Urinary bFGF Research Articles

Prognostic impact of blood and urinary angiogenic factor levels at diagnosis and during treatment in patients with osteosarcoma: a prospective study

BackgroundAngiogenesis is essential for the progression and metastatic spread of solid tumours. Expression of vascular endothelial growth factor (VEGF) has been linked to poor survival among osteosarcoma patients but the clinical relevance of monitoring blood and urine angiogenic factors is uncertain. The aim of this study was to determine the prognostic significance of blood VEGF and blood and urinary basic fibroblast growth factor (bFGF) levels in osteosarcoma patients, both at diagnosis and during treatment.MethodsPatients with localised or metastatic osteosarcoma enrolled in OS2005 and OS2006 studies between 2005 and 2011 were prospectively included in this study. VEGF and bFGF levels in serum and plasma and bFGF levels in urine were measured by ELISA at diagnosis, before surgery, and at the end of treatment. Endpoints considered for the prognostic analysis were histological response, progression-free and overall survival. Kruskal-Wallis tests were used to compare the distribution of baseline biomarker values across the different subgroups, and paired sample Wilcoxon rank tests were used to analyze changes over time. Association between biomarker levels and outcomes were assessed in multivariable models (logistic regression for histologic response, and Cox models for survival).ResultsSamples were available at diagnosis for 269 patients (54% males; age ≤ 18 years: 73%; localised disease in 68%, doubtful lung lesions in 17%, and metastases in 15%). High serum VEGF and bFGF levels were observed in respectively 61% and 51% of patients. Serum and plasma VEGF values were not strongly correlated with one another (r = 0.53). High serum and plasma VEGF levels were significantly more frequent in patients with large tumours (≥10 cm; p = 0.003 and p = 0.02, respectively). VEGF levels fell significantly during pre-operative chemotherapy (p < 0.0001). No significant correlation was found between this variation and either the histological response, progression-free survival or overall survival (p = 0.26, p = 0.67, and p = 0.87, respectively). No significant association was found between blood or urinary bFGF levels and clinical characteristics, histological response, or survival.ConclusionsLevels of VEGF and bFGF angiogenic factors are high in most osteosarcoma patients, but have no significant impact on response to chemotherapy or outcome in this large prospective series.OS 2006 trial registration numberclinicaltrials.gov NCT00470223; date of registration: May 3th 2007.

Using urinary bFGF and TIMP3 levels to predict the presence of juvenile pilocytic astrocytoma and establish a distinct biomarker signature.

OBJECTIVE The authors report the use of urinary biomarkers as a novel, noninvasive technique to detect juvenile pilocytic astrocytomas (JPAs), capable of distinguishing JPAs from other CNS diseases, including other brain tumors. Preliminary screening of an array of tumors implicated proteases (including matrix metalloproteinases [MMPs]) and their inhibitors (tissue inhibitors of metalloproteinase [TIMPs]) as well as growth factors (including basic fibroblast growth factor [bFGF]) as candidate biomarkers. These data led the authors to hypothesize that tissue inhibitor of metalloproteinase 3 (TIMP3) and bFGF would represent high-probability candidates as JPA-specific biomarkers. METHODS Urine was collected from 107 patients, which included children with JPA (n = 21), medulloblastoma (n = 17), glioblastoma (n = 9), arteriovenous malformations (n = 25), moyamoya (n = 14), and age- and sex-matched controls (n = 21). Biomarker levels were quantified with enzyme-linked immunosorbent assay, tumor tissue expression was confirmed with immunohistochemical analysis, and longitudinal biomarker expression was correlated with imaging. Results were subjected to univariate and multivariate statistical analyses. RESULTS Using optimal urinary cutoff values of bFGF > 1.0 pg/μg and TIMP3 > 3.5 pg/μg, multiplexing bFGF and TIMP3 predicts JPA presence with 98% accuracy. Multiplexing bFGF and MMP13 distinguishes JPA from other brain tumor subtypes with up to 98% accuracy. Urinary biomarker expression correlated with both tumor immunohistochemistry and in vitro tumor levels. Urinary bFGF and TIMP3 decrease following successful tumor treatment and correlate with changes in tumor size. CONCLUSIONS This study identifies 2 urinary biomarkers-bFGF and TIMP3-that successfully detect one of the most common pediatric brain tumors with high accuracy. These data highlight potential benefits of urinary biomarkers and support their utility as diagnostic tools in the treatment of children with JPA.

