Serum Vascular Endothelial Growth factor-D Research Articles

Clinical features of pulmonary hypertension in lymphangioleiomyomatosis

Objective: To describe the prevalence of lymphangioleiomyomatosis-pulmonary hypertension (LAM-PH), to explore the clinical features of patients with LAM-PH, and to evaluate the role of pulmonary artery optical coherence tomography (OCT) in the diagnosis of LAM-PH. Methods: Among 234 patients diagnosed with LAM in our center from June 2017 to August 2023, echocardiography was performed in 167 patients, 15 patients with PH indicated by echocardiography were selected as the LAM-PH group. From the remaining 152 patients, 32 patients were randomly selected as the control group. We compared the demographic data, clinical manifestations, pulmonary function, blood gas analysis, and serum vascular endothelial growth factor D (VEGF-D) levels between the two groups. We also evaluated the data from right heart catheterization in five patients and the images from optical coherence tomography of pulmonary arteries in two patients. Results: Echocardiography showed pulmonary hypertension in 15 patients (8.98%). Compared with the control group, LAM-PH group had a higher proportion of patients receiving oxygen therapy. Patients with PH had lower FEV1, FVC, FEV1/FVC, DLCO and higher serum VEGF-D levels compared with those without PH. Right heart catheterization was performed in five patients. Five patients had a pre-capillary pattern and three of these patients had severe pulmonary hypertension. Optical coherence tomography showed that there were no obvious abnormalities in the intima and lumen of the blood vessels in the two patients. Conclusions: The prevalence of PH in LAM is low. Patients in the LAM-PH group had more severe hypoxemia, worse lung function and higher serum VEGF-D levels than those in the control group. PH in LAM is mainly pre-capillary. Optical coherence tomography can evaluate the pulmonary artery vascular condition and help to identify the cause of pulmonary hypertension in LAM patients.

Abstract 15495: Serial Measurement of Vascular Endothelial Growth Factor-D in Heart Failure: The PREHOSP-CHF Study

Background: Vascular endothelial growth factor-D (VEGF-D) is a secreted glycoprotein that can act as lymphangiogenic and angiogenic growth factors. We recently reported that VEGF-D appeared to be a prognostic marker for major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death or heart failure hospitalization (HF), in patients with HF. However, the prognostic value of changes of VEGF-D is unknown. Methods: The PREHOSP-CHF study is a nationwide prospective survey of patients with HF in Japan. Serum VEGF-D levels were measured in 203 patients (mean age, 75 years; male, 62%; mean ejection fraction, 45%) at both baseline and 6-month follow-up. We set the cut-off level of VEGF-D as 366 pg/ml, based on the ROC analysis of the entire cohort of the PREHOSP-CHF study. We defined increased VEGF-D as transition from low VEGF-D to high VEGF-D and decreased VEGF-D as transition from high to low. We investigated the association of changes of VEGF-D levels with the incidence of MACE after 6 months. Results: Mean VEGF-D levels at baseline and 6-month follow-up were 449±199 pg/ml and 519±230 pg/ml, respectively. During the 2-year follow-up, 18 patients developed MACE before 6-month follow-up, and 42 patients developed MACE after 6-month follow up. Based on levels of VEGF-D at baseline, patients with high VEGF-D showed significantly higher incidence of MACE than those without. After excluding the patients developed MACE before 6-month follow-up, 11 of 105 patients with high VEGF-D moved to the low VEGF-D group at 6-month follow-up, and 34 of 78 patients with low VEGF-D moved to the high VEGF-D group. Landmark analysis after 6 months showed that incidence of MACE was significantly higher in patients with increased VEGF-D than those without in the low VEGF-D group, and tended to be lower in patients with deceased VEGF-D than those without in the high VEGF-D group. After adjustment for ejection fraction, N-terminal B-type natriuretic peptide levels, and VEGF-D levels at baseline, increased VEGF-D were also significantly associated with the incidence of MACE after 6 months (hazard ratio per 10 pg/ml increase, 1.02; 95% confidence interval 1.00-1.03; P=0.04). Conclusions: In patients with HF, changes in VEGF-D might serve as a prognostic marker for MACE.

