Diagnostic value of serum vascular endothelial growth factor-D in Korean patients with lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare multisystemic disorder characterized by the proliferation of abnormal smooth muscle-like cells. Although serum vascular endothelial growth factor-D (VEGF-D) is currently used as a diagnostic biomarker for LAM, its diagnostic value in Korean patients is unclear. OBJECTIVES: To evaluate the diagnostic value of serum VEGF-D for LAM in Korean patients. DESIGN: A multicenter prospective cohort study. METHODS: Serum samples were prospectively collected from five medical institutions, from patients with LAM (n = 40) and controls (n = 24; healthy participants = 3, other cystic lung diseases = 13, idiopathic pulmonary fibrosis = 4, idiopathic nonspecific interstitial pneumonia = 4). Serum VEGF-D levels were measured using the enzyme-linked immunosorbent assay, and the diagnostic value was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: The mean age of patients with LAM was 44.5 years, and all were female (controls: 47.8 years; female: 70.8%, p < 0.001). The serum VEGF-D levels were significantly higher in patients with LAM than those in the control group (median: 708.9 pg/mL vs 325.3 pg/mL, p < 0.001). In the ROC curve analysis, serum VEGF-D levels showed good predicting performance for LAM diagnosis (area under the curve = 0.918) with an optimal cut-off value of 432.7 pg/mL (sensitivity = 85.0%, specificity = 87.5%). When 800 pg/mL was used as the cut-off value, the specificity of serum VEGF-D for LAM diagnosis increased to 100.0%. CONCLUSION: Our results suggest that serum VEGF-D may be a useful biomarker for diagnosing LAM in Korean patients, similar to previous reports.

Blood test for diagnosis of lymphangioleiomyomatosis in Korea: role of vascular endothelial growth factor-DIn this study, we discuss a blood test to diagnose a rare lung disease, called lymphangioleiomyomatosis (LAM). LAM primarily affects women, especially during their childbearing years, and can cause serious lung problems such as damage and cyst (air-filled sac) formation. The blood test looks for a special protein in the blood, called vascular endothelial growth factor-D (VEGF-D). If someone has a lot of this protein, it usually means that they have LAM. We have found that when VEGF-D levels are high, the test can effectively separate LAM from other lung diseases. We also found that raising this threshold to higher levels made it much more likely to correctly distinguish a group of people who do not have the disease from patients with LAM. Our study is important because it's the first to show the usefulness of blood VEGF-D testing in Korean LAM patients, and because it suggests an easier and less inconvenient way for physicians to diagnose LAM in Koreans. Our findings are an important step in improving the management of Korean patients with LAM.

[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.

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

OBJECTIVE: This study aimed to investigate maternal serum vascular endothelial growth factor (VEGF) C and D levels in patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

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

ABSTRACT: 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.

Soluble Immune-Related Proteins as New Candidate Serum Biomarkers for the Diagnosis and Progression of Lymphangioleiomyomatosis.

Background: The goal of this study was to analyze serum from lymphangioleiomyomatosis (LAM) patients and healthy controls to identify novel biomarkers that could shed light on disease diagnosis and pathogenesis. Methods: From April 2017 to October 2019, qualified serum samples were obtained to explore differences in 59 immune proteins between 67 LAM patients and 49 healthy controls by the Luminex method. Results: We characterized 22 serum immune proteins that were differentially expressed in LAM patients compared with healthy people. Fifty-nine proteins were then classified into eight categories according to their biological function, and the results showed that LAM patients displayed significantly higher levels of growth factors (p = 0.006) and lower levels of costimulatory molecules (p = 0.008). LAG-3 was not only likely to have better predictive value than VEGF-D but also showed a significant difference between patients without elevated VEGF-D and healthy people. IL-18 was positively correlated with lung function and six-minute walk test (6MWT) distance and negatively correlated with St. George's Respiratory Questionnaire (SGRQ) score and pulmonary artery systolic pressure (PASP), which suggested that IL-18 was related to disease severity. PD-1 was significantly different between patients with pneumothorax and/or chylothorax and those without complications. Conclusion: We performed a large-scale serum immune factor analysis of LAM. Our study provides evidence that LAG-3 may be a novel candidate serum biomarker for the diagnosis of LAM. Future independent validation in prospective studies is warranted.

Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial.

BACKGROUND: Immunotherapy is being tested in early-stage non-small cell lung cancer (NSCLC), and achieving higher rates of complete pathological responses (CPR) as compared to standard of care. Early identification of CPR patients has vital clinical implications. In this study, we focused on basal peripheral immune cells and their treatment-related changes to find biomarkers associated to CPR. METHODS: Blood from 29 stage IIIA NSCLC patients participating in the NADIM trial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment. More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phenotype and plasma soluble factors were analyzed. RESULTS: Neoadjuvant chemoimmunotherapy altered more than 150 immune parameters. At diagnosis, 11 biomarkers associated to CPR were described, with an area under the ROC curve >0.70 and p-value <.05. CPR patients had significantly higher levels of CD4+ PD-1+ cells, NKG2D, and CD56 expression on T CD56 cells, intensity of CD25 expression on CD4+ CD25hi+ cells and CD69 expression on intermediate monocytes; but lower levels of CD3+ CD56- CTLA-4+ cells, CD14++ CD16+ CTLA-4+ cells, CTLA-4 expression on T CD56 cells and lower levels of b-NGF, NT-3, and VEGF-D in plasma compared to non-CPR. Post treatment, CPR patients had significantly higher levels of CD19 expression on B cells, BCMA, 4-1BB, MCSF, and PARC and lower levels of MPIF-1 and Flt-3L in plasma compared to non-CPR. CONCLUSIONS: Patients achieving CPR seem to have a distinctive peripheral blood immune status at diagnosis, even showing different immune response to treatment. These results reinforce the different biology behind CPR and non-CPR responses.

Circulating HLA-G and its association with cardiovascular markers in pregnancy.

Human Leukocyte Antigen-G (HLA-G) prevents the activity of immune cells and is decreased in women with preeclampsia. We aimed to investigate the associations between circulating soluble HLA-G (sHLA-G) and 92 cardiovascular disease-related biomarkers from a previously published multiplex study in women with preeclampsia and controls. We found 15 markers significantly associated with circulating sHLA-G in univariate analyses. After multivariable adjusted regression, only proto-oncogene tyrosine-protein kinase Src (SRC) and vascular endothelial growth factor D were significantly associated with sHLA-G. Low SRC, previously observed in the circulation of preeclamptic women, may be regulated by low sHLA-G, and reflect decreased trophoblast differentiation and syncytical formation.

Vascular endothelial growth factor D is a biomarker of fluid overload in haemodialysis patients.

BACKGROUND: Improved understanding and assessment of the complex physiology of volume regulation in haemodialysis (HD) patients are required to improve patient care and reduce mortality associated with fluid overload (FO). METHODS: We searched for FO-related biomarkers among 184 peptides associated with cardiovascular disease in a cohort of 30 HD patients. First, we assessed the direct impact of HD on the peptides of interest by comparing plasma concentrations before and after treatment. Then, we compared cardiovascular peptide profiles between patients with and without FO as defined by bioimpedance analysis (BIA). The plasma concentration of selected candidate biomarkers for FO was determined by enzyme-linked immunosorbent assay (ELISA) and correlated with previously described FO-related clinical and laboratory parameters. For validation, results were confirmed in an independent cohort of 144 HD patients. RESULTS: We found seven peptides positively [NT-proBNP, B-type natriuretic peptide (BNP), vascular endothelial growth factor D (VEGFD), tumour necrosis factor-related apoptosis-inducing ligand receptor 2, growth differentiation factor 15, tumour necrosis factor ligand superfamily member 13B, chitinase-3-like protein 1] and five negatively (leptin, renin, epidermal growth factor receptor, interleukin-1 receptor antagonist, myeloblastin) correlated to FO. In addition to natriuretic peptides, VEGFD emerged as third peptide highly correlated with BIA (ρ = 0.619, P < 0.0001). In line with this, VEGFD concentration verified by ELISA correlated with BIA, BNP and soluble CD146 but not with vascular endothelial growth factor C (VEGFC). Notably, levels of VEGFD were unrelated to cardiac systolic function (P = 0.63), contrary to BNP (P = 0.0003). Finally, we observed that 1-year all-cause mortality was higher in patients with high BNP (P = 0.0002), FO (defined by BIA, P = 0.04) and high VEGFD (P = 0.02), but not with high VEGFC (P = 0.48). CONCLUSION: VEGFD is a novel FO-related biomarker with unique diagnostic and prognostic properties.