Determination of basic fibroblast growth factor (bFGF) level in urine from infants and young children with cutaneous hemangioma

Objective To determine the changes of urine bFGF level in the progression of cutaneous hemangioma,and to provide an objective index for the monitoring of hemangioma occurrence and development.Methods Enzyme-linked immunosorbent assay (ELISA) was used to determine the bFGF level in urine samples from 27 infants and young children with proliferative cutaneous hemangioma before and after treatment with low-dose superficial X-ray,and from 30 normal control infants and young children.Results The urine bFGF level was significantly higher in the patients before treatment than in those 3 months after the treatment and normal controls(t = 3.793,0.206,both P ＜ 0.05),while no significant difference was observed in the urine bFGF level between the treated patients and controls (t = 0.505,P ＞ 0.05).Conclusions Measurement of urine bFGF level by ELISA is a convenient and reliable method ,which may provide an objective index for the monitoring of hemangioma occurrence and development. Key words: Hemangioma; Fibroblast growth factor 2; X-ray therapy

The role of serum basic fibroblast growth factor, estradiol and urine basic fibroblast growth factor in differentiating infantile haemangiomas from vascular malformations

To investigate the role of serum basic fibroblast growth factor (bFGF), estradiol (E2) and urine bFGF in differentiating infantile haemangiomas from vascular malformations. Between October 2007 and January 2009, 97 patients with haemangiomas and 25 patients with vascular malformations who had not been treated previously were included in this prospective study. Forty-eight patients with cleft lip and/or palate were selected as controls. The age of all subjects ranged from 1 to 30 months. The serum and urine levels of bFGF were determined by enzyme-linked immunosorbent assay (ELISA). The serum levels of E2 were examined via radioimmunoassay. All data were analysed with SPSS 11.5 software package. The concentration of serum and urine bFGF was significantly different among the three groups (haemangiomas, vascular malformations and controls) (P = 0.027, P = 0.001). Significantly different urine bFGF levels were found in patients with proliferating and involuting haemangiomas (P = 0.04). The serum E2 levels were significantly higher in patients with haemangiomas than vascular malformations (P = 0.001) and controls (P = 0.001). Serum bFGF and E2 as well as urine bFGF can be used to supplement the clinical diagnosis of congenital vascular anomalies. Urine bFGF combined with serum E2 may be the most potential markers for diagnosing haemangiomas and determining the proliferating stage of haemangiomas.

Evaluation of the role of serum vascular endothelial growth factor and urinary basic fibroblast growth factor in differential diagnosis of vascular anomalies

To evaluate the role of serum vascular endothelial growth factor (VEGF) and urine basic fibroblast growth factor (bFGF) in the differential diagnosis of vascular anomalies by receiver operating characteristic curve. Using the method of enzyme linked immunosorbent assay (ELISA), 364 cases of various vascular anomalies (proliferating hemangiomas, n = 146; hemangiomas, n = 106; vascular malformations, n = 112) and 440 cases of various vascular anomalies (proliferating hemangiomas, n = 154; involuting hemangiomas, n = 148; vascular malformations, n = 138) subjects were examined for the serum levels of VEGF and the urine bFGF respectively. Nonparametric statistical tests were used for data analysis. The VEGF levels of proliferating hemangioma, involuting hemangioma, vascular malformation and control groups were analyzed by the Kruskal-Wallis test. When there was significance (P < 0.05), a subgroup analysis was performed by the Mann-Whitney U test. A receiver operator characteristic (ROC) curve was constructed for both the serum levels of VEGF and urine bFGF to determine the optimal diagnostic cut-off to differentiate proliferating hemangioma from involuting hemangioma, vascular malformation and controls. The serum level of VEGF and the urine bFGF in proliferating hemangiomas were significantly higher than those in involuting hemangiomas, vascular malformations and negative controls (P < 0.01). And the differences among the latter three groups were not statistically significant (P > 0.05). The optimal diagnostic cut-off point of serum VEGF and urine bFGF to differentiate proliferating hemangioma from involuting hemangioma, vascular malformation and controls was 99.6 pg/mg and 0.16 ng/mmol respectively. The area under ROC curve, the sensitivity and specificity were 99.7%, 99.3%, 99.7% and 91.9%, 98.7%, 71.1% respectively. The differences of the area under ROC curve of serum VEGF and urine bFGF showed no statistical significance (P > 0.05). Serum VEGF and urine bFGF are helpful for differentiating proliferating hemangioma from involuting hemangioma, vascular malformation and controls. Both parameters have higher values of clinical application.