Determinants of Progression and Mortality in Lymphangioleiomyomatosis

Lymphangioleiomyomatosis is a progressive diffuse cystic lung disease with approximately 85%survival at 10 years. The determinants of disease progression and mortality after the introduction of sirolimus therapy and vascular endothelial growth factor D (VEGF-D) as a biomarker have not been well defined. Which factors, including VEGF-D and sirolimus therapy, influence disease progression and survival prognosis in patients with lymphangioleiomyomatosis? The progression dataset and the survival dataset included 282 and 574 patients, respectively, from Peking Union Medical College Hospital, Beijing, China. A mixed-effects model was used to compute the rate of decline in FEV1, and generalized linear models were used to identify variables affecting FEV1 decline. A Cox proportional hazards model was used to explore the association between clinical variables and the outcomes of death or lung transplantation in patients with lymphangioleiomyomatosis. VEGF-D levels and sirolimus treatment were associated with FEV1 changes and survival prognosis. Compared with patients with VEGF-D of< 800 pg/mL at baseline, patients with VEGF-D of≥ 800 pg/mL lost FEV1 faster (SE, -38.86mL/y; 95%CI, -73.90 to -3.82mL/y; P= .031). The 8-year cumulative survival rates of patients with VEGF-D of≥ 2,000 pg/mL and< 2,000 pg/mL were 82.9%and 95.1%, respectively (P= .014). The generalized linear regression model also demonstrated the benefit of delaying the decline of FEV1 by 65.56mL/y (95%CI, 29.06-102.06mL/y) in patients treated with sirolimus compared with those without sirolimus (P< .001). The 8-year risk of death was reduced by 85.1%(hazard ratio, 0.149; 95%CI, 0.075-0.299) after sirolimus treatment. After inverse treatment probability weighting, the risks of death in the sirolimus group were reduced by 85.6%. CT scan results of grade III severity were associated with worse progression than results of grades I or II severity. Patients with baseline FEV1 of 70%predicted or St. George's Respiratory Questionnaire Symptoms domain 50 or higher predicted a higher risk of worse survival. Serum VEGF-D levels, a biomarker of lymphangioleiomyomatosis, are associated with disease progression and survival. Sirolimus therapy is associated with slower disease progression and better survival in patients with lymphangioleiomyomatosis. ClinicalTrials.gov; No.: NCT03193892; URL: www. gov.

Safety and Efficacy of Combined Resveratrol and Sirolimus in Lymphangioleiomyomatosis

A critical need exists to develop remission-inducing therapies for lymphangioleiomyomatosis. Is the addition of resveratrol safe and more efficacious than sirolimus alone in patients with lymphangioleiomyomatosis? We conducted a phase 2, dose-escalating, open-label trial of resveratrol in patients with lymphangioleiomyomatosis receiving a stable regimen of sirolimus. Resveratrol was started at 250mg/d and escalated every 8weeks to maximum dose of 1,000mg/d over 24weeks. The primary outcome was≥ 42%decline in serum vascular endothelial growth factor D (VEGF-D) levels on combined therapy compared with baseline VEGF-D levels on sirolimus. Secondary objectives included an assessment of the safety profile and the effect on lung function and health-related quality of life (HRQOL). Longitudinal change in outcome measures was assessed using linear mixed models. Adverse effects were tabulated using the National Cancer Institute's Common Terminology Criteria for Adverse Events version4. Twenty-five patients with lymphangioleiomyomatosis with a median age of 51 years were enrolled. Pulmonary function parameters at study inclusion were: FEV1: median absolute, 1.72 L; 64%predicted; FVC: median absolute, 2.99 L; 96%predicted; and diffusing capacity of the lungs for carbon monoxide: median absolute, 14.68mL/mmHg/min; 37%predicted. The median serum VEGF-D value at baseline was 617 pg/mL. Patients entered the study with a median sirolimus dose of 2mg/d with median trough level of 6.3ng/mL. Despite some GI side effects, the addition of resveratrol was well tolerated. Although the primary outcome was not met, a statistically significant reduction in serum VEGF-D levels and improvement in HRQOL during the study was found. The addition of resveratrol was safe and well tolerated in patients with lymphangioleiomyomatosis taking sirolimus and was associated with modest improvement in HRQOL. Larger controlled trials of this combination might be warranted to assess definitively the usefulness of resveratrol as an additive therapy in lymphangioleiomyomatosis. ClinicalTrials.gov; No.: NCT03253913; URL: www. gov.

