyme-linked immunosorbent assays. RESULTSZ: The number of lymphatic vessels in patients with SSc was significantly decreased compared with healthy control subjects. Mean relative transcript levels of FIGF (VEGF-D) and FLT4 (Flt-4) in skin tissue from patients with SSc were significantly increased compared with healthy control subjects. By the analysis of the association between serum VEGF-D levels and the clinical or laboratory features, we found that patients with SSc with higher serum VEGF-D levels more frequently have skin ulcers than those with normal VEGF-D levels. A systemic increase of VEGF-D, as well as local overexpression of FIGF and FLT4, may be the cause of disturbed lymphangiogenesis in SSc skin and play a role in the pathogenesis of SSc. We showed the possibility that regulation of VEGF-D/Flt-4 signalling could lead to new treatment of skin ulcers in SSc by controlling the formation of lymphatic vessels.

Serum Vascular Endothelial Growth Factors A, C and D in Human Breast Tumors

Available evidence suggests that vascular endothelial growth factor (VEGF) a potent regulator of vasculogenesis and tumor angiogenesis may be a predictor of recurrence in breast cancer patients. We sought to determine whether VEGF serum levels (VEGF-A, VEGF-C and VEGF-D) in 377 patients with malignant and benign breast tumors differ and whether there is association between vascular growth factors, clinicopathologic features and prognosis. There was no significant difference in investigated circulating angiogenic markers between patients with malignant and non malignant lesions. We found strong correlation between VEGF-A and VEGF-D and between VEGF- C and VEGF-D. Besides serum VEGF-D levels and estrogen receptor (ER) expressions no other correlations between VEGF and clinicopathologic variables were observed. However, elevated VEGF-A and VEGF-C concentrations were associated with increased number of erythrocytes, leukocytes and platelets. In Cox model values of angiogenic serum markers and recognized prognostic markers in breast cancer, VEGF-C turned out as independent prognostic factor. Our study is the first analysis showing correlation between serum concentrations of three angiogenic factors: VEGF-A, VEGF-C, VEGF-D. Associations between angiogenic cytokines and number of blood cells may be due to release of VEGF from platelets and leucocytes. Prognostic role of VEGF is still uncertain, though VEGF-C has a potential to serve as a prognostic marker.

Serum Vascular Endothelial Growth Factor-D Levels in Patients With Lymphangioleiomyomatosis Reflect Lymphatic Involvement

Lymphangioleiomyomatosis (LAM) is a rare multisystem disorder affecting primarily women of child-bearing age, and characterized by cystic lung destruction, tumors of the kidney (angiomyolipomas [AMLs]), and involvement of the axial lymphatics (lymphangioleiomyomas). Patients with LAM experience loss of pulmonary function attributed to the proliferation of abnormal-appearing smooth muscle-like cells (LAM cells). It is possible to group the LAM population by the presence or absence of extrapulmonary involvement (eg, AMLs, lymphangioleiomyomas, chylous effusions). Serum vascular endothelial growth factor (VEGF)-D, a lymphangiogenic factor, is higher in LAM patients than in healthy volunteers and has been proposed as a tool in the differential diagnosis of cystic lung disease. We assessed serum VEGF-D concentrations in relationship to clinical phenotype in LAM patients. Serum VEGF-D levels were quantified by enzyme immunosorbent assay for 111 patients with LAM and 40 healthy volunteers. VEGF-D levels in patients with pulmonary LAM, with or without extrapulmonary manifestations, were compared to those of healthy volunteers. Serum VEGF-D levels were greater in patients with LAM compared to those of healthy volunteers (p < 0.001). However, when patient samples were grouped based on the extent of lymphatic extrapulmonary involvement (eg, lymphangioleiomyomas and adenopathy), the statistical difference was maintained only for patients with LAM with lymphatic involvement (p < 0.001), not for those patients whose disease was restricted to the lung. Serum VEGF-D levels are a good biomarker for lymphatic involvement (area under the curve [AUC], 0.845; p < 0.0001), and a fair predictor for LAM disease (AUC, 0.751; p < 0.0001). Serum levels correlated to CT scan grade (p = 0.033). Serum VEGF-D concentration is a measure of lymphatic involvement in patients with LAM.