Serum levels of basic fibroblastic growth factor (bFGF) in children with vascular anomalies: Another insight into endothelial growth

Objectives Dysregulation of angiogenesis has been proposed to play a central role in hemangioma pathogenesis. The aim of the study was to determine the peripheral and local serum levels of bFGF in patients with hemangiomas and vascular malformations (VM). Design and m ethods The study group consisted of 52 children with infantile hemangioma, 14 with VM and 36 healthy patients. bFGF serum levels were analyzed by an ELISA assay. Urinary bFGF was determined in 11 individuals with hemangioma. Results The serum peripheral bFGF concentrations in children with proliferating hemangiomas were lower than in healthy controls ( p = 0,03). There was no correlation between the measured cytokine level and hemangioma size, as well as patients’ age. The serum local bFGF levels in 29 children with hemangiomas were higher than in the peripheral blood ( p = 0.022). Urinary bFGF in hemangioma patients did not differ statistically from healthy controls. Conclusions (1) Determination of bFGF serum levels is not helpful in differentiating the phases of hemangioma growth and distinguishing hemangiomas from VM; (2) serum levels of bFGF cannot distinguish between extrinsic and intrinsic theories of endothelial cell proliferation in hemangiomas.

Quantitative image analysis of intra-tumoral bFGF level as a molecular marker of paclitaxel resistance

BackgroundThe role of basic fibroblast growth factor (bFGF) in chemoresistance is controversial; some studies showed a relationship between higher bFGF level and chemoresistance while other studies showed the opposite finding. The goal of the present study was to quantify bFGF levels in archived tumor tissues, and to determine its relationship with chemosensitivity.MethodsWe established an image analysis-based method to quantify and convert the immunostaining intensity of intra-tumor bFGF to concentrations; this was accomplished by generating standard curves using human xenograft tumors as the renewable tissue source for simultaneous image analysis and ELISA. The relationships between bFGF concentrations and tumor chemosensitivity of patient tumors (n = 87) to paclitaxel were evaluated using linear regression analysis.ResultsThe image analysis results were compared to our previous results obtained using a conventional, semi-quantitative visual scoring method. While both analyses indicated an inverse relationship between bFGF level and tumor sensitivity to paclitaxel, the image analysis method, by providing bFGF levels in individual tumors and therefore more data points (87 numerical values as opposed to four groups of staining intensities), further enabled the quantitative analysis of the relationship in subgroups of tumors with different pathobiological properties. The results show significant correlation between bFGF level and tumor sensitivity to the antiproliferation effect, but not the apoptotic effect, of paclitaxel. We further found stronger correlations of bFGF level and paclitaxel sensitivity in four tumor subgroups (high stage, positive p53 staining, negative aFGF staining, containing higher-than-median bFGF level), compared to all other groups. These findings suggest that the relationship between intra-tumoral bFGF level and paclitaxel sensitivity was context-dependent, which may explain the previous contradictory findings on the merit of using plasma or urine bFGF level as a prognostic indicator.ConclusionThe present study established a quantitative image analysis method that enabled the measurement of intratumoral bFGF level in archived tissues. The ability to quantify a potential biomarker provided the opportunity to study the relationship between the biomarker and chemosensitivity in tumor subgroups and thereby enabled hypothesis generation for additional translational research.