A NOVEL CASE OF LYMPHANGIOLEIOMYOMATOSIS AND PULMONARY LIGHT CHAIN DEPOSITION DISEASE

A NOVEL CASE OF LYMPHANGIOLEIOMYOMATOSIS AND PULMONARY LIGHT CHAIN DEPOSITION DISEASE

VEGF-D Serum Level as a Potential Predictor of Lymph Node Metastasis and Prognosis in Vulvar Squamous Cell Carcinoma Patients.

BackgroundRadical 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.MethodsWe 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.ResultsHigh 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.ConclusionsThe 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.

Lymphangioleiomyomatosis Association with Underlying Genotype in Patients with Tuberous Sclerosis Complex.

Rationale: Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease caused by mutations in the tuberous sclerosis complex (TSC) genes TSC1 and TSC2.Objectives: To examine the association between TSC mutation subtypes and the prevalence of LAM in women with TSC.Methods: Adult women seen at the Cincinnati Children's Hospital Medical Center's TSC clinic were stratified into the following three groups: those with TSC1 mutation, those with TSC2 mutation, and those with no mutation identified (NMI). Individual TSC manifestations were ascertained by blinded review of chest computed tomographic scans (LAM, multifocal micronodular pneumocyte hyperplasia, and sclerotic bone lesions) and chart review (all other manifestations). The association between mutation status and TSC manifestations was assessed by the Wilcoxon rank-sum test.Results: Our cohort consisted of 55 TSC women, including 30/55 (55%) with TSC2, 12/55 (22%) with TSC1, and 13/55 (23%) with NMI. Twenty-three women (42%) had characteristic cysts consistent with LAM, of whom 16 had TSC2 mutations and seven had NMI. The prevalence of LAM was higher in women with TSC2 mutations compared with women with TSC1 mutations (16/29 [55%] vs. 0/12; P = 0.003). Similarly, renal angiomyolipomas were more common in women with TSC2 mutations compared with women with TSC1 mutations (29/30 [97%] vs. 6/12 [50%]; P = 0.01). There was no association between TSC mutation subtype and the presence of multifocal micronodular pneumocyte hyperplasia, sclerotic bone lesions, and skin or brain involvement. Serum VEGF-D (vascular endothelial growth factor-D) concentrations (median [95% confidence interval]) tended to be higher in patients harboring TSC2 mutations compared with patients with TSC1 mutations (725 pg/ml [612-1,317] vs. 331 pg/ml [284-406]; P = 0.03) and in patients with LAM compared with patients without LAM (725 pg/ml [563-1,609] vs. 429 pg/ml [357-773]; P = 0.02).Conclusions: LAM and angiomyolipomas are more common in women with TSC harboring TSC2 mutations compared with women with TSC1 mutations. Serum VEGF-D is a useful biomarker to suggest the presence of LAM in women with TSC.