Distinct Characteristics of VEGF-D and VEGF-C to Predict Mortality in Patients With Suspected or Known Coronary Artery Disease.

Background VEGF-D (vascular endothelial growth factor D) and VEGF-C are secreted glycoproteins that can induce lymphangiogenesis and angiogenesis. They exhibit structural homology but have differential receptor binding and regulatory mechanisms. We recently demonstrated that the serum VEGF-C level is inversely and independently associated with all-cause mortality in patients with suspected or known coronary artery disease. We investigated whether VEGF-D had distinct relationships with mortality and cardiovascular events in those patients. Methods and Results We performed a multicenter, prospective cohort study of 2418 patients with suspected or known coronary artery disease undergoing elective coronary angiography. The serum level of VEGF-D was measured. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death and major adverse cardiovascular events defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. During the 3-year follow-up, 254 patients died from any cause, 88 died from cardiovascular disease, and 165 developed major adverse cardiovascular events. After adjustment for possible clinical confounders, cardiovascular biomarkers (N-terminal pro-B-type natriuretic peptide, cardiac troponin-I, and high-sensitivity C-reactive protein), and VEGF-C, the VEGF-D level was significantly associated with all-cause death and cardiovascular death but not with major adverse cardiovascular events.. Moreover, the addition of VEGF-D, either alone or in combination with VEGF-C, to the model with possible clinical confounders and cardiovascular biomarkers significantly improved the prediction of all-cause death but not that of cardiovascular death or major adverse cardiovascular events. Consistent results were observed within patients over 75 years old. Conclusions In patients with suspected or known coronary artery disease undergoing elective coronary angiography, an elevated VEGF-D value seems to independently predict all-cause mortality.

Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study.

BACKGROUND: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.

Elevated plasma tyrosine kinases VEGF-D and HER4 in heart failure patients decrease after heart transplantation in association with improved haemodynamics.

Receptor tyrosine kinases (RTKs) are implicated in cardiovascular growth and remodelling. We aimed to identify the plasma levels of RTKs and related proteins and their association with haemodynamic alterations in heart failure (HF) and related pulmonary hypertension (PH) following heart transplantation (HT). Using proximity extension assay, 28 RTKs and related proteins were analysed in plasma from 20 healthy controls and 26 HF patients before and 1-year after HT. In end-stage HF, out of 28 RTKs, plasma vascular endothelial growth factor-D (VEGF-D) and human epidermal growth factor-4 (HER4) were elevated compared to controls (p < 0.001), but decreased (p < 0.0001) and normalised after HT. Following HT, plasma changes (Δ) of VEGF-D correlated with Δmean pulmonary artery pressure (rs = 0.65, p = 0.00049), Δpulmonary artery wedge pressure (rs = 0.72, p < 0.0001), Δpulmonary arterial compliance (PAC) (rs = - 0.52, p = 0.0083) and Δpulmonary vascular resistance (PVR) (rs = 0.58, p = 0.0032). ΔHER4 correlated with Δmean right atrial pressure (rs = 0.51, p = 0.012), ΔNT-proBNP (rs = 0.48, p = 0.016) and Δcardiac index (rs = - 0.56, p = 0.0044). In HF patients following HT, normalisation of VEGF-D reflected reversal of passive pulmonary congestion and restored PAC and PVR; whereas the normalisation of HER4 reflected decreased volume overload and improved cardiac function. The precise function of these proteins, their potential clinical use and pathophysiological relation in HF and related PH remain to be elucidated.