Increased Expression of Urinary Matrix Metalloproteinases Parallels the Extent and Activity of Vascular Anomalies

Matrix metalloproteinases (MMPs) and the angiogenic proteins basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been implicated in mechanisms of human cancer and metastasis. Assays were conducted on the urine of patients with vascular anomalies (tumors and malformations), relatively common and occasionally life-threatening disorders for which few therapies exist. We sought to determine whether these angiogenesis modulators are present in the urine and whether their expression is associated with the extent and clinical course of the vascular lesion. A total of 217 patients with vascular anomalies and 74 age-matched control subjects participated. Urinary MMP expression was determined by substrate gel electrophoresis. Urinary bFGF and VEGF levels were measured by enzyme-linked immunosorbent assay. Each patient was assigned to 1 of 2 categories (tumor or malformation) and 1 of 9 specific groups. Extent of the vascular lesion and activity were scored by a blinded clinician. Urinary high molecular weight (hMW) MMPs and bFGF were significantly increased in patients with vascular tumors (53%) and vascular malformations (41%), compared with control subjects (22%). These percentages increased as a function of extent of the lesion and disease activity. hMW MMPs were increased in 4 groups: infantile hemangioma, other vascular neoplasms, lymphatic malformation and capillary-lymphaticovenous malformations, and extensive and unremitting capillary malformation and arteriovenous malformation. No significant differences among the groups were detected for low molecular weight MMPs or VEGF. Expression patterns of hMW MMPs and bFGF in the urine of patients with tumors and malformations are consistent with their different clinical behavior. These data represent the first evidence that MMPs are elevated in the urine of children with vascular anomalies. These data also suggest that the increased expression of urinary MMPs parallels the extent and activity of vascular anomalies in children. In addition to tumors, vascular malformations are angiogenesis dependent, suggesting that progression of a vascular malformation might be suppressed by angiogenic inhibitors, which would target bFGF and MMPs.

Phase II Study of Thalidomide in Escalating Doses for Follicular (F-NHL) and Small Lymphocytic Lymphoma (Sll): CALGB Study 50002.

Background: Thalidomide has marked activity in both untreated and heavily pretreated myeloma. Its activity in part is believed to be due to inhibition of bFGF and VEGF induced angiogenesis. Elevated levels of bFGF in serum and urine have correlated with decreased survival in lymphoma possibly through up-regulation of BCL-2.Methods: 25 patients (pts) with previously treated F-NHL and SLL were registered and treated on this multi-institutional study from July 2001–April 2004 to evaluate the efficacy and safety of oral thalidomide in this patient group. Pts had B-cell SLL (7: 36.8%), F-NHL grade 1 (7: 36.8%), grade 2 (3: 15.8%) and grade 3 (2: 10.1%) NHL. Pts were eligible for entry with up to 3 prior chemotherapy (CT) and 2 immunotherapy (IT) regimens provided performance status was ≥ 1. Pts with new onset of B-symptoms, rising LDH, rapid tumor growth or greater than one year from initial diagnosis were required to undergo repeat lymph node biopsy to exclude recent transformation. Pts with CNS involvement, prior peripheral neuropathy >gr 1, HIV+, and pregnant or nursing women were also excluded. Pts were required to have Cr <2 x ULN, AST/ALT <2.5 x ULN and an ANC > 750. Median age at study entry was 60 years (36–87). Prior therapy was evaluated in 20 pts and 17/20 had received multi-agent CT while 12/20 pts received prior IT. Thalidomide was initiated at a dose of 200 mg daily and escalated by 100 mg daily every 1–2 weeks as tolerated with a maximal dose of 800 mg/d. If ≥ gr 2 peripheral neuropathy or ≥ gr 3 somnolence or mood changes occurred, the dose was held for one week and restarted at 50% of the prior daily dosage.Results: The median daily dose was 400 mg (range 50–800 mg). There was 1 complete response (CRu-residual abnormality) in a pt with SLL and one partial response in a pt with F-NHL grade 1 (ORR 8%: 95%CI: 1–26%). 16 pts had progressive disease during therapy and 2 died of disease soon after stopping therapy due to adverse events. One patient continues on therapy without progression of disease to date. The remaining 4 pts were taken off of therapy prior to the first 3 month evaluation. The reason for withdrawal was pt refusal (2) and adverse events (2). The median event free survival was 2.6 months (95% CI:1.4–4.4 mos) with a median overall survival of 23.3 months. Toxicity information on 24/25 pts revealed 4 (17%) with grade 4 neutropenia with 1/4 febrile as well. The most common grade 3 toxicities were anemia (13%), dyspnea (13%), fatigue (8%) and neurologic toxicities consisting of somnolence, dizziness, depression and anxiety (21%). Peripheral sensory neuropathy was reported as gr 2 in 8% and gr 3 in 8%. However, 38% of pts were reported as experiencing gr 2 fatigue. There were no grade 5 toxicities.Conclusion: These phase II trial results in a pretreated pt population demonstrate that, despite an acceptable toxicity profile, thalidomide has only minimal efficacy in F- NHL and SLL.