Novel folliculin gene mutation and an elevated serum vascular endothelial growth factor-D level in the context of cystic lung disease

Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant genetic disorder characterized by the development of benign cutaneous neoplasms, renal tumors, and pulmonary cysts. Caused by mutations in the folliculin (FLCN) gene on chromosome 17, the pulmonary manifestations observed in BHD include multiple subpleural cysts that are frequently associated with pneumothorax. Diffuse cystic lung disease is also commonly encountered in lymphangioleiomyomatosis (LAM), either in isolation or in the context of tuberous sclerosis complex (TS). The diagnosis of BHD is confirmed by identifying pathogenic FLCN germline mutations. Modern evidence, however, supports using serum vascular endothelial growth factor-D (VEGF-D) levels in differentiating LAM from other cystic lung diseases, including BHD, with high specificity. This case report describes the unique finding of an elevated VEGF-D serum level (1290 pg/ml) in a patient with cystic lung disease, bilateral pneumothorax and a novel disease-causing mutation (E280X) in the FLCN gene.

Effects of yoga on exercise capacity in patients with lymphangioleiomyomatosis: a nonrandomized controlled study

ObjectiveTo evaluate the effects of yoga on exercise capacity and quality of life in patients with lymphangioleiomyomatosis (LAM), a rare cystic lung disease in women.Patients and methodsThis was a nonrandomized, controlled study conducted in Beijing, China (August 27, 2017 – April 26, 2018). Twenty-six participants were allocated to the intervention (yoga) group (n = 13) or control group (n = 13). The yoga intervention involved a 24-week program of yoga class training for 90 min once a week and no fewer than 2 at-home sessions per week (at least 15 min per session). The 6-min walking distance (6MWD), lung function, serum vascular endothelial growth factor-D (VEGF-D) levels, quality of life, and symptoms of anxiety and depression were measured at baseline, 12-week and 24-week follow-up. An incremental cardiopulmonary exercise test was conducted at baseline and the 24-week follow-up.ResultsEleven patients completed the yoga training program. The yoga group exhibited improvements in the following outcomes versus those of the control group: 6MWD (+ 55 ± 29 m vs + 18 ± 49 m, P = 0.04), anaerobic threshold (3.4 ± 2.4 ml/min/kg vs 1.6 ± 1.4 ml/min/kg, P = 0.035) and peak work load (11.7 ± 14.6 W vs 0.2 ± 9.1 W, P = 0.027). There was no significant difference in peak oxygen consumption (VO2peak), lung function, VEGF-D level, and quality of life between the yoga and control groups. No adverse effects were found in the yoga group.ConclusionYoga is a feasible and safe intervention for pulmonary rehabilitation and potentially improves exercise capacity in patients with LAM.Trial registration(Clinical trial registration number at www.chictr.org.cn: ChiCTR-OON-1701274)

Long-term efficacy and safety of sirolimus therapy in patients with lymphangioleiomyomatosis

BackgroundSirolimus has been confirmed to be effective for lymphangioleiomyomatosis (LAM), a rare multisystem neoplastic disease in women. The long-term effects of sirolimus treatment for LAM, however, are largely unknown. We aimed to analyze the long-term efficacy and safety of sirolimus therapy for LAM with 4-year follow-up.MethodsIn total, 142 sporadic LAM patients who took sirolimus for 1–4 years were retrospectively enrolled for this analysis. The variables used for analysis included pulmonary function tests, arterial blood gas analysis, 6-min walking distance (6MWD), St. George’s Respiratory Questionnaires (SGRQ) and serum vascular endothelial growth factor-D (VEGF-D) levels before and after the initiation of sirolimus therapy. The rates of change (slope) in those variables were calculated, and adverse events were also analyzed.ResultsIn total, 122, 83, 60 and 32 patients out of 142 were followed for 1, 2, 3 and 4 years respectively. Sirolimus treatment improved the change rate in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) compared with the data before treatment (FEV1, − 10 ± 15 vs. − 178 ± 36 ml/y, P < 0.001 and FVC, 54 ± 22 vs.-72 ± 68 ml/y, P < 0.05). In comparison to the baseline measurements, significant improvements were observed in FEV1 at the first year; FVC at 1–2 years; arterial oxygen levels, 6MWD, and SGRQ at 1–3 years; and VEGF-D at 1–4 years. Overall, all variables stabilized or improved during the 4 years of observation. Adverse events related to sirolimus were mild.ConclusionSirolimus therapy is effective at improving or stabilizing pulmonary function, oxygen levels, exercise capacity, and quality of life in patients with LAM for up to 4 years. VEGF-D is maintained at a lower level for 4 years after treatment. Adverse events related to sirolimus were mild.