Vascular Endothelial Growth Factor-D Is Increased in Serum of Patients with Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease characterized by an abnormal proliferation of smooth muscle-like cells (LAM cells) in the lung and along the axial lymphatics. LAM demonstrates a heterogeneous clinical course, but there is no serum surrogate marker available for assessing the disease severity or predicting the disease progression. Since the authors have recently demonstrated the extensive LAM-associated lymphangiogenesis and its potential role in progression and metastasis of LAM cells, they hypothesized that serum levels of lymphangiogenic growth factors might be increased in LAM and become a surrogate marker for disease severity. VEGF-A, VEGF-C, and VEGF-D in serum of 44 patients with LAM were measured by enzyme-linked immunosorbant assay. Only VEGF-D was significantly increased in LAM patients as compared with age- and gender-matched healthy volunteers (n=24) (LAM vs. control, geometric mean 95% CI; 1069.3 pg/mL (809.4 approximately 1412.6) vs. 295.9 pg/mL (262.6 approximately 333.5), p<0.0001). Serum VEGF-D levels negatively correlated with variables of pulmonary function tests, FEV1/FVC (forced expiratory volume in one second/forced vital capacity) (r=-0.365, p<0.05) and %DLco/VA (the percentage of diffusing capacity for carbon monoxide/alveolar volume to the predicted value) (r=-0.560, p<0.001). As expected, the group who received hormone therapy showed more deteriorated pulmonary function with higher serum VEGF-D levels than the group who was just observed without hormone therapy. Immunohistochemical examination of lung specimens demonstrated the positive immunoreactivity of LAM cells for VEGF-D. Serum VEGF-D levels may be a valuable surrogate marker for evaluating the disease severity in LAM.

Analysis of the VEGF family and their receptors in serum/plasma of patients with pre-invasive and invasive cervical cancer

5016 Background: The vascular endothelial growth factor (VEGF) family and their receptors are essential regulators of angiogenesis and lymphangiogenesis. This study examined the significance of circulating VEGF, VEGF-C, VEGF-D and their receptors VEGFR-1 and VEGFR-2 in patients with preinvasive and invasive cancer in relation to conventional prognostic parameters. Methods: Blood samples were obtained from 125 women before initial treatment (CIN I-III n = 50; FIGO stage I-IV n = 51; relapse n = 24). Plasma (p) and serum(s) levels of pVEGF, sVEGF-D, sVEGFR-1, sVEGFR-2 (R&amp;D Systems, USA) and sVEGF-C (IBL, Japan) were determined by using a quantitative sandwich enzyme-linked immunosorbent assay (ELISA). Results: The highest level of pVEGF (p = 0.007) and sVEGFR-2 (p = 0.014) were detected in patients with recurrent disease, whereas the highest level of sVEGF-D (p = 0.046) were measured in patients with preinvasive lesions (CIN I-III). Furthermore, significantly elevated levels of sVEGF-C (p = 0.021) were detected in early stages (FIGO I-II) in comparison with advanced stages (FIGO III-IV) of cervical cancer. No significant difference in concentration was observed between the various grades of cervical intraepithelial neoplasia (CIN I-III). Correlations between conventional prognostic markers such as lymph node status (N0/N1), lymphangioinvasion (L0/L1), angioinvasion (V0/V1) and grading (G1/G2/G3) were investigated. Increased plasma levels of VEGF (p = 0.036) correlate with the dissemination of tumor cells to regional lymph nodes (N1),whereas serum VEGF-D levels were significantly decreased in women with lymph-node involvement (N1) (p = 0.045) and vascular invasion (L1) (p = 0.019). None of these members of the VEGF family were found to correlate significantly with histological subtype (squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma) or grading of the tumor cells (G1/G2/G3). Conclusions: These results show that circulating concentrations of VEGF are associated with the stage of disease. In an early stage of cervical cancer a switch to a lymphangiogenic phenotype (VEGF-D, VEGF-C) might be possible. No significant financial relationships to disclose.