Urinary Basic Fibroblast Growth Factor in Bladder Cancer Patients

Introduction: Angiogenesis plays a significant role in the growth and progress of cancer, thus we evaluated the levels of urinary basic fibroblast growth factor (bFGF) in bladder cancer (Ca) patients and investigated any possible correlation between this angiogenic factor with tumor stage and grade. Materials and Methods: Urine samples from 41 patients with bladder Ca, 11 patients with history of bladder Ca but negative follow-up cystoscopy, 18 patients with benign prostate hyperplasia (BPH) and 15 normal healthy volunteers were assayed using an enzyme-linked immunosorbent assay for bFGF. Resulting values were normalized against urine creatinine and expressed as pg/g. Results: The median urinary bFGF level of patients with active disease, history of bladder carcinoma and negative follow-up cystoscopy, BPH, and healthy volunteers were 2,717, 1,009, 1,414 and 1,100 pg/g, respectively. There was a statistically significant difference between median bFGF levels of patients with active bladder Ca and those of the other groups (p = 0.000). Eleven patients with invasive bladder Ca had a median bFGF value of 6,880 pg/g that was significantly increased (p = 0.002) compared to the median of 2,312 pg/g of those with superficial tumors (Ta 14, T1 16). Grades 1, 2 and 3 carcinoma were found in 5, 19 and 17 patients which had a median bFGF of 2,717, 1,762 and 3,617 pg/g, respectively, but the difference was not statistically significant (p = 0.13). Conclusions: Our results confirm the implication of bFGF in the biology of bladder cancer, and demonstrate that urinary bFGF concentration seems to be significantly related to the stage but not to the grade of the disease supporting the proposed mechanisms of release of bFGF. Further studies are required in order to validate the potential clinical applications of bFGF for specific groups of bladder cancer patients.

Prognostic value of plasma vascular endothelial growth factor in hormone-sensitive advanced stage prostate cancer: An exploratory analysis

4683 Background: We report an exploratory analysis on the prognostic value of plasma vascular endothelial growth factor (pVEGF) in hormone sensitive advanced prostate cancer patients undergoing androgen deprivation therapy (ADT). Methods: Patients (n=40) on clinical trials with measurements of angiogenesis markers were followed till radiological progression and/or death (events). All pVEGF and basic fibroblast growth factor (bFGF) measurements were performed in platelet poor plasma using commercially available ELISA kits. bFGF was also measured in urine. Wilcoxon rank sum test was used to compare median VEGF levels in patient groups with and without above events. Results: At 18 months follow-up (range 18–24 months), 40% (15/40) patients have experienced events (6 radiological progression, 6 deaths following a radiological progression, and 3 deaths with no radiological progression). Median pVEGF levels of all patients and comparison between patients with and without events are shown in table 1. 30/40 patients with advanced hormone-sensitive disease received ADT as primary prostate treatment without any preceding definitive prostate therapy. Median pVEGF of these patients during ADT with and without events is also shown and compared in table 1. Plasma and urine bFGF was measurable in four patients, none of whom has had an event. Conclusions: We found limited prognostic value of pVEGF in hormone sensitive prostate cancer in this exploratory analysis. A larger study population in this stage may identify subgroups of hormone sensitive prostate cancer patients in whom circulatory angiogenesis markers may have prognostic or predictive value, which could assist in guiding therapeutic interventions with anti angiogenic agents during this stage. No significant financial relationships to disclose.