Serum vascular endothelial growth factor-D as a diagnostic and therapeutic biomarker for lymphangioleiomyomatosis.

BackgroundIn lymphangioleiomyomatosis (LAM), tuberous sclerosis gene mutations activate the mechanistic target of the rapamycin pathway, resulting in vascular endothelial growth factor-D (VEGF-D) overproduction. While the utility of serum VEGF-D testing for the diagnosis of LAM is outlined in ATS/JRS LAM Guidelines, the assay has not been fully validated for Asian populations. Our aims were to validate serum VEGF-D testing in Japan, by directly comparing measurements in Japan and the U.S., determining the diagnostic cut-off for serum VEGF-D levels among the Japanese women with typical thin walled cystic change on CT, and determining the performance of VEGF-D as a prognostic biomarker.Subjects and methodsWe determined serum VEGF-D levels from 108 LAM patients, 14 disease controls, and 51 healthy volunteers from the Japanese population. Measurements of 61 LAM patients were compared to those from the principal VEGF-D laboratory in the U.S at Cincinnati Children’s Hospital Medical Center. We correlated baseline serum VEGF-D levels with baseline and longitudinal clinical data to determine how pregnancy, sirolimus or gonadotrophin-releasing hormone (GnRH) agonists influence serum VEGF-D levels.ResultsSerum VEGF-D measurements in Japan and the U.S. were very similar. Baseline serum VEGF-D levels effectively distinguished LAM from other diseases and healthy volunteers at a cut-off level of 645 pg/ml and were diagnostically specific at 800 pg/ml, consistent with the recommendations of the ATS/JRS LAM Guidelines. Baseline serum VEGF-D correlated negatively with the DLco baseline % predicted and with the annual decrease in DLco % predicted. There was no significant association between baseline serum VEGF-D level and the outcomes of death or transplant. Serum VEGF-D levels markedly decreased during treatment with sirolimus, but not with GnRH analogues. Serum VEGF-D levels of most LAM patients did not increase over time, and neither pregnancy nor menopause significantly modulated serum VEGF-D levels.ConclusionsSerum VEGF-D is a useful diagnostic and therapeutic biomarker for LAM. Satisfactory precision and international inter-laboratory agreement of the clinical assay support VEGF-D recommendations in the ATS/JRS LAM Guidelines for the Japanese population.

Concentration of Serum Vascular Endothelial Growth Factor (VEGF-D) and Its Correlation with Functional and Clinical Parameters in Patients with Lymphangioleiomyomatosis from a Brazilian Reference Center.