Hereditary angioedema attack: what happens to vasoactive mediators?

Hereditary angioedema is a disabling, life-threatening condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) leading to bradykinin accumulation and recurrent episodes of edema attack. Vascular leakage is a complex process sustained by the coordinated production of several permeabilizing factors including vascular endothelial growth factors (VEGFs), angiopoietins (ANGPTs) and phospholipase A2 enzymes (PLA2). We previously reported that patients with C1-INH-HAE in remission have increased plasma levels of VEGFs, ANGPTs and secreted PLA2. In this study, we sought to analyze plasma levels of these mediators in 15 patients with C1-INH-HAE during the acute attack compared to remission. Plasma concentrations of VEGF-A, VEGF-C and VEGF-D were not altered during attack compared to remission. Moreover, VEGF-D concentrations were not altered also in remission phase compared to controls. Concentrations of ANGPT1, a vascular stabilizer, were increased during attacks compared to symptoms-free periods, whereas ANGPT2 levels were not altered. The ANGPT2/ANGPT1 ratio was decreased during angioedema attacks. Platelet activating factor acetylhydrolase activity was increased in patients with C1-INH-HAE in remission compared to controls and was decreased during angioedema attacks. Our results emphasize the complexity by which several vasoactive mediators are involved not only in the pathophysiology of C1-INH-HAE, but also during angioedema attacks and its resolution.

Associations between maternal inflammation during pregnancy and infant birth outcomes in the Seychelles Child Development Study.

PROBLEM: Markers of maternal inflammation may determine infant birth outcomes. METHOD OF STUDY: Maternal serum samples were collected at 28 weeks gestation (n = 1418) in the Seychelles Child Development Study Nutrition Cohort 2 and analyzed for immune markers by MSD multiplex assay, including cytokines from the Th1 (IFN-γ, IL-1ß, IL-2 and TNF-α) and Th2 (IL-4, IL-5, IL-10) subsets, with IL-6, MCP-1, TARC, sFlt-1 and VEGF-D. Associations of log-transformed immune markers with birthweight, length, head circumference and gestational age were assessed by multiple linear regression models, which were adjusted for maternal age, BMI, parity, child sex, gestational age and socioeconomic status. RESULTS: Neither total Th1, Th2 nor Th1:Th2 were significantly associated with any birth outcome. However, the angiogenesis marker VEGF-D was predictive of a lower birthweight, (ß = -0.058, P = 0.017) and birth length (ß = -0.088, P = 0.001) after adjusting for covariates. Higher concentrations of CRP were predictive of a lower birthweight (ß = -0.057, P = 0.023) and IL-2 (ß = 0.073, P = 0.009) and the chemokine MCP-1 (ß = 0.067, P = 0.016) were predictive of a longer gestational age. CONCLUSIONS: In our cohort of healthy pregnant women, we found no evidence for associations between the Th1 or Th2 inflammatory markers with birth outcomes. However, VEGF-D and CRP appear to predict lower birthweight and IL-2 and MCP-1 a longer gestation. Greater understanding is required of the variation in these immune markers at different gestational stages, as well as the factors which may regulate their balance in healthy pregnancy. n = 233.

Angiogenesis modulatory factors in subjects with chronic ocular complications of Sulfur Mustard exposure: A case-control study.