Pulmonary Capillary Hemangiomatosis With Atypical Endotheliomatosis : Successful Antiangiogenic Therapy With Doxycycline

We report here our experience in achieving remission in a 20-year-old man with pulmonary capillary hemangiomatosis (PCH) with atypical endotheliomatosis following therapy with doxycycline. PCH is a rare disorder characterized by proliferating capillaries that invade the pulmonary interstitium and alveolar septae, and occlude the pulmonary vasculature. The patient's symptoms, lung function, and radiographic findings had worsened despite treatment with both prednisone and alpha-interferon. He was considered to be a candidate for transplantation. Given the elevated levels of basic fibroblast growth factor (bFGF) in urine and the capillary proliferation noted on biopsy specimens, we elected to treat the patient with doxycycline, a matrix metalloproteinase and angiogenesis inhibitor. Following several weeks of therapy, a gradual resolution of symptoms was noted, with normalization of pulmonary function test results and urine bFGF levels. After 18 months of therapy, the patient remains in complete remission.

Basic Fibroblast Growth Factor among Children with Diarrhea-Associated Hemolytic Uremic Syndrome

Diarrhea-associated hemolytic uremic syndrome (D+HUS) is characterized by endothelial injury and activation of inflammatory cytokines. Basic fibroblast growth factor (bFGF) is an angiogenic peptide released in response to vascular damage. The plasma concentrations and urinary excretion of bFGF during the course of D+HUS were determined, in comparison with the levels of various inflammatory cytokines, and changes were correlated with clinical and laboratory features of the disease. Serial plasma and urine samples were collected from 31 children with D+HUS, during the acute (days 1 to 7 of hospitalization) and recovery (through day 60 after discharge from the hospital) phases of the disease. The patients were enrolled in the multicenter trial of SYNSORB Pk (SYNSORB Biotech, Calgary, Alberta, Canada) treatment for D+HUS. bFGF, interleukin-1alpha (IL-1alpha), IL-8, and tumor necrosis factor-alpha levels were determined with enzyme-linked immunosorbent assays. bFGF was detected in urine and plasma samples more frequently than were IL-1alpha, IL-8, and tumor necrosis factor-alpha. There was an acute increase in urinary bFGF excretion, which returned to normal during convalescence. Urinary excretion of bFGF during the acute phase was higher among patients who required dialysis, compared with those who did not (48.9 +/- 15.0 and 28.9 +/- 9.0 pg/ml, respectively; P < 0.05). Plasma bFGF concentrations were persistently elevated throughout the period of hospitalization and the follow-up period among patients with D+HUS. Urinary excretion and plasma levels of bFGF were comparable for the SYNSORB Pk-treated (n = 19) and placebo-treated (n = 12) groups. Measurements of urinary and plasma concentrations of bFGF among patients with D+HUS may be useful indices for assessment of the severity of acute renal disease and the timing and adequacy of the systemic angiogenic process during early convalescence.

Successful Antiangiogenic Therapy of Giant Cell Angioblastoma With Interferon Alfa 2b: Report of 2 Cases

We describe 2 cases of angioblastoma, a rare, destructive pediatric tumor, treated with interferon alfa 2b (IFNalpha2b). The first patient is a 10-month-old male who presented with an ulcerated palatal neoplasm that could not be completely resected. The second is a male neonate with a congenital tumor of the right hand that invaded the hypothenar eminence, destroying the fourth and fifth metacarpals. Biopsy in both patients was interpreted as giant cell angioblastoma. Angioblastoma is rare; there is only 1 reported case that necessitated amputation of an upper extremity, also initially recommended for our patient. Because there is little experience with chemotherapy, permission was granted to employ an antiangiogenic regimen of IFNalpha2b. The angiogenic protein, basic fibroblast growth factor (bFGF), was abnormally elevated in both patients. Both patients received IFNalpha2b. In the first child, it was used after incomplete resection, because biopsy-proven tumor was present at the margin and in the nasopharynx. Biopsies 15 months after initiation of IFN2alphab were negative for tumor. Therapy was stopped after 3 years. Eighteen months later, the patient remains disease-free. In the second child, IFNalpha2b was started after debridement of the ulcerated tumor. Over 11 months, the tumor completely regressed and there was bony regeneration of the metacarpals. The fifth digit was amputated because of damage to the metacarpophalangeal joint by the tumor. IFNalpha2b therapy was discontinued after 1 year of treatment, and the child remains disease-free 2 years and 8 months later. In conclusion, this report demonstrates that: 1) a bFGF-overexpressing low-grade tumor can respond to IFNalpha2b in a manner similar to life-threatening infantile hemangiomas, 2) urinary bFGF levels can help guide IFNalpha dosage in such patients, and 3) although bFGF-mediated tumor angiogenesis is inhibited by IFNalpha, physiologic angiogenesis seems to be unaffected.