Serum vascular endothelial growth factor-D (VEGF-D) is a lymphangiogenic growth factor that is considered a valuable tool in the diagnosis of lymphangioleiomyomatosis (LAM). Previous studies have reported a wide variability in VEGF-D serum levels in LAM patients and it seems to be associated with pulmonary impairment and lymphatic involvement. We conducted a cross-sectional study from 2009 to 2017 that evaluated VEGF-D serum levels in a cohort of LAM patients who were never treated with mTOR inhibitors and compared them to healthy age-matched volunteers. Clinical and functional parameters were assessed and correlated with their respective serum VEGF-D levels. One hundred and four patients were included in the analysis. Serum VEGF-D levels were higher in LAM patients compared to healthy controls: 796 (404-1588) versus 162 (117-232)pg/mL, respectively (p < 0.001). Patients with tuberous sclerosis complex-LAM, TSC-LAM (20%), had higher levels of VEGF-D when compared to patients with sporadic LAM (80%) [1005 (641-2732) vs. 772 (370-1383), p = 0.05]. Serum VEGF-D levels were weakly correlated with DLCO (r = - 0.26, p = 0.001) and lymphatic involvement was more frequent in those with serum VEGF-D levels equal or above 800pg/mL (35% vs. 13%, p = 0.02). In LAM, serum VEGF-D is weakly associated with lung function impairment and strongly associated with lymphatic involvement. VEGF-D is validated for use in Brazilian patients with LAM whose characteristics must be accounted for when evaluating their serum VEGF-D levels.

Long-Term Effect of Sirolimus on Serum Vascular Endothelial Growth Factor D Levels in Patients With Lymphangioleiomyomatosis

Sirolimus reduces serum levels of vascular endothelial growth factor D (VEGF-D); the size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas; and stabilizes lung function in patients with lymphangioleiomyomatosis (LAM). To determine whether reductions in VEGF-D levels are sustained over time, as well as parallel changes in lung function and lymphatic disease, we evaluated 25 patients with LAM and measured VEGF-D levels, lung function, and extent of lymphatic disease before and during sirolimus therapy. Treatment with sirolimus stabilized FEV1 and diffusion capacity for carbon monoxide (Dlco) over a period of 4.5 ± 1.6 years, caused resolution of lymphatic disease, and reduced the size of angiomyolipomas and VEGF-D levels (3,720 ± 3,020 pg/mL to 945 ± 591 pg/mL; P< .0001). Yearly changes in FEV1 %predicted and Dlco %predicted were reduced from -7.4%± 1.4%to -0.3%± 0.5%(P< .001) and -6.4%± 0.9%to -0.4%± 0.5%(P< .001), respectively. Lower VEGF-D levels correlated with sirolimus therapy (P<.001), but no significant relationship was observed between reduction in VEGF-D levels and FEV1 and Dlco during sirolimus therapy. The magnitude of VEGF-D decline was not related to the effect on lung function. Patients with lymphatic disease had higher serum VEGF-D levels, a greater reduction in VEGF-D levels, and better long-term sustained improvement in lung function during sirolimus therapy than did those without lymphatic disease. Sirolimus therapy stabilizes lung function over many years of therapy while producing a sustained reduction in VEGF-D levels in patients with elevated levels preceding therapy. An association was not demonstrated between the magnitude of VEGF-D decline and the beneficial effect of sirolimus on lung function. Persistent improvement in lung function was observed in patients with lymphatic disease.

Serum Vascular Endothelial Growth Factor-D in Patients With Cystic Lung Diseases

Serum Vascular Endothelial Growth Factor-D in Patients With Cystic Lung Diseases

Correlation of serum vascular endothelial growth factor-D concentration with clinical presentation and course of lymphangioleiomyomatosis