BACKGROUND: Chronic ocular complications of Sulfur Mustard (SM) exposure leads to severe ocular morbidity during time. The aim of this study was to compare serum levels of Interleukin 17 (IL-17), IL-12, vascular endothelial growth factor (VEGF)-C, VEGF-D and nitric oxide (NO) in SM-exposed patients versus the control group and to measure tear concentration of VEGF-C only in the SM-exposed group. METHODS: In this prospective case control, 128 SM-exposed patients and 31 healthy control subjects were included. In the case group ocular manifestations were classified to three subgroups of mild (19 cases), moderate (31 cases) and severe (78 cases) forms of disease. Serum levels of IL-17, IL-12, NO, VEGF-C and VEGF-D, in all subjects and tear concentration of VEGF-C in SM-exposed group was evaluated. RESULTS: All subjects were male and mean ±â€¯standard deviation (SD) of age in the case and control groups were 44.9 ±â€¯8.8 and 40.9 ±â€¯10.1 years, respectively. Except for significantly lower serum level of IL-17 (p < 0.001) and NO (p = 0.003), other values were not significantly different. The tear concentration of VEGF-C and serum level of IL-12 were not different between subgroups in the SM-exposed group, yet were significantly lower among those with abnormally dilated and tortuous conjunctival vessels and corneal pannus, respectively (p = 0.01, p = 0.015). CONCLUSIONS: Exposure to SM significantly reduced serum level of IL-17 and NO in the delayed phase, yet did not influence VEGF-C; VEGF-D or IL-12.

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

BACKGROUND: Sirolimus 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. METHODS: In 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. RESULTS: In 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. CONCLUSION: Sirolimus 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.

Phase II trial of nintedanib in patients with bevacizumab-resistant recurrent epithelial ovarian, tubal, and peritoneal cancer.

BACKGROUND: Bevacizumab provides benefit in epithelial ovarian cancer (EOC), yet resistance to bevacizumab often occurs. We determined if nintedanib, a tyrosine kinase inhibitor of VEGF, FGF, and PDGF receptors has antitumor activity in bevacizumab-resistant recurrent EOC, tubal, and peritoneal cancer. METHODS: This phase II study evaluated nintedanib 200 mg/day until disease progression or unacceptable toxicity. The primary objective was 6-month progression free survival (PFS6m). Secondary objectives were response rate and toxicity. Simon two-stage optimal design was used. Baseline angiogenic plasma biomarkers were measured. RESULTS: 27 patients were enrolled evaluable for PFS; 26 were evaluable for PFS6m. The median age was 65 years (range 44-73); 89.9% had high-grade serous EOC; 70% received at least >2 prior chemotherapies; and 81% (22/27) had chemoresistant disease. With median follow up of 15.6 months (range 2-38) the PFS6m rate was 11.5% (3/26). Three participants had long duration of disease control (8-16 months). Median PFS and overall survival were 1.8 and 16 months, respectively. Response rate was 7.4% (2/27 PR). Thirty-seven percent (10/27) had stable disease, while 56% (15/27) had progressive disease. Adverse events included Grade 3 liver enzyme elevation (15%), Grade 3 diarrhea (7%), Grade 2 fatigue (7%), and Grade 2 nausea/vomiting (15%). PD patients exhibited higher levels of CD73, IL6, and VEGFD (p < 0.05) compared to PR/SD patients. IL6 was associated with worse PFS (p = 0.03). CONCLUSIONS: Single-agent nintedanib has minimal activity in an unselected bevacizumab-resistant EOC population. Nintedanib was tolerable and toxicities were manageable. Plasma CD73, IL6, and VEGFD were identified as prognostic markers for progressive disease, and IL6 was associated with worse PFS confirming similar observations made in patients treated with other anti-angiogenic agents.

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

BACKGROUND: In 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 METHODS: We 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. RESULTS: Serum 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. CONCLUSIONS: Serum 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.