Correlations between basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and clinical features of pulmonary arterial hypertension (PAH)

PAH is the result of abnormal pulmonary vascular growth. Elevations in bFGF and VEGF have been noted in animal models, but growth factors that cause PAH in humans are unknown. We measured serum and urine bFGF and VEGF in 76 stable pts with PAH (primary pulmonary hypertension (PPH)=51, collagen vascular disease (CVD)=15, congenital heart disease (CHD)=10), and 10 controls. Growth factors were correlated against age, gender, etiology, NYHA Functional Class, current medications, and hemodynamics.

Changes in detrusor and urinary growth factors according to detrusor function after partial bladder outlet obstruction in the rat

Objectives. To investigate the changes in detrusor and urinary growth factors according to detrusor function after partial bladder outlet obstruction in the rat. Growth factors have been reported to play a role in the remodeling of the bladder after obstruction. Methods. Female rats (n = 40) were used and divided into three groups: sham-operated control, 2-week mild obstruction, and 2-week severe obstruction. The voided urine was collected and the detrusor contractility to electrical stimulation recorded. mRNA expression and the urinary concentration of transforming growth factor beta-1 (TGF-β1) and basic fibroblast growth factor (bFGF) were analyzed. Results. The contractile response to electrical stimulation was increased in the mild obstruction group ( P <0.05) but decreased in the severe obstruction group ( P <0.05). The detrusor mRNA expression of TGF-β1 in the mild obstruction group was not different from that in the control group. However, in the severe obstruction group, the mRNA expression of TGF-β1 increased. The detrusor mRNA expression of bFGF was gradually increased in the mild and severe obstruction groups. The urinary concentration of TGF-β1 in the mild obstruction group was not significantly different from that in the control group. However, in the severe obstruction group, the concentration of TGF-β1 was significantly increased ( P <0.05). The concentration of urinary bFGF was too small to compare the results in each group. Conclusions. Growth factors such as TGF-β1 and bFGF change in mRNA expression according to bladder function, and urinary TGF-β1 reflects the change of detrusor mRNA. Thus, changes in TGF-β1 may be a marker to evaluate detrusor function.

Quantification of angiogenesis stimulators in children with solid malignancies.

Humoral angiogenesis stimulators including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been implicated in the pathogenesis of solid malignancies. However, it has remained unclear whether both stimulators contribute to the development and progression of solid malignancies of children. The aim of the present study was to determine whether VEGF and bFGF are elevated in body fluids of children with solid malignancies and, if so, whether these elevated levels correlate with clinical parameters. Using enzyme-linked immunosorbent assays (ELISAs), we quantified VEGF and bFGF in serum (n = 107) and urine (n = 57) of healthy children and of children with solid malignancies (serum: n(VEGF) = 69, n(bFGF) = 60; urine: n(VEGF) or n(bFGF) = 13). Finally, we compared patients' pre-therapeutic and post-therapeutic levels. Serum VEGF was elevated in children with several solid tumors (Ewing's sarcoma, primitive neuroectodermal tumours, malignant lymphoma, Langerhans cell histiocytosis and medulloblastoma). In contrast, serum bFGF, urinary bFGF or urinary VEGF were not significantly elevated. Upon successful therapy, elevated pre-therapeutic serum VEGF levels declined to levels present in healthy children. VEGF could contribute to the progression of pediatric solid malignancies, and serum VEGF could be used to monitor therapeutic response. Furthermore, the determination of angiogenesis stimulators could identify patients eligible for anti-angiogenic therapy.

Urinary basic fibroblast growth factor: A noninvasive marker of progressive cystic renal disease in a child

Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary condition with an estimated incidence of 1 in 20,000 live births. Various growth factors have been implicated in the causation of this disease. We describe a child with ARPKD whose levels of urinary basic fibroblast growth factor (bFGF) were markedly elevated. The concentrations of bFGF increased further following right nephrectomy, in response to the compensatory growth of the remaining kidney. We hypothesize that measurement of urinary bFGF may be useful as a noninvasive marker to assess progression of cystic renal development.