BackgroundIncreased serum vascular endothelial growth factor D (VEGF-D) concentration has been accepted as a diagnostic marker in lymphangioleiomyomatosis (LAM). The study was performed to evaluate the correlation of VEGF-D with clinical presentation and course of LAM. MaterialThe study group comprised of 48 women with LAM (27 with sLAM, 9 with sLAM and lymphangioma (sLAM-LYM) and 12 patients with TSC/LAM). Patients were assessed at the time of VEGF-D examination, and pulmonary function parameters were compared with those, obtained one year before. VEGF-D serum concentration was measured by ELISA method. ResultsPatients with TSC/LAM and sLAM-LYM displayed higher concentrations of VEGF-D than patients with sLAM (2682 ± 1347 pg/mL and 2223 ± 1184 pg/mL vs.1281 ± 791 pg/mL; p = 0.0002, p = 0.009) respectively. Patients with sLAM and VEGF-D concentration <800 pg/mL (sLAM-L) had better lung function as assessed by FEV1 (2.38 ± 0.88 L vs. 1.75 ± 0.8 L; p < 0.015) and DL,CO (5.8 ± 2.25 vs. 3.93 ± 1.74 mL/min/mmHg; p < 0.028), had higher blood oxygenation, then those with VEGF-D >800 pg/mL (sLAM-H). Significant yearly increase of TLC (390 ± 700 mL; p < 0.021) and RV (340 ± 790 mL; p < 0.03), and decrease of distance in 6MWT (−30 ± 50 m; p = 0.04) were observed in sLAM-H group. Lung function parameters remained constant in sLAM-L patients. Patients with sLAM-H displayed higher yearly decline of FVC (120 vs. 50 mL; p = 0.035) and increase of TLC (390 vs. −80 mL; p = 0.038) and RV (340 vs. 90 mL; p = 0.045) than sLAM-L patients. Negative correlations between VEGF-D concentration and DL,CO, PaO2, PaCO2, and positive with HRCT grading, and desaturation in 6MWT were noticed in sLAM patients without lymphangioma. ConclusionsSerum VEGF-D is the useful biomarker of LAM extension, and might also prove predictive towards therapeutic decision.

St. George's Respiratory Questionnaire Has Longitudinal Construct Validity in Lymphangioleiomyomatosis

BackgroundLymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that causes shortness of breath, hypoxemia, and impaired health-related quality of life (HRQL). Whether St. George's Respiratory Questionnaire (SGRQ), a respiratory-specific HRQL instrument, captures longitudinal changes in HRQL in patients with LAM is unknown. MethodsUsing data from the Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus trial, we performed analyses to examine associations between SGRQ scores and values for four external measures (anchors). Anchors included (1) FEV1, (2) diffusing capacity of the lung for carbon monoxide, (3) distance walked during the 6-min walk test, and (4) serum vascular endothelial growth factor-D. ResultsSGRQ scores correlated with the majority of anchor values at baseline, 6 months, and 12 months. Results from longitudinal analyses demonstrated that SGRQ change scores tracked changes over time in values for each of the four anchors. At 12 months, subjects with the greatest improvement from baseline in FEV1 experienced the greatest improvement in SGRQ scores (Symptoms domain, −13.4 ± 14.6 points; Activity domain, −6.46 ± 8.20 points; Impacts domain, −6.25 ± 12.8 points; SGRQ total, −7.53 ± 10.0 points). Plots of cumulative distribution functions further supported the longitudinal validity of the SGRQ in LAM. ConclusionsIn LAM, SGRQ scores are associated with variables used to assess LAM severity. The SGRQ is sensitive to change in LAM severity, particularly when change is defined by FEV1, perhaps the most clinically relevant and prognostically important variable in LAM. The constellation of results here supports the validity of the SGRQ as capable of assessing longitudinal change in HRQL in LAM.

The role of vascular endothelial growth factor-D in diagnosis of lymphangioleiomyomatosis (LAM)

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. 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). Serum VEGF-D was significantly increased in definite LAM group, compared with that of health control (median: 3841.9pg/mL vs 405.5pg/mL respectively, p<0.001). The optimal cut-off point for definite LAM diagnosis was 850.7pg/mL. In probable LAM group, the majority of patients (92.9%) had serum VEGF-D level over 850.7pg/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). Serum VEGF-D should be added to the current diagnosis algorithm to enhance definitive diagnosis for LAM.

Clinical utility of diagnostic guidelines and putative biomarkers in lymphangioleiomyomatosis

BackgroundLymphangioleiomyomatosis is a rare disease occurring almost exclusively in women. Diagnosis often requires surgical biopsy and the clinical course varies between patients with no predictors of progression. We evaluated recent diagnostic guidelines, clinical features and serum biomarkers as diagnostic and prognostic tools.MethodsSerum vascular endothelial growth factor-D (VEGF-D), angiotensin converting enzyme (ACE), matrix metalloproteinases (MMP) -2 and -9, clinical phenotype, thoracic and abdominal computerised tomography, lung function and quality of life were examined in a cohort of 58 patients. 32 healthy female controls had serum biomarkers measured.ResultsSerum VEGF-D, ACE and total MMP-2 levels were elevated in patients. VEGF-D was the strongest discriminator between patients and controls (median = 1174 vs. 332 pg/ml p < 0.0001 with an area under the receiver operating characteristic curve of 0.967, 95% CI 0.93-1.01). Application of European Respiratory Society criteria allowed a definite diagnosis without biopsy in 69%. Adding VEGF-D measurement to ERS criteria further reduced the need for biopsy by 10%. VEGF-D was associated with lymphatic involvement (p = 0.017) but not the presence of angiomyolipomas.ConclusionsCombining ERS criteria and serum VEGF-D reduces the need for lung biopsy in LAM. VEGF-D was associated with lymphatic disease but not lung function.

Decreased serum vascular endothelial growth factor‐D levels in metastatic patients with differentiated thyroid carcinoma

Vascular endothelial growth factor-D (VEGF-D) has been identified as one of the lymphangiogenic growth factors involved in metastatic diffusion. The aim of this study is to evaluate the serum VEGF-D levels in patients with differentiated thyroid cancer at different conditions of disease. We studied prospectively the VEGF-D plasma levels in 96 subjects affected by differentiated thyroid cancer. The patients were divided into three groups according to the clinical and biochemical findings: patients with no evidence of disease (Cured), patients with pathological (>1 ng/ml) stimulated thyroglobulin (Tg) (Path-Tg/rhTSH) levels only after rhTSH and patients with elevated basal Tg levels (Path-Tg/LT4). The serum VEGF-D concentrations in patients of group Cured were not different from the controls, while group Path-Tg/rhTSH showed baseline serum VEGF-D levels significantly lower than group Cured and controls (P < 0·001 and P < 0·01, respectively). Moreover, the patients of group Path-Tg/LT4 showed median serum cytokine concentrations at baseline not significantly different from the patients of group Path-Tg/rhTSH. The rhTSH stimulation did not modify the difference in serum VEGF-D levels in patients of group Cured and group Path-Tg/rhTSH. Our data demonstrate that the VEGF-D serum levels are reduced in patients with metastases of differentiated thyroid cancer, regardless of the degree of metastatic spread. It is possible that some other molecule produced by the tumoral tissue could affect the VEGF-D physiologically produced of from different tissues, thus conducting to a decrease in the VEGF-D found in blood of patients with evidence of metastatic differentiated thyroid cancer.

Serum vascular endothelial growth factor-D levels correlate with cervical lymph node metastases in papillary thyroid carcinoma

The aim of this multicenter study was to evaluate the clinical relevance of serum vascular endothelial growth factor-D (VEGF-D) in papillary thyroid carcinoma (PTC). This prospective study consisted of 74 patients with primary PTC and 15 patients with benign thyroid nodules treated from 2008 to 2009. VEGF-D concentration was compared with patient clinicopathologic features and lymph node metastases. There was no significant difference in mean serum VEGF-D levels between the PTC and benign thyroid nodule groups. Within the PTC group, serum VEGF-D levels were significantly higher in patients with lymph node metastases than in patients without metastases (241.92 vs. 213.89 pg/ml, respectively; P = 0.035). Receiver operating characteristic curve analysis revealed that preoperative serum VEGF-D levels were predictive of lymph node metastases in the patients >45 years. Serum VEGF-D level that was correlated with the presence of cervical lymph node metastases in PTC patients might be a useful prognostic indicator.