Basic Fibroblast Growth Factor: A Missing Link between Collagen VII, Increased Collagenase, and Squamous Cell Carcinoma in Recessive Dystrophic Epidermolysis Bullosa

Patients with recessive dystrophic epidermolysis bullosa (RDEB) have deficiencies of collagen type VII and have elevated levels of fibroblast collagenase, and a greatly increased risk of cutaneous squamous cell carcinoma. Patients with other genetic blistering disorders do not have elevated collagenase or an increased risk of squamous cell carcinoma, despite chronic wounding. The connection between collagen type VII deficiency, increased collagenase, and squamous cell carcinoma is not understood. Urine from 81 patients with RDEB (39 patients), junctional epidermolysis bullosa (JEB; 12 patients), and epidermolysis bullosa simplex (EBS; 30 patients), as well as unaffected family members of RDEB patients (33 patients), was tested for the presence of basic fibroblast growth factor (bFGF) using a sensitive radioimmunoassay. These patients included many who were enrolled in the Epidermolysis Bullosa Registry and others who were referred by their physicians. Fifty-one percent of patients with RDEB had elevated levels (> 5000 pg/g) of urinary bFGF. In contrast, none of the patients with JEB had elevated levels of bFGF. Twenty-one percent of clinically unaffected family members had elevated levels of bFGF, and 13% of patients with EBS had elevated levels of bFGF. The frequency of elevated bFGF values among all groups was statistically significant (p = 0.002), and the levels of bFGF in RDEB patients were significantly elevated compared with those of other groups (p < 0.05). We have found that patients with RDEB have elevated levels of bFGF, which may contribute to increased fibroblast collagenase and the development of squamous cell carcinoma. These results suggest a novel treatment for RDEB, namely, angiogenesis inhibitors, which may antagonize the effects of bFGF in this disorder. There are currently no other means of treatment for this disorder, which has a high morbidity and mortality rate.

Elevated ocular levels of vascular endothelial growth factor in patients with von Hippel-Lindau disease

Von Hippel Lindau disease (VHL) is a rare autosomal dominant inherited disorder characterized by highly vascularized tumors in various organs. The abundant presence of endothelial cells in VHL tumors strongly suggest a role of the VHL tumor suppressor gene in the regulation of angiogenesis. Recently, in vitro studies have shown that the VHL tumor suppressor gene regulates the expression of vascular endothelial growth factor (VEGF). We investigated whether VHL patiens have increased levels of VEGF in their body fluids. The concentration of VEGF was measured in fluid of the anterior chamber of the eye, serum, urine, and fluid from renal cysts of VHL patients and unaffected individuals by ELISA. In addition, levels of basic fibroblast growth factor (bFGF), interleukin-8 (IL-8) and endothelin-1 (ET-1) were measured in urine and serum of VHL patients and control subjects. In 80% of the VHL patients VEGF was detectable in aqueous fluid of the anterior chamber of their eyes. A strong positive correlation (r = 0.90) was found between the age of VHL patients and ocular VEGF concentrations. At comparable age, VEGF levels in ocular fluid of VHL patients were significantly higher (P < 0.001) than in unaffected subjects. No correlation was found between VEGF concentration and the presence of retinal angiomas. A 10 and 16 fold increase of VEGF concentration was seen in fluid from two independent VHL-related cysts as compared with VEGF serum levels of the same patient. The mean concentration of VEGF in serum of VHL patients (n = 15) (319 +/- 84 pg/ml) was higher than in matched controls (238 +/- 68 pg/ml; P = NS). The mean concentration of VEGF in urine of VHL patients (128 +/- 36 pg/ml) was lower than in matched controls (183 +/- 25 pg/ml; P = NS). Concentrations of VEGF did not correlate with the presence of VHL-related tumors. No differences were observed between concentrations of bFGF, IL-8 and ET-1 in serum and urine of VHL patients and matched controls. These findings support a role for the VHL tumor suppressor gene in the in vivo regulation of VEGF.